Characterizing neuroinflammation and identifying prenatal diagnostic markers for neural tube defects through integrated multi-omics analysis.

BACKGROUND: Neural Tube Defects (NTDs) are congenital malformations of the central nervous system resulting from the incomplete closure of the neural tube during early embryonic development. Neuroinflammation refers to the inflammatory response in the nervous system, typically resulting from damage to neural tissue. Immune-related processes have been identified in NTDs, however, the detailed relationship and underlying mechanisms between neuroinflammation and NTDs remain largely unclear. In this study, we utilized integrated multi-omics analysis to explore the role of neuroinflammation in NTDs and identify potential prenatal diagnostic markers using a murine model. METHODS: Nine public datasets from Gene Expression Omnibus (GEO) and ArrayExpress were mined using integrated multi-omics analysis to characterize the molecular landscape associated with neuroinflammation in NTDs. Special attention was given to the involvement of macrophages in neuroinflammation within amniotic fluid, as well as the dynamics of macrophage polarization and their interactions with neural cells at single-cell resolution. We also used qPCR assay to validate the key TFs and candidate prenatal diagnostic genes identified through the integrated analysis in a retinoic acid-induced NTDs mouse model. RESULTS: Our analysis indicated that neuroinflammation is a critical pathological feature of NTDs, regulated both transcriptionally and epigenetically within central nervous system tissues. Key alterations in gene expression and pathways highlighted the crucial role of STATs molecules in the JAK-STAT signaling pathway in regulating NTDs-associated neuroinflammation. Furthermore, single-cell resolution analysis revealed significant polarization of macrophages and their interaction with neural cells in amniotic fluid, underscoring their central role in mediating neuroinflammation associated with NTDs. Finally, we identified a set of six potential prenatal diagnostic genes, including FABP7, CRMP1, SCG3, SLC16A10, RNASE6 and RNASE1, which were subsequently validated in a murine NTDs model, indicating their promise as prospective markers for prenatal diagnosis of NTDs. CONCLUSIONS: Our study emphasizes the pivotal role of neuroinflammation in the progression of NTDs and underlines the potential of specific inflammatory and neural markers as novel prenatal diagnostic tools. These findings provide important clues for further understanding the underlying mechanisms between neuroinflammation and NTDs, and offer valuable insights for the future development of prenatal diagnostics.

Symptom effects and central mechanism of acupuncture in patients with functional gastrointestinal disorders: a systematic review based on fMRI studies.

BACKGROUND: Functional gastrointestinal disorders (FGIDs) are closely related to disorders of brain-gut interaction. FGIDs are the dominant disease of acupuncture treatment, which can improve the symptoms and emotional state. AIM: To evaluate the results and quality of the available clinical evidence and to summarize the central mechanism and effect of acupuncture on FGIDs. METHODS: PubMed, EMBASE, Web of science, Cochrane Library, China National Knowledge Infrastructure (CNKI) were searched by computer to collect the randomized controlled trials (RCTs), which contained central mechanisms via fMRI research of acupuncture in the treatment of FGIDs patients. The search time limit was from the establishment of the database to June 22, 2022. Two researchers independently screened the literature, extracted data, and evaluated the quality. RESULTS: Ten RCTs involving fMRI data were included in this study, including 4 Functional dyspepsia (FD) studies, 3 irritable bowel syndrome (IBS) studies, and 3 functional constipation (FC) studies. The score of improvements in both gastrointestinal symptoms and psychological symptoms showed that acupuncture could significantly improve the clinical symptoms of FGIDs patients, including abdominal pain, abdominal distension, frequency of defecation, and stool characteristics, and could relieve anxiety and depression symptoms of patients. Acupuncture could regulate brain functional connections and functional activity in FGIDs patients, mainly including insula, anterior cingulate cortex, prefrontal cortex, thalamus, hippocampus, amygdala and other brain regions. CONCLUSION: Acupuncture can improve gastrointestinal symptoms and psychological status in FGIDs patients, and regulate functional connectivity and activity of brain regions such as insula, ACC, PFC, thalamus, HIPP, amygdala, etc. These changes in brain activity may related to visceral sensation, pain regulation, emotion, but further studies of high quality are still necessary.

