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• Hydroxy-α-sanshool induced liver injury in mice and had hepatotoxicity. • Hydroxy-α-sanshool induced liver lipid metabolism disorder, leading to abnormal accumulation of liver lipid. • Hydroxy-α-sanshool-induced hepatic lipid accumulation is associated with AMPK inactivation. • Hydroxy-α-sanshool induces lipid synthesis and mitochondrial dysfunction by inhibiting AMPK signaling pathway, leading to liver lipid metabolism disorders. With the increasing awareness of the safety of traditional Chinese medicine and food, as well as in-depth studies on the pharmacological activity and toxicity of Zanthoxylum armatum DC. (ZADC), it has been found that ZADC is hepatotoxic. However, the toxic substance basis and mechanism of action have not been fully elucidated. Hydroxy-α-sanshool (HAS) belongs to an amide compound in the fruits of ZADC, which may be hepatotoxic. However, the specific effects of HAS, including liver toxicity, are unclear. The objectives of this research was to determine how HAS affects hepatic lipid metabolism, identify the mechanism underlying the accumulation of liver lipids by HAS, and offer assurances on the safe administration of HAS. An in vivo experiment was performed by gavaging C57 BL/6 J mice with various dosages of HAS (5, 10, and 20 mg/kg). Biochemical indexes were measured, and histological analysis was performed to evaluate HAS hepatotoxicity. Hepatic lipid levels were determined using lipid indices and oil red O (ORO) staining. Intracellular lipid content were determined by biochemical analyses and ORO staining after treating HepG2 cells with different concentrations of HAS in vitro. Mitochondrial membrane potential, respiratory chain complex enzymes, and ATP levels were assessed by fluorescence labeling of mitochondria. The levels of proteins involved in lipogenesis and catabolism were determined using Western blotting. Mice in the HAS group had elevated alanine and aspartate aminotransferase blood levels as well as increased liver index compared with the controls. The pathological findings showed hepatocellular necrosis. Serum and liver levels of triglycerides, total cholesterol, and low-density lipoprotein cholesterol levels were increased, whereas high-density lipoprotein cholesterol levels decreased. The ORO staining findings demonstrated elevated liver lipid levels. In vitro experiments demonstrated a notable elevation in triglyceride and total cholesterol levels in the HAS group. ATP, respiratory chain complex enzyme gene expression, mitochondrial membrane potential, and mitochondrial number were reduced in the HAS group. The levels of lipid synthesis-associated proteins (ACC, FASN, and SREBP-1c) were increased, and lipid catabolism-associated protein levels (PPARα and CPT1) and the p-AMPK/AMPK ratio were decreased in vivo and in vitro. HAS has hepatotoxic effects, which can induce fatty acid synthesis and mitochondrial function damage by inhibiting the AMPK signaling pathway, resulting in aberrant lipid increases. [Display omitted] [ABSTRACT FROM AUTHOR]

Mule ducks tend to accumulate abundant fat in their livers via feeding, which leads to the formation of a fatty liver that is several times larger than a normal liver. However, the mechanism underlying fatty liver formation has not yet been elucidated. Fibroblast growth factor 1 (FGF1), a member of the FGF superfamily, is involved in cellular lipid metabolism and mitosis. This study aims to investigate the regulatory effect of FGF1 on lipid metabolism disorders induced by complex fatty acids in primary mule duck liver cells and elucidate the underlying molecular mechanism. Hepatocytes were induced by adding 1,500:750 µmol/L oleic and palmitic acid concentrations for 36 h, which were stimulated with FGF1 concentrations of 0, 10, 100, and 1000 ng/mL for 12 h. The results showed that FGF1 significantly reduced the hepatic lipid droplet deposition and triglyceride content induced by complex fatty acids; it also reduced oxidative stress; decreased reactive oxygen species fluorescence intensity and malondialdehyde content; upregulated the expression of antioxidant factors nuclear factor erythroid 2 related factor 2 (Nrf2), HO-1, and NQO-1; significantly enhanced liver cell activity; promoted cell cycle progression; inhibited cell apoptosis; upregulated cyclin-dependent kinase 1 (CDK1) and BCL-2 mRNA expression; and downregulated Bax and Caspase-3 expression. In addition, FGF1 promoted AMPK phosphorylation, activated the AMPK pathway, upregulated AMPK gene expression, and downregulated the expression of SREBP1 and ACC1 genes, thereby alleviating excessive fat accumulation in liver cells induced by complex fatty acids. In summary, FGF1 may alleviate lipid metabolism disorders induced by complex fatty acids in primary mule duck liver cells by activating the AMPK signaling pathway. [ABSTRACT FROM AUTHOR]

In this study, we examined the impact of adding Lactobacillus to the diet on fat distribution and meat quality of Sunit lambs. For 90 days, twenty-four lambs (19.31 ± 0.47 kg) were fed diets that contained 0 (NP), 6 (P1), 12 (P2), or 24 (P3) g of Lactobacillus casei /d. The results suggested that dietary supplementation with Lactobacillus decreased serum triglyceride in Sunit lambs (P < 0.001). The loin muscle area displayed notable increases in the P1 group (P < 0.05). Meanwhile, tail and visceral fat deposition of lambs were reduced when Lactobacillus was added to the diet (P < 0.05). Compared with the NP group, the values of shear force and cooking loss of in the P1 group exhibited a significant reduction, and intramuscular fat content increased significantly (P < 0.05). Additionally, the P1 group showed an increase in polyunsaturated fatty acids and a decrease in saturated fatty acids in the longissimus thoracis and biceps femoris muscles (P < 0.05). The P1 group showed downregulation of protein kinase AMP-activated catalytic subunit alpha 2 (AMPKα2) and carnitine palmitoyltransferase 1B expression in the longissimus thoracis muscle (P < 0.05). However, there was an upregulation of acetyl-CoA carboxylase (ACC), sterol regulatory element binding transcription factor 1 (SREBF1), and fatty acid synthase (FASN) expression (P < 0.05). In conclusion, feeding Sunit lambs 6 g/d of Lactobacillus as a dietary supplement may be a valuable way to improve fat distribution and meat quality. The AMPK/ACC and AMPK/SREBF1/FASN signaling pathways may be involved in this outcome. • Lactobacillus supplementation improved the lipid metabolism in Sunit lamb. • Supplementing with 6 g/d of Lactobacillus increased intramuscular fat accumulation. • Adding 6 g/d of Lactobacillus improved the fatty acid composition of Sunit lamb. • AMPK signaling pathway has a critical role in improved fat deposition in Sunit lamb. [ABSTRACT FROM AUTHOR]

