Pharmacokinetic Interactions Between Tegoprazan and the Combination of Clarithromycin, Amoxicillin and Bismuth in Healthy Chinese Subjects: An Open-Label, Single-Center, Multiple-Dosage, Self-Controlled, Phase I Trial.

BACKGROUND: Tegoprazan is a potassium-competitive acid blocker that inhibits gastric acid and which may be used for eradicating Helicobacter pylori. This study focuses on the pharmacokinetic interaction and safety between tegoprazan and the combination of clarithromycin, amoxicillin and bismuth in healthy Chinese subjects. METHODS: An open-label, three-period, single-center, multiple-dosage, single-sequence, phase I trial was conducted in 22 healthy subjects. In period 1, the subjects took tegoprazan 50 mg twice daily for 7 days, and in period 2 they were administered clarithromycin 500 mg, amoxicillin 1000 mg and bismuth potassium citrate 600 mg twice daily for 7 days (days 14-20). Tegoprazan, clarithromycin, amoxicillin and bismuth potassium citrate were then administered in combination for 7 days (days 21-27) in period 3. Blood samples were collected up to 12 h after the last dose of each period. Safety assessments were performed in each period. RESULTS: The geometric mean ratios (GMRs) [90% confidence interval (CI)] of maximum plasma concentration at steady state (Cmax,ss) and area under the plasma concentration-time curve over the dosing interval (AUCτ) at steady state were 195.93% (175.52-218.71%) and 287.54% (263.28-314.04%) for tegoprazan and 423.23% (382.57-468.22%) and 385.61% (354.62-419.30%) for tegoprazan metabolite M1, respectively. The GMRs (90% CI) of Cmax,ss and AUCτ were 83.69% (77.44-90.45%) and 110.30% (102.74-118.41%) for clarithromycin, 126.25% (114.73-138.93%) and 146.94% (135.33-159.55%) for 14-hydroxyclarithromycin, 75.89% (69.73-82.60%) and 94.34% (87.94-101.20%) for amoxicillin, and 158.43% (125.43-200.11%) and 183.63% (156.42-215.58%) for bismuth, respectively. All reported adverse events were mild. The frequency of adverse events during the coadministration stage was not higher than that during the single- or triple-drug administration stages. CONCLUSION: The plasma exposure of tegoprazan, M1, 14-hydroxyclarithromycin and bismuth was increased after the coadministration of tegoprazan, clarithromycin, amoxicillin and bismuth. The coadministration exhibited favorable safety and tolerability. CLINICAL TRIALS REGISTRATION: CTR20230643.

Spindle apparatus coiled-coil protein 1 (SPDL1) serves as a novel prognostic biomarker in triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) has a poor prognosis, an ineffective diagnosis, and a high degree of aggressiveness. Therefore, novel therapeutic targets for TNBC urgently need to be identified. METHODS: Through a series of bioinformatics analyses, including analysis of differential gene expression, protein-protein interaction (PPI) network, univariate cox regression, immune infiltration, pathway enrichment, etc, as well as auxiliary immunohistochemistry (IHC) and protein quantitativae analysis, to explore prognostic marker for TNBC. RESULTS: In TNBC tissues, we found that SPDL1 (CCDC99) was considerably overexpressed at both the mRNA and protein levels compared to that in normal and non-TNBC tissues. Additionally, we found that SPDL1-high expression was strongly linked to poor prognosis in TNBC patients. Excessive SPDL1 expression was positively correlated with tumor growth and strongly linked to the cell cycle, DNA replication, and the p53 signaling pathway. In addition, CIBERSORT analysis revealed that SPDL1 can affect the tumor immune microenvironment (TME) in TNBC, encourage the development of TNBC and act as a potential prognostic biomarker for TNBC. Patients with SPDL1-high expression were more sensitive to AZD8055. Notably, we discovered that SPDL1 is highly expressed in the majority of malignancies and may have an impact on the pancancer prognosis. CONCLUSIONS: SPDL1 can serve as a novel prognostic marker for TNBC and pancancer patients.

Synergistic effects and molecular mechanisms of DL-3-n-butylphthalide combined with dual antiplatelet therapy in acute ischemic stroke.

