Choline metabolism in regulating inflammatory bowel disease-linked anxiety disorders: A multi-omics exploration of the gut-brain axis.

Anxiety and depression caused by inflammatory bowel disease (IBD) negatively affect the mental health of patients. Emerging studies have demonstrated that the gut-brain axis (GBA) mediates IBD-induced mood disorders, but the underlying mechanisms of these findings remain unknown. Therefore, it's vital to conduct comprehensive research on the GBA in IBD. Multi-omics studies can provide an understanding of the pathological mechanisms of the GBA in the development of IBD, helping to uncover the mechanisms underlying the onset and progression of the disease. Thus, we analyzed the prefrontal cortex (PFC) of Dextran Sulfate Sodium Salt (DSS)-induced IBD mice using transcriptomics and metabolomics. We observed increased mRNA related to acetylcholine synthesis and secretion, along with decreased phosphatidylcholine (PC) levels in the PFC of DSS group compared to the control group. Fecal metagenomics also revealed abnormalities in the microbiome and lipid metabolism in the DSS group. Since both acetylcholine and PC are choline metabolites, we posited that the DSS group may experience choline deficiency and choline metabolism disorders. Subsequently, when we supplemented CDP-choline, IBD mice exhibited improvements, including decreased anxiety-like behaviors, reduced PC degradation, and increased acetylcholine synthesis in the PFC. In addition, administration of CDP-choline can restore imbalances in the gut microbiome and disruptions in lipid metabolism caused by DSS treatment. This study provides compelling evidence to suggest that choline metabolism plays a crucial role in the development and treatment of mood disorders in IBD. Choline and its metabolites appear to have a significant role in maintaining the stability of the GBA.

Development of a tongue image-based machine learning tool for the diagnosis of gastric cancer: a prospective multicentre clinical cohort study.

Background: Tongue images (the colour, size and shape of the tongue and the colour, thickness and moisture content of the tongue coating), reflecting the health state of the whole body according to the theory of traditional Chinese medicine (TCM), have been widely used in China for thousands of years. Herein, we investigated the value of tongue images and the tongue coating microbiome in the diagnosis of gastric cancer (GC). Methods: From May 2020 to January 2021, we simultaneously collected tongue images and tongue coating samples from 328 patients with GC (all newly diagnosed with GC) and 304 non-gastric cancer (NGC) participants in China, and 16 S rDNA was used to characterize the microbiome of the tongue coating samples. Then, artificial intelligence (AI) deep learning models were established to evaluate the value of tongue images and the tongue coating microbiome in the diagnosis of GC. Considering that tongue imaging is more convenient and economical as a diagnostic tool, we further conducted a prospective multicentre clinical study from May 2020 to March 2022 in China and recruited 937 patients with GC and 1911 participants with NGC from 10 centres across China to further evaluate the role of tongue images in the diagnosis of GC. Moreover, we verified this approach in another independent external validation cohort that included 294 patients with GC and 521 participants with NGC from 7 centres. This study is registered at ClinicalTrials.gov, NCT01090362. Findings: For the first time, we found that both tongue images and the tongue coating microbiome can be used as tools for the diagnosis of GC, and the area under the curve (AUC) value of the tongue image-based diagnostic model was 0.89. The AUC values of the tongue coating microbiome-based model reached 0.94 using genus data and 0.95 using species data. The results of the prospective multicentre clinical study showed that the AUC values of the three tongue image-based models for GCs reached 0.88-0.92 in the internal verification and 0.83-0.88 in the independent external verification, which were significantly superior to the combination of eight blood biomarkers. Interpretation: Our results suggest that tongue images can be used as a stable method for GC diagnosis and are significantly superior to conventional blood biomarkers. The three kinds of tongue image-based AI deep learning diagnostic models that we developed can be used to adequately distinguish patients with GC from participants with NGC, even early GC and precancerous lesions, such as atrophic gastritis (AG). Funding: The National Key R&D Program of China (2021YFA0910100), Program of Zhejiang Provincial TCM Sci-tech Plan (2018ZY006), Medical Science and Technology Project of Zhejiang Province (2022KY114, WKJ-ZJ-2104), Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer (JBZX-202006), Natural Science Foundation of Zhejiang Province (HDMY22H160008), Science and Technology Projects of Zhejiang Province (2019C03049), National Natural Science Foundation of China (82074245, 81973634, 82204828), and Chinese Postdoctoral Science Foundation (2022M713203).

Effects of Massa Medicata Fermentata on the intestinal pathogenic flagella bacteria and visceral hypersensitivity in rats with irritable bowel syndrome.