• ZEA promoted TM4 cells autophagy and modulated the AMPK/mTOR/P70S6K signaling pathways. • AMPK signaling pathway is involved in ZEA-induced autophagy in TM4 cells. • ZEA induced endoplasmic reticulum stress led to Ca2+ release in the lumen of the endoplasmic reticulum and activated CaMKKβ. • ZEA induced autophagy via Ca2+ mediated CaMKKβ /AMPK pathway in TM4 cells. Zearalenone (ZEA) is a prevalent non-steroidal estrogenic mycotoxin produced mainly by Fusarium contamination. Our previous study showed that ZEA induces the autophagy of Sertoli cells (SCs). However, the underlying mechanisms are still unknown. Several studies have indicated that the increasing level of cytoplasmic Ca2+ could induce autophagy through CaMKKβ and AMPK pathways. Thus in order to investigate the potential mechanism underlying ZEA-induced autophagy, the activity of calmodulin-dependent kinase kinase β(CaMKKβ)and AMP-activated protein kinase (AMPK) signaling pathway in ZEA-infected TM4 cells was studied. In the present study, ZEA activated the CaMKKβ and AMPK signaling pathways. The AMPK inhibitor and activator significantly inhibited and stimulated the effect of ZEA on AMPK, the transformation from LC3I to LC3II, and the distribution of LC3 dots. In addition, cytosolic calcium (Ca2+) was increased gradually with the concentration of ZEA. After treatment of ZEA-infected cells with 1, 2-bis (2-aminophenoxy) ethane-N, N, N', N'- tetraacetic acid- tetraac etoxymethyl ester (BAPTA-AM) and 2-aminoethyl diphenylborinate (2-APB), the intracellular concentration of Ca2+ reduced significantly. Also, the activities of CaMKKβ and AMPK and subsequent autophagy decreased. Moreover, the antioxidant NAC significantly decreased activities of AMPK and autophagy -related protein. Therefore, it can be speculated that ROS- mediated ER-stress induced by ZEA activates AMPK via Ca2+-CaMKKβ leading to autophagy in TM4 cells. [ABSTRACT FROM AUTHOR]

• Theaflavin inhibits african swine fever virus (ASFV) replication ex vivo in primary porcine alveolar macrophages. • Theaflavin inhibits ASFV replication via the AMPK signaling pathway. • Intracellular cholesterol and glycerides decreased with theaflavin treatment. • Theaflavin may be a lead compound for anti- ASFV drug development. African swine fever virus (ASFV) is the etiological agent of African swine fever (ASF), which is one of the most harmful swine diseases in the pig industry because of its nearly 100% mortality rate in domestic pigs and results in incalculable economic loss. Ever since ASF was initially reported, scientists have worked to develop anti-ASF vaccines; however, currently no clinically effective vaccine for ASF is available. Therefore, the development of novel measures to prevent ASFV infection and transmission is essential. In this study, we aimed to investigate the anti-ASF activity of theaflavin (TF), a natural compound mainly isolated from black tea. We found that TF potently inhibited ASFV replication at non-cytotoxic concentrations ex vivo in primary porcine alveolar macrophages (PAMs). Mechanistically, we found that TF inhibited ASFV replication by acting on cells rather than interacting directly with ASFV to inhibit viral replication. Further, we found that TF upregulated the AMPK (5′-AMP-activated protein kinase) signaling pathway in ASFV-infected and uninfected cells, and treatment with the AMPK agonist MK8722 upregulated the AMPK signaling pathway and inhibited ASFV proliferation in a dose-dependent manner. Notably, the effects of TF on AMPK activation and ASFV inhibition were partially reversed by the AMPK inhibitor dorsomorphin. In addition, we found that TF down-regulated the expression of genes related to lipid synthesis and decreased the intracellular accumulation of total cholesterol and total triglycerides in ASFV-infected cells, suggesting that TF may inhibit ASFV replication by disrupting lipid metabolism. In summary, our results demonstrated that TF is an ASFV infection inhibitor and revealed the mechanism by which ASFV replication is inhibited, providing a novel mechanism and potential lead compound for the development of anti-ASFV drugs. [ABSTRACT FROM AUTHOR]

