Monophosphate-activated Protein Kinase Pathway Research Articles

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

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

Oxymatrine relieves non-alcoholic fatty liver disease by promoting the sirtuin 1/adenosine 5‘-monophosphate-activated protein kinase pathway and peroxisome proliferator activated receptor alpha-mediated hepatic fatty acid oxidation

Non-alcoholic fatty liver disease (NAFLD) is a liver disease without approved treatment. Oxymatrine (OMT) has protective effects in various liver diseases. We aimed to investigate the roles and mechanisms of OMT in NAFLD. NAFLD models were established using high-fat and high-sucrose diet-fed rats and oleic acid (OA)-stimulated hepatocytes, respectively. Then, OMT was used to treat the NAFLD models, with metformin as a positive control. Liver damage, lipid accumulation and hepatic lipid profile of NAFLD rats were assessed. Peroxisome proliferator activated receptor alpha (PPARα), sirtuin 1 (Sirt1)/adenosine 5‘-monophosphate-activated protein kinase (AMPK) pathway- and fatty acid oxidation (acyl-CoA oxidase 1 and carnitine palmitoyltransferase 1A)-associated proteins were measured both in vivo and in vitro. Furthermore, hepatocytes were transfected with si-Sirt1 and oe-PPARα to verify the mechanisms of OMT in NAFLD. NAFLD rats supplemented with OMT displayed reduced liver damage and lipid accumulation. After OMT intervention, the liver lipid profile of NAFLD rats was changed greatly, most of the top differentially expressed lipid metabolites were triglyceride, moreover, diacylglycerol content was decreased in NAFLD rats. OMT activated the Sirt1/AMPK pathway and PPARα, and upregulated acyl-CoA oxidase 1 and carnitine palmitoyltransferase 1A expressions in NAFLD models. In vitro, OMT enhanced viability, and improved lipid accumulation in OA-stimulated hepatocytes. However, the protective functions of OMT in OA-exposed hepatocytes were offset by Sirt1 knockdown, while PPARα overexpression further counteracted the effects of Sirt1 knockdown. OMT could relieve NAFLD by promoting Sirt1/AMPK pathway- and PPARα-mediated hepatic fatty acid oxidation, indicating that OMT is a potential approach for NAFLD treatment.

Interaction between energy level and starch: fat ratio on intestinal energy metabolism of layer pullets

During the growing period, the gastrointestinal tract of layer pullets is not yet well developed and may be susceptible to dietary energy level. The energy level and composition might impact the intestinal energy metabolism of layer pullets. To test this hypothesis, a total of 480 “Jing Tint 6” layer pullets were used in an 8-week study and allocated to 4 groups, each consisting of 8 replicates, with 15 birds per replicate. Pullets were treated with low or high starch: fat ratios (LS, 10:1; HS, 20:1) in a 2 × 2 factorial arrangement with regular energy (RE, 11.85 and 11.68 MJ/kg for birds from 6 to 10 weeks of age and 11 to 14 weeks of age, respectively) or low energy (LE, 0.55 MJ/kg lower than RE) levels. A significant interaction (P < 0.05) showed that HS increased glandular stomach weight and the jejunal villus length to crypt depth ratio (VCR) in LE diets, but decreased these parameters in RE diets. Dietary energy reduction impaired energy metabolism in the ileum (P < 0.05) mainly via decreasing the gene expression of enzymes involved in the tricarboxylic acid (TCA) cycle (α-ketoglutarate dehydrogenase complex [α-KGDH]; isocitrate dehydrogenase (NAD (+)) [IDH] catalytic; citrate synthase [CS]) and adenosine triphosphate (ATP) synthesis, reducing contents of phosphoenolpyruvate (PEP) and adenylate energy charges (AEC) and down-regulating the adenosine monophosphate-activated protein kinase (AMPK) pathway. HS stimulated AMPKα phosphorylation, increased protein abundance of peroxisome proliferator activated-receptor gamma coactivator 1α (PGC1α) and improved contents of amino acids (aspartate, glutamate, glutamine, alanine and threonine) and malate in the ileum regardless of energy levels (P < 0.05). By an interaction (P < 0.05), the transition from LS to HS diets up-regulated ileal gene expression of AMPKα1 and decreased content of adenosine monophosphate (AMP), accompanied by higher AEC but only in birds fed with LE diets. Collectively, these results suggest that low energy feeding may not be enough for maintaining intestinal energy homeostasis in layer pullets and emphasizes the importance of a relatively high starch: fat ratio in restoring energy metabolism in the ileum.

