Search Results (1,963)

Exosomes derived from mesenchymal stem cells have shown promise in treating metabolic disorders, yet their specific mechanisms remain largely unclear. This study investigates the protective effects of exosomes from human umbilical cord Wharton’s jelly mesenchymal stem cells (hWJMSCs) against adiposity and insulin resistance in high-fat diet (HFD)-induced obese mice. HFD-fed mice treated with hWJMSC-derived exosomes demonstrated improved gut barrier integrity, which restored immune balance in the liver and adipose tissues by reducing macrophage infiltration and pro-inflammatory cytokine expression. Furthermore, these exosomes normalized lipid metabolism including lipid oxidation and lipogenesis, which alleviate lipotoxicity-induced endoplasmic reticulum (ER) stress, thereby decreasing fat accumulation and chronic tissue inflammation in hepatic and adipose tissues. Notably, hWJMSC-derived exosomes also promoted browning and thermogenic capacity of adipose tissues, which was linked to reduced fibroblast growth factor 21 (FGF21) resistance and increased adiponectin production. This process activated the AMPK-SIRT1-PGC-1α pathway, highlighting the role of the FGF21–adiponectin axis. Our findings elucidate the molecular mechanisms through which hWJMSC-derived exosomes counteract HFD-induced metabolic dysfunctions, supporting their potential as therapeutic agents for metabolic disorders. Full article

Oxidative stress is a key factor in the development of chronic diseases such as type 2 diabetes, cardiovascular diseases, and liver disorders. Antioxidant therapies that target oxidative damage show significant promise in preventing and treating these conditions. Berberine, an alkaloid derived from various plants in the Berberidaceae family, enhances cellular defenses against oxidative stress through several mechanisms. It activates the AMP-activated protein kinase (AMPK) pathway, which reduces mitochondrial reactive oxygen species (ROS) production and improves energy metabolism. Furthermore, it boosts the activity of key antioxidant enzymes like superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), thus protecting cells from oxidative damage. These actions make berberine effective in managing diseases like type 2 diabetes, cardiovascular conditions, and neurodegenerative disorders. Silymarin, a flavonolignan complex derived from Silybum marianum, is particularly effective for liver protection. It activates the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, enhancing antioxidant enzyme expression and stabilizing mitochondrial membranes. Additionally, silymarin reduces the formation of ROS by chelating metal ions, and it also diminishes inflammation. This makes it beneficial for conditions like non-alcoholic fatty liver disease (NAFLD) and alcohol-related liver disorders. This review aims to highlight the distinct mechanisms by which berberine and silymarin exert their antioxidant effects. Full article

The constant increase in the elderly population presents significant challenges in addressing new social, economic, and health problems concerning this population. With respect to health, aging is a primary risk factor for age-related diseases, which are driven by interconnected molecular hallmarks that influence the development of these diseases. One of the main mechanisms that has attracted more attention to aging is autophagy, a catabolic process that removes and recycles damaged or dysfunctional cell components to preserve cell viability. The autophagy process can be induced or deregulated in response to a wide range of internal or external stimuli, such as starvation, oxidative stress, hypoxia, damaged organelles, infectious pathogens, and aging. Natural compounds that promote the stimulation of autophagy regulatory pathways, such as mTOR, FoxO1/3, AMPK, and Sirt1, lead to increased levels of essential proteins such as Beclin-1 and LC3, as well as a decrease in p62. These changes indicate the activation of autophagic flux, which is known to be decreased in cardiovascular diseases, neurodegeneration, and cataracts. The regulated administration of natural compounds offers an adjuvant therapeutic alternative in age-related diseases; however, more experimental evidence is needed to support and confirm these health benefits. Hence, this review aims to highlight the potential benefits of natural compounds in regulating autophagy pathways as an alternative approach to combating age-related diseases. Full article

Juglanin (kaempferol 3-O-α-L-arabinofuranoside) is a flavonol glycoside occurring in many plants, including its commercial sources Juglans regia, Polygonum aviculare and Selliguea hastata. Recent extensive studies have explored the potential of using juglanin in various pathological conditions, including cardiovascular disorders, central nervous and skeletal system disorders, metabolic syndrome, hepatic injury, and cancers. The results indicated a wide range of effects, like anti-inflammatory, anti-oxidant, anti-fibrotic, anti-thrombotic, anti-angiogenic, hepatoprotective, hypolipidemic, hypoglycemic, anti-apoptotic (normal cells), and pro-apoptotic (cancer cells). The health-promoting properties of juglanin can be attributed to its influence on many signaling pathways, associated with SIRT1, AMPK, Nrf2, STING, TLR4, MAPKs, NF-κB, AKT, JAK, and their downstream genes. This review primarily summarizes the current knowledge of molecular mechanisms, pharmacokinetics, biocompatibility, and human use safety of juglanin. In addition, the most promising new plant sources and other existing challenges and prospects have also been reviewed and discussed, aiming to provide direction and rationale for the further development and broader pharmaceutical application of juglanin. Full article

