Identification and characterization of a 25-lncRNA prognostic signature for early recurrence in hepatocellular carcinoma.

BACKGROUND: Early recurrence is the major cause of poor prognosis in hepatocellular carcinoma (HCC). Long non-coding RNAs (lncRNAs) are deeply involved in HCC prognosis. In this study, we aimed to establish a prognostic lncRNA signature for HCC early recurrence. METHODS: The lncRNA expression profile and corresponding clinical data were retrieved from total 299 HCC patients in TCGA database. LncRNA candidates correlated to early recurrence were selected by differentially expressed gene (DEG), univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses. A 25-lncRNA prognostic signature was constructed according to receiver operating characteristic curve (ROC). Kaplan-Meier and multivariate Cox regression analyses were used to evaluate the performance of this signature. ROC and nomogram were used to evaluate the integrated models based on this signature with other independent clinical risk factors. Gene set enrichment analysis (GSEA) was used to reveal enriched gene sets in the high-risk group. Tumor infiltrating lymphocytes (TILs) levels were analyzed with single sample Gene Set Enrichment Analysis (ssGSEA). Immune therapy response prediction was performed with TIDE and SubMap. Chemotherapeutic response prediction was conducted by using Genomics of Drug Sensitivity in Cancer (GDSC) pharmacogenomics database. RESULTS: Compared to low-risk group, patients in high-risk group showed reduced disease-free survival (DFS) in the training (p < 0.0001) and validation cohort (p = 0.0132). The 25-lncRNA signature, AFP, TNM and vascular invasion could serve as independent risk factors for HCC early recurrence. Among them, the 25-lncRNA signature had the best predictive performance, and combination of those four risk factors further improves the prognostic potential. Moreover, GSEA showed significant enrichment of "E2F TARGETS", "G2M CHECKPOINT", "MYC TARGETS V1" and "DNA REPAIR" pathways in the high-risk group. In addition, increased TILs were observed in the low-risk group compared to the high-risk group. The 25-lncRNA signature negatively associates with the levels of some types of antitumor immune cells. Immunotherapies and chemotherapies prediction revealed differential responses to PD-1 inhibitor and several chemotherapeutic drugs in the low- and high-risk group. CONCLUSIONS: Our study proposed a 25-lncRNA prognostic signature for predicting HCC early recurrence, which may guide postoperative treatment and recurrence surveillance in HCC patients.

Yolk-Shelled Gold@Cuprous Oxide Nanostructures with Hot Carriers Boosting Photocatalytic Performance.

Plasmonic Au nanoparticles (NPs) have been commonly used to enhance the photocatalytic activity of Cu2O. Till now, core-shell Au NP@Cu2O composites have been reported in previous studies. Yet, these Au@Cu2O composites only exhibit visible light response. Other special Au nanostructures, such as Au nanorods (NRs) or Au nanobipyramids (NBPs), which possess near-infrared light absorption, were rarely used to endow the near-infrared light response for Cu2O. In this work, for the first time, we used Au NPs, Au NRs, and Au NBPs and employed a handy and universal method to synthesize a series of yolk-shelled Au@Cu2O composites. The results showed that the yolk-shelled Au@Cu2O composites had much higher photocatalytic activity than their solid-shelled ones and pure Cu2O. More importantly, yolk-shelled Au NR@Cu2O and Au NBP@Cu2O composites indeed presented excellent near-infrared light-driven photocatalytic activity, which were impossible for Au NP@Cu2O and pure Cu2O. This outstanding performance for yolk-shelled Au NR@Cu2O and Au NBP@Cu2O could be attributed to the transfer of abundant hot electrons from Au NRs or Au NBPs to Cu2O, and the timely utilization of hot holes on Au through the rich pore channels on their yolk-shelled structure. Furthermore, yolk-shelled Au@Cu2O also showed better stability than pure Cu2O, owing to the migration of the oxidizing holes from Cu2O to Au driven by the built-in electric field. This work may give a guide to fabricate controllable and effective photocatalysts based on plasmonic metals and semiconductors with full solar light-driven photocatalytic activities in the future.

