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1.
bioRxiv ; 2024 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-38585861

RESUMO

Prostate cancer (PCa) is the most prevalent cancer affecting American men. Castration-resistant prostate cancer (CRPC) can emerge during hormone therapy for PCa, manifesting with elevated serum prostate-specific antigen (PSA) levels, continued disease progression, and/or metastasis to the new sites, resulting in a poor prognosis. A subset of CRPC patients shows a neuroendocrine (NE) phenotype, signifying reduced or no reliance on androgen receptor (AR) signaling and a particularly unfavorable prognosis. In this study, we incorporated computational approaches based on both gene expression profiles and protein-protein interaction (PPI) networks. We identified 500 potential marker genes, which are significantly enriched in cell cycle and neuronal processes. The top 40 candidates, collectively named as CDHu40, demonstrated superior performance in distinguishing NE prostate cancer (NEPC) and non-NEPC samples based on gene expression profiles compared to other published marker sets. Notably, some novel marker genes in CDHu40, absent in the other marker sets, have been reported to be associated with NEPC in the literature, such as DDC, FOLH1, BEX1, MAST1, and CACNA1A. Importantly, elevated CDHu40 scores derived from our predictive model showed a robust correlation with unfavorable survival outcomes in patients, indicating the potential of the CDHu40 score as a promising indicator for predicting the survival prognosis of those patients with the NE phenotype. Motif enrichment analysis on the top candidates suggests that REST and E2F6 may serve as key regulators in the NEPC progression. Significance: our study integrates gene expression variances in multiple NEPC studies and protein-protein interaction network to pinpoint a specific set of NEPC maker genes namely CDHu40. These genes and scores based on their gene expression levels effectively distinguish NEPC samples and underscore the clinical prognostic significance and potential mechanism.

2.
Sci Rep ; 13(1): 22190, 2023 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-38092845

RESUMO

HP501 is a highly selective renal urate transporter 1 (URAT1) inhibitor used for treating hyperuricemia. This study aimed to evaluate the tolerability, pharmacokinetics, and pharmacodynamics of HP501 in male Chinese patients. Patients with hyperuricemia were sequentially assigned to receive oral doses of HP501 (30, 50, 60, 90, and 120 mg) as a single dose on Day 1 and as once-daily doses from Days 4 to 13. Safety, pharmacokinetic, and pharmacodynamic data were collected. Multiple oral doses of HP501 were well-tolerated in all the cohorts. The most common adverse events (≥ 10% of patients) of any grade regardless of drug relationship were gout flare (14 patients, 25.93%), diarrhea (12 patients, 22.22%), elevated ALT (8 patients, 14.81%), hypertriglyceridemia (7 patients, 12.96%), dry mouth (7 patients, 12.96%) and oral ulcer (7 patients, 12.96%). All adverse events were mild or moderate. The Cmax and exposure (AUC) of HP501 was approximately dose-proportional between 30 and 120 mg. A dose-dependent serum uric acid (UA)-lowering effect was observed in the dose range of 30 to 60 mg and the serum UA lowering effect was similar between 90 and 120 mg on day 13, indicating that the maximal serum UA lowering effect of HP501 was achieved at 90 mg in the patients with hyperuricemia. In conclusion, the tolerability, pharmacokinetics, and pharmacodynamics supported 90 mg HP501 for subsequent clinical studies of this highly selective URAT1 inhibitor.Clinical Trial registration: No. CTR20212259 ( http://www.chinadrugtrials.org.cn/ ) was registered in September 2021, and No. CTR20222257 was registered in September 2022.


