Frontostriatal circuit dysfunction leads to cognitive inflexibility in neuroligin-3 R451C knockin mice.

Cognitive and behavioral rigidity are observed in various psychiatric diseases, including in autism spectrum disorder (ASD). However, the underlying mechanism remains to be elucidated. In this study, we found that neuroligin-3 (NL3) R451C knockin mouse model of autism (KI mice) exhibited deficits in behavioral flexibility in choice selection tasks. Single-unit recording of medium spiny neuron (MSN) activity in the nucleus accumbens (NAc) revealed altered encoding of decision-related cue and impaired updating of choice anticipation in KI mice. Additionally, fiber photometry demonstrated significant disruption in dynamic mesolimbic dopamine (DA) signaling for reward prediction errors (RPEs), along with reduced activity in medial prefrontal cortex (mPFC) neurons projecting to the NAc in KI mice. Interestingly, NL3 re-expression in the mPFC, but not in the NAc, rescued the deficit of flexible behaviors and simultaneously restored NAc-MSN encoding, DA dynamics, and mPFC-NAc output in KI mice. Taken together, this study reveals the frontostriatal circuit dysfunction underlying cognitive inflexibility and establishes a critical role of the mPFC NL3 deficiency in this deficit in KI mice. Therefore, these findings provide new insights into the mechanisms of cognitive and behavioral inflexibility and potential intervention strategies.

Simulation of mangrove suitable habitat in the Guangdong-Hong Kong-Macao Area under the background of climate change.

Climate change has resulted in great influence on the geographical distribution of species. Mangrove forests are one of the most precious ecosystems on the planet, yet they are being threatened by the habitat destruction and degradation under the situation of global warming. Seeking suitable areas for planting mangroves to tackle climate change has been gradually popular in ecological restoration. In this study, we applied the Maximum Entropy algorithm to assess the contribution of environmental factors on mangrove distribution, simulated mangrove suitable habitat for present and future (scenario of SSP245-2070s), and used kernel density analysis for identifying priority of mangrove reserve construction. Results indicate that mean diurnal range and elevation made the highest contribution on mangrove distribution. At present, the mangrove habitat suitability along the western coast of the Guangdong-Hong Kong-Macao Area (GHMA) was the highest while that along the eastern coast was the lowest. By 2070s, mangrove suitable areas would show a decreasing trend under SSP245 scenario. High suitable areas (HSAs) would change fastest and shift to northeast in the same direction as dominant environmental factors. For further mangrove restoration, it is advisable to select sites with high suitability density in the future but low reclamation density at present as prior mangrove reserves, and these sites distribute along the northeastern and northwestern coast of Zhanjiang, Yangjiang and Jiangmen, the Pearl River Estuary and Honghai Bay of Shanwei. Meanwhile, regions with lower suitability density but higher reclamation density could be listed as secondary mangrove reserves.

A novel antimicrobial peptide M1-8 targets the lysosomal pathway to inhibit autolysosome formation and promote apoptosis in liver cancer cells.

Lysosomes, a central regulator of autophagy, play a critical role in tumour growth. Lysosomal protease cathepsin D can initiate apoptosis when released from lysosomes into the cytosol. In this study, we observed that Musca domestica cecropin (Mdc) 1-8 (M1-8), a small anti-tumour peptide derived from Mdc, inhibits hepatoma cell growth by blocking autophagy-lysosome fusion. This effect is likely achieved by targeting lysosomes to activate lysosomal protease D. Additionally, we examined whether lysosomal content and cathepsin D release were involved in M1-8-induced apoptosis. After exposure to M1-8, human hepatoma HepG2 cells rapidly co-localized with lysosomes, disrupted lysosomal integrity, caused leakage of lysosomal protease cathepsin D, caspase activation and mitochondrial membrane potential changes; and promoted cell apoptosis. Interestingly, in M1-8-treated HepG2 cells, autophagic protein content increased and the lysosome-autophagosome fusion was inhibited, suggesting that M1-8 can cause apoptosis through autophagy and lysosomes. This result indicates that a small accumulation of autophagy and autolysosome inhibition in cells can cause cell death. Taken together, these data suggest a novel insight into the regulatory mechanisms of M1-8 in autophagy and lysosomes, which may facilitate the development of M1-8 as a potential cancer therapeutic agent.

