Monophosphate-activated Protein Kinase Signaling Research Articles

Probiotic cheese improves alcohol metabolism and alleviates alcohol-induced liver injury via the SIRT1/AMPK signaling pathway

Excessive alcohol intake leads to alcoholic liver injury via hepatic acetaldehyde accumulation. Some probiotic bacteria, such as Lactiplantibacillus plantarum and Bifidobacterium, are known to have the ability to break down acetaldehyde; however, there is a lack of evidence on their efficacy in functional food applications. In this study, probiotic cheese containing Lactococcus lactis LB1022 and Lactiplantibacillus plantarum LB1418 was evaluated for its function in inducing alcohol metabolism and alleviating alcohol-induced hepatic injury. Probiotic cheese ameliorated alcohol metabolism induced by alcohol dehydrogenase and aldehyde dehydrogenase, enhanced the sirtuin-1 (SIRT1)/adenosine monophosphate-activated protein kinase (AMPK) signaling, and inhibited the nuclear factor kappa light chain enhancer of activated B cells (NF-κB) pathway. Interestingly, probiotic cheese also induced peroxisome proliferator-activated receptor α and prevented fat formation and inflammation in the liver. Taken together, probiotic cheese containing Lc. lactis LB1022 and Lb. plantarum LB1418 could induce alcohol metabolism and alleviate alcohol-induced liver injury by regulating SIRT1 in fatty acid oxidation, AMPK in lipogenesis, and NF-κB in inflammation.

Colquhounia Root Tablet Promotes Autophagy and Inhibits Apoptosis in Diabetic Nephropathy by Suppressing CD36 Expression In Vivo and In Vitro.

Rat models of DN were established using streptozotocin (STZ). The primary metabolic parameters were assessed. The pathological changes of the rat kidney were investigated, and RNA sequencing was performed for each group. Renal tissue apoptosis was detected using the TUNEL assay. In rats and high glucose- (Hg-) induced HK-2 cells, RT-qPCR and western blot were used to analyze the expression of related genes and proteins. Hg medium was used to establish the diabetic kidney environment. The CCK-8 assay and flow cytometry were used to assess cell viability and apoptosis, respectively. Transmission electron microscopy was used to evaluate autophagy in vitro. CRT treatment significantly reduced albuminuria and renal tissue damage in DN rats. Furthermore, CRT administration inhibited apoptosis and promoted autophagy in DN rat kidney tissues. CRT downregulated CD36 expression and activated the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway in DN rat kidney tissues. CRT intervention inhibited Hg-induced apoptosis and reversed autophagy in HK-2 cells. Moreover, overexpression of CD36 suppressed the beneficial effects of CRT. Our study is the first to report that CRT inhibited apoptosis and promoted autophagy in vivo and in vitro, which was achieved by reducing CD36 expression and activating the AMPK pathway. Therefore, CRT may be an effective drug to treat DN.

Targeting the adenosine monophosphate-activated protein kinase signalling pathway by bempedoic acid attenuates Angiotensin II-induced cardiac remodelling in renovascular hypertension in rats

The crosstalk between the renin-angiotensin system and Adenosine monophosphate-activated protein kinase (AMPK) gained significant interest due to their involvement in the pathogenesis of several cardiovascular diseases. Angiotensin II (Ang II) plays a crucial role in developing cardiac remodelling by inducing energy imbalance, inflammation, oxidative and endoplasmic reticulum stress, and transforming growth factor-β (TGF-β)-induced fibrosis. Ang II directly or through extracellular signal-regulated kinase (ERK) activation impairs AMPK signalling with well-known antioxidant, anti-inflammatory, and anti-fibrotic effects. AimThis study aimed to investigate the role of bempedoic acid, a novel antihyperlipidemic drug, in attenuating hypertension-induced cardiac remodelling in rats by modulating Ang II-induced damage and activating the AMPK signalling pathway. MethodSixty adult male Sprague Dawley rats were randomly allocated into the Sham control group, Hypertensive group, Captopril group (30 mg/kg), and Bempedoic acid group (30 mg/kg). Hypertension was induced by left renal artery ligation in all groups except the Sham control group. Treatment with captopril and bempedoic acid started 14 days post-surgy and lasted two weeks. Finally, Hemodynamic measurements and electrocardiographic examination were done followed by heart tissue samples collection for biochemical, histopathological, and immunohistochemical examinations. Key findingsBempedoic acid preserved the cardiac function and electrocardiogram patterns. It inhibited endoplasmic reticulum stress, exhibited antioxidant activity, and increased endothelial nitric oxide synthase activity. Bempedoic acid interfered with ERK signalling pathways, including nuclear factor-κB and TGF-β, exerting anti-inflammatory and anti-fibrotic effects. SignificanceThese findings indicate the cardioprotective and antihypertrophic activity of bempedoic acid, which are suggested to result from energy-independent AMPK downstream signalling activation.

