Naturally derived metabolites are valuable resources for drug research and development, and play an important role in the treatment of diseases. As the "second genome" of the body, gut microbiota is rich in metabolic enzymes, which interacts with external substances such as drugs, thus affecting the progression of diseases. This article summarizes the interaction between gut microbiota-producing enzymes and natural medicines, and focuses on the impact of this interaction on disease progression, hoping to provide new ideas for the development and pharmacological mechanism of natural medicines.

Gut microbiota is a complex and dynamic system, and is essential for the health of the body. As the "second genome" of the body, it can establish communication with the important organs by regulating intestinal nerves, gastrointestinal hormones, intestinal barrier, immunity and metabolism, thus affecting host′s physiological functions. Short chain fatty acid (SCFA), known as one important metabolite of intestinal microbiota, is regarded as a significant messenger of the gut-organ communication, due to its extensive regulation in the body′s immunity, metabolism, endocrine and signal transduction. In this review, we summarize the interaction between gut-liver/brain/kidney/lung axis and diseases, and focus on the role and mechanism of SCFA in the gut-organ communication, hoping to provide new ideas for the treatment of the related diseases.

The purpose of this study was to investigate the effects of post-traumatic stress disorder (PTSD) on electrophysiological characteristics of glutamatergic and GABAergic neurons in dorsal hippocampus (dHPC) and ventral hippocampus (vHPC) in mice, and to elucidate the mechanisms underlying the plasticity of hippocampal neurons and memory regulation after PTSD. Male C57Thy1-YFP/GAD67-GFP mice were randomly divided into PTSD group and control group. Unavoidable foot shock (FS) was applied to establish PTSD model. The spatial learning ability was explored by water maze test, and the changes in electrophysiological characteristics of glutamatergic and GABAergic neurons in dHPC and vHPC were examined using whole-cell recording method. The results showed that FS significantly reduced the movement speed, and enhanced the number and percentage of freezing. PTSD significantly prolonged the escape latency in localization avoidance training, shortened the swimming time in the original quadrant, extended the swimming time in the contralateral quadrant, and increased absolute refractory period, energy barrier and inter-spike interval of glutamatergic neurons in dHPC and GABAergic neurons in vHPC, while decreased absolute refractory period, energy barrier and inter-spike interval of GABAergic neurons in dHPC and glutamatergic neurons in vHPC. These results suggest that PTSD can damage spatial perception of mice, down-regulate the excitability of dHPC and up-regulate the excitability of vHPC, and the underlying mechanism may involve the regulation of spatial memory by the plasticity of neurons in dHPC and vHPC.
Mice ; Male ; Animals ; Stress Disorders, Post-Traumatic ; Hippocampus ; Spatial Learning ; GABAergic Neurons

Humans ; Female ; Prevalence ; Breast Neoplasms ; Cancer Survivors ; Non-alcoholic Fatty Liver Disease ; Liver

The aim of this study was to investigate the efficacy and mechanism of Dengzhan Shengmai (DZSM) against nonalcoholic fatty liver diseases (NAFLD). The animal experiment program was reviewed and approved by the Ethics Committee of Institute of Materia Medica, Chinese Academy of Medical Sciences. The NAFLD model of Syrian golden hamsters was established by high fat diets. After 6 weeks of DZSM treatment, the serum lipid, hepatic lipid accumulation, liver function and inflammatory response were determined. The regulations of gut microbiota and short-chain fatty acids were detected by 16S rRNA gene sequencing and gas chromatography-mass spectrometry method, respectively. The gut barrier function was evaluated by enzyme linked immunosorbent assay (ELISA), reverse transcription-quantitative polymerase chain reaction (RT-qPCR), Western blot and histopathological methods and further verified in HepG2 cells. The results showed that the efficacy of DZSM against NAFLD was remarkably reduced after removal of the gut microbiota. The study of mechanism showed that DZSM significantly regulated the composition of gut microbiota, promoted the production and absorption of intestinal short-chain fatty acids, then leading to the reduction of hepatic lipid accumulation. Moreover, after DZSM treatment, the decreased lipopolysaccharide (LPS) level by improving the intestinal barrier function significantly inhibited the hepatic inflammation through down-regulating Toll like receptor 4 (TLR4)-nuclear factor kappa B (NFKB) signaling pathway. These results indicate that DZSM inhibits NAFLD via regulating intestinal microenvironment.