Lipids and Inflammation: Novel Molecular Targets and Therapeutic Implications.

Atherosclerotic cardiovascular disease represents the most common cause of death worldwide. Altered cholesterol metabolism and inflammation are major cardiovascular risk factors that underpin atherosclerotic plaque growth and destabilization. While initial evidence considered dyslipidemia and inflammation as independent atherogenic actors, growing evidence has revealed that several molecular mechanisms implicated in cholesterol metabolism participate in multiple inflammatory signalling pathways. In particular, proprotein convertase subtilisin/kexin type 9, adenosine monophosphate-activated protein kinase pathway, oxidized low-density lipoproteins, and lipoprotein (a) have been demonstrated to share concurrent atherogenic and inflammatory properties. Novel lipid-lowering therapies targeting these molecular pathways have been implemented. Mechanistic and clinical studies have addressed their hypolipidemic potential and explored their role in atherosclerosis-related vascular inflammation, and ongoing randomized clinical trials are investigating their prognostic role. The purpose of this review was to dive into the signalling pathways linking cholesterol metabolism and inflammation and outline the current evidence on the anti-inflammatory activities of the novel lipid-lowering drugs.

Different Short-Chain Fatty Acids Unequally Modulate Intestinal Homeostasis and Reverse Obesity-Related Symptoms in Lead-Exposed High-Fat Diet Mice.

Our previous study showed that heavy metal lead (Pb) exposure exacerbates high-fat-diet (HFD)-induced metabolic damage and significantly depletes the gut microbiota-derived metabolite short-chain fatty acid (SCFA) levels. However, it remains unclear whether SCFA is a key metabolite involved in accelerating adverse consequences after Pb exposure. In this study, we explored the effects of exogenous supplementation of acetate, propionate, and butyrate on a metabolic disorder model in Pb-exposed HFD mice. We found that three SCFA interventions attenuated glycolipid metabolism disorders and liver damage, with butyrate performing the best effects in improving obesity-related symptoms. All three SCFA promoted the abundance of Muribaculaceae and Muribaculum, acetate specifically enriched Christensenellaceae, Blautia, and Ruminococcus, and butyrate specifically enriched Parasutterella, Rikenella, Prevotellaceae_UCG-001, and Bacteroides, which contributed to the positive promotion of SCFA production forming a virtuous cycle. Besides, butyrate inhibited Gram-negative bacteria Escherichia-Shigella. All of these events alleviated the intestinal Th17/Treg imbalance and inflammatory response through crosstalk between the G protein-coupled receptor (GPR)/histone deacetylase 3 (HDAC3) and lipopolysaccharide (LPS)/toll-like receptors 4 (TLR4)/nuclear factor κ-B (NF-κB) pathways and ultimately improved the intestinal barrier function. SCFA further upregulated the monocarboxylate transporter 1 (MCT1) and GPR43/adenosine 5'-monophosphate-activated protein kinase (AMPK) pathways to inhibit hepatic lipid accumulation. Overall, SCFA, especially butyrate, is an effective modulator to improve metabolic disorders in obese individuals exposed to heavy metals by targeting gut microecology.

