Zuojin pill improves chronic unpredictable stress-induced depression-like behavior and gastrointestinal dysfunction in mice via the theTPH2/5-HT pathway.

BACKGROUND: The complex bidirectional communication between the gastrointestinal tract and the brain is associated with mental disorders such as depression; serotonin, as a crucial neurotransmitter in the communication system between the central nervous system and the gastrointestinal tract, has effects on regulating gastrointestinal motility and sensation and improving psychosomatic status. Zuojin pill is used as a traditional Chinese medicine formula for the treatment of gastrointestinal disorders. This study explored the effects of Zuojin pill on the improvement of depression and gastrointestinal function in CUMS mice via TPH2 and its mechanism. PURPOSE: The aim of this study was to investigate whether Zuojin pill could improve depression and concomitant gastrointestinal dysfunction, and to reveal whether Zuojin pill could work through the regulation of the tryptophan hydroxylase 2 (TPH2) pathway. METHODS: The CUMS model was established to observe the effects of Zuojin pill on depression-like behavior and gastrointestinal function in mice. Nissler staining and HE staining were used to observe the structure of hippocampal neurons and intestinal mucosa respectively. 5-HT levels in serum, hippocampus, and intestinal tissues were measured by ELISA, and TPH2 expression in hippocampus and intestinal nerves was observed by WB and immunofluorescence. In order to investigate the protective effect and mechanism of Zuojin pill on PC12 cells, CORT used an in vitro model to produce PC12 cell damage. RESULTS: Our study showed that Zuojin pill ameliorated depression-like behavior and gastrointestinal dysfunction in CUMS mice, elevated BDNF, 5-HT, and TPH2 expression in the hippocampus, and restored the ratio of dopaminergic and GABAergic neurons between intestinal muscles. In vitro experiments showed that Zuojin pill exerted a protective effect on neurons by regulating TPH2 ubiquitination and thus inhibiting CORT-induced apoptosis of PC12 cells. CONCLUSION: Zuojin pill improves chronic unpredictable stress-induced depression-like behavior and gastrointestinal dysfunction in mice via the TPH2/5-HT pathway. Therefore, TPH2 may be a potential therapeutic target for depression with gastrointestinal dysfunction.

Zuojinwan ameliorates CUMS-induced depressive-like behavior through inducing ubiquitination of MyD88 via SPOP/MyD88/NF-κB pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Zuojinwan (ZJW) is a traditional Chinese medicine compound, which is often used clinically to treat gastritis and has anti-inflammatory activity. It was found that ZJW is involved in suppressing the expression of inflammatory factors, and neuroinflammation is thought to be associated with the development of depression. AIM OF THE STUDY: In this study, we investigated whether ZJW could exert antidepressant effects by regulating MyD88 ubiquitination in depressed mice and attempted to elucidate the possible mechanisms. MATERIALS AND METHODS: Six active compounds of Zuojinwan (ZJW) were identified by HPLC. Then, the effects of ZJW on depression-like behavior in mice were investigated by constructing a chronic unpredictable mild stimulation (CUMS) mouse model. Meanwhile, the effect of ZJW on hippocampal neurons was investigated by Nissl staining. In addition, western blotting, PCR, ELISA, co-immunoprecipitation and immunostaining were used to explore whether ZJW could inhibit neuroinflammation through SPOP/MyD88/NF-κB pathway and thus produce antidepressant effects. Finally, we constructed the AAV-Sh-SPOP virus vector to silence SPOP and verify the mechanism of ZJW's antidepressant action. RESULTS: ZJW could dramatically ameliorate the depressive behavior induced by CUMS stimulation and alleviate hippocampal neuronal damage. CUMS stimulation resulted in decreased SPOP expression, impaired MyD88 ubiquitination, and activation of downstream NF-κB signaling, which could be reversed by ZJW. In addition, ZJW could significantly ameliorate the abnormal activation of microglia, and the excessive levels of pro-inflammatory factors were inhibited. By blocking the expression of SPOP, we found that ZJW exerted anti-inflammatory and antidepressant effects mainly by promoting the ubiquitination of MyD88 and inhibiting the activation of downstream inflammatory signals. CONCLUSION: In conclusion, ZJW possesses alleviating effects on depression induced by CUMS stimulation. ZJW can inhibit neuroinflammation and improve neuroinflammation-induced depression-like behaviors through SPOP/MyD88/NF-κB pathway.