Modulation of the Microbiome-Fat-Liver Axis by Lactic Acid Bacteria: A Potential Alleviated Role in High-Fat-Diet-Induced Obese Mice.

The major characteristics of obesity are abnormal lipid metabolism, chronic inflammation, and imbalanced gut microbiota. It has been reported that lactic acid bacteria (LAB) possess potential for alleviating obesity, considering which the strain-specific functions and diverse mechanisms and the roles and mechanisms of various LAB are worthy of investigation. This study aimed to validate and investigate the alleviating effects and underlying mechanisms of three LAB strains, Lactiplantibacillus plantarum NCUH001046 (LP), Limosilactobacillus reuteri NCUH064003, and Limosilactobacillus fermentum NCUH003068 (LF), in high-fat-diet-induced obese mice. The findings demonstrated that the three strains, particularly LP, suppressed body weight gain and fat deposition; ameliorated lipid disorders, liver and adipocyte morphology, and chronic low-grade inflammation; and reduced lipid synthesis via activating the adenosine 5'-monophosphate-activated protein kinase (AMPK) signaling pathway. In addition, LP and LF decreased the enrichment of bacteria positively correlated with obesity, like Mucispirillum, Olsenella, and Streptococcus, but facilitated the growth of beneficial bacteria negatively correlated with obesity, like Roseburia, Coprococcus, and Bacteroides, along with increasing the short-chain fatty acid levels. It is deduced that the underlying alleviating mechanism of LP was to modulate the hepatic AMPK signaling pathway and gut microbiota by the microbiome-fat-liver axis to alleviate obesity development. In conclusion, as a diet supplement, LP has promising potential in obesity prevention and treatment.

Effect of bempedoic acid on angiotensin-II induced hypertension and vascular tissue remodelling in renal hypertensive rats through AMPK multiple signalling pathways modulation.

Angiotensin II (Ang II), the effector of the renin-angiotensin system (RAS), is a key player in the pathogenesis of chronic hypertension, accompanied by vascular tissue resistance, remodelling, and damage. Chronic activation of Ang II receptor 1 (AT-1R) impairs multiple cellular targets implicated in cellular protection and survival, including adenosine Monophosphate-activated protein kinase (AMPK) signalling. In addition, it induces oxidative damage, endoplasmic reticulum (ER) stress, and fibrotic changes in resistance vessels. Our study investigated the antihypertensive and antifibrotic effects of bempedoic acid, a first-in-class antihyperlipidemic drug that targets adenosine triphosphate-citrate lyase enzyme to inhibit cholesterol synthesis. We also studied the modulation of multiple AMPK signalling pathways by bempedoic acid in a chronic hypertension model in rats. Sixty male Sprague-Dawley rats were divided into four groups: sham group, hypertensive group, standard captopril group, and bempedoic treated group. All groups underwent left renal artery ligation except the sham group. Fourteen days post-surgery, captopril and bempedoic acid were administered with a dose of 30mg/kg/day orally to captopril-standard and bempedoic acid-treated groups for two weeks, respectively. In mesenteric resistance arteries, bempedoic acid activated AMPK energy independently and augmented AMPK multiple cellular targets to adapt to Ang II-induced cellular stress. It exerted antioxidant activity, increased endothelial nitric oxide synthase, and reversed the ER stress. Bempedoic acid maintained vascular integrity and prevented vascular remodelling by inhibiting extracellular signal-regulated kinase (ERK)/transforming growth factor-β fibrotic pathway. These effects were reflected in the improved hemodynamic measurements.

Metabolic Syndrome and Cardiac Remodeling Due to Mitochondrial Oxidative Stress Involving Gliflozins and Sirtuins.

