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Neurobiology of Disease Aug 2024Multiple sclerosis (MS) is an autoimmune and neurodegenerative disease leading to demyelination and axonal loss. Current treatments are immunomodulatory or...
Multiple sclerosis (MS) is an autoimmune and neurodegenerative disease leading to demyelination and axonal loss. Current treatments are immunomodulatory or immunosuppressive drugs acting on the inflammatory component. However, these treatments do not adequately address the crucial aspect of neuroprotection. Recently, an association between an altered balance of adipokines and MS has been proposed as both a risk factor for developing MS and a chronic disease aggravating factor. Specifically, a decrease of apelin plasma levels in MS patients compared to controls correlates with the number of relapses and disease severity. Here we report a dramatic downregulation of apelin levels in the CNS of EAE mice which is also detected in MS patients brain samples compared to controls. Exploiting innovative design and synthesis techniques, we engineered a novel fluorinated apelin-13 peptide characterized by enhanced plasmatic stability compared to its native counterpart. With this peptide, we assessed the potential therapeutic benefits of apelin preventive supplementation in the EAE mouse model. We show that the fluorinated Apelin-13 peptide ameliorates EAE clinical score and preserves myelin content in the EAE MOG model recapitulating the progressive form of disease. These results combined with ex-vivo experiments in brain organotypic slices and in vitro studies in neurons and primary microglia and macrophages suggest that apelin has neuroprotective effects and influences the microglia/macrophages function.
Topics: Animals; Neuroprotective Agents; Encephalomyelitis, Autoimmune, Experimental; Mice; Multiple Sclerosis; Mice, Inbred C57BL; Female; Humans; Intercellular Signaling Peptides and Proteins; Brain; Disease Models, Animal; Microglia; Apelin
PubMed: 38844244
DOI: 10.1016/j.nbd.2024.106552 -
Journal of Sports Science & Medicine Jun 2024Breast cancer survivors with obesity are at a high risk of cancer recurrence, comorbidity, and mortality. This review aims to systematically evaluate the effects of... (Meta-Analysis)
Meta-Analysis Review
Combined Aerobic and Resistance Training Improves Body Composition, Alters Cardiometabolic Risk, and Ameliorates Cancer-Related Indicators in Breast Cancer Patients and Survivors with Overweight/Obesity: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
Breast cancer survivors with obesity are at a high risk of cancer recurrence, comorbidity, and mortality. This review aims to systematically evaluate the effects of combined aerobic and resistance training (CART) on body composition, lipid homeostasis, inflammation, adipokines, cancer-related fatigue, sleep, and quality of life in breast cancer patients and survivors with overweight/obesity. An electronic search was conducted in PubMed, Web of Science, Scopus, Science Direct, Cochrane, and Google Scholar databases from inception up to January 8, 2024. Randomized controlled trials (RCTs) meeting the inclusion criteria were selected for the analysis. The Cochrane risk of bias tool was used to assess eligible studies, and the GRADE method to evaluate the quality of evidence. A random-effects model was used, and data were analyzed using mean (MD) and standardized mean differences (SMD) for continuous variables with 95% confidence intervals (CI). We assessed the data for risk of bias, heterogeneity, sensitivity, reporting bias, and quality of evidence. A total of 17 randomized controlled trials were included in the systematic review involving 1,148 female patients and survivors (mean age: 54.0 ± 3.4 years). The primary outcomes showed significant improvements in body mass index (SMD -0.57 kg/m, = 0.04), body fat (SMD -0.50%, = 0.02), fat mass (SMD -0.63 kg, = 0.04), hip circumference (MD -3.14 cm, = 0.02), and fat-free mass (SMD 1.03 kg, < 0.001). The secondary outcomes indicated significant increases in high-density lipoprotein cholesterol (MD -0.05 mmol/L, = 0.008), natural killer cells (SMD 0.42%, = 0.04), reductions in triglycerides (MD -81.90 mg/dL, < 0.01), total cholesterol (SMD -0.95 mmol/L, < 0.01), tumor necrosis factor α (SMD -0.89 pg/mL, = 0.03), and leptin (SMD -0.63 ng/mL, = 0.03). Also, beneficial alterations were found in cancer-related fatigue (SMD -0.98, = 0.03), sleep (SMD -1.17, < 0.001), and quality of life (SMD 2.94, = 0.02) scores. There was very low to low confidence in the estimated effect of most of the outcomes. The present findings reveal that CART could be considered an adjunct therapy in supporting the conventional clinical approach observed following exercise. However, further high-quality research is needed to evaluate whether CART would be a valuable intervention to lower aggressive pharmacologic use in breast cancer patients with overweight/obesity.
