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Adeno-associated viruses (AAVs) have emerged as promising tools for gene therapy due to their safety and efficacy in delivering therapeutic genes or gene editing sequences to various tissues and organs. AAV serotype 9 (AAV9), among AAV serotypes, stands out for its ability to efficiently target multiple tissues, thus holding significant potential for clinical applications. However, existing methods for purifying AAVs are cumbersome, expensive, and often yield inconsistent results. In this study, we explore a novel purification strategy utilizing Dynabeads™ CaptureSelect™ magnetic beads. The AAV9 magnetic beads capture AAV9 with high specificity and recovery between 70 and 90%, whereas the AAVX magnetic beads did not bind to the AAV9. Through continuous interaction with AAVs in solution, these beads offer enhanced clearance of genomic DNA and plasmids even in the absence of endonuclease. The beads could be regenerated at least eight times, and the used beads could be stored for up to six months and reused without a significant reduction in recovery. The potency of the AAV9-purified vectors in vivo was comparable to that of iodixanol purified vectors. [ABSTRACT FROM AUTHOR]

Recent research into laminopathic lipodystrophies—rare genetic disorders caused by mutations in the LMNA gene—has greatly expanded our knowledge of their complex pathology and metabolic implications. These disorders, including Hutchinson-Gilford progeria syndrome (HGPS), Mandibuloacral Dysplasia (MAD), and Familial Partial Lipodystrophy (FPLD), serve as crucial models for studying accelerated aging and metabolic dysfunction, enhancing our understanding of the cellular and molecular mechanisms involved. Research on laminopathies has highlighted how LMNA mutations disrupt adipose tissue function and metabolic regulation, leading to altered fat distribution and metabolic pathway dysfunctions. Such insights improve our understanding of the pathophysiological interactions between genetic anomalies and metabolic processes. This review merges current knowledge on the phenotypic classifications of these diseases and their associated metabolic complications, such as insulin resistance, hypertriglyceridemia, hepatic steatosis, and metabolic syndrome, all of which elevate the risk of cardiovascular disease, stroke, and diabetes. Additionally, a range of published therapeutic strategies, including gene editing, antisense oligonucleotides, and novel pharmacological interventions aimed at addressing defective adipocyte differentiation and lipid metabolism, will be explored. These therapies target the core dysfunctional lamin A protein, aiming to mitigate symptoms and provide a foundation for addressing similar metabolic and genetic disorders. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is the most common liver disorder worldwide, with an estimated global prevalence of more than 31%. Metabolic dysfunction-associated steatohepatitis (MASH), formerly known as non-alcoholic steatohepatitis (NASH), is a progressive form of MASLD characterized by hepatic steatosis, inflammation, and fibrosis. This review aims to provide a comprehensive analysis of the extrahepatic manifestations of MASH, focusing on chronic diseases related to the cardiovascular, muscular, and renal systems. A systematic review of published studies and literature was conducted to summarize the findings related to the systemic impacts of MASLD and MASH. The review focused on the association of MASLD and MASH with metabolic comorbidities, cardiovascular mortality, sarcopenia, and chronic kidney disease. Mechanistic insights into the concept of lipotoxic inflammatory "spill over" from the MASH-affected liver were also explored. MASLD and MASH are highly associated (50%-80%) with other metabolic comorbidities such as impaired insulin response, type 2 diabetes, dyslipidemia, hypertriglyceridemia, and hypertension. Furthermore, more than 90% of obese patients with type 2 diabetes have MASH. Data suggest that in middle-aged individuals (especially those aged 45-54), MASLD is an independent risk factor for cardiovascular mortality, sarcopenia, and chronic kidney disease. The concept of lipotoxic inflammatory "spill over" from the MASH-affected liver plays a crucial role in mediating the systemic pathological effects observed. Understanding the multifaceted impact of MASH on the heart, muscle, and kidney is crucial for early detection and risk stratification. This knowledge is also timely for implementing comprehensive disease management strategies addressing multiorgan involvement in MASH pathogenesis. [ABSTRACT FROM AUTHOR]

Background: The beneficial effects of fibroblast growth factor 21 (FGF21) and sodium butyrate (NaB) on protection against cholestasis-induced liver fibrosis are not well known. This study aimed to explore the effects of FGF21 and NaB on bile duct ligation (BDL)-induced liver fibrosis. Methods: Wild-type (WT) and FGF21 knockout (KO) mice received BDL surgery for 14 days. Liver fibrosis was assessed by Masson's staining for fibrosis marker expressions at the mRNA or protein levels. Adenovirus-mediated FGF21 overexpression in the WT mice was assessed against BDL damage. BDL surgeries were performed in WT and FGF21 KO mice that were administered either phosphate-buffered saline or NaB. The effects of NaB on the energy metabolism and gut microbiota were assessed using stable metabolism detection and 16S rRNA gene sequencing. Results: BDL-induced liver fibrosis in the WT mice was accompanied by high induction of FGF21. Compared to the WT mice, the FGF21 KO mice showed more severe liver fibrosis induced by BDL. FGF21 overexpression protected against BDL-induced liver fibrosis, as proved by the decreasing a-SMA at both the mRNA and protein levels. NaB administration enhanced the glucose and energy metabolisms as well as remodeled the gut microbiota. NaB alleviated BDL-induced liver fibrosis in the WT mice but aggravated the same in FGF21 KO mice. Conclusion: FGF21 plays a key role in alleviating cholestasis-induced liver damage and fibrosis. NaB has beneficial effects on cholestasis in an FGF21-dependent manner. NaB administration can thus be a novel nutritional therapy for treating cholestasis via boosting FGF21 signaling and regulating the gut microbiota. [ABSTRACT FROM AUTHOR]

Purpose: The potential efficacy of metformin in breast cancer (BC) has been hotly discussed but never conclusive. This genetics-based study aimed to evaluate the relationships between metformin targets and BC risk. Methods: Metformin targets from DrugBank and genome-wide association study (GWAS) data from IEU OpenGWAS and FinnGen were used to investigate the breast cancer (BC)-metformin causal link with various Mendelian Randomization (MR) methods (e.g., inverse-variance-weighting). The genetic association between type 2 diabetes (T2D) and the drug target of metformin was also analyzed as a positive control. Sensitivity and pleiotropic tests ensured reliability. Results: The primary targets of metformin are PRKAB1, ETFDH and GPD1L. We found a causal association between PRKAB1 and T2D (odds ratio [OR] 0.959, P = 0.002), but no causal relationship was observed between metformin targets and overall BC risk (PRKAB1: OR 0.990, P = 0.530; ETFDH: OR 0.986, P = 0.592; GPD1L: OR 1.002, P = 0.806). A noteworthy causal relationship was observed between ETFDH and estrogen receptor (ER)-positive BC (OR 0.867, P = 0.018), and between GPD1L and human epidermal growth factor receptor 2 (HER2)-negative BC (OR 0.966, P = 0.040). Other group analyses did not yield positive results. Conclusion: The star target of metformin, PRKAB1, does not exhibit a substantial causal association with the risk of BC. Conversely, metformin, acting as an inhibitor of ETFDH and GPD1L, may potentially elevate the likelihood of developing ER-positive BC and HER2-negative BC. Consequently, it is not advisable to employ metformin as a standard supplementary therapy for BC patients without T2D. [ABSTRACT FROM AUTHOR]

Obesity has become a pandemic, as currently more than half a billion people worldwide are obese. The etiology of obesity is multifactorial, and combines a contribution of hereditary and behavioral factors, such as nutritional inadequacy, along with the influences of environment and reduced physical activity. Two types of adipose tissue widely known are white and brown. While white adipose tissue functions predominantly as a key energy storage, brown adipose tissue has a greater mass of mitochondria and expresses the uncoupling protein 1 (UCP1) gene, which allows thermogenesis and rapid catabolism. Even though white and brown adipocytes are of different origin, activation of the brown adipocyte differentiation program in white adipose tissue cells forces them to transdifferentiate into "beige" adipocytes, characterized by thermogenesis and intensive lipolysis. Nowadays, researchers in the field of small molecule medicinal chemistry and gene therapy are making efforts to develop new drugs that effectively overcome insulin resistance and counteract obesity. Here, we discuss various aspects of white-to-beige conversion, adipose tissue catabolic re-activation, and non-shivering thermogenesis. [ABSTRACT FROM AUTHOR]