To address the mechanistic pathways focusing on mitochondria dysfunction, oxidative stress, sirtuins imbalance, and other contributors in patient with metabolic syndrome and cardiovascular disease. Sodium glucose co-transporter type 2 (SGLT-2) inhibitors deeply influence these mechanisms. Recent randomized clinical trials have shown impressive results in improving cardiac function and reducing cardiovascular and renal events. These unexpected results generate the need to deepen our understanding of the molecular mechanisms able to generate these effects to help explain such significant clinical outcomes. Cardiovascular disease is highly prevalent among individuals with metabolic syndrome and diabetes. Furthermore, mitochondrial dysfunction is a principal player in its development and persistence, including the consequent cardiac remodeling and events. Another central protagonist is the renin-angiotensin system; the high angiotensin II (Ang II) activity fuel oxidative stress and local inflammatory responses. Additionally, sirtuins decline plays a pivotal role in the process; they enhance oxidative stress by regulating adaptive responses to the cellular environment and interacting with Ang II in many circumstances, including cardiac and vascular remodeling, inflammation, and fibrosis. Fasting and lower mitochondrial energy generation are conditions that substantially reduce most of the mentioned cardiometabolic syndrome disarrangements. In addition, it increases sirtuins levels, and adenosine monophosphate-activated protein kinase (AMPK) signaling stimulates hypoxia-inducible factor-1β (HIF-1 beta) and favors ketosis. All these effects favor autophagy and mitophagy, clean the cardiac cells with damaged organelles, and reduce oxidative stress and inflammatory response, giving cardiac tissue protection. In this sense, SGLT-2 inhibitors enhance the level of at least four sirtuins, some located in the mitochondria. Moreover, late evidence shows that SLGT-2 inhibitors mimic this protective process, improving mitochondria function, oxidative stress, and inflammation. Considering the previously described protection at the cardiovascular level is necessary to go deeper in the knowledge of the effects of SGLT-2 inhibitors on the mitochondria function. Various of the protective effects these drugs clearly had shown in the trials, and we briefly describe it could depend on sirtuins enhance activity, oxidative stress reduction, inflammatory process attenuation, less interstitial fibrosis, and a consequent better cardiac function. This information could encourage investigating new therapeutic strategies for metabolic syndrome, diabetes, heart and renal failure, and other diseases.

Surfactin alleviated hyperglycaemia in mice with type 2 diabetes induced by a high-fat diet and streptozotocin

Type 2 diabetes mellitus (T2DM) is associated with liver dysfunction and intestinal dysbiosis. Bioactive peptides (BAPs) have been reported to ameliorate T2DM by preventing oxidative damage to the liver. Bacillus amyloliquefaciens fmb50 produces the lipopeptide surfactin with a wide range of biological activities. The effects of surfactin on T2DM, on the other hand, have not been studied. In the present study, 80 mg/kg body weight surfactin supplementation lowered fasting blood glucose (FBG) levels by 21.05 % and insulin resistance (IR) by 18.18 % compared with those in the T2DM group, reduced inflammation, and increased antioxidant activity in mice with T2DM induced by a high-fat diet (HFD) and streptozotocin (STZ). According to further research, surfactin administration reduced Firmicutes-to-Bacteroidetes ratios while increasing Bifidobacterium abundance by 20 times and the level of the tight junction protein Occludin by 18.38 % and ZO-1 by 66.60 %. Furthermore, surfactin also improved hepatic glucose metabolism by activating the adenosine monophosphate-activated protein kinase (AMPK) signalling pathway, increasing glycogen synthesis and glucose transporter 2 (GLUT2) protein expression while reducing glucose-6-phosphatase (G6Pase) protein expression. In addition, the increased Bifidobacterium abundance indirectly reduced the liver burden of the metabolic products indole, cresol and amine produced by saprophytic bacteria. All of these findings revealed that surfactin not only ameliorated HFD/STZ-induced gut dysbiosis and preserved intestinal barrier integrity but also enhanced hepatic glucose metabolism and detoxification function in T2DM mice. The gut microbiota appeared to be important in controlling glucose metabolism, IR, fat accumulation, inflammation and antioxidation, according to Spearman’s correlation coefficients. All data indicated that surfactin alleviated hyperglycaemia in mice with T2DM induced by HFD/STZ.

