AMP-activated Protein Kinase Pathway Research Articles

Resveratrol-driven macrophage polarization: unveiling mechanisms and therapeutic potential

Resveratrol, a polyphenolic compound known for its diverse biological activities, has demonstrated multiple pharmacological effects, including anti-inflammatory, anti-aging, anti-diabetic, anti-cancer, and cardiovascular protective properties. Recent studies suggest that these effects are partly mediated through the regulation of macrophage polarization, wherein macrophages differentiate into pro-inflammatory M1 or anti-inflammatory M2 phenotypes. Our review highlights how resveratrol modulates macrophage polarization through various signaling pathways to achieve therapeutic effects. For example, resveratrol can activate the senescence-associated secretory phenotype (SASP) pathway and inhibit the signal transducer and activator of transcription (STAT3) and sphingosine-1-phosphate (S1P)-YAP signaling axes, promoting M1 polarization or suppressing M2 polarization, thereby inhibiting tumor growth. Conversely, it can promote M2 polarization or suppress M1 polarization by inhibiting the NF-κB signaling pathway or activating the PI3K/Akt and AMP-activated protein kinase (AMPK) pathways, thus alleviating inflammatory responses. Notably, the effect of resveratrol on macrophage polarization is concentration-dependent; moderate concentrations tend to promote M1 polarization, while higher concentrations may favor M2 polarization. This concentration dependence offers new perspectives for clinical treatment but also underscores the necessity for precise dosage control when using resveratrol. In summary, resveratrol exhibits significant potential in regulating macrophage polarization and treating related diseases.

IP6K1 rewires LKB1 signaling to mediate hyperglycemic endothelial senescence.

Diabetes is a major risk factor for cardiovascular disease, but the molecular mechanisms underlying diabetic vasculopathy have been elusive. Here we report that inositol hexakisphosphate kinase 1 (IP6K1) mediates hyperglycemia-induced endothelial senescence by rewiring the liver kinase B1 (LKB1) signaling from activating the adenosine monophosphate-activated protein kinase (AMPK) pathway to the p53 pathway. We found that hyperglycemia upregulated IP6K1, which disrupts the Hsp/Hsc70 and carboxyl terminus of Hsc70-interacting protein (CHIP)-mediated LKB1 degradation, leading to increased expression levels of LKB1. High glucose also strengthens the binding of IP6K1 to AMPK, suppressing the LKB1-mediated AMPK activation. Thus, the elevated LKB1 does not lead to the activation of the AMPK pathway. Instead, it binds more to p53, resulting in p53-dependent endothelial senescence. Endothelial-specific deletion of IP6K1 alleviates, whereas endothelial-specific overexpression of IP6K1 exaggerates the hyperglycemia-induced endothelial senescence. This study reveals a regulatory mechanism of IP6K1 in switching the LKB1/AMPK pathway to LKB1/p53 pathway. IP6K1 represents a potential therapeutic target for treating hyperglycemia-induced endothelial dysfunction.

Exploring the Therapeutic Role of Flavonoids Through AMPK Activation in Metabolic Syndrome: A Narrative Review.

Metabolic syndrome (MetS) is a cluster of interrelated metabolic abnormalities that significantly elevate the risk of cardiovascular disease, obesity, and diabetes. Flavonoids, a diverse class of bioactive polyphenolic compounds found in plant-derived foods and beverages, have garnered increasing attention as potential therapeutic agents for improving metabolic health. This review provides a comprehensive analysis of the therapeutic effects of flavonoids in the context of the MetS, with a particular focus on their modulation of the AMP-activated protein kinase (AMPK) pathway. AMPK serves as a central regulator of cellular energy balance, glucose metabolism, and lipid homeostasis, making it a critical target for metabolic intervention. Through a systematic review of the literature up to April 2024, preclinical studies across various flavonoid subclasses, including flavonols, and flavan-3-ols, were analysed to elucidate their mechanistic roles in metabolic regulation. Many studies suggests that flavonoids enhance glycolipid metabolism by facilitating glucose transporter 4 (GLUT4) translocation and activating the AMPK pathway, thereby improving glycemic control in diabetes models. In obesity-related studies, flavonoids demonstrated significant inhibitory effects on lipid synthesis, reduced adipogenesis, and attenuated proinflammatory cytokine secretion via AMPK activation. These findings show the broad therapeutic potential of flavonoids in addressing the MetS and its associated disorders. While these preclinical insights highlight flavonoids as promising natural agents for metabolic health improvement, it is important to note that their excessive concentrations may disrupt these pathways, potentially leading to metabolic imbalance and cytotoxicity. Further studies and clinical trials are essential to determine optimal dosing regimens, formulations, and the long-term safety and efficacy of flavonoids. This review highlights the importance of flavonoids for natural interventions targeting MetS and its comorbidities, offering a foundation for future translational research.