Assuntos
Gota , Hiperuricemia , Humanos , Masculino , Hiperuricemia/tratamento farmacológico , Gota/tratamento farmacológico , Ácido Úrico , Exacerbação dos Sintomas , Uricosúricos/uso terapêutico , China
3.
Nutrients ; 15(21)2023 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-37960154

RESUMO

Structural changes in the gut microbiota are closely related to the development of functional constipation, and regulating the gut microbiota can improve constipation. Rifaximin is a poorly absorbed antibiotic beneficial for regulating gut microbiota, but few studies have reported its effects on constipation. The purpose of this study was to investigate the effect of rifaximin on loperamide-induced constipation in SD rats. The results showed that rifaximin improved constipation by increasing serum 5-HT, SP, and the mRNA expression of AQP3, AQP8, and reducing the mRNA expression of TLR2 and TLR4. In addition, rifaximin could regulate the gut microbiota of constipated rats, such as increasing the potentially beneficial bacteria Akkermansia muciniphila and Lactobacillus murinus, reducing the Bifidobacterium pseudolongum. According to metabolomics analysis, many serum metabolites, including bile acids and steroids, were changed in constipated rats and were recovered via rifaximin intervention. In conclusion, rifaximin might improve loperamide-induced constipation in rats by increasing serum excitatory neurotransmitters and neuropeptides, modulating water metabolism, and facilitating intestinal inflammation. Muti-Omics analysis results showed that rifaximin has beneficial regulatory effects on the gut microbiota and serum metabolites in constipated rats, which might play critical roles in alleviating constipation. This study suggests that rifaximin might be a potential strategy for treating constipation.


Assuntos
Microbioma Gastrointestinal , Loperamida , Ratos , Animais , Loperamida/efeitos adversos , Rifaximina/efeitos adversos , Ratos Sprague-Dawley , Constipação Intestinal/induzido quimicamente , Constipação Intestinal/tratamento farmacológico , RNA Mensageiro
4.
Nutrients ; 15(17)2023 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-37686889

RESUMO

Irritable bowel syndrome (IBS) is a common gastrointestinal disease. The efficacy of different probiotics in treating IBS remains controversial. This network meta-analysis aimed to compare and rank the outcome-specific efficacy of different probiotic strains or combinations in adults with IBS. We searched the literature up to June 2023. Randomized controlled trials (RCTs) that evaluated the efficacy of probiotics in IBS were included. A frequentist framework was used to perform this study. In total, 9253 participants from 81 RCTs were included in the study. Four probiotic strains and five mixtures were significantly superior to placebo in improving IBS Symptom Severity Scale, among which Lactobacillus acidophilus DDS-1 ranked first (surface under the cumulative ranking, SUCRA, 92.9%). A mixture containing five probiotics (SUCRA, 100%) ranked first in improving the IBS-Quality of life. Bacillus coagulans MTCC 5856 (SUCRA, 96.9%) and Bacillus coagulans Unique IS2 (SUCRA, 92.6%) were among the most effective probiotics for improving abdominal pain. Three probiotic strains and two mixtures were effective in alleviating abdominal bloating. Four probiotic strains and a mixture were significantly superior to placebo in reducing the bowel movement frequency in diarrhea-predominant IBS (IBS-D). Bacillus coagulans MTCC 5856 (SUCRA, 99.6%) and Saccharomyces cerevisiae CNCM I-3856 (SUCRA, 89.7%) were among the most effective probiotics for improving the Bristol stool form scale of IBS-D. Only some probiotics are effective for particular outcomes in IBS patients. This study provided the first ranking of outcome-specific efficacy of different probiotic strains and combinations in IBS. Further studies are needed to confirm these results.


Assuntos
Bacillus coagulans , Síndrome do Intestino Irritável , Probióticos , Adulto , Humanos , Síndrome do Intestino Irritável/terapia , Metanálise em Rede , Dor Abdominal/terapia , Probióticos/uso terapêutico , Saccharomyces cerevisiae
5.
Thorac Cancer ; 14(18): 1764-1773, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37140020