Intestinal Reg4 deficiency confers susceptibility to high-fat diet-induced liver steatosis by increasing intestinal fat absorption in mice

Regenerating gene family member 4 (REG4) is a novel marker for enteroendocrine cells and is selectively expressed in specialised enteroendocrine cells of the small intestine. However, the exact roles of REG4 are largely unknown. In this study we investigate the effects of REG4 on the development of dietary fat-dependent liver steatosis and the mechanisms involved. Mice with intestinal-specific Reg4 deficiency (Reg4 ΔIEC ) and Reg4-floxed alleles (Reg4 fl/fl ) were generated to investigate the effects of Reg4 on diet-induced obesity and liver steatosis. Serum levels of REG4 were also measured in children with obesity using ELISA. Reg4 ΔIEC mice fed a high-fat diet demonstrated significantly increased intestinal fat absorption and were prone to obesity and hepatic steatosis. Importantly, Reg4 ΔIEC mice exhibit enhanced activation of adenosine monophosphate-activated protein kinase (AMPK) signalling and increased protein abundance of the intestinal fat transporters, as well as enzymes involved in triglyceride synthesis and packaging at the proximal small intestine. Moreover, REG4 administration reduced fat absorption, and decreased the expression of intestinal fat absorption-related proteins in cultured intestinal cells possibly via the CaMKK2-AMPK pathway. Serum REG4 levels were markedly lower in children with obesity with advanced liver steatosis (p <0.05). Serum REG4 levels were inversely correlated with levels of liver enzymes, homeostasis model assessment of insulin resistance, low-density lipoprotein cholesterol, and triglycerides. Our findings directly link Reg4 deficiency with increased fat absorption and obesity-related liver steatosis, and suggest that REG4 may provide a potential target for prevention and treatment of liver steatosis in children. Hepatic steatosis is a key histological feature of non-alcoholic fatty liver disease, which is the leading chronic liver disease in children leading to the development of metabolic diseases; however, little is known about mechanisms induced by dietary fat. Intestinal REG4 acts as a novel enteroendocrine hormone reducing high-fat-diet-induced liver steatosis with decreasing intestinal fat absorption. REG4 may be a novel target for treatment of paediatric liver steatosis from the perspective of crosstalk between intestine and liver.

Lead intoxication-induced exosomes promote autophagy and apoptosis in renal proximal tubule cells by activating the adenosine 5'-monophosphate-activated protein kinase signaling.

Lead (Pb) intoxication is known to damage the proximal tubules of kidney. Autophagy and apoptosis have been shown to be involved in a variety of renal injuries, but the underlying mechanisms remain largely unknown. In this study, we constructed a mice model of Pb intoxication and validated it against lead concentrations in blood and urine. Electron microscopy revealed that Pb promoted the accumulation of autophagosomes. Subsequent immunofluorescence and western blotting revealed that Pb intoxication suppressed the autophagic flux. Next, exosomes were isolated and extracted through ultracentrifugation, and were further identified by diameter analysis and marker detection. We also demonstrated that autophagy and apoptosis were enhanced in renal cells with exosomes of Pb expose. Furthermore, the specific mechanisms were explored by RNA sequencing and it was found that several targeted genes regulated by differential exosomal miRNAs and lncRNAs. Target genes accumulated in several signaling pathways, especially the adenosine 5'-monophosphate-activated protein kinase(AMPK) signaling. We found that Pb intoxication-induced exosomes activated the AMPK signaling in renal proximal tubule cells. Furthermore, autophagy and apoptosis assays showed that GSK-690693, an AMPK inhibitor, significantly alleviated exosome-induced renal injuries by Pb intoxication. In conclusion, Pb-mediated exosome-induced autophagy and apoptosis via activating the AMPK signaling contributing to Pb-induced nephrotoxicity in renal cells.

Effect and mechanisms of dexmedetomidine combined with macrophage migration inhibitory factor inhibition on the expression of inflammatory factors and AMPK in mice.