Interlinking the Cross Talk on Branched Chain Amino Acids, Water Soluble Vitamins and Adipokines in the Type 2 Diabetes Mellitus Etiology.

Type 2 Diabetes Mellitus (T2DM) is an etiologically diverse metabolic dysfunction that, if untreated, leads to chronic hyperglycemia. Understanding the etiology of T2DM is critical, as it represents one of the most formidable medical challenges of the twenty-first century. Traditionally, insulin resistance has been recognized as the primary risk factor and a well-known consequence of type 2 diabetes. Emerging evidence suggests that branched-chain amino acids (BCAAs), adipokines, and deficiencies in water-soluble vitamins, such as thiamine and pyridoxine, play significant roles in the development of insulin resistance, a key feature of T2DM. These factors are interconnected through the AMP-activated protein kinase (AMPK) pathway, which regulates various metabolic processes, including glucose transport, lipid synthesis, and inflammatory responses. Dysregulation of AMPK is linked to insulin resistance and metabolic syndrome-related illnesses. Understanding the interplay between BCAAs, adipokines, vitamins, and AMPK may offer new therapeutic targets for the prevention and treatment of diabetes mellitus.

Salinity stress impairs disease resistance in white shrimp, Penaeus vannamei through AMPK pathway, ameliorated by dietary glucose-mediated energy homeostasis.

This study presents a comprehensive examination of the physiological adaptations of white shrimp (Penaeus vannamei) to low-salinity conditions and evaluates the effects of supplementing dietary glucose on disease resistance. Compared to the control group, shrimp cultured at a salinity of 4psu exhibit significantly elevated expression levels of adenosine 5'-monophosphate-activated protein kinase (AMPK) in the hepatopancreas, which leads to increased energy expenditure and a corresponding reduction in resistance to infection by Vibrio alginolyticus. The suppression of AMPK via dsAMPK treatment markedly enhances disease resistance. Moreover, shrimp raised in low salinity conditions exhibit downregulation of mTOR-associated molecules, including Lipin-1 and hypoxia-inducible factor 1-α (HIF-1α), both of which are essential for immune regulation. Metabolic assessments revealed reduced ATP levels and disrupted ATP/AMP and ATP/ADP ratios, indicating energy imbalance under low salinity stress. Notably, supplementing the diet with 1% glucose significantly increased glycogen reserves and ATP content, stabilized hemolymph glucose levels, and upregulated glycolysis-related genes, thereby optimizing energy metabolism and enhancing resilience to stress. This study underscores that AMPK activation in response to low salinity conditions leads to increased energy expenditure, which in turn lowers disease resistance. Furthermore, it underscores the critical role of strategic dietary management in maintaining energy homeostasis and improving disease resistance in white shrimp under stressful environmental conditions associated with climate change, offering valuable insights for aquaculture nutrition strategies.

Metformin-based nanomedicines for reprogramming tumor immune microenvironment.