Objective: To investigate the effect of Massa Medicata Fermentata (MMF) on the changes of pathogenic flagellar bacteria and visceral hypersensitivity in rats with diarrhea irritable bowel syndrome (IBS-D). Methods: Thirty adult SD rats were randomly divided into normal control group (n = 10), model control group (n = 10), and MMF group (n = 10). Acetic acid enema combined with restraint stress was used to build the IBS-D visceral hypersensitivity model; Abdominal withdrawal reflex (AWR) test was used to assess the visceral sensitivity of rats; 16SrRNA sequencing was used to analyze the changes of intestinal bacteria in each group, and the content of pathogenic flagellated bacteria were quantitatively counted; The content of flagellin in colonic mucosa was detected by ELISA; TLR5 protein in colonic mucosa of rats was detected by Western Blot. Results: After IBS-D modeling, the visceral sensitivity of rats was significantly higher in the model control group than that in the normal control group (p = 0.0061), while it was significantly decreased in MMF group compared with the model control group (p = 0.0217), but without significant difference compared with the normal control group (p = 0.6851). The number of fecal Bifidobacterium and Lactobacillus in the model group were significantly decreased compared with the normal control group (p < 0.0001); While they were significantly increased in the MMF group compared with the model control group and normal control group (p = 0.009; p < 0.0001). The amount of fecal pathogenic flagellated bacteria in the model group was significantly increased compared with the normal control group (p = 0.001); However it was significantly reduced in MMF group compared with the model group (p = 0.026), which has no statistically difference with the normal control group (p = 0.6486). The content of flagellin in colonic mucosa was significantly increased in the model group when compared with the normal control group (p < 0.0001), and it was decreased in MMF group compared with the normal control group (p < 0.0001), but there was no statistical difference with the normal control group (p = 0.6545). The expression level of TLR5 protein in colonic mucosa of rat was significantly increased in model control group compared with the normal control group (p = 0.0034), However, it was significantly decreased in MMF group compared with normal control group (p = 0.0019), but it was no statistical difference with the normal control group (p = 0.7519). Conclusion: MMF can reduce visceral hypersensitivity by decreasing the content of pathogenic flagellated bacteria and their flagellin and inhibiting its specific receptor TLR5 protein expression in colonic mucosa in IBS-D rats.

Psoralen induces hepatotoxicity by covalently binding to glutathione-S-transferases and the hepatic cytochrome P450.

BACKGROUND: Psoraleae Fructus has been widely used in China and its surroundings; however, Psoraleae Fructus and its compound preparation have been reported recently to cause liver injury in clinics. Thus, its safe use has attracted increasing attention. The possible mechanism is related to the metabolism of psoralen, but it still needs further clarification. PURPOSE: The present study was designed to evaluate the toxicity of psoralen and investigate the potentially related molecular mechanisms using chemical biology methods combined with animal experiments to provide evidence for the rational clinical use of psoralen. METHODS: An in vivo experiment was conducted with a time series of 20-80 mg/kg psoralen to verify its toxic performance. Target capture and click reactions were used to investigate direct targets of psoralen. Selectivity for different glutathione-S-transferase (GST) subtypes in the liver and inhibition of cytochrome P450 (CYP450) were also detected. RESULTS: Psoralen build-up in the liver is the primary cause of liver damage. Our study revealed the mechanism by which psoralen induces liver injury. Psoralen can bind directly to CYP2D6, CYP3A4, GST-α, and GST-µ and inhibit their activities, causing the depletion of glutathione (GSH) in vivo, which in turn induces hepatic damage. The special structure of α,ß-unsaturated lactones in psoralen facilitates its attachment to its target; therefore, complementing psoralen with GSH can efficiently protect the liver from damage. CONCLUSIONS: Psoralen causes a disorder in drug metabolism by inhibiting the activity of CYPs and GSTs, causing exhaustion of GSH, and subsequently leading to liver damage. The co-administration of GSH and psoralen is an effective way to avoid liver injury in clinical settings.

Association of Helicobacter pylori enrichment in colorectal adenoma tissue on clinical and pathological features of adenoma.

OBJECTIVE: To investigate the enrichment of Helicobacter pylori (Hp) in adenoma tissue of patients with colorectal adenoma, and analyze the correlation between the enrichment and the clinical and pathological characteristics of colorectal adenoma. METHODS: The data of 1,622 patients undergoing gastrointestinal endoscopy in the Endoscopy Center of Wenzhou Integrated Traditional Chinese and Western Medicine Hospital affiliated to Zhejiang University of Traditional Chinese Medicine from January 2019 to June 2021 were retrospectively collected. The general data, gastric Hp infection, clinical and pathological features of colorectal adenoma, methylene blue staining of adenoma Hp, immunohistochemistry of adenoma Hp and immunofluorescence staining of adenoma TLR5 protein. were compared between the colorectal adenoma group (743 cases) and the control group (879 cases). RESULTS: There were 361 gastric Hp positive cases in the colorectal adenoma group, with a positive rate of 48.59%, and 331 gastric Hp positive cases in the control group, with a positive rate of 37.66%, and the difference was statistically significant (P < 0.001). Gastric Hp infection significantly correlates with the Hp enrichment in colorectal adenomas (OR: 28.449; 95%CI: 18.188-44.500; P < 0.001). Moreover, we found that Hp enrichment in colorectal adenomas was correlated with the diameter, pathological type, and malignancy of adenoma (OR: 3.536; 3.652; 2.833; all P < 0.001). Expression TLR5 protein was also increased in Hp-enriched adenoma tissue. CONCLUSION: There is a correlation between gastric Hp infection and intestinal Hp enrichment. The intestinal Hp enrichment significantly correlates with the clinical and pathological characteristics of colorectal adenomas, and its tumor-promoting effect may be related to the up-regulation of mucosal TLR5 expression.