RESUMO

BACKGROUND: In response to therapeutic treatments, cancer cells can exhibit a variety of resistance phenotypes including neuroendocrine differentiation (NED). NED is a process by which cancer cells can transdifferentiate into neuroendocrine-like cells in response to treatments, and is now widely accepted as a key mechanism of acquired therapy resistance. Recent clinical evidence has suggested that non-small cell lung cancer (NSCLC) can also transform into small cell lung cancer (SCLC) in patients treated with EGFR inhibitors. However, whether chemotherapy induces NED to confer therapy resistance in NSCLC remains unknown. METHODS: We evaluated whether NSCLC cells can undergo NED in response to chemotherapeutic agents etoposide and cisplatin. By Knock-down of PRMT5 or pharmacological inhibition of PRMT5 to identify its role in the NED process. RESULTS: We observed that both etoposide and cisplatin can induce NED in multiple NSCLC cell lines. Mechanistically, we identified protein arginine methyltransferase 5 (PRMT5) as a critical mediator of chemotherapy-induced NED. Significantly, the knock-down of PRMT5 or pharmacological inhibition of PRMT5 suppressed the induction of NED and increased the sensitivity to chemotherapy. CONCLUSION: Taken together, our results suggest that targeting PRMT5 may be explored as a chemosensitization approach by inhibiting chemotherapy-induced NED.


Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Cisplatino/farmacologia , Etoposídeo/farmacologia , Diferenciação Celular , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/metabolismo
6.
J Gastroenterol Hepatol ; 38(7): 1072-1082, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-36869260

RESUMO

Irritable bowel syndrome (IBS) is a relatively common functional gastrointestinal disease with a disturbance of intestinal bacteria. Bile acids, gut microbiota, and the host have close and complex interactions, which play a central role in modulating host immune and metabolic homeostasis. Recent studies suggested that the bile acid-gut microbiota axis played a key role in the development of IBS patients. In order to investigate the role of bile acids in the pathogenesis of IBS and present potentially relevant clinical implications, we conducted a literature search on intestinal interactions between bile acid and gut microbiota. The intestinal crosstalk between bile acids and gut microbiota shapes the compositional and functional alterations in IBS, manifesting as gut microbial dysbiosis, disturbed bile acid pathway, and alteration of the microbial metabolites. Collaboratively, bile acid conducts the pathogenesis of IBS through the alterations of the farnesoid-X receptor and G protein-coupled receptor. Diagnostic markers and treatments targeting the bile acids and its receptor showed promising potential in the management of IBS. Bile acids and gut microbiota play a key role in the development of IBS and make attractive biomarkers for treatments. Individualized therapy aiming at bile acids and its receptor may provide significant diagnostic and requires further investigation.


Assuntos
Gastroenteropatias , Microbioma Gastrointestinal , Síndrome do Intestino Irritável , Microbiota , Humanos , Síndrome do Intestino Irritável/microbiologia , Ácidos e Sais Biliares
7.
Comput Struct Biotechnol J ; 20: 5873-5885, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36382181

RESUMO

Metastatic and locally advanced prostate cancer is treated by pharmacological targeting of androgen synthesis and androgen response via androgen signaling inhibitors (ASI), most of which target the androgen receptor (AR). However, ASI therapy invariably fails after 1-2 years. Emerging clinical evidence indicates that in response to ASI therapy, the AR-positive prostatic adenocarcinoma can transdifferentiate into AR-negative neuroendocrine prostate cancer (NEPC) in 17-25 % treated patients, likely through a process called neuroendocrine differentiation (NED). Despite high clinical incidence, the epigenetic pathways underlying NED and ASI therapy-induced NED remain unclear. By utilizing a combinatorial single cell and bulk mRNA sequencing workflow, we demonstrate in a time-resolved manner that following AR inhibition with enzalutamide, prostate cancer cells exhibit immediate loss of canonical AR signaling activity and simultaneous morphological change from epithelial to NE-like (NEL) morphology, followed by activation of specific neuroendocrine (NE)-associated transcriptional programs. Additionally, we observed that activation of NE-associated pathways occurs prior to complete repression of epithelial or canonical AR pathways, a phenomenon also observed clinically via heterogenous AR status in clinical samples. Our model indicates that, mechanistically, ASI therapy induces NED with initial morphological change followed by deactivation of canonical AR target genes and subsequent de-repression of NE-associated target genes, while retaining AR expression and transcriptional shift towards non-canonical AR activity. Coupled with scRNA-seq and CUT&RUN analysis, our model system can provide a platform for screening of potential therapeutic agents that may prevent ASI-induced NED or reverse the NED process.

