Activating AMPK Pathway Research Articles

Multi-omics joint analysis reveals that the Miao medicine Yindanxinnaotong formula attenuates non-alcoholic fatty liver disease

BackgroudNon-alcoholic fatty liver disease (NAFLD) is a growing chronic liver disease worldwide, and no effective agent is approved yet for this condition. Traditional Chinese Medicine (TCM), which has been practiced for thousands of years in China and other Asian countries, is considered an important source for identifying novel medicines for various diseases. Miao medicine Yindanxinnaotong formula (YDX) is a classical TCM for the treatment of hyperlipidemia disease by reducing blood lipid content, while the role of YDX have not been clarified in NAFLD. PurposeTo investigate the protective effect of YDX on NAFLD in mice induced by high fat diet (HFD) and clarify the potential mechanism. MethodsNAFLD mice model was constructed by receiving HFD for 10-week period with or without YDX administration. Lipid profiles, biochemical indicators, and histopathological staining were performed to evaluate the extent of hepatic lipid accumulation and hepatic steatosis. 16S rRNA sequencing was used to determine the gut microbial composition. Serum metabolomics was further used to investigate the changes in plasma biomarkers for NAFLD-associated by UPLC-Q-TOF/MS analysis. Subsequently, liver transcriptomics was employed to identify differentially expressed genes and explore regulatory pathways. Then, lipid metabolism–related proteins and inflammation factors were examined by Western blot and ELISA. ResultsYDX reduced body weight gain, liver index and inflammatory cytokines levels, along with improved hepatic steatosis, serum lipid profile, sensitivity to insulin and also tolerance to glucose, and enhanced oxidative defense system in HFD-induced mice. Also, YDX remarkedly affected gut microbiota diversity and community richness and decreased the ratio of Firmicutes/Bacteroidetes. Meanwhile, YDX also reduced the production of harmful lipid metabolites in the sera of NAFLD mice, such as LPC(18:0), LPC(18:1) and carnitine. Notably, consistent with liver transcriptomics results, YDX downregulated the expression of proteins implicated in de novo lipid synthesis (Srebp-1c, Acaca, Fasn, Scd-1, and Cd36) and pro-inflammatory cytokines (IL-6 and TNF-α), and increased the expression of proteins-related fatty acid β-oxidation (Ampkα, Ppar-α, and Cpt-1) in the liver by activating Ampk pathway. ConclusionYDX is promisingly an effective therapy for preventing NAFLD by modulating the Ampk pathway, inhibiting gut microbiota disorder, and reducing the production of harmful lipid metabolites.

SGLT2 inhibitor downregulated oxidative stress via activating AMPK pathway for cardiorenal (CR) protection in CR syndrome rodent fed with high protein diet

This study tested the hypothesis that empagliflozin (EMPA) therapy effectively protected renal and heart functions via downregulating reactive oxygen species (ROS) and activating AMPK signaling in cardiorenal syndrome (CRS) (induced by doxorubicin-5/6 nephrectomy) rats. In vitro result showed that underwent p-Cresol treatment, the H9C2/NRK-52E cell viabilities, were significantly suppressed, whereas cellular levels of ROS and early/late apoptosis of these cells were significantly increased that were significantly reversed by EMPA treatment (all p < 0.001). The protein levels of the cell-stress/oxidative signaling (p-PI3K/p-Akt/p-mTOR/NOXs/p-DRP1) were significantly activated, whereas the mitochondrial biogenesis signaling (p-AMPK/SIRT-1/TFAM/PGC-1α) was significantly repressed in these two cell lines treated by p-Cresol and all of these were significantly reversed by EMPA treatment (all p < 0.001). Male-adult-SD rats were categorized into groups 1 [sham-operated control (SC)]/2 [SC + high protein diet (HPD) since day 1 after CKD induction]/3 (CRS + HPD)/4 (CRS + HPD+EMPA/20 mg/kg/day) and heart/kidney were harvested by day 60. By day 63, the renal function parameters (creatinine/BUN/proteinuria)/renal artery restrictive index/cellular levels of ROS/inflammation were significantly increased in group 3 than in groups 1/2, whereas heart function exhibited an opposite pattern of ROS among the groups, and all of these parameters were significantly reversed by EMPA treatment (all p < 0.0001). The protein levels of inflammation/ oxidative-stress/cell-stress signalings were highest in group 2, lowest in group 1 and significantly lower in group 4 than in group 2, whereas the AMPK-mitochondrial biogenesis displayed an opposite manner of oxidative-stress among the groups (all p < 0.0001). EMPA treatment effectively protected the heart/kidney against CRS damage via suppressing ROS signaling and upregulating AMPK-mediated mitochondrial biogenesis.

