Search

Purpose: Xianglian Zhixie Tablet (XLZXT), a classical traditional Chinese medicine formulation, is commonly used to treat Ulcerative Colitis (UC) in China. However, the therapeutic mechanisms of XLZXT for UC have yet to be fully understood. This study aimed to investigate the curative benefits of XLZXT and its associated mechanisms for healing UC in mice.Methods: In the present study, the 1% dextran sulfate sodium (DSS) solution was used to establish the UC model in C57BL/6N mice. To investigate the therapeutic effects of XLZXT on DSS-induced UC mice, several parameters were measured, including DAI score, colon length, spleen index, pathological changes in colon tissue, and levels of inflammatory factors in plasma and colon tissue. By investigating the gut microbiota, assessing the levels of intestinal mucosal protein expression, and looking at the proteins involved in the TLR4/MyD88/NF-B p65 signaling pathway, the mechanisms of XLZXT impact on UC were investigated. Mouse feces were examined for patterns of gut microbiota expression using high-throughput sequencing of 16S rRNA.Results: XLZXT effectively alleviated UC symptoms and colon pathological damage in DSS-induced UC mice. It improved body weight loss, stool consistency, and hematochezia, while also repairing colon damage. Moreover, it down-regulated pro-inflammatory cytokines (such as TNF-α, IL-1β, and IL-6), and up-regulated anti-inflammatory cytokines (such as IL-10). XLZXT also increased the expression of MUC-2, Occludin and ZO-1, while decreasing the expression of NF-κB, MyD88 and TLR4. Additionally, it regulated gut microbiota disorder by increasing the abundance of beneficial bacteria and reducing the adhesion of intestinal harmful bacteria.Conclusion: XLZXT demonstrated therapeutic effects on DSS-induced UC mice. The mechanisms may be associated with repairing the intestinal mucosal barrier, regulating the TLR4/MyD88/NF-κB p65 signaling pathway, and restoring the balance of gut microbiota.Plain Language Summary: This is the first study to probe the therapeutic potential of XLZXT for UC. Our findings indicated that XLZXT could effectively alleviate the clinical symptoms of UC and in-depth apparently modify the levels of relevant cytokines in the organism to maintain the system homeostasis. Our results suggested that XLZXT might treat DSS-induced UC by repairing the intestinal mucosa barrier, regulating the TLR4/MyD88/NF-κB p65 signaling pathway, and restoring gut microbiota balance. [ABSTRACT FROM AUTHOR]

Dehydrocostus lactone (DL) is among the representative ingredients of traditional Chinese medicine (TCM), with excellent anticancer, antibacterial, and anti-inflammatory activities. In this study, an advanced strategy based on ultra-high-performance liquid chromatography–quadrupole-Orbitrap high-resolution mass spectrometry (UHPLC–Q-Orbitrap HRMS) was integrated to comprehensively explore the metabolic fate of DL in rats. First, prior to data collection, all biological samples (plasma, urine, and feces) were concentrated and purified using solid-phase extraction (SPE) pre-treatment technology. Then, during data collection, in the full-scan (FS) data-dependent acquisition mode, FS-ddMS2 was intelligently combined with FS-parent ion list (PIL)-dynamic exclusion (DE) means for targeted monitoring and deeper capture of more low-abundance ions of interest. After data acquisition, data-mining techniques such as high-resolution extracted ion chromatograms (HREICs), multiple mass defect filters (MMDFs), diagnostic product ions (DPIs), and neutral loss fragments (NLFs) were incorporated to extensively screen and profile all the metabolites in multiple dimensions. As a result, a total of 71 metabolites of DL (parent drug included) were positively or tentatively identified. The results suggested that DL in vivo mainly underwent hydration, hydroxylation, dihydrodiolation, sulfonation, methylation, dehydrogenation, dehydration, N-acetylcysteine conjugation, cysteine conjugation, glutathione conjugation, glycine conjugation, taurine conjugation, etc. With these inferences, we successfully mapped the "stepwise radiation" metabolic network of DL in rats, where several drug metabolism clusters (DMCs) were discovered. In conclusion, not only did we provide a refined strategy for inhibiting matrix effects and fully screening major-to-trace metabolites, but also give substantial data reference for mechanism investigation, in vivo distribution visualization, and safety evaluation of DL. [ABSTRACT FROM AUTHOR]