Design and synthesis of 1H-benzo[d]imidazole selective HDAC6 inhibitors with potential therapy for multiple myeloma.

Pan-HDAC inhibitors exhibit significant inhibitory activity against multiple myeloma, however, their clinical applications have been hampered by substantial toxic side effects. In contrast, selective HDAC6 inhibitors have demonstrated effectiveness in treating multiple myeloma. Compounds belonging to the class of 1H-benzo[d]imidazole hydroxamic acids have been identified as novel HDAC6 inhibitors, with the benzimidazole group serving as a specific linker for these inhibitors. Notably, compound 30 has exhibited outstanding HDAC6 inhibitory activity (IC50 = 4.63 nM) and superior antiproliferative effects against human multiple myeloma cells, specifically RPMI-8226. Moreover, it has been shown to induce cell cycle arrest in the G2 phase and promote apoptosis through the mitochondrial pathway. In a myeloma RPMI-8226 xenograft model, compound 30 has demonstrated significant in vivo antitumor efficacy (T/C = 34.8%) when administered as a standalone drug, with no observable cytotoxicity. These findings underscore the immense potential of compound 30 as a promising therapeutic agent for the treatment of multiple myeloma.

Reduced smooth muscle-fibroblasts transformation potentially decreases intestinal wound healing and colitis-associated cancer in ageing mice.

Cancer and impaired tissue wound healing with ageing are closely related to the quality of life of the elderly population. Given the increased incidence of cancer and the population ageing trend globally, it is very important to explore how ageing impairs tissue wound healing and spontaneous cancer. In a murine model of DSS-induced acute colitis and AOM/DSS-induced colitis-associated cancer (CAC), we found ageing significantly decreases intestinal wound healing and simultaneous CAC initiation, although ageing does not affect the incidence of AOM-induced, sporadic non-inflammatory CRC. Mechanistically, reduced fibroblasts were observed in the colitis microenvironment of ageing mice. Through conditional lineage tracing, an important source of fibroblasts potentially derived from intestinal smooth muscle cells (ISMCs) was identified orchestrating intestinal wound healing and CAC initiation in young mice. However, the number of transformed fibroblasts from ISMCs significantly decreased in ageing mice, accompanied by decreased intestinal wound healing and decreased CAC initiation. ISMCs-fibroblasts transformation in young mice and reduction of this transformation in ageing mice were also confirmed by ex-vivo intestinal muscular layer culture experiments. We further found that activation of YAP/TAZ in ISMCs is required for the transformation of ISMCs into fibroblasts. Meanwhile, the reduction of YAP/TAZ activation in ISMCs during intestinal wound healing was observed in ageing mice. Conditional knockdown of YAP/TAZ in ISMCs of young mice results in reduced fibroblasts in the colitis microenvironment, decreased intestinal wound healing and decreased CAC initiation, similar to the phenotype of ageing mice. In addition, the data from intestine samples derived from inflammatory bowel disease (IBD) patients show that activation of YAP/TAZ also occurs in ISMCs from these patients. Collectively, our work reveals an important role of the ageing stromal microenvironment in intestinal wound healing and CAC initiation. Furthermore, our work also identified a potential source of fibroblasts involved in colitis and CAC.

Corrigendum: Wenshen-Jianpi prescription, a Chinese herbal medicine, improves visceral hypersensitivity in a rat model of IBS-D by regulating the MEK/ERK signal pathway.

[This corrects the article DOI: 10.3389/fphar.2022.955421.].

Directed Evolution of Laccase for Improved Thermal Stability Facilitated by Droplet-Based Microfluidic Screening System.

Laccases are attractive biocatalysts for industry due to their broad substrate spectrum, the use of oxygen as final electron acceptor, and water as the sole byproduct. Increasing efforts have been devoted to the engineering of laccases to improve their properties. The droplet-based microfluidic screening (DMFS) technology can accelerate the screening procedure and probe the large sequence space. In this study, a DMFS system including a heating step and picoinjection was used to sort large laccase libraries, yielding 12 variants with enhanced thermotolerance. All the obtained amino acid substitutions are distributed on the surface of the laccase. Interestingly, recombination of three identified substitutions of Asp to Asn on the surface resulted in the best variant M20, exhibiting 24.0-fold higher remaining activity at 58.8 °C and 1.9-3.4-fold higher remaining activity after incubation in organic solvents solution (20% (v/v) methanol and ethanol) and ionic liquid solution (20% (v/v) 1-ethyl-3-methylimidazolium ethyl sulfate) for 12 h. Furthermore, molecular dynamic simulations revealed that the recombination of the three beneficial substitutions, Asp98Asn, Asp474Asn, and Asp340Asn on the surface introduced more hydrogen bonds compared to the wild type, which made M20 more thermostable. This study highlighted the importance of the DMFS system for an efficient identification of beneficial long-distance amino acid substitutions.

