Search Results (77)

Glucagon-like peptide-1 (GLP-1) has emerged as a pivotal regulator in the management of glucose homeostasis, glycogen metabolism, and energy balance, positioning it as a critical therapeutic target for addressing obesity, metabolic syndrome, and type 2 diabetes mellitus (T2DM). GLP-1 receptor agonists (GLP-1RAs) have shown promise for improving glycemic control and reducing weight through appetite regulation, delayed gastric emptying, and energy expenditure modulation. This narrative review explores the mechanisms of GLP-1-mediated glycogen metabolism and energy expenditure, particularly in key tissues—pancreas, liver, skeletal muscle, and adipose tissue. In the pancreas, GLP-1 enhances insulin secretion and beta-cell function. In the liver, it promotes glycogen synthesis via insulin-dependent and potential insulin-independent pathways, involving protein kinase B (AKT) and AMP-activated protein kinase (AMPK) signaling. Skeletal muscle benefits from GLP-1 through increased glucose uptake, AMPK activation, and mitochondrial function, facilitating glycogen storage. In adipose tissue, GLP-1 stimulates brown adipose tissue (BAT) thermogenesis and energy expenditure, contributing to weight loss. This increase in energy expenditure, along with enhanced glycogen metabolism, is a plausible mechanism for the weight loss observed with GLP-1RAs. Despite these advances, significant knowledge gaps remain, particularly regarding the direct hepatic effects of GLP-1, the extent to which it modulates glycogen metabolism in vivo, and its impact on thermogenesis in humans. Future research focusing on both the tissue-specific actions of GLP-1 and its systemic role in energy homeostasis and metabolic regulation will be essential for optimizing its therapeutic potential. Full article

Anthracyclines play an irreplaceable role in cancer treatment, although their clinical application is limited due to severe side effects such as arrhythmia, cardiomyopathy, and myocardial infarction. The currently available clinical drugs for treating anthracycline-induced cardiotoxicity (AIC) are limited by numerous drawbacks, including the side effects of the therapeutic agents, single treatment mechanisms, and individual patient variations. Therefore, novel drugs with broader applicability and multitarget synergistic protective effects are, therefore, urgently needed. Ginsenosides, the primary bioactive constituents of plants belonging to the genus Panax (family Araliaceae), exhibit a wide range of pharmacological activities, including anti-inflammatory, antioxidative, and antitumor effects, and have demonstrated cardioprotective properties against AIC. This article examines the mechanisms of AIC and the modulatory effects of ginsenosides on these mechanisms. This review highlights the potential molecular targets and signaling pathways through which ginsenosides exert therapeutic effects on AIC, including the regulation of oxidative-stress-related pathways such as Keap1/Nrf2, MAPK, STAT, PI3K/Akt, and AMPK; the restoration of mitochondrial function; the modulation of autophagy; and the inhibition of pyroptosis, ferroptosis, and apoptosis. Therefore, this review serves as a theoretical basis and provides a research direction for future investigation regarding the prevention and treatment of AIC with ginsenosides, as well as clinical translation studies. Full article

Insulin resistance is more common in the elderly, and with the improvement in people’s living standards and changes in lifestyle habits, the incidence of insulin resistance in other age groups is also increasing year by year. Overweight and obesity caused by abnormal fat metabolism or accumulation can significantly reduce glucose intake, which is the direct cause of insulin resistance and the trigger for the occurrence and development of type II diabetes. This article reviews and analyzes relevant literature on empirical research on the effect of regular exercise on improving insulin resistance. It was found that the most important step in carbohydrate metabolism is the translocation of glucose transporter 4 (GLUT4) to the cell membrane, carrying water-soluble glucose through the lipid soluble cell membrane to complete carbohydrate transport. The process of glucose transporter protein translocation to the cell membrane can be driven by two different signaling pathways: one is the insulin information transfer pathway (ITP), the second is to induce the ITP of monophosphate-activated protein kinase (AMPK) through hypoxia or muscle contraction. For type II diabetes patients, the insulin signal transmission pathway through insulin receptors (IRS₁, IRS₂) and phosphatidylinositol 3-kinase (PI3K) (PI3K) is damaged, which results in the decrease in glucose absorption stimulated by insulin in skeletal muscle, while the noninsulin signal transmission pathway of AMPK in these patients is normal. It can be seen that regular exercise can regulate glucose intake and the metabolism of skeletal muscle, improve insulin resistance, reduce fasting blood glucose and glycosylated hemoglobin in diabetes patients, and thus, effectively regulate blood glucose. However, many steps in the molecular mechanism of how exercise training improves systemic insulin resistance are still not fully understood, and further discussion is needed in the future. Full article