Aberrant expression of TRIM proteins has been correlated with poor prognosis and metastasis in many cancers, with many TRIM proteins acting as key oncogenic factors. TRIM proteins are actively involved in many cancer signaling pathways, such as p53, Akt, NF-κB, MAPK, TGFβ, JAK/STAT, AMPK and Wnt/β-catenin. Therefore, this review attempts to summarize how three of the most studied TRIMs in recent years (i.e., TRIM25, TRIM28 and TRIM59) are involved directly and indirectly in the crosstalk between the signaling pathways. A brief overview of the key signaling pathways involved and their general cross talking is discussed. In addition, the direct interacting protein partners of these TRIM proteins are also highlighted in this review to give a picture of the potential protein–protein interaction that can be targeted for future discovery and for the development of novel therapeutics against cancer. This includes some examples of protein partners which have been proposed to be master switches to various cancer signaling pathways. Full article

Phloroglucinol (PHG), an analgesic and spasmolytic drug, shows promise in preventing high-fat-diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) and insulin resistance. In Wistar rats, 10 weeks of PHG treatment did not prevent HFD-induced weight gain but significantly mitigated fasting hyperglycemia, impaired insulin responses, and liver steatosis. This protective effect was not linked to hepatic lipogenesis or AMP-activated protein kinase (AMPK) activation. Instead, PHG improved mitochondrial function by reducing oxidative stress, enhancing ATP production, and increasing anti-oxidant enzyme activity. PHG also relaxed gastric smooth muscles via potassium channel activation and nitric oxide (NO) signaling, potentially delaying gastric emptying. A pilot intervention in pre-diabetic men confirmed PHG’s efficacy in improving postprandial glycemic control and altering lipid metabolism. These findings suggest PHG as a potential therapeutic for NAFLD and insulin resistance, acting through mechanisms involving mitochondrial protection, anti-oxidant activity, and gastric motility modulation. Further clinical evaluation is warranted to explore PHG’s full therapeutic potential. Full article

The impact of aging on body composition and glucose metabolism is not well established in C57BL/6J mice, despite being a common pre-clinical model for aging and metabolic research. The purpose of this study was to examine the effect of advancing age on body composition, in vivo glucose metabolism, and skeletal muscle AKT expression in young (Y: 4 months old, n = 7), old (O: 17–18 months old, n = 10), and very old (VO: 26–27 month old, n = 9) male C57BL/6J mice. Body composition analysis, assessed by nuclear magnetic resonance, demonstrated O mice had a significantly greater fat mass and body fat percentage when compared to Y and VO mice. Furthermore, VO mice had a significantly greater lean body mass than both O and Y mice. We also found that the VO mice had greater AKT protein levels in skeletal muscle compared to O mice, an observation that explains a portion of the increased lean body mass in VO mice. During glucose tolerance (GT) testing, blood glucose values were significantly lower in the VO mice when compared to the Y and O mice. No age-related differences were observed in insulin tolerance (IT). We also assessed the glucose response to AMPK activation by 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR). The change in blood glucose following AICAR administration was significantly reduced in VO mice compared to Y and AG mice. Our findings indicate that lean body mass and AKT2 protein expression in muscle are significantly increased in VO mice compared to O mice. The increase in AKT2 likely plays a role in the greater lean body mass observed in the oldest of old mice. Finally, despite the increased GT, VO mice appear to be resistant to AMPK-mediated glucose uptake. Full article