Wenshen-Jianpi prescription, a Chinese herbal medicine, improves visceral hypersensitivity in a rat model of IBS-D by regulating the MEK/ERK signal pathway.

The goal of the study was to analyze whether WJP can alleviate visceral hypersensitivity in IBS-D model rats. In this study, 36 Sprague-Dawley (SD) rats aged 4 weeks old were randomly divided into two groups: the model group (n = 27) and the control group (n = 9). The rat model of IBS-D was established by modified compound methods for 4 weeks. After the modification, IBS-D rats were randomly divided into three groups, namely, the IBS-D model group (n = 9), the positive drug group (n = 9), and the WJP group (n = 9), with different interventions, respectively. The control group was fed and allowed to drink water routinely. The Bristol stool scale scores were used to assess the severity of diarrhea. Abdominal withdrawal reflex (AWR) scores were used to assess visceral sensitivity. Expression of TNF-α was measured, and histopathological examinations were performed to assess colon inflammation in IBS-D model rats. Key factors of the MEK/ERK signal pathway in the tissue of the colon and hippocampus were measured to analyze the mechanism of WJP. Compared with the control group, the Bristol stool scale scores in the model group were significantly increased (p < 0.0001). The scores of the WJP group were significantly decreased compared with the model group (p = 0.0001). Compared with the control group, AWR scores in the model group at each pressure level were significantly increased (p = 0.0003, p < 0.0001, p = 0.0007, and p = 0.0009). AWR scores of the WJP group were significantly decreased compared with the model group (p = 0.0003, p = 0.0007, p = 0.0007, and p = 0.0009). Compared with the control group, the model group had significantly higher expression of TNF-α in the colon tissue (p < 0.0001). However, the WJP group had significantly lower level of TNF-α compared with the model group (p < 0.0001). Meanwhile, compared with the control group, the relative expression of the proteins of p-MEK1/2, p-ERK1, and p-ERK2 in the colon tissue was significantly increased in the model group (p < 0.0001). Compared with the model group, the relative expression of the proteins in the colon tissue were significantly decreased in the WJP group (p < 0.0001, p = 0.0019, and p = 0.0013). Compared with the control group, the relative expression of the proteins of p-MEK1/2, p-ERK1, and p-ERK2 in the hippocampus tissue were significantly increased in the model group (p < 0.0001). Compared with the model group, the relative expression of the proteins in the hippocampus tissue were significantly decreased in the WJP group (p = 0.0126, p = 0.0291, and p = 0.0145). The results indicated that WJP can alleviate visceral hypersensitivity in IBS-D model rats, possibly mediated by downregulating the expression of TNF-α, p-MEK1/2, p-ERK1, and p-ERK2 in the colon tissue. At the same time, WJP also affects downregulating the expression of p-MEK1/2, p-ERK1, and p-ERK2 in the hippocampus tissue.

A novel membrane-bound interleukin-2 promotes NK-92 cell persistence and anti-tumor activity.

A major challenge in natural killer (NK) cell immunotherapy is the limited persistence of NK cells in vivo. However, the proliferation of NK cells is dependent on cytokines such as interleukin-2 (IL-2). Although IL-2 is a critical cytokine for NK cell activation and survival, IL-2 administration in adoptive NK cell therapy can induce adverse toxicities. To improve the persistence of NK cells and attenuate the systemic toxicity of IL-2, we constructed a cell-restricted artificial IL-2, named membrane-bound IL-2 (mbIL-2), comprising human IL-2 and human IL-2Rα joined by a classic linker. We found that mbIL-2-activated NK-92 cells can survive and proliferate in vitro and in vivo, independent of exogenous IL-2, while mbIL-2-expressing NK-92 cells do not support bystander cell survival or proliferation. Additionally, mbIL-2 enhanced NK-92 cell-mediated antitumor activity by tuning the IL-2 receptor downstream signals and NK cell receptor repertoire expression. To conclude, our novel mbIL-2 improves NK-92 cell persistence and enhances NK-92 cell-mediated antitumor activity. NK-92 cells genetically modified to express the novel mbIL-2 with potential significance for clinical development.