Vitamin D deficiency is very common worldwide, particularly in old age, when people are at the highest risk of the negative adverse consequences of hypovitaminosis D. Additionally to the recognized functions in the regulation of calcium absorption, bone remodeling, and bone growth, vitamin D plays a key role as a hormone, which is supported by various enzymatic, physiological, metabolic, and pathophysiological processes related to various human organs and systems. Accruing evidence supports that vitamin D plays a key role in pancreatic islet dysfunction and insulin resistance in type 2 diabetes. From an epidemiological viewpoint, numerous studies suggest that the growing incidence of type 2 diabetes in humans may be linked to the global trend of prevalent vitamin D insufficiency. In the past, this association has raised discussions due to the equivocal results, which lately have been more convincing of the true role of vitamin D supplementation in the prevention of incident type 2 diabetes. Most meta-analyses evaluating this role have been conducted in adults or young older persons (50–60 years old), with only one focusing on older populations, even if this is the population at greater risk of both hypovitaminosis D and type 2 diabetes. Therefore, we conducted an update of the previous systematic review and meta-analysis examining whether hypovitaminosis D (low serum 25OHD levels) can predict incident diabetes in prospective longitudinal studies among older adults. We found that low 25OHD was associated with incident diabetes in older adults even after adjusting for several relevant potential confounders, confirming and updating the results of the only previous meta-analysis conducted in 2017. [ABSTRACT FROM AUTHOR]

Adipose tissue is a multifunctional organ that regulates many physiological processes such as energy homeostasis, nutrition, the regulation of insulin sensitivity, body temperature, and immune response. In this review, we highlight the relevance of the different mediators that control adipose tissue activity through a systematic review of the main players present in white and brown adipose tissues. Among them, inflammatory mediators secreted by the adipose tissue, such as classical adipokines and more recent ones, elements of the immune system infiltrated into the adipose tissue (certain cell types and interleukins), as well as the role of intestinal microbiota and derived metabolites, have been reviewed. Furthermore, anti-obesity mediators that promote the activation of beige adipose tissue, e.g., myokines, thyroid hormones, amino acids, and both long and micro RNAs, are exhaustively examined. Finally, we also analyze therapeutic strategies based on those mediators that have been described to date. In conclusion, novel regulators of obesity, such as microRNAs or microbiota, are being characterized and are promising tools to treat obesity in the future. [ABSTRACT FROM AUTHOR]

Background: Increasing evidence indicates that immune response underlies the pathology of type 2 diabetes (T2D). Nevertheless, the specific inflammatory regulators involved in this pathogenesis remain unclear. Methods: We systematically explored circulating inflammatory proteins that are causally associated with T2D via a bidirectional Mendelian randomization (MR) study and further investigated them in prevalent complications of T2D. Genetic instruments for 91 circulating inflammatory proteins were derived from a genome-wide association study (GWAS) that enrolled 14,824 predominantly European participants. Regarding the summary-level GWASs of type 2 diabetes, we adopted the largest meta-analysis of European population (74,124 cases vs. 824,006 controls) and a prospective nested case-cohort study in Europe (9,978 cases vs. 12,348 controls). Summary statistics for five complications of T2D were acquired from the FinnGen R9 repository. The inverse variance-weighted method was applied as the primary method for causal inference. MR-Egger, weighted median and maximum likelihood methods were employed as supplementary analyses. Results from the two T2D studies were combined in a meta-analysis. Sensitivity analyses and phenotypewide association studies (PheWAS) were performed to detect heterogeneity and potential horizontal pleiotropy in the study. Results: Genetic evidence indicated that elevated levels of TGF-a (OR = 1.16, 95% CI = 1.15-1.17) and CX3CL1 (OR = 1.30, 95% CI = 1.04-1.63) promoted the occurrence of T2D, and increased concentrations of FGF-21 (OR = 0.87, 95% CI = 0.81-0.93) and hGDNF (OR = 0.96, 95% CI = 0.95-0.98) mitigated the risk of developing T2D, while type 2 diabetes did not exert a significant influence on said proteins. Elevated levels of TGF-a were associated with an increased risk of ketoacidosis, neurological complications, and ocular complications in patients with T2D, and increased concentrations of FGF-21 were potentially correlated with a diminished risk of T2D with neurological complications. Higher levels of hGDNF were associated with an increased risk of T2D with peripheral vascular complications, while CX3CL1 did not demonstrate a significant association with T2D complications. Sensitivity analyses and PheWAS further ensure the robustness of our findings. Conclusion: This study determined four circulating inflammatory proteins that affected the occurrence of T2D, providing opportunities for the early prevention and innovative therapy of type 2 diabetes and its complications. [ABSTRACT FROM AUTHOR]

Exercise has many beneficial effects that provide health and metabolic benefits. Signaling molecules are released from organs and tissues in response to exercise stimuli and are widely termed exerkines, which exert influence on a multitude of intricate multi-tissue processes, such as muscle, adipose tissue, pancreas, liver, cardiovascular tissue, kidney, and bone. For the metabolic effect, exerkines regulate the metabolic homeostasis of organisms by increasing glucose uptake and improving fat synthesis. For the anti-inflammatory effect, exerkines positively influence various chronic inflammation-related diseases, such as type 2 diabetes and atherosclerosis. This review highlights the prospective contribution of exerkines in regulating metabolism, augmenting the anti-inflammatory effects, and providing additional advantages associated with exercise. Moreover, a comprehensive overview and analysis of recent advancements are provided in this review, in addition to predicting future applications used as a potential biomarker or therapeutic target to benefit patients with chronic diseases. [ABSTRACT FROM AUTHOR]

Introduction: Herbal medicines are commonly used by many people with diabetes in addition to standard treatment. Plants contain numerous known and unknown compounds that may exacerbate or ameliorate diabetes complications. Therefore, it is crucial to be aware of the side effects of these herbs before prescribing them. This study aimed to investigate the effects of hydroalcoholic extracts of Securigera securidaca (HESS) seeds alone and in combination with glibenclamide on the angiogenic/anti-angiogenic balance in streptozotocin (STZ)-induced diabetic rats. Methods: Groups involved in this animal study included diabetic and healthy controls, three doses of HESS, glibenclamide, and combination therapy. Serum samples were collected and analyzed for a vascular endothelial growth factor (VEGF), fibroblast growth factor 21 (FGF21), fetal liver kinase 1 (FLK-1), soluble fms-like tyrosine kinase 1 (sFLT-1), and transforming growth factor -beta (TGF-β). Results: Induction of diabetes increased VEGF, FGF21, and TGF-β serum levels and decreased circulating FLK-1 and sFLT-1 factors. Herbal extract, except TGF-β, had little effect on the above blood levels even at the highest doses. Glibenclamide was more effective than the highest dose of HESS in improving the vascular complications of diabetes. Combination therapy with the highest dose of HESS partly enhanced the glibenclamide effects. Conclusion: Compared with glibenclamide as a standard chemical drug, HESS had no significant effects on the blood levels of the pro/anti-angiogenesis factor in diabetic rats. Glibenclamide attenuated the levels of the biomarkers and its effects were somewhat enhanced in combination with the highest dose of HESS. [ABSTRACT FROM AUTHOR]

