2024

Jump to: 2023, 2022, 2021

15 pages, 1325 KiB

Open AccessArticle

Metabolomics of Plasma in XLH Patients with Arterial Hypertension: New Insights into the Underlying Mechanisms

by Luis Carlos López-Romero, José Jesús Broseta, Marta Roca-Marugán, Juan R. Muñoz-Castañeda, Agustín Lahoz and Julio Hernández-Jaras

Int. J. Mol. Sci. 2024, 25(6), 3545; https://doi.org/10.3390/ijms25063545 - 21 Mar 2024

Viewed by 624

Abstract

X-linked hypophosphatemia (XLH) is a rare genetic disorder that increases fibroblast growth factor 23 (FGF23). XLH patients have an elevated risk of early-onset hypertension. The precise factors contributing to hypertension in XLH patients have yet to be identified. A multicenter cross-sectional study of [...] Read more.

X-linked hypophosphatemia (XLH) is a rare genetic disorder that increases fibroblast growth factor 23 (FGF23). XLH patients have an elevated risk of early-onset hypertension. The precise factors contributing to hypertension in XLH patients have yet to be identified. A multicenter cross-sectional study of adult patients diagnosed with XLH. Metabolomic analysis was performed using ultra-performance liquid chromatography (UPLC) coupled to a high-resolution mass spectrometer. Twenty subjects were included, of which nine (45%) had hypertension. The median age was 44 years. Out of the total, seven (35%) subjects had a family history of hypertension. No statistically significant differences were found between both groups for nephrocalcinosis or hyperparathyroidism. Those with hypertension exhibited significantly higher levels of creatinine (1.08 ± 0.31 mg/dL vs. 0.78 ± 0.19 mg/dL; p = 0.01) and LDL-C (133.33 ± 21.92 mg/dL vs. 107.27 ± 20.12 mg/dL, p = 0.01). A total of 106 metabolites were identified. Acetylcarnitine (p = 0.03), pyruvate p = (0.04), ethanolamine (p = 0.03), and butyric acid (p = 0.001) were significantly different between both groups. This study is the first to examine the metabolomics of hypertension in patients with XLH. We have identified significant changes in specific metabolites that shed new light on the potential mechanisms of hypertension in XLH patients. These findings could lead to new studies identifying associated biomarkers and developing new diagnostic approaches for XLH patients. Full article

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27 pages, 778 KiB

Open AccessReview

Changes in Cells Associated with Insulin Resistance

by Leszek Szablewski

Int. J. Mol. Sci. 2024, 25(4), 2397; https://doi.org/10.3390/ijms25042397 - 18 Feb 2024

Viewed by 1394

Abstract

Insulin is a polypeptide hormone synthesized and secreted by pancreatic β-cells. It plays an important role as a metabolic hormone. Insulin influences the metabolism of glucose, regulating plasma glucose levels and stimulating glucose storage in organs such as the liver, muscles and adipose [...] Read more.

Insulin is a polypeptide hormone synthesized and secreted by pancreatic β-cells. It plays an important role as a metabolic hormone. Insulin influences the metabolism of glucose, regulating plasma glucose levels and stimulating glucose storage in organs such as the liver, muscles and adipose tissue. It is involved in fat metabolism, increasing the storage of triglycerides and decreasing lipolysis. Ketone body metabolism also depends on insulin action, as insulin reduces ketone body concentrations and influences protein metabolism. It increases nitrogen retention, facilitates the transport of amino acids into cells and increases the synthesis of proteins. Insulin also inhibits protein breakdown and is involved in cellular growth and proliferation. On the other hand, defects in the intracellular signaling pathways of insulin may cause several disturbances in human metabolism, resulting in several chronic diseases. Insulin resistance, also known as impaired insulin sensitivity, is due to the decreased reaction of insulin signaling for glucose levels, seen when glucose use in response to an adequate concentration of insulin is impaired. Insulin resistance may cause, for example, increased plasma insulin levels. That state, called hyperinsulinemia, impairs metabolic processes and is observed in patients with type 2 diabetes mellitus and obesity. Hyperinsulinemia may increase the risk of initiation, progression and metastasis of several cancers and may cause poor cancer outcomes. Insulin resistance is a health problem worldwide; therefore, mechanisms of insulin resistance, causes and types of insulin resistance and strategies against insulin resistance are described in this review. Attention is also paid to factors that are associated with the development of insulin resistance, the main and characteristic symptoms of particular syndromes, plus other aspects of severe insulin resistance. This review mainly focuses on the description and analysis of changes in cells due to insulin resistance. Full article

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13 pages, 1501 KiB

Open AccessArticle

Separation of Lipoproteins for Quantitative Analysis of ¹⁴C-Labeled Lipid-Soluble Compounds by Accelerator Mass Spectrometry

by Jennifer C. Chuang, Andrew J. Clifford, Seung-Hyun Kim, Janet A. Novotny, Peter B. Kelly, Dirk M. Holstege and Rosemary L. Walzem

Int. J. Mol. Sci. 2024, 25(3), 1856; https://doi.org/10.3390/ijms25031856 - 03 Feb 2024

Viewed by 612

Abstract

To date, ¹⁴C tracer studies using accelerator mass spectrometry (AMS) have not yet resolved lipid-soluble analytes into individual lipoprotein density subclasses. The objective of this work was to develop a reliable method for lipoprotein separation and quantitative recovery for biokinetic modeling purposes. [...] Read more.

To date, ¹⁴C tracer studies using accelerator mass spectrometry (AMS) have not yet resolved lipid-soluble analytes into individual lipoprotein density subclasses. The objective of this work was to develop a reliable method for lipoprotein separation and quantitative recovery for biokinetic modeling purposes. The novel method developed provides the means for use of small volumes (10–200 µL) of frozen plasma as a starting material for continuous isopycnic lipoprotein separation within a carbon- and pH-stable analyte matrix, which, following post-separation fraction clean up, created samples suitable for highly accurate ¹⁴C/¹²C isotope ratio determinations by AMS. Manual aspiration achieved 99.2 ± 0.41% recovery of [5-¹⁴CH₃]-(2R, 4′R, 8′R)-α-tocopherol contained within 25 µL plasma recovered in triacylglycerol rich lipoproteins (TRL = Chylomicrons + VLDL), LDL, HDL, and infranatant (INF) from each of 10 different sampling times for one male and one female subject, n = 20 total samples. Small sample volumes of previously frozen plasma and high analyte recoveries make this an attractive method for AMS studies using newer, smaller footprint AMS equipment to develop genuine tracer analyses of lipophilic nutrients or compounds in all human age ranges. Full article

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2023

Jump to: 2024, 2022, 2021

21 pages, 998 KiB

Open AccessReview

Actionable Driver Events in Small Cell Lung Cancer

by Mirian Gutiérrez, Irene Zamora, Michael R. Freeman, Ignacio J. Encío and Mirja Rotinen

Int. J. Mol. Sci. 2024, 25(1), 105; https://doi.org/10.3390/ijms25010105 - 20 Dec 2023

Viewed by 883

Abstract

Small cell lung cancer (SCLC) stands out as the most aggressive form of lung cancer, characterized by an extremely high proliferation rate and a very poor prognosis, with a 5-year survival rate that falls below 7%. Approximately two-thirds of patients receive their diagnosis [...] Read more.

Small cell lung cancer (SCLC) stands out as the most aggressive form of lung cancer, characterized by an extremely high proliferation rate and a very poor prognosis, with a 5-year survival rate that falls below 7%. Approximately two-thirds of patients receive their diagnosis when the disease has already reached a metastatic or extensive stage, leaving chemotherapy as the remaining first-line treatment option. Other than the recent advances in immunotherapy, which have shown moderate results, SCLC patients cannot yet benefit from any approved targeted therapy, meaning that this cancer remains treated as a uniform entity, disregarding intra- or inter-tumoral heterogeneity. Continuous efforts and technological improvements have enabled the identification of new potential targets that could be used to implement novel therapeutic strategies. In this review, we provide an overview of the most recent approaches for SCLC treatment, providing an extensive compilation of the targeted therapies that are currently under clinical evaluation and inhibitor molecules with promising results in vitro and in vivo. Full article

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15 pages, 2502 KiB

Open AccessArticle

MiR-221-3p/222-3p Cluster Expression in Human Adipose Tissue Is Related to Obesity and Type 2 Diabetes

by Adriana-Mariel Gentile, Said Lhamyani, María Mengual-Mesa, Eduardo García-Fuentes, Francisco-Javier Bermúdez-Silva, Gemma Rojo-Martínez, Mercedes Clemente-Postigo, Alberto Rodriguez-Cañete, Gabriel Olveira and Rajaa El Bekay

Int. J. Mol. Sci. 2023, 24(24), 17449; https://doi.org/10.3390/ijms242417449 - 13 Dec 2023

Viewed by 757

Abstract

The progression of obesity and type 2 diabetes (T2D) is intricately linked with adipose tissue (AT) angiogenesis. Despite an established network of microRNAs (miRNAs) regulating AT function, the specific role of angiogenic miRNAs remains less understood. The miR-221/222 cluster has recently emerged as [...] Read more.

The progression of obesity and type 2 diabetes (T2D) is intricately linked with adipose tissue (AT) angiogenesis. Despite an established network of microRNAs (miRNAs) regulating AT function, the specific role of angiogenic miRNAs remains less understood. The miR-221/222 cluster has recently emerged as being associated with antiangiogenic activity. However, no studies have explored its role in human AT amidst the concurrent development of obesity and T2D. Therefore, this study aims to investigate the association between the miR-221-3p/222-3p cluster in human AT and its regulatory network with obesity and T2D. MiR-221-3p/222-3p and their target gene (TG) expression levels were quantified through qPCR in visceral (VAT) and subcutaneous (SAT) AT from patients (n = 33) categorized based on BMI as normoweight (NW) and obese (OB) and by glycemic status as normoglycemic (NG) and type 2 diabetic (T2D) subjects. In silico analyses of miR-221-3p/222-3p and their TGs were conducted to identify pertinent signaling pathways. The results of a multivariate analysis, considering the simultaneous expression of miR-221-3p and miR-222-3p as dependent variables, revealed statistically significant distinctions when accounting for variables such as tissue depot, obesity, sex, and T2D as independent factors. Furthermore, both miRNAs and their TGs exhibited differential expression patterns based on obesity severity, glycemic status, sex, and type of AT depot. Our in silico analysis indicated that miR-221-3p/222-3p cluster TGs predominantly participate in angiogenesis, WNT signaling, and apoptosis pathways. In conclusion, these findings underscore a promising avenue for future research, emphasizing the miR-221-3p/222-3p cluster and its associated regulatory networks as potential targets for addressing obesity and related metabolic disorders. Full article

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19 pages, 4608 KiB

Open AccessArticle

Transcriptomics of MASLD Pathobiology in African American Patients in the Washington DC Area ^†

by Tanmoy Mondal, Coleman I. Smith, Christopher A. Loffredo, Ruth Quartey, Gemeyel Moses, Charles D. Howell, Brent Korba, Bernard Kwabi-Addo, Gail Nunlee-Bland, Leanna R. Rucker, Jheannelle Johnson and Somiranjan Ghosh

Int. J. Mol. Sci. 2023, 24(23), 16654; https://doi.org/10.3390/ijms242316654 - 23 Nov 2023

Viewed by 957

Abstract

Metabolic-dysfunction-associated steatotic liver disease (MASLD) is becoming the most common chronic liver disease worldwide and is of concern among African Americans (AA) in the United States. This pilot study evaluated the differential gene expressions and identified the signature genes in the disease pathways [...] Read more.

Metabolic-dysfunction-associated steatotic liver disease (MASLD) is becoming the most common chronic liver disease worldwide and is of concern among African Americans (AA) in the United States. This pilot study evaluated the differential gene expressions and identified the signature genes in the disease pathways of AA individuals with MASLD. Blood samples were obtained from MASLD patients (n = 23) and non-MASLD controls (n = 24) along with their sociodemographic and medical details. Whole-blood transcriptomic analysis was carried out using Affymetrix Clarion-S Assay. A validation study was performed utilizing TaqMan Arrays coupled with Ingenuity Pathway Analysis (IPA) to identify the major disease pathways. Out of 21,448 genes in total, 535 genes (2.5%) were significantly (p < 0.05) and differentially expressed when we compared the cases and controls. A significant overlap in the predominant differentially expressed genes and pathways identified in previous studies using hepatic tissue was observed. Of note, TGFB1 and E2F1 genes were upregulated, and HMBS was downregulated significantly. Hepatic fibrosis signaling is the top canonical pathway, and its corresponding biofunction contributes to the development of hepatocellular carcinoma. The findings address the knowledge gaps regarding how signature genes and functional pathways can be detected in blood samples (‘liquid biopsy’) in AA MASLD patients, demonstrating the potential of the blood samples as an alternative non-invasive source of material for future studies. Full article

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12 pages, 500 KiB

Open AccessReview

Age-Dependent Changes in the Effects of Androgens on Female Metabolic and Body Weight Regulation Systems in Humans and Laboratory Animals

by Takeshi Iwasa, Hiroki Noguchi, Risa Tanano, Erika Yamanaka, Asuka Takeda, Kou Tamura, Hidenori Aoki, Tatsuro Sugimoto, Hikari Sasada, Takaaki Maeda, Saki Minato, Shota Yamamoto, Hiroaki Inui, Tomohiro Kagawa, Atsuko Yoshida, Ayuka Mineda, Mari Nii, Riyo Kinouchi, Kanako Yoshida, Yuri Yamamoto and Takashi Kaji Show full author list Hide full author list

Int. J. Mol. Sci. 2023, 24(23), 16567; https://doi.org/10.3390/ijms242316567 - 21 Nov 2023

Viewed by 755

Abstract

In recent years, the effects of androgens on metabolic and body weight regulation systems and their underlying mechanisms have been gradually revealed in females. In women and experimental animals of reproductive age, androgen excess can adversely affect metabolic functioning, appetite, and body weight [...] Read more.