Objective: To analyze the current adherence to imatinib in patients with gastrointestinal stromal tumors (GIST) in China and its influencing factors. Methods: A cross-sectional survey was conducted. Study period: from October 1, 2020 to November 31, 2020. Study subjects: GIST patients taking imatinib who were diagnosed and treated in public tertiary level A general hospitals or oncology hospitals; those who had not been pathologically diagnosed, those who never received imatinib, or those who had taken imatinib in the past but stopped afterwards were excluded. The Questionnaire Star online surgery platform was used to design a questionnaire about the adherence to adjuvant imatinib therapy of Chinese GIST patients. The link of questionnaire was sent through WeChat. The questionnaire contained basic information of patients, medication status and Morisky Medication Adherence Scale. Results: A total of 2162 questionnaires from 31 provinces, autonomous regions, and municipalities were collected, of which 2005 were valid questionnaires, with an effective rate of 92.7%. The survey subjects included 1104 males and 901 females, with a median age of 56 (22-91) years old. Working status: 609 cases (30.4%) in the work unit, 729 cases (36.4%) of retirement, 667 cases of flexible employment or unemployment (33.3%). Education level: 477 cases (23.8%) with bachelor degree or above, 658 cases (32.8%) of high school, 782 cases (39.0%) of elementary or junior high school, 88 cases (4.4%) without education. Marital status: 1789 cases (89.2%) were married, 179 cases (8.9%) divorced or widowed, 37 cases (1.8%) unmarried. Two hundred and ninety-four patients (14.7%) had metastasis when they were first diagnosed, including 203 liver metastases, 52 peritoneal metastases, and 39 other metastases. One thousand eight hundred and sixty-nine patients underwent surgical treatment, of whom 1642 (81.9%) achieved complete resection. The median time of taking imatinib was 25 (1-200) months. Common adverse reactions of imatinib included 1701 cases (84.8%) of periorbital edema, 1031 cases (51.4%) of leukopenia, 948 cases (47.3%) of fatigue, 781 cases (39.0%) of nausea and vomiting, 709 cases (35.4%) of rash, and 670 cases (33.4%) of lower extremity edema. The score of the Morisky Medication Adherence Scale showed that 392 cases (19.6%) had poor adherence, 1023 cases (51.0%) had moderate adherence, and 590 cases (29.4%) had good adherence. Univariate analysis showed that gender, age, work status, economic income, residence, education level, marriage, the duration of taking medication and adverse reactions were associated with adherence to adjuvant imatinib therapy (all P<0.05). Multivariate analysis showed that female (OR=1.264, P=0.009), non-retirement (OR=1.454, P=0.001), monthly income ≤4000 yuan (OR=1.280, P=0.036), township residents (OR=1.332, P=0.005), unmarried or divorced or widowed (OR=1.362, P=0.026), the duration of imatinib medication >36 months (OR=1.478, P<0.001) and adverse reactions (OR=1.719, P=0.048) were independent risk factors for poor adherence to adjuvant imatinib. Among patients undergoing complete resection, 324 (19.7%) had poor adherence, 836 (50.9%) had moderate adherence, and 482 (29.4%) had good adherence. Meanwhile, 55 patients with good adherence (11.4%) developed recurrence after surgery, 121 patients with moderate adherence (14.5%) developed recurrence, 61 patients with poor adherence (18.8%) developed recurrence, and the difference was statistically significant (P=0.017). Conclusions: The adherence to adjuvant therapy with imatinib in Chinese GIST patients is relatively poor. Females, non-retirement, monthly income ≤4000 yuan, township residents, unmarried or divorced or widowed, the duration of imatinib medication >36 months, and adverse reactions are independently associated with poor adherence of GIST patients. Those with poor adherence have a higher risk of recurrence after surgery. Positive interventions based on the above risk factors are advocated to improve the prognosis of patients with GIST.
Aged ; Aged, 80 and over ; Antineoplastic Agents/therapeutic use* ; Chemotherapy, Adjuvant ; Cross-Sectional Studies ; Female ; Gastrointestinal Stromal Tumors/drug therapy* ; Humans ; Imatinib Mesylate/therapeutic use* ; Male ; Middle Aged ; Neoplasm Recurrence, Local/drug therapy*

