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14 pages, 2298 KiB

Open AccessArticle

Sustained Effectiveness and Safety of Therapeutic miR-10a/b in Alleviating Diabetes and Gastrointestinal Dysmotility without Inducing Cancer or Inflammation in Murine Liver and Colon

by Rajan Singh, Se Eun Ha, Han Sung Park, Sushmita Debnath, Hayeong Cho, Gain Baek, Tae Yang Yu and Seungil Ro

Int. J. Mol. Sci. 2024, 25(4), 2266; https://doi.org/10.3390/ijms25042266 - 14 Feb 2024

Viewed by 688

Abstract

microRNAs (miRNAs) are key regulators of both physiological and pathophysiological mechanisms in diabetes and gastrointestinal (GI) dysmotility. Our previous studies have demonstrated the therapeutic potential of miR-10a-5p mimic and miR-10b-5p mimic (miR-10a/b mimics) in rescuing diabetes and GI dysmotility in murine models of [...] Read more.

microRNAs (miRNAs) are key regulators of both physiological and pathophysiological mechanisms in diabetes and gastrointestinal (GI) dysmotility. Our previous studies have demonstrated the therapeutic potential of miR-10a-5p mimic and miR-10b-5p mimic (miR-10a/b mimics) in rescuing diabetes and GI dysmotility in murine models of diabetes. In this study, we elucidated the safety profile of a long-term treatment with miR-10a/b mimics in diabetic mice. Male C57BL/6 mice were fed a high-fat, high-sucrose diet (HFHSD) to induce diabetes and treated by five subcutaneous injections of miR-10a/b mimics for a 5 month period. We examined the long-term effects of the miRNA mimics on diabetes and GI dysmotility, including an assessment of potential risks for cancer and inflammation in the liver and colon using biomarkers. HFHSD-induced diabetic mice subcutaneously injected with miR-10a/b mimics on a monthly basis for 5 consecutive months exhibited a marked reduction in fasting blood glucose levels with restoration of insulin and significant weight loss, improved glucose and insulin intolerance, and restored GI transit time. In addition, the miR-10a/b mimic-treated diabetic mice showed no indication of risk for cancer development or inflammation induction in the liver, colon, and blood for 5 months post-injections. This longitudinal study demonstrates that miR-10a/b mimics, when subcutaneously administered in diabetic mice, effectively alleviate diabetes and GI dysmotility for 5 months with no discernible risk for cancer or inflammation in the liver and colon. The sustained efficacy and favorable safety profiles position miR-10a/b mimics as promising candidates in miRNA-based therapeutics for diabetes and GI dysmotility. Full article

(This article belongs to the Special Issue Feature Papers in Molecular Endocrinology and Metabolism)

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16 pages, 4044 KiB

Open AccessArticle

CXCL12 Neutralizing Antibody Promotes Hair Growth in Androgenic Alopecia and Alopecia Areata

by Mei Zheng, Min-Ho Kim, Sang-Gyu Park, Won-Serk Kim, Sang-Ho Oh and Jong-Hyuk Sung

Int. J. Mol. Sci. 2024, 25(3), 1705; https://doi.org/10.3390/ijms25031705 - 30 Jan 2024

Viewed by 1525

Abstract

We had previously investigated the expression and functional role of C-X-C Motif Chemokine Ligand 12 (CXCL12) during the hair cycle progression. CXCL12 was highly expressed in stromal cells such as dermal fibroblasts (DFs) and inhibition of CXCL12 increased hair growth. Therefore, we further [...] Read more.

We had previously investigated the expression and functional role of C-X-C Motif Chemokine Ligand 12 (CXCL12) during the hair cycle progression. CXCL12 was highly expressed in stromal cells such as dermal fibroblasts (DFs) and inhibition of CXCL12 increased hair growth. Therefore, we further investigated whether a CXCL12 neutralizing antibody (

α

CXCL12) is effective for androgenic alopecia (AGA) and alopecia areata (AA) and studied the underlying molecular mechanism for treating these diseases. In the AGA model, CXCL12 is highly expressed in DFs. Subcutaneous (s.c.) injection of

α

CXCL12 significantly induced hair growth in AGA mice, and treatment with

α

CXCL12 attenuated the androgen-induced hair damage in hair organ culture. Androgens increased the secretion of CXCL12 from DFs through the androgen receptor (AR). Secreted CXCL12 from DFs increased the expression of the AR and C-X-C Motif Chemokine Receptor 4 (CXCR4) in dermal papilla cells (DPCs), which induced hair loss in AGA. Likewise, CXCL12 expression is increased in AA mice, while s.c. injection of

α

CXCL12 significantly inhibited hair loss in AA mice and reduced the number of CD8⁺, MHC-I⁺, and MHC-II⁺ cells in the skin. In addition, injection of

α

CXCL12 also prevented the onset of AA and reduced the number of CD8⁺ cells. Interferon-

γ

(IFN

γ

) treatment increased the secretion of CXCL12 from DFs through the signal transducer and activator of transcription 3 (STAT3) pathway, and

α

CXCL12 treatment protected the hair follicle from IFN

γ

in hair organ culture. Collectively, these results indicate that CXCL12 is involved in the progression of AGA and AA and antibody therapy for CXCL12 is promising for hair loss treatment. Full article

(This article belongs to the Special Issue Feature Papers in Molecular Endocrinology and Metabolism)

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19 pages, 4734 KiB

Open AccessArticle

Early Castration in Horses Does Not Impact Osteoarticular Metabolism

by Marion Rouge, Florence Legendre, Razan Elkhatib, Christelle Delalande, Juliette Cognié, Fabrice Reigner, Philippe Barrière, Stefan Deleuze, Vincent Hanoux, Philippe Galéra and Hélène Bouraïma-Lelong

Int. J. Mol. Sci. 2023, 24(23), 16778; https://doi.org/10.3390/ijms242316778 - 26 Nov 2023

Cited by 1 | Viewed by 1026

Abstract

The castration of stallions is traditionally performed after puberty, at around the age of 2 years old. No studies have focused on the effects of early castration on osteoarticular metabolism. Thus, we aimed to compare early castration (3 days after birth) with traditional [...] Read more.