In recent years, the effects of androgens on metabolic and body weight regulation systems and their underlying mechanisms have been gradually revealed in females. In women and experimental animals of reproductive age, androgen excess can adversely affect metabolic functioning, appetite, and body weight regulation. In addition, excess androgens can increase the risk of metabolic disorders, such as obesity, insulin resistance, and diabetes. These unfavorable effects of androgens are induced by alterations in the actions of hypothalamic appetite-regulatory factors, reductions in energy expenditure, insulin resistance in skeletal muscle, and β-cell dysfunction. Interestingly, these unfavorable effects of androgens on metabolic and body-weight regulation systems are neither observed nor evident in ovariectomized animals and post-menopausal women, indicating that the adverse effects of androgens might be dependent on the estrogen milieu. Recent findings may provide novel sex- and age-specific strategies for treating metabolic diseases. Full article

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24 pages, 5349 KiB

Open AccessArticle

The Interplay of Permeability, Metabolism, Transporters, and Dosing in Determining the Dynamics of the Tissue/Plasma Partition Coefficient and Volume of Distribution—A Theoretical Investigation Using Permeability-Limited, Physiologically Based Pharmacokinetic Modeling

by Lu Gaohua, Mian Zhang, Caroline Sychterz, Ming Chang and Brian James Schmidt

Int. J. Mol. Sci. 2023, 24(22), 16224; https://doi.org/10.3390/ijms242216224 - 12 Nov 2023

Viewed by 1496

Abstract

A permeability-limited physiologically based pharmacokinetic (PBPK) model featuring four subcompartments (corresponding to the intracellular and extracellular water of the tissue, the residual plasma, and blood cells) for each tissue has been developed in MATLAB/SimBiology and applied to various what-if scenario simulations. This model [...] Read more.

A permeability-limited physiologically based pharmacokinetic (PBPK) model featuring four subcompartments (corresponding to the intracellular and extracellular water of the tissue, the residual plasma, and blood cells) for each tissue has been developed in MATLAB/SimBiology and applied to various what-if scenario simulations. This model allowed us to explore the complex interplay of passive permeability, metabolism in tissue or residual blood, active uptake or efflux transporters, and different dosing routes (intravenous (IV) or oral (PO)) in determining the dynamics of the tissue/plasma partition coefficient (Kp) and volume of distribution (Vd) within a realistic pseudo-steady state. Based on the modeling exercise, the permeability, metabolism, and transporters demonstrated significant effects on the dynamics of the Kp and Vd for IV bolus administration and PO fast absorption, but these effects were not as pronounced for IV infusion or PO slow absorption. Especially for low-permeability compounds, uptake transporters were found to increase both the Kp and Vd at the pseudo-steady state (Vdss), while efflux transporters had the opposite effect of decreasing the Kp and Vdss. For IV bolus administration and PO fast absorption, increasing tissue metabolism was predicted to elevate the Kp and Vdss, which contrasted with the traditional derivation from the steady-state perfusion-limited PBPK model. Moreover, metabolism in the residual blood had more impact on the Kp and Vdss compared to metabolism in tissue. Due to its ability to offer a more realistic description of tissue dynamics, the permeability-limited PBPK model is expected to gain broader acceptance in describing clinical PK and observed Kp and Vdss, even for certain small molecules like cyclosporine, which are currently treated as perfusion-limited in commercial PBPK platforms. Full article

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15 pages, 1800 KiB

Open AccessArticle

Synergic Action of Systemic Risedronate and Local Rutherpy in Peri-implantar Repair of Ovariectomized Rats: Biomechanical and Molecular Analysis

by Bruna Kaori Namba Inoue, Laura Vidoto Paludetto, Naara Gabriela Monteiro, Fábio Roberto de Souza Batista, Igor Lebedenco Kitagawa, Roberto Santana da Silva, Cristina Antoniali, Paulo Noronha Lisboa Filho and Roberta Okamoto

Int. J. Mol. Sci. 2023, 24(22), 16153; https://doi.org/10.3390/ijms242216153 - 10 Nov 2023

Cited by 1 | Viewed by 757

Abstract

Postmenopausal osteoporosis and poor dietary habits can lead to overweightness and obesity. Bisphosphonates are the first-line treatment for osteoporosis. However, some studies show that they may increase the risk of osteonecrosis of the jaw. Considering the antimicrobial, angiogenic and vasodilatory potential of nitric [...] Read more.

Postmenopausal osteoporosis and poor dietary habits can lead to overweightness and obesity. Bisphosphonates are the first-line treatment for osteoporosis. However, some studies show that they may increase the risk of osteonecrosis of the jaw. Considering the antimicrobial, angiogenic and vasodilatory potential of nitric oxide, this study aims to evaluate the local activity of this substance during the placement of surface-treated implants. Seventy-two Wistar rats were divided into three groups: SHAM (SHAM surgery), OVX + HD (ovariectomy + cafeteria diet), and OVX + HD + RIS (ovariectomy + cafeteria diet + sodium risedronate treatment), which were further subdivided according to the surface treatment of the future implant: CONV (conventional), TE10, or TE100 (TERPY at 10 or 100 μM concentration); n = 8 per subgroup. The animals underwent surgery for implant installation in the proximal tibia metaphysis and were euthanized after 28 days. Data obtained from removal torque and RT-PCR (OPG, RANKL, ALP, IBSP and VEGF expression) were subjected to statistical analysis at 5% significance level. For biomechanical analysis, TE10 produced better results in the OVX + HD group (7.4 N/cm, SD = 0.6819). Molecular analysis showed: (1) significant increase in OPG gene expression in OVX groups with TE10; (2) decreased RANKL expression in OVX + HD + RIS compared to OVX + HD; (3) significantly increased expressions of IBSP and VEGF for OVX + HD + RIS TE10. At its lowest concentration, TERPY has the potential to improve peri-implant conditions. Full article

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26 pages, 5983 KiB

Open AccessArticle

Host Genetic Background Effect on Body Weight Changes Influenced by Heterozygous Smad4 Knockout Using Collaborative Cross Mouse Population

by Nayrouz Qahaz, Iqbal M. Lone, Aya Khadija, Aya Ghnaim, Osayd Zohud, Nadav Ben Nun, Aysar Nashef, Imad Abu El-Naaj and Fuad A. Iraqi

Int. J. Mol. Sci. 2023, 24(22), 16136; https://doi.org/10.3390/ijms242216136 - 09 Nov 2023

Viewed by 775

Abstract

Obesity and its attendant conditions have become major health problems worldwide, and obesity is currently ranked as the fifth most common cause of death globally. Complex environmental and genetic factors are causes of the current obesity epidemic. Diet, lifestyle, chemical exposure, and other [...] Read more.

Obesity and its attendant conditions have become major health problems worldwide, and obesity is currently ranked as the fifth most common cause of death globally. Complex environmental and genetic factors are causes of the current obesity epidemic. Diet, lifestyle, chemical exposure, and other confounding factors are difficult to manage in humans. The mice model is helpful in researching genetic BW gain because genetic and environmental risk factors can be controlled in mice. Studies in mouse strains with various genetic backgrounds and established genetic structures provide unparalleled opportunities to find and analyze trait-related genomic loci. In this study, we used the Collaborative Cross (CC), a large panel of recombinant inbred mouse strains, to present a predictive study using heterozygous Smad4 knockout profiles of CC mice to understand and effectively identify predispositions to body weight gain. Male C57Bl/6J Smad4+/− mice were mated with female mice from 10 different CC lines to create F1 mice (Smad4+/−x CC). Body weight (BW) was measured weekly until week 16 and then monthly until the end of the study (week 48). The heritability (H2) of the assessed traits was estimated and presented. Comparative analysis of various machine learning algorithms for predicting the BW changes and genotype of mice was conducted. Our data showed that the body weight records of F1 mice with different CC lines differed between wild-type and mutant Smad4 mice during the experiment. Genetic background affects weight gain and some lines gained more weight in the presence of heterozygous Smad4 knockout, while others gained less, but, in general, the mutation caused overweight mice, except for a few lines. In both control and mutant groups, female %BW had a higher heritability (H2) value than males. Additionally, both sexes with wild-type genotypes showed higher heritability values than the mutant group. Logistic regression provides the most accurate mouse genotype predictions using machine learning. We plan to validate the proposed method on more CC lines and mice per line to expand the literature on machine learning for BW prediction. Full article

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12 pages, 8414 KiB

Open AccessArticle

Changes in Melatonin Concentration in a Clinical Observation Study under the Influence of Low-Frequency Magnetic Fields (Magnetic Stimulation in Men with Low Back Pain)—Results of Changes in an Eight-Point Circadian Profile

by Marta Woldańska-Okońska, Anna Kubsik-Gidlewska and Kamil Koszela

Int. J. Mol. Sci. 2023, 24(21), 15860; https://doi.org/10.3390/ijms242115860 - 01 Nov 2023

Viewed by 765

Abstract

The aim of this study was to assess the changes in melatonin concentration under the influence of magnetic stimulation in men with low back pain. A total of 15 men were used in this study, divided into two groups. In Group 1, consisting [...] Read more.

The aim of this study was to assess the changes in melatonin concentration under the influence of magnetic stimulation in men with low back pain. A total of 15 men were used in this study, divided into two groups. In Group 1, consisting of seven men, the M1P1 Viofor JPS program was used twice a day for 8 min, at 08:00 and 13:00. In Group 2, consisting of eight men, the M2P2 Viofor JPS program was used once a day for 12 min at 10:00. The application was subjected to the whole body of patients. The treatments in both groups lasted 3 weeks, for 5 days each week, with breaks on weekends. The diurnal melatonin profile was determined the day before exposure and the day after the last treatment, as well as at one-month follow-up. Blood samples were collected eight times a day. In both programs, magnetic stimulation did not reduce the nocturnal peak of melatonin concentration. After exposure, prolonged secretion of melatonin was observed until the morning hours. The impact of the magnetic field was maintained 1 month after the end of the application. The effect of the magnetic field was maintained for 1 month from the end of the application, which confirms the thesis about the occurrence of the phenomenon of biological hysteresis. The parameters of the magnetic fields, the application system, and the time and length of the application may affect the secretion of melatonin. Full article

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14 pages, 2962 KiB

Open AccessArticle

Myocardial Fibrosis and Steatosis in Patients with Aortic Stenosis: Roles of Myostatin and Ceramides

by Elena Zoico, Anna Giani, Tanaz Saatchi, Vanni Rizzatti, Gloria Mazzali, Francesco Fantin, Giovanni Benfari, Francesco Onorati, Silvia Urbani and Mauro Zamboni

Int. J. Mol. Sci. 2023, 24(21), 15508; https://doi.org/10.3390/ijms242115508 - 24 Oct 2023

Viewed by 853

Abstract

Aortic stenosis (AS) involves progressive valve obstruction and a remodeling response of the left ventriculum (LV) with systolic and diastolic dysfunction. The roles of interstitial fibrosis and myocardial steatosis in LV dysfunction in AS have not been completely characterized. We enrolled 31 patients [...] Read more.

Aortic stenosis (AS) involves progressive valve obstruction and a remodeling response of the left ventriculum (LV) with systolic and diastolic dysfunction. The roles of interstitial fibrosis and myocardial steatosis in LV dysfunction in AS have not been completely characterized. We enrolled 31 patients (19 women and 12 men) with severe AS undergoing elective aortic valve replacement. The subjects were clinically evaluated, and transthoracic echocardiography was performed pre-surgery. LV septal biopsies were obtained to assess fibrosis and apoptosis and fat deposition in myocytes (perilipin 5 (PLIN5)), or in the form of adipocytes within the heart (perilipin 1 (PLIN1)), the presence of ceramides and myostatin were assessed via immunohistochemistry. After BMI adjustment, we found a positive association between fibrosis and apoptotic cardiomyocytes, as well as fibrosis and the area covered by PLIN5. Apoptosis and PLIN5 were also significantly interrelated. LV fibrosis increased with a higher medium gradient (MG) and peak gradient (PG). Ceramides and myostatin levels were higher in patients within the higher MG and PG tertiles. In the linear regression analysis, increased fibrosis correlated with increased apoptosis and myostatin, independent from confounding factors. After adjustment for age and BMI, we found a positive relationship between PLIN5 and E/A and a negative correlation between septal S’, global longitudinal strain (GLS), and fibrosis. Myostatin was inversely correlated with GLS and ejection fraction. Fibrosis and myocardial steatosis altogether contribute to ventricular dysfunction in severe AS. The association of myostatin and fibrosis with systolic dysfunction, as well as between myocardial steatosis and diastolic dysfunction, highlights potential therapeutic targets. Full article

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13 pages, 1868 KiB

Open AccessArticle

Multi-Omics of Familial Thoracic Aortic Aneurysm and Dissection: Calcium Transport Impairment Predisposes Aortas to Dissection

by Shota Tomida, Tamaki Ishima, Daigo Sawaki, Yasushi Imai, Ryozo Nagai and Kenichi Aizawa

Int. J. Mol. Sci. 2023, 24(20), 15213; https://doi.org/10.3390/ijms242015213 - 16 Oct 2023

Viewed by 984

Abstract

Several genetic defects, including a mutation in myosin heavy chain 11 (Myh11), are reported to cause familial thoracic aortic aneurysm and dissection (FTAAD). We recently showed that mice lacking K1256 of Myh11 developed aortic dissection when stimulated with angiotensin II, despite [...] Read more.

Several genetic defects, including a mutation in myosin heavy chain 11 (Myh11), are reported to cause familial thoracic aortic aneurysm and dissection (FTAAD). We recently showed that mice lacking K1256 of Myh11 developed aortic dissection when stimulated with angiotensin II, despite the absence of major pathological phenotypic abnormalities prior to stimulation. In this study, we used a comprehensive, data-driven, unbiased, multi-omics approach to find underlying changes in transcription and metabolism that predispose the aorta to dissection in mice harboring the Myh11 K1256del mutation. Pathway analysis of transcriptomes showed that genes involved in membrane transport were downregulated in homozygous mutant (Myh11^ΔK/ΔK) aortas. Furthermore, expanding the analysis with metabolomics showed that two mechanisms that raise the cytosolic Ca²⁺ concentration—multiple calcium channel expression and ADP–ribose synthesis—were attenuated in Myh11^ΔK/ΔK aortas. We suggest that the impairment of the Ca²⁺ influx attenuates aortic contraction and that suboptimal contraction predisposes the aorta to dissection. Full article

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25 pages, 2447 KiB

Open AccessReview

Hormonal Imbalances in Prader–Willi and Schaaf–Yang Syndromes Imply the Evolution of Specific Regulation of Hypothalamic Neuroendocrine Function in Mammals

by Maria Camila Hoyos Sanchez, Tara Bayat, Rebecca R. Florke Gee and Klementina Fon Tacer

Int. J. Mol. Sci. 2023, 24(17), 13109; https://doi.org/10.3390/ijms241713109 - 23 Aug 2023

Cited by 2 | Viewed by 1800

Abstract

The hypothalamus regulates fundamental aspects of physiological homeostasis and behavior, including stress response, reproduction, growth, sleep, and feeding, several of which are affected in patients with Prader–Willi (PWS) and Schaaf–Yang syndrome (SYS). PWS is caused by paternal deletion, maternal uniparental disomy, or imprinting [...] Read more.