Hepatoprotective effects of Xiaoyao San formula on hepatic steatosis and inflammation via regulating the sex hormones metabolism.

The modified Xiaoyao San (MXS) formula is an adjuvant drug recommended by the National Health Commission of China for the treatment of liver cancer, which has the effect of preventing postoperative recurrence and metastasis of hepatocellular carcinoma and prolonging patient survival. However, the molecular mechanisms underlying that remain unclear. To investigate the role and mechanisms of MXS in ameliorating hepatic injury, steatosis and inflammation. A choline-deficient/high-fat diet-induced rat nonalcoholic steatohepatitis (NASH) model was used to examine the effects of MXS on lipid accumulation in primary hepatocytes. Liver tissues were collected for western blotting and immunohistochemistry (IHC) assays. Lipid accumulation and hepatic fibrosis were detected using oil red staining and Sirius red staining. The serum samples were collected for biochemical assays and NMR-based metabonomics analysis. The inflammation/lipid metabolism-related signaling and regulators in liver tissues were also detected to reveal the molecular mechanisms of MXS against NASH. MXS showed a significant decrease in lipid accumulation and inflammatory response in hepatocytes under metabolic stress. The western blotting and IHC results indicated that MXS activated AMPK pathway but inhibited the expression of key regulators related to lipid accumulation, inflammation and hepatic fibrosis in the pathogenesis of NASH. The metabonomics analysis systemically indicated that the arachidonic acid metabolism and steroid hormone synthesis are the two main target metabolic pathways for MXS to ameliorate liver inflammation and hepatic steatosis. Mechanistically, we found that MXS protected against NASH by attenuating the sex hormone-related metabolism, especially the metabolism of male hormones. MXS ameliorates inflammation and hepatic steatosis of NASH by inhibiting the metabolism of male hormones. Targeting male hormone related metabolic pathways may be the potential therapeutic approach for NASH.

Genipin Activates Autophagy and Promotes Myoblast Differentiation by Activating AMPK Pathway.

Cultured meat technology is expected to solve problems such as resource shortages and environmental pollution, but the muscle fiber differentiation efficiency of cultured meat is low. Genipin is the active compound derived from Gardenia jasminoides Ellis, which has a variety of activities. Additionally, genipin serves as a noncytotoxic agent for cross-linking, which is suitable as a foundational scaffold for in vitro tissue regeneration. However, the impact of genipin on myoblast differentiation remains to be studied. The research revealed that genipin was found to improve the differentiation efficiency of myoblasts. Genipin improved mitochondrial membrane potential by activating the AMPK signaling pathway of myoblasts, promoting mitochondrial biogenesis, and mitochondrial network remodeling. Genipin activated autophagy in myoblasts and maintained cellular homeostasis. Autophagy inhibitors blocked the pro-differentiation effect of genipin. These results showed that genipin improved the differentiation efficiency of myoblasts, which provided a theoretical basis for the development of cultured meat technology.

SLC7A11-ROS/αKG-AMPK axis regulates liver inflammation through mitophagy and impairs liver fibrosis and NASH progression

The changes of inflammation and metabolism are two features in nonalcoholic steatohepatitis (NASH). However, how they interact to regulate NASH progression remains largely unknown. Our works have demonstrated the importance of solute carrier family 7 member 11 (SLC7A11) in inflammation and metabolism. Nevertheless, whether SLC7A11 regulates NASH progression through mediating inflammation and metabolism is unclear. In this study, we found that SLC7A11 expression was increased in liver samples from patients with NASH. Upregulated SLC7A11 level was also detected in two murine NASH models. Functional studies showed that SLC7A11 knockdown or knockout had augmented steatohepatitis with suppression of inflammatory markers in mice. However, overexpression of SLC7A11 dramatically alleviated diet-induced NASH pathogenesis. Mechanically, SLC7A11 decreased reactive oxygen species (ROS) level and promoted α-ketoglutarate (αKG)/prolyl hydroxylase (PHD) activity, which activated AMPK pathway. Furthermore, SLC7A11 impaired expression of NLRP3 inflammasome components through AMPK-mitophagy axis. IL-1β release through NLRP3 inflammasome recruited myeloid cells and promoted hepatic stellate cells (HSCs) activation, which contributed to the progression of liver injury and fibrosis. Anti-IL-1β and anakinra might attenuate the hepatic inflammatory response evoked by SLC7A11 knockdown. Moreover, the upregulation of SLC7A11 in NASH was contributed by lipid overload-induced JNK-c-Jun pathway. In conclusions, SLC7A11 acts as a protective factor in controlling the development of NASH. Upregulation of SLC7A11 is protective by regulating oxidation, αKG and energy metabolism, decreasing inflammation and fibrosis.