Type 2 diabetes mellitus (T2DM) remains a significant global health issue, marked by insulin resistance and disrupted glucose metabolism. AMP-activated protein kinase (AMPK) serves as a key regulator of cellular energy balance, playing a crucial role in enhancing insulin sensitivity, promoting glucose uptake, and reducing glucose production in the liver. Recently, there has been growing interest in plant-derived flavonoids as natural activators of AMPK, offering a promising complementary approach to conventional diabetes treatments. This review delves into ten flavonoids identified as AMPK activators, including baicalein, dihydromyricetin, bavachin, 7-O-MA, derrone, and alpinumisoflavone. Their activation mechanisms are explored, which include both direct binding to the AMPK complex and indirect pathways involving upstream signaling. Through molecular docking studies, the binding affinities and interaction profiles of these flavonoids with AMPK are assessed, revealing varying levels of activation potential. Notably, baicalein and dihydromyricetin showed strong binding to the α1 subunit of AMPK, indicating high potential for robust activation. Additionally, this review provides a thorough analysis of the pharmacokinetic properties and drug-likeness of these flavonoids using the SwissADME tool, focusing on aspects such as ADME (Absorption, Distribution, Metabolism, and Excretion). While the overall profiles of these compounds are promising, issues like solubility and possible drug–drug interactions are areas that need further refinement. In summary, plant-derived flavonoids emerge as a promising avenue for developing new natural therapies for T2DM. Moving forward, research should aim at optimizing these compounds for clinical application, elucidating their specific mechanisms of AMPK activation, and confirming their efficacy in T2DM treatment. This review highlights the potential of flavonoids as safer and more holistic alternatives or adjuncts to current diabetes therapies. Full article

Background/Objectives: Metallic nanoparticles (NPs) exhibit interesting radiosensitizing effects, and finding a way to accurately deliver them appears to be crucial. Due to their tumor tropism, mesenchymal stem cells (MSCs) represent a strategic approach. Therefore, we aimed to evaluate the impact of core–shell Fe₃O₄@Au NPs on the functionality of human pulmonary MSCs (HPMSCs). Methods/Results: The results showed that 100 µg/mL Fe₃O₄@Au NPs, accumulated in HPMSCs (revealed by Prussian blue staining), did not alter cell viability as assessed by cell counting, MTT, and LDH assays. However, caspase 9 and Bcl2 gene expression, evaluated by RT-qPCR, was regulated 72 h after exposure to the NPs. Moreover, the NPs also decreased proinflammatory cytokine/chemokine secretions, except for CXCL8 (ELISA). These modulations were associated with the downregulation of AMPK gene expression at 24 h. In contrast, the NPs did not modulate VEGF, PI3K, or PDGF gene expression. Nevertheless, a decrease in VEGF secretion was observed after 24 h of exposure to the NPs. Interestingly, the Fe₃O₄@Au NPs did not modulate Nrf2 gene expression, but they did regulate the expression of the genes encoding Nox4 and HMOX-1. Additionally, the NPs increased ROS production, suggesting a redox imbalance. Conclusions: Finally, the Fe₃O₄@Au NPs did not affect the HPMSCs’ viability or proangiogenic/tumorigenic markers. These findings are encouraging for investigating the effects of Fe₃O₄@Au NPs delivered by HPMSCs to tumor sites in combination with radiation. Full article

In recent years, the prevalence of non-alcoholic fatty liver disease (NAFLD) has risen annually, yet due to the intricacies of its pathogenesis and therapeutic challenges, there remains no definitive medication for this condition. This review explores the intricate relationship between the intestinal microbiome and the pathogenesis of NAFLD, emphasizing the substantial roles played by Lactobacillus plantarum and Bifidobacterium bifidum. These probiotics manipulate lipid synthesis genes and phosphorylated proteins through pathways such as the AMPK/Nrf2, LPS-TLR4-NF-κB, AMPKα/PGC-1α, SREBP-1/FAS, and SREBP-1/ACC signaling pathways to reduce hepatic lipid accumulation and oxidative stress, key components of NAFLD progression. By modifying the intestinal microbial composition and abundance, they combat the overgrowth of harmful bacteria, alleviating the inflammatory response precipitated by dysbiosis and bolstering the intestinal mucosal barrier. Furthermore, they participate in cellular immune regulation, including CD4⁺ T cells and Treg cells, to suppress systemic inflammation. L. plantarum and B. bifidum also modulate lipid metabolism and immune reactions by adjusting gut metabolites, including propionic and butyric acids, which inhibit liver inflammation and fat deposition. The capacity of probiotics to modulate lipid metabolism, immune responses, and gut microbiota presents an innovative therapeutic strategy. With a global increase in NAFLD prevalence, these insights propose a promising natural method to decelerate disease progression, avert liver damage, and tackle associated metabolic issues, significantly advancing microbiome-focused treatments for NAFLD. Full article