The hypothalamus regulates fundamental aspects of physiological homeostasis and behavior, including stress response, reproduction, growth, sleep, and feeding, several of which are affected in patients with Prader–Willi (PWS) and Schaaf–Yang syndrome (SYS). PWS is caused by paternal deletion, maternal uniparental disomy, or imprinting defects that lead to loss of expression of a maternally imprinted region of chromosome 15 encompassing non-coding RNAs and five protein-coding genes; SYS patients have a mutation in one of them, MAGEL2. Throughout life, PWS and SYS patients suffer from musculoskeletal deficiencies, intellectual disabilities, and hormonal abnormalities, which lead to compulsive behaviors like hyperphagia and temper outbursts. Management of PWS and SYS is mostly symptomatic and cures for these debilitating disorders do not exist, highlighting a clear, unmet medical need. Research over several decades into the molecular and cellular roles of PWS genes has uncovered that several impinge on the neuroendocrine system. In this review, we will discuss the expression and molecular functions of PWS genes, connecting them with hormonal imbalances in patients and animal models. Besides the observed hormonal imbalances, we will describe the recent findings about how the loss of individual genes, particularly MAGEL2, affects the molecular mechanisms of hormone secretion. These results suggest that MAGEL2 evolved as a mammalian-specific regulator of hypothalamic neuroendocrine function. Full article

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14 pages, 2758 KiB

Open AccessArticle

Trapa bispinosa Roxb. Pericarp Extract Exerts 5α-Reductase Inhibitory Activity in Castrated Benign Prostatic Hyperplasia Model Mice

by Takashi Fujita, Tomoko Aoyama, Tomohiro Uemura, Shouko Takeshita, Takuto Yamasaki, Hiroko Heijou and Koji Morimoto

Int. J. Mol. Sci. 2023, 24(14), 11765; https://doi.org/10.3390/ijms241411765 - 21 Jul 2023

Viewed by 1026

Abstract

Trapa bispinosa Roxb. pericarp extract (TBE) has a polyphenol-rich composition and exhibits potent antioxidant and anti-glycation activities in vitro. In the present study, we investigated the inhibitory effects of TBE on 5α-reductase in vitro using LNCaP cells and in vivo using a mouse [...] Read more.

Trapa bispinosa Roxb. pericarp extract (TBE) has a polyphenol-rich composition and exhibits potent antioxidant and anti-glycation activities in vitro. In the present study, we investigated the inhibitory effects of TBE on 5α-reductase in vitro using LNCaP cells and in vivo using a mouse model of castrated benign prostatic hyperplasia. TBE showed concentration-dependent inhibitory effects in the 5α-reductase (5αR) activity assay. In a reporter assay using AR-Luc/LNCaP cells, TBE inhibited the activity induced by testosterone, but not that induced by dihydrotestosterone. TBE also suppressed prostate cell proliferation, prostate-specific antigens, and transmembrane protease serine 2 expression in a castrated benign prostatic hyperplasia mouse model. In addition, ellagic acid, but not gallic acid, decreased 5αR and AR-Luc activities. Together, these results suggest a potential role for TBE in benign prostatic hyperplasia through inhibition of 5αR. Full article

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8 pages, 1132 KiB

Open AccessCommunication

Role of Nitric Oxide in the Altered Calcium Homeostasis of Platelets from Rats with Biliary Cirrhosis

by Masoud Akbari Aghdam, Paola Romecín, Joaquín García-Estañ and Noemí M. Atucha

Int. J. Mol. Sci. 2023, 24(13), 10948; https://doi.org/10.3390/ijms241310948 - 30 Jun 2023

Viewed by 769

Abstract

Introduction: Previously, we found that intracellular calcium (Ca²⁺) homeostasis is altered in platelets from an experimental model of liver cirrhosis, namely the bile-duct-ligated (BDL) rat. These alterations are compatible with the existence of a hypercoagulable state. Objective: In the present study, [...] Read more.

Introduction: Previously, we found that intracellular calcium (Ca²⁺) homeostasis is altered in platelets from an experimental model of liver cirrhosis, namely the bile-duct-ligated (BDL) rat. These alterations are compatible with the existence of a hypercoagulable state. Objective: In the present study, we analyzed the role of nitric oxide in the abnormal calcium signaling responses of an experimental cirrhosis model, the bile duct-ligated rat. Methods: Chronic treatment with L-NAME was used to inhibit NO production in a group of control and BDL animals, and the responses compared to those obtained in a control and BDL untreated group (n = 6 each). The experiments were conducted on isolated platelets loaded with fura-2, using fluorescence spectrometry. Results: Chronic treatment with L-NAME increased thrombin-induced Ca²⁺ release from internal stores in both control and BDL rats. However, the effect was significantly greater in the BDL rats (p < 0.05). Thrombin-induced calcium entry from the extracellular space was also elevated but at lower doses and, similarly in both control and BDL platelets, treated with the NO synthesis inhibitor. Capacitative calcium entry was also enhanced in the control platelets but not in platelets from BDL rats treated with L-NAME. Total calcium in intracellular stores was elevated in untreated platelets from BDL rats, and L-NAME pretreatment significantly (p < 0.05) elevated these values both in controls and in BDL but significantly more in the BDL rats (p < 0.05). Conclusions: Our results suggest that nitric oxide plays a role in the abnormal calcium signaling responses observed in platelets from BDL rats by interfering with the mechanism that releases calcium from the internal stores. Full article

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17 pages, 3453 KiB

Open AccessReview

Skeletal-Vascular Interactions in Bone Development, Homeostasis, and Pathological Destruction

by Haruhisa Watanabe, Nako Maishi, Marie Hoshi-Numahata, Mai Nishiura, Atsuko Nakanishi-Kimura, Kyoko Hida and Tadahiro Iimura

Int. J. Mol. Sci. 2023, 24(13), 10912; https://doi.org/10.3390/ijms241310912 - 30 Jun 2023

Cited by 1 | Viewed by 1307

Abstract

Bone is a highly vascularized organ that not only plays multiple roles in supporting the body and organs but also endows the microstructure, enabling distinct cell lineages to reciprocally interact. Recent studies have uncovered relevant roles of the bone vasculature in bone patterning, [...] Read more.

Bone is a highly vascularized organ that not only plays multiple roles in supporting the body and organs but also endows the microstructure, enabling distinct cell lineages to reciprocally interact. Recent studies have uncovered relevant roles of the bone vasculature in bone patterning, morphogenesis, homeostasis, and pathological bone destruction, including osteoporosis and tumor metastasis. This review provides an overview of current topics in the interactive molecular events between endothelial cells and bone cells during bone ontogeny and discusses the future direction of this research area to find novel ways to treat bone diseases. Full article

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13 pages, 4156 KiB

Open AccessArticle

Plasma Lipidomics Analysis Reveals the Potential Role of Lysophosphatidylcholines in Abdominal Aortic Aneurysm Progression and Formation

by Ting Xie, Chuxiang Lei, Wei Song, Xunyao Wu, Jianqiang Wu, Fangyuan Li, Yanze Lv, Yuexin Chen, Bao Liu and Yuehong Zheng

Int. J. Mol. Sci. 2023, 24(12), 10253; https://doi.org/10.3390/ijms241210253 - 16 Jun 2023

Cited by 1 | Viewed by 995

Abstract

Abdominal aortic aneurysm (AAA) is hallmarked by irreversible dilation of the infrarenal aorta. Lipid deposition in the aortic wall and the potential importance of a lipid disorder in AAA etiology highlight the need to explore lipid variation during AAA development. This study aimed [...] Read more.

Abdominal aortic aneurysm (AAA) is hallmarked by irreversible dilation of the infrarenal aorta. Lipid deposition in the aortic wall and the potential importance of a lipid disorder in AAA etiology highlight the need to explore lipid variation during AAA development. This study aimed to systematically characterize the lipidomics associated with AAA size and progression. Plasma lipids from 106 subjects (36 non-AAA controls and 70 AAA patients) were comprehensively analyzed using untargeted lipidomics. An AAA animal model was established by embedding angiotensin-II pump in ApoE^-/- mice for four weeks and blood was collected at 0, 2 and 4 weeks for lipidomic analysis. Using a false-discovery rate (FDR) < 0.05, a group of lysophosphatidylcholines (lysoPCs) were specifically decreased in AAA patients and mice. LysoPCs were principally lower in the AAA patients with larger diameter (diameter > 50 mm) than those with a smaller size (30 mm < diameter < 50 mm), and levels of lysoPCs were also found to be decreased with modelling time and aneurysm formation in AAA mice. Correlation matrices between lipids and clinical characteristics identified that the positive correlation between lysoPCs and HDL-c was reduced and negative correlations between lysoPCs and CAD rate, lysoPCs and hsCRP were converted to positive correlations in AAA compared to control. Weakened positive correlations between plasma lysoPCs and circulating HDL-c in AAA suggested that HDL-lysoPCs may elicit instinctive physiological effects in AAA. This study provides evidence that reduced lysoPCs essentially underlie the pathogenesis of AAA and that lysoPCs are promising biomarkers for AAA development. Full article

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14 pages, 4218 KiB

Open AccessArticle

A Network Pharmacology and Multi-Omics Combination Approach to Reveal the Effect of Strontium on Ca²⁺ Metabolism in Bovine Rumen Epithelial Cells

by Panpan Tan, Chenxu Zhao, Yong Dong, Zixin Zhang, Linshan Mei, Yezi Kong, Fangyuan Zeng, Yongqiang Wen, Baoyu Zhao and Jianguo Wang

Int. J. Mol. Sci. 2023, 24(11), 9383; https://doi.org/10.3390/ijms24119383 - 27 May 2023

Cited by 2 | Viewed by 1653

Abstract

Strontium (Sr) belongs to the same group in the periodic table as calcium (Ca). Sr level can serve as an index of rumen Ca absorption capacity; however, the effects of Sr on Ca²⁺ metabolism are unclear. This study aims to investigate the [...] Read more.

Strontium (Sr) belongs to the same group in the periodic table as calcium (Ca). Sr level can serve as an index of rumen Ca absorption capacity; however, the effects of Sr on Ca²⁺ metabolism are unclear. This study aims to investigate the effect of Sr on Ca²⁺ metabolism in bovine rumen epithelial cells. The bovine rumen epithelial cells were isolated from the rumen of newborn Holstein male calves (n = 3, 1 day old, 38.0 ± 2.8 kg, fasting). The half maximal inhibitory concentration (IC50) of Sr-treated bovine rumen epithelial cells and cell cycle were used to establish the Sr treatment model. Transcriptomics, proteomics, and network pharmacology were conducted to investigate the core targets of Sr-mediated regulation of Ca²⁺ metabolism in bovine rumen epithelial cells. The data of transcriptomics and proteomics were analyzed using bioinformatic analysis (Gene Ontology and Kyoto Encyclopedia of genes/protein). Quantitative data were analyzed using one-way ANOVA in GraphPad Prism 8.4.3 and the Shapiro–Wilk test was used for the normality test. Results presented that the IC50 of Sr treatment bovine rumen epithelial cells for 24 h was 43.21 mmol/L, and Sr increased intracellular Ca²⁺ levels. Multi-omics results demonstrated the differential expression of 770 mRNAs and 2436 proteins after Sr treatment; network pharmacology and reverse transcriptase polymerase chain reaction (RT-PCR) revealed Adenosylhomocysteine hydrolase-like protein 2 (AHCYL2), Semaphoring 3A (SEMA3A), Parathyroid hormone-related protein (PTHLH), Transforming growth factor β2 (TGF-β2), and Cholesterol side-chain cleavage enzyme (CYP11A1) as potential targets for Sr-mediated Ca²⁺ metabolism regulation. Together these results will improve the current comprehension of the regulatory effect of Sr on Ca²⁺ metabolism and pave a theoretical basis for Sr application in bovine hypocalcemia. Full article

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18 pages, 3493 KiB

Open AccessArticle

Temperature-Dependent Effects of Eicosapentaenoic Acid (EPA) on Browning of Subcutaneous Adipose Tissue in UCP1 Knockout Male Mice

by Yujiao Zu, Mandana Pahlavani, Latha Ramalingam, Shasika Jayarathne, Jose Andrade, Shane Scoggin, William T. Festuccia, Nishan S. Kalupahana and Naima Moustaid-Moussa

Int. J. Mol. Sci. 2023, 24(10), 8708; https://doi.org/10.3390/ijms24108708 - 13 May 2023

Cited by 1 | Viewed by 1540

Abstract

Uncoupling protein 1 (UCP1) plays a central role in thermogenic tissues by uncoupling cellular respiration to dissipate energy. Beige adipocytes, an inducible form of thermogenic cells in subcutaneous adipose tissue (SAT), have become a major focus in obesity research. We have previously shown [...] Read more.

Uncoupling protein 1 (UCP1) plays a central role in thermogenic tissues by uncoupling cellular respiration to dissipate energy. Beige adipocytes, an inducible form of thermogenic cells in subcutaneous adipose tissue (SAT), have become a major focus in obesity research. We have previously shown that eicosapentaenoic acid (EPA) ameliorated high-fat diet (HFD)-induced obesity by activating brown fat in C57BL/6J (B6) mice at thermoneutrality (30 °C), independently of UCP1. Here, we investigated whether ambient temperature (22 °C) impacts EPA effects on SAT browning in wild-type (WT) and UCP1 knockout (KO) male mice and dissected underlying mechanisms using a cell model. We observed resistance to diet-induced obesity in UCP1 KO mice fed HFD at ambient temperature, with significantly higher expression of UCP1-independent thermogenic markers, compared to WT mice. These markers included the fibroblast growth factor 21 (FGF21) and sarco/endoplasmic reticulum Ca²⁺-ATPase 2b (SERCA2b), suggesting the indispensable role of temperature in beige fat reprogramming. Surprisingly, although EPA induced thermogenic effects in SAT-derived adipocytes harvested from both KO and WT mice, EPA only increased thermogenic gene and protein expression in the SAT of UCP1 KO mice housed at ambient temperature. Collectively, our findings indicate that the thermogenic effects of EPA, which are independent of UCP1, occur in a temperature-dependent manner. Full article

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15 pages, 3489 KiB

Open AccessArticle

Serelaxin Alleviates Fibrosis in Thyroid-Associated Ophthalmopathy via the Notch Pathway

by Anqi Sun, Huijing Ye, Zhihui Xu, Jingqiao Chen, Wei Xiao, Te Zhang, Xiaotong Sha, Shaowei Bi, Tianyi Zhou and Huasheng Yang

Int. J. Mol. Sci. 2023, 24(9), 8356; https://doi.org/10.3390/ijms24098356 - 06 May 2023

Cited by 1 | Viewed by 1523

Abstract

Fibrosis is the late stage of thyroid-associated ophthalmopathy (TAO), resulting in serious complications. Effective therapeutic drugs are still lacking. We aimed to explore the mechanism of TAO fibrosis and to find a targeted drug. High-throughput RNA sequencing was performed on orbital connective tissues [...] Read more.