Schisanhenol ameliorates non-alcoholic fatty liver disease via inhibiting miR-802 activation of AMPK-mediated modulation of hepatic lipid metabolism

Non-alcoholic fatty liver disease (NAFLD), characterized by hepatic steatosis, is a common metabolic liver disease worldwide. Currently, satisfactory drugs for NAFLD treatment remain lacking. Obesity and diabetes are the leading causes of NAFLD, and compounds with anti-obesity and anti-diabetic activities are considered suitable candidates for treating NAFLD. In this study, biochemical and histological assays revealed that a natural lignan schisanhenol (SAL) effectively decreased lipid accumulation and improved hepatic steatosis in free fatty acid (FFA)-treated HepG2 cells and high-fat diet (HFD)-induced NAFLD mice. Further, molecular analyses, microRNA (miRNA)-seq, and bioinformatics analyses revealed that SAL may improve NAFLD by targeting the miR-802/adenosine monophosphate-activated protein kinase (AMPK) pathway. Liver-specific overexpression of miR-802 in NAFLD mice significantly impaired SAL-mediated liver protection and decreased the protein levels of phosphorylated (p)-AMPK and PRKAB1. Dual-luciferase assay analysis further confirmed that miR-802 inhibits hepatic AMPK expression by binding to the 3' untranslated region of mouse Prkab1 or human PRKAA1. Additionally, genetic silencing of PRKAA1 blocked SAL-induced AMPK pathway activation in FFA-treated HepG2 cells. The results demonstrate that SAL is an effective drug candidate for treating NAFLD through regulating miR-802/AMPK-mediated lipid metabolism.

Upregulation of p300 in paclitaxel-resistant TNBC: implications for cell proliferation via the PCK1/AMPK axis.

To explore the role of p300 in the context of paclitaxel (PTX) resistance in triple-negative breast cancer (TNBC) cells, focusing on its interaction with the phosphoenolpyruvate carboxykinase 1 (PCK1)/adenosine monophosphate-activated protein kinase (AMPK) pathway. The expression of p300 and PCK1 at the messenger ribonucleic acid (mRNA) level was detected using a quantitative polymerase chain reaction. The GeneCards and GEPIA databases were used to investigate the relationship between p300 and PCK1. The MDA-MB-231/PTX cell line, known for its PTX resistance, was chosen to understand the specific role of p300 in such cells. The Lipofectamine™ 3000 reagent was used to transfer the p300 small interfering RNA and the overexpression of PCK1 plasmid into MDA-MB-231/PTX. The expression levels of p300, PCK1, 5'AMPK and phosphorylated AMPK (p-AMPK) were determined using the western blot test. In TNBC cancer tissue, the expression of p300 was increased compared with TNBC paracancerous tissue (P < 0.05). In the MDA-MB-231 cell line of TNBC, the expression of p300 was lower than in the PTX-resistant TNBC cells (MDA-MB-231/PTX) (P < 0.05). The PCK1 expression was decreased in the TNBC cancer tissue compared with TNBC paracancerous tissue, and the PCK1 expression was reduced in MDA-MB-231/PTX than in MDA-MB-231 (P < 0.05) indicating that PCK1 was involved in the resistance function. Additionally, p-AMPK was decreased in MDA-MB-231/PTX compared with MDA-MB-231 (P < 0.05). The adenosine triphosphate (ATP) level was also detected and was significantly lower in MDA-MB-231/PTX than in MDA-MB-231 (P < 0.05). Additionally, cell proliferation increased significantly in MDA-MB-231/PTX at 48 and 72 h (P < 0.05) suggesting that MDA-MB-231/PTX cells obtained the resistance function which was associated with AMPK and ATP level. When p300 was inhibited, p-AMPK and ATP levels elevated in MDA-MB-231/PTX (P < 0.05). When PCK1 was suppressed, the ATP consumption rate decreased, and cell proliferation increased (P < 0.05). However, there were no changes in p300. In MDA-MB-231/PTX, p300 can inhibit p-AMPK and ATP levels by inhibiting PCK1 expression. Our findings suggest that targeting p300 could modulate the PCK1/AMPK axis, offering a potential therapeutic avenue for overcoming PTX resistance in TNBC.

Mulberrin extends lifespan in Caenorhabditis elegans through detoxification function.