Tuberculosis patients with diabetes, have higher sputum baciUary load, delayed sputum conversion, higher rates of drug resistance, higher lung cavitary involvement and extra-pulmonary TB infection, which is called as "Diabetes-Tuberculosis Nexus". However, recently we have shown a reciprocal relationship between latent tuberculosis infection and insulin resistance, which has not been reported before. In this review, we would first discuss about the immune-endocrine network, which operates during pre-diabetes and incipient diabetes and how it confers protection against LTBI. The ability of IR to augment anti-TB immunity and the immunomodulatory effect of LTBI to quench IR were discussed, under IR-LTB antagonism. The ability of diabetes to impair anti-TB immunity and ability of active TB to worsen glycemic control, were discussed under "Diabetes-Tuberculosis Synergy". The concept of "Fighter Genes" and how they confer protection against TB but susceptibility to IR was elaborated. Finally, we conclude with an evolutionary perspective about how IR and LTBI co-evolved in endemic zones, and have explained the molecular basis of "IR-LTB" Antagonism" and "DM-TB Synergy", from an evolutionary perspective. [ABSTRACT FROM AUTHOR]

The concurrent research compares the results of a geodetic baseline through Global Navigation Satellite System (GNSS) measurements with low-cost GNSS receivers, geodetic receivers, and additional electronic distance measurements (EDM) with a total station, in order to determine whether low-cost GNSS receivers and antennas are suitable for topographic–geodetic work depending on the precision obtained. Fifteen different campaigns were carried out (October 4–8, 2022) with five different combinations of receivers and antennas for the establishment of the baseline: geodetic GNSS equipment–geodetic GNSS equipment, geodetic GNSS equipment–low-cost GNSS kit, low-cost GNSS kit–geodetic GNSS equipment, low-cost GNSS receiver with geodetic antenna–low-cost GNSS receiver with geodetic antenna, and low-cost GNSS kit–low-cost GNSS kit. It is important to note that the low-cost GNSS kit includes the C099-F9P application board for ZED-F9P of U-Blox with patch antenna U-Blox ANN-MB-00 multiband GNSS antenna and ground plane. Similarly, another EDM campaign was realized (October 10, 2022) in order to carry out a statistical hypothesis test related to the length calculated through static relative positioning. The results show that all combinations fit with a certainty of 95% of similarity to the length of the EDM (39.6116 m) showing differences up to 5.1 mm. In relation to the coordinates, the maximum variations were found to be less than 1.2 cm and the azimuth showed similitude between them, which demonstrates that the distances, coordinates, and orientations are consistent with the final solutions of the geodetic GNSS equipment. [ABSTRACT FROM AUTHOR]

Background: Aging is a holistic change that has a major impact on the immune system, and immunosenescence contributes to the overall progression of aging. The bone marrow is the most important hematopoietic immune organ, while the spleen, as the most important extramedullary hematopoietic immune organ, maintains homeostasis of the human hematopoietic immune system (HIS) in cooperation with the bone marrow. However, the overall changes in the HIS during aging have not been described. Here, we describe a hematopoietic immune map of the spleen and bone marrow of young and old mice using single-cell sequencing and flow cytometry techniques. Results: We observed extensive, complex changes in the HIS during aging. Compared with young mice, the immune cells of aged mice showed a marked tendency toward myeloid differentiation, with the neutrophil population accounting for a significant proportion of this response. In this change, hypoxia-inducible factor 1-alpha (Hif1α) was significantly overexpressed, and this enhanced the immune efficacy and inflammatory response of neutrophils. Our research revealed that during the aging process, hematopoietic stem cells undergo significant changes in function and composition, and their polymorphism and differentiation abilities are downregulated. Moreover, we found that the highly responsive CD62L + HSCs were obviously downregulated in aging, suggesting that they may play an important role in the aging process. Conclusions: Overall, aging extensively alters the cellular composition and function of the HIS. These findings could potentially give high-dimensional insights and enable more accurate functional and developmental analyses as well as immune monitoring in HIS aging. [ABSTRACT FROM AUTHOR]

The improvement of human living conditions has led to an increase in average life expectancy, creating a new social and medical problem—aging, which diminishes the overall quality of human life. The aging process of the body begins with the activation of effector signaling pathways of aging in cells, resulting in the loss of their normal functions and deleterious effects on the microenvironment. This, in turn, leads to chronic inflammation and similar transformations in neighboring cells. The cumulative retention of these senescent cells over a prolonged period results in the deterioration of tissues and organs, ultimately leading to a reduced quality of life and an elevated risk of mortality. Among the most promising methods for addressing aging and age-related illnesses are pharmacological, genetic, and cellular therapies. Elevating the activity of aging-suppressing genes, employing specific groups of native and genetically modified cells, and utilizing senolytic medications may offer the potential to delay aging and age-related ailments over the long term. This review explores strategies and advancements in the field of anti-aging therapies currently under investigation, with a particular emphasis on gene therapy involving adeno-associated vectors and cell-based therapeutic approaches. [ABSTRACT FROM AUTHOR]

Aims: Recent years have witnessed an increasing research interest in the roles of transcription factor (TF)-gene regulatory network in type 2 diabetes mellitus (T2DM). Thus, we sought to characterize the mechanistic insights based on the TF-gene regulatory network in skeletal muscle atrophy in T2DM. Methods: Differentially expressed TFs (DETFs) and mRNAs (DEmRNAs) were obtained in T2DM-related gene expression profiles (GSE12643, GSE55650, GSE166502, and GSE29221), followed by WGCNA, and GO and KEGG enrichment analyses. Next, the iRegulon plug-in unit of Cytoscape software was used to construct a TF-mRNA regulatory network. Besides, RT-qPCR and ChIP-seq were utilized to measure the expression of CEBPA and FGF21 in the skeletal muscle tissues or cells of T2DM rat models. At last, the effect of overexpression of FGF21 on the autophagy-lysosomal pathway was examined in skeletal muscle cells of T2DM rats. Results: Totally, 12 DETFs and 102 DEmRNAs were found in the skeletal muscle tissues of T2DM samples. The DEmRNAs were mainly enriched in the autophagy-lysosomal pathway. CEBPA affected the skeletal muscle atrophy in T2DM by regulating 5 target genes via the autophagy-lysosomal pathway. CEBPA could target FGF21. In addition, the expression of CEBPA was elevated, while the expression of FGF21 was diminished in the skeletal muscle tissues or cells of T2DM rats. The CEBPA-FGF21 regulatory network promoted skeletal muscle atrophy in T2DM by activating the autophagy-lysosomal pathway. Conclusion: The CEBPA-FGF21 regulatory network may participate in the T2DM-induced skeletal muscle atrophy by regulating the autophagy-lysosomal pathway. Thus, our study provides interesting targets for prevention of skeletal muscle atrophy in T2DM. [ABSTRACT FROM AUTHOR]

Accumulating evidence supports that physical exercise (EX) is the most effective non-pharmacological strategy to improve brain health. EX prevents cognitive decline associated with age and decreases the risk of developing neurodegenerative diseases and psychiatric disorders. These positive effects of EX can be attributed to an increase in neurogenesis and neuroplastic processes, leading to learning and memory improvement. At the molecular level, there is a solid consensus to involve the neurotrophin brain-derived neurotrophic factor (BDNF) as the crucial molecule for positive EX effects on the brain. However, even though EX incontestably leads to beneficial processes through BDNF expression, cellular sources and molecular mechanisms underlying EX-induced cerebral BDNF overproduction are still being elucidated. In this context, the present review offers a summary of the different molecular mechanisms involved in brain’s response to EX, with a specific focus on BDNF. It aims to provide a cohesive overview of the three main mechanisms leading to EX-induced brain BDNF production: the neuronal-dependent overexpression, the elevation of cerebral blood flow (hemodynamic hypothesis), and the exerkine signaling emanating from peripheral tissues (humoral response). By shedding light on these intricate pathways, this review seeks to contribute to the ongoing elucidation of the relationship between EX and cerebral BDNF expression, offering valuable insights into the potential therapeutic implications for brain health enhancement. [ABSTRACT FROM AUTHOR]

