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1.
J Med Chem ; 2021 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-33591748

RESUMO

SAR efforts directed at identifying RORγt inverse agonists structurally different from our clinical compound 1 (BMS-986251) led to tricyclic-carbocyclic analogues represented by 3-7 and culminated in the identification of 3d (BMS-986313), with structural differences distinct from 1. The X-ray co-crystal structure of 3d with the ligand binding domain of RORγt revealed several key interactions, which are different from 1. The in vitro and in vivo PK profiles of 3d are described. In addition, we demonstrate robust efficacy of 3d in two preclinical models of psoriasis-the IMQ-induced skin lesion model and the IL-23-induced acanthosis model. The efficacy seen with 3d in these models is comparable to the results observed with 1.

2.
Bioanalysis ; 13(3): 147-159, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33543654

RESUMO

Background: Surrogate monoclonal antibodies (mAbs) used in preclinical in vivo studies can be challenging to quantify due to lack of suitable immunoaffinity reagents or unavailability of the mAb protein sequence. Generic immunoaffinity reagents were evaluated to develop sensitive LC-MS/MS assays. Peptides of unknown sequence can be used for selective LC-MS quantification. Results: anti-mouse IgG1 was found to be an effective immunoaffinity reagent, enabling quantification of mouse IgG1 mAbs in mouse serum. Selective peptides of unknown sequence were applied for multiplex LC-MS quantification of two rat mAbs co-dosed in mouse. Conclusion: Generic anti-mouse IgG subtype-specific antibodies can be used to improve assay sensitivity and peptides of unknown sequence can be used to quantify surrogate mAbs when the mAb protein sequence in unavailable.

3.
Chemosphere ; 263: 127868, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32828052

RESUMO

Microcystins-LR (MCLR) is a potent reproductive system toxin. We have previously shown that MCLR induced endoplasmic reticulum (ER) stress and apoptosis in testis. ER is the main calcium storage site in cells, and its calcium homeostasis plays an important role in the regulation of apoptosis. Hence, in the present study, we have investigated the role of calcium (Ca2+) in inducing apoptosis and how it affect the mitochondria and endoplasmic reticulum in TM4 cells. Our study found that MCLR induced an increase in Ca2+ concentration in TM4 cells. Compared to the controls, MCLR induced phosphorylation of calmodulin-dependent protein kinase II (CaMKII) which was involved in MAPKs activation, resulting in the induction of mitochondrial apoptosis pathways. Ca2+ chelator Bapta-AM partially reversed MCLR-induced apoptosis, confirming the possible involvement of calcium homeostasis disruption after MCLR exposure. Meanwhile, MCLR activated unfolded protein response and activated the ER apoptotic pathway by activating caspase-12. In addition, exposure to MCLR causes mitochondrial defects and increased apoptosis by up-regulating caspase 3 and cytosol cytochrome c expression. Collectively, these results demonstrated that MCLR disturbed calcium homeostasis, which caused ER-mitochondria dysfunction, ultimately promoted cell apoptosis in Sertoli cells.


Assuntos
Cálcio , Estresse do Retículo Endoplasmático , Apoptose , Homeostase , Masculino , Microcistinas , Células de Sertoli
4.
Eur J Cancer Prev ; 30(1): 113-119, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32032154

RESUMO

We aimed to detect the expression of specific LncRNAs in exosomes isolated from the serum of patients with precancerous lesions and to study the effect of these serum exosomes on the activity of GES-1 cells in patients with precancerous lesions, as well as the activity of all-trans retinoic acid on GES-1 cells with or without the exosomes. Exosomes were extracted from the serum of patients with precancerous lesions and normal controls. Based on our previous sequencing results, quantitative real time-PCR was used to detect differentially expressed LncRNAs. Exosomes from the serum of patients with precancerous lesions were cocultured with GES-1 cells, and 5 µM all-trans retinoic acid was added as an intervention. Changes in cell viability and expression of LncHOXA10 were observed. Compared with the blank group, the proliferation activity of GES-1 cells cocultured with exosomes derived from the serum of patients with precancerous lesions was increased (P < 0.01), the proportion of cells in S phase was increased (P < 0.05). After adding 5 µM all-trans retinoic acid, the viability of cells decreased significantly (P < 0.01), the proportion of cells in S phase decreased significantly (P < 0.05). The expression of LncHOXA10 was decreased (P < 0.05). All-trans retinoic acid can conduct its chemopreventive effects by inhibiting the expression of LncHOXA10, thereby reducing the activity of LncHOXA10 in GES-1 cells cocultured with serum exosomes from patients with precancerous lesions.

