Search

The effect of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47), a persistent environmental pollutant commonly used as a flame retardant in various consumer products, on pancreatitis has not been clearly elucidated, although it has been reported to be toxic to the liver, nervous system, and reproductive system. Acute pancreatitis (AP) and chronic pancreatitis (CP) models were induced in this study by intraperitoneal injection of caerulein. The aim was to investigate the impact of BDE-47 on pancreatitis by exposing the animals to acute (1 week) or chronic (8 weeks) doses of BDE-47 (30 mg/kg in the low-concentration group and 100 mg/kg in the high-concentration group). Additionally, BDE-47 was utilized to stimulate mouse bone marrow-derived macrophages, pancreatic primary stellate cells, and acinar cells in order to investigate the impact of BDE-47 on pancreatitis. In vivo experiments conducted on mice revealed that chronic exposure to BDE-47, rather than acute exposure, exacerbated the histopathological damage of AP and CP, leading to elevated fibrosis in pancreatic tissue and increased infiltration of inflammatory cells in the pancreas. In vitro experiments showed that BDE-47 can promote the expression of the inflammatory cytokines Tnf-α and Il-6 in M1 macrophages, as well as promote acinar cell apoptosis through the activation of the PERK and JNK pathways via endoplasmic reticulum stress. The findings of this study imply chronic exposure to BDE-47 may exacerbate the progression of both AP and CP by inducing acinar cell apoptosis and dysregulating inflammatory responses., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Methylglyoxal (MGO), a cytotoxic byproduct of glycolysis in biological systems, can induce endothelial cells dysfunction, implicated in diabetic vascular complications. Pterostilbene (PTS), a naturally occurring resveratrol derivative, is involved in various pharmacological activities. This study aimed to explore the effects of PTS on MGO induced cytotoxicity in human umbilical vein endothelial cells (HUVECs) and the underlying mechanisms for the first time. In the current study, it has been demonstrated that PTS could enhance the level of glyoxalase 1 (GLO-1) and elevate glutathione (GSH) content to active the glyoxalase system, resulting in elimination of the toxic MGO as well as advanced glycation end products (AGEs) in HUVECs. Meanwhile, PTS could also suppress oxidative stress and thus exert cytoprotective effects by elevating Nrf2 nuclear translocation and the corresponding down-stream antioxidant enzymes in MGO induced HUVECs. In addition, PTS could alleviate MGO induced apoptosis in HUVECs via inhibition of oxidative stress and associated downstream mitochondria-dependent signaling apoptotic cascades, as characterized by preventing caspases family activation. Taken together, these findings suggest that PTS could protect against MGO induced endothelial cell cytotoxicity by regulating glyoxalase, oxidative stress and apoptosis, suggesting that PTS could be beneficial in the treatment of diabetic vascular complications., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Phorbol esters and their derivatives, such as TPA, have been reported as potential natural antitumor products, with some derivatives entering clinical research for leukemia treatment. In this study, 16 phorbol derivatives were synthesized from phorbol, and their anti-leukemia activity against Jurkat, HL-60, and K562 were tested. The results showed that several derivatives had anti-leukemia activity, with 5B demonstrating the strongest cytotoxic activity against the K562 cell line (IC50 = 0.24 ± 0.04 μM). Based on the IC50 values, a structure-activity relationship was established. When the substituent contained an aromatic group, phorbol derivatives esterified with long-chain organic acids at three reactive hydroxyl groups (C12-OH, C13-OH, and C20-OH) had better activity. When aryl groups were absent from the substituent groups, phorbol derivatives esterified with short-chain organic acids at two hydroxyl groups had better activity. Derivatives esterified with heterocyclic acids, either tri-substituted or di-substituted, showed a significant decrease in cytotoxicity. The mechanism of anti-leukemia activity was explored through flow cytometry, which indicated that phorbol esters inhibited the growth of leukemia cells by inducing apoptosis, leading to cell death. Molecular docking data of compound 5B docking to PKC δ C1B suggested that substituent groups should not be too large, and caution should be taken when substituting C20-OH. Overall, these findings provide valuable insights into the design of more effective phorbol esters as anti-leukemia agents, but further research is needed to confirm their safety and efficacy in clinical settings. [ABSTRACT FROM AUTHOR]

