Jianpi Jiedu decoction suppresses colorectal cancer growth by inhibiting M2 polarization of TAMs through the tryptophan metabolism-AhR pathway.

BACKGROUND: Traditional Chinese medicine, JianpiJiedu decoction (JPJDF), has been utilized in colorectal cancer (CRC) treatment for over forty years. The potential of JPJDF to inhibit CRC through modulation of intestinal microbiota and their metabolites remains uncertain. AIMS: This study aims to further investigate the therapeutic mechanisms of JPJDF in CRC. METHODS: CAC mouse models were developed using azoxymethane (AOM) and dextran sulfate sodium (DSS). Intestinal tissues and contents underwent 16S rRNA gene sequencing and untargeted metabolomics analysis. Serum levels of IL-1ß and TNF-α were measured using ELISA. Immunohistochemistry was utilized to assess the expression of Ki67, ZO-1, Occludin, CD68, and CD206. Furthermore, western blotting was performed to evaluate the protein expression of AhR and NF-κB. RESULTS: JPJDF inhibited colorectal tumourigenesis in AOM/DSS treated mice, while also suppressing tumor cell proliferation and upregulating the expression of tight junction proteins. The results of 16S rRNA gene sequencing analysis revealed that JPJDF altered intestinal microbiota composition by increasing the abundance of beneficial bacteria. Additionally, JPJDF reduced tryptophan metabolites, effectively alleviating inflammation and significantly restoring intestinal barrier function in CAC mice. Molecular biology experiments confirmed that JPJDF suppressed the expression levels of AhR and M2-type tumor-associated macrophages, thereby promoting anti-tumor immunity and exerting inhibitory effects on CAC growth. CONCLUSION: JPJDF can regulate the tryptophan metabolism-AhR pathway by modulating the gut microbiota, reducing intestinal inflammation, improving intestinal barrier function, enhancing anti-tumor immunity, and effectively inhibiting CAC growth.

Jianpi Jiedu decoction reverses 5-fluorouracil resistance in colorectal cancer by suppressing the xCT/GSH/GPX4 axis to induce ferroptosis.

Introduction: Innate and acquired chemoresistance in colorectal cancer (CRC) often results in 5-fluorouracil (5-FU) treatment failure. This study aimed to investigate the potential of Jianpi Jiedu (JPJD) decoction to reverse 5-FU resistance in CRC and clarify its potential mechanism of action. Methods: The CCK-8 assay was employed to assess cell activity. Flow cytometry was employed to assess various parameters including cell apoptosis, cell cycle distribution, P-glycoprotein (P-gp) activity, reactive oxygen species levels, and lipid peroxidation. Metabolomics analysis was conducted to identify differentially expressed metabolites. Western blotting was utilized for protein expression analysis. Results: In this study, we demonstrated that the combined JPJD and 5-FU treatment reversed 5-FU resistance in HCT8/5-FU cells, inducing cell apoptosis, causing G2/M-phase cell cycle arrest, and reducing P-gp protein expression and activity. Metabolomics analysis revealed ferroptosis as a key pathway in the development of 5-FU resistance. Furthermore, the combination treatment reversed drug resistance primarily by impacting ferroptosis and triggering critical ferroptosis events through the suppression of the cystine/glutamate transporter (xCT)/glutathione (GSH)/glutathione peroxidase (GPX4) axis. Conclusion: JPJD decoction primarily suppressed the xCT/GSH/GPX4 axis to trigger ferroptosis, thereby effectively reversing 5-FU resistance in colorectal cancer (CRC).

Mapping the intellectual structure and landscape of nano-drug delivery systems in colorectal cancer.