COX6C expression driven by copy amplification of 8q22.2 regulates cell proliferation via mediation of mitosis by ROS-AMPK signaling in lung adenocarcinoma

Copy number variations (CNVs) play a vital role in regulating genes expression and tumorigenesis. We explored the copy number alterations in early-stage lung adenocarcinoma using high-throughput sequencing and nucleic acid flight mass spectrometry technology, and found that 8q22.1-22.2 is frequently amplified in lung adenocarcinoma tissues. COX6C localizes on the region and its expression is notably enhanced that driven by amplification in lung adenocarcinoma. Knockdown of COX6C significantly inhibits the cell proliferation, and induces S-G2/M cell cycle arrest, mitosis deficiency and apoptosis. Moreover, COX6C depletion causes a deficiency in mitochondrial fusion, and impairment of oxidative phosphorylation. Mechanistically, COX6C-induced mitochondrial deficiency stimulates ROS accumulation and activates AMPK pathway, then leading to abnormality in spindle formation and chromosome segregation, activating spindle assemble checkpoint, causing mitotic arrest, and ultimately inducing cell apoptosis. Collectively, we suggested that copy amplification-mediated COX6C upregulation might serves as a prospective biomarker for prognosis and targeting therapy in patients with lung adenocarcinoma.

Ultrasound-targeted microbubble technology facilitates SAHH gene delivery to treat diabetic cardiomyopathy by activating AMPK pathway

Diabetic cardiomyopathy (DCM) is a cardiovascular complication with no known cure. In this study, we evaluated the combination of ultrasound-targeted microbubble destruction (UTMD) and cationic microbubbles (CMBs) for cardiac S-adenosyl homocysteine hydrolase (SAHH) gene transfection as potential DCM therapy. Models of high glucose/fat (HG/HF)-induced H9C2 cells and streptozotocin-induced DCM rats were established. Ultrasound-mediated SAHH delivery using CMBs was a safe and noninvasive approach for spatially localized drug administration both invitro and invivo. Notably, SAHH overexpression increased cell viability and antioxidative stress and inhibited apoptosis of HG/HF-induced H9C2 cells. Likewise, UTMD-mediated SAHH delivery attenuated apoptosis, oxidative stress, cardiac fibrosis, and myocardial dysfunction in DCM rats. Activation of the AMPK/FOXO3/SIRT3 signaling pathway may be a key mechanism mediating the role of SAHH in regulating myocardial injury. Thus, UTMD-mediated SAHH transfection may be an important advancement in cardiac gene therapy for restoring ventricular function after DCM.

Tomatidine ameliorates high-fat-diet/streptozocin (HFD/STZ)-induced type 2 diabetes mellitus in mice

Objective To investigate the effects of tomatidine (Td) on the progression of type 2 diabetes mellitus (T2DM) in mice and uncover the mechanism. Methods T2DM mice model was induced by high-fat diet (HFD) and intrabitoneal injection of streptozotocin (STZ). The mice were grouped as follows: 1, control; 2, T2D; 3, T2D + tomatidine (5 mg/kg); 4, T2D + tomatidine (10 mg/kg); 5, T2D + tomatidine (20 mg/kg). Fasting blood glucose was detected by glucose metre and fasting insulin was detected by the kit to determine the effect of Td on T2DM mice. ELISA, qPCR, and Immunoblot assays were performed to detect the effects of Td on the hepatic glucose homeostasis and inflammation of mice. Immunoblot assays further confirmed the mechanism. Results Td improved blood glucose and insulin resistance in T2DM mice. In addition, Td improved liver function and lipid metabolism disorder in T2DM mice. Td also affected the liver glucose homeostasis related genes in T2DM mice. Td alleviated serum inflammation in T2DM mice. We further found that Td activated AMPK pathway, therefore ameliorating T2DM. Conclusion Td ameliorated HFD/STZ-induced T2DM in mice, suggesting that it could serve as a drug of T2DM.