Background/Objectives: Metabolites produced by gut microbiota play an important role in the crosstalk between the gut and other organs. Although HYA (10-hydroxy-cis-12-octadecenoic acid), a linoleic acid metabolite produced by lactic acid bacteria represented by Lactobacillus, has been shown to exert physiological effects such as metabolic improvement and anti-inflammation in the host, its direct action on adipose tissue and the mechanism remains unknown. Methods: The effect of HYA administration on adipocyte size in mice fed a high-fat diet was examined. In 3T3-L1 mature adipocytes treated with HYA, the amount of intracellular lipid droplets was evaluated by Oil red O staining, gene expression by real-time qPCR, phosphorylation of AMP-activated protein kinase (AMPK) by immunoblotting, and intracellular Ca²⁺ concentration with calcium imaging. Results: Administration of HYA, but not linoleic acid, to obese mice fed a high-fat diet significantly reduced adipocyte size. To investigate whether the inhibition of adipocyte hypertrophy by HYA has a direct effect on adipocytes, 3T3-L1 adipocytes were treated with HYA, which significantly decreased the amount of intracellular lipid droplets in these cells. Gene expression analysis by real-time PCR showed decreased expression of genes related to lipogenesis such as FAS and ACC1, and increased expression of CPT1A, which is involved in fatty acid oxidation. Mechanistically, HYA was found to activate AMPK in adipocytes by increasing intracellular Ca²⁺ concentration. Conclusions: HYA suppresses adipocyte hypertrophy by activating AMPK in adipocytes. HYA may be a potential therapeutic for obesity and related metabolic disorders. Full article

Ovarian cancer (OC) is a highly aggressive malignancy with a poor prognosis, necessitating novel therapeutic strategies. Fucoxanthin (FX), a marine-derived carotenoid from Laminaria japonica, has demonstrated promising anticancer potential. This study revealed that FX exerts multiple anticancer effects in OC by inhibiting cell proliferation, invasion, and migration, while inducing various forms of programmed cell death (PCD). FX triggered PANoptosis (apoptosis, necroptosis, and pyroptosis) and ferroptosis. FX treatment regulated key markers associated with PANoptosis, including apoptosis (Bcl-2, cleaved caspase-3), pyroptosis (GSDME), and necroptosis (RIPK3). Additionally, FX treatment modulated ferroptosis-related markers, such as SLC7A11 and GPX4, while increasing reactive oxygen species (ROS) and Fe²⁺ levels and disrupting mitochondrial function. Proteomic and molecular docking analyses identified AMP-activated protein kinase (AMPK) as a direct FX target, activating the AMPK/Nrf2/HMOX1 pathway to promote ferroptosis. In vivo, FX significantly reduced tumor growth in OC xenograft models, accompanied by enhanced ferroptosis marker expression. These findings demonstrate that FX induces ferroptosis through the AMPK/Nrf2/HMOX1 pathway and promotes PANoptosis via distinct mechanisms, highlighting its potential as a marine-derived therapeutic agent for OC. Full article

Gestational diabetes mellitus (GDM) affects placental metabolism, influencing both maternal and fetal outcomes. This study investigated the expression of metabolic regulators—Pyruvate Kinase M2 (PKM2), AMP-activated protein kinase (AMPK), and mTOR pathway components—in placental tissues from GDM pregnancies managed with either insulin (GDM-I) or dietary interventions (GDM-D). We hypothesize that metabolic adaptation in GDM is differentially regulated by treatment modality. This study analyzed 30 cases, including 10 control pregnancies,10 GDM-D cases, and 10 GDM-I cases. Analytical methods included immunofluorescence and immunoblotting. We observed an upregulation of PKM2 in both GDM-I and GDM-D placentas, suggesting enhanced glycolytic adaptation under GDM-induced metabolic stress. AMPK expression was significantly elevated in GDM-I and moderately increased in GDM-D placentas, potentially compensating for insulin resistance by promoting glucose uptake and energy homeostasis. Furthermore, mTOR pathway activation differed by treatment type, suggesting a treatment-specific mTOR response. The metabolic changes observed suggest that treatment modality in GDM may have direct implications for maternal and fetal health. Our findings indicate that while insulin and dietary management support metabolic adaptation in GDM, they do so through distinct mechanisms. These findings support a personalized approach in GDM treatment, where patient-specific metabolic responses should guide therapeutic decisions. Full article