The differences in muscle development potential between male and female ducks lead to variations in body weight, significantly affecting the growth of the Muscovy duck meat industry. The aim of this study is to explore the regulatory mechanisms for the muscle development differences between genders. Muscovy ducks of both sexes were selected for measurements of body weight, growth traits, hormone levels, and muscle gene expression. The results show that male ducks compared to females had greater weight and growth traits (p < 0.05). Compared to male ducks, the level of serum testosterone in female ducks was decreased, and the estradiol levels were increased (p < 0.05). The RNA-seq analysis identified 102 upregulated and 49 downregulated differentially expressed genes. KEGG analysis revealed that among the top 10 differentially enriched pathways, the AMPK signaling pathway is closely related to muscle growth and development. Additionally, the mRNA and protein levels of CD36, CPT1A, LPL, and SREBP1 were increased and the P-AMPK protein level decreased in the female ducks compared to the male ducks (p < 0.05). In conclusion, muscle development potential difference between male and female ducks is regulated by sex hormones. This process is likely mediated through the activation of the AMPK pathway. Full article

Background: This study investigates the hypolipidemic effects of a mixed extract of Salvia miltiorrhiza and Paeonia lactiflora (USCP119) in HFD-fed hamsters and in vitro cellular models. Methods: Over an 8-week period, HFD-fed hamsters were assigned to one of six groups: normal diet, HFD control, HFD with 50 mg/kg USCP119, HFD with 100 mg/kg USCP119, HFD with 50 mg/kg USCP119 twice daily (BID), and HFD with omega-3 fatty acids. Key outcomes assessed included body weight, serum triglycerides (TG), total cholesterol (TC), liver weight, hepatic TG levels, and epididymal fat. In cellular models, the impact of USCP119 on lipid accumulation and adipogenic markers was evaluated. Results: USCP119 treatment at 50 mg/kg BID resulted in the lowest weight gain (15.5%) and the most significant reductions in serum TG and hepatic TG levels compared to the HFD control. The 100 mg/kg dose also led to substantial reductions in serum TG and TC levels and notable decreases in low-density lipoprotein cholesterol. USCP119 at 50 mg/kg once daily reduced TG and TC levels but was less effective than the higher doses. In cellular models, USCP119 was non-toxic up to 400 µg/mL and effectively reduced lipid accumulation, modulated adipogenic markers, and enhanced AMPK signaling, improving lipid metabolism and insulin sensitivity. Conclusions: All USCP119 treatments demonstrated effectiveness in managing hyperlipidemia and related metabolic disorders, with variations in impact depending on the dosage. The ability of USCP119 to reduce fat accumulation, improve lipid profiles, and enhance insulin sensitivity highlights its potential as a valuable dietary supplement for addressing high-fat diet-induced hyperlipidemia and metabolic disturbances. Full article

We planned to explore the protective activities of extract of Phyllanthus emblica L. (EPE) on insulin resistance and metabolic disorders including hyperlipidemia, visceral obesity, and renal dysfunction in high-fat diet (HFD)-progressed T2DM mice. Mice treatments included 7 weeks of HFD induction followed by EPE, fenofibrate (Feno), or metformin (Metf) treatment daily for another 4-week HFD in HFD-fed mice. Finally, we harvested blood to analyze some tests on circulating glycemia and blood lipid levels. Western blotting analysis was performed on target gene expressions in peripheral tissues. The present findings indicated that EPE treatment reversed the HFD-induced increases in blood glucose, glycosylated HbA1_C, and insulin levels. Our findings proved that treatment with EPE in HFD mice effectively controls hyperglycemia and hyperinsulinemia. Our results showed that EPE reduced blood lipid levels, including a reduction in blood triglyceride (TG), total cholesterol (TC), and free fatty acid (FFA); moreover, EPE reduced blood leptin levels and enhanced adiponectin concentrations. EPE treatment in HFD mice reduced BUN and creatinine in both blood and urine and lowered albumin levels in urine; moreover, EPE decreased circulating concentrations of inflammatory NLR family pyrin domain containing 3 (NLRP3) and kidney injury molecule-1 (KIM-1). These results indicated that EPE displayed antihyperglycemic and antihyperlipidemic activities but alleviated renal dysfunction in HFD mice. The histology examinations indicated that EPE treatment decreased adipose hypertrophy and hepatic ballooning, thus contributing to amelioration of lipid accumulation. EPE treatment decreased visceral fat amounts and led to improved systemic insulin resistance. For target gene expression levels, EPE enhanced AMP-activated protein kinase (AMPK) phosphorylation expressions both in livers and skeletal muscles and elevated the muscular membrane glucose transporter 4 (GLUT4) expressions. Treatment with EPE reduced hepatic glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) expressions to suppress glucose production in the livers and decreased phosphorylation of glycogen synthase kinase 3β (GSK3β) expressions to affect hepatic glycogen synthesis, thus convergently contributing to an antidiabetic effect and improving insulin resistance. The mechanism of the antihyperlipidemic activity of EPE involved a decrease in the hepatic phosphorylation of mammalian target of rapamycin complex C1 (mTORC1) and p70 S6 kinase 1 (S6K1) expressions to improve insulin resistance but also a reduction in hepatic sterol regulatory element binding protein (SREBP)-1c expressions, and suppression of ACC activity, thus resulting in the decreased fatty acid synthesis but elevated hepatic peroxisome proliferator-activated receptor (PPAR) α and SREBP-2 expressions, resulting in lowering TG and TC concentrations. Our results demonstrated that EPE improves insulin resistance and ameliorates hyperlipidemia in HFD mice. Full article