Therapeutic efficacy of human adipose mesenchymal stem cells in Crohn's colon fibrosis is improved by IFN-γ and kynurenic acid priming through indoleamine 2,3-dioxygenase-1 signaling.

BACKGROUND: Inflammatory bowel diseases (IBD) are chronic relapsing-remitting inflammatory diseases of the gastrointestinal tract that are typically categorized into two subtypes: Crohn's disease (CD) and ulcerative colitis (UC). Although MSCs therapy has achieved encouraging outcomes in IBD therapy, objective responses are limited in colon fibrosis stenosis owing to the complicated microenvironment of CD and MSCs heterogeneity of quality. Here, we chose IFN-γ and kynurenic acid (KYNA) to overcome the low response and heterogeneity of human adipose-derived MSCs (hADSCs) to treat IBD and expand the therapeutic effects based on the excellent ability of IFN-γ and KYNA to promote indoleamine 2,3-dioxygenase-1 (IDO-1) signaling, providing a potential protocol to treat IBD and fibrosis disease. METHODS: hADSCs were isolated, cultured, and identified from human abdominal adipose tissue. The CD pathology-like acute colitis and chronic colon fibrosis rat model was induced by 2,4,6-trinitrobenzen sulfonic acid (TNBS). hADSCs were pretreated in vitro with IFN-γ and KYNA and then were transplanted intravenously at day 1 and 3 of TNBS administration in colitis along with at day 1, 15, and 29 of TNBS administration in chronic colonic fibrosis. Therapeutic efficacy was evaluated by body weights, disease activity index, pathological staining, real-time PCR, Western blot, and flow cytometry. For knockout of IDO-1, hADSCs were transfected with IDO-1-targeting small gRNA carried on a CRISPR-Cas9-lentivirus vector. RESULTS: hADSCs treated with IFN-γ and KYNA significantly upregulated the expression and secretion of IDO-1, which has effectively ameliorated CD pathology-like colitis injury and fibrosis. Notably, the ability of hADSCs with IDO-1 knockout to treat colitis was significantly impaired and diminished the protective effects of the primed hADSCs with IFN-γ and KYNA. CONCLUSION: Inflammatory cytokines IFN-γ- and KYNA-treated hADSCs more effectively alleviate TNBS-induced colitis and colonic fibrosis through an IDO-1-dependent manner. Primed hADSCs are a promising new strategy to improve the therapeutic efficacy of MSCs and worth further research.

Chinese Herbal Medicine for Functional Dyspepsia With Psychological Disorders: A Systematic Review and Meta-Analysis.

