Discovery of a natural small-molecule AMP-activated kinase activator that alleviates nonalcoholic steatohepatitis.

Non-alcoholic steatohepatitis (NASH) is a primary cause of cirrhosis and hepatocellular carcinoma. Unfortunately, there is no approved drug treatment for NASH. AMP-activated kinase (AMPK) is an important metabolic sensor and whole-body regulator. It has been proposed that AMPK activators could be used for treating metabolic diseases such as obesity, type 2 diabetes and NASH. In this study, we screened a marine natural compound library by monitoring AMPK activity and found a potent AMPK activator, candidusin A (CHNQD-0803). Further studies showed that CHNQD-0803 directly binds recombinant AMPK with a KD value of 4.728 × 10-8 M and activates AMPK at both molecular and intracellular levels. We then investigated the roles and mechanisms of CHNQD-0803 in PA-induced fat deposition, LPS-stimulated inflammation, TGF-ß-induced fibrosis cell models and the MCD-induced mouse model of NASH. The results showed that CHNQD-0803 inhibited the expression of adipogenesis genes and reduced fat deposition, negatively regulated the NF-κB-TNFα inflammatory axis to suppress inflammation, and ameliorated liver injury and fibrosis. These data indicate that CHNQD-0803 as an AMPK activator is a novel potential therapeutic candidate for NASH treatment. Supplementary Information: The online version contains supplementary material available at 10.1007/s42995-023-00168-z.

[Clinical Management of Non-Variceal Upper Gastrointestinal Bleeding].

Non-variceal upper gastrointestinal bleeding (NVUGIB) is defined as bleeding proximal to the ligament of Treitz in the absence of varices. As a common clinical problem, NVUGIB entails a heavy burden on the healthcare system. In addition to endoscopic hemostasis, evaluation and treatment before and after endoscopy are also of critical importance for the clinical management of NVUGIB patients. In recent years, based on the rapid development of endoscopic technology and clinical management of NVUGIB, the research evidence and clinical guidelines have been updated internationally, while some clinical decisions remain controversial. In this article, we mainly reviewed and discussed the current status of NVUGIB patient management before, during, and after endoscopy, aiming to deepen the understanding of the disease for clinicians, and to promote standardized management of patients with NVUGIB.

Mechanisms underlying antidepressant effect of transcutaneous auricular vagus nerve stimulation on CUMS model rats based on hippocampal α7nAchR/NF-κB signal pathway.

BACKGROUND: Stress-induced neuroinflammation was considered to play a critical role in the pathogenesis of depression. Transcutaneous auricular vagus nerve stimulation (taVNS) is a relatively non-invasive alternative treatment for patients suffering from major depressive disorder. The anti-inflammatory signal of vagus nerve is mediated by α7 nicotinic acetylcholine receptor (α7nAchR), and the hippocampus, the region with the most distribution of α7nAchR, regulates emotions. Here, we investigated the role of α7nAchR mediating hippocampal neuroinflammation in taVNS antidepressant effect though homozygous α7nAChR (-/-) gene knockout and α7nAchR antagonist (methyllycaconitine, MLA). METHODS: There were control, model, taVNS, α7nAChR(-/-) + taVNS, hippocampus (Hi) MLA + taVNS and Hi saline + taVNS groups. We used the chronic unpredicted mild stress (CUMS) method to establish depressive model rats for 42 days, excepting control group. After the successful modeling, except the control and model, the rats in the other groups were given taVNS, which was applied through an electroacupuncture apparatus at the auricular concha (2/15 Hz, 2 mA, 30 min/days) for 21 days. Behavioral tests were conducted at baseline, after modeling and after taVNS intervention, including sucrose preference test (SPT), open field test (OFT) and forced swimming test (FST). These tests are widely used to evaluate depression-like behavior in rats. The samples were taken after experiment, the expressions of α7nAchR, NF-κB p65, IL-1ß and the morphology of microglia were detected. RESULTS: Depression-like behavior and hippocampal neuroinflammation in CUMS model rats were manifested by down-regulated expression of α7nAchR, up-regulated expression of NF-κB p65 and IL-1ß, and the morphology of microglia was in amoebic-like activated state. TaVNS could significantly reverse the above-mentioned phenomena, but had rare improvement effect for α7nAChR(-/-) rats and Hi MLA rats. CONCLUSION: The antidepressant effect of taVNS is related to hippocampal α7nAchR/NF-κB signal pathway.

[Analysis of differential genes related to dormancy release of Paris polyphylla var. chinensis seeds by transcriptome sequencing].

The study aims at exploring the expression of differential genes and related metabolic pathways in the process of seed dormancy release. The dormant embryo and the dormant released embryo of Paris polyphylla var. chinensis were used as the test materials, a new generation high-throughput sequencing methods to sequence the transcriptome of the samples was used to carry out systematic bioinformatics analysis. We obtained 62 882 650 and 62 263 366 clean reads from the DNA libraries of the samples before and after dormancy breaking. A total of 69 248 differentially expressed genes(DEGs) were obtained, 56 426 up-regulated genes and 12 822 down-regulated genes. There are 138 267 differentially expressed genes in the process of embryo dormancy release, which were annotated by GO function to 58 subclasses of biological processes, molecular functions and cell components. The annotated differentially expressed genes were closely related to metabolic processes, biological regulation, cell component synthesis and enzyme catalytic activity. We found 139 metabolic pathways through pathway analysis of 58 722 differentially expressed genes. Before and after dormancy, DEGs were mainly enriched in carbon metabolism, secondary metabolite biosynthesis and polysaccharide metabolism. Based on the annotation results in KEGG database, we found 16 metabolic pathways related to the dormancy release of P. polyhoylla var. chinensis. A large number of differentially expressed genes were involved in embryo morphogenesis, polysaccharide decomposition and protein synthesis during seed development and dormancy release. It involves the interaction of multiple metabolic pathways and constitutes a complex regulation network for dormancy relief.

[Bibliometric analysis on clinical trials of auricular acupuncture treatment of obesity].

OBJECTIVE: To review the current situation of researches on auricular acupuncture treatment for obesity by using bibliometric analysis, so as to provide a reference for clinical application and experimental research in the future. METHODS: Articles written in both Chinese and English and published from the time of establishment of the following databases were collected from databases of CNKI, Wanfang, PubMed and Web of Science by using key words of "otopoint sticking" "otopoint seed-pres-sing" "auriculotherapy" "ear/auricular acupuncture" "auricular pressure" "auricular-plaster therapy" "acupuncture and auricular pressure" "auriculopressure" "transcutaneous vagus nerve stimulation (taVNS)" "obesity" "adiposity" "adiposis" and "fatty". The articles met our inclusive criteria were analyzed for summarizing their publication years, involved journals, research organizations and selected acupoints. RESULTS: A total of 61 qualified Chinese and 44 English articles were retrieved and published in 45 and 25 journals, respectively. The commonly-used acupoints are "Endocrine" "Stomach" "Spleen" "Shenmen" "Hunger point" "Sanjiao" "Lung" and "Subcortex". The employed auricular acupoint therapy mainly includes auricular acupressure, ear acupuncture, auricular vagus nerve stimulation, and auricular laser radiation. CONCLUSION: Current clinical literature on auricular acupuncture treatment of obesity is relatively lower in quality. Thus, strict research protocols and randomized controlled clinical trials with multiple centers and larger samples are definitely necessary for providing reliable evidence for clinical treatment of obesity by using auricular acupuncture therapy.