Evaluation of the anti-inflammatory and antioxidant pharmcodynamic compoents of naoxintong capsules as a basis of broad spectrum effects.

CONTEXT: Naoxintong capsule (NXT) is one of the most prevalent Traditional Chinese Medicine formulations in the treatment of coronary heart disease (CHD), yet the action of pharmacodynamic components remains unclear. OBJECTIVE: To determine the basis by which pharmacodynamic components of NXT may be effective in the treatment of CHD. MATERIALS AND METHODS: The protective effect of NXT (0.01-100 µg/mL) on 293 T and hy926 cells was determined by MTT assay for 24 h. Afterwards, to investigate the pharmacodynamic material basis of NXT in anti-inflammatory and antioxidant effects, based on previous UPLC/Q-TOF analysis, 293 T and hy926 cells were divided into control (treated with solvent), model (incubated with TNF-α, LPS or H2O2), intervention (treated with UPLC components) and positive groups. After 24 h of treatment, all cells were tested to verify the screening results. MOE software was applied to dock bioactive compounds with phosphoinositide 3-kinase (PI3K), then the protein expression and phosphate levels were determined by western blotting. RESULTS: NXT could significantly inhibit the expression of NF-κB, MMP-9 and NO in cells with IC50 values of 0.1178, 0.1182 and 0.1094 µg/mL. Based on the screening results, six components of NXT were identified (calycosin, ferulic acid, salvianolic acid B, ononin, salvianolic acid E, and salvianolic acid F) which can inhibit NF-κB, MMP-9, and NO simultaneously, while exerting cytoprotective effects by inhibiting the activation of the PI3K/AKT pathway under different conditions by virtue of their advantageous interaction with PI3K. CONCLUSIONS: These ingredients have outstanding therapeutic potential and may provide a scientific basis for the future application and research of NXT.

Effect of total glucosides of paeony and Tripterygium wilfordii polyglycosides on erythrocyte methotrexate polyglutamates in rats, analysed using ultra-high-performance liquid chromatography-tandem mass spectrometry.

OBJECTIVES: The aim of the study was to explore the effect of total glucosides of paeony (TGP) and Tripterygium wilfordii polyglycosides (TWP) on erythrocyte methotrexate polyglutamates (MTXPGs), the metabolites of methotrexate (MTX). METHODS: An ultra-high-performance liquid chromatography (UPLC)-tandem mass spectrometry (MS/MS) method was developed to determine MTXPGs. The effects of MTXPGs were analysed using 24 male Sprague-Dawley rats that were randomly divided into the MTX alone, MTX-TGP combined, and MTX-TWP combined groups. Rats were administered MTX at a dose of 0.9 mg/kg once a week, TGP at 0.054 g/kg and TWP at 1.8 mg/kg three times a day. Venous blood (1.0 ml) was collected at weeks 2, 4, 6, 9, 12 and 15 and then analysed using the developed UPLC-MS/MS method. KEY FINDINGS: Specificity, linear range, inter-and intra-day precision, recovery, matrix effect and stability of MTXPGs met the standard regulations. This method was successfully used for the detection of MTXPGs. After administration of MTX alone, erythrocyte MTXPGs increased and accumulated in a time- and dose-dependent manner. Compared to MTX alone, the combination with TGP significantly decreased the content of total MTXPGs and short-chain MTXPGs (Methotrexate [MTX/MTXPG1] and 4-amino-10-methylpteroyldiglutamic acid [MTXPG2], P < 0.05), but had no significant effect on long-chain MTXPGs (4-amino-10-methylpteroyltriglutamic acid [MTXPG3], P > 0.05) and very long-chain MTXPGs (4-amino-10-methylpteroyltetraglutamic acid [MTXPG4] and 4-amino-10-methylpteroylpentaglutamic acid [MTXPG5], P > 0.05) at week 15. The combination of MTX with TWP had no significant effect on the content of total MTXPGs, short-chain MTXPGs and long-chain MTXPGs (P > 0.05), but it significantly decreased the content of very long-chain MTXPGs (P < 0.05) at week 15. CONCLUSIONS: The UPLC-MS/MS method was successfully used to determine MTXPGs in rat erythrocytes. TGP and TWP in combination with MTX affected the production of MTXPGs of different chain lengths in erythrocytes.

