Berberine mitigates diclofenac-induced intestinal mucosal mechanical barrier dysfunction through the restoration of autophagy by inhibiting exosome-mediated lncRNA H19.

Small intestine damage caused by diclofenac is called diclofenac enteropathy. Berberine (BBR), a class of isoquinoline alkaloids derived from Berberis vulgaris and Phellodendron amurense, is widely used in intestinal diseases. The present study evaluated the protective effect of BBR on the intestinal mucosal mechanical barrier in diclofenac enteropathy and its possible action mechanism. The in vitro animal experiment revealed that BBR downregulated the expression of long non-coding RNA H19 (lncRNA H19) in the small intestine and exosomes. In the co-culture experiment involving exosomes and intestinal epithelial cell-6 (IEC-6) cells, the results of qRT-PCR, western blotting, and immunofluorescence assays demonstrated that the elevated expression of lncRNA H19 in the small intestine, conveyed via exosomes derived from the diclofenac group, suppressed the expression levels of autophagy-associated protein 5 (Atg 5) and light chain 3 (LC 3), as well as and the tight junction (TJ) proteins zonula occludens-1 (ZO-1), claudin-1, and occluding, relative to the control group. BBR treatment attenuated exosomal lncRNA H19 levels, upregulated the expression of Atg5 and LC3 expression, enhanced TJ protein expression, and increased the light chain 3 (LC3)-II/LC3-I ratio. These findings significantly elucidated that BBR promoted the restoration of autophagy in IECs by inhibiting exosomal lncRNA H19, thereby mitigating the impairment of the intestinal mucosal mechanical barrier function in diclofenac enteropathy. The process involving exosomal lncRNA H19 regulating autophagy, thereby affecting the intestinal mucosal mechanical barrier, offers a novel perspective for the application of BBR in the treatment of diclofenac enteropathy.

Pure total flavonoids from Citrus ameliorate NSAIDs-induced intestinal mucosal injury via regulation of exosomal LncRNA H19 and protective autophagy.

Introduction: Non-steroid anti-inflammatory drugs (NSAIDs) are a class of prescription drugs with antipyretic, analgesic, anti-inflammatory, and antiplatelet effects. However, long-term use of NSAIDs will disrupt the intestinal mucosal barrier, causing erosion, ulcers, bleeding, and even perforation. Pure total flavonoids from Citrus (PTFC) is extracted from the dried peel of Citrus, showing a protective effect on intestinal mucosal barrier with unclear mechanisms. Methods: In the present study, we used diclofenac (7.5 mg kg-1, i.g.) to induce a rat model of NSAIDs-related intestinal lesions. PTFC (50, 75, 100 mg·kg-1 d-1, i.g.) was administered 9 days before the initial diclofenac administration, followed by co-administration on the last 5 days. Exosomes were identified by western blotting and transmission electron microscopy (TEM), and then co-cultured with IEC-6 cells. The expression of long non-coding RNA (lncRNA) H19, autophagy-related 5 (Atg5), ZO-1, Occludin, and Claudin-1 were detected by quantitative real-time PCR (qRT-PCR). The expression of light chain 3 (LC3)-I, LC3-II, ZO-1, Occludin and Claudin-1 proteins was tested by western blotting. The localization of both exosomes and autophagosomes was examined by immunofluorescent technique. Results: The treatment of PTFC attenuated intestinal mucosal mechanical barrier function disturbance in diclofenac-induced NSAIDs rats. IEC-6 cells co-cultured with NSAIDs rats-derived exosomes possessed the lowest levels of protective autophagy, and severe intestinal barrier injuries. Cells co-cultured with the exosomes extracted from rats administrated PTFC exhibited an improvement of autophagy and intestinal mucosal mechanical barrier function. The prevention effect was proportional to the concentration of PTFC administered. Conclusion: PTFC ameliorated NSAIDs-induced intestinal mucosal injury by down-regulating exosomal lncRNA H19 and promoting autophagy.

Selection of Peptide-Bismuth Bicycles Using Phage Display.