Plant secondary metabolites are known to be valuable agents to hamper inflammation owing to their multiple mechanisms of action. This study investigates the molecular mechanisms underlying the anti-inflammatory effects of vicenin-2 in lipopolysaccharide (LPS)-stressed THP-1 cells. After ascertaining the safety of vicenin-2 in our in vitro model, we assessed the anti-inflammatory potential of this flavonoid. Indeed, it counteracted the increase of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 levels, as well as the overexpression of both inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 caused by the exposure of THP-1 cells to LPS. Acknowledged the role of SIRT1 in the inflammatory process, we focused our attention on this enzyme. Our results showed that LPS dramatically decreased the expression of SIRT1, whereas vicenin-2 restored the levels of this enzyme to those of unexposed cells. These effects were also observed in terms of acetylated p53, a SIRT1 substrate. Notably, we observed that vicenin-2 did not act as a direct activator of SIRT1. Therefore, we investigated the potential involvement of AMP-activated protein kinase (AMPK), an upstream activator of SIRT1. Of note, by blocking AMPK by dorsomorphin, the protective effects of vicenin-2 on SIRT1 expression and activity were lost, suggesting the engagement of this kinase. Consequently, the blockage of AMPK caused a downstream loss of the anti-inflammatory effect of vicenin-2, which was no longer able to decrease both the activation of nuclear factor (NF)-κB and the production of cytokines induced by LPS. Finally, docking simulation suggested that vicenin-2 might act as an activator of Ca²⁺/calmodulin-dependent protein kinase kinase β (CaMKKβ), one of the regulators of AMPK. Overall, our results suggest that the anti-inflammatory effects of vicenin-2 may be due to the interaction with the CaMKKβ-AMPK-SIRT1 axis. Full article

Sodium-glucose cotransporter 2 inhibitors (SGLT2is), commonly known as flozins, have garnered attention not only for their glucose-lowering effects in type 2 diabetes mellitus (T2DM) but also for their cardioprotective properties. This review examines the mechanisms underlying the anti-fibrotic effects of SGLT2is, with a focus on key clinical trials and preclinical models. SGLT2is, mainly empagliflozin and dapagliflozin, have demonstrated significant reductions in heart failure-related hospitalizations, cardiovascular death, and fibrosis markers, independent of their glucose-lowering effects. The cardioprotective benefits appear to stem from direct actions on cardiac tissues, modulation of inflammatory responses, and improvements in metabolic parameters. In animal models of heart failure, SGLT2is were demonstrated to reduce cardiac fibrosis through mechanisms involving AMPK activation, reduced oxidative stress, and inhibition of pro-fibrotic pathways, not only through the inhibition of SGLT2 present on cardiac cells but also by targeting several other molecular targets. These findings confirm their efficacy in the treatment of heart failure and align with evidence from human trials, supporting the potential involvement of multiple pathways in mediating cardiac fibrosis. These results also provide a promising basis for clinical trials specifically targeting pathways shared with SGLT2is. Full article

Background/Objectives: Complex regional pain syndrome (CRPS) is characterized by severe pain and reduced functionality, which can significantly affect an individual’s quality of life. The current treatment of CRPS is challenging. However, recent advances in diagnostic and treatment methods show promise for improving patient outcomes. This review aims to place the question of CRPS in a broader context and highlight the objectives of the research for future directions in the management of CRPS. Methods: This study involved a comprehensive literature review. Results: Research has identified three primary pathophysiological pathways that may explain the clinical variability observed in CRPS: inflammatory mechanisms, vasomotor dysfunction, and maladaptive neuroplasticity. Investigations into these pathways have spurred the development of novel diagnostic and treatment strategies focused on N-Methyl-D-aspartate Receptor Antagonists (NMDA), Toll-like receptor 4 (TLR-4), α1 and α2 adrenoreceptors, as well as the identification of microRNA (miRNA) biomarkers. Treatment methods being explored include immune and glial-modulating agents, intravenous immunoglobulin (IVIG) therapy, plasma exchange therapy, and neuromodulation techniques. Additionally, there is ongoing debate regarding the efficacy of other treatments, such as free radical scavengers, alpha-lipoic acid (ALA), dimethyl fumarate (DMF), adenosine monophosphate-activated protein kinase (AMPK) activators such as metformin, and phosphodiesterase-5 inhibitors such as tadalafil. Conclusions: The controversies surrounding the mechanisms, diagnosis, and treatment of CRPS have prompted researchers to investigate new approaches aimed at enhancing understanding and management of the condition, with the goal of alleviating symptoms and reducing associated disabilities. Full article