Interaction of NF-κB and Wnt/ß-catenin Signaling Pathways in Alzheimer's Disease and Potential Active Drug Treatments.

The most important neuropathological features of Alzheimer's disease (AD) are extracellular amyloid-ß protein (Aß) deposition, tau protein hyperphosphorylation and activation of neurometabolic reaction in the brain accompanied by neuronal and synaptic damage, and impaired learning and memory function. According to the amyloid cascade hypothesis, increased Aß deposits in the brain to form the core of the senile plaques that initiate cascade reactions, affecting the synapses and stimulating activation of microglia, resulting in neuroinflammation. A growing number of studies has shown that NF-κB and Wnt/ß-catenin pathways play important roles in neurodegenerative diseases, especially AD. In this review, we briefly introduce the connection between neuroinflammation-mediated synaptic dysfunction in AD and elaborated on the mechanism of these two signaling pathways in AD-related pathological changes, as well as their interaction. Based on our interest in natural compounds, we also briefly introduce and conduct preliminary screening of potential therapeutics for AD.

Physalis alkekengi var. franchetii Extracts Exert Antitumor Effects on Non-Small Cell Lung Cancer and Multiple Myeloma by Inhibiting STAT3 Signaling.

BACKGROUND: Physalis alkekengi var. franchetii is an herb that possesses various ethnopharmacological applications. Herein, our current study focuses on the antitumor effect of a combination of physalins, which are regarded as the most representative secondary metabolites from calyces of Physalis alkekengi var. franchetii. MATERIALS AND METHODS: We mainly investigated the antitumor activity of the physalins extracted from Physalis alkekengi var. franchetii on both solid and hematologic cancers. The main cells used in this study were NCI-H1975 and U266 cells. The major assays used were the CCK-8 assay, Western blot analyses, immunofluorescence assay and Annexin V assay, and a xenograft mouse model was used. RESULTS: The results showed that physalins exhibited a strong antitumoural effect on both non-small cell lung cancer (NSCLC) and multiple myeloma (MM) cells by suppressing constitutive STAT3 activity and further inhibiting the downstream target gene expression induced by STAT3 signaling, which resulted in the enhanced apoptosis of tumor cells. Moreover, physalins significantly reduced tumor growth in xenograft models of lung cancer. CONCLUSION: Collectively, these findings demonstrated that the physalins from Physalis alkekengi var. franchetii may potentially act as cancer preventive or chemotherapeutic agents for NSCLC and MM by inhibiting the STAT3 signaling pathway. The present study served as a promising guide to further explore the precise mechanism of Physalis alkekengi var. franchetii in cancer treatment.

Dual-screening of anti-inflammatory and antioxidant active ingredients of shenxiang suhe pill and its potential multi-target therapy for coronary heart disease.

BACKGROUND: Shenxiang Suhe Pill (SXSHP), a Chinese medicine formula, is widely used in clinic to treat coronary heart disease (CHD). However, due to the complex composition of SXSHP, its underlying mechanisms and pharmacodynamic properties are still unknown. In this paper, we try to define the compounds of SXSHP by dual-screening the active ingredients with anti-inflammation and antioxidant effects and predict its multi-target-pathway in CHD therapy using network pharmacology. METHODS: The chemical constituents in SXSHP were analyzed by UPLC/Q-TOF. Then, the active ingredients with the anti-inflammation and antioxidant effects were dual-screened by in vitro experiments. Ingenuity pathway analysis (IPA) was used to analyze and predict the potential targets and pathways of the anti-inflammatory and antioxidant effects of SXSHP. RESULTS: A total of 38 chemical constituents were identified in SXSHP, among which we screened six anti-inflammatory compounds: luteolin, isorhamnetin-3-O-beta-d-glucoside, 4-hydroxy-3-methoxycinnamaldehyde, benzoic acid, kaempferol-3-O-glucuronide acid, and blumeatin; and five antioxidant compounds: vanillin, eugenol, muscone, luteolin, and asiatic acid. IPA showed that eugenol, muscone, and 4-hydroxy-3-methoxycinnamaldehyde were closely related to the HIF-1 and IL-15 signaling pathways, which protect against oxidative stress and inflammation, respectively. CONCLUSIONS: Among the 38 ingredients in SXSHP, the anti-inflammatory pharmacological effects of isorhamnetin-3-O-beta-d-glucoside, blumeatin and 4-hydroxy-3-methoxycinnamaldehyde were reported for the first time. According to the network pharmacology analysis, eugenol, 4-hydroxy-3-methoxycinnamaldehyde and muscone are involved in the antioxidant HIF-1 pathway and the anti-inflammatory IL-15 pathway, and that may be the mechanism of SXSHP in the treatment of CHD.