Background: Colorectal cancer (CRC) is a prevalent malignancy affecting the digestive tract, and its incidence has been steadily rising over the years. Surgery remains the primary treatment modality for advanced colorectal cancer, complemented by chemotherapy. The development of drug resistance to chemotherapy is a significant contributor to treatment failure in colorectal cancer. Nanodrug delivery systems (NDDS) can significantly improve the delivery and efficacy of antitumor drugs in multiple ways. However, there is a lack of visualization of NDDS research structures and research hotspots in the field of colorectal cancer, and the elaboration of potential research areas remains to be discovered. Objective: To comprehensively explore the current research status and development trend of NDDS in CRC research. Methods: Bibliometric analysis of articles and reviews on NDDS for CRC published between 2002 and 2022 using tools including CiteSpace, VOSviewer, R-bibliometrix, and Microsoft Excel was performed. Results: A total of 1866 publications authored by 9,870 individuals affiliated with 6,126 institutions across 293 countries/regions were included in the analysis. These publications appeared in 456 journals. Abnous Khalil has the highest number of publications in this field. The most published journals are the International Journal of Nanomedicine, International Journal of Pharmaceutics, and Biomaterials. Notably, the Journal of Controlled Release has the highest citation count and the third-highest H-index. Thematic analysis identified "inflammatory bowel disease"," "oral drug delivery," and "ulcerative colitis" as areas requiring further development. Keyword analysis revealed that "ulcerative colitis," "exosomes," and "as1411"have emerged as keywords within the last 2 years. These emerging keywords may become the focal points of future research. Conclusion: Our findings reveal the current research landscape and intellectual structure of NDDS in CRC research which helps researchers understand the research trends and hot spots in this field.

Global research trends and focus on the link between rheumatoid arthritis and neutrophil extracellular traps: a bibliometric analysis from 1985 to 2023.

Rheumatoid arthritis (RA) is an autoimmune disease that currently has an unknown cause and pathogenesis, and is associated with many complications and a high disability rate. The neutrophil extracellular trap network (NETs) is a newly discovered mechanism that allows neutrophils to capture and kill pathogens. Multiple studies in recent years have highlighted its relevance to the progression of rheumatoid arthritis. Despite the growing number of studies indicating the crucial role of NETs in RA, there has been no bibliometric review of research hotspots and trends in this area. In this study, we retrieved articles related to NETs in RA from the Web of Science Core Collection (WoSCC) database from 1985 to 2023 and used visualization tools such as Citespace, VOSviewer, Tableau Public, and Microsoft Office Excel 2021 to analyze the data. After screening, we included a total of 416 publications involving 2,334 researchers from 1,357 institutions in 167 countries/regions, with relevant articles published in 219 journals. The U.S., China, and Germany are the top 3 countries/regions with 124, 57, and 37 publications respectively. Mariana J. Kaplan is the most published author, and journals such as Frontiers in Immunology and International Journal of Molecular Sciences have had a significant impact on research in this field. The clinical application of PAD enzymes and their inhibitors, and the drug development of NETs as therapeutic targets for RA is a trend for future research. Our study provides a comprehensive bibliometric analysis and summary of NETs in RA publications, which will aid researchers in conducting further scientific research.

Global research trends and focus on the link between colorectal cancer and gut flora: a bibliometric analysis from 2001 to 2021.

Background: Colorectal cancer (CRC) is a highly prevalent cancer, and the global healthcare system bears a significant burden due to its incidence. Modulating the gut microbiota is a promising approach to enhance the efficacy of CRC treatment and reduce its adverse effects. The causal relationship between specific microorganisms' presence and CRC development has been widely validated. However, few studies have investigated this relationship using bibliometric methods. Therefore, this study analyzed the research hotspots and trends in human gut microbiology and CRC over the last two decades from a bibliometric perspective. The study aims to provide novel insights into basic and clinical research in this field. Methods: The articles and reviews on gut microbiota in CRC were obtained from the Web of Science Core Collection (WOSCC) on November 2, 2022. CiteSpace and VOSviewer were used to conduct the bibliometric and knowledge-map analysis. Results: A total of 2,707 publications were obtained, with a rapid increase in the number of publications since 2015. The United States and China are the main contributors in this field and have established a network of partnerships in several countries. 414 academic journals have published articles on this topic. The author with the highest number of publications is Jun Yu from the Chinese University of Hong Kong. In addition to "intestinal flora" and "colorectal cancer," high frequency terms in the keyword co-occurrence network analysis included inflammatory bowel disease, Fusobacterium nucleatum, inflammation, long-chain fatty acids, ulcerative colitis, bile acids, and resistant starch. Analysis of keyword trends using burst testing revealed that biomarkers, abnormal crypt foci, bifidobacteria, ß-glucuronidase, short-chain fatty acids, bile acids, and DNA methylation are at the forefront of research in this area. Conclusion: The findings of this study provide a bibliometric analysis and visualization of the key research areas in gut microbiota and CRC over the past 20 years. The results suggest that the role of gut microbiota in CRC and its underlying mechanisms should be closely monitored, particularly in the areas of biomarkers, metabolic pathways, and DNA methylation, which may emerge as hot topics in this field.