In skeletal muscle, the increased proportion of type I muscle fibers has the potential to improve muscle atrophy and prevent human metabolic diseases. Protocatechuic acid (PCA), as a kind of anthocyanin metabolite, has antioxidant and anti-inflammatory physiological activities. The purpose of this experiment was to use mice and C2C12 myotubes to examine if PCA can induce the transformation of muscle fiber and the mechanisms involved. We found that PCA significantly increased the expression of slow myosin heavy chain (MyHC), and markedly decreased the expression of fast MyHC in gastrocnemius muscle of mice and C2C12 myotubes. In addition, PCA also enhanced the antioxidant capacity and promoted mitochondrial biogenesis in mice. Importantly, the AMP-activated protein kinase (AMPK) signaling pathway was activated and AMPK inhibitor compound C attenuated the positive effect of PCA on myofiber conversion. To sum up, we revealed that PCA was able to promote the conversion of skeletal muscle fiber from type II to type I through the AMPK signaling pathway. Protocatechuic acid (PCA) improves the antioxidant capacity, mitochondrial biogenesis in mice, and promotes skeletal muscle fiber type transformation from type II to type I. In addition, AMPK signaling pathway mediates PCA-induced muscle fiber type transformation. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • Transcriptomics and metabolomics were used to analyze the mechanism of XGHP in COPD. • XGHP regulates fatty acid metabolism through AMPK signaling pathway. • Increasing unsaturated fatty acid biosynthesis can improve energy homeostasis in COPD. Xixin-Ganjiang Herb Pair (XGHP), a classic combination treatment to warm the lungs and dissolve phlegm, is widely used in the treatment of various pulmonary diseases. Chronic obstructive pulmonary disease (COPD) refers to a group of chronic obstructive airway diseases that can seriously harm human health. However, the effective components, targets, and pathways that underlie XGHP in the treatment of COPD remain unclear. Therefore, this study initially identified the effective components of XGHP through the use of UPLC–MS/MS and pharmacologic methods of traditional Chinese medicine. Secondly, transcriptomic analysis of the lung tissues of rats revealed the pharmacodynamic transcripts of each group, and metabolomics analysis revealed the differential metabolites associated with XGHP treatment. Finally, molecular docking of effective components with transcriptome genes was performed and western blotting was performed in order to determine the expression of related proteins in rat lung tissue. Overall, 30 effective components of XGHP were identified, including L-asarinin, 6-gingerol, sesamin, kaempferol, and quercetin. Transcriptomic studies demonstrated that expression of 386 genes recovered after XGHP treatment, and that they were mainly enriched in the oxidative phosphorylation and AMPK signaling pathways. According to the metabolomics studies, expression of eight metabolites differed between the COPD and the XGHP groups. These metabolites were mainly involved the biosynthesis of unsaturated fatty acids. Finally, the transcriptomic and metabolomics data were integrated. FASN and SCD in AMPK signaling pathway were directly linked to certain metabolites, including linoleic acid, palmitic acid, and oleic acid. These results indicate that XGHP can inhibit pAMPK expression and negatively regulate FASN and SCD expression during treatment of COPD in order to enhance the biosynthesis of unsaturated fatty acids and maintain energy homeostasis. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) has become a major public health problem affecting the elderly population, and there is currently no effective treatment. Although the pathogenesis of AD is unclear, neurotoxicity induced by oxidative stress plays an important role in the progression of AD. Ginseng, the root and rhizome of Panax ginseng C. A. Meyer, is used not only as an herbal medicine but also as a functional food to support bodily functions. Ginsenoside Rk3 (Rk3), the main bioactive component in ginseng, has a strong antioxidant effect and has not been reported in AD. In this study, we showed that Rk3 improved neuronal apoptosis, decreased intracellular reactive oxygen species (ROS) production and restored mitochondrial membrane potential in PC12 and primary neuronal cells. In vivo, we found that Rk3 improved spatial learning and memory deficit in precursor protein (APP)/presenilin 1 (PS1) double transgenic mouse model of AD. Additionally, Rk3 increases glutathione reductase (GSH) and superoxide dismutase (SOD) levels while inhibits malondialdehyde (MDA) production, apoptosis and activation of glial cells in APP/PS1 mice. Mechanistically, we found that the protective effect of Rk3 is in correlation with the activation of AMPK/Nrf2 signaling pathway. In conclusion, the findings of this study provide support for Rk3 as a new strategy for the treatment of AD. [Display omitted] • Ginsenoside Rk3, a bioactive component in ginseng, exhibits neuroprotective effects in PC12 cells and primary neuronal cells. • Rk3 significantly alleviates AD pathology with the therapeutic effect better than that of donepezil. • The protective effect of Rk3 is associated with the activation of AMPK/Nrf2 signaling pathway. • Ginsenoside Rk3 is expected to be a potential therapeutic drug for AD. [ABSTRACT FROM AUTHOR]

The incident of lipid metabolism disorders has obviously increased under the undue pursuit of efficiency, which had seriously threatened to the health development of poultry industry. As an important cholesterol-derived intermediate, though dehydroepiandrosterone (DHEA) has the fat-reduction effect in animals and humans, but the underlying mechanism still poorly understood. Herein, the present study aimed to investigate the regulatory effects and its molecular mechanism of DHEA on disturbance of lipid metabolism induced by oleic acid (OA) in primary chicken hepatocytes. The hepatocytes were treated with 0, 0.1, 1, 10 μM DHEA for 4 h, and then supplemented with 0 or 0.5 mM OA stimulation for another 24 h. Our findings demonstrated that DHEA treatment effectively reduced TG content and alleviated lipid droplet deposition in OA-induced hepatocytes. DHEA inhibited the lipogenesis related factors (ACC, FAS, SREBP-1c , and ACLY) mRNA level and increased the lipolysis key factors (CPT-1 and PPARα) mRNA levels. In addition, DHEA obviously elevated the protein levels of CPT-1A, p-ACC, and ECHS1; whereas decreased the protein levels of FAS and SREBP-1 in hepatocytes stimulated by OA. Furthermore, DHEA promoted the phosphorylation of AMP-activated protein kinase (AMPK) and inhibited the phosphorylation of mammalian target of rapamycin (mTOR). Mechanistically, the hepatocytes were pre-treated with AMPK inhibitor compound C or AMPK activator AICAR before addition of DHEA treatment, and the results certified that DHEA activated cAMP/AMPK pathway and which subsequently led the inhibition of mTOR signal, which finally reduced the fat excessive accumulation in OA-stimulated hepatocytes. Collectively, our study unveiled that DHEA protects against the lipid metabolism disorders triggered by OA stimulation through activation of AMPK-mTOR signaling pathway, which prompts the value of DHEA as a potential nutritional supplement in regulating the lipid metabolism and its related disease in poultry. [ABSTRACT FROM AUTHOR]