Immunotherapy has transformed current cancer management, and it has achieved significant progress over last decades. However, an immunosuppressive tumor microenvironment (TME) diminishes the effectiveness of immunotherapy by suppressing the activity of immune cells and facilitating tumor immune-evasion. Adenosine monophosphate-activated protein kinase (AMPK), a key modulator of cellular energy metabolism and homeostasis, has gained growing attention in anti-tumor immunity. Metformin is usually considered as a cornerstone in diabetes management, and its role in activating the AMPK pathway has also been extensively explored in cancer therapy although the findings on its role remain inconsistent. Metformin in a nanomedicine formulation has been found to hold potential in reprogramming the immunosuppressive TME through immunometabolic modulation of both tumor and immune cells. This review elaborates the foundation and progress of immunometabolic reprogramming of the TME via metformin-based nanomedicines, offering valuable insights for the next generation of cancer therapy.

A mitochondria-interfering nanocomplex cooperates with photodynamic therapy to boost antitumor immunity.

Immunotherapeutics against triple-negative breast cancer (TNBC) hold great promise. In this work, we provide a combination therapy for simultaneous increasing tumor immunogenicity and down-regulating programmed cell death ligand 1 (PD-L1) to boost antitumor immunity in TNBC. We prepare bis (diethyldithiocarbamate)-copper/indocyanine green nanoparticles (CuET/ICG NPs) simply in aqueous with one-pot method. CuET/ICG NPs interfere mitochondria, reduce oxygen consumption, and alleviate tumor hypoxia to potentiate photodynamic therapy (PDT) for amplifying immunogenic cell death (ICD). Meanwhile, mitochondria dysfunction leads to energy stress and activates AMPK pathway. As a result, CuET/ICG NPs downregulates membrane PD-L1 (mPD-L1) on both 4T1 cancer cells and cancer stem cells (CSCs) through AMP-activated protein kinase (AMPK)-mediated pathway in hypoxia. Cooperatively, the combinational therapy activates antitumor immunity and triggers long lasting immune memory response to resist tumor re-challenge. Our study represents an attempt that conquers tumor immunosuppressive microenvironment with simple biomedical materials and multimodality treatments.

Copper-coordination driven brain-targeting nanoassembly for efficient glioblastoma multiforme immunotherapy by cuproptosis-mediated tumor immune microenvironment reprogramming

Limited drug accumulation and an immunosuppressive microenvironment are the major bottlenecks in the treatment of glioblastoma multiforme (GBM). Herein, we report a copper-coordination driven brain-targeting nanoassembly (TCe6@Cu/TP5 NPs) for site-specific delivery of therapeutic agents and efficient immunotherapy by activating the cGAS-STING pathway and downregulating the expression of PD-L1. To achieve this, the mitochondria-targeting triphenylphosphorus (TPP) was linked to photosensitizer Chlorin e6 (Ce6) to form TPP-Ce6 (TCe6), which was then self-assembled with copper ions and thymopentin (TP5) to obtain TCe6@Cu/TP5 NPs. This nanoassembly effectively accumulated in tumor sites through the copper transport mechanism. Meanwhile, TCe6@Cu/TP5 could induce mitochondrial impairment by photodynamic therapy (PDT) mediated reactive oxygen species (ROS) accumulation and Cu2+ triggered cuproptosis, resulting in evoking the AMP-activated protein kinase (AMPK) pathway to degrade PD-L1, and activating the cGAS-STING pathway to enhance anti-tumor immunity. Moreover, TP5 significantly promoted the proliferation and differentiation of dendritic cells (DCs) and T lymphocytes to further amplify the cancer immunity cycle. Collectively, our TCe6@Cu/TP5 NPs effectively facilitate drug accumulation and activate systemic antitumor immunity in vitro and in vivo, providing an innovative solution across the BBB that potentiates GBM immunotherapy.Graphical

Ytterbium Doping-Retooled Prussian Blue for Tumor Metabolism Interference Therapy.