Animals ; Apoptosis ; Brain/metabolism* ; Male ; Phosphatidylinositol 3-Kinases/metabolism* ; Rats ; Rats, Sprague-Dawley ; Subarachnoid Hemorrhage/drug therapy* ; Thyroxine/pharmacology*

Objective: To explore the role and related mechanism of mammalian sterile 20-like kinase 1(Mst-1)in regulating hypoxia reoxygenation (HR) induced myocardial cell autophagy and apoptosis. Methods: Enzyme digestion method combined with differential adherent method was used to culture neonatal mouse myocardial cells. HR model was established by hypoxia for 24 hours and reoxygenation for 6 hours. The experimental groups including control group (normal cultured cardiomyocytes), Mst-1 empty virus group (cardiomyocytes transfected with recombinant lentiviral empty vector for 48 hours), Mst-1 knockdown group (recombinant lentivirus carrying Mst-1small interfering RNA (siRNA) was transfected into cardiomyocytes for 48 hours), Mst-1 overexpression group (cardiomyocytes were transfected with recombinant lentivirus carrying Mst-1 gene for 48 hours), HR group (cardiomyocytes exposed to HR), Mst-1 knockdown+HR group (HR model of cardiomyocyte was established 48 hours after transfection with recombinant lentivirus carrying Mst-1siRNA) and Mst-1 overexpression+HR group (HR model of cardiomyocyte was established 48 hours after transfection with recombinant lentivirus carrying Mst-1 gene). Real-time fluorescence quantitative RCR (qPCR) and Western blot were used to detect the relative expression of Mst-1 mRNA and protein in the cells, immunofluorescence staining was used to detect cardiomyocyte troponin T (cTnT), and autophagosomes and autophagy enzyme changes. TUNEL method was used to detect myocardial cell apoptosis, Western blot was adopted to detect autophagy-related protein microtubule-related protein 1 light chain 3 (LC3) Ⅱ/LC3 Ⅰ, P62 and apoptosis-related protein cleaved-caspase 9, pro-caspase 9, cleaved-caspase-3, pro-caspase-3, and myeloid leukemia 1 (MCL-1) expression. MCL-1 inhibitor A1210477 was used to validate the signaling pathway of Mst-1 on regulating cardiomyocyte apoptosis and autophagy. Results: Immunofluorescence detection revealed that the cultured cells expressed cardiomyocyte-specific marker cTnT. The expression of Mst-1 in cardiomyocytes increased in HR model. Lentiviral transfection could effectively inhibit or overexpress Mst-1 in treated cells. The levels of autophagosomes and autophagolysosomes in cardiomyocytes undergoing HR and in Mst-1 overexpression+HR group were lower than those of control group, while autophagosomes and autophagolysosomes in cardiomyocytes of Mst-1 knockdown+HR group was significantly higher than in the HR group (all P<0.05). The TUNEL results showed that the proportion of TUNEL positive cells was significantly increased in the HR group and Mst-1 overexpression+HR group than in the control group, while the proportion of TUNEL positive cells was significantly decreased in the Mst-1 knockdown group+HR group as compared to the HR group (all P<0.05). Western blot results showed that the LC3 Ⅱ/LC3 Ⅰ levels were significantly lower, while the expression levels of P62, cleaved-caspase-9 and cleaved-caspase-3 were significantly higher in the HR group and Mst-1 overexpression+HR group than in control group (all P<0.05). The LC3 Ⅱ/LC3 Ⅰ value was significantly higher, and the expression levels of P62, cleaved-caspase-9 and cleaved-caspase-3 were significantly lower in the Mst-1 knockdown+HR group than in the HR group (P both<0.05). The expression level of P-MCL-1 protein was significantly lower in cardiomyocytes of HR and Mst-1 overexpression+HR group than in control group, and the expression level of P-MCL-1 protein was higher in Mst-1 knockdown+HR group than in HR group (P both<0.05). The recovery experiment showed that inhibiting MCL-1 in cells can block the regulatory effect of Mst-1 siRNA on cell autophagy and apoptosis. Conclusion: Inhibiting Mst-1 expression in cardiomyocytes can promote the autophagy of cardiomyocytes induced by hypoxic reoxygenation and reduce the apoptosis of cardiomyocytes via activating McL-1.
Animals ; Apoptosis ; Autophagy ; Hypoxia ; Mice ; Myocytes, Cardiac ; Signal Transduction