Mulberrin, a naturally occurring flavone found in mulberry and Romulus Mori, exhibits diverse biological functions. Here, we showed that mulberrin extended both the lifespan and healthspan in C. elegans. Moreover, mulberrin increased the worms' resistance to toxicants and activated the expression of detoxification genes. The longevity-promoting effect of mulberrin was attenuated in nuclear hormone receptor (NHR) homologous nhr-8 and daf-12 mutants, indicating that the lifespan extending effects of mulberrin in C. elegans may depend on nuclear hormone receptors NHR-8/DAF-12. Further analyses revealed the potential associations between the longevity effects of mulberrin and the insulin/insulin-like growth factor signaling (IIS) and adenosine 5'-monophosphate-activated protein kinase (AMPK) pathways. Together, our findings suggest that mulberrin may prolong lifespan and healthspan by activating detoxification functions mediated by nuclear receptors.

The Roles and Regulatory Mechanisms of Tight Junction Protein Cingulin and Transcription Factor Forkhead Box Protein O1 in Human Lung Adenocarcinoma A549 Cells and Normal Lung Epithelial Cells.

Tight junction (TJ) protein cingulin (CGN) and transcription factor forkhead box protein O1 (FOXO1) contribute to the development of various cancers. Histone deacetylase (HDAC) inhibitors have a potential therapeutic role for some cancers. HDAC inhibitors affect the expression of both CGN and FOXO1. However, the roles and regulatory mechanisms of CGN and FOXO1 are unknown in non-small cell lung cancer (NSCLC) and normal human lung epithelial (HLE) cells. In the present study, to investigate the effects of CGN and FOXO1 on the malignancy of NSCLC, we used A549 cells as human lung adenocarcinoma and primary human lung epithelial (HLE) cells as normal lung tissues and performed the knockdown of CGN and FOXO1 by siRNAs. Furthermore, to investigate the detailed mechanisms in the antitumor effects of HDAC inhibitors for NSCLC via CGN and FOXO1, A549 cells and HLE cells were treated with the HDAC inhibitors trichostatin A (TSA) and Quisinostat (JNJ-2648158). In A549 cells, the knockdown of CGN increased bicellular TJ protein claudin-2 (CLDN-2) via mitogen-activated protein kinase/adenosine monophosphate-activated protein kinase (MAPK/AMPK) pathways and induced cell migration, while the knockdown of FOXO1 increased claudin-4 (CLDN-4), decreased CGN, and induced cell proliferation. The knockdown of CGN and FOXO1 induced cell metabolism in A549 cells. TSA and Quisinostat increased CGN and tricellular TJ protein angulin-1/lipolysis-stimulated lipoprotein receptor (LSR) in A549. In normal HLE cells, the knockdown of CGN and FOXO1 increased CLDN-4, while HDAC inhibitors increased CGN and CLDN-4. In conclusion, the knockdown of CGN via FOXO1 contributes to the malignancy of NSCLC. Both HDAC inhibitors, TSA and Quisinostat, may have potential for use in therapy for lung adenocarcinoma via changes in the expression of CGN and FOXO1.

Lead exposure exacerbates liver injury in high-fat diet-fed mice by disrupting the gut microbiota and related metabolites.

Lead (Pb) is a widespread toxic endocrine disruptor that could cause liver damage and gut microbiota dysbiosis. However, the causal relationship and underlying mechanisms between the gut microbiota and Pb-induced liver injury are unclear. In this study, we investigated the metabolic toxicity caused by Pb exposure in normal chow (Chow) and high-fat diet (HFD) mice and confirmed the causal relationship by fecal microbial transplantation (FMT) and antibiotic cocktail experiments. The results showed that Pb exposure exacerbated HFD-induced hepatic lipid deposition, fibrosis, and inflammation, but it had no significant effect on Chow mice. Pb increased serum lipopolysaccharide (LPS) levels and induced intestinal inflammation and barrier damage by activating TLR4/NFκB/MLCK in HFD mice. Furthermore, Pb exposure disrupted the gut microbiota, reduced short-chain fatty acid (SCFA) concentrations and the colonic SCFA receptors, G protein-coupled receptor (GPR) 41/43/109A, in HFD mice. Additionally, Pb significantly inhibited the hepatic GPR109A-mediated adenosine 5'-monophosphate-activated protein kinase (AMPK) pathway, resulting in hepatic lipid accumulation. FMT from Pb-exposed HFD mice exacerbated liver damage, disturbed lipid metabolic pathways, impaired intestinal barriers, and altered the gut microbiota and metabolites in recipient mice. However, mice exposed to HFD + Pb and HFD mice had similar levels of these biomarkers in microbiota depleted by antibiotics. In conclusion, our study provides new insights into gut microbiota dysbiosis as a potential novel mechanism for human health related to liver function impairment caused by Pb exposure.