DL-3-n-butylphthalide (NBP) is isolated from the seeds of Apium graveolens L., and has been recently used as a neuroprotective agent for acute ischemic stroke. The present study aimed to determine the efficacy and safety of the combined use of dual antiplatelet therapy (DAPT) and NBP for treating of acute ischemic stroke in rats and to explore the synergistic mechanism of this treatment strategy in rat middle cerebral artery occlusion models. The efficacy of DAPT combined with NBP was evaluated by determining neurological deficits, infarction status, and histological changes. Changes in body weight, blood glucose level, blood count, and serum biochemical parameters were detected to evaluate the safety. To explore the synergistic pharmacological mechanism, the mRNA expression and protein levels of key proteins in the pyroptosis-inflammatory pathway, and the pyroptosis ratio of microglias were examined. Compared with the administration of NBP or DAPT alone, combination of them significantly improved neurological deficits, reduced infarct area, and repaired tissue injury and inflammation after cerebral ischemia. No hepatorenal toxicity was observed. The mRNA expression and protein levels of key proteins in the pyroptosis-inflammation pathway, and the pyroptosis ratio of microglias were significantly downregulated in the combined administration group than in the monotherapy group. We demonstrated that the combined use of NBP and DAPT exhibits better efficacy and high safety and plays a synergistic role by inhibiting the pyroptosis-inflammation pathway in the brain tissues, particularly in microglial cells.

Effects of Yinzhihuang on Alleviating Cyclosporine A-Induced Cholestatic Liver Injury via Farnesoid X Receptor-Mediated Regulation of Transporters and Enzymes in Vitro and in Vivo.

Yinzhihuang (YZH), a traditional Chinese medicine prescription, was widely used to treat cholestasis. Cholestatic liver injury limited the use of the immunosuppressive drug cyclosporine A (CsA) in preventing organ rejection after solid organ transplantation. Clinical evidences suggested that YZH could enhance bile acids and bilirubin clearance, providing a potential therapeutic strategy against CsA-induced cholestasis. Nevertheless, it remains unclear whether YZH can effectively alleviate CsA-induced cholestatic liver injury, as well as the molecular mechanisms responsible for its hepatoprotective effects. The purpose of the present study was to investigate the hepatoprotective effects of YZH on CsA-induced cholestatic liver injury and explore its molecular mechanisms in vivo and vitro. The results demonstrated that YZH significantly improved the CsA-induced cholestatic liver injury and reduced the level of liver function markers in serum of Sprague-Dawley (SD) rats. Targeted protein and gene analysis indicated that YZH increased bile acids and bilirubin efflux into bile through the regulation of multidrug resistance-associated protein 2 (Mrp2), bile salt export pump (Bsep), sodium taurocholate cotransporting polypeptide (Ntcp) and organic anion transporting polypeptide 2 (Oatp2) transport systems, as well as upstream nuclear receptors farnesoid X receptor (Fxr). Moreover, YZH modulated enzymes involved in bile acids synthesis and bilirubin metabolism including Cyp family 7 subfamily A member 1 (Cyp7a1) and uridine 5'-diphosphate (UDP) glucuronosyltransferase family 1 member A1 (Ugt1a1). Furthermore, the active components geniposidic acid, baicalin and chlorogenic acid exerted regulated metabolic enzymes and transporters in LO2 cells. In conclusion, YZH may prevent CsA-induced cholestasis by regulating the transport systems, metabolic enzymes, and upstream nuclear receptors Fxr to restore bile acid and bilirubin homeostasis. These findings highlight the potential of YZH as a therapeutic intervention for CsA-induced cholestasis and open avenues for further research into its clinical applications.

Naringenin prevents non-alcoholic steatohepatitis by modulating the host metabolome and intestinal microbiome in MCD diet-fed mice.