Panax ginseng C. A. Meyer is a traditional Chinese herbal medicine, which has been used in China for more than 2000 years. Its traditional effect of "invigorating vitality" is mainly reflected in anti-fatigue. However, due to the difficulty of identification of polysaccharide structure, there are few reports on homogeneous ginseng polysaccharide, and the molecular mechanism of its anti-fatigue effect remains to be further explored. In order to find the homogenous ginseng polysaccharide with the most anti-fatigue effect, this study is for the first time extracted, isolated and structurally identified polysaccharide monomer from Mountain Cultivated Ginseng (MCG). Then the anti-fatigue activity and molecular mechanism were studied. The structure of ginseng acidic polysaccharide APS-1 prepared by high performance gel permeation chromatography (HPGPC) was determined by acid hydrolysis/HPLC, methylation/GC-MS and NMR analysis. Anti-fatigue effect was evaluated by exhaustive swimming model, and AMPK axis-related proteins were detected by Western blot. APS-1 significantly prolonged fatigue tolerance time, alleviated accumulation of BLA, LDH and BUN, increased activities of SOD and CAT, alleviated oxidative damage caused by MDA, increased activity of CK, regulated glycolysis, and alleviated muscle fiber contraction. The expressions of LKB1, p-AMPK, PGC-1 α and Glut4 in muscle were significantly up-regulated. The anti-fatigue effect of APS-1 was significantly, and the molecular mechanism may be related to the activation of AMPK axis signaling pathway to improve glucose uptake and mitochondrial function. [Display omitted] • The homogenous polysaccharide APS-1 was isolated and identified from Panax ginseng. • APS-1 regulates metabolite accumulation, oxidative damage and energy metabolism. • The anti-fatigue effect of APS-1 is related to AMPK axis signaling pathway. [ABSTRACT FROM AUTHOR]

Chemical investigation of the plant Gymnema latifolium led to the isolation of seven undescribed 23-glycosyl oleanane triterpenoids, gymlatinosides GLF1-GLF7, and two known compounds, gymnemosides D and E. The structures of the isolated compounds were elucidated using diverse spectroscopic methods. The extract of G. latifolium and all isolated compounds significantly enhanced 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxyglucose (2-NBDG) uptake into 3T3-L1 adipocytes at 20 μM. Among them, gymlatinosides GLF2 and gymlatinosides GLF4 showed particularly potent stimulatory effects on glucose uptake in a dose-dependent manner. Further investigation revealed that gymlatinosides GLF2 at 20 μM upregulated the expression of phosphorylated AMPK (p -AMPK). The results suggested that gymlatinosides GLF2 may enhance glucose uptake via regulating the AMPK signaling pathway. Seven undescribed 23-glycosyl oleanane triterpenoids were isolated from Gymnema latifolium. All isolated compounds significantly enhanced 2-NBDG uptake into 3T3-L1 adipocytes. Compound 2 strongly upregulated the expression of phosphorylated AMPK (p -AMPK). [Display omitted] • Seven undescribed 23-glycosyl oleanane glycosides (1 – 7) were isolated from Gymnema latifolium. • All isolated compounds were evaluated for glucose uptake activity by using 2-NBDG in 3T3-L1 adipocytes. • Compounds 2 and 4 may enhance glucose uptake by controlling the AMPK pathway. [ABSTRACT FROM AUTHOR]

• Sidechain modification types affect advanced glycation end-products transmembrane transport. • Isoleucine, alanine, threonine, and glutamine residues help peptide transmembrane transport. • Dietary advanced glycation end-products impairs cellular energy homeostasis. • Dietary advanced glycation end-products interferes AMPK-SIRT6 signaling. • Major hazard factors of advanced glycation end-products are their free fractions. Advanced glycation end-products (AGEs) are a chemically heterogeneous set of modifications widely found in processed foods. Due to uncertain bioavailability, dietary AGEs regulate energy homeostasis through mechanisms that largely remain unclear. In this study, selective transmembrane transport of AGEs with different modification types from glycated β-casein digest were identified and compared. The results showed that only a few types of free and peptide-bound AGEs can easily cross the Caco-2 monolayers and thus exert their effects. A combination of biochemical assays, mitochondrial analyses, and comparative experiments identified that the effect of AGEs on cellular energy homeostasis comes mainly from their free fractions. Mechanistically, free AGEs arrest the mitochondrial differentiation and mtDNA repair by intervening in the function of thymidine phosphorylase, and interfering with mitochondrial energy production by inhibiting the activation of AMPK-SIRT6 signaling pathway. These results demonstrate mechanisms by which processed foods cause mitochondrial dysfunction and lead to dysfunctional energy homeostasis. [ABSTRACT FROM AUTHOR]

Bioactivity guided phytochemical investigation led to isolation of six undescribed furostanol saponins, furoasparoside A-F along with five known compounds, gallic acid, methyl gallate, quercetin-3-O- β -glucopyranoside, liquiritigenin 4׳-O - β- apiofuranosyl-(1 → 2)- β -glucopyranoside and β -glucogallin for the first time from the roots of Asparagus racemosus. Isolated saponins were screened for their antidiabetic potential in L6-GLUT4 myc myotubes in vitro followed by an in vivo evaluation in streptozocin-induced diabetic rats and db/db mice. Furoasparoside E produced a notable decrease in the postprandial blood glucose profile, in leptin receptor-deficient db/db mice, type 2 diabetes model. The effect of furoasparoside E on GLUT4 translocation was found to be mediated by the AMPK-dependent signaling pathway in L6-GLUT4 myc myotubes. Moreover, it emerged as a stable plant metabolite with higher bioavailability and efficacy in in vivo pharmacokinetic studies. Therefore, these studies indicated that furoasparoside E may serve as a propitious lead for the management of type 2 diabetes and its secondary complications from natural source. [Display omitted] • Six undescribed furostanol saponins were isolated from Asparagus racemosus. • Furoasparoside E showed significant in vitro increase in surface level of GLUT4 myc at 10 μM. • It showed comparable blood glucose lowering effect with metformin in STZ induced diabetic rats. • It demonstrated improvement in glucose metabolism in db/db mice model. • Furoasparoside E followed activation of AMPK-dependent signaling pathway. [ABSTRACT FROM AUTHOR]