Cysteine conjugation is widely used to constrain phage displayed peptides for the selection of cyclic peptides against specific targets. In this study, the nontoxic Bi3+ ion was used as a cysteine conjugation reagent to cross-link peptide libraries without compromising phage infectivity. We constructed a randomized 3-cysteine peptide library and cyclized it with Bi3+, followed by a selection against the maltose-binding protein as a model target. Next-generation sequencing of selection samples revealed the enrichment of peptides containing clear consensus sequences. Chemically synthesized linear and Bi3+ cyclized peptides were used for affinity validation. The cyclized peptide showed a hundred-fold better affinity (0.31 ± 0.04 µM) than the linear form (39 ± 6 µM). Overall, our study proved the feasibility of developing Bi3+ constrained bicyclic peptides against a specific target using phage display, which would potentially accelerate the development of new peptide-bismuth bicycles for therapeutic or diagnostic applications.

Intestinal microbiota regulates the gut-thyroid axis: the new dawn of improving Hashimoto thyroiditis.

Intestinal microbiota plays an indispensable role in the host's innate immune system, which may be related to the occurrence of many autoimmune diseases. Hashimoto thyroiditis (HT) is one of the most common autoimmune diseases, and there is plenty of evidence indicating that HT may be related to genetics and environmental triggers, but the specific mechanism has not been proven clearly. Significantly, the composition and abundance of intestinal microbiota in patients with HT have an obvious difference. This phenomenon led us to think about whether intestinal microbiota can affect the progress of HT through some mechanisms. By summarizing the potential mechanism of intestinal microflora in regulating Hashimoto thyroiditis, this article explores the possibility of improving HT by regulating intestinal microbiota and summarizes relevant biomarkers as therapeutic targets, which provide new ideas for the clinical diagnosis and treatment of Hashimoto thyroiditis.

The Snf5-Hsf1 transcription module synergistically regulates stress responses and pathogenicity by maintaining ROS homeostasis in Sclerotinia sclerotiorum.

The SWI/SNF complex is guided to the promoters of designated genes by its co-operator to activate transcription in a timely and appropriate manner to govern development, pathogenesis, and stress responses in fungi. Nevertheless, knowledge of the complexes and their co-operator in phytopathogenic fungi is still fragmented. We demonstrate that the heat shock transcription factor SsHsf1 guides the SWI/SNF complex to promoters of heat shock protein (hsp) genes and antioxidant enzyme genes using biochemistry and pharmacology. This is accomplished through direct interaction with the complex subunit SsSnf5 under heat shock and oxidative stress. This results in the activation of their transcription and mediates histone displacement to maintain reactive oxygen species (ROS) homeostasis. Genetic results demonstrate that the transcription module formed by SsSnf5 and SsHsf1 is responsible for regulating morphogenesis, stress tolerance, and pathogenicity in Sclerotinia sclerotiorum, especially by directly activating the transcription of hsp genes and antioxidant enzyme genes counteracting plant-derived ROS. Furthermore, we show that stress-induced phosphorylation of SsSnf5 is necessary for the formation of the transcription module. This study establishes that the SWI/SNF complex and its co-operator cooperatively regulate the transcription of hsp genes and antioxidant enzyme genes to respond to host and environmental stress in the devastating phytopathogenic fungi.

Correlations between China's socioeconomic status, disease burdens, and pharmaceuticals and personal care product levels in wastewater.