Non-alcoholic steatohepatitis (NASH) is a severe inflammatory phase of the non-alcoholic fatty liver disease (NAFLD) spectrum and can progress to advanced stages of NAFLD if left untreated. This study uses multi-omics data to elucidate the underlying mechanism of naringenin's reported benefit in alleviating (NASH). Male mice were fed a NASH-inducing (methionine-choline-deficient) MCD diet with or without naringenin supplementation for 6 weeks. Naringenin prevented NASH-induced histopathological liver damage and reversed the abnormal levels of hepatic triglyceride (TG)/total cholesterol (TC), serum TG/TC, serum alanine aminotransferase/aspartate transaminase, and hepatic malondialdehyde and glutathione. Importantly, naringenin intervention significantly modulated the relative abundance of gut microbiota and the host metabolomic profile. We detected more than 700 metabolites in the serum and found that the gut genus levels of Anaeroplasma and the [Eubacterium] nodatum group were closely associated with xanthine, 2-picoline, and securinine, respectively. Tuzzerella alterations showed the highest number of associations with host endogenous metabolites such as FAHFA (8:0/10:0), FFA (20:2), carnitine C8:1, tridecanedioic acid, securinine, acetylvaline, DL-O-tyrosine, and Phe-Asn. This study indicates that the interplay between host serum metabolites and gut microbiota may contribute to the therapeutic effect of naringenin against NASH.

Pharmacokinetics and Pharmacodynamics of Lansoprazole/Sodium Bicarbonate Immediate-release Capsules in Healthy Chinese Subjects: An Open, Randomized, Controlled, Crossover, Single-, and Multiple-dose Trial.

Proton pump inhibitors (PPIs) differ in onset of action and bioavailability. This trial was conducted to investigate the pharmacokinetics and pharmacodynamics of an immediate-release capsule formulation containing lansoprazole 30 mg and sodium bicarbonate 1100 mg (T preparation) in healthy Chinese subjects. This was an open, single-center, randomized, single and multiple oral doses, and two-period crossover study in 30 healthy subjects. After single- and multiple-dose oral administration, blood samples were obtained and lansoprazole concentration in serum was measured for pharmacokinetic analysis. Meanwhile, the intragastric pH was monitored continuously to evaluate the pharmacodynamics of the investigational drugs. The Tmax of the T preparation was 0.5 hours, while the Tmax of the R preparation was 1.5 hours after multiple doses, which indicated that the absorption speed of the T preparation was significantly faster than that of the R preparation. The same characteristics also existed after single-dose administration. The area under the curve (AUC)ss of the T preparation was bio-equivalent to that of the R preparation under steady state. The time percentage of intragastric pH > 4.0 for the T preparation was higher than that of the R preparation after 1 hour for both single- and multiple-dose. It suggested compared with R preparation, the time percentage of intragastric pH > 4.0 met the criteria for superiority after 1 hour administration for the T preparation. In addition, no serious adverse events occurred in this study. Across this study, the T preparation was better than the R preparation at improving drug absorption and increasing intragastric pH, and had a favorable safety profile.

A pharmacokinetics interaction study of antiplatelet agents aspirin and clopidogrel combined with dl-3-n-butylphthalide in rats by liquid chromatography-tandem mass spectrometry.

A sensitive and specific high-performance liquid chromatography-tandem mass spectrometry method has been developed to determine the pharmacokinetic interactions of the antiplatelet agents aspirin and clopidogrel combined with dl-3-n-butylphthalide. For the determination of aspirin metabolite salicylic acid, clopidogrel inactive metabolite SR26334 and NBP prototype drug in rat plasma, plasma samples were prepared by precipitation of proteins using methanol containing 0.1% formic acid, followed by centrifugation. Chromatography was performed on a C18 column, eluting with a gradient of acetonitrile (with 0.1% formic acid)-water (with 0.1% formic acid). The detection adopted electrospray ion source and positive ion multiple reaction monitoring modes. The linear detection response range of salicylic acid is 80-80,000 ng/ml, and the linear detection response range of SR26334 and dl-3-n-butylphthalide is 10-10,000 ng/ml. Our study revealed that dl-3-n-butylphthalide affected the pharmacokinetics of aspirin and clopidogrel when administered to rats.

Challenges of Anti-Mesothelin CAR-T-Cell Therapy.

