Cerebral ischemia is a series of harmful reactions, such as acute necrosis of tissue, inflammation, apoptosis, autophagy, and blood-brain barrier injury, due to the insufficient blood supply to the brain. Inflammatory response and gut microbiota imbalance are important concomitant factors of cerebral ischemia and may increase the severity of cerebral ischemia through the gut-brain axis. Qishiwei Zhenzhu pills (QSW) contain more than 70 kinds of medicinal materials, which have the effects of anti-cerebral infarction, anti-convulsion, anti-dementia, and so on. It is a treasure of Tibetan medicine commonly used in the treatment of cerebral ischemia in Tibetan areas. In this study, we gave rats QSW (66.68 mg/kg) once by gavage in advance and then immediately established the rat middle cerebral artery occlusion (MCAO) model. After 24 hours of treatment, the neuroprotection, intestinal pathology, and gut microbiota were examined. The results showed that QSW could significantly reduce the neurobehavioral abnormalities and cerebral infarction rate in MCAO rats. Furthermore, qPCR, western blot, and immunohistochemistry results showed that QSW could effectively inhibit IL-6, IL-1β, and other inflammatory factors so as to effectively reduce the inflammatory response of MCAO rats. Furthermore, QSW could improve intestinal integrity and reduce intestinal injury. 16S rRNA sequencing showed that QSW could significantly improve the gut microbiota disorder of MCAO rats. Specifically, at the phylum level, it can regulate the abundance of Firmicutes and Proteobacteria in the gut microbiota of rats with MCAO. At the genus level, it can adjust the abundance of Escherichia and Shigella. At the species level, it can adjust the abundance of Lactobacillus johnsonii and Lactobacillus reuteri. All in all, this study is the first to show that QSW can reduce the severity of cerebral ischemia-reperfusion injury by regulating gut microbiota and inhibiting the inflammatory response.
The aim of this study is to determine 18 elements in Tibetan medicine Qishiwei Zhenzhu pills (QSW) and their absorption, distribution, and excretion in rats with cerebral ischemia. Microwave digestion and inductively coupled plasma mass spectrometry (ICP-MS) were used to determine 18 elements of QSW in simulated gastrointestinal (GI) juice. Rats were given QSW (66.68 mg/kg) followed by middle cerebral artery occlusion (MCAO). Sham rats received saline and were not subjected to MCAO. ICP-MS was applied to determine the content of 18 elements in hepatic venous blood, abdominal aortic blood, brain, liver, kidney, hair, urine, and feces 24 h after MCAO. In vitro results showed that the extraction rate of Mn, Cu, Sr, Pb, Au, and Hg of QSW in gastric juice (1 h) was higher than that in water, and the contents of Cu, Au, Sr, and As were higher in intestinal juice (4 h) than in water. In vivo results showed that the contents of elements in the blood were quite low, and QSW increased Ni, Cr, Sr, Co, and V in artery blood and decreased V in venous blood. Elements in the tissues were also low, and QSW increased brain Li but decreased Cr and Cd; QSW increased kidney Ag and Cs and liver Mn but decreased liver Ni. QSW increased urinary excretion of Li, Sr, Hg, Cs, and V; QSW increased Hg content in hair but decreased Ni. Stool is the main excretion pathway of the elements in QSW, with Ba, Mn, Sr, Cd, V, Cu, Cs, Li, Pb, Ag, Hg, Cr, As, and Co the highest. In summary, this study examined the distribution of 18 elements in QSW-treated MCAO rats. The accumulation of these elements in blood and tissues was extremely low, and the majority was excreted in feces within 24 h, highlighting the importance of the gut-microbiota-brain axis in QSW-mediated brain protection.
ABSTRACT. Inflammation plays an important role in cerebral ischemia reperfusion, which can cause severe damage to the brain and may lead to cerebral hemorrhage transformation. p38-mitogen-activated protein kinase (p38mapk) has been implicated in the etiology of a number of diseases because it is a cause of inflammation, but comparatively little research has been carried out into its role in the etiology of ischemia reperfusion. We investigated the expression of p38mapk in cerebral ischemia reperfusion to gain a better understanding of its potential role in hemorrhagic transformation (HT). One hundred rats were randomly divided into three groups: an ischemia reperfusion group, an ischemia group, and a sham-operated group. We carried out neurological deficit assessments, infarct volume measurements, histopathological examinations, and immunohistochemistry analyses. p38mapk was 2 Y.Q. Song et al. Genetics and Molecular Research 15 (3): gmr.15038492 overexpressed in the ischemia reperfusion group, which exhibited severe tissue damage and greater edema than the other two groups. These results suggest that p38mapk plays an important role in cerebral ischemia reperfusion, and may be one of the causes of HT.