The castration of stallions is traditionally performed after puberty, at around the age of 2 years old. No studies have focused on the effects of early castration on osteoarticular metabolism. Thus, we aimed to compare early castration (3 days after birth) with traditional castration (18 months of age) in horses. Testosterone and estradiol levels were monitored from birth to 33 months in both groups. We quantified the levels of biomarkers of cartilage and bone anabolism (CPII and N-MID) and catabolism (CTX-I and CTX-II), as well as of osteoarthritis (HA and COMP) and inflammation (IL-6 and PGE₂). We observed a lack of parallelism between testosterone and estradiol synthesis after birth and during puberty in both groups. The extra-gonadal synthesis of steroids was observed around the 28-month mark, regardless of the castration age. We found the expression of estrogen receptor (ESR1) in cartilage and bone, whereas androgen receptor (AR) expression appeared to be restricted to bone. Nevertheless, with respect to osteoarticular metabolism, steroid hormone deprivation resulting from early castration had no discernable impact on the levels of biomarkers related to bone and cartilage metabolism, nor on those associated with OA and inflammation. Consequently, our research demonstrated that early castration does not disrupt bone and cartilage homeostasis. Full article

(This article belongs to the Special Issue Feature Papers in Molecular Endocrinology and Metabolism)

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14 pages, 2309 KiB

Open AccessArticle

Garcinia cambogia Extract Increased Hepatic Levels of Lipolysis-Stimulated Lipoprotein Receptor and Lipids in Mice on Normal Diet

by Marine Hanse, Samina Akbar, Hamed Layeghkhavidaki and Frances T. Yen

Int. J. Mol. Sci. 2023, 24(22), 16298; https://doi.org/10.3390/ijms242216298 - 14 Nov 2023

Viewed by 771

Abstract

Garcinia cambogia extract (GCE) is a popular weight-loss supplement that also lowers plasma triglyceride (TG) levels. We hypothesized that GCE-mediated inhibition of ATP citrate lyase and thereby hepatic TG production could lead to compensatory mechanisms, including increased hepatic TG uptake via lipoprotein receptors. [...] Read more.

Garcinia cambogia extract (GCE) is a popular weight-loss supplement that also lowers plasma triglyceride (TG) levels. We hypothesized that GCE-mediated inhibition of ATP citrate lyase and thereby hepatic TG production could lead to compensatory mechanisms, including increased hepatic TG uptake via lipoprotein receptors. GCE (20 mg/day) administered 40 days orally to female C57BL/6Rj mice on a standard chow diet led to a decrease in both plasma fasting and post-prandial TG-rich lipoprotein levels, but with no significant change in body weight gain. Lipolysis stimulated lipoprotein receptor (LSR) protein levels, but not those of LDL-receptor, were increased as compared to controls. Mouse Hepa1-6 cells treated with the GCE active ingredient, hydroxycitrate, also led to increased LSR protein levels. Hepatic total cholesterol, TG, and muscle TG contents were higher in GCE-treated animals as compared to controls, whereas adipose TG levels were unchanged. LSR and LDL-receptor protein levels were correlated with liver total cholesterol, but only LDL-receptor was associated with liver TG. These results show that GCE treatment in mice on a standard chow diet led to significantly increased liver and muscle lipids, with no significant change in adipose tissue TG levels, which should be considered in the long-term use of GCE. Full article

(This article belongs to the Special Issue Feature Papers in Molecular Endocrinology and Metabolism)

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25 pages, 5068 KiB

Open AccessArticle

Anti-Rheumatoid Arthritis Pharmacodynamic Substances Screening of Periploca forrestii Schltr.: Component Analyses In Vitro and In Vivo Combined with Multi-Technical Metabolomics

by Jia Sun, Zuying Zhou, Yang Zhou, Ting Liu, Yueting Li, Zipeng Gong, Yang Jin, Lin Zheng and Yong Huang

Int. J. Mol. Sci. 2023, 24(18), 13695; https://doi.org/10.3390/ijms241813695 - 05 Sep 2023

Viewed by 974

Abstract

The purpose of this study was to elucidate the metabolic action patterns of P. forrestii against rheumatoid arthritis (RA) using metabolomics, and to obtain its potential effective substances for treating RA. First, the therapeutic effects of P. forrestii against RA were confirmed; second, [...] Read more.