[Display omitted] • Developed a novel structure of LSD1 small molecule inhibitor through rational design. • 10e was optimized through rational design, which showed significant inhibitory activity against LSD1 in vitro. 10e exhibited a significant tumor inhibition rate in vivo. A new set of compounds known as sulfonyl benzoyl hydrazide derivatives were synthesized and tested using cellular assays. Through systematic optimization starting from general structure S-1, compound 10e emerged as highly promising. It exhibited potent inhibitory activity with an IC 50 value of 0.8 nM and possessed moderate clogP. Compounds 10e significantly inhibited solid tumor cells proliferation. Additionally, 10e induced apoptosis and arrested the cell cycle. Furthermore, in vivo studies using an HCT116 xenograft model showed substantial growth inhibition of tumors, accompanied by a favorable safety profile. These findings underscored compound 10e as a novel LSD1 inhibitor with robust efficacy both in vitro and in vivo , establishing it as a promising lead compound for further anticancer drug development. [ABSTRACT FROM AUTHOR]

Human dihydroorotate dehydrogenase (DHODH), the enzyme that catalyzes the rate‐limiting step in de novo pyrimidine biosynthesis, is considered to be an attractive target for potential treatment of autoimmune disease and cancer. Here, we present a novel class of human DHODH inhibitors with high inhibitory potency. The high‐resolution crystal structures of human DHODH complexed with various agents reveal the details of their interactions. Comparisons with the binding modes of teriflunomide and brequinar provide insights that may facilitate the development of new inhibitors targeting human DHODH. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC), a malignancy with high mortality and recurrence rates, has very limited options for treatment strategies. Dehydrocostus lactone (DL) is the principal quality marker extracted from Aucklandia lappa Decne. and has been demonstrated to possess excellent anticancer activity. The key purpose of this study was to explore the therapeutic effects and potential mechanisms of DL on HCC. The effect of DL on the cell viability of HCC cell lines (HepG2 and SK-HEP-1) and normal human hepatocyte cell line (L-O2) was examined by CCK8, colony formation, and BeyoClickTMEdU-488 assays; Hoechst 33,258 staining and flow cytometry were utilized to determine the impact of DL on apoptosis; the sensitivity of HCC cells to DL was explored by adding Z-VAD-fmk. In addition, the expression of apoptosis-related proteins Bax, Bcl-2, and PARP was detected by western blotting; the expression of p-H2AX was investigated by western blotting and immunofluorescence staining; cell cycle distribution was observed using flow cytometry; the migration ability and invasiveness of HCC cells were assessed by wound healing assay and transwell assay; immunoblotting was applied to visualize the levels of EMT markers in the two HCC cell lines. Transcriptome sequencing was performed to reveal the underlying mechanisms of DL anti-tumor; western blotting and qRT-PCR were employed to verify the mRNA and protein abundance of p53, p21, and CDK2; HepG2 xenograft in mice was used to test the anti-tumor effects of DL in vivo. DL suppressed the proliferation of HCC cell lines (HepG2 and SK-HEP-1) but had little effect on a normal human liver cell line (L-O2). In addition, DL also induced apoptotic death of the HCC cells by activating Bax and downregulating Bcl-2. The antiproliferative effects of DL could be attributed to increased DNA damage and G1-phase cell cycle arrest. Moreover, DL inhibited HCC cell invasiveness and migration in vitro by decreasing the levels of β-catenin, N-cadherin, and TCF8/ZEB1, and increasing the E-cadherin level. RNA sequencing indicated that DL exerted its anti-hepatoma effects partly via regulation of p53-p21-CDK2 signaling. These results were validated by our in vivo experiments, in which DL markedly suppressed the growth of HepG2 xenografts in a mouse model without any toxic side effects, which corresponded to decreased expression of Ki67 and MMP9 in the tumor tissues. DL has significant anti-cancer effects in both in vivo and in vitro HCC models, and therefore could be further developed as a promising drug for the treatment of HCC. [ABSTRACT FROM AUTHOR]

A precise and sensitive LC method was developed and further validated for the determination of enantiomeric purity of ( S)- N-[2-(3-{ trans-4-hydroxy-4-[5-(pyrimidin-2-yl)pyridin-2-yl] cyclohexylamino} pyrrolidin-1-yl)-2-oxoethyl]-3-(trifluoromethyl) benzamide (PF-04136309). Baseline separation with a resolution higher than 1.8 was accomplished within 40 min using a CHIRALPAK AD (250 × 4.6 mm; particle size 5 μm) column, with n-hexane:2-propanol (70:30 v/v) as mobile phase at a flow rate of 1 mL min. The eluted analytes were subsequently detected with a UV detector at 260 nm. The effects of mobile phase components and temperature on enantiomeric selectivity as well as the resolution of enantiomers were thoroughly investigated. The calibration curves were plotted within a concentration range between 0.01 and 1 mg mL ( n = 9), and recoveries between 98.17 and 101.28 % were obtained, with relative standard deviation (RSD) lower than 1.44 %. The LOD and LOQ for PF-04136309 were 3.59 and 11.54 μg mL and for its enantiomer were 3.39 and 11.28 μg mL, respectively. The developed method was demonstrated to be accurate, robust and sensitive for the determination of enantiomeric purity of PF-04136309, especially for the analysis of bulk samples. [ABSTRACT FROM AUTHOR]