Topics: Humans; Breast Neoplasms; Female; Resistance Training; Cancer Survivors; Randomized Controlled Trials as Topic; Body Composition; Obesity; Quality of Life; Cardiometabolic Risk Factors; Adipokines; Exercise; Fatigue; Sleep; Overweight
PubMed: 38841642
DOI: 10.52082/jssm.2024.366 -
Heliyon Jun 2024and design Mild vascular inflammation promotes the pathogenesis of hypertension. Asprosin, a newly discovered adipokine, is closely associated with metabolic diseases....
OBJECTIVE
and design Mild vascular inflammation promotes the pathogenesis of hypertension. Asprosin, a newly discovered adipokine, is closely associated with metabolic diseases. We hypothesized that asprosin might led to vascular inflammation in hypertension via NLRP3 inflammasome formation. This study shows the importance of asprosin in the vascular inflammation of hypertension.
METHODS
Primary vascular smooth muscle cells (VSMCs) were obtained from the aorta of animals, including spontaneously hypertensive rats (SHR), Wistar-Kyoto rats (WKY), NLRP3 and wild-type mice. Studies were performed in VSMCs , as well as WKY and SHR .
RESULTS
Asprosin expressions were up-regulated in VSMCs and media of arteries in SHR. Asprosin overexpression promoted NLRP3 inflammasome activation via Toll-like receptor 4 (TLR4), accompanied with activation of NFκB signaling pathway in VSMCs. Exogenous asprosin protein showed similar roles in promoting NLRP3 inflammasome activation. Knockdown of asprosin restrained NLRP3 inflammasome and p65-NFκB activation in VSMCs of SHR. NLRP3 inhibitor MCC950 or NFκB inhibitor BAY11-7082 attenuated asprosin-caused VSMC proliferation and migration. Asprosin-induced interleukin-1β production, proliferation and migration were attenuated in NLRP3 VSMCs. Local asprosin knockdown in common carotid artery of SHR attenuated inflammation and vascular remodeling.
CONCLUSIONS
Asprosin promoted NLRP3 inflammasome activation in VSMCs by TLR4-NFκB pathway, and thereby stimulates VSMCs proliferation, migration, and vascular remodeling of SHR.
PubMed: 38841464
DOI: 10.1016/j.heliyon.2024.e31659 -
Frontiers in Veterinary Science 2024Osteoartritis (OA) is a debilitating disease affecting both humans and animals. In the early stages, OA is characterized by damage to the extracellular matrix (ECM) and... (Review)
Review
Osteoartritis (OA) is a debilitating disease affecting both humans and animals. In the early stages, OA is characterized by damage to the extracellular matrix (ECM) and apoptosis and depletion of chondrocytes. OA progression is characterized by hyaline cartilage loss, chondrophyte and osteophyte formation, thickening of the joint capsule and function loss in the later stages. As the regenerative potential of cartilage is very limited and osteoarthritic changes are irreversible, prevention of OA, modulation of existing osteoarthritic joint inflammation, reducing joint pain and supporting joint function are the only options. Progression of OA and pain may necessitate surgical intervention with joint replacement or arthrodesis as end-stage procedures. In human medicine, the role of adipokines in the development and progression of OA has received increasing interest. At present, the known adipokines include leptin, adiponectin, visfatin, resistin, progranulin, chemerin, lipocalin-2, vaspin, omentin-1 and nesfatin. Adipokines have been demonstrated to play a pivotal role in joint homeostasis by modulating anabolic and catabolic balance, autophagy, apoptosis and inflammatory responses. In small animals, in terms of dogs and cats, naturally occurring OA has been clearly demonstrated as a clinical problem. Similar to humans, the etiology of OA is multifactorial and has not been fully elucidated. Humans, dogs and cats share many joint related degenerative diseases leading to OA. In this review, joint homeostasis, OA, adipokines and the most common joint diseases in small animals leading to naturally occurring OA and their relation with adipokines are discussed. The purpose of this review is highlighting the translational potential of OA and adipokines research in small animal patients.