Chimeric antigen receptor (CAR)-T-cell therapy is a kind of adoptive T-cell therapy (ACT) that has developed rapidly in recent years. Mesothelin (MSLN) is a tumor-associated antigen (TAA) that is highly expressed in various solid tumors and is an important target antigen for the development of new immunotherapies for solid tumors. This article reviews the clinical research status, obstacles, advancements and challenges of anti-MSLN CAR-T-cell therapy. Clinical trials on anti-MSLN CAR-T cells show that they have a high safety profile but limited efficacy. At present, local administration and introduction of new modifications are being used to enhance proliferation and persistence and to improve the efficacy and safety of anti-MSLN CAR-T cells. A number of clinical and basic studies have shown that the curative effect of combining this therapy with standard therapy is significantly better than that of monotherapy.

Antidepressant Shugan Jieyu Capsule Alters Gut Microbiota and Intestinal Microbiome Function in Rats With Chronic Unpredictable Mild Stress -Induced Depression.

Shugan Jieyu Capsule (SG) has been widely used in China to treat mild to moderate depression. Hypericum perforatum L. (St John's Wort, SJW) is the main ingredient of SG and has been used as herbal medicine to treat depression in western countries. However, it is known that SJW has low bioavailability and does not easily get through the blood-brain barrier. Therefore, how SG plays an antidepressant effect in the central nervous system (CNS) remains an urgent problem to be solved. Mounting research has described the relationship between antidepressants and intestinal microbiota to illuminate antidepressive mechanisms in the CNS. We aimed to investigate the effects of therapy with SG on the function of gut microbiota and intestinal microbiota in rats with chronic unpredictable mild stress (CUMS)-induced depression. The psychophysiological state and the hypothalamic-pituitary-adrenal axis function of rats are evaluated through behavioral experiments, corticosterone levels, serotonin levels, and adrenal index measurements. 16S rDNA amplicon sequencing is used to test the changes in gut microbiota and make functional predictions of genes. With treatment of SG, the depression-like behaviors of CUMS-induced rats were reversed; the corticosterone levels and the adrenal index decreased significantly; the level of serotonin increased significantly; and the alpha and beta diversity analysis of microbiota showed an increase in the richness and uniformity of the flora were increased. SG regulated the relative abundance of Actinobacteria, Erysipelotrichaceae, Bifidobacteriaceae, Atopobiaceae, Dubosiella, and Bifidobacterium; Linear discriminant analysis effect size analysis demonstrated that Lactobacillaceae (family level), Lactobacillus (genus level), Lactobacillales (order level), Bacilli (class level), and Lactobacillus-reuteri (species level) were biomarkers in the SG group samples, and also likely to modulate metabolic pathways, such as those involved in carbohydrate metabolism, amino acid metabolism, and signal transduction. These data clearly illustrated the effect of SG on gut microbiome, thus laying the foundation for uncovering more insights on the therapeutic function of the traditional Chinese antidepressants. The potential of SG on mechanisms of antidepression to alter gut microbiota and intestinal microbiome function exposed to CUMS can be explored.

A Bibliometric Analysis of Triptolide and the Recent Advances in Treating Non-Small Cell Lung Cancer.

In recent decades, natural products derived from plants and their derivatives have attracted great interest in the field of disease treatment. Triptolide is a tricyclic diterpene extracted from Tripterygium wilfordii, a traditional Chinese medicine, which has shown excellent therapeutic potential in the fields of immune inflammation and cancer treatment. In this study, 1,106 Web-of-Science-indexed manuscripts and 1,160 Chinese-National-Knowledge-Infrastructure-indexed manuscripts regarding triptolide published between 2011 and 2021 were analyzed, mapping the co-occurrence networks of keywords and clusters using CiteSpace software. The research frontier and development trend were determined by keyword frequency and cluster analysis, which can be used to predict the future research development of triptolide. Non-small cell lung cancer (NSCLC) is most common in lung cancer patients, accounting for about 80% of all lung cancer patients. New evidence suggests that triptolide effectively inhibits the development and metastasis of NSCLC by the induction of apoptosis, reversion of EMT, and regulation of gene expression. Specifically, it acts on NF-κB, MAPKs, P53, Wnt/ß-catenin, and microRNAs (miRNAs), signaling pathways and molecular mechanisms. Consequently, this article reviews the research progress of the anti-NSCLC effect of triptolide. In addition, attenuated studies on triptolide and the potential of tumor immunotherapy are also discussed.