Drug repurposing refers to excavating clinically approved drugs for new clinical indications, effectively shortening the cost and time of clinical evaluation due to the established molecular structure, pharmacokinetics, and pharmacodynamics. In this sense, clinically approved Prussian blue (PB) has received considerable attention, by virtue of its unique optical, magnetic, and enzymatic performance. Nevertheless, the clinical transformation of PB-based nanodrugs remains restricted owing to their complex synthetic formulation and constrained therapeutic performance. Herein, inspired by diagnostic and therapeutic superiorities of lanthanide ions, a series of ytterbium (Yb)-containing PB nanoparticles (NPs) are synthesized in one step through interstitial Yb-doping, which aims to improve the anticancer efficacy of PB and expand the biological application orientation of Yb ions. Through a systematic comparative analysis, involving microscopic morphology, size distribution, elemental composition, raw material utilization rate, and crystal structure, Yb-enriched PB NPs with better-balanced indexes are identified as an antineoplastic drug candidate. In parallel, their anticancer mechanisms are associated with the mammalian target of rapamycin (mTOR) and adenosine monophosphate-activated protein kinase (AMPK) pathways, thus disturbing anabolism, catabolism, and homeostasis. Therefore, this study attempts to implement the concept of drug repurposing and lays the foundation for next-generation theranostic nanodrugs.

The microbial metabolite imidazole propionate dysregulates bone homeostasis by inhibiting AMP-activated protein kinase (AMPK) signaling

Microbial metabolites provide numerous benefits to the human body but can also contribute to diseases such as obesity, diabetes, cancer, and bone disorders. However, the role of imidazole propionate (ImP), a histidine-derived metabolite produced by the intestinal microbiome, in bone metabolism and the development of osteoporosis is still poorly understood. In this study, we investigated the role of ImP and its underlying mechanisms in regulating bone homeostasis. When ImP was administered to 8-week-old mice for 4 weeks, bone loss was observed, along with a decrease in alkaline phosphatase-positive osteoblast cells. Additionally, bone marrow stromal cells (BMSCs) isolated from ImP-treated mice exhibited reduced osteogenic potential. In BMSCs from control mice, ImP treatment inhibited BMP2-induced osteoblast differentiation while promoting adipocyte differentiation. However, ImP had no effect on RANKL-induced osteoclast differentiation or activity in bone marrow macrophages. Mechanistically, ImP treatment increased p38γ phosphorylation and decreased AMPK (T172) phosphorylation in BMSCs. Suppression of p38γ expression using si-p38γ reversed the inhibitory effects of ImP on osteoblast differentiation, with a concurrent increase in AMPK (T172) phosphorylation. Conversely, ImP stimulated adipocyte differentiation by decreasing AMPK (T172) phosphorylation. Treatment with the AMPK agonist metformin significantly reversed the inhibitory effects of ImP on osteoblast differentiation and the promotion of adipocyte differentiation, along with enhanced AMPK (T172) phosphorylation. These findings suggest that the microbial metabolite ImP may disrupt bone homeostasis by stimulating p38γ phosphorylation and inhibiting the AMPK pathway, presenting a potential therapeutic target for managing metabolic bone diseases.

Coniferaldehyde activates autophagy and enhances oxidative stress resistance and lifespan of Caenorhabditis elegans via par-4/aak-2/skn-1 pathway.

Aging represents the gradual accumulation of alterations within an organism over time. The physical and chemical characteristics of our cells gradually change as we age, making it more difficult for our tissues and organs to self-regulate, regenerate, and maintain their structural and functional integrity. AMP- activated protein kinase (AMPK), a well-known sensor of cellular energy status acts as a central regulator of an integrated signalling network that control homeostasis, metabolism, stress resistance, cell survival and autophagy. Coniferaldehyde (CFA), a phenolic compound found in many edible plants, has multiple biological and pharmacological functions. Our findings demonstrated that 50µM CFA could significantly activate autophagy and reduce oxidative stress, which enhanced the activity of antioxidant enzymes and increased resistance under oxidative stress. CFA treatment could efficiently decrease reactive oxygen species (ROS) levels and positively enhance the expression of antioxidant genes in Caenorhabditis elegans (C. elegans). On the other hand, CFA did not have any role in the lifespan extension of the several mutants linked to the AAK-2/AMPK pathway and it promotes SKN-1 (Skinhead-1) localization into the nucleus, which modulates downstream gene gst-4 (Glutathione S-transferase). In depth investigations revealed that CFA could lower oxidative stress and enhance the lifespan of C. elegans by activating the PAR-4/LKB-1-AAK-2/AMPK-SKN-1/NRF-2 pathway, with crucial involvement of bec-1 and lgg-1 genes for autophagy mediated lifespan extension. This study might contribute to understanding the interactions and mechanisms that allow natural compounds like CFA to treat age-related disorders among several species.

