Introduction: Aconite is a form of traditional Chinese medicine (TCM) that has been widely used to treat diarrhea for thousands of years. However, it is not clear whether the anti-diarrhea role of aconite aqueous extract (AA) is associated with regulation of the gut microbiota or with bile acid (BA) metabolism. This study aimed to confirm whether AA exerts its anti-diarrhea effects by regulating the gut microbiota and BA metabolism. Methods: The therapeutic effect of AA in a mouse model of diarrhea was measured based on analysis of body weight, fecal water content, diarrhea scores, intestinal propulsion rate, colonic pathology, and colonic immunohistochemistry. In addition, 16S rRNA high-throughput sequencing was conducted to analyze the effect of AA on the gut microbiota, and targeted metabolomics was employed to analyze the effect of AA on metabolism of BAs. Results: The results showed that treatment with AA reduced fecal water content and diarrhea scores, inhibited intestinal propulsion rate and pathological changes in the colon, and increased AQP3 and AQP4 content in the colon. In addition, AA was found to be capable of regulating the gut microbiota. Effects included increasing its richness (according to the ACE and Chao1 indices); altering the gut microbiota community structure (PCA, PCoA, and NMDS); increasing the relative abundance of norank_f_Muribaculaceae , Ruminococcus , Lachnospiraceae_NK4A136_group , Prevotellaceae_UCG-001 , and norank_f_norank_o_Clostridia_UCG-014 ; and decreasing the relative abundance of Escherichia-Shigella , unclassified_f_Ruminococcaceae , Ruminococcus_torques_group , and Parasutterella . More importantly, AA significantly increased fecal TCA (a primary BA) and DCA, LCA, GDCA, dehydro-LCA, and 12-keto-LCA (secondary BAs), thus restoring BA homeostasis. Moreover, AA increased the ratios of DCA/CA, DCA/TCA, and LCA/CDCA and decreased the ratios of TLCA/LCA, GLCA/LCA, and TUDCA/UDCA. Conclusion: The anti-diarrhea effect of AA was associated with restoration of the gut microbiota and BA metabolism-related homeostasis. The results of this study provide insights into the application of AA and the treatment of diarrhea.
Gut barrier is not only part of the digestive organ but also an important immunological organ for the hosts. The disruption of gut barrier can lead to various diseases such as obesity and colitis. In recent years, traditional Chinese medicine (TCM) has gained much attention for its rich clinical experiences enriched in thousands of years. After orally taken, TCM can interplay with gut microbiota. On one hand, TCM can modulate the composition and function of gut microbiota. On the other hand, gut microbiota can transform TCM compounds. The gut microbiota metabolites produced during the actions of these interplays exert noticeable pharmacological effects on the host especially gut barrier. Recently, a large number of studies have investigated the repairing and fortifying effects of TCM on gut barriers from the perspective of gut microbiota and its metabolites. However, no review has summarized the mechanism behand this beneficiary effects of TCM. In this review, we first briefly introduce the unique structure and specific function of gut barrier. Then, we summarize the interactions and relationship amidst gut microbiota, gut microbiota metabolites and TCM. Further, we summarize the regulative effects and mechanisms of TCM on gut barrier including physical barrier, chemical barrier, immunological barrier, and microbial barrier. At last, we discuss the effects of TCM on diseases that are associated gut barrier destruction such as ulcerative colitis and type 2 diabetes. Our review can provide insights into TCM, gut barrier and gut microbiota.
3091 Purpose. R, S-HDAC-42 (NSC 731438), an inhibitor of histone deacetylase, has been found to possess potent cytotoxicity in the NCI 60-cell line screen with a mean GI50 of 0.2 μM. The S-enantiomer of HDAC-42 (s-HDAC-42; NSC 736012) is the more potent isomer. The purpose of this study was to develop a highly sensitive LC-MS assay for the analysis of s-HDAC-42 in plasma and to characterize its pharmacokinetics in mice. Methods. A liquid chromatograph-triple quadrupole mass spectrometer (LC-MS) with electrospray (ESI) ionization was used for quantification. Plasma (0.1 mL) was spiked with s-HDAC-42 and the internal standard, hesperetin and then extracted with ethyl acetate. The extracts were subjected to ESI LC-MS using a BetaBasic C8 column with isocratic elution. Positive ion selected reaction monitor (MRM) mode with ion transitions at m/z 313.2-133.2 for s-HDAC-42 and m/z 303.2-177.2 for hesperetin was used for quantification. The assay method was validated in mouse plasma. Pharmacokinetics (PK) of s-HDAC-42 in CD1F2 mice was studied following i.v. bolus administration at 20 mg/kg and p.o dose at 50 mg/kg. Results. The Lower limit of quantification (LLOQ) for s-HDAC-42 was found to be 2 ng/ml (6 nM), in mouse plasma. Linearity was demonstrated between the LLOQ to 1000 ng/mL (3.2 μM). The within-day coefficients of variation (CVs) were found to be 14.7%, 9.5%, and 6.6% at 2, 5, 50 ng/mL (0.006, 0.016, 0.16 μM), the lower concentration range, while 6.1%, 6.0%, and 1.8% at 50, 500, 1000 ng/mL (0.16, 1.6, 3.2 μM), the higher range of concentration (n=6). The corresponding between-day CVs were found to be 8.8, 8.8, 0.6, 8.2, 1.4 and 0.6%, respectively. Plasma protein-binding of s-HDAC-42 was 95-98% at low μM range. Following an i.v. bolus dose at 20 mg/kg, plasma concentration reached ∼49 μM then decreased to 0.02 μM at 48 hr. The data were found to fit to a two-compartment model with an initial and terminal half life of 0.38 hr and 10.1 hr, respectively. The AUC value was 43.7 μM.hr and the total body clearance was 1.47 L/h/kg at 20 mg/kg. s-HDAC-42 was absorbed rapidly following a 50 mg/kg p.o. dose and plasma concentration reached 14.7 μM at 0.17 h and also declined biexponentially with time. The oral bioavailability was found to be 27.4%. Conclusion. An ESI LC-MS/MS method for s-HDAC-42 in plasma with low nM sensitivity has been developed and used to characterize the pharmacokinetics of s-HDAC-42 in mice. Oral absorption was rapid and bioavailability was moderate. In support of RAID #276 (C-S Chen) through NCI-N01-CM-52205.