• BMSC-Exos can protect neurons from excitotoxicity induced by glutamate. • The neuroprotective effect of BMSC-Exos is achieved by alleviating neuronal apoptosis. • BMSC-Exos alleviate neuronal apoptosis via PI3K/Akt/mTOR signaling. Many central nervous system diseases are closely related to nerve damage caused by dysregulation of the endogenous neurotransmitter glutamate. Exosomes derived from bone marrow mesenchymal stem cells (BMSC-Exos) play an important role in improving injury and regeneration functions. However, its mechanism remains unknown. Therefore, the aim of this study is to investigate whether and how BMSC-Exos improve neurotoxicity caused by glutamate and to fill the gap in the literature. In this study, glutamate-treated HT22 cells were first exposed to mouse-derived BMSC-Exos at different concentrations to observe their effects on HT22 apoptosis. Next, we treated glutamate-treated HT22 cells with mouse-derived BMSC-Exos. We then inhibited the PI3K/Akt/mTOR signaling pathways using the PI3K/Akt inhibitor and the mTOR inhibitor, respectively, and observed the protective effect of mouse-derived BMSC-Exos on HT22 cells treated with glutamate. Our results show that BMSC-Exos reduced apoptosis triggered by glutamate stimulation, increased cell vitality, and decreased the levels of proapoptotic proteins while increasing the levels of anti-apoptotic proteins. The protective effect of BMSC-Exos was weakened when PI3K/Akt inhibitor and mTOR inhibitor were added. To sum up, we draw the following conclusions: BMSC-Exos can reduce neuronal apoptosis and apoptosis-related protein expression after glutamate stimulation by regulating the PI3K/Akt/mTOR signaling pathway. [ABSTRACT FROM AUTHOR]

Poria cocos polysaccharides (PCP) are abundant in Poria cocos (Schw.) Wolf (Poria). This is a common traditional Chinese medicine used to treat gastrointestinal and liver diseases. Poria cocos dispel dampness and enhance gastrointestinal functions, strongly affecting the treatment of non-alcoholic fatty liver disease. Still, the mechanism is not yet clear. The latest research found that protecting the integrity of the intestinal barrier can slow down the progression of non-alcoholic fatty liver disease (NAFLD). Hence, our research ought to explore the protective mechanism of PCP on the intestinal barrier under a high-fat diet and to clarify the relationship between intestinal barrier damage and steatohepatitis. H&E staining was done to evaluate pathological damage, whereas Nile red and oil red O staining was conducted to evaluate hepatic fat infiltration. Immunofluorescence staining and immunohistochemical staining were used to detect protein expression and locations. Bone marrow-derived macrophages were isolated for in vitro experiments. ONOO- and ROS fluorescent probes and MDA, SOD, and GSH kits assessed the levels of nitrogen and oxidative stress. LPS levels were detected with a Limulus Amebocyte Lysate assay. The Western blot analysis and reverse transcription-quantitative PCR detected the expression of related proteins and genes. The Elisa kit detected the level of the inflammatory factors in the cell supernatant. For the vivo NAFLD experiments, in briefly, mice were randomly chosen to receive either a High-fat diet or control diet for 12 weeks. Drug treatments started after 4 weeks of feeding. Zebrafish larvae were raised separately in fish water or 7 mM thioacetamide as the control or model group for approximately 72 h. In the therapy groups, different concentrations of PCP were added to the culture environment at the same time. In zebrafish, we determined the safe concentration of PCP and found that PCP could effectively reduce the pathological damage in the liver and intestines induced by the NAFLD model. In mice, PCP could slow down weight gain, hyperlipidemia, and liver steatosis caused by a high-fat diet. More importantly, PCP could reduce the destruction of the gut-vascular barrier and the translocation of endotoxins caused by a high-fat diet. Further, we found that PCP could inhibit intestinal pyroptosis by regulating PARP-1. Pyroptosis inhibitors, such as MCC950, could effectively protect the intestinal and liver damage induced by a high-fat diet. We also found that pyroptosis mainly occurred in intestinal macrophages. PCP could effectively improve the survival rate of bone marrow-derived macrophages in a high-fat environment and inhibit pyroptosis. These results indicated that PCP inhibited the pyroptosis of small intestinal macrophages to protect the intestinal barrier integrity under a high-fat diet. This resulted in decreased endotoxin translocation and progression of steatohepatitis. [Display omitted] • The therapeutic effect of Poria cocos polysaccharides on NAFLD was demonstrated from the gut-liver axis. • High-Fat Diet aggravates the gut vascular barrier disruption via macrophages-pyroptosis in NAFLD. • Poria cocos polysaccharides inhibited NLRP3-mediated pyroptosis to ameliorate small intestine barrier injury. [ABSTRACT FROM AUTHOR]