The purpose of this study was to elucidate the metabolic action patterns of P. forrestii against rheumatoid arthritis (RA) using metabolomics, and to obtain its potential effective substances for treating RA. First, the therapeutic effects of P. forrestii against RA were confirmed; second, the chemical composition of P. forrestii was analyzed, and 17 prototypes were absorbed into blood; subsequently, plasma metabolomics studies using UPLC-Triple-TOF-MS/MS and GC-MS were performed to disclose the metabolomics alterations in groups, which revealed 38 altered metabolites after drug intervention. These metabolites were all associated with the arthritis pathophysiology process (−log(p) > 1.6). Among them, sorted by variable important in projection (VIP), the metabolites affected (VIP ≥ 1.72) belonged to lipid metabolites. Finally, Pearson’s analysis between endogenous metabolites and exogenous compounds was conducted to obtain potential pharmacological substances for the P. forrestii treatment of RA, which showed a high correlation between five blood-absorbed components and P. forrestii-regulated metabolites. This information provides a basis for the selection of metabolic action modes for P. forrestii clinical application dosage, and potential pharmacological substances that exerted anti-RA effects of P. forrestii were discovered. The study provided an experimental basis for further research on pharmacoequivalence, molecular mechanism validation, and even the development of new dosage forms in the future. Full article

(This article belongs to the Special Issue Feature Papers in Molecular Endocrinology and Metabolism)

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16 pages, 3245 KiB

Open AccessArticle

A Re-Purposing Strategy: Sub-Lethal Concentrations of an Eicosanoid Derived from the Omega-3-Polyunsaturated Fatty Acid Resolvin D1 Affect Dual Species Biofilms

by Angela Maione, Annalisa Buonanno, Marilena Galdiero, Elisabetta de Alteriis, Francesco Petrillo, Michele Reibaldi, Marco Guida and Emilia Galdiero

Int. J. Mol. Sci. 2023, 24(16), 12876; https://doi.org/10.3390/ijms241612876 - 17 Aug 2023

Cited by 1 | Viewed by 786

Abstract

The fungal species Candida parapsilosis and the bacterial species Staphylococcus aureus may be responsible for hospital-acquired infections in patients undergoing invasive medical interventions or surgical procedures and often coinfect critically ill patients in complicating polymicrobial biofilms. The efficacy of the re-purposing therapy has [...] Read more.

The fungal species Candida parapsilosis and the bacterial species Staphylococcus aureus may be responsible for hospital-acquired infections in patients undergoing invasive medical interventions or surgical procedures and often coinfect critically ill patients in complicating polymicrobial biofilms. The efficacy of the re-purposing therapy has recently been reported as an alternative to be used. PUFAs (polyunsaturated fatty acids) may be used alone or in combination with currently available traditional antimicrobials to prevent and manage various infections overcoming antimicrobial resistance. The objectives of the study were to evaluate the effects of Resolvin D1 (RvD1) as an antimicrobial on S. aureus and C. parapsilosis, as well as the activity against the mixed biofilm of the same two species. Microdilution assays and time–kill growth curves revealed bacterial and fungal inhibition at minimum concentration values between 5 and 10 μg mL⁻¹. In single-species structures, an inhibition of 55% and 42% was reported for S. aureus and C. parapsilosis, respectively. Moreover, RvD1 demonstrated an eradication capacity of 60% and 80% for single- and mixed-species biofilms, respectively. In association with the inhibition activity, a downregulation of genes involved in biofilm formation as well as ROS accumulation was observed. Eradication capability was confirmed also on mature mixed biofilm grown on silicone platelets as shown by scanning electron microscopy (SEM). In conclusion, RvD1 was efficient against mono and polymicrobial biofilms in vitro, being a promising alternative for the treatment of mixed bacterial/fungal infections. Full article

(This article belongs to the Special Issue Feature Papers in Molecular Endocrinology and Metabolism)

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17 pages, 3482 KiB

Open AccessArticle

Sex Lethal Gene Manipulates Gonadal Development of Medaka, Oryzias latipes, through Estrogenic Interventions

by Tapas Chakraborty, Sipra Mohapatra, Michiya Matsuyama, Yoshitaka Nagahama and Kohei Ohta

Int. J. Mol. Sci. 2022, 23(24), 15496; https://doi.org/10.3390/ijms232415496 - 07 Dec 2022

Cited by 1 | Viewed by 1513

Abstract

Germ cells are pivotal for gonadal sexuality maintenance and reproduction. Sex lethal (sxl), the somatic sex determining gene of Drosophila, is the known regulator and initiator of germ cell femininity in invertebrates. However, the role of the Sxl homologue has [...] Read more.

Germ cells are pivotal for gonadal sexuality maintenance and reproduction. Sex lethal (sxl), the somatic sex determining gene of Drosophila, is the known regulator and initiator of germ cell femininity in invertebrates. However, the role of the Sxl homologue has rarely been investigated in vertebrates. So, we used medaka to clarify the role of sxl in vertebrate gonadogenesis and sexuality and identified two Sxl homologues, i.e., Sxl1a and Sxl1b. We found that sxl1a specifically expresses in the primordial germ cells (PGC), ovary, (early gonia and oocytes), while sxl1b distributions are ubiquitous. An mRNA overexpression of sxl1a accelerated germ cell numbers in 10 DAH XY fish, and sxl1a knockdown (KD), on the other hand, induced PGC mis-migration, aberrant PGC structuring and ultimately caused significant germ cell reduction in XX fish. Using an in vitro promoter analysis and in vivo steroid treatment, we found a strong link between sxl1a and estrogenic germ cell-population maintenance. Further, using sxl1a-KD and erβ2-knockout fish, we determined that sxl1 acts through erβ2 and controls PGC sexuality. Cumulatively, our study highlights the novel role of sxl1a in germ cell maintenance and sexual identity assignment and thus might become a steppingstone to understanding the commonalities of animal sexual development. Full article

(This article belongs to the Special Issue Feature Papers in Molecular Endocrinology and Metabolism)

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17 pages, 3204 KiB

Open AccessArticle

Insulin-Induced Recurrent Hypoglycemia Up-Regulates Glucose Metabolism in the Brain Cortex of Chemically Induced Diabetic Rats

by Susana Cardoso and Paula I. Moreira

Int. J. Mol. Sci. 2021, 22(24), 13470; https://doi.org/10.3390/ijms222413470 - 15 Dec 2021

Cited by 3 | Viewed by 2994

Abstract

Diabetes is a chronic metabolic disease that seriously compromises human well-being. Various studies highlight the importance of maintaining a sufficient glucose supply to the brain and subsequently safeguarding cerebral glucose metabolism. The goal of the present work is to clarify and disclose the [...] Read more.