Association between abnormal plasma metabolism and brain atrophy in alcohol-dependent patients.

Objective: In this study, we aimed to characterize the plasma metabolic profiles of brain atrophy and alcohol dependence (s) and to identify the underlying pathogenesis of brain atrophy related to alcohol dependence. Methods: We acquired the plasma samples of alcohol-dependent patients and performed non-targeted metabolomic profiling analysis to identify alterations of key metabolites in the plasma of BA-ADPs. Machine learning algorithms and bioinformatic analysis were also used to identify predictive biomarkers and investigate their possible roles in brain atrophy related to alcohol dependence. Results: A total of 26 plasma metabolites were significantly altered in the BA-ADPs group when compared with a group featuring alcohol-dependent patients without brain atrophy (NBA-ADPs). Nine of these differential metabolites were further identified as potential biomarkers for BA-ADPs. Receiver operating characteristic curves demonstrated that these potential biomarkers exhibited good sensitivity and specificity for distinguishing BA-ADPs from NBA-ADPs. Moreover, metabolic pathway analysis suggested that glycerophospholipid metabolism may be highly involved in the pathogenesis of alcohol-induced brain atrophy. Conclusion: This plasma metabolomic study provides a valuable resource for enhancing our understanding of alcohol-induced brain atrophy and offers potential targets for therapeutic intervention.

Synoviolin inhibits the inflammatory cytokine secretion of Müller cells by reducing NLRP3.

The pro-inflammatory cytokines secreted by Müller cells aggregate retinal cell loss and vascularization in diabetic retinopathy (DR). The deubiquitinase BRCA1-BRCA2-containing complex subunit 3 (BRCC3)-mediated nucleotide-binding domain and leucine-rich repeat receptor containing a pyrin domain 3 (NLRP3) inflammasome activation participate in this progress. This study aims to clarify whether the E3 ubiquitin ligase synoviolin (SYVN1) relieves DR via regulating the BRCC3/NLRP3 axis. The DR model was established using streptozotocin-induced mice. Immunofluorescence staining with anti-CD31, anti-glutamine synthetase, and anti-vimentin was performed to identify DR and Müller cells. Levels of pro-inflammatory cytokines, including interleukin-1ß, tumor necrosis factor-α, IL-6, and IL-18, in murine serum and Müller cell supernatants were determined. Co-immunoprecipitation (Co-IP) and ubiquitination assays were used to clarify the interactions among SYVN1, BRCC3, and NLRP3. SYVN1 was reduced and BRCC3 was increased in DR retina and high glucose (HG)-induced Müller cells. Overexpressing 1 promoted the ubiquitination and degradation of BRCC3 and reduced the secretion of proinflammatory cytokines in HG-induced Müller cells. The simultaneous overexpression of 1 and Brcc3 restored the reduction of pro-inflammatory cytokines caused by the overexpression of 1 alone. Co-IP experiments confirmed the interaction between BRCC3 and NLRP3. SYVN1-mediated BRCC3 downregulation promoted NLRP3 ubiquitination and reduced pro-inflammatory cytokine secretion. 1 overexpression reduced retinal vascularization and inflammatory cytokine secretion in DR mice. SYVN1 has a protective effect on DR, whose molecular mechanisms are partly through SYVN1-mediated ubiquitination of BRCC3 and the subsequent downregulation of NLRP3.