SGLT2 inhibitors and AMPK: The road to cellular housekeeping?

Sodium-glucose co-transporter-2 (SGLT2) inhibitors, known as Gliflozins, are a class of Glucose-lowering drugs in adults with type 2 diabetes (T2D) that induce glucosuria by blocking SGLT2 co-transporters in the proximal tubules. Several lines of evidence suggest that SGLT2 inhibitors regulate multiple mechanisms associated with the regulation of varying cellular pathways. The 5'-adenosine monophosphate-activated protein kinase (AMPK) pathway plays an important role in metabolic homeostasis by influencing cellular processes. Recently, it has been shown that SGLT2 inhibitors can affect the AMPK pathway in differing physiological and pathological ways, resulting in kidney, intestinal, cardiovascular, and liver protective effects. Additionally, they have therapeutic effects on nonalcoholic fatty liver disease and diabetes mellitus-associated complications. In this review, we summarize the results of studies of AMPK-associated therapeutic effects of SGLT2 inhibitors in different organelle functions.

Betanin from Beetroot (Beta vulgaris L.) Regulates Lipid Metabolism and Promotes Fat Browning in 3T3-L1 Adipocytes.

Fat browning, which converts white adipose tissue to brown, has attracted attention as a promising strategy for the treatment of obesity. Betanin (BT) has been reported to have potential anti-obesity activity. 3T3-L1 cells were differentiated for 7 days during BT treatment. The BT concentration range for the study was determined using an MTT assay, and lipid accumulation was evaluated by Oil-Red-O staining. The expression of protein level was analyzed by Western blot. Immunofluorescence images were performed with confocal microscopy to visually show the amount and location of thermogenesis factor uncoupling protein1 (UCP1) and mitochondria. qRT-PCR was performed to evaluate mRNA expression. BT inhibited lipid accumulation and increased the expression of UCP1, peroxisome-proliferator-activated receptor gamma (PPARγ), and PPARγ coactivator-1 alpha (PGC-1α). In addition, the increases in beige adipocyte-specific markers were observed, supporting BT-mediated browning of the fat tissue. The UCP1 was localized in the inner membrane of the mitochondria, and its expression was associated with mitochondrial activation. Consistent with this, the mRNA expression of mitochondrial biogenesis markers increased in 3T3-L1 cells after BT treatment. Immunofluorescence staining also indicated an increased number of mitochondria and UCP1, respectively. Moreover, BT inhibited lipogenesis and enhanced lipolysis and fatty acid oxidation. This mechanism has been suggested to be mediated by an adenosine monophosphate-activated protein kinase (AMPK) pathway. BT induces fat browning and regulates lipid metabolism via the AMPK-mediated pathway in 3T3-L1 cells, suggesting that BT can be a promising candidate for controlling obesity.