Research progress of anti-environmental factor stress mechanism and anti-stress tolerance way of Saccharomyces cerevisiae during the brewing process.

Saccharomyces cerevisiae plays a decisive role in the brewing of alcohol products, and the ideal growth and fermentation characteristics can give the pure flavor of alcohol products. However, S. cerevisiae can be affected profoundly by environmental factors during the brewing process, which have negative effects on the growth and fermentation characteristics of S. cerevisiae, and seriously hindered the development of brewing industry. Therefore, we summarized the environmental stress factors (ethanol, organic acids, temperature and osmotic pressure) that affect S. cerevisiae during the brewing process. Their impact mechanisms and the metabolic adaption of S. cerevisiae in response to these stress factors. Of note, S. cerevisiae can increase the ability to resist stress factors by changing the cell membrane components, expressing transcriptional regulatory factors, activating the anti-stress metabolic pathway and enhancing ROS scavenging ability. Meantime, the strategies and methods to improve the stress- tolerant ability of S. cerevisiae during the brewing process were also introduced. Compared with the addition of exogenous anti-stress substances, mutation breeding and protoplast fusion, it appears that adaptive evolution and genetic engineering are able to generate ideal environmental stress tolerance strains of S. cerevisiae and are more in line with the needs of the current brewing industry.

Integrated network analysis and experimental verification of the mechanisms employed by Compound Jixuecao Decoction to improve endoplasmic reticulum stress and apoptosis in chronic renal failure.

ETHNOPHARMACOLOGICAL RELEVANCE: Compound Jixuecao Decoction (CJD) is a traditional Chinese herbal medicine prescribed in China to treat chronic renal failure (CRF). Previous studies have shown that CJD affects cell apoptosis and proliferation. However, the mechanism of its renal protective action has not been characterized. AIM OF THE STUDY: To explore the mechanism(s) underlying the effect of CJD on endoplasmic reticulum stress (ERS) and apoptosis in the treatment of CRF using network pharmacology, molecular docking, molecular dynamics simulations, and in vivo studies. MATERIALS AND METHODS: The compounds comprising CJD were extracted from the Traditional Chinese Medicine Systems Pharmacology Database. A Swiss target prediction database and similarity integration approach were employed to identify potential targets of these components. The GeneCards and DisGeNET databases were used to identify targets associated with CRF, apoptosis, and ERS. The STRING database was employed to analyze the protein-protein interactions (PPIs) associated with drug-disease crossover. A chemical composition-shared target network was established, and critical pathways were identified through gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. The Protein Data Bank database was used to search key proteins, while molecular docking and dynamics simulations were performed between the top four CJD active ingredients and proteins involved in apoptosis and ERS in CRF. Subsequent in vivo studies using a 5/6 nephrectomy rat model of CRF were performed to verify the findings. RESULTS: The 80 compounds identified in CJD yielded 875 target genes, of which 216 were potentially related to CRF. PPI network analysis revealed key targets via topology filtering. Enrichment analysis, molecular docking, and molecular dynamics simulation results suggested that CJD primarily targets mitofusin-2 (MFN2), B-cell lymphoma-2 (BCL2), BAX, protein kinase RNA-like ER kinase (PERK), and C/EBP homologous protein (CHOP) during CRF treatment. In vivo, CJD significantly increased the abundance of MFN2, BCL2, and significantly reduced the abundance of BAX, PERK, CHOP proteins in kidney tissues, indicating that CJD could improve apoptosis and ERS in CRF rats. CONCLUSIONS: This study provides evidence that CJD effectively delays CFR through modulation of the MFN2 and PERK-eIF2α-ATF4-CHOP signaling pathways.