Tryptophan regulates food intake in growing pigs by modulating hypothalamic AMPK-mTOR signaling pathway.

Tryptophan (Trp) is an essential amino acid acting as a key nutrition factor regulating animal growth and development. But how Trp modulates food intake in pigs is still not well known. Here, we investigated the effect of dietary supplementation of Trp with different levels on food intake of growing pigs. The data showed that dietary Trp supplementation with the standardized ileal digestibility (SID) Trp to Lysine (Lys) ratio at both 0.18 and 0.20 significantly increased the food intake by activating the expression of orexigenic gene agouti-related peptide (AgRP) and inhibiting the expression of anorexigenic gene pro-opiomelanocortin (POMC), cocaine- and amphetamine-regulated transcript (CART) and melanocortin receptor 4 (MC4R) in the hypothalamus. Meanwhile, the level of anorexigenic hormones appetite-regulating peptide YY (PYY) in the duodenum and serum, and Leptin receptor in the duodenum were also significantly decreased. Importantly, both the kynurenine and serotonin metabolic pathways were activated upon dietary Trp supplementation to downregulate MC4R expression in the hypothalamus. Further mechanistic studies revealed that the reduced MC4R expression activated the hypothalamic AMP-activated protein kinase (AMPK) pathway, which in turn inhibited the mTOR /S6K1 activity to stimulate food intake. Together, our study unravels the orexigenic effect of dietary Trp supplementation in pigs and expands its potential application in developing nutrition intervention strategy in pig production.

Evolutionary novelty of Apolipoprotein D facilitates metabolic plasticity in lepidopteran wings.

Understanding metabolic plasticity of animal evolution is a fundamental challenge in evolutionary biology. Owing to the diversification of insect wing morphology and dynamic energy requirements, the molecular adaptation mechanisms underlying the metabolic pathways in wing evolution remain largely unknown. This study reveals the pivotal role of the duplicated Apolipoprotein D (ApoD) gene in lipid and energy homeostasis in the lepidopteran wing. ApoD underwent significant expansion in insects, with gene duplication and consistent retention observed in Lepidoptera. Notably, duplicated ApoD2 was highly expressed in lepidopteran wings and encoded a unique C-terminal tail, conferring distinct ligand-binding properties. Using Bombyx mori as a model organism, we integrated evolutionary analysis, multiomics, and in vivo functional experiments to elucidate the way duplicated ApoD2 mediates lipid trafficking and homeostasis via the AMP-activated protein kinase pathway in wings. Moreover, we revealed the specific expression and functional divergence of duplicated ApoD as a key mechanism regulating lipid homeostasis in the lepidopteran wing. These findings highlight an evolutionary scenario in which neofunctionalization conferred a novel role of ApoD in shaping adaptive lipid metabolic regulatory networks during wing phenotypic evolution. Overall, we provide in vivo evidence for the functional differentiation of duplicate genes in shaping adaptive metabolic regulatory networks during phenotypic evolution.

Semaglutide Improves Myocardial Perfusion and Performance in a Large Animal Model of Coronary Artery Disease.