Sennoside A protects mitochondrial structure and function to improve high-fat diet-induced hepatic steatosis by targeting VDAC1.

Mitochondrial dysfunction is mainly associated with high-fat-diet (HFD)-induced hepatic steatosis. Sennoside A (SA), a commonly used clinical stimulant laxative, is reported to improve energy metabolism and insulin resistance. However, the effect and mechanism of SA on HFD-induced hepatic steatosis remain largely unknown. The aim of this study was to determine the effect and mechanism of SA on HFD-induced hepatic steatosis in mice. We examined the liver and body weight of mice to evaluate the physical changes in the liver. Hematoxylin and eosin (H&E) and oil red O staining were used to detect the lipid accumulation. The mitochondrial structure and function were tested by transmission electron microscopy and the Seahorse XF24 Analyzer. Furthermore, mitochondrial complexes I, II, and IV and voltage-dependent anion channel 1 (VDAC1) protein activity were detected to understand the mechanism of the protective effect on mitochondria. As a result, damage to the structure and function in the hepatic mitochondria of HFD-induced hepatic steatosis was observed in mice. The structural damage was in the form of loss of cristae, mitochondrial swelling, vacuolization and even rupturing of the outer mitochondrial membrane (OMM). Functional alterations were found by activation of complex I and deficiency in complexes II and IV. The VDAC1 activity and the total ATP in the liver tissue was increased under hepatic steatosis conditions. The above effects were reversed by SA. These data suggest that inhibition of VDAC1 may be an underlying mechanism of SA for protecting mitochondria in HFD-induced hepatic steatosis in mice. Thus, VDAC1 may be a promising target for treating fatty liver disease.

Anti-Inflammatory Constituents from Bidens frondosa.

A new polyacetylene glucoside (3E,5E,11E)-tridecatriene-7,9-diyne-1,2,13-triol-2-O-ß-D-glucopyranoside (1), a new phenylpropanoid glucoside 2'-butoxyethylconiferin (2), and a new flavonoid glycoside 8,3',4'-trihydroxyflavone-7-O-(6''-O-p-coumaroyl)-ß-D-glucopyranoside (3), have been isolated from Bidens frondosa together with fifty-three known compounds 4-56. The structures of these compounds were established by spectroscopic methods. mainly ESIMS, 1D- and 2D-NMR spectroscopic data. and comparison with literature data. Compounds 1-34, 36, 39, 43, 47, 51, and 52 were tested for inhibition of nuclear factor kappa B (NF-κB) in 293-NF-κB-luciferase report cell line induced by lipopolysaccharide (LPS), and compounds 1, 2, 3, 9, 15, 21, 24 and 51 were tested for the production of TNF-α, IL-1ß, IL-6, IL-10 in RAW 264.7 macrophages induced by LPS. In conclusion, the isolated compounds 1, 2, 3, 9, 15, 21, 24 and 51 exhibited significant activity in anti-inflammatory activity assays.

Metabolic basis of solute carrier transporters in treatment of type 2 diabetes mellitus.

Solute carriers (SLCs) constitute the largest superfamily of membrane transporter proteins. These transporters, present in various SLC families, play a vital role in energy metabolism by facilitating the transport of diverse substances, including glucose, fatty acids, amino acids, nucleotides, and ions. They actively participate in the regulation of glucose metabolism at various steps, such as glucose uptake (e.g., SLC2A4/GLUT4), glucose reabsorption (e.g., SLC5A2/SGLT2), thermogenesis (e.g., SLC25A7/UCP-1), and ATP production (e.g., SLC25A4/ANT1 and SLC25A5/ANT2). The activities of these transporters contribute to the pathogenesis of type 2 diabetes mellitus (T2DM). Notably, SLC5A2 has emerged as a valid drug target for T2DM due to its role in renal glucose reabsorption, leading to groundbreaking advancements in diabetes drug discovery. Alongside SLC5A2, multiple families of SLC transporters involved in the regulation of glucose homeostasis hold potential applications for T2DM therapy. SLCs also impact drug metabolism of diabetic medicines through gene polymorphisms, such as rosiglitazone (SLCO1B1/OATP1B1) and metformin (SLC22A1-3/OCT1-3 and SLC47A1, 2/MATE1, 2). By consolidating insights into the biological activities and clinical relevance of SLC transporters in T2DM, this review offers a comprehensive update on their roles in controlling glucose metabolism as potential drug targets.