The presence of pharmaceutical and personal care products (PPCPs) in domestic wastewater can potentially indicate socioeconomic status and disease burdens. However, current knowledge is limited to the correlation between specific pharmaceuticals and diseases. This study aims to explore the associations between socioeconomic status, disease burdens, and PPCP levels in domestic wastewater at a national level. Samples from 171 wastewater influents across China were used to measure PPCPs, and the per capita consumption of PPCPs was calculated. Results showed that the 31 targeted PPCPs were widely present in wastewater with varying occurrence characteristics. The mean consumption levels of different PPCPs varied greatly, ranging from 0.03 to 110723.15 µg/d/capita. While there were no significant regional differences in the overall pattern of PPCP consumption, 22 PPCPs showed regional variations between Northern China and Southern China. PPCPs with similar usage purposes exhibited similar distribution patterns. Disease burden (70.1%) was the main factor affecting most PPCP consumption compared to socioeconomic factors (26.4%). Through correlation analyses, specific types of PPCPs were identified that were highly associated with socioeconomic status and disease burdens, such as hypertension-bezafibrate, brucellosis-quinolones, sulfonamides, hepatitis-triclosan, triclocarban, socioeconomic development-fluoxetine, and people's living standards-gemfibrozil. Despite some uncertainties, this study provides valuable insights into the relationship between PPCPs in domestic wastewater and socioeconomic status and human health.

Priority control sequence of 34 typical pollutants in effluents of Chinese wastewater treatment plants.

The identification of the priority control sequence of pollutants in effluents of wastewater treatment plants (WWTPs) has important implications for the management of water quality. This study chose 34 typical pollutants based on their representativeness and detection rates in municipal wastewater. The occurrence frequency and concentration of these pollutants in 168 Chinese WWTP effluents were measured at the national level. The data on in vitro toxicity (67 assays) and in vivo toxicity (216 species) for target pollutants were obtained from the public toxicity database and our experimental data. An environmental health prioritization index (EHPi) method was proposed to integrate the occurrence frequency, concentration, removal rate, and in vitro and in vivo toxicity to determine the priority control sequence of target pollutants. Ethynyl estradiol, 17ß-estradiol, estrone, diclofenac, and atrazine were the top 5 pollutants identified by the EHPi score. Several pollutants with high EHPi scores showed spatial differences. Besides the EHPi method which was from the single pollutant perspective, the combined toxicity of pollutants (300 pairs of binary combinations) was also measured based on in vitro toxicity assays to evaluate the key pollutants from the pollutant-pollutant interacting perspective. The pollutants (such as ofloxacin and acetaminophen) that could have significant synergetic effects with many other pollutants are worthy of prior attention. This study shed new light on the identification of the priority control sequence of pollutants in WWTP effluents. The results provide meaningful data for the effective management and control of wastewater water quality.

TLR5 Signaling in the Regulation of Intestinal Mucosal Immunity.

Toll-like receptor 5 (TLR5) is a pattern recognition receptor that specifically recognizes flagellin and consequently plays a crucial role in the control of intestinal homeostasis by activating innate and adaptive immune responses. TLR5 overexpression, on the other hand, might disrupt the intestinal mucosal barrier, which serves as the first line of defense against harmful microbes. The intestine symbiotic bacteria, mucous layer, intestinal epithelial cells (IECs), adherens junctions (such as tight junctions and peripheral membrane proteins), the intestinal mucosal immune system, and cytokines make up the intestinal mucosal barrier. Impaired barrier function has been linked to intestinal illnesses such as inflammatory bowel disease (IBD). IBD is a persistent non-specific inflammatory illness of the digestive system with an unknown cause. It is now thought to be linked to infection, environment, genes, immune system, and the gut microbiota. The significance of immunological dysfunction in IBD has received more attention in recent years. The purpose of this paper is to explore TLR5's position in the intestinal mucosal barrier and its relevance to IBD.

Prediction of the tetramer protein complex interaction based on CNN and SVM.

Protein-protein interactions play an important role in life activities. The study of protein-protein interactions helps to better understand the mechanism of protein complex interaction, which is crucial for drug design, protein function annotation and three-dimensional structure prediction of protein complexes. In this paper, we study the tetramer protein complex interaction. The research has two parts: The first part is to predict the interaction between chains of the tetramer protein complex. In this part, we proposed a feature map to represent a sample generated by two chains of the tetramer protein complex, and constructed a Convolutional Neural Network (CNN) model to predict the interaction between chains of the tetramer protein complex. The AUC value of testing set is 0.6263, which indicates that our model can be used to predict the interaction between chains of the tetramer protein complex. The second part is to predict the tetramer protein complex interface residue pairs. In this part, we proposed a Support Vector Machine (SVM) ensemble method based on under-sampling and ensemble method to predict the tetramer protein complex interface residue pairs. In the top 10 predictions, when at least one protein-protein interaction interface is correctly predicted, the accuracy of our method is 82.14%. The result shows that our method is effective for the prediction of the tetramer protein complex interface residue pairs.