Coronary artery disease is the leading cause of death worldwide. It imposes an enormous symptomatic burden on patients, leaving many with residual disease despite optimal procedural therapy and up to one-thirds with debilitating angina amenable neither to procedures, nor to current pharmacological options. Semaglutide (SEM), a GLP-1 (glucagon-like peptide 1) agonist originally approved for management of diabetes, has garnered substantial attention for its capacity to attenuate cardiovascular risk. Although subgroup analyses in patients indicate promise, studies explicitly designed to isolate the impact of SEM on the sequelae of coronary artery disease, independently of comorbid diabetes or obesity, are lacking. Yorkshire swine (n=17) underwent placement of an ameroid constrictor around the left circumflex coronary artery to induce coronary artery disease. Oral SEM was initiated postoperatively at 1.5 mg and scaled up in 2 weeks to 3 mg in treatment animals (n=8) for a total of 5 weeks, while control animals (n=9) received no drug. All then underwent myocardial harvest with acquisition of perfusion and functional data using microsphere injection and pressure-volume loop catheterization. Immunoblotting, immunohistochemistry, and immunofluorescence were performed on the most ischemic myocardial segments for mechanistic elucidation. SEM animals exhibited improved left ventricular ejection fraction, both at rest and during rapid myocardial pacing (both P<0.03), accompanied by increased perfusion to the most ischemic myocardial region at rest and during rapid pacing (both P<0.03); reduced perivascular and interstitial fibrosis (both P<0.03); and apoptosis (P=0.008). These changes were associated with increased activation of the endothelial-protective AMPK (AMP-activated protein kinase) pathway (P=0.005), coupled with downstream increases in eNOS (endothelial NO synthase; P=0.014). This study reveals the capacity of oral SEM to augment cardiac function in the chronically ischemic heart in a highly translational large animal model, likely through AMPK-mediated improvement in endothelial function and perfusion to the ischemic myocardium.

Fermented Gold Kiwifruit Protects Mice Against Non-Alcoholic Fatty Liver Disease in a High-Fat Diet Model

Gold kiwifruit is known for its high vitamin C content and various benefits. This study investigated the effects and molecular mechanisms of fermented gold kiwifruit (FGK) in a mouse model of high-fat diet (HFD)-induced obesity and hepatic steatosis. FGK powder was prepared using five strains of lactic acid bacteria: L. paracasei, Lc. lactis, L. acidophilus, L. casei, and L. helveticus. ICR mice were fed an HFD for 8 weeks to induce obesity and hepatic steatosis, and FGK supplementation was evaluated for its therapeutic potential. FGK administration significantly reduced serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol, triglyceride, and glucose compared to the HFD-only group. Histopathological analysis showed that FGK reduced lipid accumulation and hepatic lesions, as confirmed by hematoxylin and eosin (H&amp;E) staining. Furthermore, administration of FGK activated the sirtuin 1(SIRT1)/adenosine monophosphate-activated protein kinase (AMPK) pathway and inhibited expression of the pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α in liver tissue. These findings suggest that FGK could reduce the severity of non-alcoholic fatty liver disease (NAFLD) by inhibiting fat synthesis, promoting fat breakdown, and suppressing inflammation in HFD-induced obese mice.

Aflatoxin B1 Promotes Pyroptosis in IPEC-J2 Cells by Disrupting Mitochondrial Dynamics through the AMPK/NLRP3 Pathway.

Aflatoxin B1 (AFB1) is one of the most toxic mycotoxins in food and feed, seriously jeopardizing the intestinal health, while the effects of AFB1 on intestinal damage remain to be well understood. This study aims to evaluate the effect of AFB1 on intestinal injury by regulating AMP-activated protein kinase (AMPK)-mediated pyroptosis in vitro. The present study showed that AFB1 led to the formation of large number of bubble-like protrusions on the cell membrane, releasing lactate dehydrogenase (LDH) and interleukin-1β (IL-1β). Stimulation with AFB1 resulted in the activation of the NOD-like receptor protein 3 (NLRP3) pathway, as indicated by the increased expression of pyroptosis-associated factor mRNAs and proteins, which ultimately led to a significant upregulation of the pyroptosis rate. Meanwhile, AFB1 caused dysfunction of mitochondrial dynamics by activating the AMPK signaling pathway as mainly evidenced by upregulating dynamin-1-like protein 1 (Drp1) mRNA and protein expression. Moreover, inhibition of NLRP3 and AMPK pathways by MCC950 and compound C, respectively, significantly alleviated AFB1-induced damage in IPEC-J2 cells, evidenced by suppressed NLRP3-mediated pyroptosis, and ameliorated AMPK-mediated mitochondrial dynamics imbalance. In conclusion, these results demonstrated that AFB1 promoted pyroptosis of IPEC-J2 cells by interfering with mitochondrial dynamics by activating the AMPK/NRLP3 pathway.