Assessment and management of neonatal pain: a best practice implementation project.

BACKGROUND AND AIMS: Neonates are exposed to varying degrees of pain during their hospitalization, which are going to have a profound impact on their lives. Interventions to alleviate neonatal pain are inadequate and inconsistent. The project aims to promote evidence-based practice (EBP) for the assessment and management of neonatal patients with acute pain and to evaluate the impact of these practices on neonatal pain in hospital. METHODS: The current project was conducted in the neonatal department of a tertiary hospital in China. Five audit criteria were developed for baseline and follow-up audits. The project used the JBI PACES software and JBI's Getting Research into Practice audit and feedback tool to take evidence-based healthcare into practice. A total of 100 neonates with acute pain procedures were evaluated at baseline and follow-up audit. RESULTS: The results showed a poor compliance of the five audit indicators in the baseline audit and a significantly improved compliance of the five audit indicators in the follow-up audit. Compared to the baseline audit, audit criterion 1 increased from 0% to 86.1%, audit criterion 2 increased from 36.1% to 82.5%, audit criterion 3 increased from 12% to 61%, audit criterion 4 increased from 0% to 66%, and audit criterion 5 increased from 6% at baseline to 71% in the follow-up audit. CONCLUSION: The project found that EBP can help nursing staff effectively manage neonatal patients who are experiencing acute painful operations. Further studies are necessary to ensure the sustainability of the criteria in the project.

RNA-seq study reveals the signaling and carbohydrate metabolism regulators involved in dormancy release by warm stratification in Paris polyphylla var. yunnanensis.

Long-term seed dormancy of Paris polyphylla var. yunnanensis limits its large-scale artificial cultivation. It is crucial to understand the regulatory genes involving in dormancy release for artificial cultivation in this species. In this study, seed dormancy of Paris polyphylla var. yunnanensis was effectively released by warm stratification (20°C) for 90 days. The freshly harvested seeds (dormant) and stratified seeds (non-dormant) were used to sequence, and approximately 147 million clean reads and 28,083 annotated unigenes were detected. In which, a total of 10,937 differentially expressed genes (DEGs) were identified between dormant and non-dormant seeds. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) classification revealed that the majority unigenes involved in signaling transduction and carbohydrate metabolism. Of them, the signaling transduction-related DEGs were mainly hormones-, reactive oxygen species (ROS)-, and transcription factor (TF)-related genes. The largest number of signaling transduction-related DEGs were auxin-responsive genes (SAUR, AUX/IAA, and ARF) and AP2-like ethylene-responsive transcription factor (ERF/AP2). Moreover, at least 29 DEGs such as α-amylase (AMY), ß-glucosidase (Bglb/Bglu/Bglx), and endoglucanase (Glu) were identified involving in carbohydrate metabolism. These identified genes provide a valuable resource to investigate the molecular basis of dormancy release in Paris polyphylla var. yunnanensis.

Effects on Cell Membrane Integrity of Pichia anomala by the Accumulating Excessive Reactive Oxygen Species under Ethanol Stress.

Ethanol stress to yeast is well recognized and exists widely during the brewing process of alcohol products. Pichia anomala is an important ester-producing yeast in the brewing process of Chinese Baijiu and other alcohol products. Therefore, it is of great significance for the alcohol products brewing industry to explore the effects of ethanol stress on the growth metabolism of P. anomala. In this study, the effects of ethanol stress on the growth, esters production ability, cell membrane integrity and reactive oxygen species (ROS) metabolism of P. anomala NCU003 were studied. Our results showed that ethanol stress could inhibit the growth, reduce the ability of non-ethyl ester compounds production and destroy the cell morphology of P. anomala NCU003. The results also showed that 9% ethanol stress produced excessive ROS and then increased the activities of antioxidant enzymes (superoxide dismutase, catalase, aseorbateperoxidase and glutathione reductase) compared to the control group. However, these increased antioxidant enzyme activities could not prevent the damage caused by ROS to P. anomala NCU003. Of note, correlation results indicated that high content of ROS could promote the accumulation of malondialdehyde content, resulting in destruction of the integrity of the cell membrane and leading to the leakage of intracellular nutrients (soluble sugar and protein) and electrolytes. These results indicated that the growth and the non-ethyl ester compounds production ability of P. anomala could be inhibited under ethanol stress by accumulating excessive ROS and the destruction of cell membrane integrity in P. anomala.