Fibrosis is the late stage of thyroid-associated ophthalmopathy (TAO), resulting in serious complications. Effective therapeutic drugs are still lacking. We aimed to explore the mechanism of TAO fibrosis and to find a targeted drug. High-throughput RNA sequencing was performed on orbital connective tissues from twelve patients with TAO and six healthy controls. Protein–protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes (STRING) database and we identified the hub gene by Cytoscape software. Additionally, the RNA sequencing results were validated by quantitative real-time polymerase chain reaction (qRT–PCR). Bioinformatic prediction identified the functions of differentially expressed genes (DEGs). Further orbital connective tissue and serum samples of the TAO and control groups were collected for subsequent experiments. Histologic staining, Western blotting (WB), qRT–PCR, enzyme-linked immunosorbent assays (ELISAs), gene overexpression through lentiviral infection or silencing gene by short interfering RNA (siRNA) were performed. We found that the relaxin signaling pathway is an important regulatory pathway in TAO fibrosis pathogenesis. Serelaxin exerts antifibrotic and anti-inflammatory effects in TAO. Furthermore, the downstream Notch pathway was activated by serelaxin and was essential to the antifibrotic effect of serelaxin in TAO. The antifibrotic effect of serelaxin is dependent on RXFP1. Full article

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18 pages, 2423 KiB

Open AccessArticle

Unraveling the Host Genetic Background Effect on Internal Organ Weight Influenced by Obesity and Diabetes Using Collaborative Cross Mice

by Aya Ghnaim, Iqbal M. Lone, Nadav Ben Nun and Fuad A. Iraqi

Int. J. Mol. Sci. 2023, 24(9), 8201; https://doi.org/10.3390/ijms24098201 - 03 May 2023

Cited by 9 | Viewed by 1441

Abstract

Type 2 diabetes mellitus (T2DM) is a severe chronic epidemic that results from the body’s improper usage of the hormone insulin. Globally, 700 million people are expected to have received a diabetes diagnosis by 2045, according to the International Diabetes Federation (IDF). Cancer [...] Read more.

Type 2 diabetes mellitus (T2DM) is a severe chronic epidemic that results from the body’s improper usage of the hormone insulin. Globally, 700 million people are expected to have received a diabetes diagnosis by 2045, according to the International Diabetes Federation (IDF). Cancer and macro- and microvascular illnesses are only a few immediate and long-term issues it could lead to. T2DM accelerates the effect of organ weights by triggering a hyperinflammatory response in the body’s organs, inhibiting tissue repair and resolving inflammation. Understanding how genetic variation translates into different clinical presentations may highlight the mechanisms through which dietary elements may initiate or accelerate inflammatory disease processes and suggest potential disease-prevention techniques. To address the host genetic background effect on the organ weight by utilizing the newly developed mouse model, the Collaborative Cross mice (CC). The study was conducted on 207 genetically different CC mice from 8 CC lines of both sexes. The experiment started with 8-week-old mice for 12 weeks. During this period, one group maintained a standard chow diet (CHD), while the other group maintained a high-fat diet (HFD). In addition, body weight was recorded bi-weekly, and at the end of the study, a glucose tolerance test, as well as tissue collection (liver, spleen, heart), were conducted. Our study observed a strong effect of HFD on blood glucose clearance among different CC lines. The HFD decreased the blood glucose clearance displayed by the significant Area Under Curve (AUC) values in both populations. In addition, variation in body weight changes among the different CC lines in response to HFD. The female liver weight significantly increased compared to males in the overall population when exposed to HFD. Moreover, males showed higher heritability values than females on the same diet. Regardless of the dietary challenge, the liver weight in the overall male population correlated positively with the final body weight. The liver weight results revealed that three different CC lines perform well under classification models. The regression results also varied among organs. Accordingly, the differences among these lines correspond to the genetic variance, and we suspect that some genetic factors invoke different body responses to HFD. Further investigations, such as quantitative trait loci (QTL) analysis and genomic studies, could find these genetic elements. These findings would prove critical factors for developing personalized medicine, as they could indicate future body responses to numerous situations early, thus preventing the development of complex diseases. Full article

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18 pages, 20508 KiB

Open AccessArticle

Casein Kinase 1α as a Novel Factor Affects Thyrotropin Synthesis via PKC/ERK/CREB Signaling

by Bingjie Wang, Jinglin Zhang, Di Zhang, Chenyang Lu, Hui Liu, Qiao Gao, Tongjuan Niu, Mengqing Yin and Sheng Cui

Int. J. Mol. Sci. 2023, 24(8), 7034; https://doi.org/10.3390/ijms24087034 - 11 Apr 2023

Cited by 1 | Viewed by 1331

Abstract

Casein kinase 1α (CK1α) is present in multiple cellular organelles and plays various roles in regulating neuroendocrine metabolism. Herein, we investigated the underlying function and mechanisms of CK1α-regulated thyrotropin (thyroid-stimulating hormone (TSH)) synthesis in a murine model. Immunohistochemistry and immunofluorescence staining were performed [...] Read more.

Casein kinase 1α (CK1α) is present in multiple cellular organelles and plays various roles in regulating neuroendocrine metabolism. Herein, we investigated the underlying function and mechanisms of CK1α-regulated thyrotropin (thyroid-stimulating hormone (TSH)) synthesis in a murine model. Immunohistochemistry and immunofluorescence staining were performed to detect CK1α expression in murine pituitary tissue and its localization to specific cell types. Tshb mRNA expression in anterior pituitary was detected using real-time and radioimmunoassay techniques after CK1α activity was promoted and inhibited in vivo and in vitro. Relationships among TRH/L-T4, CK1α, and TSH were analyzed with TRH and L-T4 treatment, as well as thyroidectomy, in vivo. In mice, CK1α was expressed at higher levels in the pituitary gland tissue than in the thyroid, adrenal gland, or liver. However, inhibiting endogenous CK1α activity in the anterior pituitary and primary pituitary cells significantly increased TSH expression and attenuated the inhibitory effect of L-T4 on TSH. In contrast, CK1α activation weakened TSH stimulation by thyrotropin-releasing hormone (TRH) by suppressing protein kinase C (PKC)/extracellular signal-regulated kinase (ERK)/cAMP response element binding (CREB) signaling. CK1α, as a negative regulator, mediates TRH and L-T4 upstream signaling by targeting PKC, thus affecting TSH expression and downregulating ERK1/2 phosphorylation and CREB transcriptional activity. Full article

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12 pages, 303 KiB

Open AccessArticle

Obesity Is Associated with Distorted Proteoglycan Expression in Adipose Tissue

by Astri J. Meen, Atanaska I. Doncheva, Yvonne Böttcher, Simon N. Dankel, Anne Hoffmann, Matthias Blüher, Johan Fernø, Gunnar Mellgren, Adhideb Ghosh, Wenfei Sun, Hua Dong, Falko Noé, Christian Wolfrum, Gunnar Pejler, Knut Tomas Dalen and Svein O. Kolset

Int. J. Mol. Sci. 2023, 24(8), 6884; https://doi.org/10.3390/ijms24086884 - 07 Apr 2023

Viewed by 1671

Abstract

Proteoglycans are central components of the extracellular matrix (ECM) and binding partners for inflammatory chemokines. Morphological differences in the ECM and increased inflammation are prominent features of the white adipose tissues in patients with obesity. The impact of obesity and weight loss on [...] Read more.

Proteoglycans are central components of the extracellular matrix (ECM) and binding partners for inflammatory chemokines. Morphological differences in the ECM and increased inflammation are prominent features of the white adipose tissues in patients with obesity. The impact of obesity and weight loss on the expression of specific proteoglycans in adipose tissue is not well known. This study aimed to investigate the relationship between adiposity and proteoglycan expression. We analyzed transcriptomic data from two human bariatric surgery cohorts. In addition, RT-qPCR was performed on adipose tissues from female and male mice fed a high-fat diet. Both visceral and subcutaneous adipose tissue depots were analyzed. Adipose mRNA expression of specific proteoglycans, proteoglycan biosynthetic enzymes, proteoglycan partner molecules, and other ECM-related proteins were altered in both human cohorts. We consistently observed more profound alterations in gene expression of ECM targets in the visceral adipose tissues after surgery (among others VCAN (p = 0.000309), OGN (p = 0.000976), GPC4 (p = 0.00525), COL1A1 (p = 0.00221)). Further, gene analyses in mice revealed sex differences in these two tissue compartments in obese mice. We suggest that adipose tissue repair is still in progress long after surgery, which may reflect challenges in remodeling increased adipose tissues. This study can provide the basis for more mechanistic studies on the role of proteoglycans in adipose tissues in obesity. Full article

28 pages, 594 KiB

Open AccessReview

Altered Tryptophan-Kynurenine Pathway in Delirium: A Review of the Current Literature

by Ang Hui Phing, Suzana Makpol, Muhammad Luqman Nasaruddin, Wan Asyraf Wan Zaidi, Nurul Saadah Ahmad and Hashim Embong

Int. J. Mol. Sci. 2023, 24(6), 5580; https://doi.org/10.3390/ijms24065580 - 15 Mar 2023

Cited by 3 | Viewed by 2263

Abstract

Delirium, a common form of acute brain dysfunction, is associated with increased morbidity and mortality, especially in older patients. The underlying pathophysiology of delirium is not clearly understood, but acute systemic inflammation is known to drive delirium in cases of acute illnesses, such [...] Read more.

Delirium, a common form of acute brain dysfunction, is associated with increased morbidity and mortality, especially in older patients. The underlying pathophysiology of delirium is not clearly understood, but acute systemic inflammation is known to drive delirium in cases of acute illnesses, such as sepsis, trauma, and surgery. Based on psychomotor presentations, delirium has three main subtypes, such as hypoactive, hyperactive, and mixed subtype. There are similarities in the initial presentation of delirium with depression and dementia, especially in the hypoactive subtype. Hence, patients with hypoactive delirium are frequently misdiagnosed. The altered kynurenine pathway (KP) is a promising molecular pathway implicated in the pathogenesis of delirium. The KP is highly regulated in the immune system and influences neurological functions. The activation of indoleamine 2,3-dioxygenase, and specific KP neuroactive metabolites, such as quinolinic acid and kynurenic acid, could play a role in the event of delirium. Here, we collectively describe the roles of the KP and speculate on its relevance in delirium. Full article

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11 pages, 3417 KiB

Open AccessArticle

Spexin2 Is a Novel Food Regulator in Gallus gallus

by Fengyan Meng, Yuping Wu, Yu Yu, Guixian Bu, Xiaogang Du, Qiuxia Liang, Xiaohan Cao, Anqi Huang, Xianyin Zeng, Linyan Huang, Fanli Kong, Yunkun Li and Xingfa Han

Int. J. Mol. Sci. 2023, 24(5), 4821; https://doi.org/10.3390/ijms24054821 - 02 Mar 2023

Viewed by 1336

Abstract

Spexin2 (SPX2), a paralog of SPX1, is a newly identified gene in non-mammalian vertebrates. Limited studies in fish have evidenced its important role in food intake and energy balance modulation. However, little is known about its biological functions in birds. [...] Read more.

Spexin2 (SPX2), a paralog of SPX1, is a newly identified gene in non-mammalian vertebrates. Limited studies in fish have evidenced its important role in food intake and energy balance modulation. However, little is known about its biological functions in birds. Using the chicken (c-) as a model, we cloned the full-length cDNA of SPX2 by using RACE-PCR. It is 1189 base pair (bp) in length and predicted to generate a protein of 75 amino acids that contains a 14 amino acids mature peptide. Tissue distribution analysis showed that cSPX2 transcripts were detected in a wide array of tissues, with abundant expression in the pituitary, testis, and adrenal gland. cSPX2 was also observed to be ubiquitously expressed in chicken brain regions, with the highest expression in the hypothalamus. Its expression was significantly upregulated in the hypothalamus after 24 or 36 h of food deprivation, and the feeding behavior of chicks was obviously suppressed after peripheral injection with cSPX2. Mechanistically, further studies evidenced that cSPX2 acts as a satiety factor via upregulating cocaine and amphetamine regulated transcript (CART) and downregulating agouti-related neuropeptide (AGRP) in hypothalamus. Using a pGL4-SRE-luciferase reporter system, cSPX2 was demonstrated to effectively activate a chicken galanin II type receptor (cGALR2), a cGALR2-like receptor (cGALR2L), and a galanin III type receptor (cGALR3), with the highest binding affinity for cGALR2L. Collectively, we firstly identified that cSPX2 serves as a novel appetite monitor in chicken. Our findings will help clarify the physiological functions of SPX2 in birds as well as its functional evolution in vertebrates. Full article

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21 pages, 373 KiB

Open AccessReview

Adipose-Derived Mesenchymal Stromal Cells in Basic Research and Clinical Applications

by Katarzyna Czerwiec, Małgorzata Zawrzykraj, Milena Deptuła, Aneta Skoniecka, Agata Tymińska, Jacek Zieliński, Adam Kosiński and Michał Pikuła

Int. J. Mol. Sci. 2023, 24(4), 3888; https://doi.org/10.3390/ijms24043888 - 15 Feb 2023

Cited by 14 | Viewed by 2478

Abstract

Adipose-derived mesenchymal stromal cells (AD-MSCs) have been extensively studied in recent years. Their attractiveness is due to the ease of obtaining clinical material (fat tissue, lipoaspirate) and the relatively large number of AD-MSCs present in adipose tissue. In addition, AD-MSCs possess a high [...] Read more.

