Mulberrin alleviates triclocarban induced hepatic apoptosis and inflammation by regulating the ROS/NF-κB pathway in grass carp.

Triclocarban (TCC) is commonly used in household, personal care and industrial products and has been frequently detected in different aquatic ecosystems. Mulberrin (Mul) is a key component of the traditional Chinese medicine Romulus Mori with antioxidant and anti-inflammatory properties. The present study aimed to investigate the hepatotoxic effects of TCC in aquatic organisms and explore the protective roles of Mul. Herein, we found that exposure to TCC at environmentally realistic concentrations (5 µg/L) could impair liver function, along with impaired antioxidant defense and infiltration of inflammatory cells. Additionally, we found that TCC increased the ratio of TUNEL staining positive cells, accompanied by upregulation of pro-apoptotic protein (Bax, caspase3 and caspase9), and downregulation of anti-apoptotic proteins (Bcl2). In contrast, Mul supplementation reversed the hepatic pathological damage, ROS elevation, and apoptosis induced by TCC, likely due to hyperactivation of nuclear factor erythroid 2-related factor 2 (Nrf2) signaling. Additionally, Mul supplementation suppressed the mRNA levels of proinflammatory factors (TNF-α, IL-1ß, IFN-γ, IL-6 and IL-8) and enhanced the mRNA levels of anti-inflammatory factors (TGFß1, TGFß2, IL4, IL10 and IL11) in the liver of carp. We also discovered that Mul supplementation suppressed TCC-induced nuclear nuclear factor κB (NF-κB) elevation. In conclusion, Mul enhances Nrf2 signaling cascades and counteracts the NF-κB inflammatory program to rescue hepatotoxicity induced by TCC, providing new insights into the hepatotoxic effects of TCC and potential protection strategies for heart injury induced by TCC.

Integration of non-targeted metabolomics with network pharmacology deciphers the anxiolytic mechanisms of Platycladi Semen extracts in CUMS mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Platycladi Semen was recorded in Shen Nong's Herbal Classic and was considered a herbal medicine with low toxicity after long-term medication. Multiple traditional Chinese medicine prescriptions containing Platycladi Semen have been used to treat insomnia. Modern clinical practitioners commonly use Platycladi Semen to treat anxiety disorders, but there are few studies on its composition and anxiolytic mechanisms. AIM OF THE STUDY: To describe the main components of Platycladi Semen and investigate its anxiolytic effects and mechanisms. MATERIALS AND METHODS: The main components of Platycladi Semen were characterized by liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS). The anxiolytic effects of oral Platycladi Semen were evaluated in chronic unpredictable mild stress (CUMS) induced mice. To explore the anxiolytic mechanisms of Platycladi Semen, serum non-targeted metabolomics combined with network pharmacology and molecular docking was performed. RESULTS: Fourteen compounds were identified in the 50% methanol extract and 11 fatty acid derivatives were identified in the methyl-esterified fatty oil of Platycladi Semen. In CUMS mice, both the aqueous extract and fatty oil of Platycladi Semen had anxiolytic effects, which were shown by the increase in the time and frequency of mice entering the open arm in the elevated plus maze (EPM) experiment. Through serum non-targeted metabolomics, 34 differential metabolites were identified, and lipid metabolic pathways such as sphingolipid metabolism, steroidogenesis, alpha-linoleic acid, and linoleic acid metabolism were enriched. Through network pharmacology, 109 targets of the main components in Platycladi Semen were identified, and the 'neuroactive ligand-receptor interaction' and 'lipid metabolism' were enriched. The molecular docking results showed that the main components in Platycladi Semen could bind to the key targets such as peroxisome proliferator-activated receptor delta (PPARD), peroxisome proliferator-activated receptor alpha (PPARA), fatty acid binding protein 5 (FABP5), fatty acid binding protein 3 (FABP3), peroxisome proliferator-activated receptor gamma (PPARG), arachidonate 5-lipoxygenase (ALOX5) and fatty acid amide hydrolase (FAAH). CONCLUSION: This study indicated that Platycladi Semen has anxiolytic effects, and the anxiolytic mechanisms may be the regulation of lipid metabolism and the neuroactive ligand-receptor interaction.

Sarco/endoplasmic reticulum Ca2+ ATPase (SERCA)-mediated ER stress crosstalk with autophagy is involved in tris(2-chloroethyl) phosphate stress-induced cardiac fibrosis.

Excessive organophosphate flame retardant (OPFR) use in consumer products has been reported to increase human disease susceptibility. However, the adverse effects of tris(2-chloroethyl) phosphate (TCEP) (a chlorinated alkyl OPFR) on the heart remain unknown. In this study, we tested whether cardiac fibrosis occurred in animal models of TCEP (10 mg/kg b.w./day) administered continuously by gavage for 30 days and evaluated the specific role of sarco/endoplasmic reticulum Ca2+ ATPase (SERCA). First, we confirmed that TCEP could trigger cardiac fibrosis by histopathological observation and cardiac fibrosis markers. We further verified that cardiac fibrosis occurred in animal models of TCEP exposure accompanied by SERCA2a, SERCA2b and SERCA2c downregulation. Notably, inductively coupled plasma-mass spectrometry (ICP-MS) analysis revealed that the cardiac concentrations of Ca2+ increased by 45.3% after TCEP exposure. Using 4-Isopropoxy-N-(2-methylquinolin-8-yl)benzamide (CDN1163, a small molecule SERCA activator), we observed that Ca2+ overload and subsequent cardiac fibrosis caused by TCEP were both alleviated. Simultaneously, the protein levels of endoplasmic reticulum (ER) markers (protein kinase R-like endoplasmic reticulum kinase (PERK), inositol requiring protein 1α (IRE1α), eukaryotic initiation factor 2 α (eIF2α)) were upregulated by TCEP, which could be abrogated by CDN1163 pretreatment. Furthermore, we observed that CDN1163 supplementation prevented overactive autophagy induced by TCEP in the heart. Mechanistically, TCEP could lead to Ca2+ overload by inhibiting the expression of SERCA, thereby triggering ER stress and overactive autophagy, eventually resulting in cardiac fibrosis. Together, our results suggest that the Ca2+ overload/ER stress/autophagy axis can act as a driver of cardiotoxicity induced by TCEP.