Effects of Jianpi Lishi Jiedu granules on colorectal adenoma patients after endoscopic treatment: study protocol for a randomized, double-blinded, placebo-controlled clinical trial.

BACKGROUND: Colorectal adenomas (CRAs) are precancerous lesions of the large intestine presenting as colorectal polyps. At present, the conventional treatment methods for CRA mainly include high-frequency electrocoagulation and electroexcision, biopsy forceps polypectomy, cauterization by laser and microwave, and other endoscopic interventions. The principal advantages conferred by these treatment strategies include less trauma, quick postoperative recovery, and simplicity to perform. However, the higher recurrence rates and insignificant improvement of postoperative symptoms after endoscopic surgery are considerable drawbacks to this approach. Besides, there is currently no effective pharmacotherapy to prevent the recurrence of CRA. Jianpi Lishi Jiedu (JLJ) granules are a form of traditional Chinese medicine (TCM) used to manage postoperative patients with CRA, which has shown a certain degree of efficacy in clinical practice. However, its effectiveness and safety profile have not been convincingly evaluated. The purpose of this study is to evaluate the clinical efficacy and safety profile of JLJ granules in the management of postoperative patients with CRA and to observe the recurrence rate of adenoma in these patients. METHODS: A randomized, double-blind, and placebo-controlled clinical trial is performed in this study. A total of 80 postoperative patients with CRA will be randomly classified into the Jianpi Lishi Jiedu granules group or the placebo control group. Patients in both groups shall receive 3 months of intervention, after which medical follow-up and safety evaluation will be performed for all of the patients. The primary outcome is the recurrence rate of adenomas within 12 months. The secondary outcomes are the cardinal TCM symptom scores, minor TCM symptom scores, Bristol Stool Scale, efficacy of TCM symptoms, safety indicators, and blinding assessment. DISCUSSION: In this study, the impact on the recurrence of adenomas and the efficacy and safety of JLJ granules in terms of improving the clinical symptoms of postoperative patients with CRA will be evaluated. TRIAL REGISTRATION: Trial registration Chinese Clinical Trial Registry ChiCTR 2100044297. Registered on March 16, 2021.

Cytotoxic effects of the biflavonoids isolated from Selaginella trichoclada on MCF-7 cells and its potential mechanism.

A new biflavonoid, (2''S)-6''-methyl-2'',3''-dihydroochnaflavone (1), along with two known ochnaflavones (2, 3), four known amentoflavones (4-7) and two known robustaflavones (8, 9) were obtained from the 70% EtOH extract of Selaginella trichoclada. The chemical structures of isolated compounds were elucidated by extensive spectroscopic analyses. Overall, compounds 1-9 displayed moderate cytotoxic effects against human breast cancer MCF-7 cell lines. Among them, compounds 2 and 8 exhibited relatively strong cytotoxic effects against MCF-7 cells with an IC50 value of 7.7 and 6.9 µΜ, respectively. The results of RNA-sequencing and KEGG functional enrichment analysis showed that 8 could induce ferroptosis in MCF-7 cells by down-regulating the expression of ferroptosis-related genes including ACSL4, NOXO1, NOXA1, ACSL5, STEAP3, LPCAT3, ATG7 and TP53. Then 8 could inhibit the expression of ACSL4 proteins through molecule docking analysis, which showed a strong interaction of - 11.89 Kcal/mol binding energy. Those results indicate that 8 could be chemotherapy agents to fight drug resistance in breast cancer by down-regulating the expression level of ACSL4 proteins via ferroptosis, which needs to be further certified in vitro.

Qi Ling decoction reduces gastric cancer cell metastasis by inhibiting MMP-9 through the PI3K/Akt signaling pathway.

OBJECTIVE: Traditional Chinese medicine has been increasingly used in the prevention and treatment of gastric cancer, especially in application of compound Chinese medicine. The aim of this study was to investigate the effect of Qi Ling decoction (QLD) on the invasion and metastasis of gastric cancer and its related signaling pathways at the cellular and molecular level in vitro, and explore the mechanism of QLD. METHODS: Scratch assay, transwell assay, and adhesion experiments were used to study the effects of QLD and its compounds on gastric cancer. Western blot was employed to detect expression of the PI3K/Akt pathway after administration of QLD. RESULTS: QLD can significantly inhibit the invasion, migration, and adhesion of gastric cancer cells in vitro. The main chemical components of QLD (diosgenin, catechins, and calycosin) can also inhibit the invasion, migration and adhesion of gastric cancer cells. Furthermore, QLD inhibits MMP-9 and affects gastric cancer cell metastasis through the PI3K/Akt pathway. CONCLUSION: QLD and its three main chemical components can inhibit the invasion, migration, and adhesion of gastric cancer cells, and the mechanism may be related to the PI3K/Akt pathway.