8.
J Med Chem ; 65(20): 13793-13812, 2022 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-36206451

RESUMO

Protein arginine methyltransferase 5 (PRMT5) is a master epigenetic regulator and an extensively validated therapeutic target in multiple cancers. Notably, PRMT5 is the only PRMT that requires an obligate cofactor, methylosome protein 50 (MEP50), to function. We developed compound 17, a novel small-molecule PRMT5:MEP50 protein-protein interaction (PPI) inhibitor, after initial virtual screen hit identification and analogue refinement. Molecular docking indicated that compound 17 targets PRMT5:MEP50 PPI by displacing the MEP50 W54 burial into a hydrophobic pocket of the PRMT5 TIM barrel. In vitro analysis indicates IC50 < 500 nM for prostate and lung cancer cells with selective, specific inhibition of PRMT5:MEP50 substrate methylation and target gene expression, and RNA-seq analysis suggests that compound 17 may dysregulate TGF-ß signaling. Compound 17 provides a proof of concept in targeting PRMT5:MEP50 PPI, as opposed to catalytic targeting, as a novel mechanism of action and supports further preclinical development of inhibitors in this class.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Proteína-Arginina N-Metiltransferases , Proteína-Arginina N-Metiltransferases/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Simulação de Acoplamento Molecular , Fator de Crescimento Transformador beta
9.
Mol Cancer Ther ; 21(3): 448-459, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35027481

RESUMO

Prostate cancer remains the second leading cause of cancer death among American men. Radiotherapy is a potentially curative treatment for localized prostate cancer, and failure to control localized disease contributes to the majority of prostate cancer deaths. Neuroendocrine differentiation (NED) in prostate cancer, a process by which prostate adenocarcinoma cells transdifferentiate into neuroendocrine-like (NE-like) cells, is an emerging mechanism of resistance to cancer therapies and contributes to disease progression. NED also occurs in response to treatment to promote the development of treatment-induced neuroendocrine prostate cancer (NEPC), a highly aggressive and terminal stage disease. We previously demonstrated that by mimicking clinical radiotherapy protocol, fractionated ionizing radiation (FIR) induces prostate cancer cells to undergo NED in vitro and in vivo. Here, we performed transcriptomic analysis and confirmed that FIR-induced NE-like cells share some features of clinical NEPC, suggesting that FIR-induced NED represents a clinically relevant model. Furthermore, we demonstrated that protein arginine methyltransferase 5 (PRMT5), a master epigenetic regulator of the DNA damage response and a putative oncogene in prostate cancer, along with its cofactors pICln and MEP50, mediate FIR-induced NED. Knockdown of PRMT5, pICln, or MEP50 during FIR-induced NED and sensitized prostate cancer cells to radiation. Significantly, PRMT5 knockdown in prostate cancer xenograft tumors in mice during FIR prevented NED, enhanced tumor killing, significantly reduced and delayed tumor recurrence, and prolonged overall survival. Collectively, our results demonstrate that PRMT5 promotes FIR-induced NED and suggests that targeting PRMT5 may be a novel and effective radiosensitization approach for prostate cancer radiotherapy.


Assuntos
Carcinoma Neuroendócrino , Neoplasias da Próstata , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Carcinoma Neuroendócrino/genética , Diferenciação Celular , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos , Recidiva Local de Neoplasia , Próstata/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/radioterapia , Proteína-Arginina N-Metiltransferases/metabolismo
10.
Cancer Res ; 80(22): 4904-4917, 2020 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-32999000

RESUMO

The majority of advanced prostate cancer therapies aim to inhibit androgen receptor (AR) signaling. However, AR reactivation inevitably drives disease progression to castration-resistant prostate cancer (CRPC). Here we demonstrate that protein arginine methyltransferase 5 (PRMT5) functions as an epigenetic activator of AR transcription in CRPC, requiring cooperation with a methylosome subunit pICln. In vitro and in xenograft tumors in mice, targeting PRMT5 or pICln suppressed growth of CRPC cells. Full-length AR and AR-V7 transcription activation required both PRMT5 and pICln but not MEP50. This activation of transcription was accompanied by PRMT5-mediated symmetric dimethylation of H4R3 at the proximal AR promoter. Further, knockdown of PRMT5 abolished the binding of pICln (but not vice versa) to the AR proximal promoter region, suggesting that PRMT5 recruits pICln to the AR promoter to activate AR transcription. Differential gene expression analysis in 22Rv1 cells confirmed that PRMT5 and pICln both regulate the androgen signaling pathway. In addition, PRMT5 and pICln protein expression positively correlated with AR and AR-V7 protein expression in CRPC tissues and their expression was highly correlated at the mRNA level across multiple publicly available CRPC datasets. Our results suggest that targeting PRMT5 or pICln may be explored as a novel therapy for CRPC treatment by suppressing expression of AR and AR splice variants to circumvent AR reactivation. SIGNIFICANCE: This study provides evidence that targeting PRMT5 can eliminate expression of AR and can be explored as a novel therapeutic approach to treat metastatic hormone-naïve and castration-resistant prostate cancer.