Effect of capsaicin on breast cancer resistance protein (BCRP/Abcg2) and pharmacokinetics of probe substrates in rats.

Breast cancer resistance protein (BCRP/Abcg2 in human, Bcrp/Abcg2 in rat), a member of the ATP-binding cassette (ABC) transporter family, acts as an efflux pump for xenobiotics, with ability to transport various drugs out of cells. Capsaicin may have the potential to modulate the function of Bcrp transport. This study was to evaluate the effects of capsaicin on the pharmacokinetics of sulfasalazine, a Bcrp substrate, in rats and investigate the mechanism of this food-drug interaction.The rats were pre-treated with 5% carboxymethylcellulose sodium (vehicle), capsaicin (3, 8, 25 mg/kg) and cyclosporine A (10 mg/kg) by gastric gavage for 7 days. On day 7, blood, liver and intestine samples were collected after sulfasalazine administered. Liquid chromatography tandem mass spectrometry (LC-MS/MS) was used to study the effects of capsaicin on the pharmacokinetics of sulfasalazine in rats. RT-PCR and western blotting were used to study the mechanism in biomolecules in rats, respectively.Compared with vehicle group, AUC0-∞ of sulfasalazine in rats were increased by 1.5-folds, 1.6-folds and 1.7-folds in 3, 8 and 25 mg/kg/d capsaicin pre-treated groups. At the same time, the CL/F in rats were decreased by 33%, 38% and 42% in the three groups. In addition, we found Bcrp mRNA levels and protein expressions in rat livers and intestines were decreased in 3, 8 and 25 mg/kg/d capsaicin-treated groups.Our study demonstrated that long-term ingestion of capsaicin significantly enhanced the AUC of sulfasalazine involved down-regulate Bcrp gene and protein expression in rat liver and intestine.

The protective effect of hypericin on postpartum depression rat model by inhibiting the NLRP3 inflammasome activation and regulating glucocorticoid metabolism.

BACKGROUND: St John's Wort (Hypericum perforatum, SJW) is widely used to treat postpartum depression (PPD) because of its high safety. Hypericin (HY) is the main effective component of SJW. The physiological roles of NLRP3 inflammasome activation and glucocorticoid metabolism are closely linked to depression. But, it remains elusive whether HY relieve PPD through targeting NLRP3 inflammasome activation or other mechanism. This study aimed to clarify the therapeutic effects of HY on PPD model rats and its underlying mechanisms in vivo. METHODS: hormone-simulated pregnancy model was used, and behavioral tests was used to assess depressive state. Inflammatory factors in serum were tested by Enzyme-linked immunosorbent assay. RESULTS: Changes in the classic behavioral tests reflected that HY could alleviate the symptoms of PPD as effective as fluoxetine (FLU). Both of HY and FLU could significantly inhibit the protein expression of NLRP3, caspase-1 in hypothalamus and decrease the levels of inflammatory factors (IL-6, IL-1ß, TNF - α) in serum. For hormone level determination, HY can not only significantly reduce the level of CORT, but also reverse the activity of 11ß - HSD2 enzyme, which is different from FLU. LIMITATIONS: More experiments will be needed to verify the target of HY. CONCLUSION: All those data suggest that HY can effectively relieve PPD by reversing glucocorticoid metabolism, increasing ER expression, and then relieve neuroinflammation.

Quantitation of six steroid hormones by ultra-performance liquid chromatography-tandem mass spectrometry in plasma and prefrontal cortex samples from rats with chronic unpredictable mild stress-induced depression.

Steroid hormones such as glucocorticoids and their metabolites are closely related to mental diseases and neuroendocrine diseases. Quantitative analysis of these substances will help in understanding their roles in related research fields. In this study, an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed to detect the concentration of corticosterone (CORT) and its metabolites, progesterone (PROG) and testosterone in rat plasma and prefrontal cortex (PFC), and was applied to investigate the changes in hormones in rats with depression induced by chronic unpredictable mild stress (CUMS). The method was shown to be linear in the quantitation range for all analytes. Intra- and inter-day accuracy and precision were between 80% and 120%. Furthermore, we found that the level of CORT in plasma and PFC increased, whereas that of 11-dehydrocorticosterone (11-DHCORT) as well as the ratio of 11-DHCORT and CORT declined in rats with CUMS-induced depression. The trends of these changes in central PFC and peripheral plasma were consistent. In conclusion, this study successfully established an UPLC-MS/MS method for simultaneous measurement of CORT and its metabolites, PROG and testosterone in rat plasma and PFC, and applied it to rats with depression. The method could be further applied to the research of depression and diseases related to these steroid hormones.