Gui Shao Tea Extracts Inhibit Gastric Cancer Growth in Vitro and in Vivo and Prolong Survival in Nude Mice.

BACKGROUND: Gui Shao Tea (GST), a long-aged tea with a Chinese herbal aroma, can treat many stubborn and malignant diseases, according to traditional Chinese medicine. This research aimed to discover and define GST, study the anti-gastric cancer effects of GST extracts and preliminarily elucidate the mechanism of action in the PI3K/Akt signaling pathway and the gut microbiota. METHODS: GST was analyzed by GC/MS and HPLC. Cell proliferation, the cell cycle and apoptosis were evaluated by a CCK8 assay and flow cytometry. The effects of GST extracts on tumor inhibition and survival time were explored by a gastric cancer xenograft model in nude mice. The PI3K/Akt signaling pathway was assessed by western blotting and immunohistochemistry. Gut microbiota detection and fecal microbiota transplantation were performed to examine whether the tumor inhibition observed in mice was related to gut microbiota changes. RESULTS: The ingredients in GST, mostly terpenes and their derivatives, were novel and more concentrated than those in tea made from the branches and leaves of the same plant species, Camellia sinensis, picked and produced the same year, while the levels of polyphenols and alkaloids were significantly reduced. In BGC-823, MGC-803, and SGC-7901 gastric cancer cells, GST extracts significantly inhibited proliferation (p = 0.037), induced G0/G1 arrest (p < 0.001) and promoted early apoptosis (p = 0.041). In mice, gastric tumor growth was significantly inhibited in both the high-dose (HTF) and middle-dose (MTF) GST-fed groups. The inhibition rate in the HTF group was 33.77% on Day 14 (p = 0.042), and that in the MTF group was 55.21% on Day 14 (p = 0.002) and 61.6% on Day 28 (p = 0.008). The survival time of MTF group mice was significantly prolonged by 22.2% (p = 0.013). GST extracts inhibited the PI3K/AKT signaling pathway in gastric cancer cells (p = 0.016) and tissues (p = 0.029), downregulated the protein p-Rb and further downregulated E2F1, thereby affecting the cell cycle and proliferation. GST extracts altered the gut microbiota in mice, but these alterations alone were insufficient to inhibit gastric cancer growth. CONCLUSIONS: We confirmed the anti-gastric cancer effects of GST extracts, which might provide new approaches and methods for research and development of gastric cancer drugs.

Mitochondria-targeting folic acid-modified nanoplatform based on mesoporous carbon and a bioactive peptide for improved colorectal cancer treatment.