Diabetes is a chronic metabolic disease that seriously compromises human well-being. Various studies highlight the importance of maintaining a sufficient glucose supply to the brain and subsequently safeguarding cerebral glucose metabolism. The goal of the present work is to clarify and disclose the metabolic alterations induced by recurrent hypoglycemia in the context of long-term hyperglycemia to further comprehend the effects beyond brain harm. To this end, chemically induced diabetic rats underwent a protocol of repeatedly insulin-induced hypoglycemic episodes. The activity of key enzymes of glycolysis, the pentose phosphate pathway and the Krebs cycle was measured by spectrophotometry in extracts or isolated mitochondria from brain cortical tissue. Western blot analysis was used to determine the protein content of glucose and monocarboxylate transporters, players in the insulin signaling pathway and mitochondrial biogenesis and dynamics. We observed that recurrent hypoglycemia up-regulates the activity of mitochondrial hexokinase and Krebs cycle enzymes (namely, pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase and succinate dehydrogenase) and the protein levels of mitochondrial transcription factor A (TFAM). Both insults increased the nuclear factor erythroid 2–related factor 2 (NRF2) protein content and induced divergent effects in mitochondrial dynamics. Insulin-signaling downstream pathways were found to be down-regulated, and glycogen synthase kinase 3 beta (GSK3β) was found to be activated through both decreased phosphorylation at Ser9 and increased phosphorylation at Y216. Interestingly, no changes in the levels of cAMP response element-binding protein (CREB), which plays a key role in neuronal plasticity and memory, were caused by hypoglycemia and/or hyperglycemia. These findings provide experimental evidence that recurrent hypoglycemia, in the context of chronic hyperglycemia, has the capacity to evoke coordinated adaptive responses in the brain cortex that will ultimately contribute to sustaining brain cell health. Full article

(This article belongs to the Special Issue Feature Papers in Molecular Endocrinology and Metabolism)

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11 pages, 2839 KiB

Open AccessArticle

Combination Therapy with a JNK Inhibitor and Hepatocyte Growth Factor for Restoration of Erectile Function in a Rat Model of Cavernosal Nerve Injury: Comparison with a JNK Inhibitor Alone or Hepatocyte Growth Factor Alone

by Junghoon Lee, Soo Woong Kim and Min Chul Cho

Int. J. Mol. Sci. 2021, 22(23), 12698; https://doi.org/10.3390/ijms222312698 - 24 Nov 2021

Cited by 2 | Viewed by 1549

Abstract

We determined if combined administration of JNK-inhibitors and HGF (hepatocyte-growth-factor) would restore erectile-function through both antiapoptotic and regenerative effects in a rat model of cavernous-nerve-crush-injury (CNCI), and compared the results with administration of JNK-inhibitor alone or HGF alone. We randomized 70 rats into [...] Read more.

We determined if combined administration of JNK-inhibitors and HGF (hepatocyte-growth-factor) would restore erectile-function through both antiapoptotic and regenerative effects in a rat model of cavernous-nerve-crush-injury (CNCI), and compared the results with administration of JNK-inhibitor alone or HGF alone. We randomized 70 rats into 5 groups: sham-surgery-group (S), CNCI (I) group, a group treated with once-daily intraperitoneal-administration of 10.0-mg/kg of JNK-inhibitors (J), a twice-weekly intracavernosal-administration of 4.2-μg HGF group (H), and a combined-treatment with 10.0-mg/kg JNK-inhibitors and 4.2-μg HGF group (J+H). We investigated erectile-responses to electrostimulation, histological-staining, caspase-3-activity-assay, and immunoblotting at two-weeks postoperatively. The three treatment groups showed improvements in erectile-responses (ICP/MAP and AUC/MAP ratios) compared to Group-I. The erectile-responses in Group-J+H were greater than those in Group-J or Group-H. The erectile-responses in Group-J+H were generally normalized. Caspase-3-activity and cJun-phosphorylation in Group-J and Group-J+H improved compared to Group-I, whereas caspase-3-activity in Group-H partially improved. Protein-expression of PECAM-1, eNOS-phosphorylation, and smooth-muscle content in Group-J+H were normalized, although those in Group-J or Group-H were partially restored. Combination therapy with JNK-inhibitors and HGF can generally normalize erectile-function through anti-apoptosis and preservation of endothelium or SM in rat CNCI model. The combined treatment appears to be superior to the respective agent alone in terms of therapeutic effects. Full article

(This article belongs to the Special Issue Feature Papers in Molecular Endocrinology and Metabolism)

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19 pages, 7475 KiB

Open AccessArticle

Effects of GLP-1RA and SGLT2i, Alone or in Combination, on Mouse Models of Type 2 Diabetes Representing Different Disease Stages

by Masao Koike, Hitoki Saito, Genta Kohno, Masahiro Takubo, Kentaro Watanabe and Hisamitsu Ishihara

Int. J. Mol. Sci. 2021, 22(21), 11463; https://doi.org/10.3390/ijms222111463 - 25 Oct 2021

Cited by 4 | Viewed by 2969

Abstract

Glucagon-like peptide-1 receptor agonist (GLP-1RA) and sodium-dependent glucose transporter 2 inhibitor (SGLT2i), in addition to lowering glucose, have pleiotropic effects on the heart, kidneys, and liver. These drugs have thus come into widespread use for treating type 2 diabetes (T2DM). However, mechanistic comparisons [...] Read more.