Associations between the 1438A/G, 102T/C, and rs7997012G/A polymorphisms of HTR2A and the safety and efficacy of antidepressants in depression: a meta-analysis.

The correlations between hydroxytryptamine receptor 2A (HTR2A) gene polymorphisms (1438A/G, 102T/C, and rs7997012G/A) and the safety and efficacy of antidepressants in depression patients were constantly reported, but conclusions are debatable. This meta-analysis ascertained forty-two studies on the efficacy (including response and remission) and side-effect issued before February 2020. Pooled analyses indicated significant associations of 1438A/G polymorphism (16 studies, 1931 subjects) and higher response within dominant model (OR: 1.40, 95% CI: 1.12-1.76); rs7997012G/A polymorphism (nine studies, 1434 subjects) and higher remission in overall models (dominant model: OR: 1.30, 95% CI: 1.01-1.66; recessive model: OR: 2.20, 95% CI: 1.53-3.16; homozygote model: OR: 2.73, 95% CI: 1.78-4.17); 102T/C polymorphism (eight studies, 804 subjects) and reduced risk of side-effect within recessive (OR: 0.57, 95% CI: 0.4-0.83) and homozygote models (OR: 0.54, 95% CI: 0.29-0.99). For depression patients, genotyping of HTR2A polymorphisms is a promising tool for estimating the outcome and side-effect of antidepressants.

A study of the mechanism of lncRNA-CR594175 in regulating proliferation and invasion of hepatocellular carcinoma cells in vivo and in vitro.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the cancers of highest incidence and mortality worldwide. The proliferation and invasion of tumor cells are the main reason for poor prognosis after HCC surgery. Long non-coding RNA (lncRNA) has been shown to play a key role in the progression of HCC. LncRNA-CR594175 is one of the highly expressed lncRNAs in HCC tumors and their metastatic tumors that we have obtained by the High-throughput screening method. METHODS: To elucidate the role of lncRNA-CR594175 in regulating the proliferation and invasion of human hepatoma cell line, HepG2, we operated through lncRNA-CR594175 silencing to inhibit the progression of HCC, either through in vitro or in vivo experiments. RESULTS: We found that lncRNA-CR594175 was lower in adjacent non-cancerous tissues than in primary HCC, and was lower in primary HCC than in its metastasis. Silencing of lncRNA-CR594175 inhibited the proliferation and invasion of HepG2 cells and growth of subcutaneous tumors. The results revealed that lncRNA-CR594175, as a RNA sponge, broke the negative regulation of hsa-miR-142-3p on Catenin, beta-1 (CTNNB1), and once lncRNA-CR594175 was silenced, the hsa-miR142-3p regained its negative regulation on CTNNB1 which can promote HCC progression by activating the wnt pathway. CONCLUSIONS: Our present study demonstrated for the first time that lncRNA-CR594175 silencing suppressed proliferation and invasion of HCC cells in vivo and in vitro by restoring the negative regulation of hsa-miR-142-3p on CTNNB1, laying a solid theoretical base for using lncRNA-CR594175 as genetic target therapy for HCC and offering a reasonable explanation for inactivation of miRNA in different tumors or in the tumor at different stages.

Effects of cyclosporin A on the pharmacokinetics and toxicities of irinotecan mediated by UGT1A1 in vitro and in vivo.