Adipose-derived mesenchymal stromal cells (AD-MSCs) have been extensively studied in recent years. Their attractiveness is due to the ease of obtaining clinical material (fat tissue, lipoaspirate) and the relatively large number of AD-MSCs present in adipose tissue. In addition, AD-MSCs possess a high regenerative potential and immunomodulatory activities. Therefore, AD-MSCs have great potential in stem cell-based therapies in wound healing as well as in orthopedic, cardiovascular, or autoimmune diseases. There are many ongoing clinical trials on AD-MSC and in many cases their effectiveness has been proven. In this article, we present current knowledge about AD-MSCs based on our experience and other authors. We also demonstrate the application of AD-MSCs in selected pre-clinical models and clinical studies. Adipose-derived stromal cells can also be the pillar of the next generation of stem cells that will be chemically or genetically modified. Despite much research on these cells, there are still important and interesting areas to explore. Full article

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20 pages, 4577 KiB

Open AccessArticle

The Comprehensive Steroidome in Complete TSPO/PBR Knockout Mice under Basal Conditions

by Philippe Liere, Guo-Jun Liu, Antoine Pianos, Ryan J. Middleton, Richard B. Banati and Yvette Akwa

Int. J. Mol. Sci. 2023, 24(3), 2474; https://doi.org/10.3390/ijms24032474 - 27 Jan 2023

Cited by 5 | Viewed by 1691

Abstract

The 18 kDa translocator protein (TSPO/PBR) is a multifunctional evolutionary highly conserved outer mitochondrial membrane protein. Decades of research has reported an obligatory role of TSPO/PBR in both mitochondrial cholesterol transport and, thus, steroid production. However, the strict dependency of steroidogenesis on TSPO/PBR [...] Read more.

The 18 kDa translocator protein (TSPO/PBR) is a multifunctional evolutionary highly conserved outer mitochondrial membrane protein. Decades of research has reported an obligatory role of TSPO/PBR in both mitochondrial cholesterol transport and, thus, steroid production. However, the strict dependency of steroidogenesis on TSPO/PBR has remained controversial. The aim of this study was to provide insight into the steroid profile in complete C57BL/6-^{Tspotm1GuWu(GuwiyangWurra)}-knockout male mice (TSPO-KO) under basal conditions. The steroidome in the brain, adrenal glands, testes and plasma was measured by gas chromatography coupled to tandem mass spectrometry (GC-MS/MS). We found that steroids present in wild-type (WT) mice were also detected in TSPO-KO mice, including pregnenolone (PREG), progestogens, mineralo-glucocorticosteroids and androgens. The concentrations of PREG and most metabolites were similar between genotypes, except a significant decrease in the levels of the 5α-reduced metabolites of progesterone (PROG) in adrenal glands and plasma and of the 5α-reduced metabolites of corticosterone (B) in plasma in TSPO-KO compared to WT animals, suggesting other regulatory functions for the TSPO/PBR. The expression levels of the voltage-dependent anion-selective channel (VDAC-1), CYP11A1 and 5α-reductase were not significantly different between both groups. Thus, the complete deletion of the tspo gene in male mice does not impair de novo steroidogenesis in vivo. Full article

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14 pages, 503 KiB

Open AccessReview

Role of Endothelial Progenitor Cells in Frailty

by Klara Komici, Angelica Perna and Germano Guerra

Int. J. Mol. Sci. 2023, 24(3), 2139; https://doi.org/10.3390/ijms24032139 - 21 Jan 2023

Viewed by 1902

Abstract

Frailty is a clinical condition closely related to aging which is characterized by a multidimensional decline in biological reserves, a failure of physiological mechanisms and vulnerability to minor stressors. Chronic inflammation, the impairment of endothelial function, age-related endocrine system modifications and immunosenescence are [...] Read more.

Frailty is a clinical condition closely related to aging which is characterized by a multidimensional decline in biological reserves, a failure of physiological mechanisms and vulnerability to minor stressors. Chronic inflammation, the impairment of endothelial function, age-related endocrine system modifications and immunosenescence are important mechanisms in the pathophysiology of frailty. Endothelial progenitor cells (EPCs) are considered important contributors of the endothelium homeostasis and turn-over. In the elderly, EPCs are impaired in terms of function, number and survival. In addition, the modification of EPCs’ level and function has been widely demonstrated in atherosclerosis, hypertension and diabetes mellitus, which are the most common age-related diseases. The purpose of this review is to illustrate the role of EPCs in frailty. Initially, we describe the endothelial dysfunction in frailty, the response of EPCs to the endothelial dysfunction associated with frailty and, finally, interventions which may restore the EPCs expression and function in frail people. Full article

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14 pages, 11962 KiB

Open AccessArticle

Low Magnesium in Conjunction with High Homocysteine and Less Sleep Accelerates Telomere Attrition in Healthy Elderly Australian

by Varinderpal S. Dhillon, Permal Deo, Philip Thomas and Michael Fenech

Int. J. Mol. Sci. 2023, 24(2), 982; https://doi.org/10.3390/ijms24020982 - 04 Jan 2023

Cited by 6 | Viewed by 2222

Abstract

The relationship between sleep and micronutrients, including magnesium, is implicated in its regulation. The effects of low magnesium and other micronutrients on sleep disruption and telomere loss are not well understood. The present study was carried out in 172 healthy elderly subjects from [...] Read more.

The relationship between sleep and micronutrients, including magnesium, is implicated in its regulation. The effects of low magnesium and other micronutrients on sleep disruption and telomere loss are not well understood. The present study was carried out in 172 healthy elderly subjects from South Australia. Plasma micronutrients including magnesium were measured. Each participant provided information about their sleep hours (<7 h or ≥7 h). Lymphocyte telomere length (TL) was measured by real-time qPCR assay. Plasma magnesium level was significantly low in subjects who sleep less than 7 h (p = 0.0002). TL was significantly shorter in people who are low in magnesium and sleep less than 7 h (p = 0.01). Plasma homocysteine (Hcy) is negatively associated with magnesium (r = −0.299; p < 0.0001). There is a significant interaction effect of magnesium and Hcy on sleep duration (p = 0.04) and TL (p = 0.003). Our results suggest that inadequate magnesium levels have an adverse impact on sleep and telomere attrition rate in cognitively normal elderly people, and this may be exacerbated by low levels of vitamin B₁₂ and folate that elevate Hcy concentration. Full article

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2022

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19 pages, 4143 KiB

Open AccessArticle

Improvement of Fertilization Capacity and Developmental Ability of Vitrified Bovine Oocytes by JUNO mRNA Microinjection and Cholesterol-Loaded Methyl-β-Cyclodextrin Treatment

by Xi Xu, Tong Hao, Emma Komba, Baigao Yang, Haisheng Hao, Weihua Du, Huabin Zhu, Hang Zhang and Xueming Zhao

Int. J. Mol. Sci. 2023, 24(1), 590; https://doi.org/10.3390/ijms24010590 - 29 Dec 2022

Cited by 1 | Viewed by 1435

Abstract

Vitrification of oocytes is crucial for embryo biotechnologies, germplasm cryopreservation of endangered and excellent female animals, and the fertility of humans. However, vitrification significantly impairs the fertilization ability of oocytes, which significantly limits its widely used application. JUNO protein, a receptor for Izumo1, [...] Read more.

Vitrification of oocytes is crucial for embryo biotechnologies, germplasm cryopreservation of endangered and excellent female animals, and the fertility of humans. However, vitrification significantly impairs the fertilization ability of oocytes, which significantly limits its widely used application. JUNO protein, a receptor for Izumo1, is involved in sperm-oocyte fusion and is an indispensable protein for mammalian fertilization, and its abundance is susceptible to vitrification. However, it is still unclear how vitrification reduces the fertilization capacity of bovine oocytes by affecting JUNO protein. This study was designed to investigate the effect of vitrification on the abundance and post-translational modifications of JUNO protein in bovine oocytes. Our results showed that vitrification did not alter the amino acid sequence of JUNO protein in bovine oocytes. Furthermore, the liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis results showed that vitrification significantly reduced the number and changed the location of disulfide bonds, and increased the number of both phosphorylation and glycosylation sites of JUNO protein in bovine oocytes. Finally, the fertilization capacity and development ability of vitrified oocytes treated with 200 pg JUNO mRNA microinjection and cholesterol-loaded methyl-β-cyclodextrin (CLC/MβCD) were similar to those of fresh oocytes. In conclusion, our results showed that vitrification of bovine oocytes did not alter the protein sequence of JUNO, but induced post-translational modifications and changed protein abundance. Moreover, the fertilization and development ability of vitrified bovine oocytes were improved by the combination treatment of JUNO mRNA microinjection and CLC/MβCD. Full article

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16 pages, 7121 KiB

Open AccessArticle

Expression and Regulation of a Novel Decidual Cells-Derived Estrogen Target during Decidualization

by Lin Lu, Yingni Chen, Zhenshan Yang, Shijin Liang, Songqi Zhu and Xiaohuan Liang

Int. J. Mol. Sci. 2023, 24(1), 302; https://doi.org/10.3390/ijms24010302 - 24 Dec 2022

Cited by 3 | Viewed by 1823

Abstract

During decidualization in rodents, uterine stromal cells undergo extensive reprogramming to differentiate into distinct cell types, forming primary decidual zones (PDZs), secondary decidual zones (SDZs), and layers of undifferentiated stromal cells. The formation of secondary decidual zones is accompanied by extensive angiogenesis. During [...] Read more.

During decidualization in rodents, uterine stromal cells undergo extensive reprogramming to differentiate into distinct cell types, forming primary decidual zones (PDZs), secondary decidual zones (SDZs), and layers of undifferentiated stromal cells. The formation of secondary decidual zones is accompanied by extensive angiogenesis. During early pregnancy, besides ovarian estrogen, de novo synthesis of estrogen in the uterus is essential for the progress of decidualization. However, the molecular mechanisms are not fully understood. Studies have shown that Cystatin B (Cstb) is highly expressed in the decidual tissue of the uterus, but the regulation and mechanism of Cstb in the process of decidualization have not been reported. Our results showed that Cstb was highly expressed in mouse decidua and artificially induced deciduoma via in situ hybridization and immunofluorescence. Estrogen stimulates the expression of Cstb through the Estrogen receptor (ER)α. Moreover, in situ synthesis of estrogen in the uterus during decidualization regulates the expression of Cstb. Silencing the expression of Cstb affects the migration ability of stromal cells. Knockdown Cstb by siRNA significantly inhibits the expression of Dtprp, a marker for mouse decidualization. Our study identifies a novel estrogen target, Cstb, during decidualization and reveals that Cstb may play a pivotal role in angiogenesis during mouse decidualization via the Angptl7. Full article

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16 pages, 3027 KiB

Open AccessArticle

Susceptibility of Human Plasma N-glycome to Low-Calorie and Different Weight-Maintenance Diets

by Helena Deriš, Petra Tominac, Frano Vučković, Arne Astrup, Ellen E. Blaak, Gordan Lauc and Ivan Gudelj

Int. J. Mol. Sci. 2022, 23(24), 15772; https://doi.org/10.3390/ijms232415772 - 12 Dec 2022

Viewed by 2188

Abstract

Aberrant plasma protein glycosylation is associated with a wide range of diseases, including diabetes, cardiovascular, and immunological disorders. To investigate plasma protein glycosylation alterations due to weight loss and successive weight-maintenance diets, 1850 glycomes from participants of the Diogenes study were analyzed using [...] Read more.

Aberrant plasma protein glycosylation is associated with a wide range of diseases, including diabetes, cardiovascular, and immunological disorders. To investigate plasma protein glycosylation alterations due to weight loss and successive weight-maintenance diets, 1850 glycomes from participants of the Diogenes study were analyzed using Ultra-High-Performance Liquid Chromatography (UHPLC). The Diogenes study is a large dietary intervention study in which participants were subjected to a low-calorie diet (LCD) followed by one of five different weight-maintenance diets in a period of 6 months. The most notable alterations of the plasma glycome were 8 weeks after the subjects engaged in the LCD; a significant increase in low-branched glycan structures, accompanied by a decrease in high-branched glycan structures. After the LCD period, there was also a significant rise in N-glycan structures with antennary fucose. Interestingly, we did not observe significant changes between different diets, and almost all effects we observed immediately after the LCD period were annulled during the weight-maintenance diets period. Full article

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17 pages, 3541 KiB

Open AccessArticle

Metformin Attenuates Inflammation and Fibrosis in Thyroid-Associated Ophthalmopathy

by Zhihui Xu, Huijing Ye, Wei Xiao, Anqi Sun, Shenglan Yang, Te Zhang, Xiaotong Sha and Huasheng Yang

Int. J. Mol. Sci. 2022, 23(24), 15508; https://doi.org/10.3390/ijms232415508 - 07 Dec 2022

Cited by 4 | Viewed by 1734

Abstract

The pathogenesis of thyroid-associated ophthalmopathy (TAO) is still unclear, and therapeutic drugs have great limitations. As metformin has multiple therapeutic effects in many autoimmune diseases, we explored the effects of metformin on TAO in an in vitro fibroblast model. We used orbital connective [...] Read more.

The pathogenesis of thyroid-associated ophthalmopathy (TAO) is still unclear, and therapeutic drugs have great limitations. As metformin has multiple therapeutic effects in many autoimmune diseases, we explored the effects of metformin on TAO in an in vitro fibroblast model. We used orbital connective tissues and fibroblasts that were obtained from TAO patients and normal controls. The activity of adenosine monophosphate-activated protein kinase (AMPK) and the levels of inflammatory or fibrotic factors were examined by immunofluorescence (IF) and immunohistochemistry (IHC). Quantitative real-time polymerase chain reaction (qPCR), cytokine quantification by enzyme-linked immunosorbent sssay (ELISA), IF, and western blotting (WB) were used to measure the expression of factors related to inflammation, fibrosis, and autophagy. To determine the anti-inflammatory and antifibrotic mechanisms of metformin, we pretreated cells with metformin, 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR, an AMPK activator) or compound C (CC, an AMPK inhibitor) for 24 h and used WB to verify the changes in protein levels in the AMPK/mammalian target of rapamycin (mTOR) pathway. We determined that the low activity of AMPK in the periorbital tissue of TAO patients may be closely related to the occurrence and development of inflammation and fibrosis, and metformin exerts multiple effects by activating AMPK in TAO. Furthermore, we suggest that AMPK may be a potential target of TAO therapy. Full article

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15 pages, 984 KiB

Open AccessReview

An Overview of the Current Known and Unknown Roles of Vitamin D₃ in the Female Reproductive System: Lessons from Farm Animals, Birds, and Fish

by Malgorzata Grzesiak, Marcelina Tchurzyk, Magdalena Socha, Andrzej Sechman and Anna Hrabia

Int. J. Mol. Sci. 2022, 23(22), 14137; https://doi.org/10.3390/ijms232214137 - 16 Nov 2022

Cited by 6 | Viewed by 2765

Abstract

Recent studies have clearly shown that vitamin D₃ is a crucial regulator of the female reproductive process in humans and animals. Knowledge of the expression of vitamin D₃ receptors and related molecules in the female reproductive organs such as ovaries, uterus, [...] Read more.