Qishiwei Zhenzhu pills (QSW) was first recorded in the Tibetan medicine classic Si Bu Yi Dian and has been used to treat “Baimai” disease, stroke, paralysis, hemiplegia, cerebral hemorrhage, and other diseases till today. This prescription contains more than 70 medicines including myrobalan, pearl, agate, opal, bezoar, coral, musk, gold, silver, and a mineral mixture Zuotai. As a result, QSW contains a large amount of mercury, copper, lead, and other trace elements. The aim of this study was to determine the 18 trace elements (lithium, beryllium, scandium, vanadium, chromium, manganese, cobalt, nickel, copper, arsenic, strontium, argentum, cadmium, cesium, barium, lead, aurum, and mercury) in 10 batches of QSW produced by 5 pharmaceutical companies (Ganlu Tibetan Medicine Co., Ltd. has 6 different batches) by direct inductively coupled plasma-mass spectrometry (ICP-MS). ICP-MS is a rapid, sensitive, accurate methodology allowing the determination of 18 elements simultaneously. The results showed that each element had an excellent linear relationship in the corresponding mass concentration range. The results showed that the rank order of the elements in QSW was copper > mercury > lead from high to low, with the mass fraction higher than 6000 μg/kg; the mass fractions of argentum, arsenic, manganese, aurum, strontium, barium, chromium, and nickel were in the range of 33–1034 μg/kg; and the mass fractions of vanadium, cobalt, lithium, beryllium, cadmium, scandium, and cesium were lower than 10 μg/kg. The reproducibility from the same manufacturer (Tibet Ganlu Tibetan Medicine Co., Ltd.) was relatively high; however, the element amounts among 5 manufacturers were different, which could affect the efficacy and toxicity of QSW. All in all, ICP-MS can be used as an effective tool for the analysis of trace elements in QSW and standard quality control needs to be enforced across different manufactures.
Background: Hua-Feng-Dan is a patent Chinese medicine for stroke recovery and various diseases. This study used GC-MS to profile its ingredients and RNA-Seq to analyze the induced adaptive response in the liver.Methods: Hua-Feng-Dan was subjected to steam distillation and solvent extraction, followed by GC-MS analysis. Mice were orally administered Hua-Feng-Dan and its “Guide drug” Yaomu for 7 days. Liver pathology was examined, and total RNA isolated for RNA-Seq, followed by bioinformatic analysis and quantitative real-time PCR (qPCR).Results: Forty-four volatile and fifty liposoluble components in Hua-Feng-Dan were profiled and analyzed by the NIST library and their concentrations quantified. The major components (>1%) in volatile (5) and liposoluble (10) were highlighted. Hua-Feng-Dan and Yaomu at hepatoprotective doses did not produce liver toxicity as evidenced by histopathology and serum enzyme activities. GO Enrichment revealed that Hua-Feng-Dan affected lipid homeostasis, protein folding, and cell adhesion. KEGG showed activated cholesterol metabolism, bile secretion, and PPAR signaling pathways. Differentially expressed genes (DEGs) were identified by DESeq2 with p < 0.05 compared to controls. Hua-Feng-Dan produced more DEGs than Yaomu. qPCR on selected genes largely verified RNA-Seq results. Ingenuity Pathways Analysis of the upstream regulator revealed activation of MAPK and adaptive responses by Hua-Feng-Dan, and Yaomu was less effective. Hua-Feng-Dan-induced DEGs were highly correlated with the Gene Expression Omnibus database of chemical-induced adaptive transcriptome changes in the liver.Conclusion: GC-MS primarily profiled volatile and liposoluble components in Hua-Feng-Dan. Hua-Feng-Dan at the hepatoprotective dose did not produce liver pathological changes but induced metabolic and signaling pathway activations. The effects of Hua-Feng-Dan on liver transcriptome changes point toward induced adaptive responses to program the liver to produce hepatoprotective effects.
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