Benzoquinone and furopyridinone derivatives from the marine-derived fungus Talaromyces sp. MCCC 3A01752.

Two new compounds, compounds 1 and 2, were obtained from the culture of a marine-derived fungus Talaromyces sp. MCCC 3A01752, together with 13 known compounds (3-15). Their structures were elucidated based on detailed analysis of NMR, HRESIMS, ECD spectra and OR value. Compound 1 exhibited antibacterial potential against Staphylococcus aureus with a MIC value of 100 µM and cytotoxic activity against gastric cancer cell line MKN1 with a IC50 value of 78.0 µM.

Gastroenterology in the Metaverse: The dawn of a new era?

2021 is known as the first Year of the Metaverse, and around the world, internet giants are eager to devote themselves to it. In this review, we will introduce the concept, current development, and application of the Metaverse and the use of the current basic technologies in the medical field, such as virtual reality and telemedicine. We also probe into the new model of gastroenterology in the future era of the Metaverse.

Long Non-Coding RNA: A Potential Strategy for the Diagnosis and Treatment of Colorectal Cancer.

Colorectal cancer (CRC), being one of the most commonly diagnosed cancers worldwide, endangers human health. Because the pathological mechanism of CRC is not fully understood, there are many challenges in the prevention, diagnosis, and treatment of this disease. Long non-coding RNAs (lncRNAs) have recently drawn great attention for their potential roles in the different stages of CRC formation, invasion, and progression, including regulation of molecular signaling pathways, apoptosis, autophagy, angiogenesis, tumor metabolism, immunological responses, cell cycle, and epithelial-mesenchymal transition (EMT). This review aims to discuss the potential mechanisms of several oncogenic lncRNAs, as well as several suppressor lncRNAs, in CRC occurrence and development to aid in the discovery of new methods for CRC diagnosis, treatment, and prognosis assessment.

The Role of lncRNAs in Regulating the Intestinal Mucosal Mechanical Barrier.

lncRNA is a transcript that is more than 200 bp in length. Currently, evidence has shown that lncRNA is of great significance in cell activity, involved in epigenetics, gene transcription, chromatin regulation, etc. The existence of an intestinal mucosal mechanical barrier hinders the invasion of pathogenic bacteria and toxins, maintaining the stability of the intestinal environment. Serious destruction or dysfunction of the mechanical barrier often leads to intestinal diseases. This review first summarizes the ability of lncRNAs to regulate the intestinal mucosal mechanical barrier. We then discussed how lncRNAs participate in various intestinal diseases by regulating the intestinal mucosal mechanical barrier. Finally, we envision its potential as a new marker for diagnosing and treating intestinal inflammatory diseases.

Potential Roles of Exosomal lncRNAs in the Intestinal Mucosal Immune Barrier.

The intestinal mucosal immune barrier protects the host from the invasion of foreign pathogenic microorganisms. Immune cells and cytokines in the intestinal mucosa maintain local and systemic homeostasis by participating in natural and adaptive immunity. Deficiency of the intestinal mucosal immune barrier is associated with a variety of intestinal illnesses. Exosomes are phospholipid bilayer nanovesicles that allow cell-cell communication by secreting physiologically active substances including proteins, lipids, transcription factors, mRNAs, micro-RNAs (miRNAs), and long noncoding RNAs (lncRNAs). Exosomal lncRNAs are involved in immune cell differentiation and the modulation of the immune response. This review briefly introduces the potential role of exosomal lncRNAs in the intestinal mucosal immune barrier and discusses their relevance to intestinal illnesses.