Single-Cell Sequencing Combined with Transcriptome Sequencing to Explore the Molecular Mechanisms Related to Skin Photoaging.

The aging of skin is a diversified biological phenomenon, influenced by a combination of genetic and environmental factors. However, the specific mechanism of skin photoaging is not yet completely elucidated. Gene expression profiles for photoaging patients were obtained from the Gene Expression Omnibus (GEO) collection. We conducted single-cell and intercellular communication investigations to identify potential gene sets. Predictive models were created using LASSO regression. The relationships between genes and immune cells were investigated using single sample gene set enrichment analysis (ssGSEA) and gene set variance analysis (GSVA). The molecular processes of important genes were studied using gene enrichment analysis. A miRNA network was created to look for target miRNAs connected with important genes, and transcriptional regulation analysis was used to identify related transcription factors. Finally, merging gene co-expression networks with drug prediction shows molecular pathways of photoaging and potential treatment targets. Furthermore, we validated the role of key genes, immune cell infiltration, and the Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) pathway in photoaging, which were identified through bioinformatics analysis, using in vivo reverse transcription quantitative PCR (RT-qPCR), immunofluorescence labeling, and Western blotting. This study discovered three key genes, including Atp2b1, Plekho2, and Tspan13, which perform crucial functions in the photoaging process. Immune cell infiltration analysis showed increased M1 macrophages and CD4 memory T cells in the photoaging group. Further signaling pathway analysis indicated that these key genes are enriched in multiple immune and metabolic pathways. The significant roles of Atp2b1, Plekho2, Tspan13, M1 macrophages infiltration, CD4 memory T cells infiltration and the AMPK pathway in photoaging was validated in vivo. This research revealed the underlying molecular mechanisms of photoaging, indicating that key genes such as Atp2b1 and Tspan13 play crucial roles in the regulation of immune cell infiltration and metabolic pathways. These findings provide a new theory for the treatment of photoaging and provide prospective targets for the advancement of relevant drugs.

C1q/tumor necrosis factor-related protein-6 suppresses the angiotensin II-induced differentiation of cardiac fibroblasts to myofibroblasts via activation of the AMPK pathway.

C1q/tumor necrosis factor-related protein-6 (CTRP6) has multiple protective effects against cardiovascular diseases. Myofibroblast differentiation plays a critical role in cardiac fibrosis under various cardiac pathological conditions. The aim of the present study was to determine the effects of CTRP6 on cardiac fibrosis, and to identify the possible mechanisms of action. Toward this end, we measured the expression of fibrotic markers, including collagen I, collagen III, CTGF, and TGFβ1, and assessed the effects of CTRP6 on cardiac fibroblast differentiation into myofibroblasts. CTRP6 inhibited the expression of the angiotensin II (Ang II)-induced myofibroblast markers α-SMA and SM22, and of profibrotic molecules, including collagen I, collagen III, CTGF, TGFβ1, MMP2, MMP9, and TIMP1. Furthermore, CTRP6 significantly attenuated the proliferation and migration of cardiac fibroblasts incubated with Ang II and activated the phosphorylation of AMP-activated protein kinase (AMPK). Incubation with an AMPK inhibitor reversed the subsequent inhibitory effects of CTRP6 on Ang II-induced myofibroblast differentiation. Therefore, CTRP6 suppresses cardiac fibrosis by inhibition of myofibroblast differentiation via AMPK pathway activation, suggesting CTRP6 as a target for the treatment of cardiac fibrosis.

Fisetin ameliorates polycystic ovary syndrome in rats via a mechanistic modulation of AMP-activated protein kinase and SIRT1 molecular pathway.