Glucagon-like peptide-1 receptor agonist (GLP-1RA) and sodium-dependent glucose transporter 2 inhibitor (SGLT2i), in addition to lowering glucose, have pleiotropic effects on the heart, kidneys, and liver. These drugs have thus come into widespread use for treating type 2 diabetes (T2DM). However, mechanistic comparisons and effects of combining these drugs have not been adequately studied. Employing diet-induced obese (DIO) mice and db/db mice as models of the early and advanced stages of T2DM, we evaluated effects of single or combined use of liraglutide (a GLP-1RA) and ipragliflozin (a SGLT2i). Treatments with liraglutide and/or ipragliflozin for 28 days improved glycemic control and reduced hepatic lipid accumulation similarly in DIO mice. In contrast, in db/db mice, despite similar favorable effects on fatty liver, liraglutide exerted no beneficial effects on glycemic control. Improved glycemic control in db/db mice treated with ipragliflozin was accompanied by increased pancreatic β-cell area and insulin content, both of which tended to rise further when ipragliflozin was combined with liraglutide. Our data suggest that liraglutide is more efficient at an earlier stage and ipragliflozin can be effective in both stages. In addition, their combined use is a potential option for treating advanced stage diabetes with fatty liver disease. Full article

(This article belongs to the Special Issue Feature Papers in Molecular Endocrinology and Metabolism)

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9 pages, 1721 KiB

Open AccessArticle

Minor Changes in Erythrocyte Osmotic Fragility in Trace Amine-Associated Receptor 5 (TAAR5) Knockout Mice

by Ilya S. Zhukov, Larisa G. Kubarskaya, Inessa V. Karpova, Anastasia N. Vaganova, Marina N. Karpenko and Raul R. Gainetdinov

Int. J. Mol. Sci. 2021, 22(14), 7307; https://doi.org/10.3390/ijms22147307 - 07 Jul 2021

Cited by 6 | Viewed by 5023

Abstract

Trace amine-associated receptors (TAARs) are a group of G protein-coupled receptors that are expressed in the olfactory epithelium, central nervous system, and periphery. TAAR family generally consists of nine types of receptors (TAAR1-9), which can detect biogenic amines. During the last 5 years, [...] Read more.

Trace amine-associated receptors (TAARs) are a group of G protein-coupled receptors that are expressed in the olfactory epithelium, central nervous system, and periphery. TAAR family generally consists of nine types of receptors (TAAR1-9), which can detect biogenic amines. During the last 5 years, the TAAR5 receptor became one of the most intriguing receptors in this subfamily. Recent studies revealed that TAAR5 is involved not only in sensing socially relevant odors but also in the regulation of dopamine and serotonin transmission, emotional regulation, and adult neurogenesis by providing significant input from the olfactory system to the limbic brain areas. Such results indicate that future antagonistic TAAR5-based therapies may have high pharmacological potential in the field of neuropsychiatric disorders. TAAR5 is known to be expressed in leucocytes as well. To evaluate potential hematological side effects of such future treatments we analyzed several hematological parameters in mice lacking TAAR5. In these mutants, we observed minor but significant changes in the osmotic fragility test of erythrocytes and hematocrit levels. At the same time, analysis of other parameters including complete blood count and reticulocyte levels showed no significant alterations in TAAR5 knockout mice. Thus, TAAR5 gene knockout leads to minor negative changes in the erythropoiesis or eryptosis processes, and further research in that field is needed. The impact of TAAR5 deficiency on other hematological parameters seems minimal. Such negative, albeit minor, effects of TAAR5 deficiency should be taken into account during future TAAR5-based therapy development. Full article

(This article belongs to the Special Issue Feature Papers in Molecular Endocrinology and Metabolism)

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17 pages, 17245 KiB

Open AccessArticle

Selective Inhibition of Genomic and Non-Genomic Effects of Thyroid Hormone Regulates Muscle Cell Differentiation and Metabolic Behavior

by Annarita Nappi, Melania Murolo, Serena Sagliocchi, Caterina Miro, Annunziata Gaetana Cicatiello, Emery Di Cicco, Rossella Di Paola, Maddalena Raia, Lucia D’Esposito, Mariano Stornaiuolo and Monica Dentice

Int. J. Mol. Sci. 2021, 22(13), 7175; https://doi.org/10.3390/ijms22137175 - 02 Jul 2021

Cited by 11 | Viewed by 2417

Abstract

Thyroid hormones (THs) are key regulators of different biological processes. Their action involves genomic and non-genomic mechanisms, which together mediate the final effects of TH in target tissues. However, the proportion of the two processes and their contribution to the TH-mediated effects are [...] Read more.

Thyroid hormones (THs) are key regulators of different biological processes. Their action involves genomic and non-genomic mechanisms, which together mediate the final effects of TH in target tissues. However, the proportion of the two processes and their contribution to the TH-mediated effects are still poorly understood. Skeletal muscle is a classical target tissue for TH, which regulates muscle strength and contraction, as well as energetic metabolism of myofibers. Here we address the different contribution of genomic and non-genomic action of TH in skeletal muscle cells by specifically silencing the deiodinase Dio2 or the β3-Integrin expression via CRISPR/Cas9 technology. We found that myoblast proliferation is inversely regulated by integrin signal and the D2-dependent TH activation. Similarly, inhibition of the nuclear receptor action reduced myoblast proliferation, confirming that genomic action of TH attenuates proliferative rates. Contrarily, genomic and non-genomic signals promote muscle differentiation and the regulation of the redox state. Taken together, our data reveal that integration of genomic and non-genomic signal pathways finely regulates skeletal muscle physiology. These findings not only contribute to the understanding of the mechanisms involved in TH modulation of muscle physiology but also add insight into the interplay between different mechanisms of action of TH in muscle cells. Full article