Epithelial ovarian cancer (EOC) exhibits a unique mode of metastasis, involving spheroid formation in the peritoneum. Our research on EOC spheroid cell biology has provided valuable insights into the signaling plasticity associated with metastasis. We speculate that EOC cells modify their biology between tumour and spheroid states during cancer dormancy, although the specific mechanisms underlying this transition remain unknown. Here, we present novel findings from direct comparisons between cultured EOC spheroids and organoids. Our results indicated that AMP-activated protein kinase (AMPK) activity was significantly upregulated and protein kinase B (Akt) was downregulated in EOC spheroids compared to organoids, suggesting a clear differential phenotype. Through RNA sequencing analysis, we further supported these phenotypic differences and highlighted the significance of cell cycle regulation in organoids. By inhibiting the G2/M checkpoint via kinase inhibitors, we confirmed that this pathway is essential for organoids. Interestingly, our results suggest that specifically targeting aurora kinase A (AURKA) may represent a promising therapeutic strategy since our cells were equally sensitive to Alisertib treatment as both spheroids and organoids. Our findings emphasize the importance of studying cellular adaptations of EOC cells, as there may be different therapeutic targets depending on the step of EOC disease progression. Full article

Traumatic optic neuropathy (TON) has been regarded a vision-threatening condition caused by either ocular or blunt/penetrating head trauma, which is characterized by direct or indirect TON. Injury happens during sports, vehicle accidents and mainly in military war and combat exposure. Earlier, we have demonstrated that remote ischemic post-conditioning (RIC) therapy is protective in TON, and here we report that AMPKα1 activation is crucial. AMPKα1 is the catalytic subunit of the heterotrimeric enzyme AMPK, the master regulator of cellular energetics and metabolism. The α1 isoform predominates in immune cells including macrophages (Mφs). Myeloid-specific AMPKα1 KO mice were generated by crossing AMPKα1^Flox/Flox and LysM^cre to carry out the study. We induced TON in mice by using a controlled impact system. Mice (mixed sex) were randomized in six experimental groups for Sham (mock); Sham (RIC); AMPKα1^F/F (TON); AMPKα1^F/F (TON+RIC); AMPKα1^F/F LysM^Cre (TON); AMPKα1^F/F LysM^Cre (TON+RIC). RIC therapy was given every day (5–7 days following TON). Data were generated by using Western blotting (pAMPKα1, ICAM1, Brn3 and GAP43), immunofluorescence (pAMPKα1, cd11b, TMEM119 and ICAM1), flow cytometry (CD11b, F4/80, CD68, CD206, IL-10 and LY6G), ELISA (TNF-α and IL-10) and transmission electron microscopy (TEM, for demyelination and axonal degeneration), and retinal oxygenation was measured by a Unisense sensor system. First, we observed retinal morphology with funduscopic images and found TON has vascular inflammation. H&E staining data suggested that TON increased retinal inflammation and RIC attenuates retinal ganglion cell death. Immunofluorescence and Western blot data showed increased microglial activation and decreased retinal ganglion cell (RGCs) marker Brn3 and axonal regeneration marker GAP43 expression in the TON [AMPKα1^F/F] vs. Sham group, but TON+RIC [AMPKα1^F/F] attenuated the expression level of these markers. Interestingly, higher microglia activation was observed in the myeloid AMPKα1^F/F KO group following TON, and RIC therapy did not attenuate microglial expression. Flow cytometry, ELISA and retinal tissue oxygen data revealed that RIC therapy significantly reduced the pro-inflammatory signaling markers, increased anti-inflammatory macrophage polarization and improved oxygen level in the TON+RIC [AMPKα1^F/F] group; however, RIC therapy did not reduce inflammatory signaling activation in the myeloid AMPKα1 KO mice. The transmission electron microscopy (TEM) data of the optic nerve showed increased demyelination and axonal degeneration in the TON [AMPKα1^F/F] group, and RIC improved the myelination process in TON [AMPKα1^F/F], but RIC had no significant effect in the AMPKα1 KO mice. The myeloid AMPKα1c deletion attenuated RIC induced anti-inflammatory macrophage polarization, and that suggests a molecular link between RIC and immune activation. Overall, these data suggest that RIC therapy provided protection against inflammation and neurodegeneration via myeloid AMPKα1 activation, but the deletion of myeloid AMPKα1 is not protective in TON. Further investigation of RIC and AMPKα1 signaling is warranted in TON. Full article