Obesity has become a global epidemic, contributing to the development of numerous chronic diseases, including diabetes, chronic kidney disease (CKD) and cardiovascular disorders. MicroRNAs (miRNAs) have emerged as key regulators in various biological processes, including metabolism, inflammation, and tissue remodeling, making them pivotal players in obesity-related pathologies. This review aims to provide comprehensive insights into the roles of miRNAs in obesity, with a particular emphasis on their involvement in the pathogenesis of CKD and cardiovascular disorders. We highlight the involvement of specific miRNAs in adipose tissue development, energy homeostasis, inflammation, and insulin resistance, contributing to the pathogenesis of obesity. Moreover, we explore the impact of miRNAs on renal fibrosis and inflammation, giving clues on their roles in the development and progression of CKD. Additionally, we discuss the influence of miRNAs on endothelial dysfunction, atherosclerosis, and cardiac remodeling, emphasizing their contribution to obesity-related cardiovascular disorders. Understanding the regulatory functions of miRNAs in these interconnected conditions holds promise for improved diagnosis, prognosis, and therapeutic interventions. Indeed, miRNAs are potential diagnostic biomarkers for obesity-related diseases, although challenges remain to be elucidated before their clinical translation. Furthermore, we highlight the emerging strategies that target miRNAs as therapeutic interventions to mitigate the detrimental effects of obesity on kidney and cardiovascular health. [ABSTRACT FROM AUTHOR]

Maintaining systemic homeostasis requires the coordination of different organs and tissues in the body. Our bodies rely on complex inter-organ communications to adapt to perturbations or changes in metabolic homeostasis. Consequently, the liver, muscle, and adipose tissues produce and secrete specific organokines such as hepatokines, myokines, and adipokines in response to nutritional and environmental stimuli. Emerging evidence suggests that dysregulation of the interplay of organokines between organs is associated with the pathophysiology of obesity and type 2 diabetes (T2D). Strategies aimed at remodeling organokines may be effective therapeutic interventions. Diet modification and exercise have been established as the first-line therapeutic intervention to prevent or treat metabolic diseases. This review summarizes the current knowledge on organokines secreted by the liver, muscle, and adipose tissues in obesity and T2D. Additionally, we highlighted the effects of diet/nutrition and exercise on the remodeling of organokines in obesity and T2D. Specifically, we investigated the ameliorative effects of caloric restriction, selective nutrients including ω3 PUFAs, selenium, vitamins, and metabolites of vitamins, and acute/chronic exercise on the dysregulation of organokines in obesity and T2D. Finally, this study dissected the underlying molecular mechanisms by which nutrition and exercise regulate the expression and secretion of organokines in specific tissues. [ABSTRACT FROM AUTHOR]

Metabolic syndrome is a complex metabolic disorder that often clinically manifests as obesity, insulin resistance/diabetes, hyperlipidemia, and hypertension. With the development of social and economic systems, the incidence of metabolic syndrome is increasing, bringing a heavy medical burden. However, there is still a lack of effective prevention and treatment strategies. Fibroblast growth factor 21 (FGF21) is a member of the human FGF superfamily and is a key protein involved in the maintenance of metabolic homeostasis, including reducing fat mass and lowering hyperglycemia, insulin resistance and dyslipidemia. Here, we review the current regulatory mechanisms of FGF21, summarize its role in obesity, diabetes, hyperlipidemia, and hypertension, and discuss the possibility of FGF21 as a potential target for the treatment of metabolic syndrome. [ABSTRACT FROM AUTHOR]

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Background: Polycystic ovary syndrome (PCOS) women have high incidences of dyslipidemia, obesity, impaired glucose tolerance (IGT), diabetes, and insulin resistance (IR) and are fragile to female infertility. Obesity and dyslipidemia may be the intermediate biological mechanism for the associations between glucose metabolism dysfunction and abnormal oogenesis and embryogenesis. Methods: This retrospective cohort study was performed at a university-affiliated reproductive center. A total of 917 PCOS women aged between 20 and 45 undergoing their first IVF/ICSI embryo transfer cycles from January 2018 to December 2020 were involved. Associations between glucose metabolism indicators, adiposity and lipid metabolism indicators, and IVF/ICSI outcomes were explored using multivariable generalized linear models. Mediation analyses were further performed to examine the potential mediation role of adiposity and lipid metabolism indicators. Results: Significant dose-dependent relationships were found between glucose metabolism indicators and IVF/ICSI early reproductive outcomes and between glucose metabolism indicators and adiposity and lipid metabolism indicators (all P < 0.05). Also, we found significant dose-dependent relationships between adiposity and lipid metabolism indicators and IVF/ICSI early reproductive outcomes (all P < 0.05). The mediation analysis indicated that elevated FPG, 2hPG, FPI, 2hPI, HbA1c, and HOMA2-IR were significantly associated with decreased retrieved oocyte count, MII oocyte count, normally fertilized zygote count, normally cleaved embryo count, high-quality embryo count, or blastocyst formation count after controlling for adiposity and lipid metabolism indicators. Serum TG mediated 6.0–31.0% of the associations; serum TC mediated 6.1–10.8% of the associations; serum HDL-C mediated 9.4–43.6% of the associations; serum LDL-C mediated 4.2–18.2% of the associations; and BMI mediated 26.7–97.7% of the associations. Conclusions: Adiposity and lipid metabolism indicators (i.e., serum TG, serum TC, serum HDL-C, serum LDL-C, and BMI) are significant mediators of the effect of glucose metabolism indicators on IVF/ICSI early reproductive outcomes in PCOS women, indicating the importance of preconception glucose and lipid management and the dynamic equilibrium of glucose and lipid metabolism in PCOS women. [ABSTRACT FROM AUTHOR]

Background: Skeletal muscle‐secreted myokines widely participate in lipids metabolism through autocrine, paracrine and endocrine actions. The myokines represented by FGF21 and Irisin can promote the browning of adipocytes and serve as promising targets for treating obesity. Although recombinant myokines replacement therapy and AAV (adeno‐associated virus)‐based myokines overexpression have shown a definite effect in ameliorating obesity, novel myokine activation strategies with higher efficacy and safety are still in pressing need. This study aimed to evaluate the therapeutic potential of a novel CRISPR‐based myokines activation strategy in obesity treatments. Methods: In this study, we used lentivirus and a single AAV vector containing dCas9‐VP64 with a single‐guide RNA to selectively activate Fgf21 and Fndc5 expression in skeletal muscles both in vitro and in vivo. The activation efficacy of the CRISPRa system was determined by qRT‐PCR, Western blotting and ELISA. The treatment effect of CRISPR‐based myokines activation was tested in 3T3‐L1‐derived adipocytes and diet‐induced obese (DIO) mice (male C57BL/6 mice, induced at 6‐week‐old for 10 weeks). Results: The virus upregulates myokines expression in both mRNA and protein levels of muscle cells in vitro and in vivo. Myokines secreted by muscle cells promoted browning of 3T3‐L1‐derived adipocytes. In vivo activation of myokines by AAVs can reduce body weight and fat mass, increase the adipocytes browning and improve glucose tolerance and insulin sensitivity in DIO mice. Conclusions: Our study provides a novel CRISPR‐based myokines activation strategy that can ameliorate obesity by promoting adipocytes browning. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) is related with the incidence of sarcopenia and cognitive impairment that reduces quality of life in the elderly. Recent evidence has demonstrated that sarcopenia is associated with cognitive dysfunction, and muscle-derived endocrine factors might contribute to cognitive function by the skeletal muscle–brain endocrine loop. This study investigated the beneficial effects of Annona muricata (AM, graviola) on multi-organ energy metabolism with muscle–brain connectivity via brain function-related myokines in mice. Body composition, fasting blood glucose level, insulin, HbA1c%, histopathological changes, and the protein levels of insulin-signaling, energy metabolism, neuroprotection, inflammation, and protein-degradation pathways were measured. AM extract (AME) treatment selectively enhanced insulin signaling in the skeletal muscle and hippocampus of T2DM mice. Furthermore, AME treatment effectively increased muscle-derived fibroblast growth factor 21 (FGF21), cathepsin-B (CTSB), irisin, brain-derived neurotrophic factor (BDNF), and liver-derived FGF21 that contribute to whole-body energy homeostasis. In particular, AME increased the levels of circulating myokines (FGF21, BDNF, irisin, and CTSB), and these were accordance with the hippocampal neurotrophic factors (BDNF and CTSB) in T2DM mice. In conclusion, we suggest that AME would be a potential nutraceutical for improving the energy metabolism associated with muscle–brain connectivity via brain function-related myokines in T2DM. [ABSTRACT FROM AUTHOR]

