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Open AccessArticle

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

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

Viewed by 225

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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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

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Angela Maione

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Annalisa Buonanno

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Marilena Galdiero

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Elisabetta de Alteriis

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

Viewed by 351

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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Open AccessArticle

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

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

Cited by 1 | Viewed by 946

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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Open AccessArticle

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

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Susana Cardoso

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Paula I. Moreira

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

Cited by 2 | Viewed by 2525

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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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

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Junghoon Lee

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Soo Woong Kim

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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 1283

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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Open AccessArticle

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

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

Cited by 2 | Viewed by 2346

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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Open AccessArticle

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

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Ilya S. Zhukov

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Larisa G. Kubarskaya

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Inessa V. Karpova

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Anastasia N. Vaganova

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Marina N. Karpenko

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Raul R. Gainetdinov

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

Cited by 4 | Viewed by 3776

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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Open AccessArticle

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

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

Cited by 11 | Viewed by 2040

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

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Olga Niwczyk

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Monika Grymowicz

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Aleksandra Szczęsnowicz

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Marta Hajbos

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Anna Kostrzak

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Michał Budzik

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Marzena Maciejewska-Jeske

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Gregory Bala

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Roman Smolarczyk

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Błażej Męczekalski

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

Viewed by 1325

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

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Ana Parra

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Lorena Padilla

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Xiomara Lucas

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Heriberto Rodriguez-Martinez

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Isabel Barranco

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Jordi Roca

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

Cited by 1 | Viewed by 1214

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

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Yulia A. Kononova

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Nikolai P. Likhonosov

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Alina Yu. Babenko

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

Cited by 4 | Viewed by 2460

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)

Open AccessReview

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

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Jelena Vekic

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Aleksandra Zeljkovic

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Aleksandra Stefanovic

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Rosaria Vincenza Giglio

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Marcello Ciaccio

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Manfredi Rizzo

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

Cited by 6 | Viewed by 2232

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

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

Cited by 7 | Viewed by 2384

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

by

Kozo Nakai

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Daisuke Tsuruta

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

Cited by 49 | Viewed by 5500

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

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Margarita A. Sazonova

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Alexander N. Orekhov

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

Cited by 33 | Viewed by 3866

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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Thermogenic Fat: Development, Physiological Function, and Therapeutic Potential

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Bruna B. Brandão

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Ankita Poojari

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Atefeh Rabiee

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

Cited by 13 | Viewed by 4271

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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Special Issue "Feature Papers in Molecular Endocrinology and Metabolism"

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