Fisetin, a polyphenolic flavonoid, exhibits numerous pharmacological activities against metabolic syndromes. The present research aims to explore the therapeutic efficacy of fisetin in experimental polycystic ovary syndrome (PCOS). Female Sprague-Dawley rats were administered mifepristone (20mg/kg/day) to induce PCOS. PCOS rats were treated with fisetin (20mg/kg and 40mg/kg) and further compared with metformin HCl, the conventional drug for PCOS. The mechanism of fisetin was explored using dorsomorphin (an AMPK inhibitor). Then, rats were sacrificed for further analysis of biochemical and histological parameters. PCOS rats exhibited irregular estrous cycles, increased serum testosterone (4.72 ± 0.139ng/ml), estradiol (750.2 ± 16.56pg/ml), LH (30.33 ± 1.563 mIU/ml), HOMA-IR (1.115 ± 0.049), TNF-α (86.59 ± 3.93pg/ml), IL-6 (55.34 ± 4.432pg/ml), and TBARS (3.867 ± 0.193µmol/mg) along with declined progesterone (11.67 ± 1.54ng/ml), FSH (13.33 ± 1.256 mIU/ml), GSH (33.47 ± 1.348µmol/mg) levels, and SOD (2.163 ± 0.298 U/mg) activity as compared to normal control group. Fisetin high dose significantly lowers testosterone (3.014 ± 0.234ng/ml), estradiol (533.7 ± 15.39pg/ml), LH (16.67 ± 1.62 mIU/ml), HOMA-IR (0.339 ± 0.20), TNF-α (46.02 ± 2.66pg/ml), IL-6 (31.77 ± 3.47pg/ml), and TBARS (1.747 ± 0.185µmol/mg) and enhances progesterone (33.17 ± 1.447ng/ml), FSH (27.17 ± 1.42 mIU/ml), GSH (60.35 ± 1.1.102µmol/mg) levels, and SOD (4.513 ± 0.607 U/mg) activity. The histology of ovarian tissues shows a significant increase in cystic follicles in PCOS rats compared with the normal control group. These alterations were attenuated with fisetin treatment. Administration of dorsomorphin with fisetin can reverse the beneficial effects of fisetin in PCOS rats. Altogether, these present findings highlight the potential of fisetin as a promising therapeutic intervention for the management of PCOS by modulating AMPK/SIRT1 signaling in rats.

IFITM1 aggravates ConA-Induced autoimmune hepatitis by promoting NKT cell activation through increased AMPK-Dependent mitochondrial function

Although interferon-induced transmembrane 1 (IFITM1) is known for its crucial role in antiviral immunity, its involvement in autoimmune hepatitis (AIH) remains largely unexplored. In this study, we observed that IFITM1 expression is markedly upregulated in a Concanavalin A (ConA)-induced AIH model, with particularly high and markedly elevated expression in natural killer T (NKT) cells. To further understand the role of IFITM1, we examined the responses of IFITM1−/− mice in a model of ConA-induced liver injury. In comparison to wild-type mice, IFITM1−/− mice exhibited reduced sensitivity in this model, as evidenced by significantly ameliorated necrosis areas, lower serum aminotransferase levels, a reduced number of intrahepatic NKT cells, and decreased expression of inflammatory factors, such as IL-1β, IL-6, IFN-γ and TNF-α. Notably, by using IFITM1-GFP mice and IFITM1−/− mice, we demonstrated that IFITM1 expression in NKT cells is crucial for their proliferation, proinflammatory cytokine production, and cytotoxic functions. Furthermore, analysis of single-cell RNA sequencingdata revealed that IFITM1 is essential for mitochondrial function, which is mediated by the AMP-activated protein kinase (AMPK) pathway. We also validated the importance of IFITM1 for the AMPK pathway and mitochondrial ATP synthesis in vivo. Together, our findings elucidate that IFITM1 could regulate NKT cell activation and survival by promoting mitochondrial function during AIH.