Background: Accumulating studies suggested that major depressive disorder (MDD) was closely related to metabolic syndrome (MetS). Important endogenous regulators fibroblast growth factors (FGFs) 19 and 21 were also reported to participate in psychiatric disorders. This study aimed to investigate the role of FGF19 and FGF21 in MDD and to explore the possible pathogenic mechanism of metabolic and cognitive dysregulation in depression. Methods: A total of 59 MDD patients and 55 healthy control participants were recruited. The serum levels of FGF19 and FGF21 and lipid profiles were measured by means of enzymatic methods. Cognitive function was measured by repeatable battery for the assessment of neuropsychological status (RBANS) scores. The gene expression of PGC-1α and FNDC5 was determined by quantitative polymerase chain reaction (PCR). Results: We found that plasma FGF19 and FGF21 levels were significantly decreased in patients with MDD. Meanwhile, triglyceride (TG) was significantly elevated and PGC-1α was significantly downregulated in MDD patients. Correlation analyses showed negative associations between TG and FGF19 levels. As for cognitive performance, both FGF19 and FGF21 levels were positively correlated with immediate memory. However, FGF19 levels were negatively correlated with language, and FGF21 levels were also negatively correlated with attention and delayed memory. Additionally, negative associations were found between FGF19 levels and PGC-1α. FGF21 levels were positively associated with PGC-1α and negatively associated with FNDC5. Conclusion: This study elucidated the role of FGF19 and FGF21 in MDD. MDD patients were confirmed to have metabolic and cognitive dysregulation, and this abnormality was linked to the decreased concentrations of FGF19 and FGF21 through the PGC-1α/FNDC5 pathway. Our results showed that the alterations of FGF19 and FGF21 levels may be a common pathogenic mechanism of metabolic and cognitive disturbances in patients with MDD. [ABSTRACT FROM AUTHOR]

Introduction: Autophagy, an innate safeguard mechanism for protecting the organism against harmful agents, is implicated in the survival of pancreatic â cells and the development of type 2 diabetes mellitus (T2DM). Potential autophagyrelated genes (ARGs) may serve as potential biomarkers for T2DM treatment. Methods: The GSE25724 dataset was downloaded from the Gene Expression Omnibus (GEO) database, and ARGs were obtained from the Human Autophagy Database. The differentially expressed autophagy-related genes (DEARGs) were screened at the intersection of ARGs and differentially expressed genes (DEGs) between T2DM and non-diabetic islet samples, which were subjected to functional enrichment analyses. A protein-protein interaction (PPI) network was constructed to identify hub DEARGs. Expressions of top 10 DEARGs were validated in human pancreatic â-cell line NES2Y and rat pancreatic INS-1 cells using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Cell viability and insulin secretion were measured after cell transfection with lentiviral vector EIF2AK3 or RB1CC1 into islet cells. Results: In total, we discovered 1,270 DEGs (266 upregulated and 1,004 downregulated genes) and 30 DEARGs enriched in autophagy- and mitophagy-related pathways. In addition, we identified GAPDH, ITPR1, EIF2AK3, FOXO3, HSPA5, RB1CC1, LAMP2, GABARAPL2, RAB7A, and WIPI1 genes as the hub ARGs. Next, qRT-PCR analysis revealed that expressions of hub DEARGs were consistent with findings from bioinformatics analysis. EIF2AK3, GABARAPL2, HSPA5, LAMP2, and RB1CC1 were both differentially expressed in the two cell types. Overexpression of EIF2AK3 or RB1CC1 promoted cell viability of islet cells and increased the insulin secretion. Discussion: This study provides potential biomarkers as therapeutic targets for T2DM. [ABSTRACT FROM AUTHOR]

Over the last decades, epidemiology and functional studies have started to reveal a pivotal role of vitamin D in both type 1 and type 2 diabetes pathogenesis. Acting through the vitamin D receptor (VDR), vitamin D regulates insulin secretion in pancreatic islets and insulin sensitivity in multiple peripheral metabolic organs. In vitro studies and both T1D and T2D animal models showed that vitamin D can improve glucose homeostasis by enhancing insulin secretion, reducing inflammation, reducing autoimmunity, preserving beta cell mass, and sensitizing insulin action. Conversely, vitamin D deficiency has been shown relevant in increasing T1D and T2D incidence. While clinical trials testing the hypothesis that vitamin D improves glycemia in T2D have shown conflicting results, subgroup and meta-analyses support the idea that raising serum vitamin D levels may reduce the progression from prediabetes to T2D. In this review, we summarize current knowledge on the molecular mechanisms of vitamin D in insulin secretion, insulin sensitivity, and immunity, as well as the observational and interventional human studies investigating the use of vitamin D as a treatment for diabetes. [ABSTRACT FROM AUTHOR]

Diabetes is a chronic disease that affects glucose metabolism, either by autoimmune-driven β-cell loss or by the progressive loss of β-cell function, due to continued metabolic stresses. Although both α- and β-cells are exposed to the same stressors, such as proinflammatory cytokines and saturated free fatty acids (e.g., palmitate), only α-cells survive. We previously reported that the abundant expression of BCL-XL, an anti-apoptotic member of the BCL-2 family of proteins, is part of the α-cell defense mechanism against palmitate-induced cell death. Here, we investigated whether BCL-XL overexpression could protect β-cells against the apoptosis induced by proinflammatory and metabolic insults. For this purpose, BCL-XL was overexpressed in two β-cell lines—namely, rat insulinoma-derived INS-1E and human insulin-producing EndoC-βH1 cells—using adenoviral vectors. We observed that the BCL-XL overexpression in INS-1E cells was slightly reduced in intracellular Ca2+ responses and glucose-stimulated insulin secretion, whereas these effects were not observed in the human EndoC-βH1 cells. In INS-1E cells, BCL-XL overexpression partially decreased cytokine- and palmitate-induced β-cell apoptosis (around 40% protection). On the other hand, the overexpression of BCL-XL markedly protected EndoC-βH1 cells against the apoptosis triggered by these insults (>80% protection). Analysis of the expression of endoplasmic reticulum (ER) stress markers suggests that resistance to the cytokine and palmitate conferred by BCL-XL overexpression might be, at least in part, due to the alleviation of ER stress. Altogether, our data indicate that BCL-XL plays a dual role in β-cells, participating both in cellular processes related to β-cell physiology and in fostering survival against pro-apoptotic insults. [ABSTRACT FROM AUTHOR]

Increasing evidence suggests that insulin resistance in type 2 diabetes mellitus (T2DM) is associated with mitochondrial dysfunction in skeletal muscle, while the underlying molecular mechanisms remain elusive. This study aims to construct a ceRNA regulatory network that is involved in mitochondrial dysfunction of skeletal muscle in T2DM. Based on GEO database analysis, differentially expressed lncRNA and mRNA profiles were identified in skeletal muscle tissues of T2DM. Next, LASSO regression analysis was conducted to predict the key lncRNAs related to T2DM, which was validated by receiver operating characteristic (ROC) analysis. Moreover, the miRNAs related to skeletal muscle in T2DM were identified by WGCNA, followed by construction of gene–gene interaction network and GO and KEGG enrichment analyses. It was found that 12 lncRNAs and 6 miRNAs were related to skeletal muscle in T2DM. Moreover, the lncRNA-miRNA-mRNA ceRNA network involving UCA1, miR-143-3p, and FGF21 was constructed. UCA1, and FGF21 were downregulated, while miR-143-3p was upregulated in skeletal muscle cells (SkMCs) exposed to palmitic acid. Additionally, ectopic expression experiments were performed in SkMCs to confirm the effects of UCA1/miR-143-3p/FGF21 on mitochondrial dysfunction by determining mitochondrial ROS, oxygen consumption rate (OCR), membrane potential, and ATP level. Overexpression of miR-143-3p increased ROS accumulation and reduced the OCR, fluorescence ratio of JC-1, and ATP level, which were reversed by upregulation of UCA1 or FGF21. Collectively, lncRNA UCA1 inhibited mitochondrial dysfunction of skeletal muscle in T2DM by sequestering miR-143-3p away from FGF21, therefore providing a potential therapeutic target for alleviating mitochondrial dysfunction of skeletal muscle in T2DM. [ABSTRACT FROM AUTHOR]