Unsaponifiable Matter from Wheat Bran Cultivated in Korea Inhibits Hepatic Lipogenesis by Activating AMPK Pathway.

Unsaponifiable matter (USM) from wheat bran, a by-product obtained from wheat milling, is abundant in health-promoting compounds such as phytosterols, tocopherols, policosanols, and alkylresorcinols. This study aimed to examine the effects of USM from the wheat bran of normal and waxy type wheat, Saekeumkang (SKK) and Shinmichal (SMC), on hepatic lipid accumulation in free fatty acid (FFA)-induced hepatocytes and to investigate the cellular mechanism. The total phytochemical contents were 46.562 g/100 g USM and 38.130 g/100 g USM from SKK and SMC, respectively. FFA treatment increased intracellular lipid accumulation by approximately 260% compared to the control group; however, treatment with USM from SKK and SMC significantly attenuated lipid accumulation in the hepatocytes in a dose-dependent manner. Moreover, USM downregulated the expression of lipogenic factors such as fatty acid synthase and sterol regulatory-element-binding protein 1c by approximately 40% compared to the FFA treatment group. Treatment with USM promoted lipolysis and positively regulated the expression of the proteins involved in β-oxidation, including peroxisome proliferator-activated receptor α and its downstream protein, carnitine palmitoyltransferase 1A. Moreover, the blockade of AMPK activation significantly abolished the inhibitory effects of USM on hepatic lipid accumulation. These results indicated that the USM from both SKK and SMC can alleviate lipid accumulation in hepatocytes in an AMPK-dependent manner. Therefore, USM from wheat bran may be useful as a therapeutic intervention for treating metabolic-dysfunction-associated fatty liver disease.

CTRP13 alleviates palmitic acid-induced inflammation, oxidative stress, apoptosis and endothelial cell dysfunction in HUVECs

C1q/tumor necrosis factor-related protein 13 (CTRP13) has been reported to participate in cardiovascular diseases. However, the role and molecular mechanism of CTRP13 in obesity-induced endothelial cell damage is still unclear. In palmitic acid (PA)-induced human umbilical vein endothelial cells (HUVECs), qRT-PCR and western blot were used to examine CTRP13 expression. CCK-8 and TUNEL assays were adopted to assess cell viability and apoptosis, respectively. ROS level and MDA content were evaluated by their commercial kits and inflammatory cytokines were measured using ELISA. Endothelial cell dysfunction was evaluated by detecting NO production and eNOS expression, and tube formation assay was performed to assess angiogenesis. AMPK pathway-related proteins were detected by western blot. The results showed that CTRP13 was downregulated in PA-induced HUVECs. CTRP13 overexpression reduced PA-induced cell viability loss and oxidative stress in HUVECs. Moreover, CTRP13 overexpression suppressed PA-induced inflammation and apoptosis, improved angiogenesis ability, and alleviated endothelial cell dysfunction in HUVECs. In addition, CTRP13 overexpression activated AMPK pathway and regulated the expressions of downstream NOX1/p38 and KLF2. Furthermore, compound C countervailed the impacts of CTRP13 overexpression on cell viability, oxidative stress, inflammation, apoptosis and endothelial function in PA-induced HUVECs. To sum up, CTRP13 overexpression may alleviate PA-induced endothelial cell damage.

Glucose promotes cell growth and casein synthesis via ATF4/Nrf2-Sestrin2- AMPK-mTORC1 pathway in dairy cow mammary epithelial cells

In the dairy industry, glucose (Glu) is used as bioactive substance to increase milk yield. However, the molecular regulation underneath needs further clarification. Here, the regulation and its molecular mechanism of Glu on cell growth and casein synthesis of dairy cow mammary epithelial cells (DCMECs) were investigated. When Glu was added from DCMECs, both cell growth, β-casein expression and the mechanistic target of rapamycin complex 1 (mTORC1) pathway were increased. Overexpression and silencing of mTOR revealed that Glu promoted cell growth and β-casein expression through the mTORC1 pathway. When Glu was added from DCMECs, both Adenosine 5'-monophosphate-activated protein kinase α (AMPKα) and Sestrin2 (SESN2) expression were decreased. Overexpression and silencing of AMPKα or SESN2 uncovered that AMPKα suppressed cell growth and β-casein synthesis through inhibiting mTORC1 pathway, and SESN2 suppressed cell growth and β-casein synthesis through activating AMPK pathway. When Glu was depleted from DCMECs, both activating transcription factor 4 (ATF4) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) expression were increased. Overexpression or silencing of ATF4 or Nrf2 demonstrated that Glu depletion promoted SESN2 expression through ATF4 and Nrf2. Together, these results indicate that in DCMECs, Glu promoted cell growth and casein synthesis via ATF4/Nrf2-SESN2-AMPK-mTORC1 pathway.