Structural modulation of gut microbiota during alleviation of non-alcoholic fatty liver disease with Gynostemma pentaphyllum in rats.

BACKGROUND: The current work aimed to assess whether Gynostemma pentaphyllum (GP), a Chinese herbal medicine, structurally modifies the gut microbiota in rats during non-alcoholic fatty liver disease (NAFLD) treatment. METHODS: High-fat diet (HFD)-induced NAFLD rats were orally administered water decoction of GP or equal amounts of distilled water per day for 4 weeks. Liver tissues were examined by histopathological observation, while intestinal tissues were examined by both histopathological and ultrastructural observations. The levels of fasting blood glucose (FBG), fasting serum insulin (FINS), total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), alanine transaminase (ALT) and aspartate transaminase (AST) were measured by enzymatic method. The levels of toll-like receptor 4 (TLR-4), tumor necrosis factor-alpha (TNF-α), interleukin-1-beta (IL-1ß) and interleukin-6 (IL-6) in both serum and hepatic tissues were measured by RT-qPCR. The protein expression level of TLR-4 in hepatic tissues was detected by western blot. The gut microbiota was assessed by 16S rRNA-based microbiota analysis. RESULTS: GP maintained intestinal integrity and reversed gut dysbiosis in high-fat diet (HFD)-induced NAFLD rats. This also reduced the ratio of Firmicutes to Bacteroidetes, enriching the abundance of beneficial bacteria (Lactococcus spp.) and inhibiting the abundance of pathogenic bacteria (Ruminococcus spp.) in the gut. The levels of pro-inflammatory cytokines (TNF-α, IL-1ß and IL-6) and the expression of TLR4 were downregulated (P < 0.05), while the insulin resistance index, HOMA-IR showed improvement by GP treatment (P < 0.05). Liver function indicators (ALT and AST) were remarkably decreased (P < 0.01). Besides, GP treatment reduced TG and LDL-C levels (P < 0.05), and increased HDL-C level (P < 0.05) compared with NAFLD group. CONCLUSION: The structural alterations of gut microbiota induced by GP are associated with NAFLD alleviation.

Modulation of resting-state brain functional connectivity by exposure to acute fourth-generation long-term evolution electromagnetic field: An fMRI study.

By now, the neurophysiological effect of electromagnetic field (EMF) exposure and its underlying regulating mechanisms are not well manifested. In this study, we aimed to investigate whether acute long-term evolution (LTE) EMF exposure could modulate brain functional connectivity using regional homogeneity (ReHo) method and seed-based analysis on resting-state functional magnetic resonance imaging (fMRI). We performed the LTE-EMF exposure experiment and acquired the resting-state brain activities before and after EMF exposure. Then we applied ReHo index to characterize the localized functional connectivity and seed-based method to evaluate the inter-regional functional connectivity. Statistical comparisons were conducted to identify the possible evidence of brain functional connectivity modulation induced by the acute LTE-EMF exposure. We found that the acute LTE-EMF exposure modulated localized intra-regional connectivity (p < 0.05, AlphaSim corrected, voxel size ≥ 18) and inter-regional connectivity in some brain regions (p < 0.05, AlphaSim corrected, voxel size ≥ 18). Our results may indicate that the approaches relying on network-level inferences could provide deeper insight into the acute effect on human functional activity induced by LTE-EMF exposure. Bioelectromagnetics. 40:42-51, 2019. © 2018 Wiley Periodicals, Inc.

Mucosa repair mechanisms of Tong-Xie-Yao-Fang mediated by CRH-R2 in murine, dextran sulfate sodium-induced colitis.