Boosting the photocatalytic performance of Cu2O for hydrogen generation by Au nanostructures and rGO nanosheets.

As a narrow band-gap semiconductor, cuprous oxide (Cu2O) has a relatively high conduction band that can exhibit high driving force for the photocatalytic generation of hydrogen under visible light. Besides, its adjustable morphologies and abundant source also make it possible to be employed as a theoretically optimal photocatalyst. However, the low charge migration and poor stability commonly limit its practical application, and various strategies have been explored in previous studies. In this study, we have novelly utilized Au nanorod (NR) and nanobipyramid (NBP) nanocrystallites as well as rGO nanosheets to boost the photocatalytic activity of Cu2O over hydrogen generation. The ternary rGO wrapped Au@Cu2O with a yolk-shelled structure (y-Au@Cu2O/rGO) was synthesized by a handy and controllable method. When excited by solar light (λ > 400 nm), it was found that the H2 yields of Cu2O/rGO, y-Au nanoparticle@Cu2O/rGO, y-Au NR@Cu2O/rGO, and y-Au NBP@Cu2O/rGO were increased in the order of 248, 702, 1582 and 1894 µmol g-1 in 4 h. The outstanding photocatalytic performances of y-Au NR@Cu2O/rGO and y-Au NBP@Cu2O/rGO could be attributed to the combination function of quick electron transfer of rGO and abundant near-infrared-light-driven hot carriers on Au NRs and NBPs that could inject into Cu2O and then a quick transfer to rGO to participate in H2 reduction. Besides the above results, it was also found that Cu2O maintained good stability after several cycling photocatalysis tests, which could be ascribed to the migration of holes from Cu2O to Au that prevented the photooxidation of Cu2O. This study may give a guide to fabricating controllable and effective photocatalysts based on plasmonic metals, semiconductors, or two-dimensional nanosheets, which possess full-solar-light-driven photocatalytic activities in the future.

The Metabolic and Non-Metabolic Roles of UCK2 in Tumor Progression.

Enhanced nucleoside metabolism is one of the hallmarks of cancer. Uridine-cytidine kinase 2 (UCK2) is a rate-limiting enzyme of the pyrimidine salvage synthesis pathway to phosphorylate uridine and cytidine to uridine monophosphate (UMP) and cytidine monophosphate (CMP), respectively. Recent studies have shown that UCK2 is overexpressed in many types of solid and hematopoietic cancers, closely associates with poor prognosis, and promotes cell proliferation and migration in lung cancer and HCCs. Although UCK2 is thought to catalyze sufficient nucleotide building blocks to support the rapid proliferation of tumor cells, we and other groups have recently demonstrated that UCK2 may play a tumor-promoting role in a catalytic independent manner by activating oncogenic signaling pathways, such as STAT3 and EGFR-AKT. By harnessing the catalytic activity of UCK2, several cytotoxic ribonucleoside analogs, such as TAS-106 and RX-3117, have been developed for UCK2-mediated cancer chemotherapy. Moreover, we have demonstrated that the concurrent targeting of the catalytic dependent and independent features of UCK2 could synergistically inhibit tumor growth. These findings suggest that UCK2 may serve as a potential therapeutic target for cancer treatment. In this mini-review, we introduced the genomic localization and protein structure of UCK2, described the role of UCK2 in tumor development, discussed the application of UCK2 in anti-tumor treatment, and proposed concurrent targeting of the catalytic and non-catalytic roles of UCK2 as a potential therapeutic strategy for cancer treatment.