Assuntos
Canais Iônicos/metabolismo , Neoplasias de Próstata Resistentes à Castração/metabolismo , Proteína-Arginina N-Metiltransferases/fisiologia , Receptores Androgênicos/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Crescimento Celular , Progressão da Doença , Regulação para Baixo , Epigênese Genética/fisiologia , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Xenoenxertos , Humanos , Canais Iônicos/antagonistas & inibidores , Canais Iônicos/genética , Masculino , Metilação , Camundongos , Transplante de Neoplasias , Regiões Promotoras Genéticas , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Proteína-Arginina N-Metiltransferases/genética , Receptores Histamínicos H2/metabolismo , Receptores Histamínicos H3/metabolismo
11.
iScience ; 23(1): 100750, 2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-31884170

RESUMO

DNA double-strand break (DSB) repair is critical for cell survival and genome integrity. Upon recognition of DSBs, repair proteins are transiently upregulated to facilitate repair through homologous recombination (HR) or non-homologous end joining (NHEJ). We present evidence that PRMT5 cooperates with pICln to function as a master epigenetic activator of DNA damage response (DDR) genes involved in HR, NHEJ, and G2 arrest (including RAD51, BRCA1, and BRCA2) to upregulate gene expression upon DNA damage. Contrary to the predominant role of PRMT5 as an epigenetic repressor, our results demonstrate that PRMT5 and pICln can activate gene expression, potentially independent of PRMT5's obligate cofactor MEP50. Targeting PRMT5 or pICln hinders repair of DSBs in multiple cancer cell lines, and both PRMT5 and pICln expression positively correlates with DDR genes across 32 clinical cancer datasets. Thus, targeting PRMT5 or pICln may be explored in combination with radiation or chemotherapy for cancer treatment.

12.
RSC Adv ; 8(25): 13871-13878, 2018 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-35539324

RESUMO

Notoginsenoside R1 (NGR1) is separate from Panax notoginsenosides (PNS), and plays a role similar to phytoestrogen in preventing and treating cardiovascular diseases. However, the protective mechanism of NGR1 in the myocardial ischemia/reperfusion injury via the estrogen receptor (ER) pathway remains unclear, which hinder its application. This study aimed to study the preventive mechanisms of NGR1 in the apoptosis of H9c2 cardiomyocytes after hypoxia/reoxygenation (H/R). NGR1 did not affect the expression of ERα and ERß proteins in normal H9c2 cardiomyocytes. However, NGR1 could upregulate the ERα and G protein-coupled receptor 30 (GPR30) proteins in H9c2 cardiomyocytes after H/R without affecting ERß levels. Moreover, it significantly affected the expression levels of PI3K and its downstream apoptosis proteins such as Bcl-2 Associated X Protein (Bax), B cell lymphoma/lewkmia-2 (Bcl-2), caspase-3, and so forth. Whereas, after adding the PI3K protein antagonist, the modulatory expression levels of PI3K and its downstream apoptosis proteins were remarkably abolished. After adding ERα and GPR30 antagonists, NGR1 had no significant effect on the expression of PI3K and its downstream Akt protein in the model group. The data of flow cytometry showed that after adding the ERα, GPR30 and PI3K antagonists, the apoptotic rate of cardiomyocytes had no significant changes compared with the model group. This study demonstrated that NGR1 protected H9c2 cardiomyocytes from the injury after H/R by affecting ERα and GPR30 to regulate the expression levels of PI3K and its downstream apoptosis proteins.