Lycorine protects against septic myocardial injury by activating AMPK-related pathways.

Cardiac dysfunction is a common complication in patients with sepsis triggering high morbidity and mortality. Lycorine (LYC), the main effective monomer component extracted from Lycoris bulbs, possesses antiviral, anti-inflammatory, analgesic, liver protection properties. In this study, the effect of LYC pre- and post-treatment as well as the underlying mechanism were evaluated in the cecal ligation and puncture (CLP) model of Balb/c mice. The survival rate, anal temperature, sepsis score, blood biochemical/routine indicators, cardiac function, sepsis-related pathophysiological processes, and AMPK signaling in septic mice were observed by echocardiography, histological staining, western blot, qPCR, and etc. LYC pretreatment attenuated myocardial injury in septic mice by improving survival rate, sepsis score, blood biochemical/routine indicators, cardiac function and structure, inhibiting inflammation and oxidative stress, improving mitochondrial function, modulating endoplasmic reticulum stress, and activating AMPK pathway. In particular, AMPK deficiency and AMPK inhibitor (Compound C) partially reversed the protective effects of LYC in septic mice. In addition, LYC posttreatment also has slight protective phenotypes on septic myocardial injury, but the effect is not as ideal as pretreatment. Taken together, these findings suggest that LYC may be a potential drug for the treatment of sepsis.

Erythropoietin exerts neuroprotective effect against hypoxic ischemic brain injury in neonatal mice by activating AMPK pathway and upregulating UCP2

Purpose: To investigate the neuroprotective effect of erythropoietin (EPO) against hypoxic-ischemic brain injury in neonatal mice, and the underlying mechanism(s) of action.&#x0D; Methods: Sixty neonatal mice were assigned to 3 groups: sham, model and EPO intervention groups, each with 20 mice. Western blot assay was used to determine changes in the protein expressions of AMPK, UCP2 and KLF2. Fluorescence intensity of reactive oxygen species (ROS) was evaluated with flow cytometry.&#x0D; Results: The protein expressions of AMPK and KLF2 in the cerebral tissues of EPO intervention mice were significantly up-regulated, relative to model mice (p &lt; 0.05), while UCP2 protein level was also significantly higher in EPO intervention mice than in model mice (p &lt; 0.05). Mean fluorescence intensity of ROS was significantly higher in the cerebral cortex of model mice than in sham mice, but it was down-regulated in the cerebral cortex of mice in EPO intervention group, relative to the model group (p &lt; 0.05).&#x0D; Conclusion: EPO exerts neuroprotective effect by activating AMPK pathway, up-regulating protein expression of UCP2, inhibiting production of mitochondrial ROS, and reducing oxidative stress in brain tissue. Thus, EPO has potentials for use in clinical practice as a neuroprotective agent.

Baicalin ameliorates high fat diet-induced nonalcoholic fatty liver disease in mice via adenosine monophosphate-activated protein kinase-mediated regulation of SREBP1/Nrf2/NF-κB signaling pathways.

Nonalcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disease around the world, imposing severe threats on human health. Unfortunately, no clinically approved drugs are available for use as yet. Baicalin (BA) is reported to have hepatoprotective effects, and it is not clear whether BA can treat NAFLD and how. Here, a high-fat diet (HFD)-induced NAFLD mouse model was established to explore the protective roles and mechanisms of BA against HFD-induced NAFLD. Physiochemical results showed that BA exhibited significantly protective effects against HFD-induced NAFLD in mice. Liver transcriptomic analysis revealed that BA attenuated HFD-induced NAFLD via activating AMPK pathway, which was confirmed by the AMPK inhibitor Compound C. Additionally, the expression changes of AMPK downstream genes demonstrated that BA exerted ameliorative effects against NAFLD through AMPK-mediated inhibition of SREBP1 and NF-κB pathways, and activation of Nrf2 pathway. Taken together, our study reveals the protective roles of BA against HFD-caused NAFLD through AMPK-mediated modulation of SREBP1/Nrf2/NF-κB pathways, suggesting that BA has potential drug development implications. Most importantly, our study creates a paradigm through the combination of molecular biology and bioinformatics for further studies of action mechanisms of biomolecules combating diseases.