AIM: To explore the significance of corticotropin-releasing hormone (CRH)-receptor (R)2 in mucosal healing of dextran sulfate sodium (DSS)-induced colitis and the effect of Tong-Xie-Yao-Fang (TXYF) on CRH-R2 expression and regulation. METHODS: Ulcerative colitis was induced in mice by administration of 3% (w/v) DSS for 7 d. Once the model was established, mice were administered urocortin-2 (30 µg/kg), a peptide which binds exclusively to CRH-R2, or various doses of aqueous TXYF extracts (2.8-11.2 g/kg), a CRH-R2 antagonist Astressin (Ast)2B (20 µg/kg), Ast2B + Ucn2, or Ast2B with various doses of aqueous TXYF extracts for 9 d. Colonic mucosal permeability was then evaluated by measuring the fluorescence intensity in serum. The colitis disease activity index (DAI), histology, body weight loss and colon length were assessed to evaluate the condition of colitis. Terminal deoxynucleotidyl transferase dUTP nick-end labeling was used to detect apoptosis of the intestinal epithelial cells. The expression level of Ki-67 represented the proliferation of colonic epithelial cells and was detected by immunohistochemistry. The expression levels of inflammation cytokines IL-6, TNF-α and CXCL-1 were examined in colon tissues using real-time PCR and ELISA kits. RESULTS: Compared with the DSS group, mice treated with the CRH-R2 antagonist Ast2B showed greater loss of body weight, shorter colon lengths (4.90 ± 0.32 vs 6.21 ± 0.34 cm, P < 0.05), and higher DAI (3.61 ± 0.53 vs 2.42 ± 0.32, P < 0.05) and histological scores (11.50 ± 1.05 vs 8.33 ± 1.03, P < 0.05). Additionally, the Ast2B group showed increased intestinal permeability (2.76 ± 0.11 µg/mL vs 1.47 ± 0.11 µg/mL, P < 0.001), improved secretion of inflammatory cytokines in colon tissue, and reduced colonic epithelial cell proliferation (4.97 ± 4.25 vs 22.51 ± 8.22, P < 0.05). Increased apoptosis (1422.39 ± 90.71 vs 983.01 ± 98.17, P < 0.001) was also demonstrated. The Ucn2 group demonstrated lower DAI (0.87 ± 0.55 vs 2.42 ± 0.32, P < 0.001) and histological scores (4.33 ± 1.50 vs 8.33 ± 1.03, P < 0.05). Diminished weight loss, longer colon length (9.58 ± 0.62 vs 6.21 ± 0.34 cm, P < 0.001), reduced intestinal permeability (0.75 ± 0.07 vs 1.47 ± 0.11 µg/mL, P < 0.001), inhibited secretion of inflammatory cytokines in colon tissue and increased colonic epithelial cell proliferation (90.04 ± 15.50 vs 22.51 ± 8.22, P < 0.01) were all observed. Reduced apoptosis (149.55 ± 21.68 vs 983.01 ± 98.17, P < 0.05) was also observed. However, significant statistical differences in the results of the Ast2B group and Ast2B + Ucn2 group were observed. TXYF was also found to ameliorate symptoms of DSS-induced colitis in mice and to promote mucosal repair like Ucn2. There were significant differences between the Ast2B + TXYF groups and the TXYF groups. CONCLUSION: CRH-R2 activates the intestinal mucosal antiinflammatory response by regulating migration, proliferation and apoptosis of intestinal epithelial cells in colitis-induced mice, and plays an important antiinflammatory role. TXYF promotes mucosal repair in colitis mice by regulating CRH-R2.

Application of VATS in Diagnosis and Treatment of Lung Cancer Complicated with Pneumothorax / Aplicação do VATS no Diagnóstico e Tratamento do Câncer de Pulmão Complicado com Pneumotórax

The paper aims to explore clinical symptoms and complication characteristic of lung cancer complicated with pneumothorax, analyze clinical diagnostic value of VATS, and elaborate on specific clinical programs and significance. To investigate diagnosis and therapeutic value of VATS for lung cancer complicated with pneumothorax, 1900 cases of patients with lung cancer complicated with pneumothorax were randomly selected as research objects to be treated with VATS, and then analysis of their clinical data was done. The clinical data showed that many patients were not clearly diagnosed before operation. In VATS operation, lung tumor tissue was removed and then immediately frozen and sliced. Appropriate surgical approach was chosen based on specific circumstances of patients. As can be known from the results, 1000 cases were treated with wedge resection of lung tumor under thoracoscopy, 900 cases were treated with assisted small incision surgery under thoracoscopy. 1400 cases of lung metastasis were treated with pleural friction fixation. All the operations were successful, with pathology being clearly diagnosed. After surgery, 8 patients had mild air leakage, which could be heal without special treatment. There was no perioperative death. The above analysis shows that VATS can clearly diagnose peripheral lung tumor, and fundamentally cure pneumothorax and lung cancer, which is thus recommended in clinic.