LncRNA XIST restrains the activation of Müller cells and inflammation in diabetic retinopathy via stabilizing SIRT1.

BACKGROUND: Recent studies have provided strong evidence that lncRNAs play a functional regulatory role in diabetic retinopathy (DR). The purpose of this study was to investigate the effect of long non-coding RNA (lncRNA) X-inactive specific transcript (XIST) in DR. METHODS: A DR mouse model was established by intraperitoneal injection of streptozotocin (STZ), and then the mouse retinal Müller cells (mMCs) were isolated from retina tissues of mice. Human retinal Müller cell line (HMCs) and mMCs and were treated with high glucose (HG) to simulate an in vitro DR model. XIST expression was detected by qRT-PCR. Next, XIST overexpression was performed in mMCs and HMCs to examine its effect on the activation of Müller cells and production of pro-inflammatory cytokines. Subsequently, the interaction between XIST and SIRT1 was verified, and the ubiquitination level of SIRT1 as well as the stability of SIRT1 protein were assessed. RESULTS: XIST was down-regulated in retinal tissues of DR mice and HG-induced HMCs. Overexpression of XIST inhibited HG-induced activation of mMCs and HMCs, and reduced the production of pro-inflammatory cytokines. XIST promoted SIRT1 expression via interacting with SIRT1 and inhibiting the ubiquitination of SIRT1. Furthermore, SIRT1 silencing partly abrogated the effect of XIST overexpression on the activation of mMCs and HMCs as well as the production of pro-inflammatory cytokines induced by HG. CONCLUSION: We concluded that XIST restrained the activation of Müller cells and the production of pro-inflammatory cytokines via stabilizing SIRT1.

Immune cell infiltration-associated signature in colon cancer and its prognostic implications.

Tumor immune cell infiltration (ICI) has been reported in various studies to be correlated with tumor diagnosis, clinical treatment sensitivity and prognosis. It is an important direction to study the characteristics of immune cell infiltration and develop new prognostic markers to improve the treatment of colon cancer. In this paper, we systematically analyzed the ICI characteristics and obtained three ICI clusters. Then, the ICI scores were constructed and its prognostic implications were discussed. From the results, the ICI score patterns were linked to a great survival difference (p<0.001). A high ICI score was characterized by a higher fraction of plasma cells, CD8+ T cells, memory resting CD4+ T cells, monocytes, eosinophils and dendritic cells, which had better prognosis. Macrophages and neutrophils were increased in low ICI score patients with decreased overall survival. Immune checkpoint molecules (PDCD1, CD274, LAG3, IDO1, CTLA-4, TIGHT and HAVCR2) were found to be significantly overexpressed in the low ICI score subgroup. In addition, we also studied the correlation between the tumor mutation burden (TMB) and ICI score. This study indicated the ICI score could serve as a potential prognostic biomarker for colon cancer patients' immunotherapy.

Identification and Validation of Six Autophagy-related Long Non-coding RNAs as Prognostic Signature in Colorectal Cancer.