Viral vectors have been used for a broad spectrum of gene therapy for both acute and chronic diseases. In the context of cancer gene therapy, viral vectors expressing anti-tumor, toxic, suicide and immunostimulatory genes, such as cytokines and chemokines, have been applied. Oncolytic viruses, which specifically replicate in and kill tumor cells, have provided tumor eradication, and even cure of cancers in animal models. In a broader meaning, vaccine development against infectious diseases and various cancers has been considered as a type of gene therapy. Especially in the case of COVID-19 vaccines, adenovirus-based vaccines such as ChAdOx1 nCoV-19 and Ad26.COV2.S have demonstrated excellent safety and vaccine efficacy in clinical trials, leading to Emergency Use Authorization in many countries. Viral vectors have shown great promise in the treatment of chronic diseases such as severe combined immunodeficiency (SCID), muscular dystrophy, hemophilia, β-thalassemia, and sickle cell disease (SCD). Proof-of-concept has been established in preclinical studies in various animal models. Clinical gene therapy trials have confirmed good safety, tolerability, and therapeutic efficacy. Viral-based drugs have been approved for cancer, hematological, metabolic, neurological, and ophthalmological diseases as well as for vaccines. For example, the adenovirus-based drug Gendicine® for non-small-cell lung cancer, the reovirus-based drug Reolysin® for ovarian cancer, the oncolytic HSV T-VEC for melanoma, lentivirus-based treatment of ADA-SCID disease, and the rhabdovirus-based vaccine Ervebo against Ebola virus disease have been approved for human use. [ABSTRACT FROM AUTHOR]

Vitamin D is a hormone involved in many physiological processes. Its active form, 1,25(OH)2D3, modulates serum calcium–phosphate homeostasis and skeletal homeostasis. A growing body of evidence has demonstrated the renoprotective effects of vitamin D. Vitamin D modulates endothelial function, is associated with podocyte preservation, regulates the renin–angiotensin–aldosterone system, and has anti-inflammatory effects. Diabetic kidney disease (DKD) is a leading cause of end-stage kidney disease worldwide. There are numerous studies supporting vitamin D as a renoprotector, potentially delaying the onset of DKD. This review summarizes the findings of current research on vitamin D and its role in DKD. [ABSTRACT FROM AUTHOR]

Progress has been made in identifying stem cell aging as a pathological manifestation of a variety of diseases, including obesity. Adipose stem cells (ASCs) play a core role in adipocyte turnover, which maintains tissue homeostasis. Given aberrant lineage determination as a feature of stem cell aging, failure in adipogenesis is a culprit of adipose hypertrophy, resulting in adiposopathy and related complications. In this review, we elucidate how ASC fails in entering adipogenic lineage, with a specific focus on extracellular signaling pathways, epigenetic drift, metabolic reprogramming, and mechanical stretch. Nonetheless, such detrimental alternations can be reversed by guiding ASCs towards adipogenesis. Considering the pathological role of ASC aging in obesity, targeting adipogenesis as an anti-obesity treatment will be a key area of future research, and a strategy to rejuvenate tissue stem cell will be capable of alleviating metabolic syndrome. [ABSTRACT FROM AUTHOR]

Endometrial cancer is becoming an increasing problem. Taking into account its pathomechanisms, we aimed to investigate whether FGF 21, an important metabolism regulator, could be used as a biomarker for endometrial cancer. The study included 233 patients who were classified into five subgroups depending on the result of the histological examination: endometrial carcinomas, sarcomas, endometrial polyps, fibroids, and normal endometrium. Statistically significantly higher FGF 21 levels were found in patients diagnosed with malignant lesions (p < 0.001). FGF 21 concentration correlated with the degree of cellular differentiation (p = 0.020) and the presence of lymph node metastases (p = 0.009). The diagnostic performance characteristics of FGF 21 as an EC diagnostic marker demonstrated an AUC of 0.677. Of all of the assessed biomarkers, FGF 21 had the highest specificity (90%), yet limited sensitivity (41%). Additionally, HE4 and CA 125 were confirmed to have roles as EC biomarkers, with a higher accuracy for HE4 (79% vs. 72%). [ABSTRACT FROM AUTHOR]

Background: Vitamin D deficiency (VDD) increases the risk for type 2 diabetes mellitus (T2DM), which might be related to insulin resistance (IR). We aimed to explore the association between the triglyceride-glucose (TyG) index, a reliable indicator of IR, and VDD in patients with T2DM. Methods: There were 1034 participants with T2DM enrolled in the Second Xiangya Hospital of Central South University. The TyG index was calculated as ln (fasting triglyceride (TG, mg/dL) × fasting blood glucose (mg/dL)/2). VDD was defined as 25-hydroxyvitamin D [25(OH)D] level <50 nmol/L. Results: Correlation analysis showed a negative association between the TyG index and 25(OH)D level. After adjustments for clinical and laboratory parameters, it was revealed that when taking the Q1 quartile of TyG index as a reference, an increasing trend of VDD prevalence was presented in the other three groups divided by TyG index quartiles, where the OR (95% CI) was 1.708 (1.132–2.576) for Q2, 2.041 (1.315–3.169) for Q3, and 2.543 (1.520–4.253) for Q4 (all p < 0.05). Conclusions: Patients with higher TyG index were more likely to have an increased risk of VDD in T2DM population, which may be related to IR. [ABSTRACT FROM AUTHOR]

Obesity causes metabolic disorders and is one of the important risk factors for diabetes. Myokines are widely involved in lipid metabolism through autocrine, paracrine and endocrine actions. FGF21 and Irisin, as representative myokines, can promote the browning of adipocytes and are potential targets for the treatment of obesity. This commentary discusses the research by Zhu et al. published in Clinical and Translational Medicine. In this study, the expression of FGF21 and FNDC5 is simultaneously activated by the CRISPRa system in vivo and in vitro. In vitro, the cell culture supernatant of C2C12 cells activated by the CRISPRa system significantly promoted the differentiation and browning of 3T3-L1 cells; in vivo, injecting of AAV9-dCas9-VP64 virus could significantly reduce the body weight and fat mass of DIO mice due to an increase in browning of adipocytes. [ABSTRACT FROM AUTHOR]

As an endocrine hormone, fibroblast growth factor 21 (FGF21) plays a crucial role in regulating lipid, glucose, and energy metabolism. Endogenous FGF21 is generated by multiple cell types but acts on restricted effector tissues, including the brain, adipose tissue, liver, heart, and skeletal muscle. Intervention with FGF21 in rodents or non-human primates has shown significant pharmacological effects on a range of metabolic dysfunctions, including weight loss and improvement of hyperglycemia, hyperlipidemia, insulin resistance, cardiovascular disease, and non-alcoholic fatty liver disease (NAFLD). Due to the poor pharmacokinetic and biophysical characteristics of native FGF21, long-acting FGF21 analogs and FGF21 receptor agonists have been developed for the treatment of metabolic dysfunction. Clinical trials of several FGF21-based drugs have been performed and shown good safety, tolerance, and efficacy. Here we review the actions of FGF21 and summarize the associated clinical trials in obesity, type 2 diabetes mellitus (T2DM), and NAFLD, to help understand and promote the development of efficient treatment for metabolic diseases via targeting FGF21. [ABSTRACT FROM AUTHOR]

