Nephrotoxicity assessment of podophyllotoxin-induced rats by regulating PI3K/Akt/mTOR-Nrf2/HO1 pathway in view of toxicological evidence chain (TEC) concept.

Adverse reactions to traditional Chinese medicine have hindered the healthy development and internationalization process of the traditional Chinese medicine industry. The critical issue that needs to be solved urgently is to evaluate the safety of traditional Chinese medicine systematically and effectively. Podophyllotoxin (PPT) is a highly active compound extracted from plants of the genus Podophyllum such as Dysosma versipellis (DV). However, its high toxicity and toxicity to multiple target organs affect the clinical application, such as the liver and kidney. Based on the concurrent effects of PPT's medicinal activity and toxicity, it would be a good example to conduct a systematic review of its safety. Therefore, this study revolves around the Toxicological Evidence Chain (TEC) concept. Based on PPT as the main toxic constituent in DV, observe the objective toxicity impairment phenotype of animals. Evaluate the serum biochemical indicators and pathological tissue sections for substantial toxic damage results. Using metabolomics, lipidomics, and network toxicology to evaluate the nephrotoxicity of PPT from multiple perspectives systematically. The results showed that PPT-induced nephrotoxicity manifested as renal tubular damage, mainly affecting metabolic pathways such as glycerophospholipid metabolism and sphingolipid metabolism. PPT inhibits the autophagy process of kidney cells through the PI3K/Akt/mTOR and Nrf2/HO1 pathways and induces the activation of oxidative stress in the body, thereby causing nephrotoxic injury. This study fully verified the feasibility of the TEC concept for the safety and toxicity evaluation of traditional Chinese medicine. Provide a research template for systematically evaluating the safety of traditional Chinese medicine.

Association Between Methylmalonic Acid and Cognition: A Systematic Review and Meta-Analysis.

Background: Methylmalonic acid (MMA) is an intermediate metabolite of human body. The content of MMA in the blood of healthy people is very low, and its concentration will increase in some diseases and elderly people. Recent studies have shown that MMA has a variety of biological functions. The correlation between MMA and cognition, one of the important functions of the nervous system, is still uncertain. Objective: Meta-analyses were performed to assess whether elevated MMA was associated with the risk of cognitive decline. Materials and Methods: Cross-sectional studies, randomized controlled studies, and case-control studies on the relationship between MMA and cognition were obtained by searching PubMed, Web of Science, EMBASE, ProQuest, WANFANG MED ONLINE, China National Knowledge Infrastructure (CNKI) and Chongqing VIP until May 2022. Two researchers independently selected studies according to inclusion and exclusion criteria, evaluated study quality and extracted data. Meta-analyses were performed using Review Manager 5.4 software. The sensitivity analysis of meta-analysis was performed by One by one exclusion method. Results: A total of 11 studies were included, including six cross-sectional studies, two randomized controlled studies, and three case-control studies, with a sample of 16,533 subjects. Meta-analysis showed that there was no significant difference in cognitive level between high-level MMA subjects and low-level MMA subjects in the general population [SMD = -2.19, 95% CI (-4.76 ∼ 0.38), Z = 1.67, P = 0.09]. In the population supplemented with VitB12, the increase of MMA level caused by VitB12 supplementation was not related to the change of cognition [SMD = 0.32, 95% CI (-0.19 ∼ 0.84) z = 1.22, P = 0.22]. There was also no significant difference in MMA levels between patients with dementia and the control group [WMD = 20.89, 95% CI (-5.13 ∼ 46.92), z = 1.57, P = 0.12]. Conclusion: In the general population, whether VitB12 is supplemented or not, there is no correlation between the increase of MMA level and the decrease of cognitive level. In dementia diseases, the level of MMA did not change significantly. High levels of MMA may not be a risk factor for cognitive impairment. The exact relationship between MMA and cognition needs further research. Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021266310], identifier [CRD42021266310].

Electroacupuncture activates enteric glial cells and protects the gut barrier in hemorrhaged rats.