Canagliflozin Attenuates Lipotoxicity in Cardiomyocytes by Inhibiting Inflammation and Ferroptosis through Activating AMPK Pathway

Diabetic cardiomyopathy (DCM) is a myocardial disease independent of other cardiovascular diseases, such as coronary heart disease, hypertension, etc. Lipotoxicity is closely related to DCM. In this study, we investigated the mechanism of lipid metabolism disturbance in DCM in HL-1 cells. Through bioinformatics and Western blotting analysis, we found that canagliflozin (CAN) significantly inhibited the expression of inflammatory factors cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Ferroptosis is mediated by lipid peroxidation. We demonstrated the presence of ferroptosis in cardiomyocytes by detecting intracellular Fe2+ content and the levels of reactive oxygen species (ROS), malondialdehyde (MDA), reduced glutathione (GSH), and mitochondrial membrane potential (MMP). CAN could significantly regulate the indicators of ferroptosis. By using specific inhibitors celecoxib (coxib), S-methylisothiourea sulfate (SMT), Ferrostatin-1 (Fer-1), and Compound C, we further found that CAN regulated inflammation and ferroptosis through AMP-activated protein (AMPK), and inflammation interacted with ferroptosis. Our study indicated that CAN attenuated lipotoxicity in cardiomyocytes by regulating inflammation and ferroptosis through activating the AMPK pathway. This study provides a new direction of myocardial lipotoxicity and some new information for the treatment of DCM.

Loss of WNK1 Suppressed the Malignant Behaviors of Hepatocellular Carcinoma Cells by Promoting Autophagy and Activating AMPK Pathway.

WNK lysine deficient protein kinase 1 (WNK1) has been shown to be highly expressed in hepatocellular carcinoma (HCC) samples and related to poor prognosis of HCC patients based on bioinformatics analysis. However, the specific function of WNK1 in HCC has not been analyzed. This study is aimed at exploring the function of WNK1 in HCC progression as well as its related molecular mechanism. After knockdown of WNK1 by small interference RNA, cell counting kit-8, colony formation, western blot, Transwell, and wound healing assays were employed to evaluate the biological behaviors of HCC cells. Immunofluorescent staining was applied to detect the effect of WNK1 on LC3 II. GSK690693 or si-AMPK was applied to block AMPK pathway. The expression of autophagy and AMPK pathway related molecules was examined by western blot assay. WNK1 was highly expressed in HCC cell lines and loss of WNK1 inhibited HCC cell proliferation, cell cycle, migration, and invasion. Additionally, we demonstrated that loss of WNK1 promoted the autophagy and activated AMPK pathway in HCC cells. While, GSK690693 treatment or si-AMPK transfection suppressed the autophagy and promoted HCC cells proliferation. However, WNK1 knockdown counteracted the effect of GSK690693 or si-AMPK in regulating HCC cell proliferation. Finally, we demonstrated that WNK1 regulated the malignant behaviors of HCC cells by modulating autophagy and AMPK pathway. The above results indicated that WNK1 may be a worthwhile target to be considered for therapy of HCC.

Effects of dietary berberine on growth performance, lipid metabolism, antioxidant capacity and lipometabolism-related genes expression of AMPK signaling pathway in juvenile black carp (Mylopharyngodon piceus) fed high-fat diets.