Colorectal cancer (CRC) is a commonly occurring tumour with poor prognosis. Autophagy-related long non-coding RNAs (lncRNAs) have received much attention as biomarkers for cancer prognosis and diagnosis. However, few studies have focused on their prognostic predictive value specifically in CRC. This research aimed to construct a robust autophagy-related lncRNA prognostic signature for CRC. Autophagy-related lncRNAs from The Cancer Genome Atlas database were screened using univariate Cox, LASSO, and multivariate Cox regression analyses, and the resulting key lncRNAs were used to establish a prognostic risk score model. Furthermore, quantitative real-time polymerase chain reaction (qRT-PCR) analysis was performed to detect the expression of several lncRNAs in cancer tissues from CRC patients and in normal tissues adjacent to the cancer tissues. A prognostic signature comprising lncRNAs AC125603.2, LINC00909, AC016876.1, MIR210HG, AC009237.14, and LINC01063 was identified in patients with CRC. A graphical nomogram based on the autophagy-related lncRNA signature was developed to predict CRC patients' 1-, 3-, and 5-year survival. Overall survival in patients with low risk scores was significantly better than in those with high risk scores (P < 0.0001); a similar result was obtained in an internal validation sample. The nomogram was shown to be suitable for clinical use and gave correct predictions. The 1- and 3-year values of the area under the receiver operating characteristic curve were 0.797 and 0.771 in the model sample, and 0.656 and 0.642 in the internal validation sample, respectively. The C-index values for the verification samples and training samples were 0.756 (95% CI = 0.668-0.762) and 0.715 (95% CI = 0.683-0.829), respectively. Gene set enrichment analysis showed that the six autophagy-related lncRNAs were greatly enriched in CRC-related signalling pathways, including p53 and VEGF signalling. The qRT-PCR results showed that the expression of lncRNAs in CRC was higher than that in adjacent tissues, consistent with the expression trends of lncRNAs in the CRC data set. In summary, we established a signature of six autophagy-related lncRNAs that could effectively guide clinical prediction of prognosis in patients with CRC. This lncRNA signature has significant clinical implications for improving the prediction of outcomes and, with further prospective validation, could be used to guide tailored therapy for CRC patients.

A Network Pharmacology Analysis of the Active Components of the Traditional Chinese Medicine Zuojinwan in Patients with Gastric Cancer.

BACKGROUND Zuojinwan (ZJW) is a traditional Chinese prescription normally used for gastritis. Several studies indicated that it could fight against gastric cancer. This study was designed to determine the potential pharmacological mechanism of ZJW in the treatment of gastric cancer. MATERIAL AND METHODS Bioactive compounds and potential targets of ZJW and related genes of gastric cancer were retrieved from public databases. Pharmacological mechanisms including crucial ingredients, potential targets, and signaling pathways were determined using protein-protein interaction (PPI) and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Virtual docking was performed to validate the findings. RESULTS Network analysis identified 47 active ZJW compounds, and 48 potential ZJW target genes linked to gastric cancer. Quercetin, beta-sitosterol, isorhamnetin, wogonin, and baicalein were identified as potential candidate agents. Our PPI analysis results combined with previously published results indicated that matrix metalloproteinases family members MMP9, MMP1, and MMP3 may play key roles in the anti-gastric cancer effect of ZJW. Molecular docking analysis showed that these crucial targets had good affinity for the representative components in ZJW. GO and KEGG enrichment analysis showed that ZJW target genes functioned in multiple pathways for treating gastric cancer, including interleukin-17 signaling and platinum drug resistance. CONCLUSIONS Our results illuminate the active ingredients, associated targets, biological processes, and signaling pathways of ZJW in the treatment of gastric cancer. This study enhances our understanding of the potential effects of ZJW in gastric cancer and demonstrates a feasible method for discovering potential drugs from Chinese medicinal formulas.

Network Pharmacology-Based Prediction and Verification of the Active Ingredients and Potential Targets of Zuojinwan for Treating Colorectal Cancer.

BACKGROUND: Zuojinwan (ZJW), a famous Chinese medicine formula, has been widely used to treat colorectal cancer (CRC). However, its bioactive compounds, potential targets, and molecular mechanism remain largely elusive. AIM: A network pharmacology-based strategy combined with molecular docking studies and in vitro validation were employed to investigate bioactive compounds, potential targets, and molecular mechanism of ZJW against CRC. MATERIALS AND METHODS: Bioactive compounds and potential targets of ZJW, as well as related genes of CRC, were acquired from public databases. Important ingredients, potential targets, and signaling pathways were determined through bioinformatics analysis, including protein-protein interaction (PPI), the Gene Ontology (GO), and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Subsequently, molecular docking and cell experiments were performed to further verify the findings. RESULTS: A total of 36 bioactive ingredients of ZJW and 163 gene targets of ZJW were identified. The network analysis revealed that quercetin, baicalein, wogonin, beta-sitosterol, and isorhamnetin may be candidate agents. The AKT1, JUN, CDKN1A, BCL2L1, and NCOA1 could become potential drug targets. The KEGG indicated that PI3K-AKT signaling pathway may play an important role in the effect of ZJW against CRC. Molecular docking suggested that quercetin, baicalein, and wogonin combined well with AKT1 and JUN. The in vitro experiment showed that quercetin, the most important ingredient of ZJW, could induce apoptosis of HCT116 cells through PI3K-Akt signaling pathway. This finding was congruent with the prediction obtained through the network pharmacology approach. CONCLUSION: This study comprehensively illuminated the active ingredients, potential targets, and molecular mechanism of ZJW against CRC. It also provided a promising approach to uncover the scientific basis and therapeutic mechanism of traditional Chinese medicine (TCM) formula treating for disease.