Oral colon-targeted drug delivery systems (OCDDs) are designed to deliver the therapeutic agents to colonic disease sites to improve the effectiveness of drug treatment, increase bioavailability, and reduce systemic side effects and are beneficial for the treatment of colorectal cancer (CRC) and inflammatory bowel disease (IBD). However, concerns about the biosafety of OCDDs are increasing, and changes in the physiological environment of the gastrointestinal tract can affect the therapeutic efficacy of the drug. Herein, we report about an orally administered colon-accumulating mitochondria-targeted drug delivery nanoplatform (M27-39@FA-MCNs), which was synthesized using the small peptide, M27-39, and folic acid (FA)-modified mesoporous carbon nanoparticles (FA-MCNs). The phenolic resin polymerized with phloroglucinol and formaldehyde (PF) was used for fabricating MCNs using a one-step soft-template method. Folic acid (FA) can be covalently combined with chitosan-modified MCNs to obtain FA-MCNs. The M27-39@FA-MCNs were stable with a spherical morphology and an average diameter of 129 nm. The cumulative release rate of M27-39@FA-MCNs in the artificial gastric fluid (pH = 1.2) and intestinal fluid (pH = 6.8) for 6 h was 87.77%. This nanoplatform maintains the advantages of both FA and MCNs to improve the bioactivity of M27-39 with high drug accumulation in colorectal tumor tissues and the ease of excretion, thus ameliorating its biosafety and targetability. Furthermore, M27-39@FA-MCNs induced tumor-cell apoptosis and inhibited tumor growth by disrupting mitochondrial energy metabolism and regulating the mitochondrial apoptosis signaling pathway and immune inflammatory response. Thus, such a mitochondria-targeting FA-modified nanoplatform based on mesoporous carbon and a bioactive peptide may provide a precise strategy for CRC treatment. STATEMENT OF SIGNIFICANCE: In this study, we constructed an orally administered colon-accumulating mitochondria-targeted drug delivery nanoplatform (M27-39@FA-MCNs), which was synthesized using the small peptide (M27-39) and folic acid-modified mesoporous carbon nanoparticles (FA-MCNs). M27-39@FA-MCNs increased the targeting ability of M27-39 toward mitochondria and colon based on the properties of FA-MCNs; they also increased M27-39 accumulation and residence time in colon tumors. Oral administration of M27-39@FA-MCNs remarkably alleviated colorectal cancer (CRC) by targeting tumor cell mitochondria and interfering with the mitochondrial energy metabolism process, and inducing apoptosis related P53/Caspase-3 mitochondrial pathway activation. Therefore, M27-39@FA-MCNs may provide a safe and precise therapeutic strategy for CRC.

Spirulina platensis aqueous extracts ameliorate colonic mucosal damage and modulate gut microbiota disorder in mice with ulcerative colitis by inhibiting inflammation and oxidative stress.

Ulcerative colitis (UC) is a chronic and recurrent inflammatory bowel disease (IBD) that has become a major gastroenterologic problem during recent decades. Numerous complicating factors are involved in UC development such as oxidative stress, inflammation, and microbiota disorder. These factors exacerbate damage to the intestinal mucosal barrier. Spirulina platensis is a commercial alga with various biological activity that is widely used as a functional ingredient in food and beverage products. However, there have been few studies on the treatment of UC using S. platensis aqueous extracts (SP), and the underlying mechanism of action of SP against UC has not yet been elucidated. Herein, we aimed to investigate the modulatory effect of SP on microbiota disorders in UC mice and clarify the underlying mechanisms by which SP alleviates damage to the intestinal mucosal barrier. Dextran sulfate sodium (DSS) was used to establish a normal human colonic epithelial cell (NCM460) injury model and UC animal model. The mitochondrial membrane potential assay 3-||(4,5-dimethylthiazol-2-yl)-2,|5-diphenyltetrazolium bromide (MTT) and staining with Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) and Hoechst 33258 were carried out to determine the effects of SP on the NCM460 cell injury model. Moreover, hematoxylin and eosin (H&E) staining, transmission electron microscopy (TEM), enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (qPCR), western blot, and 16S ribosomal DNA (rDNA) sequencing were used to explore the effects and underlying mechanisms of action of SP on UC in C57BL/6 mice. In vitro studies showed that SP alleviated DSS-induced NCM460 cell injury. SP also significantly reduced the excessive generation of intracellular reactive oxygen species (ROS) and prevented mitochondrial membrane potential reduction after DSS challenge. In vivo studies indicated that SP administration could alleviate the severity of DSS-induced colonic mucosal damage compared with the control group. Inhibition of inflammation and oxidative stress was associated with increases in the activity of antioxidant enzymes and the expression of tight junction proteins (TJs) post-SP treatment. SP improved gut microbiota disorder mainly by increasing antioxidant enzyme activity and the expression of TJs in the colon. Our findings demonstrate that the protective effect of SP against UC is based on its inhibition of pro-inflammatory cytokine overproduction, inhibition of DSS-induced ROS production, and enhanced expression of antioxidant enzymes and TJs in the colonic mucosal barrier.