Background and Aims: Functional dyspepsia (FD) is closely associated with gut-brain interaction disorder (DGBI), characterized by the interaction of gastrointestinal symptoms and central nervous system dysregulation. Chinese herbal medicine (CHM) has a good concurrent effect in the treatment of FD, especially for patients with concurrent psychological disorders. A meta-analysis was designed to evaluate the efficacy and safety of CHMs in the treatment of FD. Methods: The PubMed, Embase, Cochrane Library, Web of Science, Chinese Biological Medical Database (CBM), Wanfang Data, China National Knowledge Infrastructure (CNKI), and China Science and Technology Journal Database (VIP) were searched to collect randomized controlled trials of FD treated with CHM. The retrieval time limit is from the establishment of the database till 11 April 2022. Two researchers independently searched databases, screened documents, extracted data, and evaluated the risk of bias of included studies. RevMan 5.4 software was used for meta-analysis. Results: A total of 11 studies including 951 patients were included. The study was divided into two parts. The first part included 5 clinical trials, including 471 patients. The experimental group was treated only with CHM and the control group was only treated with placebo. The results of first part showed that the total effective rate of CHM in the treatment of FD was higher than that in the placebo group (84.5 vs. 49.4%) [relative risk (RR) = 1.76; 95% confidence interval (CI) (1.13, 2.75); P = 0.01]. In addition, CHM treatment could reduce the total symptom score [standardized mean difference (SMD) = -10.05; 95% CI (-13.50, -6.59); Z = 5.70; P < 0.0001] and depression score [SMD = -7.68; 95% CI (-14.43, -0.94); Z = 2.23; P = 0.03]. The second part included 6 clinical trials, including 480 patients. The experimental group was only treated with CHM and the control group was treated with prokinetic agents combined with flupentixol melitracen (deanxit). The results of second part showed that the total effective rate of CHM in the treatment of FD was higher than that of the control group (92.6 vs. 78.8%) [RR = 1.17; 95% CI (1.09, 1.26), P < 0.0001]. In addition, CHM treatment could reduce HAMA score [mean difference (MD) = -3.19; 95% CI (-3.79, -2.59); Z = 10.40; P < 0.00001], HAMD score [MD = -4.32; 95% CI (-6.04, -2.61); Z = 4.94; P < 0.00001], and gastric emptying rate [MD = 12.62; 95% CI (5.84, 19.40); Z = 3.65; P = 0.0003]. The results of the two parts of the meta-analysis showed no serious adverse reactions, and there was no significant difference in the adverse reactions between the experimental group and the control group [MD = 1.14; 95% CI (0.53, 2.42); Z = 0.33; P = 0.74]; [MD = 0.14; 95% CI (0.01, 2.67); Z = 1.30; P = 0.19]. Conclusion: The current evidence shows that CHM treatment has great potential and safety in alleviating the symptoms of FD and improving the psychological disorders of anxiety and depression in patients with FD. Limited by the quantity and quality of the included studies and other biases, the above conclusions need more high-quality studies to be verified. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier [CRD42022311129].

Effects and Mechanisms of Acupuncture on Diarrhea-Predominant Irritable Bowel Syndrome: A Systematic Review.

Background: Irritable bowel syndrome (IBS) is a common disorder of gut-brain interaction with challenging treatment. According to evidence-based studies, acupuncture is likely to be a promising therapy and subservient adjunct for IBS. Mechanism study of acupuncture based on related clinical trials of high quality, nevertheless, is still vacant. Aim: This study aims to assess the results and qualities of current clinical evidence and conclude the relevant pathophysiological mechanisms and therapeutic effects of acupuncture on IBS with diarrhea (IBS-D). Methods: Literature from four databases, namely, PubMed, Cochrane Library, EMBASE, and Web of Science, was systematically searched to obtain eligible randomized controlled trials (RCTs), which contained mechanism research of acupuncture treatment in IBS-D patients. Two independent reviewers completed data extraction and quality evaluation using the RevMan 5.4.1 software. Results: Ten trials that covered 19 items related to mechanism research were included in this review. Acupuncture was reported to improve IBS-D symptoms and quality of life, with positive effects in regulating brain-gut peptides, cerebral activities, neuroendocrine functions, psychological state, and inflammatory GI and hypersensitive intestinal tracts. Conclusion: Acupuncture has potential influence on pathophysiology alterations such as regulating brain-gut peptides, altering cerebral connectivity and activity, promoting neuroendocrine functions and mental state, and mitigating inflammation as well as hypersensitivity of bowels in IBS-D patients, but further studies of high quality are still necessary. Systematic Review Registration: [https://www.crd.york.ac.uk/PROSPERO], identifier [CRD42022320331].

3D Printing Mini-Capsule Device for Islet Delivery to Treat Type 1 Diabetes.