Insulin resistance onset in skeletal muscle is characterized by the impairment of insulin signaling, which reduces the internalization of glucose, known as glucose uptake, into the cell. Therefore, there is a deficit of intracellular glucose, which is the main source for energy production in the cell. This may compromise cellular viability and functions, leading to pathological dysfunction. Skeletal muscle fibers continuously generate reactive oxygen and nitrogen species (RONS). An excess of RONS produces oxidative distress, which may evoke cellular damage and dysfunction. However, a moderate level of RONS, which is called oxidative eustress, is critical to maintain, modulate and regulate cellular functions through reversible interactions between RONS and the components of cellular signaling pathways that control those functions, such as the facilitation of glucose uptake. The skeletal muscle releases peptides called myokines that may have endocrine and paracrine effects. Some myokines bind to specific receptors in skeletal muscle fibers and might interact with cellular signaling pathways, such as PI3K/Akt and AMPK, and facilitate glucose uptake. In addition, there are cytokines, which are peptides produced by non-skeletal muscle cells, that bind to receptors at the plasma membrane of skeletal muscle cells and interact with the cellular signaling pathways, facilitating glucose uptake. RONS, myokines and cytokines might be acting on the same signaling pathways that facilitate glucose uptake in skeletal muscle. However, the experimental studies are limited and scarce. The aim of this review is to highlight the current knowledge regarding the role of RONS, myokines and cytokines as potential signals that facilitate glucose uptake in skeletal muscle. In addition, we encourage researchers in the field to lead and undertake investigations to uncover the fundamentals of glucose uptake evoked by RONS, myokines, and cytokines. [ABSTRACT FROM AUTHOR]

Fibroblast growth factor 21 (FGF-21) is a protein that is involved in the regulation of glucose, lipids, and energy metabolism. To act on target tissues, endocrine FGF-21 binds preferably to FGF receptor 1 (FGFR1) in the presence of the coreceptor named β-klotho (KLB). Some of the effects of FGF-21 include increased fatty acid oxidation, glucose uptake, insulin sensitivity, and thermogenesis, which can regulate body weight and glycemia control. By exerting such metabolic effects, the therapeutic potential of FGF-21 for the treatment of obesity and diabetes has been investigated. Physical exercise has been widely used for the prevention and treatment of obesity. Several mechanisms mediate the effects of physical exercise, including the FGF-21 pathway. Studies have shown that physical exercise increases the concentration of circulating and tissue FGF-21 in animals, while contradictory results are still observed in humans. Considering the metabolic role of FGF-21 and the chance of physical exercise to induce FGF-21 secretion, in this review we explore the potential of physical exercise-induced FGF-21 modulation as a strategy for prevention and treatment of obesity. [ABSTRACT FROM AUTHOR]

Elevated levels of circulating fibroblast growth factor 21 (FGF21) have been reported in patients with hyperuricemia. However, the effect of FGF21 in hyperuricemic nephropathy (HN) remains unexplored. Here, we investigated the effect and mechanism of action of FGF21 on HN. HN model was induced with adenine and potassium oxysalt in wild‐type C57BL/6 mice and FGF21−/− mice. For in vitro studies, human renal tubular epithelial (HK‐2) cells were exposed to uric acid with/without FGF21 or β‐Klotho‐siRNA. Here, we reported aggravated renal dysfunction and structural damage in the FGF21−/− mice compared to the wild‐type mice. These were evident in the upsurge of inflammatory factors IL‐1β, TNF‐α, IL‐6, and IL‐18; fibrotic markers Collagen I and α‐SMA; and oxidation products ROS and MDA. However, exogenous administration of FGF21 to wild‐type HN mice significantly reversed these negative effects. In terms of mechanism, FGF21 significantly inhibited NF‐κB/NLRP3 and TGF‐β1/Smad3 pathways and promoted nuclear translocation of Nrf2 both in vivo and in vitro. Furthermore, the silencing of β‐Klotho was marked by the attenuation of the improved effect of FGF21 on cell damage. In conclusion, our studies revealed that exogenous FGF21 treatment significantly improved HN, which was achieved by the inhibition of inflammation, fibrosis, and oxidative stress. [ABSTRACT FROM AUTHOR]

The prevalence of type 1 diabetes (T1D) is rising steadily. A potential contributor to the rise is vitamin D. In this systematic review, we examined the literature around vitamin D and T1D. We identified 22 papers examining the role of vitamin D in cultured β-cell lines, islets, or perfused pancreas, and 28 papers examining vitamin D in humans or human islets. The literature reports strong associations between T1D and low circulating vitamin D. There is also high-level (systematic reviews, meta-analyses) evidence that adequate vitamin D status in early life reduces T1D risk. Several animal studies, particularly in NOD mice, show harm from D-deficiency and benefit in most studies from vitamin D treatment/supplementation. Short-term streptozotocin studies show a β-cell survival effect with supplementation. Human studies report associations between VDR polymorphisms and T1D risk and β-cell function, as assessed by C-peptide. In view of those outcomes, the variable results in human trials are generally disappointing. Most studies using 1,25D, the active form of vitamin D were ineffective. Similarly, studies using other forms of vitamin D were predominantly ineffective. However, it is interesting to note that all but one of the studies testing 25D reported benefit. Together, this suggests that maintenance of optimal circulating 25D levels may reduce the risk of T1D and that it may have potential for benefits in delaying the development of absolute or near-absolute C-peptide deficiency. Given the near-complete loss of β-cells by the time of clinical diagnosis, vitamin D is much less likely to be useful after disease-onset. However, given the very low toxicity of 25D, and the known benefits of preservation of C-peptide positivity for long-term complications risk, we recommend considering daily cholecalciferol supplementation in people with T1D and people at high risk of T1D, especially if they have vitamin D insufficiency. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes (T2D) is a common chronic disease with many serious complications. Celastrol can prevent and treat type 2 diabetes by reversing insulin resistance in a number of ways. However, the specific mechanisms by which celastrol prevents and treats T2D are not well understood. The aim of this study was to explore the key gene targets and potential signaling pathway mechanisms of celastrol for the treatment of T2D. Methods: GSE184050 was downloaded from the Gene Expression Omnibus online database. Blood samples from patients and healthy individuals with T2D were analyzed to identify differentially expressed genes (DEGs), and a protein-protein interaction network (PPI) was constructed. Key gene analysis of DEGs was performed using the MCODE plugin in Cystoscope as well as the Hubba plugin, and intersections were taken to obtain hub genes, which were displayed using a Venn diagram. Enrichment analysis was then performed via the ClueGo plugin in Cytoscape and validated using Gene Set Enrichment Analysis. The therapeutic targets of celastrol were then analyzed by pharmacophore network pharmacology, intersected to identify the therapeutic targets of celastrol, enriched for all targets, and intersected to obtain the signaling pathways for celastrol treatment. The protein structures of the therapeutic targets were predicted using the artificial intelligence AlphaFold2. Finally, molecular docking was used to verify whether celastrol could be successfully docked to the predicted targets. Results: 618 DEGs were obtained, and 9 hub genes for T2D were identified by the MCODE and Hubba plug-ins, including ADAMTS15, ADAMTS7, ADAMTSL1, SEMA5B, ADAMTS8, THBS2, HBB, HBD and HBG2. The DEG-enriched signaling pathways mainly included the ferroptosis and TGF-beta signaling pathways. A total of 228 target genes were annotated by pharmacophore target analysis, and the therapeutic targets were identified, including S100A11, RBP3, HBB, BMP7 and IQUB, and 9 therapeutic signaling pathways were obtained by an intersectional set. The protein structures of the therapeutic targets were successfully predicted by AlphaFold2, and docking was validated using molecular docking. Conclusion: Celastrol may prevent and treat T2D through key target genes, such as HBB, as well as signaling pathways, such as the TGF-beta signaling pathway and type II diabetes mellitus. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD), an age-related neurodegenerative disorder, is currently incurable. Imbalanced amyloid-beta (Aβ) generation and clearance are thought to play a pivotal role in the pathogenesis of AD. Historically, strategies targeting Aβ clearance have typically focused on central clearance, but with limited clinical success. Recently, the contribution of peripheral systems, particularly the liver, to Aβ clearance has sparked an increased interest. In addition, AD presents pathological features similar to those of metabolic syndrome, and the critical involvement of brain energy metabolic disturbances in this disease has been recognized. More importantly, the liver may be a key regulator in these abnormalities, far beyond our past understanding. Here, we review recent animal and clinical findings indicating that liver dysfunction represents an early event in AD pathophysiology. We further propose that compromised peripheral Aβ clearance by the liver and aberrant hepatic physiological processes may contribute to AD neurodegeneration. The role of a hepatic synthesis product, fibroblast growth factor 21 (FGF21), in the management of AD is also discussed. A deeper understanding of the communication between the liver and brain may lead to new opportunities for the early diagnosis and treatment of AD. [ABSTRACT FROM AUTHOR]