Irinotecan (CPT-11) is a broad spectrum agent for the treatment of solid tumor malignancies, despite severe diarrhea is limiting its widespread usage. The local effects of SN-38 in the small intestine were considered to be responsible for the irinotecan-induced delayed diarrhea. It was proposed that cyclosporin A (CsA) inhibiting biliary excretion could attenuate this side effect, but in fact, it could not improve the therapeutic index of irinotecan. At present, most studies focused on the inhibition of bile excretion by cyclosporin A through the transporters MRP2 and MDR1 and its effect the irinotecan treatment in vivo. However, UDP glucuronyltransferase-1 polypeptide A1 (UGT1A1) was related to a significantly altered disposition of irinotecan and its metabolites, and was therefore associated with irinotecan-induced toxicity. This study focused on UGT1A1-mediated conversion of SN-38 to SN-38G, and systematically investigated the CsA-irinotecan interactions in vitro and in vivo. After treatment with 10 mg·kg-1 CsA for 7 days, the bile excretion of irinotecan and its metabolites decreased and AUC0-∞ increased significantly. The AUC0-∞ (SN-38G)/AUC0-∞ (SN-38) was significantly reduced when compared with that in vehicle-treated rats. In the liver microsome incubation system, the IC50 of CsA for UGT1A1 enzyme was 9.4 µM. Furthermore, the UGT1A1 mRNA and protein expression levels were significantly reduced. The present study indicated that CsA treatment could enhance the systemic exposure and toxicity of SN-38 by inhibiting the UGT1A1 enzyme. The inhibition of UGT1A1 enzyme might be a critical factor in the failure of CsA improving irinotecan's treatment index.

The hepatoprotective effects of XCHD and MgIG against methotrexate-induced liver injury and inflammation in rats through suppressing the activation of AIM2 inflammasomes.

BACKGROUND: Recent studies have shown that drug-induced liver injury may be related to the immune response activated by drugs. A cytosolic dsDNA inflammasome called absent in melanoma 2 (AIM2) was found to be associated with aseptic inflammation. The present study aimed to explore the effects of on the liver injury and inflammation in methotrexate (Mtx)-induced rats. METHODS: Sprague Dawley (SD) rats were selected and classified into 4 groups randomly, includes control group, Mtx group, Mtx-Xiaochaihu decoction (XCHD) group and Mtx-magnesium isoglycyrrhizinate (MgIG) group. Light microscopy was used to examine histological specimens after hematoxylin-eosin (HE) staining. The AST levels in liver tissue and blood serum ALT in the rats were assessed with enzyme linked immunosorbent assay (ELISA). Then AIM2 expression and inflammatory factors, including caspase-1, IL-18, and IL-1ß, in the liver biopsy specimens of rats were detected by immunohistochemistry. Furthermore, the correlation between inflammatory and AIM2 expression factors was comprehensively analyzed. RESULTS: Functional and structural hepatotoxicity can be caused by the exposure to Mtx, which was supported by the improved biochemical marker levels and the worse histopathological changes in liver tissue. Compared with the Mtx group, the levels of liver enzymes ALT and AST, histological deterioration in the liver tissues were effectively decreased by XCHD and MgIG treatment, respectively. In addition, the expression of AIM2, caspase-1 and IL-1ß was observably higher in the Mtx group, which was apparently inhibited in the Mtx-XCHD and Mtx-MgIG groups. There was no obvious change in IL-18 expression among four groups. AIM2 expression were positively associated with the severity of liver inflammation and had a higher relevance with caspase-1 expression. CONCLUSIONS: AIM2 inflammasome in hepatocytes has a significant effect on the development of Mtx-induced liver injury, which can be ameliorated by both XCHD and MgIG treatment. The latent mechanism and potential signal pathway require further study.

Development of an underivatized LC-MS/MS method for quantitation of 14 neurotransmitters in rat hippocampus, plasma and urine: Application to CUMS induced depression rats.