Recent studies have clearly shown that vitamin D₃ is a crucial regulator of the female reproductive process in humans and animals. Knowledge of the expression of vitamin D₃ receptors and related molecules in the female reproductive organs such as ovaries, uterus, oviduct, or placenta under physiological and pathological conditions highlights its contribution to the proper function of the reproductive system in females. Furthermore, vitamin D₃ deficiency leads to serious reproductive disturbances and pathologies including ovarian cysts. Although the influence of vitamin D₃ on the reproductive processes of humans and rodents has been extensively described, the association between vitamin D₃ and female reproductive function in farm animals, birds, and fish has rarely been summarized. In this review, we provide an overview of the role of vitamin D₃ in the reproductive system of those animals, with special attention paid to the expression of vitamin D₃ receptors and its metabolic molecules. This updated information could be essential for better understanding animal physiology and overcoming the incidence of infertility, which is crucial for optimizing reproductive outcomes in female livestock. Full article

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22 pages, 4074 KiB

Open AccessArticle

Peripheral Gonadotropin-Inhibitory Hormone (GnIH) Acting as a Novel Modulator Involved in Hyperphagia-Induced Obesity and Associated Disorders of Metabolism in an In Vivo Female Piglet Model

by Lei Chen, Xin Zhang, Xingxing Song, Dongyang Han, Kaiou Han, Wenhao Xu, Rongrong Luo, Yajie Cao, Yan Shi, Chengcheng Liu, Changlin Xu, Zixin Li, Yinan Li and Xun Li

Int. J. Mol. Sci. 2022, 23(22), 13956; https://doi.org/10.3390/ijms232213956 - 12 Nov 2022

Viewed by 1406

Abstract

Apart from the well-established role of the gonadotropin-inhibitory hormone (GnIH) in the regulation of the reproductive functions, much less is known about the peripheral role of the GnIH and its receptor in the metabolic processes. On account of pig being an excellent model [...] Read more.

Apart from the well-established role of the gonadotropin-inhibitory hormone (GnIH) in the regulation of the reproductive functions, much less is known about the peripheral role of the GnIH and its receptor in the metabolic processes. On account of pig being an excellent model for studies of food intake and obesity in humans, we investigated the peripheral effects of the GnIH on food intake and energy homeostasis and revealed the underlying mechanism(s) in female piglets in vivo. Compared to the vehicle-treated group, intraperitoneally injected GnIH significantly increased the food intake and altered the meal microstructure both in the fasting and ad libitum female piglet. GnIH-triggered hyperphagia induced female piglet obesity and altered islet hormone secretion in the pancreas, accompanied with dyslipidemia and hyperglycemia. Interestingly, GnIH decreased the glucose transport capacity and glycogen synthesis, whereas it increased the gluconeogenesis in the liver, while it also induced an insulin resistance in white adipose tissue (WAT) via inhibiting the activity of AKT-GSK3-β signaling. In terms of the lipid metabolism, GnIH reduced the oxidation of fatty acids, whereas the elevated fat synthesis ability in the liver and WAT was developed though the inhibited AMPK phosphorylation. Our findings demonstrate that peripheral GnIH could trigger hyperphagia-induced obesity and an associated glycolipid metabolism disorder in female piglets, suggesting that GnIH may act as a potential therapeutic agent for metabolic syndrome, obesity and diabetes. Full article

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16 pages, 2482 KiB

Open AccessArticle

Hypo-Osmoregulatory Roles of Vasotocinergic and Isotocinergic Systems in the Intestines of Two European Sea Bass Lineages

by Quanquan Cao, Eva Blondeau-Bidet and Catherine Lorin-Nebel

Int. J. Mol. Sci. 2022, 23(21), 13636; https://doi.org/10.3390/ijms232113636 - 07 Nov 2022

Viewed by 1287

Abstract

European sea bass (Dicentrarchus labrax) are a major aquaculture species that live in habitats with fluctuating salinities that are sometimes higher than in seawater (SW). Atlantic and West-Mediterranean genetic lineages were compared regarding intestinal neuropeptide receptor expression in SW (36%) and [...] Read more.

European sea bass (Dicentrarchus labrax) are a major aquaculture species that live in habitats with fluctuating salinities that are sometimes higher than in seawater (SW). Atlantic and West-Mediterranean genetic lineages were compared regarding intestinal neuropeptide receptor expression in SW (36%) and following a two-week transfer to hypersalinity (HW, 55%). Phylogenetic analysis revealed seven neuropeptide receptors belonging to the arginine vasotocine (AVTR) family and two isotocin receptors (ITR). Among AVTR paralogs, the highest mRNA levels were recorded for v1a2, with a two- to fourfold upregulation in the European sea bass intestinal sections after transfer of fish to HW. Principal component analysis in posterior intestines showed that v1a2 expression grouped together with the expression and activity of main ion transporters and channels involved in solute-coupled water uptake, indicating a possible role of this receptor in triggering water absorption. v1a1 expression, however, was decreased or did not change after transfer to hypersaline water. Among ITR paralogs, itr1 was the most expressed paralog in the intestine and opposite expression patterns were observed following salinity transfer, comparing intestinal sections. Overall, different expression profiles were observed between genetic lineages for several analyzed genes which could contribute to different osmotic stress-related responses in D. labrax lineages. Full article

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12 pages, 1896 KiB

Open AccessArticle

Effect of Copper on the Function of Isolated Porcine Kidneys Stored Using Simple Hypothermia

by Aneta Ostróżka-Cieślik, Barbara Dolińska and Florian Ryszka

Int. J. Mol. Sci. 2022, 23(21), 13031; https://doi.org/10.3390/ijms232113031 - 27 Oct 2022

Viewed by 996

Abstract

Renal ischemia in the peri-transplant period causes a number of changes that adversely affect the initiation of normal vital functions in grafts after transplantation. To minimise the extent of ischemic damage, organs are stored in preservation fluid. The components of the fluid are [...] Read more.

Renal ischemia in the peri-transplant period causes a number of changes that adversely affect the initiation of normal vital functions in grafts after transplantation. To minimise the extent of ischemic damage, organs are stored in preservation fluid. The components of the fluid are supposed to ensure stabilisation of the cell cytoskeleton, protect against oxygen free radicals, reduce cell swelling, and ensure endothelial cell integrity. The aim of this study was to analyse the protective effect of Cu²⁺, as a component of Biolasol preservative fluid, in the prevention of nephron damage occurring during the graft storage period. Analyses of the effectiveness of copper in the presence of prolactin added to Biolasol fluid were also carried out. Forty isolated pig slaughter kidneys were used in the study, avoiding the use of laboratory animals. The kidneys were stored using simple hypothermia. After 2 h and 48 h of graft storage, selected biochemical indicators of renal function were determined in the collected perfusates. The addition of Cu²⁺ at a dose of 1 µg/L to the composition of Biolasol fluid was found to affect the generation of ischemic damage in the isolated pig kidney. The intensity of the occurrence of these processes is exacerbated by the presence of prolactin at a dose of 0.1 µg/L. Full article

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22 pages, 6932 KiB

Open AccessArticle

Integrated Metabolomics and Network Pharmacology to Decipher the Latent Mechanisms of Protopanaxatriol against Acetic Acid-Induced Gastric Ulcer

by Cuizhu Wang, Luying Tan, Juntong Liu, Dongxing Fu, Caixia Wang, Pingya Li, Zhuo Li and Jinping Liu

Int. J. Mol. Sci. 2022, 23(20), 12097; https://doi.org/10.3390/ijms232012097 - 11 Oct 2022

Cited by 5 | Viewed by 1932

Abstract

Gastric ulcer (GU) is a peptic disease with high morbidity and mortality rates affecting approximately 4% of the population throughout the world. Current therapies for GU are limited by the high relapse incidence and side effects. Therefore, novel effective antiulcer drugs are urgently [...] Read more.

Gastric ulcer (GU) is a peptic disease with high morbidity and mortality rates affecting approximately 4% of the population throughout the world. Current therapies for GU are limited by the high relapse incidence and side effects. Therefore, novel effective antiulcer drugs are urgently needed. Ginsenosides have shown good anti-GU effects, and the major intestinal bacterial metabolite of ginsenosides, protopanaxatriol (PPT), is believed to be the active component. In this study, we evaluated the anti-GU effect of PPT in rats in an acetic acid-induced GU model. High (H-PPT) and medium (M-PPT) doses of PPT (20.0 and 10.0 mg/mg/day) significantly reduced the ulcer area and the ET-1, IL-6, EGF, SOD, MDA and TNF-α levels in serum were regulated by PPT in a dose-dependent manner. We also investigated the mechanisms of anti-GU activity of PPT based on metabolomics coupled with network pharmacology strategy. The result was that 16 biomarkers, 3 targets and 3 metabolomic pathways were identified as playing a vital role in the treatment of GU with PPT and were further validated by molecular docking. In this study, we have demonstrated that the integrated analysis of metabolomics and network pharmacology is an effective strategy for deciphering the complicated mechanisms of natural compounds. Full article

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16 pages, 4057 KiB

Open AccessArticle

Orlistat Mitigates Oxidative Stress-Linked Myocardial Damage via NF-κβ- and Caspase-Dependent Activities in Obese Rats

by Zaidatul Akmal Othman, Zaida Zakaria, Joseph Bagi Suleiman, Khairul Mohd Fadzli Mustaffa, Nur Asyilla Che Jalil, Wan Syaheedah Wan Ghazali, Ninie Nadia Zulkipli and Mahaneem Mohamed

Int. J. Mol. Sci. 2022, 23(18), 10266; https://doi.org/10.3390/ijms231810266 - 06 Sep 2022

Cited by 5 | Viewed by 1747

Abstract

Oxidative stress contributes to major complications of obesity. This study intended to identify whether orlistat could mitigate myocardial damage in obese animal models. The tested rats were divided into two groups and fed either with normal chow (n = 6 per group) [...] Read more.

Oxidative stress contributes to major complications of obesity. This study intended to identify whether orlistat could mitigate myocardial damage in obese animal models. The tested rats were divided into two groups and fed either with normal chow (n = 6 per group) or with a high-fat diet (HFD) for 6 weeks to induce obesity (n = 12 per group). Obese rats were further subjected to treatment either with distilled water (OB group) or orlistat 10 mg/kg/day (OB + OR group). Key indices of oxidative stress, inflammation, and apoptosis were assessed using an immunohistochemical-based technique and real-time PCR. The OB group showed significant increases of oxidative stress markers (TBARs and PCO), with significant decreases of anti-oxidant markers (Nrf2, SOD, CAT, and GPx). Furthermore, mRNA expression of pro-inflammatory markers (TNF-α and NF-κβ) and pro-apoptosis markers (Bax, Caspase-3, Caspase-8, and Caspase-9) were significantly upregulated in the OB group. Obese rats developed pathological changes of myocardial damages as evidenced by the presence of myocardial hypertrophy and inflammatory cells infiltration. Orlistat dampened the progression of myocardial damage in obese rats by ameliorating the oxidative stress, and by inhibiting NF-κβ pathway and caspase-dependent cell apoptosis. Our study proposed that orlistat could potentially mitigate oxidative stress-linked myocardial damage by mitigating inflammation and apoptosis, thus rationalizing its medical usage. Full article

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14 pages, 946 KiB

Open AccessArticle

Elevated Oxytocin Receptor Blood Concentrations Predict Higher Risk for, More, and Earlier 24-Month Hospital Readmissions after In-Patient Detoxification in Males with Alcohol Use Disorder

by Christiane Mühle, Massimiliano Mazza, Christian Weinland, Claudia von Zimmermann, Patrick Bach, Falk Kiefer, Valery Grinevich, Iulia Zoicas, Johannes Kornhuber and Bernd Lenz

Int. J. Mol. Sci. 2022, 23(17), 9940; https://doi.org/10.3390/ijms23179940 - 01 Sep 2022

Cited by 2 | Viewed by 1571

Abstract

Alcohol use disorder (AUD) is a major global mental health challenge. Knowledge concerning mechanisms underlying AUD and predictive biomarkers of AUD progression and relapse are insufficient. Recently, addiction research is focusing attention on the oxytocin system. However, to our knowledge, blood concentrations of [...] Read more.

Alcohol use disorder (AUD) is a major global mental health challenge. Knowledge concerning mechanisms underlying AUD and predictive biomarkers of AUD progression and relapse are insufficient. Recently, addiction research is focusing attention on the oxytocin system. However, to our knowledge, blood concentrations of the oxytocin receptor (OXTR) have not yet been studied in AUD. Here, in sex-separated analyses, OXTR serum concentrations were compared between early-abstinent in-patients with AUD (113 men, 87 women) and age-matched healthy controls (133 men, 107 women). The OXTR concentrations were correlated with sex hormone and oxytocin concentrations and alcohol-related hospital readmissions during a 24-month follow-up. In male patients with AUD, higher OXTR concentrations were found in those with an alcohol-related readmission than in those without (143%; p = 0.004), and they correlated with more prospective readmissions (ρ = 0.249; p = 0.008) and fewer days to the first readmission (ρ = −0.268; p = 0.004). In men and women, OXTR concentrations did not significantly differ between patients with AUD and controls. We found lower OXTR concentrations in smokers versus non-smokers in female patients (61%; p = 0.001) and controls (51%; p = 0.003). In controls, OXTR concentrations correlated with dihydrotestosterone (men, ρ = 0.189; p = 0.030) and testosterone concentrations (women, ρ = 0.281; p = 0.003). This clinical study provides novel insight into the role of serum OXTR levels in AUD. Future studies are encouraged to add to the available knowledge and investigate clinical implications of OXTR blood concentrations. Full article

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22 pages, 1391 KiB

Open AccessReview

mTOR: A Potential New Target in Nonalcoholic Fatty Liver Disease

by Jiayao Feng, Shuting Qiu, Shipeng Zhou, Yue Tan, Yan Bai, Hua Cao, Jiao Guo and Zhengquan Su

Int. J. Mol. Sci. 2022, 23(16), 9196; https://doi.org/10.3390/ijms23169196 - 16 Aug 2022

Cited by 21 | Viewed by 4475

Abstract

The global prevalence of nonalcoholic fatty liver disease (NAFLD) continues to rise, yet effective treatments are lacking due to the complex pathogenesis of this disease. Although recent research has provided evidence for the “multiple strikes” theory, the classic “two strikes” theory has not [...] Read more.