Transplantation of encapsulated islets has been shown to hold a promising potential treatment for type 1 diabetes (T1D). However, there are several obstacles to overcome, such as immune rejection by the host of the grafts, sustainability of islet function, and retrievability or replacement of the encapsulated system, hinder their clinical applications. In this study, mini-capsule devices containing islets were fabricated by using digital light processing (DLP) 3D printing. To ensure a high survival rate and low immunogenicity of the fabricated islets, 20s was selected as the most suitable printing condition. Meanwhile, the mini-capsule devices with a groove structure were fabricated to prevent islet cells leakage. Subcutaneous transplantations of encapsulated islets in immunocompetent C57BL/6 mice indicated significant improvement in the symptoms of streptozotocin-induced hyperglycemia without any immunosuppression treatment for at least 15 weeks. In vivo intraperitoneal glucose tolerance tests (IPGTT) performed at different time points demonstrated therapeutically relevant glycemic ameliorate of the device. The implants retrieved after 15 weeks still contained viable and adequate numbers of islet cells. The results of this study indicate that the proposed mini-capsule device can deliver sufficient islet cell mass, prevent islet cells leakage, and maintain long-term cell survival while allowing easy retrieval. Furthermore, the proposed encapsulated islets may help with T1D cellular treatment by overcoming the obstacles of islet transplantation.

A specific upregulated long noncoding RNA in colorectal cancer promotes cancer progression.

Long noncoding RNA (lncRNA) plays a crucial role in the pathogenesis of various diseases, including colorectal cancer (CRC). The gene mutations of adenomatous polyposis coli (APC) were found in most patients with CRC. They function as important inducers of tumorigenesis. Based on our microarray results, we identified a specific upregulated lncRNA in CRC (SURC). Further analysis showed that high SURC expression correlated with poorer disease-free survival and overall survival in patients with CRC. Furthermore, we found that mutated APC genes can promote the transcription of SURC by reducing the degradation of ß-catenin protein in CRC. Functional assays revealed that knockdown of SURC impaired CRC cell proliferation, colony formation, cell cycle, and tumor growth. Additionally, SURC promotes CCND2 expression by inhibiting the expression of miR-185-5p in CRC cells. In conclusion, we demonstrate that SURC is a specific upregulated lncRNA in CRC and the SURC/miR-185-5p/CCND2 axis may be targetable for CRC diagnosis and therapy.

Efficacy of Wumei Baijiang prescription on regulatory T cells / helper T cells Immune balance in mice with ulcerative coliti.

OBJECTIVE: To observe the therapeutic effect of Wumei Baijiang prescription empirical prescription of Lu Zhizheng, on experimental ulcerative colitis (UC) mice, and to investigate the mechanism of the prescription in UC from the perspective of the immune balance of regulatory T cells (Treg) and helper T cells (Th17). METHODS: Sixty C57BL/6 mice were randomly divided into 6 groups: normal group, model group, Chinese medicine group (high, medium and low dose group of Wumei Baijiang prescription) and control group (mesalazine sustained-release granules). Except for the normal group, the other groups used 2.5% dextran sulfate sodium to induce UC mice model. At the end of the model, the Chinese medicine group was given high, medium and low dose administration of Wumei Baijiang prescription, the control group was given slow-release granules of mesalazine, and the model group was given equal volume saline for 10 d. The changes of food intake, body weight, disease activity index (DAI) score, length of large intestine and histopathology were observed. The number of Treg, Th17, CD4+, CD8+ cells in spleen was detected by flow cytometry. The expression of tumor necrosis factor-α (TNF-α), interleukin-10 (IL-10) and C-reactive protein (CRP) in serum was detected by enzyme-linked immunosorbent assay. RESULTS: The middle and high-dose groups of Wumei Baijiang prescription were superior to the model group in terms of increasing food intake and body weight of colitis mice, restoring colon morphology, improving pathological damage, and reducing DAI (P < 0.05). There was no statistical difference with the mesalazine group (P > 0.05). Compared with the model group, the spleen Treg and CD4+ of the mice in the high and middle dose groups of Wumei Baijiang prescription were higher, while Th17 and CD8+ were lower (P < 0.05), and there was no statistical difference compared with the mesalazine group (P > 0.05). In addition, compared with the model group, the serum levels of TNF- and CRP in mice with high and middle doses of Wumei Baijiang prescription and mesalazine group were lower (P < 0.05), and IL-10 content was higher ( P < 0.05). CONCLUSIONS: Wumei Baijiang prescription can improve the general conditions of colitis mice, such as diarrhea, hematochezia, weight loss, and mucosal damage. The mechanism may be related to the regulation of Treg/Th17 immune balance.