Background/Objectives: The antioxidant/antiapoptotic features of dapagliflozin (DPG) have mediated its beneficial actions against several experimental models. However, no studies have been conducted to determine whether DPG mitigates the renal injury triggered by cadmium (Cd). Herein, DPG was studied for its potential to attenuate kidney damage in Cd-intoxicated rats, as well as to unravel the mechanisms involving oxidative events, autophagy, and apoptosis. Methods: Histopathological analysis, immunohistochemical staining, and ELISA were conducted on kidney tissue samples. Results: Cd administration (5 mg/kg/day; p.o.) prompted significant renal damage, as evidenced by histopathological changes, elevated kidney injury molecule-1 (KIM-1) expression, and increased serum creatinine and urea. Interestingly, DPG (1 mg/kg/day; p.o.) significantly mitigated these harmful effects without affecting renal Cd metal accumulation. Mechanistically, DPG curbed Cd-induced renal pro-oxidant response and stimulated the antioxidant sirtuin 1 (SIRT1)/nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/heme oxygenase 1 (HO-1) axis. Moreover, DPG restored autophagy by decreasing sequestosome-1/protein 62 (SQSTM-1/p62) accumulation and stimulating the AMP-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR) pathway. In tandem, DPG suppressed Cd-induced apoptosis by lowering renal Bcl-2 associated-x protein (Bax) and cytochrome C (Cyt C) levels and caspase 3 activity. Conclusions: These findings indicate that DPG attenuates Cd-induced nephrotoxicity by enhancing the SIRT1/Nrf2/HO-1 antioxidant pathway, promoting AMPK/mTOR-directed autophagy, and inhibiting apoptotic cell death. Full article

Muscle atrophy, an age-related condition, presents a growing healthcare concern within the context of global population aging. While studies have investigated Hirsutella sinensis for its potential antifatigue properties, reports on its active components remain limited. This study evaluated the efficacy of H. sinensis mycelium extract on muscle health, utilizing a 1:1 water–ethanol preparation administered to C57BL/6 mice exhibiting acute hind leg atrophy. The results indicated no adverse effects, with significant improvements in muscle endurance and soleus muscle mass observed over a 14-day period. To further elucidate the mechanisms and effects of H. sinensis mycelium on dexamethasone-induced muscle atrophy, the water extract was fractionated into components of <3.5 kDa, 3.5–10 kDa, and >10 kDa using dialysis membranes. The investigation utilized a C2C12 cell atrophy model, induced by dexamethasone, to analyze the expression of relevant genes via qPCR. The results demonstrated that the <3.5 kDa and >10 kDa fractions significantly upregulated the expression of Myh2 and Myh7 genes while simultaneously downregulating the expression of MuRF-1 and Atrogin-1. It is noteworthy that the <3.5 kDa fraction exclusively enhanced MYHC protein expression and suppressed AMPK expression, as confirmed by Western blot analysis. This comprehensive pilot study suggests that the low-molecular-weight fraction of H. sinensis mycelium exhibits considerable potential for muscle mass preservation and atrophy mitigation. As a result, it offers a promising direction for the development of supplements aimed at addressing fatigue and preventing muscle atrophy. Full article

Neurodegenerative diseases (NDDs) are currently the most widespread neuronal pathologies in the world. Among these, the most widespread are Alzheimer’s disease (AD), dementia, Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD)—all characterized by a progressive loss of neurons in specific regions of the brain leading to varied clinical symptoms. At the basis of neurodegenerative diseases, an emerging role is played by genetic mutations in the leucine-rich repeat kinase 2 (LRRK2) gene that cause increased LRRK2 activity with consequent alteration of neuronal autophagy pathways. LRRK2 kinase activity requires GTPase activity which functions independently of kinase activity and is required for neurotoxicity and to potentiate neuronal death. Important in the neurodegeneration process is the upregulation of casein kinase (CK), which causes the alteration of the AMPK pathway by enhancing the phosphorylation of α-synuclein and huntingtin proteins, known to be involved in PD and HD, and increasing the accumulation of the amyloid-β protein (Aβ) for AD. Recent research has identified CK of the kinases upstream of LRRK2 as a regulator of the stability of the LRRK2 protein. Based on this evidence, this review aims to understand the direct involvement of individual kinases in NDDs and how their crosstalk may impact the pathogenesis and early onset of neurodegenerative diseases. 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