The Effects and Mechanisms of Sennoside A on Inducing Cytotoxicity, Apoptosis, and Inhibiting Metastasis in Human Chondrosarcoma Cells.

Currently, developing therapeutic strategies for chondrosarcoma (CS) remains important. Sennoside A (SA), a dianthrone glycoside from Senna and Rhubarb, is widely used as an irritant laxative, weight-loss agent, or dietary supplement, which possesses various bioactive properties such as laxative, antiobesity, and hypoglycemic activities. For the first time, our results suggested that cell proliferation and metastasis were inhibited by SA in CS SW1353 cells. SA induced cell growth arrest by inhibiting cell proliferation. The changes of N-cadherin and E-cadherin levels, the markers associated with epithelial mesenchymal transition (EMT), suggested the EMT-related mechanism of SA in inhibiting cell metastasis. Besides, SA significantly stimulated apoptosis in CS SW1353 cells, leading to cell death. The increase of Bax/Bcl2 ratio confirmed that the internal mitochondrial pathway of apoptosis was regulated by SA. In addition, the prediction of network pharmacology analysis suggested that the possible pathways of SA treatment for CS included the Wnt signaling pathway. Notably, the protein levels of the components in the Wnt pathway, such as Wnt3a, ß-catenin, and c-Myc, were downregulated by SA in CS SW1353 cells. To sum up, these results demonstrated that the suppression of the growth, metastasis and the stimulation of cytotoxicity, and apoptosis mediated by SA in CS SW1353 cells were possibly caused by the inhibition of the Wnt/ß-catenin pathway, indicating an underlying therapeutic prospect of SA for chondrosarcoma.

Minocycline alleviates abnormal microglial phagocytosis of synapses in a mouse model of depression.

BACKGROUND: As antidepressants commonly used in the clinic have proved to be problematic, it is urgent to gain an updated understanding of the pathogenesis of depression and find potential therapeutic targets. Since both functional brain imaging studies and autopsy reports indicated that there is indeed a loss of synapses in depressed patients, it is necessary to explore the mechanism of this process. METHODS: We firstly investigated the effect of chronic social defeat stress (CSDS), a mouse model of depression, on behaviors, synapses, microglia, and microglial phagocytosis of synapses in mice. Then, as it is unclear whether microglial phagocytosis leads to synaptic loss, or synaptic loss induces the microglial clearance in CSDS mice, we used minocycline, a microglial activation inhibitor, to inhibit the microglial phagocytosis of synapses and study its effect on synapses and behaviors in CSDS mice. RESULTS: Our results showed that the expression levels of PSD-95 in the hippocampal dentate gyrus (DG) of CSDS mice were significantly reduced, while the microglia were significantly activated and the Iba1+CD68+ cell (phagocytic microglia) density was increased. We co-labeled the synaptic protein PSD-95 with the microglia marker Iba1 and found that the microglia in the hippocampal DG of CSDS mice contained significantly more PSD-95 engulfed puncta, which revealed that microglia in CSDS mice abnormally phagocytized synapses. Moreover, our results indicated that minocycline treatment dampened microglial activation, decreased the phagocytic microglia density, reduced abnormal microglial phagocytosis of synapses, reversed synaptic loss, and alleviated behavioral impairment in CSDS mice. CONCLUSIONS: Under depressive pathological conditions, the activated microglia may abnormally engulf neuronal synapses causing synaptic loss and behavioral impairments. Thus, microglial phagocytosis may be a novel therapeutic target for the treatment of depression.

Pharmacology, Toxicology, and Metabolism of Sennoside A, A Medicinal Plant-Derived Natural Compound.

