Autism patient-derived SHANK2BY29X mutation affects the development of ALDH1A1 negative dopamine neuron.

Autism spectrum disorder (ASD) encompasses a range of neurodevelopmental conditions. Different mutations on a single ASD gene contribute to heterogeneity of disease phenotypes, possibly due to functional diversity of generated isoforms. SHANK2, a causative gene in ASD, demonstrates this phenomenon, but there is a scarcity of tools for studying endogenous SHANK2 proteins in an isoform-specific manner. Here, we report a point mutation on SHANK2, which is found in a patient with autism, located on exon of the SHANK2B transcript variant (NM_133266.5), hereby SHANK2BY29X. This mutation results in an early stop codon and an aberrant splicing event that impacts SHANK2 transcript variants distinctly. Induced pluripotent stem cells (iPSCs) carrying this mutation, from the patient or isogenic editing, fail to differentiate into functional dopamine (DA) neurons, which can be rescued by genetic correction. Available SMART-Seq single-cell data from human midbrain reveals the abundance of SHANK2B transcript in the ALDH1A1 negative DA neurons. We then show that SHANK2BY29X mutation primarily affects SHANK2B expression and ALDH1A1 negative DA neurons in vitro during early neuronal developmental stage. Mice knocked in with the identical mutation exhibit autistic-like behavior, decreased occupancy of ALDH1A1 negative DA neurons and decreased dopamine release in ventral tegmental area (VTA). Our study provides novel insights on a SHANK2 mutation derived from autism patient and highlights SHANK2B significance in ALDH1A1 negative DA neuron.

Hazards of microplastics exposure to liver function in fishes: A systematic review and meta-analysis.

Microplastics (5 mm - 1 µm) have become one of the major pollutants in the environment. Numerous studies have shown that microplastics can have negative impacts on aquatic organisms, affecting their liver function levels. However, the extent of these effects and their potential toxicological mechanisms are largely unknown. In this study, a meta-analysis and systematic review were conducted to assess the effects of microplastics on fish liver function and summarize the potential toxicological mechanisms of microplastic-induced liver toxicity. The meta-analysis results indicate that compared to the control group, exposure to microplastics significantly affects fish liver indicators: aspartate aminotransferase (AST) (p < 0.001), alanine aminotransferase (ALT) (p < 0.001), alkaline phosphatase (ALP) (p < 0.001), total protein (TP) (p < 0.001), and lactate dehydrogenase (LDH) (p < 0.001), including oxidative stress indicators: superoxide dismutase (SOD) (p < 0.001), glutathione S-transferase (GST) (p < 0.001), glutathione (GSH) (p < 0.001), and malondialdehyde (MDA) (p < 0.001) in fish liver. For fish living in different environments, the potential toxicological mechanisms of microplastics exposure on fish liver may exhibit some differences. For freshwater fish, the mechanism may be that microplastics exposure causes overproduction of reactive oxygen species (ROS) in fish hepatocyte mitochondria. ROS promotes the expression of toll-like receptor 2 (TLR2) and activates downstream molecules myeloid differentiation factor 88 (MyD88) and tumor necrosis factor receptor-associated factor 6 (TRAF6) of the TLR2 signaling pathway, leading to phosphorylation of NF-κB p65. This leads to the release of inflammatory factors and oxidative stress and inflammation in fish liver. In addition, for seawater fish, the mechanism may be that microplastics exposure can cause damage or death of fish hepatocytes, leading to continuous pathological changes, inflammation, lipid and energy metabolism disorders, thereby causing significant changes in liver function indexes.

Extraction, structural characterization and biological activities of polysaccharides from mulberry leaves: A review.

In recent years, plant polysaccharides have garnered attention for their impressive biological activity. Mulberry leaves have a long history of medicinal and edible use in China, polysaccharide is one of the main active components of mulberry leaves, mainly consist of xylose, arabinose, fructose, galactose, glucose and mannose, etc. The extraction methods of mulberry leaves polysaccharides (MLPs) mainly include hot water extraction, microwave-assisted extraction, ultrasonic extraction, enzyme-assisted extraction, and co-extraction. The separation and purification of MLPs involve core steps such as decolorization, protein removal, and chromatographic separation. In terms of pharmacological effects, MLPs exhibit excellent activity in reducing blood glucose, anti-oxidation, immune regulation, anti-tumor, antibacterial, anti-coagulation, and regulation of gut microbiota. Currently, there is a considerable amount of research on MLPs, however, there is a lack of systematic summarization. This review summarizes the research progress on the extraction, structural characterization, and pharmacological activities of MLPs, and points out existing shortcomings and suggests reference solutions, aiming to provide a basis for further research and development of MLPs.

Effect of natural polysaccharides on alcoholic liver disease: A review.