Protective effect of steroidal saponins on heat stress in the liver of largemouth bass (Micropterus salmoides) revealed by metabolomic analysis

With global warming, high water temperature events are becoming more frequent in summer. The liver of the largemouth bass (Micropterus salmoides) is particularly sensitive to heat stress, especially in the rapid growth period with high nutrient concentration. In this experiment, a metabolomic analysis was conducted to reveal how steroidal saponins alleviated high temperature stress in largemouth bass. Fish were divided into three groups, two groups fed the basic diet, the third group fed the experimental diet contained steroidal saponins. After the fish ingested the diets for four weeks, the heat temperature stress test began. The first group fed basic diet without the heat stress (C), and the second group fed basic diet with the heat stress (H), and the third group fed experimental diet containing steroidal saponins with heat stress (HS). After 1-week of heat stress, metabolic analysis showed that high temperature stress mainly affected phospholipid metabolism, fatty acid metabolism, glutathione metabolism and bile metabolism in the fish livers of H group. The expression of genes glutathione peroxidase and heme oxygenase-1 were decreased and the nuclear factor kappa-B activated inflammation in fish feeding in group H. The adenosine 5′-monophosphate-activated protein kinase pathway was activated in the HS group. Compare to the fish in H group, those metabolism observed in fish in HS group were greatly improved, similar to the C group. Thus, steroidal saponins could help relieve the liver burden when largemouth bass facing heat stress in summer.

Corilagin attenuates airway inflammation and collagen deposition in ovalbumin-induced asthmatic mice

Objective: To investigate the effects of corilagin on inflammation and collagen deposition in ovalbumin (OVA)-induced asthma mouse model and uncover the mechanism. Methods: We constructed a mouse model of OVA-induced asthma. Enzyme-linked-immunosorbent serologic assays were conducted to detect the effects of corilagin on cytokines and Immunoglobulin E (IgE) production. Hematoxylin and eosin staining was used to show pathological features in lung tissues. Masson trichrome assay was used to examine collagen deposition. In addition, the lung function was detected by mouse lung function apparatus. Immunoblot was used to confirm the mechanism. Results: Corilagin alleviates OVA-induced cytokine and IgE production. In addition, corilagin alleviates OVA-induced pathological changes and collagen deposition in lung tissues. Corilagin also suppressed airway resistance and lung function in mice. Mechanically, corilagin activated the adenosine monophosphate-activated protein kinase (AMPK) pathway in lung tissues. Conclusion: Corilagin attenuates airway inflammation and collagen deposition in OVA-induced asthmatic mice via AMPK pathway.

Radiosensitising Effects of Metformin Added to Concomitant Chemoradiotherapy with Cisplatin in Cervical Cancer

AimsThe role of metformin on the radiosensitising effect of cisplatin is not clear. Here we investigated the radiosensitising effect of metformin alone and combined with cisplatin in HeLa cells, as well as the implications of the adenosine monophosphate-activated protein kinase (AMPK) pathway on the radiosensitising effect. Materials and methodsHeLa cells were treated with ionising radiation, metformin, cisplatin, A769662 (AMPK activator) and dorsomorphin (AMPK inhibitor) or in combination. A cell proliferation assay, Western blot and flow cytometry were carried out. ResultsMetformin potentiated cisplatin cytotoxicity when administered 4 h before ionising radiation. Although the radiosensitising effects of metformin and cisplatin alone were observed, which is more apparent at high ionising radiation doses, the metformin–cisplatin combination did not increase the radiosensitivity of cisplatin at any ionising radiation dose. Dorsomorphin alone significantly decreased cell proliferation and potentiated the radiosensitising effects of cisplatin with ionising radiation. Administration of A769662 24 h prior to cisplatin treatment resulted in an increased AMPK level that yielded resistance to cisplatin, but this effect was not observed in HeLa cells concomitantly treated with A769662 and cisplatin. ConclusionsModulation of AMPK may have a role in cervical cancer treatment. Increased AMPK levels result in higher sensitivity to ionising radiation but causes resistance to cisplatin. Dorsomorphin is proven to be a potent radiosensitising agent. The use of metformin alone may be an option as a radiosensitiser during high-dose ionising radiation (e.g. intracavitary brachytherapy).