o artigo pretende explorar sintomas clínicos e complicações características do câncer de pulmão complicado com pneumotórax, analisar o valor do diagnóstico clínico do VATS e elaborar programas e significados clínicos específicos. Para investigar o diagnóstico e valor terapêutico do VATS para câncer de pulmão complicado com pneumotórax, 1900 casos de pacientes com câncer de pulmão complicado com pneumotórax foram selecionados aleatoriamente como objetos de pesquisa para serem tratados com VATS e, em seguida, foi feita a análise de seus dados clínicos. Os dados clínicos mostraram que muitos pacientes não foram corretamente diagnosticados antes da operação. Na operação VATS, o tecido do tumor pulmonar foi removido e imediatamente congelado e cortado em fatias. A abordagem cirúrgica apropriada foi escolhida com base em circunstâncias específicas dos pacientes. Como pode ser conhecido a partir dos resultados, 1000 casos foram tratados com ressecção em cunha do tumor pulmonar sob toracoscopia, 900 casos foram tratados com cirurgia de incisão pequena assistida sob toracoscopia. 1400 casos de metástases pulmonares foram tratados com fixação de fricção pleural. Todas as operações foram bem-sucedidas, sendo a patologia claramente diagnosticada. Após a cirurgia, 8 pacientes apresentaram vazamento de ar leve, que pode ser curado sem tratamento especial. Não houve morte perioperatória. A análise acima mostra que a VATS pode diagnosticar claramente o tumor pulmonar periférico, e fundamentalmente curar pneumotórax e câncer de pulmão, o que é recomendado na clínica.

Heart function and thoracic aorta gene expression profiling studies of ginseng combined with different herbal medicines in eNOS knockout mice.

Ginseng, a popular herbal remedy, is often used in combination with other drugs to achieve the maximum therapeutic response. Shenfu (SFI) and Shenmai injection (SMI) have been widely used to treat cardiovascular disease in China. Our study explored the cardiovascular protection of SFI and SMI in eNOS knockout mice to investigate the differences and similarities of the two ginseng-combinations. Transthoracic echocardiography was performed to evaluate the left ventricular structure and function at baseline and 3, 7, and 14 days after drug administration. Agilent Gene Expression microarrays were used to demonstrate the gene expression profiling of the thoracic aorta. Ingenuity Pathway Analysis was performed to evaluate the mechanism improved by SFI and SMI in eNOS knockout mice. Both SFI and SMI could modulate Gadd45 Signaling from TOP15 canonical pathways. Moreover, SFI showed a better effect in the early treatment stage and improved myocardial function via GATA4, GATA6 and COL3A1. Meanwhile, SMI exerted better protective effects at the chronic stage, which may be related to endothelium protection by VEGFA and ACE. The advantage of multi-target by drug combination in progression of complex diseases should be noticed. The appropriate adjustment of drug combination could lead to a better accurate medical care in clinic.

Huang Gan Formula Eliminates the Oxidative Stress Effects of Advanced Oxidation Protein Products on the Divergent Regulation of the Expression of AGEs Receptors via the JAK2/STAT3 Pathway.

Chronic kidney disease (CKD) has a high prevalence and low cure rate and represents a significant health issue. Oxidative stress is common in CKD due to metabolic disorders, inflammation, and impaired renal function changing normal proteins into advanced oxidation protein products (AOPPs). Huang Gan formula (HGF) is a new type of traditional Chinese herbal medicine. Although we previously investigated the protective effects of HGF against oxidative stress, the mechanism of HGF in CKD is still not fully understood. In this study, we used western blotting, quantitative polymerase chain reaction, and biochemical assays to show that HGF significantly decreased AOPP-induced oxidative stress damage. Moreover, the protective effects of HGF might be associated with upregulation of the advanced glycation end product receptor 1 (AGE-R1) and downregulation of the receptor for advance glycation end products (RAGE). Treatment with HGF and the Janus kinase 2 (JAK2) inhibitor, AG4-90, significantly attenuated AOPP-induced JAK2/STAT3 protein levels. These findings indicate that HGF inhibits AOPP-mediated biological responses by inactivating the JAK2/STAT3 pathway. In conclusion, HGF eliminated AOPP-induced effects in human mesangial cells (HMCs) by interrupting JAK2/STAT3 signaling, which altered RAGE/AGE-R1 expression and reduced oxidative stress in CKD.

Identification of NF-κB inhibitors following Shenfu injection and bioactivity-integrated UPLC/Q-TOF-MS and screening for related anti-inflammatory targets in vitro and in silico.

ETHNOPHARMACOLOGICAL RELEVANCE: Shenfu injection (SFI) is a commercial medicinal product approved by the China Food and Drug Administration that is widely used in the treatment of stroke and coronary heart disease. However, the material basis and the mechanism of SFI are not fully understood. AIM OF THE STUDY: With network pharmacology analysis, our research committed to identify the anti-inflammatory ingredients and mechanism of SFI by combining high-throughput screening. MATERIALS AND METHODS: We developed a bioactivity-based UPLC/Q-TOF-MS method followed by network pharmacology and identified the anti-inflammatory active ingredients of SFI from two different perspectives of network computing and high throughput screening. Then we verified the anti-inflammatory effect of SFI in vitro with endothelial cells. After detecting the cell viability, the expression of interleukin-6 (IL-6), inhibitor of nuclear factor kappa-B kinase (IKK), phosphorylated IKK, phosphorylated NF-κB and phosphorylated IκB-α from the supernatant were determined. RESULTS: SFI could significantly suppress inflammatory responses, and the mechanism may be via an NF-κB-dependent pathway. The results of high throughput screening (HTS) revealed that protopanaxadiol glycosides (ginsenosides Rb1, Rb2, Rb3, Rc and Rd), protopanaxatriol glycosides (ginsenosides Rg1, Rg2, Re, Rf and F1), diester-type alkaloids (fuziline and neoline) and aconine derivatives (mesaconine and benzoyl-mesaconine) have anti-NF-κB activity. The three compounds (including benzoyl-mesaconine, fuziline and neoline) are the first reported SFI compounds to have NF-κB inhibitor activity. CONCLUSIONS: SFI may play a critical role in counteracting inflammation through the NF-κB signaling pathway. The active ingredients are protopanaxadiol glycosides, protopanaxatriol glycosides, diester-type alkaloids and aconine derivatives.