Neuronal dendrites and dendritic spines are essential for normal synaptic transmission and may be critically involved in the pathophysiology of various neurological disorders, including depression. Emerging data supports the role of mitochondria in dendritic protrusions in modulating the development and morphological plasticity of spines. Mitophagy, a mitochondria-specific form of autophagy, is the fundamental process of clearing damaged mitochondria to maintain cellular homeostasis. As a brain-specific microRNA, miR-134 is localized to the synaptodendritic compartment of hippocampal neurons and negatively regulates the development of dendritic spines. However, the role of miR-134 in mitophagy related to dendritic deficits in the pathophysiology of depression remains unclear. In this study, we showed that miR-134-5p knockdown abrogated depression-like behavioral symptoms and corrected aberrant spine morphology in hippocampal neurons of chronic unpredictable mild stress (CUMS) mice. Moreover, knockdown of miR-134-5p triggered autophagy in dendrites, improved mitochondrial impairment, and induced the generation of autophagosomes in the hippocampus of CUMS mice. We further found that AMP-activated protein kinase (AMPK), which mediates the impairment of defective mitochondria via mitophagy, can bind directly to miR-134-5p and is negatively regulated by this miRNA. This study demonstrates that miR-134-5p exerts an enormous effect on dendritic deficits by promoting AMPK-mediated mitophagy and provides a potential new target for antidepressant drug research and development. [Display omitted] • CUMS induced depression-like behavior is accompanied by hippocampal neuron damage and dendritic spine reduction. • Knockdown of miR-134-5p improved depression-like behavior and hippocampal dendritic spine morphology in CUMS mice. • Knockdown of miR-134-5p activated mitophagy in the hippocampal dendrites of CUMS mice. • Knockdown of miR-134-5p rescued hippocampal dendritic spine anomalies by targeting AMPK-mediated mitophagy. [ABSTRACT FROM AUTHOR]

[Display omitted] • MCGAPs is a potential anti-fatigue nutrient. • MCGAPs can eliminate the excessive accumulation of metabolites. • MCGAPs can relieve oxidative stress damage. • MCGAPs can modify the kinetics of energy substrates mobilization. • MCGAPs relieved fatigue by regulating AMPK axis signaling pathway. Ginseng is usually considered as a functional food and herbal medicine, and it has anti-fatigue activity, which is of great attention and expectation. Based on the comparison of Mountain Cultivated Ginseng (MCG) with Cultivated Ginseng (CG), this study aimed to explore the material basis and mechanism of Ginseng in anti-fatigue effects. The results showed that the Mountain Cultivated Ginseng acidic polysaccharides (MCGAPs) had obvious advantages, which significantly prolonged the fatigue tolerance time, alleviated the accumulation of BLA, LDH, BUN and MDA, increased the activities of SOD, CAT and CK, regulated glycolysis and alleviated muscle fiber contraction. It also significantly upregulated the expression of AMPK axis related proteins in mice muscle. Preliminary results exhibited the anti-fatigue effect of MCG was significantly better than CG, which was mainly due to the difference of acidic polysaccharide. The findings supported the potential of MCGAPs to be used as a functional ingredient for anti-fatigue. [ABSTRACT FROM AUTHOR]

Background: Doxorubicin-induced cardiotoxicity (DIC) limits the clinical application of the drug in treatment of cancers and imposes a severe health burden on the patients. Therefore, there is an urgent need to develop alternative therapeutic strategies or drugs to minimize DIC. Salidroside is a phenylpropanoid glycoside extracted from Rhodiola rosea with multiple biological effects such as anti-inflammation and antioxidant properties. However, its mechanism of action in DIC is still poorly understood.Purpose: The present study was aimed to investigate the role of salidroside in DIC and associated mechanism of action for the described effects.Methods: Cardiac dysfunction was induced through treatment of mice with doxorubicin in vivo and in vitro. The mechanism of action of salidroside was investigated using western blot assay, qPCR, immunofluorescence, histochemistry, echocardiography, and high-content imaging system.Results: Results of the current study found that treatment of mice with salidroside significantly improved doxorubicin-induced cardiac dysfunction, ferroptosis-like cell damage, and fibrosis in vivo. Further, it was noted that salidroside inhibited ferroptosis in vivo and in vitro by limiting iron accumulation, restoring GPX4-dependent antioxidant capacity, and preventing lipid peroxidation at the cellular or mitochondrial levels. Mechanistically, salidroside inhibited DOX-induced mitochondrial ROS, Fe2+, and lipid peroxidation as well as restored mitochondrial membrane potential by promoting mitochondrial biogenesis, improving mitochondrial iron-sulfur clusters, and restoring mitochondrial OXPHOS complexes, thereby improving mitochondrial function. In addition, AMPK is a key protein that coordinates mitochondria, metabolism, and ferroptosis. Therefore, it was found that compound C (CC), an AMPK inhibitor, disrupted the regulation of cellular lipid metabolism and mitochondrial function of salidroside as well as led to failure of the protective effect of salidroside against ferroptotic cell death.Conclusions: The present study evidently demonstrated the cardioprotective effects of salidroside against doxorubicin-induced cardiomyopathy. Further, salidroside markedly down-regulated ferroptotic cell death by activating AMPK-dependent signaling pathways including regulating abnormal fatty acid metabolism and maintaining mitochondrial function. Therefore, salidroside is can be exploited to develop a novel medication for clinical DIC and salidroside may represent a novel treatment that improves recovery from DIC by targeting ferroptosis. [ABSTRACT FROM AUTHOR]

Highlights: [•] 1,3-DCP (0.1–1mg/kg/day) did not affect food intake and body weight of C57BL/6J mice. [•] 1,3-DCP (0.1–1mg/kg/day) increased serum TC, TG and LDL-C, decreased HDL-C in mice. [•] 1,3-DCP (0.1–1mg/kg/day) increased relative liver weight, hepatic TG and TC in mice. [•] 1,3-DCP (0.1–1mg/Kg/day) increased adipose tissue weight and adipocyte size in mice. [•] 1,3-DCP induced hyperlipidemia at least partially through AMPK signaling pathway. [Copyright &y& Elsevier]

Highlights: [•] Lipid and glucose homeostasis effects of mango leaf were reported firstly. [•] The homeostasis effects may be related to PI3K/AKT and AMPK signaling pathway. [•] Three kinds of benzophenone glucosides were detected in muscle and liver. [•] Effects of tissue distributed compounds were discussed. [Copyright &y& Elsevier]