The global prevalence of nonalcoholic fatty liver disease (NAFLD) continues to rise, yet effective treatments are lacking due to the complex pathogenesis of this disease. Although recent research has provided evidence for the “multiple strikes” theory, the classic “two strikes” theory has not been overturned. Therefore, there is a crucial need to identify multiple targets in NAFLD pathogenesis for the development of diagnostic markers and targeted therapeutics. Since its discovery, the mechanistic target of rapamycin (mTOR) has been recognized as the central node of a network that regulates cell growth and development and is closely related to liver lipid metabolism and other processes. This paper will explore the mechanisms by which mTOR regulates lipid metabolism (SREBPs), insulin resistance (Foxo1, Lipin1), oxidative stress (PIG3, p53, JNK), intestinal microbiota (TLRs), autophagy, inflammation, genetic polymorphisms, and epigenetics in NAFLD. The specific influence of mTOR on NAFLD was hypothesized to be divided into micro regulation (the mechanism of mTOR’s influence on NAFLD factors) and macro mediation (the relationship between various influencing factors) to summarize the influence of mTOR on the developmental process of NAFLD, and prove the importance of mTOR as an influencing factor of NAFLD regarding multiple aspects. The effects of crosstalk between mTOR and its upstream regulators, Notch, Hedgehog, and Hippo, on the occurrence and development of NAFLD-associated hepatocellular carcinoma are also summarized. This analysis will hopefully support the development of diagnostic markers and new therapeutic targets in NAFLD. Full article

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16 pages, 2730 KiB

Open AccessArticle

Attainment of Sexual Maturity and Gonadotropin Priming in Gilts Determine Follicular Development, Endocrine Milieu and Response to Ovulatory Triggers

by Pawel Likszo, Katarzyna Gromadzka-Hliwa, Jan Klos, Monika M. Kaczmarek and Adam J. Ziecik

Int. J. Mol. Sci. 2022, 23(16), 9190; https://doi.org/10.3390/ijms23169190 - 16 Aug 2022

Viewed by 1467

Abstract

The routine procedure of estrous cycle synchronization in pigs allows for the use of gonadotropins to stimulate ovarian activity. The applied protocols of eCG and hFSH priming similarly affected development of ovarian follicles in two classes 3–6 mm and >6 mm of diameter, [...] Read more.

The routine procedure of estrous cycle synchronization in pigs allows for the use of gonadotropins to stimulate ovarian activity. The applied protocols of eCG and hFSH priming similarly affected development of ovarian follicles in two classes 3–6 mm and >6 mm of diameter, however, the number of small follicles (<3 mm) was 2-fold higher in hFSH- than in eCG-primed prepubertal gilts. The attainment of sexual maturity increased concentration of estradiol, testosterone and androstenedione in the follicular fluid of hFSH/eCG-primed gilts, however, prostaglandin E2 and F2α metabolite increased in mature hFSH- and eCG-primed gilts, respectively. The maturity increased mRNA and/or protein expression of key steroidogenic enzymes, prostaglandin synthases or luteinizing hormone receptors in follicular walls. Both hormonal primers played a moderate role in affecting expression of steroidogenic enzymes in follicular walls. In vitro studies showed higher estradiol production in r-hLH (p = 0.04)- and r-hCG (p = 0.049)-stimulated follicular walls of mature gilts than in prepubertal hFSH-primed gilts. Both ovulatory triggers decreased the abundance of LHCG/FSH mRNA receptors in follicular walls, which mimic downregulation of these receptors by a preovulatory LH surge, confirmed in vivo. These data revealed the importance of sexual maturity in the protection of the estrogenic environment, and the selective, moderate role of eCG and FSH in the activation of steroidogenic enzymes in preovulatory follicles. Full article

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15 pages, 2313 KiB

Open AccessArticle

Metabolic Effects of the Waist-To-Hip Ratio Associated Locus GRB14/COBLL1 Are Related to GRB14 Expression in Adipose Tissue

by Chang Sun, Franz Förster, Beate Gutsmann, Yusef Moulla, Christine Stroh, Arne Dietrich, Michael R. Schön, Daniel Gärtner, Tobias Lohmann, Miriam Dressler, Michael Stumvoll, Matthias Blüher, Peter Kovacs, Jana Breitfeld and Esther Guiu-Jurado

Int. J. Mol. Sci. 2022, 23(15), 8558; https://doi.org/10.3390/ijms23158558 - 02 Aug 2022

Cited by 3 | Viewed by 1787

Abstract

GRB14/COBLL1 locus has been shown to be associated with body fat distribution (FD), but neither the causal gene nor its role in metabolic diseases has been elucidated. We hypothesize that GRB14/COBLL1 may act as the causal genes for FD-related SNPs (rs10195252 and rs6738627), [...] Read more.

GRB14/COBLL1 locus has been shown to be associated with body fat distribution (FD), but neither the causal gene nor its role in metabolic diseases has been elucidated. We hypothesize that GRB14/COBLL1 may act as the causal genes for FD-related SNPs (rs10195252 and rs6738627), and that they may be regulated by SNP to effect obesity-related metabolic traits. We genotyped rs10195252 and rs6738627 in 2860 subjects with metabolic phenotypes. In a subgroup of 560 subjects, we analyzed GRB14/COBLL1 gene expression in paired visceral and subcutaneous adipose tissue (AT) samples. Mediation analyses were used to determine the causal relationship between SNPs, AT GRB14/COBLL1 mRNA expression, and obesity-related traits. In vitro gene knockdown of Grb14/Cobll1 was used to test their role in adipogenesis. Both gene expressions in AT are correlated with waist circumference. Visceral GRB14 mRNA expression is associated with FPG and HbA1c. Both SNPs are associated with triglycerides, FPG, and leptin levels. Rs10195252 is associated with HbA1c and seems to be mediated by visceral AT GRB14 mRNA expression. Our data support the role of the GRB14/COBLL1 gene expression in body FD and its locus in metabolic sequelae: in particular, lipid metabolism and glucose homeostasis, which is likely mediated by AT GRB14 transcript levels. Full article

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19 pages, 2083 KiB

Open AccessArticle

Validated Growth Rate-Dependent Regulation of Lipid Metabolism in Yarrowia lipolytica

by Naghmeh Poorinmohammad, Jing Fu, Bob Wabeke and Eduard J. Kerkhoven

Int. J. Mol. Sci. 2022, 23(15), 8517; https://doi.org/10.3390/ijms23158517 - 31 Jul 2022

Cited by 6 | Viewed by 2233

Abstract

Given the strong potential of Yarrowia lipolytica to produce lipids for use as renewable fuels and oleochemicals, it is important to gain in-depth understanding of the molecular mechanism underlying its lipid accumulation. As cellular growth rate affects biomass lipid content, we performed a [...] Read more.

Given the strong potential of Yarrowia lipolytica to produce lipids for use as renewable fuels and oleochemicals, it is important to gain in-depth understanding of the molecular mechanism underlying its lipid accumulation. As cellular growth rate affects biomass lipid content, we performed a comparative proteomic analysis of Y. lipolytica grown in nitrogen-limited chemostat cultures at different dilution rates. After confirming the correlation between growth rate and lipid accumulation, we were able to identify various cellular functions and biological mechanisms involved in oleaginousness. Inspection of significantly up- and downregulated proteins revealed nonintuitive processes associated with lipid accumulation in this yeast. This included proteins related to endoplasmic reticulum (ER) stress, ER–plasma membrane tether proteins, and arginase. Genetic engineering of selected targets validated that some genes indeed affected lipid accumulation. They were able to increase lipid content and were complementary to other genetic engineering strategies to optimize lipid yield. Full article

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17 pages, 2011 KiB

Open AccessArticle

Possible Role of GnIH as a Novel Link between Hyperphagia-Induced Obesity-Related Metabolic Derangements and Hypogonadism in Male Mice

by Rongrong Luo, Lei Chen, Xingxing Song, Xin Zhang, Wenhao Xu, Dongyang Han, Jianyu Zuo, Wen Hu, Yan Shi, Yajie Cao, Runwen Ma, Chengcheng Liu, Changlin Xu, Zixin Li and Xun Li

Int. J. Mol. Sci. 2022, 23(15), 8066; https://doi.org/10.3390/ijms23158066 - 22 Jul 2022

Cited by 2 | Viewed by 1594

Abstract

Gonadotropin-inhibitory hormone (GnIH) is a reproductive inhibitor and an endogenous orexigenic neuropeptide that may be involved in energy homeostasis and reproduction. However, whether GnIH is a molecular signal link of metabolism and the reproductive system, and thus, regulates reproductive activity as a function [...] Read more.

Gonadotropin-inhibitory hormone (GnIH) is a reproductive inhibitor and an endogenous orexigenic neuropeptide that may be involved in energy homeostasis and reproduction. However, whether GnIH is a molecular signal link of metabolism and the reproductive system, and thus, regulates reproductive activity as a function of the energy state, is still unknown. In the present study, we investigated the involvement of GnIH in glycolipid metabolism and reproduction in vivo, and in the coupling between these two processes in the testis level. Our results showed that chronic intraperitoneal injection of GnIH into male mice not only increased food intake and altered meal microstructure but also significantly elevated body mass due to the increased mass of liver and epididymal white adipose tissue (eWAT), despite the loss of testicular weight. Furthermore, chronic intraperitoneal administration of GnIH to male mice resulted in obesity-related glycolipid metabolic derangements, showing hyperlipidemia, hyperglycemia, glucose intolerance, and insulin resistance through changes in the expression of glucose and lipid metabolism-related genes in the pancreas and eWAT, respectively. Interestingly, the expression of GnIH and GPR147 was markedly increased in the testis of mice under conditions of energy imbalance, such as fasting, acute hypoglycemia, and hyperglycemia. In addition, chronic GnIH injection markedly inhibited glucose and lipid metabolism of mice testis while significantly decreasing testosterone synthesis and sperm quality, inducing hypogonadism. These observations indicated that orexigenic GnIH triggers hyperphagia-induced obesity-related metabolic derangements and hypogonadism in male mice, suggesting that GnIH is an emerging candidate for coupling metabolism and fertility by involvement in obesity and metabolic disorder-induced reproductive dysfunction of the testes. Full article

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20 pages, 753 KiB

Open AccessReview

The Activity of Prebiotics and Probiotics in Hepatogastrointestinal Disorders and Diseases Associated with Metabolic Syndrome

by Alicia Rodríguez-Pastén, Nury Pérez-Hernández, Javier Añorve-Morga, Rubén Jiménez-Alvarado, Raquel Cariño-Cortés, Teresa Sosa-Lozada and Eduardo Fernández-Martínez

Int. J. Mol. Sci. 2022, 23(13), 7229; https://doi.org/10.3390/ijms23137229 - 29 Jun 2022

Cited by 9 | Viewed by 3372

Abstract

The components of metabolic syndrome (MetS) and hepatogastrointestinal diseases are widespread worldwide, since many factors associated with lifestyle and diet influence their development and correlation. Due to these growing health problems, it is necessary to search for effective alternatives for prevention or adjuvants [...] Read more.

The components of metabolic syndrome (MetS) and hepatogastrointestinal diseases are widespread worldwide, since many factors associated with lifestyle and diet influence their development and correlation. Due to these growing health problems, it is necessary to search for effective alternatives for prevention or adjuvants in treating them. The positive impact of regulated microbiota on health is known; however, states of dysbiosis are closely related to the development of the conditions mentioned above. Therefore, the role of prebiotics, probiotics, or symbiotic complexes has been extensively evaluated; the results are favorable, showing that they play a crucial role in the regulation of the immune system, the metabolism of carbohydrates and lipids, and the biotransformation of bile acids, as well as the modulation of their central receptors FXR and TGR-5, which also have essential immunomodulatory and metabolic activities. It has also been observed that they can benefit the host by displacing pathogenic species, improving the dysbiosis state in MetS. Current studies have reported that paraprobiotics (dead or inactive probiotics) or postbiotics (metabolites generated by active probiotics) also benefit hepatogastrointestinal health. Full article

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15 pages, 3133 KiB

Open AccessArticle

Copper Modulates Mitochondrial Oxidative Phosphorylation to Enhance Dermal Papilla Cells Proliferation in Rex Rabbits

by Fan Li, Hongli Liu, Xiaojing Wu, Mengqi Liu, Zhengkai Yue, Lei Liu and Fuchang Li

Int. J. Mol. Sci. 2022, 23(11), 6209; https://doi.org/10.3390/ijms23116209 - 01 Jun 2022

Cited by 5 | Viewed by 1857

Abstract

Copper (Cu) is an important coenzyme factor in cell signaling, such as cytochrome c oxidase (Complex IV). Metabolism plays an important role in regulating the fate of mammalian cells. The aim of this study is to experimentally investigate the effect of copper on [...] Read more.

Copper (Cu) is an important coenzyme factor in cell signaling, such as cytochrome c oxidase (Complex IV). Metabolism plays an important role in regulating the fate of mammalian cells. The aim of this study is to experimentally investigate the effect of copper on cell metabolism in the dermal papilla cells of the Rex rabbit. In this study, Cu promoted proliferation of dermal papilla cells (p = 0.0008) while also increasing levels of cellular CIII, CIV, Complex IV and ATP. Moreover, fifty metabolites that were significantly different between Cu and controls were identified as potential biomarkers of Cu stimulation. Copper-stimulated cells had altered levels of arachidonic acid derivatives, S-glutamic acid, and citric acid, which were primarily linked to two different pathways: arachidonic acid metabolism (p < 0.0001) and alanine, aspartate and glutamate metabolism (p = 0.0003). The addition of Cu can increase the proliferation of Rex rabbit dermal papilla cells. Increased levels of ubiquinol-cytochrome c reductase complex core protein 2 (CIII) and cytochrome c oxidase subunit 1 (CIV) were associated with the increased levels of cellular cytochrome c oxidase (Complex IV) and adenosine triphosphate (ATP). In a word, copper promotes cell proliferation by maintaining the function of the cellular mitochondrial electron transport chain (ETC) pathway. Full article

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15 pages, 2230 KiB

Open AccessArticle

The Role of Insulin-like Peptide in Maintaining Hemolymph Glucose Homeostasis in the Pacific White Shrimp Litopenaeus vannamei

by Manwen Su, Xiaojun Zhang, Jianbo Yuan, Xiaoxi Zhang and Fuhua Li

Int. J. Mol. Sci. 2022, 23(6), 3268; https://doi.org/10.3390/ijms23063268 - 17 Mar 2022

Cited by 8 | Viewed by 2216

Abstract

Insulin-like peptide (ILP) has been identified in various crustaceans, but whether it has a similar function in regulating hemolymph glucose as vertebrate insulin is unclear. We analyzed the components of hemolymph sugar in the Pacific white shrimp, Litopenaeus vannamei, and investigated the [...] Read more.