Lonicerae flos polysaccharides improve nonalcoholic fatty liver disease by activating the adenosine 5'-monophosphate-activated protein kinase pathway and reshaping gut microbiota.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver cirrhosis and cancer. Lonicerae flos polysaccharides (LPs) have been shown to be effective in treating metabolic diseases; however, the therapeutic effects and underlying molecular mechanisms of LPs in NAFLD remain unclear. The objective of this study was to investigate the morphological characterization of Lonicerae flos polysaccharides (LPs) and the mechanism of LPs in relieving NAFLD. The morphology of LPs was observed using atomic force microscopy (AFM), X-ray diffraction (XRD), thermal weight (TG), and thermal weight derivative (DTG); NAFLD mice were treated with LPs at the same time as they were induced with a Western diet, and then the indexes related to glycolipid metabolism, fibrosis, inflammation, and autophagy in the serum and liver of the mice were detected. The atomic force microscope analysis results indicated that the LPs displayed sugar-chain aggregates, exhibited an amorphous structure, and were relatively stable in thermal cracking at 150 °C. It was also found that LPs exerted therapeutic effects in NAFLD. The LPs prevented high-fat and -cholesterol diet-induced NAFLD progression by regulating glucose metabolism dysregulation, insulin resistance, lipid accumulation, inflammation, fibrosis, and autophagy. Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) inhibitor compound C abrogated LP-induced hepatoprotection in mice with NAFLD. The LPs further treated NAFLD by reshaping the structure of the gut microbiota, in which Desulfovibrio bacteria plays a key roles. Lonicerae flos polysaccharides exert protective effects against NAFLD in mice by improving the structure of the intestinal flora and activating the AMPK signaling pathway. © 2023 Society of Chemical Industry.

Tricin-enriched Zizania latifolia ameliorates non-alcoholic fatty liver disease through AMPK-dependent pathways.

This study aimed to identify and elucidate the mechanism underlying the protective effect of tricin-enriched Zizania latifolia (Z. latifolia) extract (ETZL) against free fatty acid (FFA)-induced lipid accumulation in vitro and non-alcoholic fatty liver disease (NAFLD) induced by a high-fat diet and fructose diet (HFD/F) in vivo. ETZL treatment significantly lowered body weight gain and decreased adipose tissue, lipid, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) levels in HFD/F-fed mice. ETZL acted on phosphorylated acetyl-CoA carboxylase (ACC) and anti-peroxisome proliferator-activated receptor α (PPARα) by activating the adenosine monophosphate-activated protein kinase (AMPK) pathway and inhibiting sterol regulatory element-binding proteins-1 (SREBP)/fatty acid synthase (FAS) signaling to inhibit de novo adipogenesis and increase fatty acid oxidation. In addition, treatment with ETZL increased nuclear factor erythroid-2-related factor 2 (Nrf2) levels to activate the antioxidant pathway. FFA-induced oxidative stress and fatty acid accumulation in HepG2 cells confirmed the improvement in fat accumulation through the AMPK and Nrf2 pathway activities of ETZL. These results suggest that ETZL ameliorates NAFLD by regulating lipid metabolism and defending against oxidative stress via AMPK-dependent pathways.

Anti-Inflammatory Effects of Adiponectin Receptor Agonist AdipoRon against Intervertebral Disc Degeneration.

Adiponectin, a hormone secreted by adipocytes, has anti-inflammatory effects and is involved in various physiological and pathological processes such as obesity, inflammatory diseases, and cartilage diseases. However, the function of adiponectin in intervertebral disc (IVD) degeneration is not well understood. This study aimed to elucidate the effects of AdipoRon, an agonist of adiponectin receptor, on human IVD nucleus pulposus (NP) cells, using a three-dimensional in vitro culturing system. This study also aimed to elucidate the effects of AdipoRon on rat tail IVD tissues using an in vivo puncture-induced IVD degeneration model. Analysis using quantitative polymerase chain reaction demonstrated the downregulation of gene expression of proinflammatory and catabolic factors by interleukin (IL)-1β (10 ng/mL) in human IVD NP cells treated with AdipoRon (2 μM). Furthermore, western blotting showed AdipoRon-induced suppression of p65 phosphorylation (p < 0.01) under IL-1β stimulation in the adenosine monophosphate-activated protein kinase (AMPK) pathway. Intradiscal administration of AdipoRon was effective in alleviating the radiologic height loss induced by annular puncture of rat tail IVD, histomorphological degeneration, production of extracellular matrix catabolic factors, and expression of proinflammatory cytokines. Therefore, AdipoRon could be a new therapeutic candidate for alleviating the early stage of IVD degeneration.