(This article belongs to the Special Issue Feature Papers in Molecular Endocrinology and Metabolism)

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Review

Jump to: Research

19 pages, 1104 KiB

Open AccessReview

Statins—Their Role in Bone Tissue Metabolism and Local Applications with Different Carriers

by Marcin Mateusz Granat, Joanna Eifler-Zydel and Joanna Kolmas

Int. J. Mol. Sci. 2024, 25(4), 2378; https://doi.org/10.3390/ijms25042378 - 17 Feb 2024

Viewed by 664

Abstract

Statins, widely prescribed for lipid disorders, primarily target 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase competitively and reversibly, resulting in reduced low-density lipoprotein cholesterol (LDL-C). This mechanism proves effective in lowering the risk of lipid-related diseases such as ischemic cerebrovascular and coronary artery diseases. Beyond their [...] Read more.

Statins, widely prescribed for lipid disorders, primarily target 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase competitively and reversibly, resulting in reduced low-density lipoprotein cholesterol (LDL-C). This mechanism proves effective in lowering the risk of lipid-related diseases such as ischemic cerebrovascular and coronary artery diseases. Beyond their established use, statins are under scrutiny for potential applications in treating bone diseases. The focus of research centers mainly on simvastatin, a lipophilic statin demonstrating efficacy in preventing osteoporosis and aiding in fracture and bone defect healing. Notably, these effects manifest at elevated doses (20 mg/kg/day) of statins, posing challenges for systematic administration due to their limited bone affinity. Current investigations explore intraosseous statin delivery facilitated by specialized carriers. This paper outlines various carrier types, characterizing their structures and underscoring various statins’ potential as local treatments for bone diseases. Full article

(This article belongs to the Special Issue Feature Papers in Molecular Endocrinology and Metabolism)

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18 pages, 565 KiB

Open AccessReview

Bones and Hormones: Interaction between Hormones of the Hypothalamus, Pituitary, Adipose Tissue and Bone

by Olga Niwczyk, Monika Grymowicz, Aleksandra Szczęsnowicz, Marta Hajbos, Anna Kostrzak, Michał Budzik, Marzena Maciejewska-Jeske, Gregory Bala, Roman Smolarczyk and Błażej Męczekalski

Int. J. Mol. Sci. 2023, 24(7), 6840; https://doi.org/10.3390/ijms24076840 - 06 Apr 2023

Cited by 3 | Viewed by 2544

Abstract

The bony skeleton, as a structural foundation for the human body, is essential in providing mechanical function and movement. The human skeleton is a highly specialized and dynamic organ that undergoes continuous remodeling as it adapts to the demands of its environment. Advances [...] Read more.

The bony skeleton, as a structural foundation for the human body, is essential in providing mechanical function and movement. The human skeleton is a highly specialized and dynamic organ that undergoes continuous remodeling as it adapts to the demands of its environment. Advances in research over the last decade have shone light on the various hormones that influence this process, modulating the metabolism and structural integrity of bone. More recently, novel and non-traditional functions of hypothalamic, pituitary, and adipose hormones and their effects on bone homeostasis have been proposed. This review highlights recent work on physiological bone remodeling and discusses our knowledge, as it currently stands, on the systemic interplay of factors regulating this interaction. In this review, we provide a summary of the literature on the relationship between bone physiology and hormones including kisspeptin, neuropeptide Y, follicle-stimulating hormone (FSH), prolactin (PRL), adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), growth hormone (GH), leptin, and adiponectin. The discovery and understanding of this new functionality unveils an entirely new layer of physiologic circuitry. Full article

(This article belongs to the Special Issue Feature Papers in Molecular Endocrinology and Metabolism)

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15 pages, 6079 KiB

Open AccessReview

Seminal Extracellular Vesicles and Their Involvement in Male (In)Fertility: A Systematic Review

by Ana Parra, Lorena Padilla, Xiomara Lucas, Heriberto Rodriguez-Martinez, Isabel Barranco and Jordi Roca

Int. J. Mol. Sci. 2023, 24(5), 4818; https://doi.org/10.3390/ijms24054818 - 02 Mar 2023

Cited by 6 | Viewed by 2010

Abstract

Seminal plasma contains numerous extracellular vesicles (sEVs). Since sEVs are apparently involved in male (in)fertility, this systematic review focused on studies specifically investigating such relationship. Embase, PubMed, and Scopus databases were searched up to 31 December 2022, primarily identifying a total of 1440 [...] Read more.

Seminal plasma contains numerous extracellular vesicles (sEVs). Since sEVs are apparently involved in male (in)fertility, this systematic review focused on studies specifically investigating such relationship. Embase, PubMed, and Scopus databases were searched up to 31 December 2022, primarily identifying a total of 1440 articles. After processing for screening and eligibility, 305 studies were selected as they focused on sEVs, and 42 of them were considered eligible because they included the word fertility or a related word such as infertility, subfertility, fertilization, and recurrent pregnancy loss in the title, objective(s), and/or keywords. Only nine of them met the inclusion criteria, namely (a) conducting experiments aimed at associating sEVs with fertility concerns and (b) isolating and adequately characterizing sEVs. Six studies were conducted on humans, two on laboratory animals, and one on livestock. The studies highlighted some sEV molecules, specifically proteins and small non-coding RNAs, that showed differences between fertile and subfertile or infertile males. The content of sEVs was also related to sperm fertilizing capacity, embryo development, and implantation. Bioinformatic analysis revealed that several of the highlighted sEV fertility-related proteins would be cross-linked to each other and involved in biological pathways related to (i) EV release and loading and (ii) plasma membrane organization. Full article