Identification of "Multiple Components-Multiple Targets-Multiple Pathways" Associated with Naoxintong Capsule in the Treatment of Heart Diseases Using UPLC/Q-TOF-MS and Network Pharmacology.

Naoxintong capsule (NXT) is a commercial medicinal product approved by the China Food and Drug Administration which is used in the treatment of stroke and coronary heart disease. However, the research on the composition and mechanism of NXT is still lacking. Our research aimed to identify the absorbable components, potential targets, and associated pathways of NXT with network pharmacology method. We explored the chemical compositions of NXT based on UPLC/Q-TOF-MS. Then, we used the five principles of drug absorption to identify absorbable ingredients. The databases of PharmMapper, Universal Protein, and the Molecule Annotation System were used to predict the main targets and related pathways. By the five principles of drug absorption as a judgment rule, we identified 63 compositions that could be absorbed in the blood in all 81 chemical compositions. Based on the constructed networks by the significant regulated 123 targets and 77 pathways, the main components that mediated the efficacy of NXT were organic acids, saponins, and tanshinones. Radix Astragali was the critical herbal medicine in NXT, which contained more active components than other herbs and regulated more targets and pathways. Our results showed that NXT had a therapeutic effect on heart diseases through the pattern "multiple components-multiple targets-multiple pathways."

CXCL13 blockade attenuates lupus nephritis of MRL/lpr mice.

The chemokine CXC ligand 13 protein (CXCL13) is reported to closely related to the disease activity and severity of systemic lupus erythematosus (SLE), moreover, the level of CXCL13 was markedly raised in kidney tissues of lupus nephritis (LN) patients. The aim of the present study was to explore whether the blockade of CXCL13 has therapeutic effects on murine LN. MRL/lpr mice received 50µg anti-CXCL13 neutralizing antibody or isotype IgG by intraperitoneal injection everyday for six weeks, and renal damage of each group was determined. Our results showed that the blockade of CXCL13 significantly reduced urine protein, serum creatinine, and dramatically attenuated renal pathology injury. Treatment with anti-CXCL13Ab also reduced serum anti-dsDNA level, renal immune complex deposition as well as inflammatory cytokines secretion. Meanwhile, Th17/Treg ratio in spleens of MRL/lpr mice was significantly decreased by the blocking of CXCL13. These findings suggested that CXCL13 may be a promising target for the therapy of LN.

Ginsenoside Rg3 antagonizes adriamycin-induced cardiotoxicity by improving endothelial dysfunction from oxidative stress via upregulating the Nrf2-ARE pathway through the activation of akt.

BACKGROUND: Adriamycin (ADM) is an antineoplastic agent that is effective against a wide range of cancers, but cardiac toxicity limits its clinical application. Ginsenoside Rg3 (Rg3), an anti-cancer active ingredient of Panax ginseng, was reported to have anti-oxidative, anti-apoptotic, and cardioprotective properties. PURPOSE: The current study aimed to investigate the possible protective effect of Rg3 against ADM-induced cardiotoxicity. STUDY DESIGN: The activity of Rg3 to improve endothelial dysfunction was processed both in vivo and in vitro. METHODS: We investigated the cardioprotective effect of Rg3 on ADM treated rats by echocardiography. The endothelial dysfunction was assessed using an aortic ring assay. Cardiac microvascular endothelial cells were cultured to investigate the effects of Rg3 on ADM-treated cells. RESULTS: Results showed that Rg3 could ameliorate the decrease in the ejection fraction and fractional shortening that was induced by ADM, and improve the left ventricular outflow. The aortic ring assay showed that Rg3 could partially recover the abnormal vascular function. In vitro studies showed that Rg3 could promote cell viability to attenuate ADM induced oxidative damage and apoptosis. This counteraction was achieved partially via activation of the Nrf2-ARE pathway through the activation of Akt. CONCLUSION: These findings elucidated the potential of Rg3 as a promising reagent for treating ADM-induced cardiotoxicity in clinic.