Insulin-like peptide (ILP) has been identified in various crustaceans, but whether it has a similar function in regulating hemolymph glucose as vertebrate insulin is unclear. We analyzed the components of hemolymph sugar in the Pacific white shrimp, Litopenaeus vannamei, and investigated the changes of hemolymph glucose concentration and the expressions of ILP and glucose metabolism genes under different treatments. We found glucose was a major component of hemolymph sugar in shrimp. Starvation caused hemolymph glucose to rise first and then decline, and the raised hemolymph glucose after exogenous glucose injection returned to basal levels within a short time, indicating that shrimp have a regulatory mechanism to maintain hemolymph glucose homeostasis. In addition, injections of bovine insulin and recombinant LvILP protein both resulted in a fast decline in hemolymph glucose. Notably, RNA interference of LvILP did not significantly affect hemolymph glucose levels, but it inhibited exogenous glucose clearance. Based on the detection of glucose metabolism genes, we found LvILP might maintain hemolymph glucose stability by regulating the expression of these genes. These results suggest that ILP has a conserved function in shrimp similar to insulin in vertebrates and plays an important role in maintaining hemolymph glucose homeostasis. Full article

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34 pages, 1293 KiB

Open AccessReview

Synergistic and Detrimental Effects of Alcohol Intake on Progression of Liver Steatosis

by Agostino Di Ciaula, Leonilde Bonfrate, Marcin Krawczyk, Gema Frühbeck and Piero Portincasa

Int. J. Mol. Sci. 2022, 23(5), 2636; https://doi.org/10.3390/ijms23052636 - 27 Feb 2022

Cited by 13 | Viewed by 4323

Abstract

Nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are the most common liver disorders worldwide and the major causes of non-viral liver cirrhosis in the general population. In NAFLD, metabolic abnormalities, obesity, and metabolic syndrome are the driving factors for liver [...] Read more.

Nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are the most common liver disorders worldwide and the major causes of non-viral liver cirrhosis in the general population. In NAFLD, metabolic abnormalities, obesity, and metabolic syndrome are the driving factors for liver damage with no or minimal alcohol consumption. ALD refers to liver damage caused by excess alcohol intake in individuals drinking more than 5 to 10 daily units for years. Although NAFLD and ALD are nosologically considered two distinct entities, they show a continuum and exert synergistic effects on the progression toward liver cirrhosis. The current view is that low alcohol use might also increase the risk of advanced clinical liver disease in NAFLD, whereas metabolic factors increase the risk of cirrhosis among alcohol risk drinkers. Therefore, special interest is now addressed to individuals with metabolic abnormalities who consume small amounts of alcohol or who binge drink, for the role of light-to-moderate alcohol use in fibrosis progression and clinical severity of the liver disease. Evidence shows that in the presence of NAFLD, there is no liver-safe limit of alcohol intake. We discuss the epidemiological and clinical features of NAFLD/ALD, aspects of alcohol metabolism, and mechanisms of damage concerning steatosis, fibrosis, cumulative effects, and deleterious consequences which include hepatocellular carcinoma. Full article

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12 pages, 1477 KiB

Open AccessArticle

In Vivo Metabolic Responses to Different Formulations of Amino Acid Mixtures for the Treatment of Phenylketonuria (PKU)

by Nadia Giarratana, Luciana Giardino, Andrea Bighinati, Giorgio Reiner and Júlio César Rocha

Int. J. Mol. Sci. 2022, 23(4), 2227; https://doi.org/10.3390/ijms23042227 - 17 Feb 2022

Cited by 2 | Viewed by 2954

Abstract

Phenylketonuria (PKU) is a rare autosomal recessive inborn error of metabolism where the mainstay of treatment is a Phe restricted diet consisting of a combination of limited amounts of natural protein with supplementation of Phe-free or low-Phe protein substitutes and special low protein [...] Read more.

Phenylketonuria (PKU) is a rare autosomal recessive inborn error of metabolism where the mainstay of treatment is a Phe restricted diet consisting of a combination of limited amounts of natural protein with supplementation of Phe-free or low-Phe protein substitutes and special low protein foods. Suboptimal outcomes may be related to the different absorption kinetics of free AAs, which have lower biological efficacy than natural proteins. Physiomimic Technology^TM is a technology engineered to prolong AA (AA-PT) release allowing physiological absorption and masking the odor and taste of free AAs. The aim of these studies was to assess the impact of AA-PT formulation on selected functional and metabolic parameters both in acute and long-term experimental studies. Adult rats in fasting conditions were randomized in different groups and treated by oral gavage. Acute AA-PT administration resulted in significantly lower BUN at 90 min versus baseline. Both BUN and glycemia were modulated in the same direction as intact casein protein. Long-term treatment with AA-PT significantly reduces the protein expression of the muscle degradation marker Bnip3L (−46%) while significantly increasing the proliferation of market myostatin (+58%). Animals dosed for 15 days with AA-PT had significantly stronger grip strength (+30%) versus baseline. In conclusion, the results suggest that the AA-PT formulation may have beneficial effects on both AA oxidation and catabolism with a direct impact on muscle as well as on other metabolic pathways. Full article

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21 pages, 44359 KiB

Open AccessArticle

Distinct Adipogenic and Fibrogenic Differentiation Capacities of Mesenchymal Stromal Cells from Pancreas and White Adipose Tissue

by Heja Aga, George Soultoukis, Mandy Stadion, Francisco Garcia-Carrizo, Markus Jähnert, Pascal Gottmann, Heike Vogel, Tim J. Schulz and Annette Schürmann

Int. J. Mol. Sci. 2022, 23(4), 2108; https://doi.org/10.3390/ijms23042108 - 14 Feb 2022

Cited by 1 | Viewed by 2410

Abstract

Pancreatic steatosis associates with β-cell failure and may participate in the development of type-2-diabetes. Our previous studies have shown that diabetes-susceptible mice accumulate more adipocytes in the pancreas than diabetes-resistant mice. In addition, we have demonstrated that the co-culture of pancreatic islets and [...] Read more.

Pancreatic steatosis associates with β-cell failure and may participate in the development of type-2-diabetes. Our previous studies have shown that diabetes-susceptible mice accumulate more adipocytes in the pancreas than diabetes-resistant mice. In addition, we have demonstrated that the co-culture of pancreatic islets and adipocytes affect insulin secretion. The aim of this current study was to elucidate if and to what extent pancreas-resident mesenchymal stromal cells (MSCs) with adipogenic progenitor potential differ from the corresponding stromal-type cells of the inguinal white adipose tissue (iWAT). miRNA (miRNome) and mRNA expression (transcriptome) analyses of MSCs isolated by flow cytometry of both tissues revealed 121 differentially expressed miRNAs and 1227 differentially expressed genes (DEGs). Target prediction analysis estimated 510 DEGs to be regulated by 58 differentially expressed miRNAs. Pathway analyses of DEGs and miRNA target genes showed unique transcriptional and miRNA signatures in pancreas (pMSCs) and iWAT MSCs (iwatMSCs), for instance fibrogenic and adipogenic differentiation, respectively. Accordingly, iwatMSCs revealed a higher adipogenic lineage commitment, whereas pMSCs showed an elevated fibrogenesis. As a low degree of adipogenesis was also observed in pMSCs of diabetes-susceptible mice, we conclude that the development of pancreatic steatosis has to be induced by other factors not related to cell-autonomous transcriptomic changes and miRNA-based signals. Full article

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16 pages, 612 KiB

Open AccessReview

Lactational Amenorrhea: Neuroendocrine Pathways Controlling Fertility and Bone Turnover

by Anna Calik-Ksepka, Monika Stradczuk, Karolina Czarnecka, Monika Grymowicz and Roman Smolarczyk

Int. J. Mol. Sci. 2022, 23(3), 1633; https://doi.org/10.3390/ijms23031633 - 31 Jan 2022

Cited by 12 | Viewed by 10181

Abstract

Lactation is a physiological state of hyperprolactinemia and associated amenorrhea. Despite the fact that exact mechanisms standing behind the hypothalamus–pituitary–ovarian axis during lactation are still not clear, a general overview of events leading to amenorrhea may be suggested. Suckling remains the most important [...] Read more.

Lactation is a physiological state of hyperprolactinemia and associated amenorrhea. Despite the fact that exact mechanisms standing behind the hypothalamus–pituitary–ovarian axis during lactation are still not clear, a general overview of events leading to amenorrhea may be suggested. Suckling remains the most important stimulus maintaining suppressive effect on ovaries after pregnancy. Breastfeeding is accompanied by high levels of prolactin, which remain higher than normal until the frequency and duration of daily suckling decreases and allows normal menstrual function resumption. Hyperprolactinemia induces the suppression of hypothalamic Kiss1 neurons that directly control the pulsatile release of GnRH. Disruption in the pulsatile manner of GnRH secretion results in a strongly decreased frequency of corresponding LH pulses. Inadequate LH secretion and lack of pre-ovulatory surge inhibit the progression of the follicular phase of a menstrual cycle and result in anovulation and amenorrhea. The main consequences of lactational amenorrhea are connected with fertility issues and increased bone turnover. Provided the fulfillment of all the established conditions of its use, the lactational amenorrhea method (LAM) efficiently protects against pregnancy. Because of its accessibility and lack of additional associated costs, LAM might be especially beneficial in low-income, developing countries, where modern contraception is hard to obtain. Breastfeeding alone is not equal to the LAM method, and therefore, it is not enough to successfully protect against conception. That is why LAM promotion should primarily focus on conditions under which its use is safe and effective. More studies on larger study groups should be conducted to determine and confirm the impact of behavioral factors, like suckling parameters, on the LAM efficacy. Lactational bone loss is a physiologic mechanism that enables providing a sufficient amount of calcium to the newborn. Despite the decline in bone mass during breastfeeding, it rebuilds after weaning and is not associated with a postmenopausal decrease in BMD and osteoporosis risk. Therefore, it should be a matter of concern only for lactating women with additional risk factors or with low BMD before pregnancy. The review summarizes the effect that breastfeeding exerts on the hypothalamus–pituitary axis as well as fertility and bone turnover aspects of lactational amenorrhea. We discuss the possibility of the use of lactation as contraception, along with this method’s prevalence, efficacy, and influencing factors. We also review the literature on the topic of lactational bone loss: its mechanism, severity, and persistence throughout life. Full article

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23 pages, 1941 KiB

Open AccessReview

Gut Microbiota and Short Chain Fatty Acids: Implications in Glucose Homeostasis

by Piero Portincasa, Leonilde Bonfrate, Mirco Vacca, Maria De Angelis, Ilaria Farella, Elisa Lanza, Mohamad Khalil, David Q.-H. Wang, Markus Sperandio and Agostino Di Ciaula

Int. J. Mol. Sci. 2022, 23(3), 1105; https://doi.org/10.3390/ijms23031105 - 20 Jan 2022

Cited by 211 | Viewed by 17895

Abstract

Gut microbiota encompasses a wide variety of commensal microorganisms consisting of trillions of bacteria, fungi, and viruses. This microbial population coexists in symbiosis with the host, and related metabolites have profound effects on human health. In this respect, gut microbiota plays a pivotal [...] Read more.

Gut microbiota encompasses a wide variety of commensal microorganisms consisting of trillions of bacteria, fungi, and viruses. This microbial population coexists in symbiosis with the host, and related metabolites have profound effects on human health. In this respect, gut microbiota plays a pivotal role in the regulation of metabolic, endocrine, and immune functions. Bacterial metabolites include the short chain fatty acids (SCFAs) acetate (C2), propionate (C3), and butyrate (C4), which are the most abundant SCFAs in the human body and the most abundant anions in the colon. SCFAs are made from fermentation of dietary fiber and resistant starch in the gut. They modulate several metabolic pathways and are involved in obesity, insulin resistance, and type 2 diabetes. Thus, diet might influence gut microbiota composition and activity, SCFAs production, and metabolic effects. In this narrative review, we discuss the relevant research focusing on the relationship between gut microbiota, SCFAs, and glucose metabolism. Full article

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18 pages, 2462 KiB

Open AccessArticle

Loss of SDHB Induces a Metabolic Switch in the hPheo1 Cell Line toward Enhanced OXPHOS

by Mouna Tabebi, Ravi Kumar Dutta, Camilla Skoglund, Peter Söderkvist and Oliver Gimm

Int. J. Mol. Sci. 2022, 23(1), 560; https://doi.org/10.3390/ijms23010560 - 05 Jan 2022

Cited by 10 | Viewed by 2900

Abstract

Background: Enzymes of tricarboxylic acid (TCA) have recently been recognized as tumor suppressors. Mutations in the SDHB subunit of succinate dehydrogenase (SDH) cause pheochromocytomas and paragangliomas (PCCs/PGLs) and predispose patients to malignant disease with poor prognosis. Methods: Using the human pheochromocytoma cell line [...] Read more.

Background: Enzymes of tricarboxylic acid (TCA) have recently been recognized as tumor suppressors. Mutations in the SDHB subunit of succinate dehydrogenase (SDH) cause pheochromocytomas and paragangliomas (PCCs/PGLs) and predispose patients to malignant disease with poor prognosis. Methods: Using the human pheochromocytoma cell line (hPheo1), we knocked down SDHB gene expression using CRISPR-cas9 technology. Results: Microarray gene expression analysis showed that >500 differentially expressed gene targets, about 54%, were upregulated in response to SDHB knock down. Notably, genes involved in glycolysis, hypoxia, cell proliferation, and cell differentiation were up regulated, whereas genes involved in oxidative phosphorylation (OXPHOS) were downregulated. In vitro studies show that hPheo1 proliferation is not affected negatively and the cells that survive by shifting their metabolism to the use of glutamine as an alternative energy source and promote OXPHOS activity. Knock down of SDHB expression results in a significant increase in GLUD1 expression in hPheo1 cells cultured as monolayer or as 3D culture. Analysis of TCGA data confirms the enhancement of GLUD1 in SDHB mutated/low expressed PCCs/PGLs. Conclusions: Our data suggest that the downregulation of SDHB in PCCs/PGLs results in increased GLUD1 expression and may represent a potential biomarker and therapeutic target in SDHB mutated tumors and SDHB loss of activity-dependent diseases. Full article

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2021

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3 pages, 191 KiB

Open AccessEditorial

Molecular Endocrinology and Metabolism in 2021: What’s New

by Manfredi Rizzo

Int. J. Mol. Sci. 2021, 22(24), 13375; https://doi.org/10.3390/ijms222413375 - 13 Dec 2021

Cited by 1 | Viewed by 2067

Abstract

The last two years, despite the very serious COronaVIrus Disease-2019 (COVID-19) pandemic, have been quite productive in the field of molecular endocrinology and metabolism and our journal section has contributed extensively on that [...] Full article

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