BACKGROUND: Positive surgical margins are independent risk factor for biochemical recurrence, local recurrence, and distant metastasis after radical prostatectomy. However, limited predictive tools are available. This study aimed to develop and validate a preoperative nomogram for predicting positive surgical margins after laparoscopic radical prostatectomy (LRP). METHODS: From January 2010 to March 2016, a total of 418 patients who underwent LRP without receiving neoadjuvant therapy at Peking University Third Hospital were retrospectively involved in this study. Clinical and pathological results of each patient were collected for further analysis. Univariable and multivariable logistic regression (backward stepwise method) were used for the nomogram development. The concordance index (CI), calibration curve analysis and decision curve analysis were used to evaluate the performance of our model. RESULTS: Of 418 patients involved in this study, 142 patients (34.0%) had a positive surgical margin on final pathology. Based on the backward selection, four variables were included in the final multivariable regression model, including the percentage of positive cores in preoperative biopsy, clinical stage, free prostate specific antigen (fPSA)/total PSA (tPSA), and age. A nomogram was developed using these four variables. The concordance index (C-index) of the nomogram was 0.722 in the development cohort and 0.700 in the bootstrap validations. The bias-corrected calibration plot showed a limited departure from the ideal line with a mean absolute error of 2.0%. In decision curve analyses, the nomogram showed net benefits in the range from 0.2 to 0.7. CONCLUSION A nomogram to predict positive surgical margins after LRP was developed and validated, which could help urologists plan surgical procedures.
Aged ; Humans ; Laparoscopy ; methods ; Male ; Margins of Excision ; Middle Aged ; Nomograms ; Prostatectomy ; methods ; Prostatic Neoplasms ; surgery ; ROC Curve ; Retrospective Studies

BACKGROUNDPlasmacytoid dendritic cells (pDCs) and cytokines play an important role in occurrence and recovery of hepatitis B virus (HBV) infection. The aim of this study was to explore the frequency and function of pDC and serum cytokine network profiles in patients with acute or chronic HBV infection.

METHODSThe healthy individuals (HI group), hepatitis B envelope antigen (HBeAg)-positive chronic HBV patients in immune tolerance (IT) phase (IT group), HBeAg-positive chronic HBV patients (CHB group), and acute HBV patients (AHB group) were enrolled in this study. The frequency of cluster of differentiation antigen 86 (CD86) + pDC and the counts of CD86 molecular expressed on surface of pDC were tested by flow cytometer. The quantitative determinations of cytokines, including Fms-like tyrosine kinase 3 ligand (Flt-3L), interferon (IFN)-α2, IFN-γ, interleukin (IL)-17A, IL-6, IL-10, transforming growth factor (TGF)-β1 and TGF-β2, were performed using Luminex multiplex technology.

RESULTSIn this study, there were 13 patients in HI group, 30 in IT group, 50 in CHB group, and 32 in AHB group. Compared with HI group, HBV infected group (including all patients in IT, CHB and AHB groups) had significantly higher counts of CD86 molecular expressed on the surface of pDC (4596.5 ± 896.5 vs. 7097.7 ± 3124.6; P < 0.001). The counts of CD86 molecular expressed on the surface of pDC in CHB group (7739.2 ± 4125.4) was significantly higher than that of IT group (6393.4 ± 1653.6, P = 0.043). Compared with IT group, the profile of cytokines of Flt-3L, IFN-γ, and IL-17A was decreased, IFN-α2 was significantly increased (P = 0.012) in CHB group. The contents of IL-10, TGF-β1, and TGF-β2 in AHB group were significantly increased compared with IT and CHB groups (all P < 0.05).

CONCLUSIONSThis study demonstrated that the function of pDC was unaffected in HBV infection. The enhanced function of pDC and IFN-α2 might involve triggering the immune response from IT to hepatitis active phase in HBV infection. Acute patients mainly presented as down-regulation of the immune response by enhanced IL-10 and TGF-β.