Exploring Discriminative Word-Level Domain Contexts for Multi-Domain Neural Machine Translation.

Owing to its practical significance, multi-domain Neural Machine Translation (NMT) has attracted much attention recently. Recent studies mainly focus on constructing a unified NMT model with mixed-domain training corpora to switch translation between different domains. In these models, the words in the same sentence are not well distinguished, while intuitively, they are related to the sentence domain to varying degrees and thus should exert different effects on the multi-domain NMT model. In this article, we are committed to distinguishing and exploiting different word-level domain contexts for multi-domain NMT. For this purpose, we adopt multi-task learning to jointly model NMT and monolingual attention-based domain classification tasks, improving the NMT model in two ways: 1) One domain classifier and one adversarial domain classifier are introduced to conduct domain classifications of input sentences. During this process, two generated gating vectors are used to produce domain-specific and domain-shared annotations for decoder; 2) We equip decoder with an attentional domain classifier. Then, the derived attentional weights are utilized to refine the model training via word-level cost weighting, so that the impacts of target words can be discriminated by their relevance to sentence domain. Experimental results on several multi-domain translations demonstrate the effectiveness of our model.

Colon tissue-accumulating mesoporous carbon nanoparticles loaded with Musca domestica cecropin for ulcerative colitis therapy.

Ulcerative colitis (UC) is a modern refractory disease with steadily increasing incidence worldwide that urgently requires effective and safe therapies. Therapeutic peptides delivered using nanocarriers have shown promising developments for the treatment of UC. We developed a novel colon-accumulating oral drug delivery nanoplatform consisting of Musca domestica cecropin (MDC) and mesoporous carbon nanoparticles (MCNs) and investigated its effects and mechanism of action for the treatment of UC. Methods: An optimized one-step soft templating method was developed to synthesize MCNs, into which MDC was loaded to fabricate MDC@MCNs. MCNs and MDC@MCNs were characterized by BET, XRD, and TEM. MDC and MDC@MCNs resistance to trypsin degradation was measured through Oxford cup antibacterial experiments using Salmonella typhimurium as the indicator. Uptake of MDC and MDC@MCNs by NCM460 cells was observed by fluorescence microscopy. The biocompatibility of MDC, MCNs, and MDC@MCNs was evaluated in three cell lines (NCM460, L02, and NIH3T3) and C57BL/6 mice. Dextran sulphate sodium was used to establish models of NCM460 cell injury and UC in mice. MTT assay, flow cytometry, and mitochondrial membrane potential assay were applied to determine the effects of MDC@MCNs on NCM460 cells injury. Additionally, a variety of biological methods such as H&E staining, TEM, ELISA, qPCR, Western blotting, and 16s rDNA sequencing were performed to explore the effects and underlying mechanism of MDC@MCN on UC in vivo. Colonic adhesion of MCNs was compared in normal and UC mice. The oral biodistributions of MDC and MDC@MCNs in the gastrointestinal tract of mice were also determined. Results: MDC@MCNs were successfully developed and exhibited excellent ability to resist destruction by trypsin and were taken up by NCM460 cells more readily than MDC. In vitro studies showed that MDC@MCNs better inhibited DSS-induced NCM460 cells damage with lower toxicity to L02 and NIH3T3 cells compared with MDC. In vivo results indicated that MDC@MCNs have good biocompatibility and significantly improved colonic injury in UC mice by effectively inhibiting inflammation and oxidative stress, maintaining colonic tight junctions, and regulating intestinal flora. Moreover, MDC@MCNs were strongly retained in the intestines, which was attributed to intestinal adhesion and aggregation of MCNs, serving as one of the important reasons for its enhanced efficacy after oral administration compared with MDC. Conclusion: MDC@MCNs alleviated DSS-induced UC by ameliorating colonic epithelial cells damage, inhibiting inflammation and oxidative stress, enhancing colonic tight junctions, and regulating intestinal flora. This colon-accumulating oral drug delivery nanoplatform may provide a novel and precise therapeutic strategy for UC.