13.
Front Pharmacol ; 8: 777, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29163163

RESUMO

Background: Guanxin Danshen formulation (GXDSF) is a traditional Chinese herbal recipe recorded in the Chinese Pharmacopeia since 1995 edition, which consists of Salviae miltiorrhizae Radix et Rhizoma, Notoginseng Radix et Rhizoma and Dalbergiae odoriferae Lignum. Our previous research suggested GXDSF had positive effect on cardiovascular disease. Therefore, the aim of this study was to elucidate the effects of GXDSF on myocardial ischemia reperfusion injury-induced left ventricular remodelling (MIRI-LVR). Methods: The effects of GXDSF on cardiac function were detected by haemodynamics and echocardiograms. The effects of GXDSF on biochemical parameters (AST, LDH and CK-MB) were analyzed. Histopathologic examinations were performed to evaluate the effect of GXDSF on cardiac structure. In addition, the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database was used to predict the main target of GXDSF. Target validation was conducted by using western blots and immunofluorescent double staining assays. Results: We found that +dp/dt and LVSP were significantly elevated in the GXDSF-treated groups compared with the MIRI-LVR model group. Left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) were increased in the GXDSF-treated groups compared with the model group. All biochemical parameters (AST, LDH and CK-MB) were considerably decreased in the GXDSF-treated groups compared with the model group. Fibrosis parameters (collagen I and III, α-SMA, and left ventricular fibrosis percentage) were decreased to different degrees in the GXDSF-treated groups compared with the model group, and the collagen III/I ratio was elevated by the same treatments. TCMSP database prediction and western blot results indicated that estrogen receptor ß (ERß) could be the main target of GXDSF. PHTPP, a selective antagonist of ERß, could inhibit the expression of ERß and the phosphorylation of PI3K and Akt in myocardial tissue induced by GXDSF, and partly normalize the improving effects of GXDSF on +dp/dt, LVEF, LVFS, LDH, CK-MB, α-SMA and myocardial fibrosis. Conclusion: Collectively, GXDSF showed therapeutic potential for use in the prevention and treatment of myocardial ischemia reperfusion injury-induced ventricular remodeling by upregulating ERß via PI3K/Akt signaling. Moreover, these findings may be valuable in understand the mechanism of disease and provide a potential therapy of MIRI-IVR.

14.
Regul Toxicol Pharmacol ; 83: 81-88, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27916537

RESUMO

Zishen Yutai pill (ZYP) is an oriental herbal formula, while hepatotoxicity assessment of ZYP was rarely evaluated. Therefore, our aim is to re-evaluate its hepatotoxicity in both normal and carbon tetrachloride (CCl4) induced chronic liver injury rats. In the normal model, two doses of ZYP (1.575 and 9.450 g kg-1 d-1; i.e. 1 × , 6 × clinical doses) were given orally to rats for 24 weeks. In the chronic liver injury model, 10% CCl4 was administered to rats abdominally twice a week at a dose of 5 mL kg-1 for 12 consecutive weeks. Administration time started from 4 weeks after the beginning of CCl4 treatment. Toxicological parameters included mortality, body weight, food consumption, clinical signs, biochemical parameters, gross observation, organ weight, necropsy findings and histopathology were monitored. In the normal model, we found no any mortality or abnormality in clinical signs, relative liver weight, biochemical parameters and histopathology in ZYP treatment groups. In the chronic liver injury model, liver damage related parameter such as ALT was elevated at the high dose of ZYP treatment in contrast to the CCl4-treated group (P < 0.01). In histopathological assessment, there were no significant difference between ZYP treatment groups and CCl4-treated group. No observed adverse effect on livers were established for 9.450 g kg-1 d-1 ZYP in the normal rats and 9.450 g kg-1 d-1 ZYP in the injury rats.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/etiologia , Medicamentos de Ervas Chinesas/toxicidade , Fígado/efeitos dos fármacos , Testes de Toxicidade Crônica , Administração Oral , Alanina Transaminase/sangue , Animais , Biomarcadores/sangue , Peso Corporal/efeitos dos fármacos , Tetracloreto de Carbono , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/patologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/administração & dosagem , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Fígado/metabolismo , Fígado/patologia , Necrose , Tamanho do Órgão/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Medição de Risco , Fatores de Tempo
15.
Zhongguo Zhong Yao Za Zhi ; 41(20): 3721-3726, 2016 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-28929647