Reperfusion after acute myocardial infarction can cause ischemia/reperfusion (I/R) injury, which not only impedes restoration of the functions of tissues and organs but may also aggravate structural tissue and organ damage and dysfunction, worsening the patient's condition. Thus, the mechanisms that underpin myocardial I/R injury need to be better understood. We aimed to examine the effect of dexmedetomidine on macrophage migration inhibitory factor (MIF) in cardiomyocytes from mice with myocardial I/R injury and to explore the mechanistic role of adenosine 5'-monophosphate-activated protein kinase (AMPK) signaling in this process. Myocardial I/R injury was induced in mice. The expression of serum inflammatory factors, reactive oxygen species (ROS), adenosine triphosphate (ATP), and AMPK pathway-related proteins, as well as myocardial tissue structure and cell apoptosis rate, were compared between mice with I/R injury only; mice with I/R injury treated with dexmedetomidine, ISO-1 (MIF inhibitor), or both; and sham-operated mice. Dexmedetomidine reduced serum interleukin (IL)-6 and tumor necrosis factor-α concentrations and increased IL-10 concentration in mice with I/R injury. Moreover, dexmedetomidine reduced myocardial tissue ROS content and apoptosis rate and increased ATP content and MIF expression. MIF inhibition using ISO-1 reversed the protective effect of dexmedetomidine on myocardial I/R injury and reduced AMPK phosphorylation. Dexmedetomidine reduces the inflammatory response in mice with I/R injury and improves adverse symptoms, and its mechanism of action may be related to the MIF-AMPK pathway.

Action Mechanism of Metformin and Its Application in Hematological Malignancy Treatments: A Review.

Hematologic malignancies (HMs) mainly include acute and chronic leukemia, lymphoma, myeloma and other heterogeneous tumors that seriously threaten human life and health. The common effective treatments are radiotherapy, chemotherapy and hematopoietic stem cell transplantation (HSCT), which have limited options and are prone to tumor recurrence and (or) drug resistance. Metformin is the first-line drug for the treatment of type 2 diabetes (T2DM). Recently, studies identified the potential anti-cancer ability of metformin in both T2DM patients and patients that are non-diabetic. The latest epidemiological and preclinical studies suggested a potential benefit of metformin in the prevention and treatment of patients with HM. The mechanism may involve the activation of the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway by metformin as well as other AMPK-independent pathways to exert anti-cancer properties. In addition, combining current conventional anti-cancer drugs with metformin may improve the efficacy and reduce adverse drug reactions. Therefore, metformin can also be used as an adjuvant therapeutic agent for HM. This paper highlights the anti-hyperglycemic effects and potential anti-cancer effects of metformin, and also compiles the in vitro and clinical trials of metformin as an anti-cancer and chemosensitizing agent for the treatment of HM. The need for future research on the use of metformin in the treatment of HM is indicated.

Sulforaphane Suppresses H2O2-Induced Oxidative Stress and Apoptosis via the Activation of AMPK/NFE2L2 Signaling Pathway in Goat Mammary Epithelial Cells.

Oxidative stress in high-yielding dairy goats adversely affects lactation length, milk quality, and the economics of dairy products. During the lactation period, goat mammary epithelial cells (GMECs) are often in a state of disordered metabolic homeostasis primarily caused by the overproduction of reactive oxygen species (ROS). Sulforaphane (SFN), an electrophilic compound that is enriched in broccoli, is a promising antioxidant agent for future potential clinical applications. The objective of the present study was to investigate the function of SFN on hydrogen peroxide (H2O2)-induced oxidative damage in primary GMECs and the underlying molecular mechanisms. Isolated GMECs in triplicate were pretreated with SFN (1.25, 2.5, and 5 μM) for 24 h in the absence or presence of H2O2 (400 μM) for 24 h. The results showed that SFN effectively enhanced superoxide dismutase (SOD) activity, elevated the ratio of glutathione (GSH)/glutathione oxidized (GSSG), and reduced H2O2-induced ROS and malondialdehyde (MDA) production and cell apoptosis. Mechanically, SFN-induced nuclear factor erythroid 2-related factor 2 (NRF2/NFE2L2) translocation to the nucleus through the activation of the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway coupled with inhibition of the caspase apoptotic pathway. In addition, GMECs were transfected with NFE2L2 small interfering RNA (NFE2L2 siRNA) for 48 h and/or treated with SFN (5 μM) for 24 h before being exposed to H2O2 (400 μM) for 24 h. We found that knockdown of NFE2L2 by siRNA abrogated the preventive effect of SFN on H2O2-induced ROS overproduction and apoptosis. Taken together, sulforaphane suppressed H2O2-induced oxidative stress and apoptosis via the activation of the AMPK/NFE2L2 signaling pathway in primary GMECs.