PubMed: 38831954
DOI: 10.3389/fvets.2024.1193702 -
Human Genomics Jun 2024Several lines of evidence suggest that leukocyte telomere length (LTL) can affect the development of prostate cancer (PC).
BACKGROUND
Several lines of evidence suggest that leukocyte telomere length (LTL) can affect the development of prostate cancer (PC).
METHODS
Here, we employed single nucleoside polymorphisms (SNPs) as instrumental variables (IVs) for LTL (n = 472,174) and conducted Mendelian randomization analysis to estimate their causal impact on PCs (79,148 patients/61,106 controls and 6311 patients/88,902 controls).
RESULTS
Every 1-s.d extension of LTL increased the risk of PCs by 34%. Additionally, the analysis of candidate mediators between LTL and PCs via two-step Mendelian randomization revealed that among the 23 candidates, Alzheimer's disease, liver iron content, sex hormone binding global levels, naive CD4-CD8-T cell% T cell, and circulating leptin levels played substantial mediating roles. There is no robust evidence to support the reverse causal relationship between LTL and the selected mediators of PCs. Adjusting for the former four mediators, rather than adjusting for circulating leptin levels, decreased the impact of LTL on PCs.
CONCLUSION
This study provides potential intervention measures for preventing LTL-induced PCs.
Topics: Humans; Male; Prostatic Neoplasms; Mendelian Randomization Analysis; Leukocytes; Polymorphism, Single Nucleotide; White People; Telomere; Telomere Homeostasis; Leptin; Genetic Predisposition to Disease; Aged; Middle Aged
PubMed: 38831447
DOI: 10.1186/s40246-024-00622-8 -
Frontiers in Endocrinology 2024Reproduction ability requires a certain amount of body fat that is necessary for ovulation, menstruation and pregnancy. Fat tissue represents an endocrine organ with...
BACKGROUND
Reproduction ability requires a certain amount of body fat that is necessary for ovulation, menstruation and pregnancy. Fat tissue represents an endocrine organ with high metabolic activity as it produces adipokines such as leptin and adiponectin. Our aim is to examine potential associations between women of reproductive age's ovarian reserves and their levels of leptin and adiponectin.
METHOD
74 women between 19 and 40 years of age consented to take part. Based on the patterns of their ovarian reserves, the women were divided into three main groups: women with adequate ovarian reserves (AOR - Group A, n=30), women with polycystic ovary syndrome (PCOS - Group B, n=31) and women with depleted ovarian reserves (DOR - Group C, n=13). Among these groups, several biochemical and demographic parameters were statistically compared.
RESULTS
Compared to the other two groups, women with DOR had statistically higher age and follicle stimulation hormone (FSH) levels. For estradiol (E2) and thyroid-stimulating hormone (TSH), no statistically significant difference was seen between the groups. In addition, women with PCOS had higher body mass index (BMI), luteinizing hormone (LH), total testosterone (TT), 17 hydroxyprogesterone (17-OHP), dehydroepiandrosterone (DHEA), anti-Mullerian hormone (AMH), and antral follicle count (AFC) than the other two groups. In line with expectations, women with DOR also had lower levels of AMH and AFC than the other two groups. Women with PCOS had higher leptin levels than the other two groups, but there was no statistically significant difference. Women with PCOS had lower levels of adiponectin than the other groups, however the difference was not statistically significant.