Sennoside A (SA) is a natural dianthrone glycoside mainly from medicinal plants of Senna and Rhubarb, and used as a folk traditional irritant laxative and slimming health food. Accumulating evidences suggest that SA possesses numerous pharmacological properties, such as laxative, anti-obesity, hypoglycemic, hepatoprotective, anti-fibrotic, anti-inflammatory, anti-tumor, anti-bacterial, anti-fungal, anti-viral, and anti-neurodegenerative activities. These pharmacological effects lay the foundation for its potential application in treating a variety of diseases. However, numerous published studies suggest that a long-term use of SA in large doses may have some adverse effects, including the occurrence of melanosis coli and carcinogenesis of colon cancer, thereby limiting its clinical use. It remains to be established whether SA or its metabolites are responsible for the pharmacological and toxicity effects. In this review, the latest advances in the pharmacology, toxicology, and metabolism of SA were summarizedbased on its biological characteristics and mechanism.

Restoration of mRNA Expression of Solute Carrier Proteins in Liver of Diet-Induced Obese Mice by Metformin.

Metformin (MET), the most common medicine for type 2 diabetes (T2DM), improves insulin sensitivity by targeting the liver, intestine and other organs. Its impact on expression of the solute carrier (Slc) transporter genes have not been reported in the mechanism of insulin sensitization. In this study, we examined Slc gene expression in the liver and colon of diet-induced obese (DIO) mice treated with MET by transcriptomic analysis. There were 939 differentially expressed genes (DEGs) in the liver of DIO mice vs lean mice, which included 34 Slc genes. MET altered 489 DEGs in the liver of DIO mice, in which 23 were Slc genes. Expression of 20 MET-responsive Slc DEGs was confirmed by qRT-PCR, in which 15 Slc genes were altered in DIO mice and their expressions were restored by MET, including Slc2a10, Slc2a13, Slc5a9, Slc6a14, Slc7a9, Slc9a2, Slc9a3, Slc13a2, Slc15a2, Slc26a3, Slc34a2, Slc37a1, Slc44a4, Slc51b and Slc52a3. While, there were only 97 DEGs in the colon of DIO mice with 5 Slc genes, whose expression was not restored by MET. The data suggest that more genes were altered in the liver over the colon by the high fat diet (HFD). There were 20 Slc genes with alteration confirmed in the liver of DIO mice and 15 of them were restored by MET, which was associated with improvement of insulin sensitivity and obesity. The restoration may improve the uptake of glucose, amino acids, mannose, fructose, 1,5-anhydro-D-glucitol and bumetanide in hepatocytes of the liver of DIO mice. The study provides new insight into the mechanism of metformin action in insulin sensitization and obesity.

The Therapeutic Effects of Acupuncture and Electroacupuncture on Cancer-related Symptoms and Side-Effects.

In addition to cancer-related death, malignant progression also leads to a series of symptoms and side-effects, which would detrimentally affect cancer patients' the quality of life, adversely influence their adherence to treatments, and, therefore, negatively affect their long-term survival. Acupuncture and electroacupuncture (EA), as two classic treatment methods in traditional Chinese medicine, have been widely employed to cure various diseases. Recently, the clinical application of acupuncture and EA in cancer patients has received great attention. In this review, we summarized the clinical application of acupuncture and EA in alleviating the cancer symptoms, reducing the cancer treatment-related side-effects, and relieving the cancer pain. The symptoms and side-effects discussed in this review include fatigue, insomnia, chemotherapy-associated dyspepsia syndrome (CADS), pain, xerostomia, and anxiety and depression. The underlying mechanisms of the therapeutic effects of acupuncture and EA might be related to the regulation of the mitochondrial function, coordination of the activity of the nervous system, adjustment of the production of neurotransmitters, and alleviation of the immune responses. In conclusion, acupuncture and EA have been proved to be beneficial for cancer patients. More research, however, is required to clarify the potential mechanisms behind acupuncture and EA for widespread adoption in clinical application.