Sour cherry ameliorates hepatic lipid synthesis in high-fat diet-induced obese mice via activation of adenosine monophosphate-activated protein kinase signaling

Sour cherry ameliorates hepatic lipid synthesis in high-fat diet-induced obese mice via activation of adenosine monophosphate-activated protein kinase signaling

Responses of complement C1q/tumor necrosis factor-related proteins to acute aerobic exercise.

Aerobic exercise is an effective therapeutic strategy to manage metabolic disorders. However, the mechanisms of aerobic exercise-induced improvements in metabolic diseases are not completely understood. Complement C1q/tumor necrosis factor-related protein (CTRP) 1, CTRP3, CTRP5, and CTRP9 have important roles in improving metabolic disorders via the adenosine monophosphate-activated protein kinase signaling pathway. In this study, we investigated the effects of acute aerobic exercise on circulating CTRP1, CTRP3, CTRP5, and CTRP9 levels in human participants. Eight healthy males with an age of 20.4±0.2years, height 173.1±1.7cm, body mass 68.0±1.8kg, body mass index 22.7±0.7kg/m2, and maximal oxygen uptake (VO2max) 51.3±2.5mL/kg/min performed acute aerobic cycling exercise at 75% of their VO2max for 30min (data are mean±standard error). Blood samples were obtained before; immediately after; and 30, 60, and 120min after exercising. Serum concentrations of CTRP1, CTRP3, CTRP5, CTRP9, tumor necrosis factor-α (TNF-α), and insulin were measured. The CTRP1 concentration significantly increased immediately after exercising and remained elevated for up to 120min (p<0.01). The CTRP3 concentration significantly increased at 60min after exercise (p<0.05), and the increasing trend continued until at least 120min after exercise (p<0.01). The CTRP5, CTRP9, TNF-α, and insulin concentrations significantly increased immediately after exercise (p<0.05, p<0.01, p<0.05, and p<0.05, respectively) and decreased thereafter. A significant correlation was observed between the peak post-exercise concentrations of CTRP1 and TNF-α (p<0.05); however, no correlation was observed between the peak post-exercise concentrations of CTRP3 and insulin. The results of this study indicate that acute aerobic exercise may enhance the secretion of CTRP1, CTRP3, CTRP5, and CTRP9 in healthy adults.

Differences in Leukocyte Transcriptomes of Morbidly Obese Patients With High Output Heart Failure: A Pilot Study.

Heart failure is characterized by alterations of gene expression that provide insight into the underlying pathophysiologic mechanisms. However, obesity-related high output heart failure (HOHF) is a specific phenotype of heart failure that has not been studied using gene expression. Our aim in this study was to examine the variances in leukocyte transcriptomes of morbidly obese patients with HOHF. In this cross-sectional study, we applied stranded total RNA-sequencing to six patients with morbid obesity and HOHF and 6 patients with morbid obesity and non-HOHF. Differential gene expression was calculated, and Ingenuity Pathway Analysis software was used to interpret the canonical pathways, functional changes, upstream regulators, and networks in these patients. We found in patients with HOHF that there were 116 differentially expressed genes with upregulation of 114 genes and downregulation of 2 genes. The differentially expressed genes were involved with cell proliferation, mitochondrial function, erythropoiesis, erythrocyte stability, and apoptosis. The top upregulated canonical pathways associated with differentially expressed genes were autophagy, adenosine monophosphate-activated protein kinase signaling, and senescence pathways. We identified GATA binding protein 1 as an upstream regulator and nuclear factor kappa-light-chain-enhancer of activated B cells associated network. We are the first to report the differential gene expression in patients with obesity-related HOHF and reveal the various pathophysiologic mechanisms underlying the disease. Further research is needed to determine the role of cellular function and maintenance, inflammation, and iron homeostasis in obesity-related HOHF.

Can Mono- or Combination Therapy of Metformin with Cimetidine and Ibuprofen be a Promising Potential Therapy for Breast Cancer?

Metformin (MET), either alone or in combination with other drugs, has been considered a promising drug in cancer therapy. MET via activation of adenosine monophosphate-activated protein kinase (AMPK) signaling pathway and inhibiting the mammalian target of rapamycin (mTOR) mediates tumor proliferation.

Fecal Bacterial Community and Metagenome Function in Asians with Type 2 Diabetes, According to Enterotypes.