(This article belongs to the Special Issue Feature Papers in Molecular Endocrinology and Metabolism)

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29 pages, 423 KiB

Open AccessReview

Metformin: Expanding the Scope of Application—Starting Earlier than Yesterday, Canceling Later

by Yulia A. Kononova, Nikolai P. Likhonosov and Alina Yu. Babenko

Int. J. Mol. Sci. 2022, 23(4), 2363; https://doi.org/10.3390/ijms23042363 - 21 Feb 2022

Cited by 5 | Viewed by 3063

Abstract

Today the area of application of metformin is expanding, and a wealth of data point to its benefits in people without carbohydrate metabolism disorders. Already in the population of people leading an unhealthy lifestyle, before the formation of obesity and prediabetes metformin smooths [...] Read more.

Today the area of application of metformin is expanding, and a wealth of data point to its benefits in people without carbohydrate metabolism disorders. Already in the population of people leading an unhealthy lifestyle, before the formation of obesity and prediabetes metformin smooths out the adverse effects of a high-fat diet. Being prescribed at this stage, metformin will probably be able to, if not prevent, then significantly reduce the progression of all subsequent metabolic changes. To a large extent, this review will discuss the proofs of the evidence for this. Another recent important change is a removal of a number of restrictions on its use in patients with heart failure, acute coronary syndrome and chronic kidney disease. We will discuss the reasons for these changes and present a new perspective on the role of increasing lactate in metformin therapy. Full article

(This article belongs to the Special Issue Feature Papers in Molecular Endocrinology and Metabolism)

21 pages, 2167 KiB

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Diabetes and Colorectal Cancer Risk: A New Look at Molecular Mechanisms and Potential Role of Novel Antidiabetic Agents

by Jelena Vekic, Aleksandra Zeljkovic, Aleksandra Stefanovic, Rosaria Vincenza Giglio, Marcello Ciaccio and Manfredi Rizzo

Int. J. Mol. Sci. 2021, 22(22), 12409; https://doi.org/10.3390/ijms222212409 - 17 Nov 2021

Cited by 11 | Viewed by 2923

Abstract

Epidemiological data have demonstrated a significant association between the presence of type 2 diabetes mellitus (T2DM) and the development of colorectal cancer (CRC). Chronic hyperglycemia, insulin resistance, oxidative stress, and inflammation, the processes inherent to T2DM, also play active roles in the onset [...] Read more.

Epidemiological data have demonstrated a significant association between the presence of type 2 diabetes mellitus (T2DM) and the development of colorectal cancer (CRC). Chronic hyperglycemia, insulin resistance, oxidative stress, and inflammation, the processes inherent to T2DM, also play active roles in the onset and progression of CRC. Recently, small dense low-density lipoprotein (LDL) particles, a typical characteristic of diabetic dyslipidemia, emerged as another possible underlying link between T2DM and CRC. Growing evidence suggests that antidiabetic medications may have beneficial effects in CRC prevention. According to findings from a limited number of preclinical and clinical studies, glucagon-like peptide-1 receptor agonists (GLP-1RAs) could be a promising strategy in reducing the incidence of CRC in patients with diabetes. However, available findings are inconclusive, and further studies are required. In this review, novel evidence on molecular mechanisms linking T2DM with CRC development, progression, and survival will be discussed. In addition, the potential role of GLP-1RAs therapies in CRC prevention will also be evaluated. Full article

(This article belongs to the Special Issue Feature Papers in Molecular Endocrinology and Metabolism)

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25 pages, 3297 KiB

Open AccessReview

A Brief History and Future Prospects of CEST MRI in Clinical Non-Brain Tumor Imaging

by Tianxin Gao, Chuyue Zou, Yifan Li, Zhenqi Jiang, Xiaoying Tang and Xiaolei Song

Int. J. Mol. Sci. 2021, 22(21), 11559; https://doi.org/10.3390/ijms222111559 - 26 Oct 2021

Cited by 9 | Viewed by 3180

Abstract

Chemical exchange saturation transfer (CEST) MRI is a promising molecular imaging tool which allows the specific detection of metabolites that contain exchangeable amide, amine, and hydroxyl protons. Decades of development have progressed CEST imaging from an initial concept to a clinical imaging tool [...] Read more.

Chemical exchange saturation transfer (CEST) MRI is a promising molecular imaging tool which allows the specific detection of metabolites that contain exchangeable amide, amine, and hydroxyl protons. Decades of development have progressed CEST imaging from an initial concept to a clinical imaging tool that is used to assess tumor metabolism. The first translation efforts involved brain imaging, but this has now progressed to imaging other body tissues. In this review, we summarize studies using CEST MRI to image a range of tumor types, including breast cancer, pelvic tumors, digestive tumors, and lung cancer. Approximately two thirds of the published studies involved breast or pelvic tumors which are sites that are less affected by body motion. Most studies conclude that CEST shows good potential for the differentiation of malignant from benign lesions with a number of reports now extending to compare different histological classifications along with the effects of anti-cancer treatments. Despite CEST being a unique ‘label-free’ approach with a higher sensitivity than MR spectroscopy, there are still some obstacles for implementing its clinical use. Future research is now focused on overcoming these challenges. Vigorous ongoing development and further clinical trials are expected to see CEST technology become more widely implemented as a mainstream imaging technology. Full article

(This article belongs to the Special Issue Feature Papers in Molecular Endocrinology and Metabolism)

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16 pages, 6204 KiB

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What Are Reactive Oxygen Species, Free Radicals, and Oxidative Stress in Skin Diseases?

by Kozo Nakai and Daisuke Tsuruta

Int. J. Mol. Sci. 2021, 22(19), 10799; https://doi.org/10.3390/ijms221910799 - 06 Oct 2021

Cited by 88 | Viewed by 8084

Abstract

Oxygen in the atmosphere is a crucial component for life-sustaining aerobic respiration in humans. Approximately 95% of oxygen is consumed as energy and ultimately becomes water; however, the remaining 5% produces metabolites called activated oxygen or reactive oxygen species (ROS), which are extremely [...] Read more.