Integrated transcriptomic and metabolomic analyses to characterize the anti-cancer effects of (-)-epigallocatechin-3-gallate in human colon cancer cells.

(-)-Epigallocatechin-3-gallate (EGCG) is the main bioactive component in tea (Camellia sinensis) catechins, and exhibits potential antitumor activity against colorectal cancer (CRC). However, the underlying mechanisms are largely unclear. We investigated the effects of EGCG on activities of CRC cells and the exact molecular mechanism. We used human colon cancer cells (HT-29) and exposed them to EGCG at various concentrations. The MTT assay, flow cytometry, and TUNEL staining were used to study the underlying mechanisms of EGCG (proliferation, apoptosis, autophagy). Western blotting was used to measure expression of marker proteins of the cell cycle, apoptosis, and autophagy. Using a combined microarray-based transcriptomic and ultra-high-performance liquid chromatography coupled with quadrupole-time-of-flight tandem mass spectrometry (UHPLC-QTOF/MS)-based metabolomic approach, we investigated the perturbed pathways induced by EGCG treatment at transcript and metabolite levels. Transcriptomic analyses showed that 486 genes were differentially expressed between untreated and EGCG-treated cells. Also, 88 differentially expressed metabolites were identified between untreated and EGCG-treated cells. The altered metabolites were involved in the metabolism of glutathione, glycerophospholipids, starch, sucrose, amino sugars, and nucleotide sugars. There was substantial agreement between the results of transcriptomics and metabolomics analyses. Our data indicate that the anticancer activity of EGCG against HT-29 cells is mediated by induction of cell-cycle arrest, apoptosis, and autophagy. EGCG modulates cancer-cell metabolic pathways. These results provide a platform for future molecular mechanistic studies of EGCG.

New peptidendrocins and anticancer chartreusin from an endophytic bacterium of Dendrobium officinale.

BACKGROUND: Endophyte has now become a potential source for the discovery of novel natural products, as they participate in biochemical pathways of their hosts and produce analogous or novel bioactive compounds. As an epiphytic plant, Dendrobium officinale is one of precious Chinese medicines with various activities. It is well known for containing diverse endophytes, but so far not much is known about their secondary metabolites. METHODS: the plant tissues were cut and cultured on agar plates to isolate and purify the endophytic bacteria from Dendrobium officinale. Taxonomical identification of strains was performed by 16s rRNA. At the same time, the crude extracts of the strains were tested for antibacterial and cytotoxic activities to screen out one endophyte, Streptomyces sp. SH-1.2-R-15 for further study. After scale-up fermentation, isolation, purification and structure elucidation by using MS, 1D/2D-NMR spectroscopic method, secondary metabolites were identified and submitted for biological activity test. RESULTS: Fifty-eight endophytic strains representing 9 genera were obtained, with 50% of strains were Streptomyces. One of the most active strain, Streptomyces sp. 1.2-R-15, was selected for bioassay-guided isolation, which led to the discovery of two new peptide-type compounds 1 and 2, as well as a bioactive chartreusin, and four other known natural products. Their structures were determined by comprehensive spectroscopic techniques. Chartreusin showed potent cytotoxicity against Hep3B2.1-7 (IC50 =18.19 µM) and H1299 (IC50 =19.74 µM) cancer cell lines, and antibacterial activity against S. aureus (IC50 =23.25 µM). CONCLUSIONS: This study highlights the endophytic bacteria from medical plant D. officinale have potential bioactivity and natural product diversity, thus implicates them as a valuable source for new anticancer and antibiotics agents.