CONCLUSION
The way we classified women in our study according to their ovarian reserves is completely consistent with what has been published internationally. The ovarian reserve in women of reproductive age is not strongly correlated with leptin and adiponectin levels. For safe conclusions, more research including a greater number of samples is required.
Topics: Humans; Female; Leptin; Adiponectin; Ovarian Reserve; Adult; Young Adult; Polycystic Ovary Syndrome; Body Mass Index; Reproduction; Ovary
PubMed: 38828407
DOI: 10.3389/fendo.2024.1369248 -
Nature and Science of Sleep 2024This investigation sought to elucidate the genetic underpinnings that connect obesity indicators, circulating blood lipid levels, adipokines levels and obstructive sleep...
PURPOSE
This investigation sought to elucidate the genetic underpinnings that connect obesity indicators, circulating blood lipid levels, adipokines levels and obstructive sleep apnea syndrome (OSAS), employing a bidirectional two-sample Mendelian randomization (MR) analysis that utilizes data derived from extensive genome-wide association studies (GWAS).
METHODS
We harnessed genetic datasets of OSAS available from the FinnGen consortium and summary data of four obesity indices (including neck circumference), seven blood lipid (including triglycerides) and eleven adipokines (including leptin) from the IEU OpenGWAS database. We primarily utilized inverse variance weighted (IVW), weighted median, and MR-Egger methods, alongside MR-PRESSO and Cochran's Q tests, to validate and assess the diversity and heterogeneity of our findings.
RESULTS
After applying the Bonferroni correction, we identified significant correlations between OSAS and increased neck circumference (Odds Ratio [OR]: 3.472, 95% Confidence Interval [CI]: 1.954-6.169, P= 2.201E-05) and decreased high-density lipoprotein (HDL) cholesterol levels (OR: 0.904, 95% CI: 0.858-0.952, P= 1.251E-04). Concurrently, OSAS was linked to lower leptin levels (OR: 1.355, 95% CI: 1.069-1.718, P= 0.012) and leptin receptor levels (OR: 0.722, 95% CI: 0.530-0.996, P= 0.047). Sensitivity analyses revealed heterogeneity in HDL cholesterol and leptin indicators, but further multiplicative random effects IVW method analysis confirmed these correlations as significant (P< 0.05) without notable heterogeneity or horizontal pleiotropy in other instrumental variables.
CONCLUSION
This investigation compellingly supports the hypothesis that OSAS could be a genetic predisposition for elevated neck circumference, dyslipidemia, and adipokine imbalance. These findings unveil potential genetic interactions between OSAS and metabolic syndrome, providing new pathways for research in this domain. Future investigations should aim to delineate the specific biological pathways by which OSAS impacts metabolic syndrome. Understanding these mechanisms is critical for developing targeted prevention and therapeutic strategies.
PubMed: 38827393
DOI: 10.2147/NSS.S460989 -
Biochemical Pharmacology Jul 2024With the progressive aging of society, there is an increasing prevalence of age-related diseases that pose a threat to the elderly's quality of life. Adipose tissue, a...
With the progressive aging of society, there is an increasing prevalence of age-related diseases that pose a threat to the elderly's quality of life. Adipose tissue, a vital energy reservoir with endocrine functions, is one of the most vulnerable tissues in aging, which in turn influences systematic aging process, including metabolic dysfunction. However, the underlying mechanism is still poorly understood. In this study, we found that NRG4, a novel adipokine, is obviously decreased in adipocyte tissues and serums during aging. Moreover, delivered recombinant NRG4 protein (rNRG4) into aged mice can ameliorate age-associated insulin resistance, glucose disorders and other metabolic disfunction. In addition, rNRG4 treatment alleviates age-associated hepatic steatosis and sarcopenia, accompanied with altered gene signatures. Together, these results indicate that NRG4 plays a key role in the aging process and is a therapeutic target for the treatment of age-associated metabolic dysfunction.