Oxygen in the atmosphere is a crucial component for life-sustaining aerobic respiration in humans. Approximately 95% of oxygen is consumed as energy and ultimately becomes water; however, the remaining 5% produces metabolites called activated oxygen or reactive oxygen species (ROS), which are extremely reactive. Skin, the largest organ in the human body, is exposed to air pollutants, including diesel exhaust fumes, ultraviolet rays, food, xenobiotics, drugs, and cosmetics, which promote the production of ROS. ROS exacerbate skin aging and inflammation, but also function as regulators of homeostasis in the human body, including epidermal keratinocyte proliferation. Although ROS have been implicated in various skin diseases, the underlying mechanisms have not yet been elucidated. Current knowledge on ROS-related and oxidative stress-related skin diseases from basic research to clinical treatment strategies are discussed herein. This information may be applied to the future treatment of skin diseases through the individual targeting of the ROS generated in each case via their inhibition, capture, or regulation. Full article

(This article belongs to the Special Issue Feature Papers in Molecular Endocrinology and Metabolism)

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12 pages, 635 KiB

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Renin-Angiotensin System in Pathogenesis of Atherosclerosis and Treatment of CVD

by Anastasia V. Poznyak, Dwaipayan Bharadwaj, Gauri Prasad, Andrey V. Grechko, Margarita A. Sazonova and Alexander N. Orekhov

Int. J. Mol. Sci. 2021, 22(13), 6702; https://doi.org/10.3390/ijms22136702 - 22 Jun 2021

Cited by 51 | Viewed by 5018

Abstract

Atherosclerosis has complex pathogenesis, which involves at least three serious aspects: inflammation, lipid metabolism alterations, and endothelial injury. There are no effective treatment options, as well as preventive measures for atherosclerosis. However, this disease has various severe complications, the most severe of which [...] Read more.

Atherosclerosis has complex pathogenesis, which involves at least three serious aspects: inflammation, lipid metabolism alterations, and endothelial injury. There are no effective treatment options, as well as preventive measures for atherosclerosis. However, this disease has various severe complications, the most severe of which is cardiovascular disease (CVD). It is important to note, that CVD is among the leading causes of death worldwide. The renin–angiotensin–aldosterone system (RAAS) is an important part of inflammatory response regulation. This system contributes to the recruitment of inflammatory cells to the injured site and stimulates the production of various cytokines, such as IL-6, TNF-a, and COX-2. There is also an association between RAAS and oxidative stress, which is also an important player in atherogenesis. Angiotensin-II induces plaque formation at early stages, and this is one of the most crucial impacts on atherogenesis from the RAAS. Importantly, while stimulating the production of ROS, Angiotensin-II at the same time decreases the generation of NO. The endothelium is known as a major contributor to vascular function. Oxidative stress is the main trigger of endothelial dysfunction, and, once again, links RAAS to the pathogenesis of atherosclerosis. All these implications of RAAS in atherogenesis lead to an explicable conclusion that elements of RAAS can be promising targets for atherosclerosis treatment. In this review, we also summarize the data on treatment approaches involving cytokine targeting in CVD, which can contribute to a better understanding of atherogenesis and even its prevention. Full article

(This article belongs to the Special Issue Feature Papers in Molecular Endocrinology and Metabolism)

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38 pages, 1390 KiB

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Thermogenic Fat: Development, Physiological Function, and Therapeutic Potential

by Bruna B. Brandão, Ankita Poojari and Atefeh Rabiee

Int. J. Mol. Sci. 2021, 22(11), 5906; https://doi.org/10.3390/ijms22115906 - 31 May 2021

Cited by 16 | Viewed by 5221

Abstract

The concerning worldwide increase of obesity and chronic metabolic diseases, such as T2D, dyslipidemia, and cardiovascular disease, motivates further investigations into preventive and alternative therapeutic approaches. Over the past decade, there has been growing evidence that the formation and activation of thermogenic adipocytes [...] Read more.

The concerning worldwide increase of obesity and chronic metabolic diseases, such as T2D, dyslipidemia, and cardiovascular disease, motivates further investigations into preventive and alternative therapeutic approaches. Over the past decade, there has been growing evidence that the formation and activation of thermogenic adipocytes (brown and beige) may serve as therapy to treat obesity and its associated diseases owing to its capacity to increase energy expenditure and to modulate circulating lipids and glucose levels. Thus, understanding the molecular mechanism of brown and beige adipocytes formation and activation will facilitate the development of strategies to combat metabolic disorders. Here, we provide a comprehensive overview of pathways and players involved in the development of brown and beige fat, as well as the role of thermogenic adipocytes in energy homeostasis and metabolism. Furthermore, we discuss the alterations in brown and beige adipose tissue function during obesity and explore the therapeutic potential of thermogenic activation to treat metabolic syndrome. Full article

(This article belongs to the Special Issue Feature Papers in Molecular Endocrinology and Metabolism)

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