Anxiolytic effects, metabolism and plasma pharmacokinetics of 3, 6' -disinapoylsucrose.

3,6'-disinapoylsucrose (DISS) is a bioactive oligosaccharide ester derived from Polygalae Radix. This study aims to explore the anxiolytic effects of DISS and further reveal the material basis by establishing the pharmacokinetics of DISS and its metabolites. Behavioral experiments such as the open field test (OFT) and elevated plus maze test (EPM) were performed to evaluate the anxiolytic effects of DISS in mice after oral administration. By UPLC-MS/MS analysis, DISS and its metabolites both in blood and cerebrospinal fluid were identified, and the pharmacokinetics of DISS and its metabolites were characterized in SD rats after oral administration of DISS (100 mg·kg-1). Oral DISS could increase the time and frequency of mice entering the central area of the field in OFT and open arm in EPM, which indicated DISS has good anxiolytic effects. We also identified DISS and its metabolites (sinapic acid (SA), 3,4,5-trimethoxycinnamic acid (TMCA), methyl-3,4,5-trimethoxycinnamate (TMCA-CH2), p-Coumaric acid (CA) and p-methoxycinnamic acid (MA)) in rat plasma and cerebrospinal fluid. The pharmacokinetic results showed that DISS was rapidly absorbed after administration and reached its highest concentration at 12 min, SA had the highest exposure level in vivo and was probably the main active form of DISS action, TMCA could maintain at a low concentration for a long time. In brief, we reported the anxiolytic effect of DISS firstly, revealed the cerebrospinal fluid distribution and pharmacokinetics of DISS and its metabolites. Our findings provide the basis for further insight into the mechanisms involved in the anxiolytic effects of DISS.

Clinical significance of CEA mRNA expression in peritoneal lavage fluid for patients with gastric cancer after radical surgery / 中国肿瘤生物治疗杂志

@#[Abstract] Objective: To investigate the expression and clinical significance of CEAmRNAin peritoneal lavage fluid for patients with gastric cancer after radical surgery. Methods: The clinical data of 139 gastric cancer patients, who underwent peritoneal lavage CEA mRNA detection after radical resection in the Comprehensive Cancer Centre of Drum Tower Hospital from January 2013 to December 2017 were retrospectively analyzed. Routine post-operative follow-up was conducted in all patients. The expression of CEA mRNA in peritoneal lavage fluid after radical resection of 139 gastric cancer patients was detected by RT-PCR. Chi-square test analysis was used to study the relationship between the expression of CEA mRNA in peritoneal lavage fluid and basic clinical features, histopathological data, hematological indicators and the recurrence pattern of GC patients. Logistic univariate and multivariate regression analyses were used to screen the influential factors affecting CEA mRNA expression. Results: CEA mRNA was positive in 44 (31.7%) of 139 patients. Analysis showed that there was no significant correlation between CEA mRNA expression and sex, age, pathological grade, Lauren type, HER2, EGFR, VEGFR and Ki67 (all P>0.05), but there was significant correlation between CEA mRNA expression and pathological type, vascular invasion, local invasion depth, lymph node metastasis and clinical AJCC stage (all P<0.05). The peritoneal recurrence rate of patients with positive CEA mRNA expression was significantly higher than that of patients with negative expression (P=0.012). Logistic univariate regression analysis showed that signet ring cell carcinoma (P=0.04, HR=2.810， 95% CI: 1.050-7.520), T stage (P=0.016，HR=6.329, 95% CI: 1.417-28.264), N stage (P=0.022，HR=3.068，95% CI: 1.172-8.027), AJCC stage (P=0.016，HR= 3.971, 95% CI: 1.295-12.173), nerve invasion (P=0.002, HR=6.738, 95% CI: 1.995-22.757) and vascular invasion (P<0.001, HR= 16.36, 95% CI: 3.85-69.512) were risk factors for positive CEA mRNA expression in peritoneal lavage fluid of patients with gastric cancer. Logistic multivariate regression analysis showed that vascular invasion (P<0.001, HR=21.314，95% CI: 4.21-107.907) was an independent risk factor for positive CEAexpression in peritoneal lavage fluid of gastric cancer patients. Conclusion: Gastric cancer patients with positive CEA mRNA in peritoneal lavage fluid have higher risk of peritoneal recurrence or metastasis and poorer prognosis. So, more aggressive anti-tumor treatments including local abdominal cavity treatment should be considered.