A series of novel tetrahydropyridine derivatives were prepared and evaluated using cell-based measurements. Systematic optimization of general structure G-1 led to the identification of compound 35 (EC 50 = 4.9 nM) and 37 (EC 50 = 8.8 nM) with high GPR119 agonism activity and moderate clog P. Through single and long-term pharmacodynamic experiments, we found that compound 35 showed a hypoglycemic effect and may have an effect on improving basal metabolic rate in DIO mice. Both in vitro and in vivo tests indicated that compound 35 was a potential potent GPR119 agonist in allusion to T2DM treatment. [ABSTRACT FROM AUTHOR]

Lysine-specific demethylase1 (LSD1) plays a crucial role in cancer and has become a promising target for cancer therapy. However, the mechanism underlying the role of LSD1 in oncogenesis is poorly understood, and more effective LSD1 inhibitors are needed. Here we report the biological activity of a novel LSD1 inhibitor named ZY0511. ZY0511 specifically inhibited LSD1 activity and the proliferation of various human cancer cells especially the HeLa and HCT116 cells. ZY0511 significantly increased the expression of DDIT4 , a known mTORC1 suppressor, which was a direct downstream target of LSD1 confirmed by ChIP-PCR. ZY0511-induced LSD1 inhibition upregulated the expression of DDIT4 by altering histone H3K4 methylation levels at its promoter, thus suppressing mTORC1 activity. Knockdown of DDIT4 attenuated the anticancer effect of ZY0511. Intraperitoneal administration of ZY0511 significantly prevented the growth of HCT116 and HeLa xenografts in mice and showed no detectable toxicity. Moreover, DDIT4 expression was correlated with the sensitivity of human cancer cells to chemotherapy. Taken together, ZY0511 showed therapeutic potential for solid tumors, the induction of DDIT4 may be used as a predictive biomarker of LSD1 inhibitors. • ZY0511 is a novel LSD1 inhibitor which inhibits cancer cells proliferation. • DDIT4 is a direct downstream target of LSD1 which is a mTORC1 negative regulator. • ZY0511 triggers DDIT4 expression through altering H3K4me1/2 level of its promoter. • DDIT4 is correlated with cancer cells' sensitivity to chemotherapy. [ABSTRACT FROM AUTHOR]

Epidemiological studies have shown that an elevated uric acid (UA) level predicts the development of metabolic syndrome and diabetes; however, there is no direct evidence of this, and the underlying mechanism remains unclear. Here, we showed that a high-UA diet triggered the expression of pro-inflammatory cytokines, activated the NF-κB pathway, and increased gliosis in the hypothalamus. Intracerebroventricular injection of UA induced hypothalamic inflammation and reactive gliosis, whereas these effects were markedly ameliorated by the inhibition of NF-κB. Moreover, magnetic resonance imaging confirmed that hyperuricemia in rodents and humans was associated with gliosis in the mediobasal hypothalamus. Importantly, the rats administered UA exhibited dyslipidemia and glucose intolerance, which were probably mediated by hypothalamic inflammation and hypothalamic neuroendocrine alterations. These results suggest that UA can cause hypothalamic inflammation via NF-κB signaling. Our findings provide a potential therapeutic strategy for UA-induced metabolic disorders. [ABSTRACT FROM AUTHOR]

[Display omitted] A series of novel procaine derivatives for intravenous anesthesia were prepared and evaluated by physicochemical properties and pharmacodynamic experiments in vivo and in vitro. Systematic optimization of procaine led to the identification of 6f , 6g , 6h , 6o , 6p and 6q with higher TI value and moderate log D. Compared with procaine (TI = 1.65), most procaine derivatives demonstrated better security, among which compound 6h (TI = 2.68) was the most notable one and showed fewer adverse events in animals. The result of hNR2B-HEK293 assay indicated that compound 6h suppressed the NMDA receptor 2B subtype channel activity and it showed more than 80% inhibitory effect at the concentration of 500 μM. [ABSTRACT FROM AUTHOR]