In this study, we systematically collected relevant literature in the past five years on the intervention of natural polysaccharides in alcoholic liver disease (ALD) and reviewed the pharmacological activities and potential mechanisms of action. Natural polysaccharides are effective in preventing liver tissue degeneration, inhibiting the alcohol-induced expression of inflammatory factors, inactivation of antioxidant enzymes, and abnormal hepatic lipid deposition. Natural polysaccharides regulate the expression of proteins, such as tight junction proteins, production of small molecule metabolites, and balance of intestinal flora in the intestinal tract to alleviate ALD. Natural polysaccharides also exert therapeutic effects by modulating inflammatory, oxidative, lipid metabolism, and other pathways in the liver. Natural polysaccharides also inhibit alcohol-induced intestinal abnormalities by regulating intestinal flora and feeding back into the liver via the gut-liver axis. However, existing research on natural polysaccharides has many shortcomings: for example, most of the natural polysaccharides for testing are total polysaccharides or crude polysaccharides, progress in research on in vivo metabolic processes and mechanisms is slow, and the degree of industrialisation is insufficient. Finally, we discuss the difficulties in studying natural polysaccharides and future directions to provide a theoretical basis for their development and application.

Protective effects and mechanisms of opuntia polysaccharide in animal models of diabetes mellitus: A systematic review and meta-analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Opuntia speciesis used in traditional medicine to treat diabetes mellitus (DM). Polysaccharide is one of the main components of Opuntia. Opuntia polysaccharide (OPS) is a kind of natural active macromolecular substance, numerous animal experiments have been conducted to treat DM, however, its protective effect and mechanism in animal models of DM has not been clarified. AIM OF THE STUDY: The aim of this study is to evaluate the efficacy of OPS on DM through a stematic review and meta-analysis of animal models, and whether its improves blood glucose (BG) levels, body weight (BW), food intake, water intake, and lipid levels, and to summarize the potential mechanism of OPS in the treatment of DM. MATERIALS AND METHODS: We searched relevant Chinese and English databases from the date of construction to March 2022, including PubMed (MEDLINE), Embase, Cochrane Library, Scopus and Web of Science, China National Knowledge Infrastructure (CNKI), Chinese Biomedicine Literature Database (CBM), Chinese Science and Technology Periodicals Database (VIP), Wanfang Database. 16 studies were included for meta-analysis. RESULTS: The results showed that compared with the model group, the OPS significantly improved BG, BW, food intake, water intake, total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C). Meta-regression and subgroup analysis showed that intervention dose, animal species, duration and modeling method may be the source of the heterogeneity. There was no statistical difference between the positive control group and the OPS treatment group in improving BW, food intake, water intake, TC, TG, HDL-C, and LDL-C. CONCLUSIONS: OPS can effectively improve the symptoms of hyperglycemia, polydipsia, polyphagia, low body weight, and dyslipidemia in DM animals. The possible protective mechanisms of OPS on DM animals are immune regulation, repair of damaged pancreatic ß cells, and inhibition of oxidative stress and cell apoptosis.

AP-1 activity is a major barrier of human somatic cell reprogramming.

Human induced pluripotent stem cells (iPSCs) technology has been widely applied to cell regeneration and disease modeling. However, most mechanism of somatic reprogramming is studied on mouse system, which is not always generic in human. Consequently, the generation of human iPSCs remains inefficient. Here, we map the chromatin accessibility dynamics during the induction of human iPSCs from urine cells. Comparing to the mouse system, we found that the closing of somatic loci is much slower in human. Moreover, a conserved AP-1 motif is highly enriched among the closed loci. The introduction of AP-1 repressor, JDP2, enhances human reprogramming and facilitates the reactivation of pluripotent genes. However, ESRRB, KDM2B and SALL4, several known pluripotent factors promoting mouse somatic reprogramming fail to enhance human iPSC generation. Mechanistically, we reveal that JDP2 promotes the closing of somatic loci enriching AP-1 motifs to enhance human reprogramming. Furthermore, JDP2 can rescue reprogramming deficiency without MYC or KLF4. These results indicate AP-1 activity is a major barrier to prevent chromatin remodeling during somatic cell reprogramming.

Identifying transposable element expression dynamics and heterogeneity during development at the single-cell level with a processing pipeline scTE.

Transposable elements (TEs) make up a majority of a typical eukaryote's genome, and contribute to cell heterogeneity in unclear ways. Single-cell sequencing technologies are powerful tools to explore cells, however analysis is typically gene-centric and TE expression has not been addressed. Here, we develop a single-cell TE processing pipeline, scTE, and report the expression of TEs in single cells in a range of biological contexts. Specific TE types are expressed in subpopulations of embryonic stem cells and are dynamically regulated during pluripotency reprogramming, differentiation, and embryogenesis. Unexpectedly, TEs are expressed in somatic cells, including human disease-specific TEs that are undetectable in bulk analyses. Finally, we apply scTE to single-cell ATAC-seq data, and demonstrate that scTE can discriminate cell type using chromatin accessibly of TEs alone. Overall, our results classify the dynamic patterns of TEs in single cells and their contributions to cell heterogeneity.