Effects of Zuojin pill on depressive behavior and gastrointestinal function in rats with chronic unpredictable mild stress: Role of the brain-gut axis.

ETHNOPHARMACOLOGICAL RELEVANCE: Zoujin pill (ZJP), a medication used to treat gastrointestinal disorders since the 15th Century in China, have been reported to exert anti-depressant effects in various models. STUDY AIM: To assess the effects of ZJP on gastrointestinal function and depressive behavior in rats under chronic unpredictable mild stress (CUMS), and to examine the underlying mechanisms related to brain-gut axis. METHODS: The rats suffered the stressor once daily for 5 weeks. ZJP (0.6 and 1.2 g/kg) and fluoxetine (15 mg/kg) as positive control were administered to the rats through gastric intubation once daily for 5 consecutive weeks. The anti-depression effects were compared by performing sucrose preference tests and open field tests. Gastrointestinal motility was investigated by determining the gastrointestinal transit rate and by electrogastrogram. The serum levels of the gastrointestinal hormone (GAS, MOT, VIP, SP), inflammatory cytokine (IL-1ß, IL-6; , TNFα) and glucagon-like peptide-1 (GLP-1) were assayed by enzyme-linked immunosorbent assay. For monoamine neurotransmitters (NE, 5-HT, DA), the levels were determined by high-performance liquid chromatography and electrochemical detection in conjunction, which was applied on the samples taken from the hypothalamus, hippocampus, and striatum. RESULTS: The depression-like symptoms among rats under CUMS were significantly relieved by ZJP administration (0.6 and 1.2 g/kg). Gastrointestinal motility was also improved by restoring gastric electrical rhythm and promoting gastrointestinal propulsion. The ZJP at 0.6 g/kg dosage obviously up-regulated 5-HT and DA levels in hippocampus. The ZJP at 1.2 g/kg dosage could increase 5-HT and DA levels in hypothalamus, striatum, and hippocampus, while down-regulated the NE level in hypothalamus and hippocampus. ZJP also reversed the alterations in serum gastrointestinal hormones. Furthermore, treatment with ZJP significantly reduced levels of IL-1ß, IL-6 and TNF-α and increased serum GLP-1 compared with the CUMS group. Fluoxetine also exerted similar anti-depressant effects in the absence of effects on gastrointestinal motility and the levels of serum hormone, inflammatory cytokine and GLP-1. CONCLUSION: ZJP imposed anti-depressant and gastrointestinal regulating functions in rats under CUMS, suggesting potential clinical application. .

Single-Center Analysis of the Potential Inappropriate Use of Intravenous Medications in Hospitalized Patients in China.

This study categorizes the types of inappropriate intravenous prescriptions in hospitalized patients in China. Prescription data from 2016 were retrospectively analyzed based on predefined categories of inappropriateness. Of the 123,521 patients included, 89.2% received intravenous medications, contributing to 80% of the patients' hospital medication costs. Of significant concern, antibiotics and traditional Chinese medicines were administered to 44.3% and 14.5% of hospitalized patients, respectively. Overall, 11.4% of all intravenous prescriptions were classified as inappropriate, with improper diluent and diluent volumes being the primary cause. A team-based collaborative approach is necessary to address this widespread issue in China.

Vitamin D protects against diabetic nephropathy: Evidence-based effectiveness and mechanism.