As a widely used traditional Chinese medicine with hot property, aconite can significantly promote energy metabolism. However, it is unclear whether the gut microbiota and bile acids contribute to the energy metabolism-promoting properties of aconite. The aim of this experiment was to verify whether the energy metabolism-promoting effect of aconite aqueous extract (AA) is related to gut microbiota and bile acid (BA) metabolism.
Sorafenib, an orally available kinase inhibitor, is the standard first-line systemic drug for advanced hepatocellular carcinoma (HCC), and it exerts potent inhibitory activity against epithelial-mesenchymal transition (EMT) and multidrug resistance (MDR) by inhibiting mitogen-activated protein kinase (MAPK) signaling in HCC. However, after long-term exposure to sorafenib, HCC cells exhibit EMT and resistance to sorafenib. The activation of AKT by sorafenib is thought to be responsible for the development of these characteristics. The present study aims to examine the underlying mechanism and seek potential strategies to reverse this resistance and the progression to EMT. Sorafenib-resistant cells showed increased metastatic and invasive ability, with a higher expression of P-glycoprotein (P-gp), compared with the parental cells. This phenomenon was at least partially due to EMT and the appearance of MDR in sorafenib-resistant HCC cells. Moreover, MDR was a downstream molecular event of EMT. Silencing Snail with siRNA blocked EMT and partially reversed the MDR, thereby markedly abolishing invasion and metastasis in sorafenib-resistant HCC cells, but silencing of MDR1 had no effect on the EMT phenotype. Additionally, HCC parental cells that were stably transfected with pCDNA3.1-Snail exhibited EMT and MDR. Two sorafenib-resistant HCC cell lines, established from human HCC HepG2 and Huh7 cells, were refractory to sorafenib-induced growth inhibition but were sensitive to MK-2206, a novel allosteric AKT inhibitor. Thus, the combination of sorafenib and MK-2206 led to significant reversion of the EMT phenotype and P-gp-mediated MDR by downregulating phosphorylated AKT. These findings underscore the significance of EMT, MDR and enhanced PI3K/AKT signaling in sorafenib-resistant HCC cells.
This study aims to explore the regulatory effect of Zinc Finger Protein 331 (ZNF331), a KRAB domain-containing transcriptional repressor, in Head and Neck Squamous Cell Carcinoma (HNSCC).
Objective
To observe changes in blood biochemistry and coagulation function before and after warm water bath rewarming in SD rats with hypothermia induced by prolonged seawater immersion.
Methods
One hundred male Sprague-Dawley rats were randomly divided into the normal control group (the NC group, without any treatment) and the hypothermia group (the HT group, exposed to seawater immersion at 20 ℃ for 24 hours). The passive rewarming sub-groups (the pR group 1, 2, 3 and 4, n=10) (exposed to seawater immersion at 20 ℃ for 24 hours + passive rewarming) were respectively executed after rewarming at hour 0, hour 3, hour 6, and hour 12). The warm-water bath rewarming sub-groups (the wR group 1, 2, 3 and 4, n=10) (exposed to seawater immersion at 20 ℃ for 24 hours+ warm-water bath rewarming) were respectively executed after rewarming at hour 0, hour 3, hour 6, and hour 12). Blood samples were taken from abdominal aorta for biochemical and coagulation detection.
Results
Zero to 3 hours after warm water bath rewarming, important parameters of hepatic and renal functions, as well as myocardial enzymes in the SD rats with hypothermia induced by prolonged seawater immersion remained at high levels or even increased to some extent. Only after 6 hours after rewarming, the above-mentioned parameters dropped considerably. However, coagulation indicators began to decline immediately after rewarming, and as compared with the passive rewarming, warm water bath rewarming could produce obviously better effects on the alleviation of abnormal hepatic and renal functions, as well as myocardial enzyme parameters (P<0.05).
Conclusion
Warm water bath rewarming could produce better effects on the recovery of serum biochemical parameters in rats with hypothermia induced by prolonged seawater immersion when compared with those of passive rewarming.
Key words:
Seawater immersion; Hypothermia; SD rat; Warm water bath rewarming; Passive rewarming; Blood biochemistry; Coagulation
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