Topics: Animals; Mice; Neuregulins; Adipocytes; Aging; Mice, Inbred C57BL; Male; Recombinant Proteins; Sarcopenia; Insulin Resistance
PubMed: 38823457
DOI: 10.1016/j.bcp.2024.116327 -
Nature Communications May 2024AgRP neurons in the arcuate nucleus of the hypothalamus (ARC) coordinate homeostatic changes in appetite associated with fluctuations in food availability and leptin...
AgRP neurons in the arcuate nucleus of the hypothalamus (ARC) coordinate homeostatic changes in appetite associated with fluctuations in food availability and leptin signaling. Identifying the relevant transcriptional regulatory pathways in these neurons has been a priority, yet such attempts have been stymied due to their low abundance and the rich cellular diversity of the ARC. Here we generated AgRP neuron-specific transcriptomic and chromatin accessibility profiles from male mice during three distinct hunger states of satiety, fasting-induced hunger, and leptin-induced hunger suppression. Cis-regulatory analysis of these integrated datasets enabled the identification of 18 putative hunger-promoting and 29 putative hunger-suppressing transcriptional regulators in AgRP neurons, 16 of which were predicted to be transcriptional effectors of leptin. Within our dataset, Interferon regulatory factor 3 (IRF3) emerged as a leading candidate mediator of leptin-induced hunger-suppression. Measures of IRF3 activation in vitro and in vivo reveal an increase in IRF3 nuclear occupancy following leptin administration. Finally, gain- and loss-of-function experiments in vivo confirm the role of IRF3 in mediating the acute satiety-evoking effects of leptin in AgRP neurons. Thus, our findings identify IRF3 as a key mediator of the acute hunger-suppressing effects of leptin in AgRP neurons.
Topics: Animals; Male; Mice; Agouti-Related Protein; Arcuate Nucleus of Hypothalamus; Fasting; Gene Expression Regulation; Hunger; Interferon Regulatory Factor-3; Leptin; Mice, Inbred C57BL; Neurons; Signal Transduction; Transcriptome; Chromatin; Epigenesis, Genetic
PubMed: 38821928
DOI: 10.1038/s41467-024-48885-y -
Journal of Cellular and Molecular... Jun 2024The Finkel-Biskis-Jinkins Osteosarcoma (c-Fos; encoded by FOS) plays an important role in several cardiovascular diseases, including atherosclerosis and stroke. However,...
The Finkel-Biskis-Jinkins Osteosarcoma (c-Fos; encoded by FOS) plays an important role in several cardiovascular diseases, including atherosclerosis and stroke. However, the relationship between FOS and venous thromboembolism (VTE) remains unknown. We identified differentially expressed genes in Gene Expression Omnibus dataset, GSE48000, comprising VTE patients and healthy individuals, and analysed them using CIBERSORT and weighted co-expression network analysis (WGCNA). FOS and CD46 expressions were significantly downregulated (FOS p = 2.26E-05, CD64 p = 8.83E-05) and strongly linked to neutrophil activity in VTE. We used GSE19151 and performed PCR to confirm that FOS and CD46 had diagnostic potential for VTE; however, only FOS showed differential expression by PCR and ELISA in whole blood samples. Moreover, we found that hsa-miR-144 which regulates FOS expression was significantly upregulated in VTE. Furthermore, FOS expression was significantly downregulated in neutrophils of VTE patients (p = 0.03). RNA sequencing performed on whole blood samples of VTE patients showed that FOS exerted its effects in VTE via the leptin-mediated adipokine signalling pathway. Our results suggest that FOS and related genes or proteins can outperform traditional clinical markers and may be used as diagnostic biomarkers for VTE.
Topics: Humans; MicroRNAs; Neutrophils; Venous Thromboembolism; Computational Biology; Proto-Oncogene Proteins c-fos; Gene Expression Regulation; Male; Gene Expression Profiling; Gene Regulatory Networks; Female; Biomarkers
PubMed: 38818568
DOI: 10.1111/jcmm.18370