RESUMO

Coronary artery heart disease (CHD) is one of the common cardiovascular diseases in clinical. The morbidity and mortality of CHD recently continue increasing in our country, which has aroused wide attention. Many studies confirm that traditional Chinese medicine has better therapeutic effect on CHD. Guanxin Danshen formula, widely used in the treatment of CHD, consists of Salviae Miltiorrhizae Radix et Rhizoma, Notoginseng Radix et Rhizoma and volatile oil from Dalbergiae Odoriferae Lignum, and has the efficacy in promoting blood circulation to resolve stasis, regulating the circulation of Qi and alleviating pain. This review summarized the pharmacologic effects and mechanism of Guanxin Danshen formula and its effective components in the treatment of CHD to provide reference for its fundamental research and clinical application.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Cardiopatias/tratamento farmacológico , Vasos Coronários/fisiopatologia , Humanos , Medicina Tradicional Chinesa , Rizoma , Salvia miltiorrhiza
16.
Yao Xue Xue Bao ; 51(7): 1047-53, 2016 07.
Artigo em Chinês | MEDLINE | ID: mdl-29897172

RESUMO

Epigenetic is a hotspot of post-genomic era research, and epigenetic modification is a mechanism in the study of cardiovascular disease. Myocardial ischemia-reperfusion injury (MIRI) is one of the problems in the cardiovascular disease, and many experimental interventions are reported in the protection of the ischemic myocardium in experimental animals. However, with the exception of early reperfusion, none has been translated into clinical practice. There is an advantage of traditional Chinese medicine (TCM) in the regulation of epigenetic modification, and pathogenesis of myocardial ischemia-reperfusion injury. This review article is prepared to cover the research progress in the treatment of myocardial ischemia-reperfusion injury by TCM with a focus on epigenetic regulation. The epigenetic regulation is documented in TCM theory through a systematic review of the protecting drugs in the MIRI development guidelines.


Assuntos
Epigênese Genética , Medicina Tradicional Chinesa , Traumatismo por Reperfusão Miocárdica/terapia , Animais , Substâncias Protetoras/farmacologia
17.
Zhongguo Zhong Yao Za Zhi ; 40(16): 3132-6, 2015 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-26790280

RESUMO

Reperfusion is the most effective treatment for acute myocardial infarction, markedly reducing mortality and morbidity. Reperfusion however induces necrotic and apoptotic damages to cardiomyocytes, that were viable prior to reperfusion, a process called myocardial ischemia/reperfusion injury(MI/RI). Over the past 30 years, hundreds of experimental interventions (both pharmacologic and nonpharmacologic) have been reported to protect the ischemic myocardium in experimental animals; however, with the exception of early reperfusion, none has been translated into clinical practice. The population-based survey assessed men have about twice the total incidence of morbidity and mortality of women, and the sex gap in morbidity tends to diminish after age 45 years. So hormone replacement therapy (HRT) is given to treat the MI/RI, and lots of studies shows that the side effect is greater for estrogen, compared with phyestrogen. In this article, we review the important pathogenesis of myocardial ischemia reperfusion injury, the prevention and limitations of HRT. And we highlight the mechanism of phyestrogens treatment the MI/RI in experiment. The aim is to provide the theoretically new way of develop the safe and effective products for the researchers.