The role of gut microbes has been suggested in type 2 diabetes (T2DM) risk. However, their results remain controversial. We hypothesized that Asians with T2DM had different fecal bacterial compositions, co-abundance networks, and metagenome functions compared to healthy individuals, according to enterotypes. This hypothesis was examined using the combined gut microbiota data from human fecal samples from previous studies. The human fecal bacterial FASTA/Q files from 36 different T2DM studies in Asians were combined (healthy, n = 3378; T2DM, n = 551), and operational taxonomic units (OTUs) and their counts were obtained using qiime2 tools. In the machine learning approaches, fecal bacteria rich in T2DM were found. They were separated into two enterotypes, Lachnospiraceae (ET-L) and Prevotellaceae (ET-P). The Shannon and Chao1 indices, representing α-diversity, were significantly lower in the T2DM group compared to the healthy group in ET-L (p &lt; 0.05) but not in ET-P. In the Shapley additive explanations analysis of ET-L, Escherichia fergusonii, Collinsella aerofaciens, Streptococcus vestibularis, and Bifidobacterium longum were higher (p &lt; 0.001), while Phocaeicola vulgatus, Bacteroides uniformis, and Faecalibacterium prausnitzii were lower in the T2DM group than in the healthy group (p &lt; 0.00005). In ET-P, Escherichia fergusonii, Megasphaera elsdenii, and Oscillibacter valericigenes were higher, and Bacteroides koreensis and Faecalibacterium prausnitzii were lower in the T2DM group than in the healthy group. In ET-L and ET-P, bacteria in the healthy and T2DM groups positively interacted with each other within each group (p &lt; 0.0001) but negatively interacted between the T2DM and healthy groups in the network analysis (p &lt; 0.0001). In the metagenome functions of the fecal bacteria, the gluconeogenesis, glycolysis, and amino acid metabolism pathways were higher, whereas insulin signaling and adenosine 5' monophosphate-activated protein kinase (AMPK) signaling pathways were lower in the T2DM group than in the healthy group for both enterotypes (p &lt; 0.00005). In conclusion, Asians with T2DM exhibited gut dysbiosis, potentially linked to intestinal permeability and the enteric vagus nervous system.

Involvement of AMPKα and MAPK-ERK/-JNK Signals in Docetaxel-Induced Human Tongue Squamous Cell Carcinoma Cell Apoptosis.

Cancers of the oral cavity can develop in the anatomic area extending from the lip, gum, tongue, mouth, and to the palate. Histologically, about 85-90% of oral cavity cancers are of the type squamous cells carcinomas (SCCs). The incidence of oral tongue SCC is higher in the tongue than any other anatomic area of the oral cavity. Here, we investigated the therapeutic effects and molecular mechanisms of docetaxel, which is a paclitaxel antitumor agent, on the cell growth of a human tongue SCC-derived SAS cell line. The results showed that docetaxel (10-300 nM) induced cytotoxicity and caspase-3 activity in SAS cells. Moreover, docetaxel (100 nM) promoted the expression of apoptosis-related signaling molecules, including the cleavages of caspase-3, caspase-7, and poly (ADP-ribose) polymerase (PARP). In mitochondria, docetaxel (100 nM) decreased the mitochondrial membrane potential (MMP) and Bcl-2 mRNA and protein expression and increased cytosolic cytochrome c protein expression and Bax mRNA and protein expression. In terms of mitogen-activated protein kinase (MAPK) and adenosine monophosphate-activated protein kinase (AMPK) signaling, docetaxel increased the expression of phosphorylated (p)-extracellular signal-regulated kinase (ERK), p-c-Jun N-terminal kinase (JNK), and p-AMPKα protein expression but not p-p38 protein expression. Moreover, the increase in caspase-3/-7 activity and Bax protein expression and decreased Bcl-2 protein expression and MMP depolarization observed in docetaxel-treated SAS cells could be reversed by treatment with either SP600125 (a JNK inhibitor), PD98059 (an MEK1/2 (mitogen-activated protein kinase kinase 1/2) inhibitor), or compound c (an AMPK inhibitor). The docetaxel-induced increases in p-JNK, p-ERK, and p-AMPKα protein expression could also be reversed by treatment with either SP600125, PD98059, or compound c. These results indicate that docetaxel induces human tongue SCC cell apoptosis via interdependent MAPK-JNK, MAPK-ERK1/2, and AMPKα signaling pathways. Our results show that docetaxel could possibly exert a potent pharmacological effect on human oral tongue SCC cell growth.