Efficacy and safety of berberine in preventing recurrence of colorectal adenomas: A systematic review and meta-analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Berberine(BBR) is a kind of isoquinoline alkaloids extracted from the rhizomes of Coptis chinensis Franch., which was the main active ingredient. Accumulating evidence has shown that it has potential pharmacological effects in preventing the recurrence of colorectal adenomas. AIM OF THE STUDY: The roles of BBR in the overall recurrence of colorectal adenoma have still not been assessed because of the limitations of the available data and the restriction of a single study. Therefore, we evaluated the effectiveness and safety of BBR in preventing the recurrence of colorectal adenomas through a systematic review and meta-analysis of available data. MATERIALS AND METHODS: We searched four English databases (PubMed (MEDLINE), the Cochrane Central Register of Controlled Trials (CENTRAL), Embase and Web of Science) and four Chinese language databases (Chinese Biomedicine (CBM), China National Knowledge Infrastructure (CNKI), Chinese Scientific Journals Database (VIP) and the WanFang Database) from their inception through October 2020. Meta-analysis was performed with RevMan5.3 software after data extraction and the quality of studies assessment. RESULTS: Three randomized controlled clinical trials were included with 1076 patients. Our results illustrated that 1-year and 2-year supplementation with BBR was associated with lower recurrence rate of colorectal adenoma (RR 0.69, 95% CI 0.57 to 0.84, p=0.0001; RR 0.75, 95% CI 0.64 to 0.88, p=0.0004). The relative risk of oral BBR for 1 year and 2 years is not comparable, for 2-year efficacy outcomes were assessed in all participants who had at least one colonoscopy with pathological evaluation after baseline (lots of participants completed the first colonoscopy but discontinued during the second follow-up interval.). Moreover, the results also suggest that BBR had more adverse events than placebo (RR 2.91, 95% CI 1.24 to 6.85, p=0.01). Through the full-text reading, no serious adverse events were observed, and constipation was the most common event which disappears once the drug is discontinued. CONCLUSION: Generally, the present study indicated that BBR has a comparable therapeutic effect on the prevention of colorectal adenomas recurrence. Adverse reactions are worthy of attention which requires additional studies to obtain a precise conclusion. PROSPERO REGISTRATION NO: CRD42020209135.

Choline-induced SLC5A7 impairs colorectal cancer growth by stabilizing p53 protein.

The members of the solute carrier (SLC) superfamily are vital membrane transporters in human cells. In the present study, we determine the expression and function of SLC5 family members in colorectal cancer (CRC). Expression analysis based on The Cancer Genome Atlas database and potential clinical relation analysis based on the Oncomine database indicate that SLC5A7 is downregulated and is predicted to correlate with the staging, and prognosis response of CRC. Additional results demonstrate that SLC5A7 is downregulated and correlates with good prognosis in patients with CRC. Ectopic expression of SLC5A7 either by overexpression, or uptake of choline efficiently inhibits CRC growth. Examination of the molecular mechanism reveals that SLC5A7 promotes p53 protein expression by directly interacting with and modifying p53 and disrupting the interaction between p53 and MDM2 in wild type p53 CRC cells. Our findings establish the clear correlation between SLC5A7 and tumour growth, providing a novel potential therapeutic target for CRC.

Study on the Effect of Antiplatelet and Gastric Mucosal Protection of Traditional Chinese Medicine Invigorating Qi and Hemostasis.