Effects of Compound Centella on Oxidative Stress and Keap1-Nrf2-ARE Pathway Expression in Diabetic Kidney Disease Rats.

The formula of Compound Centella mainly contains 3 traditional Chinese herbs: Centella asiatica (L.) Urb. (JiXueCao), Astragalus Membranaceus Fish. (HuangQi), and Tripterygium wilfordii Hook. f. (LeiGongTeng). Though this formula is effective for treating diabetic kidney disease (DKD) in clinic, the exact mechanism is still unclear. This study aims to investigate the effect and antioxidant mechanism of Compound Centella on DKD rats. High-performance liquid chromatography (HPLC) was applied to analyse 3 herbs in Compound Centella. Sprague-Dawley rats were divided into the normal group (NG), DKD group (DKDG), Compound Centella group (CCG), and losartan group (LG), with 8 rats in each group. On the first day of the experiment, rats in the NG were fed with ordinary -feed, while the other groups were fed with high-fat and high-sugar feed. On the 29th day, except the NG, the other 3 groups received a single intraperitoneal injection of streptozocin (STZ, 35 mg/kg). Fasting blood glucose (FBG) was measured on the 1st day, 32nd day, 46th day, 56th day, 84th day, and 112th day. Total protein/creatinine ratio of urine was determined by the phenol red assay on the 1st day and 112th day. Serum creatinine (Scr) was determined by an automatic biochemical analyser on the 112th day. Kidneys were collected on the 112th day for analysis and evaluation. Periodic acid-Schiff (PAS) staining, hematoxylin-eosin (HE) staining, and transmission electron microscopy were used to observe kidney pathological changes. The mRNA and protein expressions of Kelch-like ECH-associated protein 1 (Keap1) and nuclear factor-erythroid 2-related factor 2 (Nrf2) in renal tissues were detected by RT-qPCR, Western blot, and immunohistochemistry. Oxidative stress was evaluated by detecting the levels of malondialdehyde (MDA) and heme oxidase-1 (HO-1). The results showed that the content of asiaticoside, astragaloside, and triptolide in the herb was 5960, 809, and 2.42 µg/g and in the Compound Centella was 340, 64, and 0.1403 µg/mL by HPLC. Compound Centella reduced the urine protein/creatinine ratio and improved renal pathology in the kidneys of DKD rats. In addition, the mRNA and protein expressions of Keap1 and Nrf2 in kidneys were upregulated by Compound Centella. The expressions of MDA were downregulated but HO-1 were upregulated by Compound Centella. Therefore, the protective effect of Compound Centella in the kidney of DKD rats may be related to regulating the Keap1-Nrf2-ARE pathway under oxidative stress, suggesting Compound Centella as a promising treatment against DKD.

Jixuecao (Herba Centellae Asiaticae) alleviates mesangial cell proliferation in IgA nephropathy by inducing mitofusin 2 expression.