Abstract: Ethnopharmacological relevance: Jinqi formula is a traditional Chinese anti-diabetic formula containing three ingredients (Coptidis rhizoma, Astragali rhadix and Lonicerae japonicae Flos). Materials and methods: The active fractions of Jinqi formula were purified and HPLC analyses were used for quality control. The anti-adipogenic effects of Jinqi formula were analyzed in vitro using 3T3-L1 cells and in vivo with KK-Ay mice. RT-PCR and Western blot were used to confirm genes and proteins of interest, respectively. Results: In vitro study showed that Jinqi formula suppressed the accumulation of triglyceride (TG) and free fatty acids (FFA) in mature 3T3-L1 cells by increasing the expression and tyrosine phosphorylation of 5′-AMP-activated protein kinase (AMPK), as well as decreasing the expression of Acetyl CoA Carboxylase (ACC), Fatty Acid Synthase (FAS) and Hormone Sensitive Lipase (HSL). In vivo study demonstrated that Jinqi formula reduced body weight without changing food intake in KK-Ay mice, and decreased the levels of serum glucose, TG, FFA. In addition, consistent with the in vitro study results, Jinqi formula increased the expression and tyrosine phosphorylation of AMPK in the liver and muscular tissues of the KK-Ay mice. Furthermore, Jingqi formula suppressed the expression of ACC and HSL and upregulated the expression of IRS-1 in the liver. Whereas in the skeletal muscles, Jingqi formula decreased the expression of ACC and increased the expression of GLUT-4 and IRS-2. Conclusions: Jingqi formula inhibits TG accumulation at least in part via the stimulation of AMPK activity in a multi-target manner. [Copyright &y& Elsevier]

Mounting evidence shows that dietary fiber (DF) alleviates lipid metabolism disorders in humans and animals by regulating the gut microbiota. However, its action mechanisms remain to be elucidated. Flammulina velutipes (F. velutipes) as an edible mushroom is widely cultivated in China and has medicinal values. As a by-product of F. velutipes , the mycorrhizae are rich in high-quality DF and therefore can be used to prepare F. velutipes DF (Fv-DF). The objective of this research aimed to explore whether and how Fv-DF attenuates lipid metabolism disorders in obese mice through the gut microbiota. Here, an obese mice model induced by high-fat diet was established to analyze the effect of Fv-DF supplementation on the lipid metabolism disorders and gut microbiota. The results showed that Fv-DF administration significantly reduced the weight gain, triglycerides and total cholesterol, low-density lipoprotein cholesterol and markedly increased the activity of enzymes related to scavenging ability of oxygen free radicals. The gut microbiota sequencing exhibited that the Fv-DF supplementation increased the level of gut beneficial bacteria, such as Prevotellaceae UCG-001 and Alloprevotella. Western blot analysis revealed the phosphorylated adenosine 5′-monophosphate (AMP)-activated protein kinase (p -AMPKα) was up-regulated, indicating that AMPK signaling pathway was activated. The activated pathway down-regulated the fatty acid synthase level to decrease lipid synthesis and up-regulated the carnitine palmitoyl transferase-1 level to increase lipid degradation. Altogether, Fv-DF supplementation alleviates lipid metabolism disorders in obese mice by regulating the gut microbiota-mediated AMPK signaling pathway. [Display omitted] (1) Fv-DF reduced the weight gain and improved physiological indexes in obese mice. (2) Fv-DF improved the abundance and composition of gut microbiota. (3) The changed microbiota activated AMPK signaling pathway. (4) AMPK pathway activation may be a major contributor to alleviate obesity. [ABSTRACT FROM AUTHOR]

Lycopene has a wide range of biological functions, especially its antioxidant capacity. However, effects of lycopene on muscle fatigue resistant and muscle fiber type conversion are unknown. In this study, we found that lycopene significantly prolonged the swimming time to exhaustion in mice. We also showed that lycopene increased the proportion of slow-twitch muscle fiber by promoting muscle fiber type conversion from fast-twitch to slow-twitch in mice and in C2C12 myotubes. The AMP-activated protein kinase (AMPK) signaling was activated by lycopene. AMPK upstream and downstream regulators including nuclear respiratory factor 1, calcium calmodulin-dependent protein kinase kinase-β, sirtuin 1 and peroxisome proliferator activated receptor-γ coactivator-1ɑ were also increased by lycopene. AMPK inhibitor compound C markedly attenuated the lycopene-induced skeletal muscle fiber type conversion in C2C12 myotubes. Taken together, we provided the first evidence that lycopene increases the proportion of slow-twitch muscle fiber through AMPK signaling pathway to improve fatigue resistant of skeletal muscle. [ABSTRACT FROM AUTHOR]

• Different levels of C. autoethanogenum protein were investigated as potential protein in GIFT juveniles. • The growth performance of the fish was significantly improved by C. autoethanogenum protein. • GIFT juveniles fed C. autoethanogenum protein could regulate energy homeostasis via AMPK/TOR/PI3K signaling pathway. • C. autoethanogenum protein could successfully be used as a sustainable protein in GIFT juvenile diets. This study investigated the effect of dietary Clostridium autoethanogenum (C. autoethanogenum) protein on growth, whole-body composition, plasma parameters, and hepatic genes expression related to growth and AMPK/TOR/PI3K signaling pathway of the genetically improved farmed tilapia (GIFT: Oreochromis niloticus) juveniles. The fish (initial weight of 0.7 ± 0.05 g) were fed with diets containing C. autoethanogenum protein at 0 g/kg (Control, diet 1), 50 g/kg (Diet 2), 100 g/kg (Diet 3), 150 g/kg (Diet 4) and 200 g/kg (Diet 5) to partially replace mainly soybean meal in triplicates. After 8 weeks feeding trial, the growth was significantly (P < 0.05) improved by dietary C. autoethanogenum protein compared with the control. Whole-body crude lipid increased in the fish group fed over 50 g/kg C. autoethanogenum protein (P < 0.05). Plasma triglycerides (TG) was significantly (P < 0.05) elevated by dietary C. autoethanogenum protein at 200 g/kg. C. autoethanogenum protein supplementation significantly (P < 0.05) up-regulated the mRNA expression of the growth-related insulin-like growth factor-1 (IGF-1). 50 g/kg and 100 g/kg dietary C. autoethanogenum protein improved the phosphorylation and protein levels of the eukaryotic initiation factor 4E binding protein 1 (4E-BP1) and ribosomal protein S6 Kinase 1 (S6K1), and the phosphorylation of the adenosine monophosphate-activated protein kinase (AMPK) compared with the control diet. The phosphorylation level of the phosphoinositide 3-kinase (PI3K) was lowered by 200 g/kg autoethanogenum protein compared with the control. The pyruvate kinase (PK) mRNA level was significantly (P < 0.05) up regulated by 100 g/kg C. autoethanogenum protein; while glucose 6-phosphatase (G6Pase) mRNA expression was down-regulated by 150 g/kg and 200 g/kg C. autoethanogenum protein compared with the control (P < 0.05). The mRNA expression of fatty acid transport protein 5 (FATP5) was significantly down-regulated by 100–200 g/kg; peroxisome proliferator-activated receptor alpha (PPARα) was significantly down-regulated by 50 g/kg; while fatty acid synthase (FAS) was significantly up-regulated by 150 g/kg and 200 g/kg C. autoethanogenum protein compared with the control (P < 0.05). The results further showed that GIFT juveniles fed with dietary C. autoethanogenum protein could regulate whole-body energy homeostasis through the AMPK signaling pathway. Therefore, C. autoethanogenum protein could successfully be used as a novel and sustainable protein in juvenile GIFT diets. [ABSTRACT FROM AUTHOR]