Obesity and its complications have become serious global health concerns recently and increasing work has been carried out to explicate the underlying mechanism of the disease development. The recognized correlations suggest oxidative stress and inflammation in expanding adipose tissue with excessive fat accumulation play important roles in the pathogenesis of obesity, as well as its associated metabolic syndromes. In adipose tissue, obesity-mediated insulin resistance strongly correlates with increased oxidative stress and inflammation. Nuclear factor erythroid 2-related factor 2 (Nrf2) has been described as a key modulator of antioxidant signaling, which regulates the transcription of various genes coding antioxidant enzymes and cytoprotective proteins. Furthermore, an increasing number of studies have demonstrated that Nrf2 is a pivotal target of obesity and its related metabolic disorders. However, its effects are controversial and even contradictory. This review aims to clarify the complicated interplay among Nrf2, oxidative stress, lipid metabolism, insulin signaling and chronic inflammation in obesity. Elucidating the implications of Nrf2 modulation on obesity would provide novel insights for potential therapeutic approaches in obesity and its comorbidities. [ABSTRACT FROM AUTHOR]

Objective: GDF11 is a member of the TGF‐β superfamily that was recently implicated as potential "rejuvenating" factor, which can ameliorate metabolic disorders. The main objective of the presented study was to closely characterize the role of GDF11 signaling in the glucose homeostasis and in the differentiation of white adipose tissue. Methods: We performed microscopy imaging, biochemical and transcriptomic analyses of adipose tissues of 9 weeks old ob/ob mice and murine and human pre‐adipocyte cell lines. Results: Our in vivo experiments employing GDF11 treatment in ob/ob mice showed improved glucose/insulin homeostasis, decreased weight gain and white adipocyte size. Furthermore, GDF11 treatment inhibited adipogenesis in pre‐adipocytes by ALK5‐SMAD2/3 activation in cooperation with the WNT/β‐catenin pathway, whose inhibition resulted in adipogenic differentiation. Lastly, we observed significantly elevated levels of the adipokine hormone adiponectin and increased glucose uptake by mature adipocytes upon GDF11 exposure. Conclusion: We show evidence that link GDF11 to adipogenic differentiation, glucose, and insulin homeostasis, which are pointing towards potential beneficial effects of GDF11‐based "anti‐obesity" therapy. [ABSTRACT FROM AUTHOR]

Background: Fibroblast growth factor 21 (FGF-21) is an evolutionarily conserved protein that plays multiple roles inmetabolic regulation. Over the past two decades, numerous studies have deepened our understanding of its various functions and its pharmacological value. Nevertheless, most clinical trials have not achieved the desired results, which raises issues regarding its clinical value. In this bibliometric analysis, we evaluated the state of FGF-21 research over the last 20 years and identified important topics, achievements, and potential future directions. Methods: Publications related to FGF-21 were collected from the Web of Science Core Collection-Science Citation Index Expanded. HistCite, VOSviewer, and CiteSpace were used for bibliometric analysis and visualization, including the analysis of annual publications, leading countries, active institutions and authors, core journals, co-cited references, and keywords. Results: Altogether, 2,490 publications related to FGF-21 were obtained. A total of 12,872 authors from 2,628 institutions in 77 countries or regions reported studies on FGF-21. The United States of America was the most influential country in FGF-21 research. Alexei Kharitonenkov, Steven A. Kliewer, and David J. Mangelsdorf were the most influential scholars, and endocrinology journals had a core status in the field. The physiological roles, clinical translation, and FGF-21-based drug development were the main topics of research, and future studies may concentrate on the central effects of FGF-21, FGF-21-based drug development, and the effects of FGF-21 on non-metabolic diseases. Conclusion: The peripheral metabolic effects of FGF-21, FGF-21-based drug development, and translational research on metabolic diseases are the three major topics in FGF-21 research, whereas the central metabolic effects of FGF-21 and the effects of FGF-21 on metabolic diseases are the emerging trends and may become the following hot topics in FGF-21 research. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the therapeutic effect of JQ-R on metabolic hypertension and its correlation with Fibroblast growth factor 21/Fibroblast growth factor receptors 1(FGF21/FGFR1) pathway. In this study, fructose-induced metabolic hypertension rats were used as hypertension models to detect the regulation effect of JQ-R on hypertension. The effects of JQ-R on blood glucose, blood lipids, serum insulin levels and other metabolic indicators of rats were also measured. The effects of JQ-R on FGF21/FGFR1 signaling pathway in model animals were detected by Real-time quantitative PCR and Western blotting. The results showed that JQ-R significantly reduce the blood pressure of model rats in a dose-dependent manner. Meanwhile, fasting insulin, fasting blood glucose, insulin resistance index, total cholesterol and triglyceride levels were significantly decreased, and glucose and lipid metabolism abnormalities were also significantly improved. JQ-R induces these changes along with FGFR1 phosphorylation, which was also detected in JQ-R treated FGF21 knockout mice. These results suggest that JQ-R can reduce blood pressure and improve glucose and lipid metabolism in fructose-induced hypertension rats. Activation of FGF21/FGFR1 signaling pathway to regulate downstream blood pressure and glucolipid metabolism-related pathways may be one of the important mechanisms of JQ-R in regulating blood pressure. [ABSTRACT FROM AUTHOR]

This clinical trial was aimed to investigate the effects of fresh table grape intake on the serum levels of the Omega-3 index, defined as the sum of eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) levels. Forty consecutive healthy subjects were randomly assigned to the control group, receiving only dietary recommendations, and the grape group receiving a daily dose of 5 g of fresh table grape per kg of body weight, for 21 days. Compared with baseline, the grape treatment produced no significant difference in the serum levels of glucose, liver transaminase, and triglycerides, with the exception of cholesterol value, which was significantly reduced in both control and grape group (180.5 ± 20.32 vs. 196.1 ± 30.0 and 181.4 ± 21.9 vs. 194.3 ± 37.5, respectively). After 4 weeks from the end of grape treatment, the analysis of single fatty acids showed a significant increase in oleic acid content (14.15 ± 1.8 vs. 12.85 ± 1.6, p < 0.05) and a significant induction of the Omega-3 index (8.23 ± 1.9 vs. 6.09 ± 1.2, p < 0.05), associated with increased serum levels of adiponectin (24.09 ± 1.08 vs. 8.8 ± 0.7, p < 0.001). In contrast, the expression of fibroblast growth factor 21 (FGF21), a molecule associated with metabolic syndrome and liver disease, was significantly reduced (37.9 ± 6.8 vs. 107.8 ± 10.1, p < 0.001). The data suggest that the intake of fresh grape improves the Omega-3 index in the serum and exerts beneficial effects on liver function through the overexpression of adiponectin and the reduction in FGF21 levels. [ABSTRACT FROM AUTHOR]