AIM: To investigate whether electroacupuncture ST36 activates enteric glial cells, and alleviates gut inflammation and barrier dysfunction following hemorrhagic shock. METHODS: Sprague-Dawley rats were subjected to approximately 45% total blood loss and randomly divided into seven groups: (1) sham: cannulation, but no hemorrhage; (2) subjected to hemorrhagic shock (HS); (3) electroacupuncture (EA) ST36 after hemorrhage; (4) vagotomy (VGX)/EA: VGX before hemorrhage, then EA ST36; (5) VGX: VGX before hemorrhage; (6) α-bungarotoxin (BGT)/EA: intraperitoneal injection of α-BGT before hemorrhage, then EA ST36; and (7) α-BGT group: α-BGT injection before hemorrhage. Morphological changes in enteric glial cells (EGCs) were observed by immunofluorescence, and glial fibrillary acidic protein (GFAP; a protein marker of enteric glial activation) was evaluated using reverse transcriptase polymerase chain reaction and western blot analysis. Intestinal cytokine levels, gut permeability to 4-kDa fluorescein isothiocyanate (FITC)-dextran, and the expression and distribution of tight junction protein zona occludens (ZO)-1 were also determined. RESULTS: EGCs were distorted following hemorrhage and showed morphological abnormalities. EA ST36 attenuated the morphological changes in EGCs at 6 h, as compared with the VGX, α-BGT and HS groups. EA ST36 increased GFAP expression to a greater degree than in the other groups. EA ST36 decreased intestinal permeability to FITC-dextran (760.5 ± 96.43 ng/mL vs 2466.7 ± 131.60 ng/mL, P < 0.05) and preserved ZO-1 protein expression and localization at 6 h after hemorrhage compared with the HS group. However, abdominal VGX and α-BGT treatment weakened or eliminated the effects of EA ST36. EA ST36 reduced tumor necrosis factor-α levels in intestinal homogenates after blood loss, while vagotomy or intraperitoneal injection of α-BGT before EA ST36 abolished its anti-inflammatory effects. CONCLUSION: EA ST36 attenuates hemorrhage-induced intestinal inflammatory insult, and protects the intestinal barrier integrity, partly via activation of EGCs.

Electroacupuncture at Zusanli (ST36) promotes gastric emptying and mucosal blood flow during oral resuscitation of scalded rats with a pyruvate-enriched ORS.

AIM: The aim of this study was to investigate the effect of electroacupuncture at ST36 (EA ST36) on gastric emptying and mucosal blood flow during intragastric resuscitation with pyruvate-enriched oral rehydration solution (Pyr-ORS) in scalded rats. METHODS: The rats were subjected to a 35% total body surface area (TBSA) of scald injury and randomly divided into five groups (N=24) and two subgroups (n=12) in each group. The Pyr-ORS was delivered intragastrically according to the Parkland formula immediately after scalding at a dose of 1 mL kg(-1) %TBSA(-1) in 1 h. In these animals, the bilateral Zusanli points (ST36) were electroacupunctured at a constant voltage (2 mA and 2-100 HZ) for 0.5 h immediately after intragastric resuscitation. At 2 and 4 h after scalding, the gastric emptying rate (GER) and gastric mucosal blood flow (GMBF) were determined, and the motilin levels of the plasma and gastric tissues were also analyzed at two time points, respectively. RESULTS: GER and GMBF were markedly decreased in groups with scalding and resuscitation, compared with the sham groups at two time points (P<0.05), but they were greatly improved in groups byEAST36 at 2 and 4 h after sustaining scald injuries (P<0.05). Bilateral vagotomy further aggravated the reduction of GER and GMBF in scalded rats. EA after gastric vagotomy failed to raise GER and GMBF. Neither EA nor vagotomy had effects on the reduced motilin levels of plasma and gastric tissues in animals after scalding. CONCLUSION: EA ST36 has a significant effect on improving gastric emptying and mucosal ischemia in the oral resuscitation of burn injury, possibly through the activation of a cholinergic nerve-dependent mechanism. In addition, EA ST36 showed no effects on motilin levels, but requires further investigations.