Adeno-associated virus-based caveolin-1 delivery via different routes for the prevention of cholesterol gallstone formation

BackgroundHepatic caveolin-1 (CAV1) is reduced in cholesterol gallstone disease (CGD). Mice with CAV1 deficiency were prone to develop CGD. However, it remains unknown whether restored hepatic CAV1 expression prevents the development of CGD.MethodsC57BL/6 mice were injected with adeno-associated virus 2/8 (AAV2/8) vectors carrying the CAV1 gene (AAV2/8CAV1) via intravenous (i.v.) or intraperitoneal (i.p.) route and then subjected to a lithogenic diet (LD) for 8 weeks. Uninjected mice were used as controls. The functional consequences of rescuing CAV1 expression by either i.v. or i.p. AAV2/8CAV1 treatment for CGD prevention and its subsequent molecular mechanisms were examined.ResultsCAV1 expression was reduced in the liver and gallbladder of LD-fed CGD mice. We discovered that AAV2/8CAV1 i.p. delivery results in higher transduction efficiency in the gallbladder than tail vein administration. Although either i.v. or i.p. injection of AAV2/8CAV1 improved liver lipid metabolic abnormalities in CGD mice but did not affect LD feeding-induced bile cholesterol supersaturation. In comparison with i.v. administration route, i.p. administration of AAV2/8CAV1 obviously increased CAV1 protein levels in the gallbladder of LD-fed mice, and i.p. delivery of AAV2/8CAV1 partially improved gallbladder cholecystokinin receptor (CCKAR) responsiveness and impeded bile cholesterol nucleation via the activation of adenosine monophosphate-activated protein kinase (AMPK) signaling, which induced a reduction in gallbladder mucin-1 (MUC1) and MUC5ac expression and gallbladder cholesterol accumulation.ConclusionCGD prevention by i.p. AAV2/8CAV1 injection in LD-fed mice was associated with the improvement of gallbladder stasis, which again supported the notion that supersaturated bile is required but not sufficient for the formation of cholesterol gallstones. Additionally, AAV treatment via the local i.p. injection offers particular advantages over the systemic i.v. route for much more effective gallbladder gene delivery, which will be an excellent tool for conducting preclinical functional studies on the maintenance of normal gallbladder function to prevent CGD.

Piperine attenuates hepatic steatosis and insulin resistance in high-fat diet-induced obesity in Sprague-Dawley rats

Substantial evidence suggests that pepper consumption is associated with a reduced risk of obesity-related complications. However, whether piperine, the main component of pepper, improves obesity-induced hepatic lipid accumulation and insulin resistance and the action mechanism of piperine still remain unclear. We hypothesized that piperine attenuates high-fat diet (HFD)-induced obesity and improves the related metabolic complications in HFD-induced obese rats. Adult Sprague-Dawley (SD) male rats were fed a control diet (CON) or an HFD for 16 weeks. Obese rats were divided into 4 groups: HFD and HFD with daily gavage of piperine 2.7 mg/kg body weight (PIP-Low), 13.5 mg/kg body weight (PIP-Medium), and 27 mg/kg body weight (PIP-High) for another 8 weeks. Rats were euthanized after an 8-hour fast, and the liver, heart, kidney, and white adipose tissue were collected and stored at –80 °C. Piperine administration significantly reduced weight gain, plasma insulin, and glucose concentration. For oral piperine at a dose of 27 mg/kg body weight, body weight significantly decreased by 5.7% compared with that in the HFD group. Additionally, oral piperine administration considerably reduced serum triglyceride concentration. Furthermore, piperine administration reversed the HFD-induced downregulation of adenosine 5′-monophosphate-activated protein kinase (AMPK) signaling molecules and increased the plasma levels of adiponectin and the messenger RNA expression of the adiponectin receptor; additionally, it increased the phosphorylation of phosphatidylinositol-3 kinase (PI3K) and protein kinase B. Overall, oral piperine administration reversed HFD-induced liver lipid accumulation and insulin resistance, possibly via the inactivation of adiponectin-AMPK and PI3K-Akt signaling. These findings imply that piperine could serve as an effective agent for healthy weight loss.