Circular RNAs and Hepatocellular Carcinoma: New Epigenetic Players With Diagnostic and Prognostic Roles.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Due to the lack of potent diagnosis and prognosis biomarkers and effective therapeutic targets, the overall prognosis of survival is poor in HCC patients. Circular RNAs (circRNAs) are a class of novel endogenous non-coding RNAs with covalently closed loop structures and implicated in diverse physiological processes and pathological diseases. Recent studies have demonstrated the involvement of circRNAs in HCC diagnosis, prognosis, development, and drug resistance, suggesting that circRNAs may be a class of novel targets for improving HCC diagnosis, prognosis, and treatments. In fact, some artificial circRNAs have been engineered and showed their therapeutic potential in treating HCV infection and gastric cancer. In this review, we introduce the potential of circRNAs as biomarkers for HCC diagnosis and prognosis, as therapeutic targets for HCC treatments and discuss the challenges in circRNA research and chances of circRNA application.

Electroacupuncture may alleviate behavioral defects via modulation of gut microbiota in a mouse model of Parkinson's disease.

OBJECTIVE: Parkinson's disease (PD) is a chronic neurodegenerative disease involving non-motor symptoms, of which gastrointestinal disorders are the most common. In light of recent results, intestinal dysfunction may be involved in the pathogenesis of PD. Electroacupuncture (EA) has shown potential effects, although the underlying mechanism remains mostly unknown. We speculated that EA could relieve the behavioral defects of PD, and that this effect would be associated with modulation of the gut microbiota. METHODS: Mice were randomly divided into three groups: control, PD + MA (manual acupuncture), and PD + EA. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) was used to establish the mouse model of PD. Rotarod performance tests, open field tests, and pole tests were carried out to assess motor deficiencies. Immunohistochemistry was conducted to examine the survival of dopaminergic neurons. 16S ribosomal RNA (rRNA) gene sequencing was applied to investigate the alterations of the gut microbiome. Quantitative real-time polymerase chain reaction (PCR) was performed to characterize the messenger RNA (mRNA) levels of pro-inflammatory and anti-inflammatory cytokines. RESULTS: We found that EA was able to alleviate the behavioral defects in the rotarod performance test and pole test, and partially rescue the significant loss of dopaminergic neurons in the substantia nigra (SN) chemically induced by MPTP in mice. Moreover, the PD + MA mice showed a tendency toward decreased intestinal microbial alpha diversity, while EA significantly reversed it. The abundance of Erysipelotrichaceae was significantly increased in PD + MA mice, and the alteration was also reversed by EA. In addition, the pro-inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α were substantially increased in the SN of PD + MA mice, an effect that was reversed by EA. CONCLUSION: These results suggest that EA may alleviate behavioral defects via modulation of gut microbiota and suppression of inflammation in the SN of mice with PD, which provides new insights into the pathogenesis of PD and its treatment.

Transcriptome Analysis of the Inhibitory Effect of Sennoside A on the Metastasis of Hepatocellular Carcinoma Cells.

Sennoside A (SA) is a bioactive component of Rheum officinale Baill. with an activity of irritant laxative, which has been reported to possess therapeutic potential in various diseases or conditions including obesity, insulin resistance, liver steatosis, prostate cancer and pancreatic cancer progression. However, whether SA has therapeutic potential in hepatocellular carcinoma (HCC) treatment remains elusive. In this study, we treated two HCC cell lines, HepG2 and SMMC-7721 with SA and found that SA selectively inhibited the growth of HCC cells by proliferation assay. SA has a good inhibitory effect on proliferation of HepG2 cells in a concentration dependent manner, but there was no effect on SMMC-7721 cells. Then we conducted transwell assays and transcriptome analysis in HCC cells and examined the effects of SA on HCC in vivo. The results showed that SA significantly inhibited the migration and invasion of HCC. Comparison of RNA-seq transcriptome profiles from control groups and SA-treated groups identified 171 and 264 differentially expressed genes (DEGs) in HepG2 and SMMC-7721 cells respectively, in which includes 2 overlapping up-regulated DEGs and 12 overlapping down-regulated DEGs between HepG2 and SMMC-7721 cells. The qPCR were applied to investigate the transcriptional level of 9 overlapping down-regulated DEGs related to cancer metastasis, and the results were consistent with RNA-seq data. The dominate pathways including Wnt signaling pathway, TNF signaling pathway, VEGF signaling pathway, and NF-κB signaling pathway were strongly inhibited by SA, which are involved in regulating cancer metastasis. Finally, we confirmed that the downregulation of KRT7 and KRT81 could inhibit HCC metastasis. This study has provided new insight into the understanding of the inhibitory effects and potential targets of SA on the metastasis of HCC.