Improved Production of Majority Cellulases in Trichoderma reesei by Integration of cbh1 Gene From Chaetomium thermophilum.

Lignocellulose is an abundant waste resource and has been considered as a promising material for production of biofuels or other valuable bio-products. Currently, one of the major bottlenecks in the economic utilization of lignocellulosic materials is the cost-efficiency of converting lignocellulose into soluble sugars for fermentation. One way to address this problem is to seek superior lignocellulose degradation enzymes or further improve current production yields of lignocellulases. In the present study, the lignocellulose degradation capacity of a thermophilic fungus Chaetomium thermophilum was firstly evaluated and compared to that of the biotechnological workhorse Trichoderma reesei. The data demonstrated that compared to T. reesei, C. thermophilum displayed substantially higher cellulose-utilizing efficiency with relatively lower production of cellulases, indicating that better cellulases might exist in C. thermophilum. Comparison of the protein secretome between C. thermophilum and T. reesei showed that the secreted protein categories were quite different in these two species. In addition, to prove that cellulases in C. thermophilum had better enzymatic properties, the major cellulase cellobiohydrolase I (CBH1) from C. thermophilum and T. reesei were firstly characterized, respectively. The data showed that the specific activity of C. thermophilum CBH1 was about 4.5-fold higher than T. reesei CBH1 in a wide range of temperatures and pH. To explore whether increasing CBH1 activity in T. reesei could contribute to improving the overall cellulose-utilizing efficiency of T. reesei, T. reesei cbh1 gene was replaced with C. thermophilum cbh1 gene by integration of C. thermophilum cbh1 gene into T. reesei cbh1 gene locus. The data surprisingly showed that this gene replacement not only increased the cellobiohydrolase activities by around 4.1-fold, but also resulted in stronger induction of other cellulases genes, which caused the filter paper activities, Azo-CMC activities and ß-glucosidase activities increased by about 2.2, 1.9, and 2.3-fold, respectively. The study here not only provided new resources of superior cellulases genes and new strategy to improve the cellulase production in T. reesei, but also contribute to opening the path for fundamental research on C. thermophilum.

Bacterial assembly during the initial adhesion phase in wastewater treatment biofilms.

Biofilm start-up is a critical and time-consuming process in moving bed biofilm reactors (MBBRs), with the procedure beginning with bacteria being statically bound on surfaces. Studies addressing this critical process have mainly focused on constructing models based on single strains, although consideration of the unstable adhesion process of structured bacterial communities remains underexplored. In this study, impedance based real-time cell analysis (RTCA) was employed to quantitatively characterize the unstable adhesion process of structured bacterial communities collected from the aerobic tanks of eight full-scale wastewater treatment plants (WWTPs). The unstable adhesion time ranged from 8.85 ± 1.53 h to 17.06 ± 0.64 h, indicating significant differences in bacterial colonization properties. Using principal components analysis (PCA), Na+, K+ and proteins were found to significantly influence the biofilm unstable adhesion process. Furthermore, the differences in unstable adhesion times were closely related to the abundance of the most abundant operational taxonomic units (OTUs). The dominant OTUs mainly belonged to Aeromonadaceae and Enterobacteriaceae, with 73% found to be negatively corelated with unstable adhesion time. Furthermore, bacterial assembly during the initial adhesion phase was driven by bacterial interactions and key OTUs (exhibiting maximum connectivity in phylogenetic molecular ecological networks (pMENs)). Analysis of pMENs indicated that bacterial cooperation was a dominant factor in the initial adhesion, which may involve bacterial co-colonization, co-aggregation and communication. Considering keystone taxa were not identified, OTUs with max connectivity in pMENs were considered as key species. Although these key species play important roles in the connection of networks, their relative abundances were low and no significant relationships were observed with the unstable adhesion time. Overall, unstable adhesion in MBBRs is regulated by the dominant bacterial species and the alleviation of environmental variables by repulsive forces, providing potential strategies of dosing quorum sensing signals and key cations at the initial adhesion phase in reactors, to facilitate initial biofilm formation.