Background: Berberine (BBR) has been widely used to treat non-alcoholic fatty liver disease (NAFLD). The metabolites of BBR were believed to contribute significantly to its pharmacological effects. Oxyberberine (OBB), a gut microbiota-mediated oxidative metabolite of BBR, has been firstly identified in our recent work.Purpose: Here, we aimed to comparatively investigate the anti-NAFLD properties of OBB and BBR.Methods: The anti-NAFLD effect was evaluated in high-fat diet-induced obese NAFLD rats with biochemical/ELISA tests and histological staining. The related gene and protein expressions were detected by qRT-PCR and Western blotting respectively. Molecular docking and dynamic simulation were also performed to provide further insight.Results: Results indicated OBB remarkably and dose-dependently attenuated the clinical manifestations of NAFLD, which (100 mg/kg) achieved similar therapeutic effect to metformin (300 mg/kg) and was superior to BBR of the same dose. OBB significantly inhibited aberrant phosphorylation of IRS-1 and up-regulated the downstream protein expression and phosphorylation (PI3K, p-Akt/Akt and p-GSK-3β/GSK-3β) to improve hepatic insulin signal transduction. Meanwhile, OBB treatment remarkably alleviated inflammation via down-regulating the mRNA expression of MCP-1, Cd68, Nos2, Cd11c, while enhancing Arg1 mRNA expression in white adipose tissue. Moreover, OBB exhibited closer affinity with AMPK in silicon and superior hyperphosphorylation of AMPK in vivo, leading to increased ACC mRNA expression in liver and UCP-1 protein expression in adipose tissue.Conclusion: Taken together, compared with BBR, OBB was more capable of maintaining lipid homeostasis between liver and WAT via attenuating hepatic insulin pathway and adipocyte inflammation, which was associated with its property of superior AMPK activator. [ABSTRACT FROM AUTHOR]

The fatty liver hemorrhage syndrome in laying hens is a disease of lipid metabolism disorders. Importantly, energy sensor AMP-activated protein kinase (AMPK) plays an essential role in homeostasis regulation of liver lipid. The current research aims to investigate the relationship between AMPK signaling pathway and lipid metabolism in laying hen hepatocytes and explore the underlying mechanisms. The steatotic hepatocytes model of laying hen was established and treated with AMPK agonist AICAR and inhibitor compound C. The results showed that the levels of triglyceride, total cholesterol, and low-density lipoprotein cholesterol significantly declined while high-density lipoprotein cholesterol level increased in the AICAR-treated steatosis group compared with the steatosis group. Furthermore, the mRNA levels of liver kinase B1 and AMP-activated protein kinase α1 declined significantly in the steatosis group compared with those in the normal group. However, AMPK activation significantly upregulated the mRNA levels of peroxisome proliferator-activated receptor α and carnitine palmitoyl transferase-1 while downregulated the mRNA levels of acetyl CoA carboxylase, fatty acid synthase, 3-hydroxy-3-methyl glutaryl coenzyme A reductase, Sn-glycerol-3-phosphate acyltransferase, and hepatocyte nuclear factor 4α. These results suggest that activated AMPK signaling pathway increases fatty acid oxidation and reduces lipid synthesis in laying hen hepatocytes, thereby ameliorating liver steatosis. [ABSTRACT FROM AUTHOR]

• HMGCR is a hub gene of PL@RM against T2DM. • Inactivation of metabolic pathway is a key pathway of PL@RM against T2DM. • AMPK is regarded as a hub signaling pathway to trigger Insulin Receptor (IR) autophosporylation. • Epicholesterol from PL@RM functioned as IR autophosphorylation against T2DM. • The mechanism of action (MOA) of epicholesterol is "IR kinase agonist" against T2DM. • A promising mechanism of epicholesterol may inactivate HMGCR to hinder cholesterol biosynthesis. Phellinus linteus (mushroom) grown on Rosa multiflora (PL@RM), exposed beneficial effect and safety on Type 2 diabetes mellitus (T2DM) from Korean folk remedies. However, its active chemical constituents and mechanism(s) against T2DM have not been confirmed. Hence, we deciphered the active compounds and mechanism(s) of PL@RM against T2DM through network pharmacology. GC–MS of PL@RM manifested 54 compounds and drug-likeness properties of these compounds were confirmed by Lipinski's rule. The compound (40) related genes were composed of Similarity Ensemble Approach (SEA) and SwissTargetPrediction (STP). The overlapping genes (61) between the two databases were identified. Besides, the T2DM related genes (4,736) were extracted from DisGeNet and OMIM database. In parallel, a Venn diagram was constructed between the overlapping genes (61) and T2DM related genes (4,736), and finally, 48 genes were picked. The interactive networks between compounds and overlapping genes were plotted and visualized by RStudio. In addition, KEGG Pathway enrichment analysis was evaluated by String. String analysis showed that the mechanisms of PL@RM against T2DM were related to 16 pathways, where inhibition of gluconeogenesis by inactivating metabolic pathways was noted as the hub pathway of PL@RM against T2DM. Besides, bubble chart indicated that activation of the AMPK signaling pathway might enhance the insulin receptor (IR) phosphorylation, which is regarded the key signaling pathway of PL@RM against T2DM. Furthermore, the autodock vina revealed the promising binding affinity energy of the epicholesterol (the most drug-likeness compound) on HMGCR (hub gene). Overall, this work hints at the therapeutic evidence of PL@RM on T2DM, and this data expound the main chemical compounds and mechanisms of PL@RM against T2DM. [ABSTRACT FROM AUTHOR]