This study aimed to investigate the effects of high-fat diet (HFD) supplemented with berberine on growth, lipid metabolism, antioxidant capacity and lipometabolism-related genes expression of AMPK signaling pathway in juvenile black carp (Mylopharyngodon piceus). Five hundred and forty healthy fish (4.04 ± 0.01g) were randomly distributed into six groups, and fed six experimental diets: normal-fat diet (NFD, 5% fat), HFD (15% fat), and four HFDs supplemented with graded levels of berberine, respectively. The results showed that, compared with fish fed NFD, HFD had no effects on the growth of fish except for reducing survival rate, whereas HFD caused extensive lipid accumulation, oxidative stress injury and hepatic abnormalities. However, compared with the HFD group, fish fed HFD containing an appropriate berberine (98.26 or 196.21mg/kg) improved the growth performance, increased hepatic lipid metabolism and antioxidant enzymes activities, and up-regulated the mRNA expression levels of ampk subunits and lipolysis genes such as pparα, cpt-1, acox, atgl and hsl (P < 0.05). Meanwhile, HFD supplemented with an appropriate berberine reduced crude lipid contents in liver and whole-body, decreased serum lipid contents, and ALT and AST activities, and down-regulated the mRNA expression levels of lipogenesis genes such as srebp-1, acc1, gpat, fas and pparγ, and lipid transporter genes such as fatp, fabp and fat/cd36 (P < 0.05). Thus, HFD supplemented with an appropriate berberine could improve growth of black carp, promote lipid metabolism and enhance antioxidant capacity. The lipid-lowering mechanism of berberine might be mediated by activating AMPK pathway, up-regulating lipolysis genes expression, and down-regulating lipogenesis and transport genes expression.

Adlay (Coix lacryma-jobi L.) Polyphenol Improves Hepatic Glucose and Lipid Homeostasis through Regulating Intestinal Flora via AMPK Pathway.

Non-alcoholic fatty liver disease (NAFLD) is a type of metabolic syndrome characterized of abnormal lipid deposition in the liver. Adlay polyphenol (AP), an effective component extracted from Coix lacryma-jobi L., has been reported that it can be used as a dietary supplement to prevent NAFLD. In this study, the mechanism and action of AP on lipid metabolism and regulation of intestinal flora are investigated. AP significantly decreases the lipid accumulation in free fatty acid-treated HepG2 cells. Western blot results indicate that AP improves lipid metabolism via activating the p-AMPK/p-ACC pathway. In vivo experiments show AP treatment significantly decreases the body weight, liver weight, hepatic triglyceride, and total cholesterol contents, as well as the serum glucose levels in high fat diet-fed mice, which may affect lipid accumulation by activating AMPK pathway and changing intestinal bacterial communities and intestinal microbiome metabolism. AP can be used as a food supplement for improving lipid metabolic dysfunction and reducing the incidence of metabolic diseases.

Narciclasine ameliorated T cell mediated acute liver injury through activating AMPK pathway

Hepatitis is closely related to cirrhosis and liver cancer, and it is vital that we develop new drugs and identify new drug targets. Traditional Chinese medicine has demonstrated excellent curative effects on liver diseases. The ingredients from Chinese herbals are important source for drug development in the treatment of hepatitis. Here, we found that narciclasine (NCS), a major component extracted from narcissus bulbs, showed hepatoprotective effect against concanavalin A (Con A) induced hepatitis. NCS treatment significantly reduced hepatocyte death, hepatic inflammatory cells infiltration, and serum cytokine levels in Con A challenged mice. We further observed that NCS directly inhibited Con A induced splenocytes proliferation and cytokine production in vitro. RNA-seq results showed that genes related to immune response were upregulated in Con A treated CD4+ T cells, which were down-regulated in the presence of NCS. Moreover, the AMPK pathway had been found activated in response to NCS treatment, suggesting a potential target for NCS targets. In conclusion, our results reveal that NCS is a powerful immunosuppressor against T cell activation, thus leading to protection against Con A induced liver injury in mice. These findings provide new insights into the use of natural products in the treatment of autoimmune hepatitis.

Normothermic liver machine perfusion as a dynamic platform for regenerative purposes: What does the future have in store for us?

Liver transplantation has become an immense success; nevertheless, far more recipients are registered on waiting lists than there are available donor livers for transplantation. High-risk, extended criteria donor livers are increasingly used to reduce the discrepancy between organ demand and supply. Especially for high-risk livers, dynamic preservation using machine perfusion can decrease post-transplantation complications and may increase donor liver utilisation by improving graft quality and enabling viability testing before transplantation. To further increase the availability of donor livers suitable for transplantation, new strategies are required that make it possible to use organs that are initially too damaged to be transplanted. With the current progress in experimental liver transplantation research, (long-term) normothermic machine perfusion may be used in the future as a dynamic platform for regenerative medicine approaches, enabling repair and regeneration of injured donor livers. Currently explored therapeutics such as defatting cocktails, RNA interference, senolytics, and stem cell therapy may assist in the repair and/or regeneration of injured livers before transplantation. This review will provide a forecast of the future utility of normothermic machine perfusion in decreasing the imbalance between donor liver demand and supply by enabling the repair and regeneration of damaged donor livers.