Sensitive and comprehensive measurement of systemic metabolites of tryptophan, phenylalanine and glutamate metabolism in biological samples is effective for understanding the pathogenesis of depression and other neurological diseases. Therefore, this study developed an underivatized liquid chromatography tandem mass spectrometry (LC-MS/MS) method for simultaneous monitoring the 3 components of glutamate metabolism in rat hippocampus and 11 components of tryptophan and phenylalanine metabolism in rat hippocampus, plasma and urine, and applied it to investigate their changes in rats induced by chronic unpredictable mild stress (CUMS). The investigated analytes are as follows: tryptophan, serotonin, 5-hydroxyindoleacetic acid, kynurenine, kynurenic acid, xanthurenic acid, 3-hydroxyanthranilic acid, quinolinic acid, phenylalanine, tyrosine, tyramine, glutamate, glutamine and gamma-aminobutyric acid. The method was verified to be sensitive and effective with satisfactory linearity, accuracies in the range of 78.2%-120.4%, and precisions less than 17.8% for all identified analytes. A series of significant changes in CUMS-induced rats can be detected: tryptophan, serotonin and tyrosine levels decreased and quinolinic acid increased in both hippocampus and plasma. In addition, the kynurenine/tryptophan ratios increased in hippocampus and plasma, the kynurenic acid/quinolinic acid ratios of plasma and urine were significantly reduced. These findings demonstrated that the CUMS procedure could lead to the central and peripheral imbalances of tryptophan and phenylalanine metabolism. In conclusion, a LC-MS/MS method for simultaneous measurement of several neurotransmitters in rat hippocampus, plasma and urine was developed and successfully applied to investigation of the central and peripheral changes in CUMS-induced rats. The method would be expected to provide applicability to the study of the mechanisms of depression and other related diseases associated with these neurotransmitters.

Clinical analysis of 547 patients with neuroendocrine tumors in a Chinese population: A single-center study.

BACKGROUND: Neuroendocrine tumors (NETs) are rare, which has resulted in a lack of published data on their epidemiology and clinical features. We therefore aimed to investigate the epidemiology, clinical features, treatments, and prognosis of patients with NETs. METHODS: The clinicopathologic characteristics of 547 patients who were pathologically diagnosed with NETs were retrospectively analyzed, including age, sex, primary and metastatic sites, symptoms, pathology, treatment, and prognosis. RESULTS: The 547 patients had a wide age range (9-87 years), with a male to female ratio of 1:1.1. The primary tumor sites included 413 in the digestive system, 74 in the lung, 15 in the mediastinum, 8 in unknown sites, and 37 in other sites. Of the 413 patients with digestive system NETs, the pancreas, rectum, and stomach were the most common primary sites. Blood metastases were found in 84 patients at initial diagnosis, and the liver, bone, and lung were the most frequent sites of metastasis. Lymph node metastases were found in 82 patients at initial diagnosis. Surgery and chemotherapy were the most widely applied treatments. Statistical analysis showed that age <50 years, female sex, lower-grade tumor, no distant metastasis, intestinal NET and surgery indicated a favorable prognosis. CONCLUSIONS: A difference between China and other countries is that small intestinal NETs are quite common in other countries but are rare in China. In China, the most common primary sites are the pancreas, rectum, and stomach. Furthermore, no unified treatments exist, though prognoses could be improved by using methods such as surgery, targeted therapies, and somatostatin analogs. CLINICAL TRIAL REGISTRATION: This study was not a clinical trial.

Pharmacokinetic effects of capsaicin on vinblastine in rats mediated by CYP3A and Mrp2.

Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide, CAP) is an important ingredient in spicy foods consumed throughout the world. Vinblastine (VBL) is a naturally occurring alkaloid prescribed to cancer patients. Many cancer patients treated with VBL were taking CAP at the same time. This study attempted to investigate the effect of CAP on the pharmacokinetics of VBL, which is the substrate of CYP3A, P-gp, and Mrp2. CAP, cyclosporine (CsA) or olive oil was given to rats for seven consecutive days, and on the seventh day, VBL (1.3 mg/kg) was administered intravenously. CsA was used as a CYP3A1/2 and transporter inhibitor, and olive oil was used as a vehicle. The results showed that pretreatment of rats with CAP (3.0 mg/kg) for seven consecutive days resulted in an increase in the AUC0-t of VBL of about 29.8% (P < 0.05) compared with the control group. Moreover, CAP decreased the CL of VBL to 75.5% (P < 0.05). At this time, CYP3A1/2 and Mrp2/Abcc2 in the liver was decreased at the mRNA and protein levels. These results demonstrate that chronic ingestion of CAP will increase systemic exposure and reduce clearance of VBL in rats. The food-drug interaction between CAP and VBL appears to be due to modulation of CYP3A1/2 and Mpr2 expression by CAP.