Regulation of microbiota-GLP1 axis by sennoside A in diet-induced obese mice.

Sennoside A (SA) is a bioactive component of Chinese herbal medicines with an activity of irritant laxative, which is often used in the treatment of constipation and obesity. However, its activity remains unknown in the regulation of insulin sensitivity. In this study, the impact of SA on insulin sensitivity was tested in high fat diet (HFD)-induced obese mice through dietary supplementation. At a dosage of 30 mg/kg/day, SA improved insulin sensitivity in the mice after 8-week treatment as indicated by HOMA-IR (homeostatic model assessment for insulin resistance) and glucose tolerance test (GTT). SA restored plasma level of glucagon-like peptide 1 (GLP1) by 90% and mRNA expression of Glp1 by 80% in the large intestine of HFD mice. In the mechanism, SA restored the gut microbiota profile, short chain fatty acids (SCFAs), and mucosal structure in the colon. A mitochondrial stress was observed in the enterocytes of HFD mice with ATP elevation, structural damage, and complex dysfunction. The mitochondrial response was induced in enterocytes by the dietary fat as the same responses were induced by palmitic acid in the cell culture. The mitochondrial response was inhibited in HFD mice by SA treatment. These data suggest that SA may restore the function of microbiota-GLP1 axis to improve glucose metabolism in the obese mice.

Restoration of GLP-1 secretion by Berberine is associated with protection of colon enterocytes from mitochondrial overheating in diet-induced obese mice.

OBJECTIVE: L-cell dysfunction is reported for GLP-1 reduction in type 2 diabetes. However, the mechanism of dysfunction remains unknown. In this study, we examined mitochondrial function in the mechanistic study in diet-induced obese (DIO) mice. SUBJECTS: C57BL/6 mice were fed a high-fat diet (HFD) for 16 weeks to establish the DIO model for GLP-1 reduction. The mice were then treated with berberine (BBR) (100 mg/kg/day) for 8 weeks to test the impact on GLP-1 expression. Mitochondrial activities of the colon enterocytes were compared among three groups of mice (lean, DIO, and DIO + BBR) at the end of treatment. Gut microbiota and short-chain fatty acids (SCFAs) were examined to understand the mitochondrial responses. A cellular model treated with palmitic acid (PA) was used in the mechanism study. RESULTS: A reduction in GLP-1 expression was observed in DIO mice with mitochondrial stress responses in the colon enterocytes. The mitochondria exhibited cristae loss, membrane rupture, and mitochondrial swelling, which was observed with an increase in ATP abundance, complex I activity, and deficiency in the activities of complexes II and IV. Those changes were associated with dysbiosis and a reduction in SCFAs in the colon of DIO mice. In the cellular model, an increase in ATP abundance, loss of mitochondrial potential, and elevation of apoptosis were induced by PA. All of the alterations in DIO mice and the cellular model were attenuated by BBR. CONCLUSION: The mitochondrial stress responses were observed in the colon enterocytes of DIO mice for GLP-1 reduction. The stress was prevented by BBR in the restoration of GLP-1 expression, in which BBR may act through direct and indirect mechanisms.