BACKGROUND: To investigate the effects of Chinese herbal medicine in tonifying qi and attaining hemostasis caused by the metabolism of the drug clopidogrel and as a result of platelet and gastric mucosa injury in an ischemia-reperfusion rat model. METHODS: A pharmacokinetic model was established to record the drug metabolism parameters of clopidogrel metabolites. Then, absorption of the drug was compared with approaches using the traditional Chinese medicine (TCM) approach of tonifying qi and establishing hemostasis, to using the drug pantoprazole and applying these approaches in combination with clopidogrel. Intragastric administration was performed, and all indicators were tested. RESULTS: The area under the curve (AUC; 0-T, 300.342 ± 35.832 mg/L* h; AUC 0-∞, 320.462 ± 40.213 mg/L* h), the plasma peak concentration (30.622 ± 9.917 mg/L*), and the peak time and half-life (7.954 ± 1.121 h) in the clopidogrel and the TCM groups were higher than those in the clopidogrel and pantoprazole groups. In terms of antiplatelet aggregation, compared with model group, the platelet aggregation rate induced by arachidonic acid (AA) and adenosine diphosphate (ADP) was significantly decreased by the TCM approach of tonifying qi and stopping bleeding (p < 0.05). The ADP, thromboxane A2, GPII B/Pa-A, CD62P and platelet factor 4 content in the TCM yiqi decoction and hemostasis approach were significantly decreased (p < 0.01). Compared with the clopidogrel group, the gastrin and motilin in the serum, the cyclooxygenase (COX)-1 and prostaglandin E2 in gastric tissue, and expression of vascular endothelial growth factor messenger ribonucleic acid in the serum were all significantly increased using TCM approach to protect against gastric mucosal injury (p < 0.05). CONCLUSION: TCM invigorating qi and hemostasis has an inhibitory effect on platelet activation. It can reduce the local inflammatory reaction at the same time as protecting gastric mucosa.

[Advances of high-throughput screening system in reengineering of biological entities].

Enzymes and cell factories are the core of industrial biotechnology. They play important roles in various fields such as medicine, chemical industry, food, agriculture, and energy. Usually, natural enzymes and cells need to be engineered to improve the catalytic efficiency, stability and enantioselectivity. Directed evolution makes it possible to rapidly improve the properties of enzymes and cell factories. Sensitive and reliable high-throughput screening approaches are the key for successful and efficient engineering of enzymes and cell factories. In this review, we first summarize the advantages and disadvantages of different screening methods and signal generation strategies as well as their application scope; we then describe the latest advances of ultra-high throughput screening technology applied in the directed evolution of enzymes and cell factories in the past three years. On this basis, we discuss the limiting factors that need to be further improved for high-throughput screening systems and forecast the future development trends of high-throughput screening methods, hoping that researchers in various fields including biotechnology and instrument development can cooperate closely to enhance the reliability and applicability of the high-throughput screening techniques.

Human placental mesenchymal stem cells ameliorate liver fibrosis in mice by upregulation of Caveolin1 in hepatic stellate cells.

BACKGROUND: Liver fibrosis (LF) is a common pathological process characterized by the activation of hepatic stellate cells (HSCs) and accumulation of extracellular matrix. Severe LF causes cirrhosis and even liver failure, a major cause of morbidity and mortality worldwide. Transplantation of human placental mesenchymal stem cells (hPMSCs) has been considered as an alternative therapy. However, the underlying mechanisms and the appropriate time window for hPMSC transplantation are not well understood. METHODS: We established mouse models of CCl4-injured LF and administered hPMSCs at different stages of LF once a week for 2 weeks. The therapeutic effect of hPMSCs on LF was investigated, according to histopathological and blood biochemical analyses. In vitro, the effect of hPMSCs and the secretomes of hPMSCs on the inhibition of activated HSCs was assessed. RNA sequencing (RNA-seq) analysis, real-time PCR array, and western blot were performed to explore possible signaling pathways involved in treatment of LF with hPMSCs. RESULTS: hPMSC treatment notably alleviates experimental hepatic fibrosis, restores liver function, and inhibits inflammation. Furthermore, the therapeutic effect of hPMSCs against mild-to-moderate LF was significantly greater than against severe LF. In vitro, we observed that the hPMSCs as well as the secretomes of hPMSCs were able to decrease the activation of HSCs. Mechanistic dissection studies showed that hPMSC treatment downregulated the expression of fibrosis-related genes, and this was accompanied by the upregulation of Caveolin-1 (Cav1) (p < 0.001). This suggested that the amelioration of LF occurred partly due to the restoration of Cav1 expression in activated HSCs. Upregulation of Cav1 can inhibit the TGF-ß/Smad signaling pathway, mainly by reducing Smad2 phosphorylation, resulting in the inhibition of activated HSCs, whereas this effect could be abated if Cav1 was silenced in advance by siRNAs. CONCLUSIONS: Our findings suggest that hPMSCs could provide multifaceted therapeutic benefits for the treatment of LF, and the TGF-ß/Cav1 pathway might act as a therapeutic target for hPMSCs in the treatment of LF.