Assuntos
Isquemia Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Fitoestrógenos/administração & dosagem , Extratos Vegetais/administração & dosagem , Animais , Humanos
18.
Am J Cancer Res ; 4(6): 850-61, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25520873

RESUMO

Neuroendocrine differentiation (NED) is a process by which prostate cancer cells transdifferentiate into neuroendocrine-like (NE-like) cancer cells. Accumulated evidence suggests that NED is associated with disease progression and therapy resistance in prostate cancer patients. We previously reported that by mimicking a clinical radiotherapy protocol, fractionated ionizing radiation (FIR) induces NED in prostate cancer cells. Interestingly, FIR-induced NED constitutes two distinct phases: a radioresistance phase in which a fraction of cells selectively survive during the first two week irradiation, and a neuroendocrine differentiation phase in which surviving cells differentiate into NE-like cancer cells during the second two week irradiation. We have also observed increased activation of the transcription factor cAMP response element binding (CREB) protein during the course of FIR-induced NED. To determine whether targeting NED can be explored as a radiosensitization approach, we employed two CREB targeting strategies, CREB knockdown and overexpression of ACREB, a dominant-negative mutant of CREB, to target both phases. Our results showed that ACREB expression increased FIR-induced cell death and sensitized prostate cancer cells to radiation. Consistent with this, knockdown of CREB also inhibited FIR-induced NED and sensitized prostate cancer cells to radiation. Molecular analysis suggests that CREB targeting primarily increases radiation-induced pre-mitotic apoptosis. Taken together, our results suggest that targeting NED could be developed as a radiosensitization approach for prostate cancer radiotherapy.

19.
Phytother Res ; 28(10): 1561-6, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24817590

RESUMO

Our study aims to ascertain the antiinflammatory activity of Veronicastrum axillare and characterize the bioactive constituents. Antiinflammatory activity of the total extract and different fractions from V. axillare was investigated by employing the xylene-induced mouse ear edema model. As a result, the ethyl acetate (EtOAc) fraction showed the highest antiinflammatory activity in vivo. From the EtOAc fraction and the inactive dichloromethane fraction, a total of five new compounds, axillasides A-C and axillactones A and B, together with four known compounds, procumboside A, buergeriside C1 , indole-3-carboxylic acid and apigenin, were isolated and identified. Their structures were elucidated on the basis of spectroscopic analysis and by comparison of their nuclear magnetic resonance data with those reported in the literature. Procumboside A, a major constituent in EtOAc fraction, showed significant antiinflammatory activity in vivo. Further studies revealed that procumboside A was a potent COX-2 inhibitor, significantly reducing the COX-2 protein level in lipopolysaccharide-stimulated RAW 264.7 macrophages.


Assuntos
Anti-Inflamatórios/farmacologia , Ácidos Cafeicos/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Glucosídeos/farmacologia , Magnoliopsida/química , Extratos Vegetais/farmacologia , Animais , Apigenina/isolamento & purificação , Apigenina/farmacologia , Ácidos Cafeicos/isolamento & purificação , Linhagem Celular , Edema/tratamento farmacológico , Glucosídeos/isolamento & purificação , Indóis/isolamento & purificação , Indóis/farmacologia , Lipopolissacarídeos , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Estrutura Molecular , Extratos Vegetais/química
20.
Pharm Biol ; 52(5): 661-3, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24405018

RESUMO

CONTEXT: Veronicastrum axillare (Sieb. et Zucc.) Yamazaki (Scrophulariaceae) embraces varieties of bioactivities such as anti-inflammatory, anti-pyresis and detoxification activity, while little is known of the phytochemical components of this medicinal plant. OBJECTIVE: To isolate and identify bioactive constituents from the whole herb of V. axillare. MATERIALS AND METHODS: Ethanol extract of the whole herb of V. axillare was subjected to successive column chromatography. Chemical structures of the compounds were elucidated by detailed spectroscopic analyses on the basis of NMR, IR and HR-MS data. RESULTS: A new monoterpenoid, axillacetal A (1) and a known analogue, tarumal (2), were isolated from the whole herb of V. axillare. The structure of tarumal (2) was also revised according to our NMR data. DISCUSSION AND CONCLUSION: This is the first report on the isolation and authentication of novel chemical constituents from V. axillare.


Assuntos
Acetatos/isolamento & purificação , Compostos Bicíclicos Heterocíclicos com Pontes/isolamento & purificação , Medicamentos de Ervas Chinesas/isolamento & purificação , Monoterpenos/isolamento & purificação , Scrophulariaceae/química , Cromatografia em Camada Fina , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Estrutura Molecular
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