Background/Objective: This study examined the anti-obesity effect of royal jelly (RJ) in rats fed with a high-fat diet by targeting the major pathways involved in adipogenesis and lipolysis. In addition, it examined whether this effect is AMPK-dependent. Methods: Five groups of adult male albino rats were used (n = 6 each as 1); the control rats were fed with a normal diet (2.9 kcal), and the other groups were as follows: control + RJ (300 mg/kg), HFD (4.75 kcal), HFD + RJ (300 mg/kg), and HFD + RJ (300 mg/kg) + dorsomorphin (an AMPK inhibitor) (0.2 mg/kg). Results: RJ was administered orally to all rats. With no changes in food and energy intake, RJ significantly reduced gains in body weight, fat weight, body mass index (BMI), the Lee index, abdominal circumference (AC), and the adiposity index (AI). It also reduced fasting glucose and insulin levels, HOMA-IR, and the circulatory levels of free fatty acids (FFAs), triglycerides, cholesterol, and LDL-c in the HFD-fed rats. RJ also increased serum glycerol levels and adiponectin levels, but reduced the serum levels of leptin, IL-6, and TNF-α. Moreover, RJ reduced the secretion of IL-6 and TNF-α from isolated WAT. At the tissue level, the HFD + RJ rats exhibited a smaller adipocyte size compared to the HFD rats. At the molecular level, RJ increased the phosphorylation of AMPK, SREBP1, and ACC-1 and increased the mRNA and protein levels of HSL and ATG in the WAT of the HFD rats. In concomitance, RJ increased the mRNA levels of PGC-α1, reduced the protein levels of PPARγ, and repressed the transcriptional activities of PPARγ, SREBP1, and C/EBPαβ in the WAT of these rats. All the aforementioned effects of RJ were prevented by co-treatment with dorsomorphin. Conclusions: RJ exerts a potent anti-obesity effect in rats that is mediated by the AMPk-dependent suppression of WAT adipogenesis and the stimulation of lipolysis. Full article

Circular RNAs (circRNAs) are a class of circular non-coding RNAs that play essential roles in the intricate and dynamic networks governing cell growth, development, and apoptosis. Resveratrol (RSV), a non-flavonoid polyphenol, is known to participate in follicular development and ovulation. In our previous research, we established a model using porcine ovarian granulosa cells (POGCs) treated with resveratrol, which confirmed its regulatory effects on long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) within these cells. However, the influence of resveratrol on circRNA expression has not been thoroughly investigated. To explore how resveratrol affects circRNA levels in POGCs, we designed an experiment with three groups: a control group (CON, n = 3, 0 μM RSV), a low-dose RSV group (LOW, n = 3, 50 μM RSV), and a high-dose RSV group (HIGH, n = 3, 100 μM RSV) for circRNA sequencing. We identified a total of 10,045 candidate circRNAs from POGCs treated with different concentrations of resveratrol (0, 50, and 100 μM). Differential expression analysis indicated that 96 circRNAs were significantly altered in the LOW vs. CON group, while 109 circRNAs showed significant changes in the HIGH vs. CON group. These circRNAs were notably enriched in biological processes associated with cell metabolism, apoptosis, and oxidative stress. Functional enrichment analysis of the host genes revealed their involvement in critical signaling pathways, including mTOR, AMPK, and apoptosis pathways. Additionally, we identified potential miRNA sponge candidates among the differentially expressed circRNAs, particularly novel_circ_0012954 and novel_circ_0004762, which exhibited strong connectivity within miRNA-target networks. Our findings provide valuable insights into the regulatory mechanisms of circRNAs in the context of resveratrol-induced apoptosis in POGCs, highlighting their potential as innovative therapeutic targets in reproductive biology. Full article