As the most important bioactive substance in Garcinia cambogia , (−)-hydroxycitric acid (HCA) is widely used in food additives to regulate obesity and diabetes in animals or humans, while the mechanism is poorly understood. The purpose of this study was to elucidate the regulatory effect and mechanism of (−)-HCA in regulating glucose and lipid metabolism in chicken primary hepatocytes. The results showed that (−)-HCA obviously decreased triglyceride content through inhibiting the fatty acid synthase protein level, and enhancing the protein level of phosphorylated acetyl CoA carboxylase, enoyl coenzyme A hydratase short chain 1 and carnitine palmitoyltransferase 1A in hepatocytes. Moreover, (−)-HCA markedly enhanced the protein level of phosphofructokinase-1, pyruvate dehydrogenase, succinate dehydrogenase A and complex IV, and which led to the enhancing of glucose uptake and catabolism in hepatocytes. Importantly, the regulation of (−)-HCA on these key factors associated with lipid and glucose metabolism in hepatocytes was mainly achieved through activation of AMP-activated protein kinase/peroxisome proliferator-activated receptor gamma coactivator 1α-nuclear respiratory factor 1 signaling pathway. These results convincingly demonstrated the mechanism of (−)-HCA's regulating on glucose and lipid metabolism, and provided a strategy in prevention of diseases associated with glycolipid metabolic abnormalities in animals, even in humans. [ABSTRACT FROM AUTHOR]

Dichlorvos is a common crop insecticide widely used by people which causes extensive and serious environmental pollution. However, it has been shown that organophosphorus poisoning causes energy metabolism and neural disorders. The overall purpose of this study was to investigate the damage to brain tissue and the changes in AMPK signaling pathway-related gene expression after dichlorvos poisoning in chickens. White-feathered broiler chickens, as the research subjects of this experiment, were divided into three groups: control group, low-dose group (77.5% dichlorvos at 1.13 mg/kg dose) and high-dose group (77.5% dichlorvos at 10.2 mg/kg dose). Clinical symptoms were observed after modeling, and an integrative analysis was conducted using HE staining microscopy, immune-histochemical microscopy, electron microscopy and PCR arrays. The results showed that the high-dose group had more obvious dyspnea, salivation, convulsion and other neurological phenomena. Pathological sections showed that nuclear disintegration of neurons was most obvious in the low-dose group, and apoptosis of brain cells was most obvious in the high-dose group, and the mitochondrial structure was destroyed in the two poisoned group, i.e. low-dose group and high-dose group. PCR arrays showed that AMPK signaling pathway was inhibited and the expressions of genes involved in energy metabolism (ACACA and PRKAA1) were significantly changed. Furthermore, genes associated with protein synthesis (EIF4EBP1) were significantly upregulated. FASN and HMGCR expressions were significantly increased. There were significant changes in the expressions of cell cycle-related genes (STK11, TP53 and FOXO3). Organophosphate poisoning can cause a lot of nuclear disintegration of brain neurons, increases cell apoptosis, disrupts the energy metabolism of mitochondrial structure, and inhibits the AMPK signaling pathway. These results provide a certain idea and basis for studying the mechanism of AMPK signaling after organophosphorus poisoning and provide a research basis for the prevention and treatment of organophosphorus poisoning. Image 1 • Severe pathological damage of chicken brain caused by dichlorvos poisoning. • The gene expression of AMPK signaling pathway in the brain of the poisoned chicken changed significantly. • After dichlorvos poisoning, the AMPK signal pathway of brain tissue can be inhibited. • Dichlorvos poisoning affects fat metabolism, protein metabolism and other related genes. [ABSTRACT FROM AUTHOR]

The objective was to analyze the effects of aerobic exercise on aging striatum stress resistance, and the adaptive mechanisms related to neurodegenerative diseases, and the occurrence, and development of neural degeneration. The 10-weeks of regular moderate-intensity aerobic exercise intervention were carried out in the aerobic exercise runner Sprague-Dawley rats. Apoptotic nuclei appeared in the striatum of aged rats, showing a tendency to relate to aging. The apoptotic index of the striatum in young, middle-aged, and old-aged rats of the aerobic exercise groups increased by 205.56%, 57%, and 68.24%. Autophagy markers Beclin l and LC 3-II expression, AMPKα1 and pAMPKα1 expression increased significantly in all age-exercise groups. The ratio of AMPKα1/pAMPKα1 increased after exercise, and the tendency of exercise to alter autophagy and cell apoptosis increased with aging. Then SirT2 mRNA was significantly upregulated in the aerobic exercise runner groups. In conclusion, we showed that the balance of autophagy and apoptosis were closely regulated by regular aerobic exercise, which affected the development of aging, and via regulation of the AMPK/SirT2 signaling pathway. • Regular aerobic exercise improved the morphological structure of striatum. The apoptosis was increased with aging, and regular aerobic exercise increased the apoptosis in aging rat striatum. • Regular aerobic exercise increased the expression level of autophagy markers Beclin l and LC3-II in aging rat striatum. • We showed that the balance of autophagy and apoptosis in the rat striatum were closely regulated by regular aerobic exercise. [ABSTRACT FROM AUTHOR]