OBJECTIVE: To investigate the effect of mitofusin 2 (Mfn2) and its downstream signaling pathway on glomerular mesangial cells (GMCs) proliferation in IgA nephropathy (IgAN), as well as the mechanism of action of Jixuecao (Herba Centellae Asiaticae, HCA) in the treatment of IgAN. METHODS: Adenovirus-mediated Mfn2 gene transfection and Mfn2 expression were analyzed by real-time polymerase chain reaction (PCR) and Western blotting. IgA1 induced the proliferation of GMCs, which were then treated with HCA. Cell proliferation was detected with cell counting kit-8 (CCK-8), and Mfn2 expression was analyzed by real-time PCR and western blotting. An IgAN animal model was also established and treated with HCA. GMCs proliferation was detected by hematoxylin-eosin staining, mitochondrial structure was analyzed by electron microscopy, mitochondrial function was determined by the Clark oxygen electrode method, and the expression of Mfn2, Phospho-extracellular regulated protein kinases1/2 (P-ERK1/2), Cyclin-dependent kinase 2 (CDK2), Phospho-p27 (p-p27), and cyclin A was analyzed by Western blotting. RESULTS: In vitro, HCA inhibited GMCs in a concentration-dependent manner in association with the upregulation of Mfn2 expression. The overexpression of Mfn2 inhibited IgA1-induced GMCs proliferation and elevated the effect of HCA. In vivo, treatment with HCA could alleviate albuminuria and creatinine and GMCs proliferation. These effects were related to the upregulation of Mfn2, p-p27 and inhibition of p-ERK1/2, CDK2, and cyclinA. Mitochondrial swelling, vacuolar degeneration, and reduction of respiratory control rate were identified in IgAN, but HCA could improve the mitochondrial structure and function. CONCLUSION: HCA inhibited GMCs proliferation via the upregulation Mfn2 and the inhibition of Ras-Raf-ERK/MAPK. We revealed that changes of mitochondrial structure and function are associated with IgAN, but that HCA can improve these mitochondrial features.

TWSG1 Is a Novel Tumor Suppressor in Gastric Cancer.

Gastric cancer has a high incidence and mortality in the world, especially in China. The pathogenesis leading to the high heterogeneity of gastric cancer remains unclear. It is believed that TWSG1 is associated with a variety of tumors, but there are few studies related to gastric cancer. To investigate the biological significance of TWSG1, we evaluated the TWSG1 expression of the clinical samples and gastric cancer cell lines (BGC-823, MGC-803, and SGC-790) via stomach cancer tissue array, real-time PCR, and western blotting. Then, we used CCK-8 and flow cytometry to detect the function and mechanism of TWSG1 in gastric cell lines. The analysis showed that TWSG1 showed decreased expression in clinical samples and BGC-823, MGC-803, and SGC-7901 cells. And, overexpressed TWSG1 inhibited the cell cycle and proliferation, TWSG1 might influence the proliferation of SGC-7901 and MGC-803 by regulating the BMP signaling. However, the influence of TWSG1 on BGC-823 cell is not associated with the BMP signaling. In conclusion, all of our findings revealed that TWSG1 maybe serves as a tumor suppressor gene in gastric cancer and potential biomarker or therapeutic target for the diagnosis and treatment of gastric cancer.

A study of lateral Schottky contacts in WSe2 and MoS2 field effect transistors using scanning photocurrent microscopy.

Schottky contacts, formed at metal/semiconductor interfaces, always have a large impact on the performance of field-effect transistors (FETs). Here, we report the experimental studies of Schottky contacts in two-dimensional (2D) transition metal dichalcogenide (TMDC) FET devices. We use scanning photocurrent microscopy (SPCM) to directly probe the spatial distribution of the in-plane lateral Schottky depletion regions at the metal/2D-TMDC interfaces. The laser incident position dependent and the gate voltage tunable polarity and magnitude of the short-circuit photocurrent reveal the existence of the in-plane Schottky depletion region laterally extending away from the metal contact edges along the channel. This lateral depletion region length is estimated to be around several microns and can be effectively tuned by the gate and drain-source biases. Our results solidify the importance of lateral Schottky depletion regions in the photoresponse of 2D TMDC optoelectronic devices.