Acadesine supplementation in a soybean oil-based diet remodels hepatic lipid and glucose metabolism in juvenile large yellow croaker (Larimichthys crocea)

Dietary high soybean oil (SO) inclusion leads to excessive hepatic lipid accumulation and metabolism disorder in fish species. This study was conducted to investigate the effects of adenosine 5’-monophosphate-activated protein kinase (AMPK) pathway activation by acadesine (AICAR) on hepatic histology and metabolism-related gene expression of juvenile large yellow croakers (Larimichthys crocea) fed with SO-based diet. In this study, fish (initial body weight 3.89 ± 0.02 g) were fed fish oil (FO)-based, SO, or SOA (SO diet supplemented with 100 mg kg−1 AICAR) diets with three replicates of each treatment for 70 days. In general, the replacement of dietary FO with SO led to excessive hepatic lipid accumulation and a glucose metabolism disorder. Histological sections and biochemical analysis of hepatic tissue consistently revealed that AICAR supplementation could partly ameliorate SO-induced excessive hepatic lipid accumulation, probably by suppressing the expression of genes related to fatty acid uptake and lipogenesis while enhancing the expression of lipolysis-related genes. Nevertheless, AICAR regulated lipid metabolism in muscle tissue in an inverse pattern to that in hepatic tissue, indicating that muscle tissue could attempt to mitigate lipid accumulation by improving lipolysis in response to the dietary inclusion of SO. Dietary AICAR partly improved glucose metabolism by reducing the expression of genes related to gluconeogenesis in hepatic tissue while increasing the expression of genes related to glucose uptake and glycolysis in muscle tissue. Collectively, dietary AICAR mitigated excessive hepatic lipid accumulation and glucose metabolism disorder. The amelioration of hepatic lipid accumulation by AICAR is likely caused by increasing lipid catabolism and decreasing lipid anabolism. The improved glucose metabolism by AICAR may be ascribed to decreased hepatic gluconeogenesis, as well as increased muscle glucose uptake and utilization.

Detachable Dual-Targeting Nanoparticles for Improving the Antitumor Effect by Extracellular Matrix Depletion.

In the tumor microenvironment (TME), the extracellular matrix (ECM) produced by cancer-associated fibroblasts (CAFs) forms a dense barrier that prevents nanodrugs from penetrating into deep tumor sites, leading to unsatisfactory therapeutic effects. Recently, it has been found that ECM depletion and using small-sized nanoparticles are effective strategies. Herein, we reported a detachable dual-targeting nanoparticle (HA-DOX@GNPs-Met@HFn) based on reducing ECM for enhancing penetration. When these nanoparticles reached the tumor site, the nanoparticles were divided into two parts in response to matrix metalloproteinase-2 overexpressed in TME, causing a decrease in the nanoparticle size from about 124 to 36 nm. One part was Met@HFn, which was detached from the surface of gelatin nanoparticles (GNPs), which effectively targeted tumor cells and released metformin (Met) under acidic conditions. Then, Met downregulated the expression of the transforming growth factor β by the adenosine monophosphate-activated protein kinase pathway to inhibit the activity of CAFs, thereby suppressing the production of ECM including α-smooth muscle actin and collagen I. The other was the small-sized hyaluronic acid-modified doxorubicin prodrug with autonomous targeting ability, which was gradually released from GNPs and internalized into deeper tumor cells. Intracellular hyaluronidases triggered the release of doxorubicin (DOX), which killed tumor cells by inhibiting DNA synthesis. The combination of size transformation and ECM depletion enhanced the penetration and accumulation of DOX in solid tumors. Therefore, the tumor chemotherapy effect was greatly improved.