Erratum: A Network Pharmacology-Based Strategy for Predicting Active Ingredients and Potential Targets of LiuWei DiHuang Pill in Treating Type 2 Diabetes Mellitus [Corrigendum].

[This corrects the article DOI: 10.2147/DDDT.S216644.].

A Network Pharmacology-Based Strategy For Predicting Active Ingredients And Potential Targets Of LiuWei DiHuang Pill In Treating Type 2 Diabetes Mellitus.

BACKGROUND: Traditional Chinese medicine (TCM) formulations have proven to be advantageous in clinical treatment and prevention of disease. LiuWei DiHuang Pill (LWDH Pill) is a TCM that was employed to treat type 2 diabetes mellitus (T2DM). However, a holistic network pharmacology approach to understanding the active ingredients and the therapeutic mechanisms underlying T2DM has not been pursued. METHODS: A network pharmacology approach including drug-likeness evaluation, oral bioavailability prediction, virtual docking, and network analysis has been used to predict the active ingredients and potential targets of LWDH Pill in the treatment of type 2 diabetes. RESULTS: The comprehensive network pharmacology approach was successfully to identify 45 active ingredients in LWDH Pill. 45 active ingredients hit by 163 potential targets related to T2DM. Ten of the more highly predictive components (such as :quercetin, Kaempferol, Stigmasterol, beta-sitosterol, Kadsurenone, Diosgenin, hancinone C, Hederagenin, Garcinone B, Isofucosterol) are involved in anti-inflammatory, anti-oxidative stress, and the reduction of beta cell damage. LWDH Pill may play a role in the treatment of T2DM and its complications (atherosclerosis and nephropathy) through the AGE-RAGE signaling pathway, TNF signaling pathway, and NF-kappa B signaling pathway. CONCLUSION: Based on a systematic network pharmacology approach, our works successfully predict the active ingredients and potential targets of LWDH Pill for application to T2DM and helps to illustrate mechanism of action on a comprehensive level. This study provides identify key genes and pathway associated with the prognosis and pathogenesis of T2DM from new insights, which also demonstrates a feasible method for the research of chemical basis and pharmacology in LWDH Pill.

Kangai Injection, a Traditional Chinese Medicine, Improves Efficacy and Reduces Toxicity of Chemotherapy in Advanced Colorectal Cancer Patients: A Systematic Review and Meta-Analysis.

OBJECTIVE: To systematically review whether the Kangai injection (KAI), which is commonly used traditional Chinese medicine, can improve the clinical efficacy of chemotherapy and relieve adverse reactions of chemotherapy in advanced colorectal cancer (CRC) patients. METHODS: A comprehensive literature search was performed in three English and three Chinese electronic databases until March 2019. The literature was screened by EndNote X8 and data were analysed by RevMan5 and Stata12.0. RESULTS: This meta-analysis consisted of twenty-eight studies, of which 2310 cases were reported. Among the 2310 cases, 1207 cases were treated with KAI combined with chemotherapy and 1103 cases were treated with chemotherapy alone. The results showed that KAI combined with chemotherapy significantly improved tumor response (Risk Ratio (RR) =1.32; 95% confidence interval (CI): 1.22-1.43; p<0.00001); Karnofsky performance status (KPS score) (Risk Ratio (RR) =1.48; 95% CI: 1.36-1.60; p<0.00001); reduced adverse drug reactions (ADRs) such as nausea and vomiting (OR =0.31; 95% CI: 0.24-0.41; p <0.00001), diarrhea (OR =0.36; 95% CI: 0.25-0.52; p<0.00001), leukopenia (OR =2.97; 95% CI:2.27-3.88; p<0.00001), thrombocytopenia (OR =0.53; 95% CI: 0.38-0.74; p<0.0002), liver dysfunction (OR =0.29; 95% CI: 0.20-0.44; p<0.00001), neurotoxicity (OR =0.51; 95% CI: 0.36-0.71; p = 0.0004); increased immune function (CD3+: MD=6.34; 95% CI: 5.52-7.16; p < 0.00001, CD4+: MD=-5.99; 95% CI: 5.20-6.78; p < 0.00001; and CD4+/CD8+: MD=0.34; 95% CI: 0.14-0.54; p < 0.0009), and prolonged survival time (OR =1.77; 95% CI: 1.25-2.50; p = 0.001). Renal dysfunction caused by chemotherapy was not affected by KAI treatment (Odds Ratio (OR) =0.53; 95%IC: 0.25-1.12; p = 0.10). CONCLUSION: KAI can increase clinical effectiveness, improve quality of life, alleviate ADRs, and prolong survival time in advanced colorectal (CRC) patients receiving chemotherapy.