Vitamin D has been suggested to harbor multiple biological activities, among them the potential of vitamin D in the protection of diabetic nephropathy (DN) has attracted special attention. Both animal studies and clinical trials have documented an inverse correlation between low vitamin D levels and DN risk, and supplementation with vitamin D or its active derivatives has been demonstrated to improve endothelial cell injury, reduce proteinuria, attenuate renal fibrosis, and resultantly retard DN progression. Vitamin D exerts its pharmacological effects primarily via vitamin D receptor, whose activation inhibits the renin-angiotensin system, a key culprit for DN under hyperglycemia. The anti-DN benefit of vitamin D can be enhanced when administrated in combination with angiotensin converting enzyme inhibitors or angiotensin II receptor blockers. Mechanistic studies reveal that pathways relevant to inflammation participate in the pathogenesis of DN, however, consumption of vitamin D-related products negatively regulates inflammatory response at multiple levels, indicated by inhibiting macrophage infiltration, nuclear factor-kappa B (NF-κB) activation, and production of such inflammatory mediators as transforming growth factor-ß(TGF-ß), monocyte chemoattractant protein 1(MCP-1), and regulated upon activation normal T cell expressed and secreted protein(RANTES). The robust anti-inflammatory property of vitamin D-related products allows them with a promising renoprotective therapeutic option for DN. This review summarizes new advances in our understanding of vitamin D-related products in the DN management.

Two natural products, trans-phytol and (22E)-ergosta-6,9,22-triene-3ß,5α,8α-triol, inhibit the biosynthesis of estrogen in human ovarian granulosa cells by aromatase (CYP19).

Aromatase is the only enzyme in vertebrates to catalyze the biosynthesis of estrogens. Although inhibitors of aromatase have been developed for the treatment of estrogen-dependent breast cancer, the whole-body inhibition of aromatase causes severe adverse effects. Thus, tissue-selective aromatase inhibitors are important for the treatment of estrogen-dependent cancers. In this study, 63 natural products with diverse structures were examined for their effects on estrogen biosynthesis in human ovarian granulosa-like KGN cells. Two compounds-trans-phytol (SA-20) and (22E)-ergosta-6,9,22-triene-3ß,5α,8α-triol (SA-48)-were found to potently inhibit estrogen biosynthesis (IC50: 1µM and 0.5µM, respectively). Both compounds decreased aromatase mRNA and protein expression levels in KGN cells, but had no effect on the aromatase catalytic activity in aromatase-overexpressing HEK293A cells and recombinant expressed aromatase. The two compounds decreased the expression of aromatase promoter I.3/II. Neither compound affected intracellular cyclic AMP (cAMP) levels, but they inhibited the phosphorylation or protein expression of cAMP response element-binding protein (CREB). The effects of these two compounds on extracellular regulated kinase (ERK), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinases (MAPKs), and AKT/phosphoinositide 3-kinase (PI3K) pathway were examined. Inhibition of p38 MAPK could be the mechanism underpinning the actions of these compounds. Our results suggests that natural products structurally similar to SA-20 and SA-48 may be a new source of tissue-selective aromatase modulators, and that p38 MAPK is important in the basal control of aromatase in ovarian granulosa cells. SA-20 and SA-48 warrant further investigation as new pharmaceutical tools for the prevention and treatment of estrogen-dependent cancers.

Fish oil-supplemented parenteral nutrition in patients following esophageal cancer surgery: effect on inflammation and immune function.

Our aim was to investigate whether adding ω-3 polyunsaturated fatty acids (PUFAs) to parenteral nutrition (PN) could reduce inflammation and improve immune function in patients following esophageal cancer surgery. In this pilot study, 60 patients with esophageal cancer were divided into 2 groups (30 patients in each group). All patients had total scores of more than or equal to 3 on the nutritional risk screening (NRS2002) test recommended by the European Society of Parenteral Enteral Nutrition, which showed that all patients had nutritional risk and should receive nutritional support. Both groups received isocaloric and isonitrogenous PN. One group received a ω-3 PUFAs supplement. Key indicators of inflammation [serum procalcitonin (PCT) level and the ratio of CD4(+) to CD8(+) (CD4(+)/CD8(+) ratio)] were determined intraoperatively and 24, 72, and 144 h postoperatively. PCT level was notably lower and CD4(+)/CD8(+) ratio was markedly higher in the ω-3 PUFAs group (P = 0.007 for PCT level and P = 0.012 for CD4(+)/CD8(+) ratio) on postoperative day 6 but not on postoperative days 1 and 3. ω-3 PUFAs supplemented PN can reduce inflammation and improve immune function in patients following esophageal cancer surgery. A larger trial is required to see whether ω-3 PUFAs supplementation of PN improves the clinical outcomes of patients following esophageal cancer surgery.