C-myc contributes to the release of Müller cells-derived proinflammatory cytokines by regulating lncRNA MIAT/XNIP pathway.

Müller cells-derived proinflammatory cytokines exert important roles in the development of DR, while the molecular mechanisms of its release were not fully elucidated. Present study aims to investigate the mechanism underlying the regulation of c-myc on the release of Müller Cells-derived proinflammatory cytokines. Streptozotocin was utilized to induce diabetes mellitus (DM) rat and glucose was used to stimulate Müller cells. The interaction between c-myc, lncRNA MIAT and TXNIP was determined by the luciferase reporter, CHIP, RNA pull-down, RIP and ubiquitylation assays. Increased c-myc protein level and concentrations of IL-1ß, TNF-α and IL-6 were found in DM rats and high glucose stimulated Müller cells. After glucose stimulation, c-myc promoted the releases of IL-1ß, TNF-α and IL-6. The up-regulation of MIAT under glucose treatment was mediated by c-myc binding to its promoter. MIAT interacted with TXNIP and increased TXNIP protein level by inhibiting its ubiquitination degradation. C-myc regulated TXNIP expression through MIAT in glucose induced Müller cells. Under glucose treatment, c-myc facilitated the release of Müller cells-derived IL-1ß, TNF-α and IL-6 by regulating MIAT/TXNIP pathway. The in vivo study further indicated that c-myc knockdown attenuated DR progression in vivo. Our results suggested a mechanism by which c-myc facilitates the release of Müller Cells-derived proinflammatory cytokines by regulating MIAT/TXNIP pathway.

miR-29a/b cluster suppresses high glucose-induced endothelial-mesenchymal transition in human retinal microvascular endothelial cells by targeting Notch2.

Several studies have previously reported that endothelial cells contributed to pathological fibrosis in proliferative diabetic retinopathy (PDR) through endothelial-mesenchymal transition (EndMT); however, the precise mechanism of this interaction has not been completely elucidated. The present study investigated the expression of microRNA (miR)-29a/b cluster in human retinal microvascular endothelial cells (HRMECs) and examined its functional role in high glucose (HG)-induced EndMT. HRMECs were exposed to glucose at concentrations of 5, 15, 30 and 50 mM for 7 days and reverse transcription-quantitative polymerase chain reaction, western blotting and immunofluorescence were conducted to determine the expression of genes associated with miR-29a/b and EndMT. A luciferase reporter gene assay was also performed to confirm the association between miR-29a/b and neurogenic locus notch homolog protein 2 (Notch2). The expression levels of miR-29a/b, and endothelial markers vascular endothelial cadherin and cluster of differentiation 31 were decreased, whereas the expression levels of Notch2 and mesenchymal markers, including α-smooth muscle actin, fibroblast-specific protein 1 (also named S100 calcium binding protein A4, S100A4), fibronectin and SNAI1 were increased in HRMECs under HG (30 nM) conditions. In addition, Notch2 was identified as a target of miR-29a and miR-29b. Overexpression of miR-29a/b downregulated the expression of Notch2 and subsequently suppressed HG-induced EndMT. Taken together, the results of the present study revealed that the miR-29/Notch2 signaling pathway may participate in the regulation of HG-induced EndMT, and may serve as a potential molecular target during fibrosis in PDR.