5.
Nutr Cancer ; : 1-17, 2020 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-33349059

RESUMO

The relationship of dairy consumption and liver cancer risk is still controversial. We conducted a meta-analysis of published cohort and case-control studies to summarize the epidemiologic evidence on the relationship between dairy products consumption and the risk of liver cancer. The literatures were screened from PubMed, EMBASE, and Cochrane Library before May 2020. A total of seven cohort studies and eight case-control studies (5,121 cases) were included. The summary relative risks (RRs) were 1.17 (95% CI: 0.87‒1.57) and 1.08 (95% CI: 0.78‒1.51) for milk and total dairy, respectively. 0.50 (95% CI: 0.27-0.91) and 1.16 (95% CI: 0.83-1.52) were yogurt, cheese, and curd. Subgroup analysis revealed that study duration, alcohol, and design were associated the RRs. Dose-response analysis showed that the liver cancer risk was decreased by 5.4% (P for linear trend = 0.002) with a 40 g/day increment of yogurt intake. These results suggested that total dairy, milk, cheese, and curd were positive associations with the liver cancer risk although they were not statistically significant, however higher yogurt intake would reduce the risk. Further studies are necessary to verify the relationship of dairy foods with cancer.

6.
Med Sci Monit ; 26: e925772, 2020 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-33219199

RESUMO

BACKGROUND Increasing evidence suggests that the alternative splicing (AS) signature plays a role in the carcinogenesis and prognosis of various cancers. However, the prognostic role of AS in gastric cancer is not clear and needs to be clarified. MATERIAL AND METHODS To identify the differentially expressed AS (DEAS) events, we performed a differential expression analysis between normal and tumor tissue. The DEAS event was further applied to construct a prognostic signature by performing univariate Cox regression analysis and least absolute shrinkage and selection operator (LASSO) analysis. The Kaplan-Meier curve analysis and receiver operating characteristic curve (ROC) analysis were used to evaluate the prognostic value of the AS signature. In addition, the network of the splicing events with splicing factors was constructed using the Cytoscape software. RESULTS A total of 30 005 alternative splicing (AS) events with 372 patients were retrieved from the SpliceSeq database and TCGA database. By performing differential expression analysis, a total of 419 alternative splicing events were screened out, including 56 upregulated and 363 downregulated. We further constructed an AS-related prognostic signature by conducting a series bioinformatics analyses. Moreover, we identified that the AS signature could serve as an independent predictor for the prognosis of GC. We also found that AS signature had a more robust and precise efficacy for prognostic prediction in GC patients. Interestingly, the areas under 3- and 5-year survival curves are similar, both of which are greater than 1-year survival curve, suggesting that the long-term predictive accuracy of our prognostic model built upon AS signature is superior. CONCLUSIONS We performed a comprehensive analysis of overall prognostic-associated AS events concerning GC and constructed a prognostic model to predict the long-term prognostic survival outcomes in GC patients. We also developed a network of splicing events with splicing factors to reveal new potential molecular diagnostic biomarkers and therapeutic targets for GC patients.

7.
J Food Biochem ; : e13537, 2020 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-33107045

RESUMO

This study investigates the hepatoprotective effect of the aqueous extract of Polygonatum sibiricum (AEPS) against ethanol-induced oxidative stress and explores underlying mechanisms. AEPS was administered by gavage to ICR mice for 30 days. The experimental mice were fed a 5% (v/v) ethanol on last 10 days and followed by a single megadose of ethanol (5 g/kg) to induce ethanol-induced liver injury. Pretreatment with AEPS significantly suppressed the ethanol-induced elevation of aminotransferase activities, total bilirubin (TBIL) level, triglyceride level, and alleviated liver histopathological lesions. Meanwhile, AEPS reduced the level of oxidative stress in the liver and significantly suppressed the mRNA levels of NOX1, p67phox, gp91phox, and CYP2E1. Additionally, AEPS significantly increased the mRNA and protein levels of Nrf2 and its downstream antioxidant genes and promoted the nuclear translocation of Nrf2 in mice liver. Therefore, AEPS can effectively reduce ethanol-induced liver injury via regulation of the Nrf2/ARE pathway. PRACTICAL APPLICATIONS: Alcohol abuse and alcoholism have become a serious public health problem worldwide. Since liver is the major organ of alcohol metabolism, the most impactful damage of alcohol occurs in the liver. Polygonatum sibiricum is a traditional Chinese galenical and it also can be used as food ingredients. Most studies have reported that polysaccharide, flavonoids and saponins are the main bioactive compounds in Polygonatum sibiricum which play important roles in anti-oxidation. AEPS is the aqueous extract of Polygonatum sibiricum and AEPS can protect the mice liver against ethanol-induced oxidative damage. Thus it can be potential antioxidants to product hepatoprotective food and the study also provides a theoretical basis for the development and application of food about Polygonatum sibiricum.

8.
Nutr Cancer ; : 1-13, 2020 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-32959699

RESUMO

Numerous long noncoding RNAs (LncRNAs) were having recently been shown to be involved in cancer development, including gastric cancer (GC). However, the precise mechanism and treatments to target these molecules have rarely been studied. Thus, we aimed to investigate the function of LncHOXA10 in gastric tumorigenesis and targeted therapy. First, we measured the differences in LncHOXA10 and retinoic acid receptor ß (RAR-ß) levels in gastric cancer tissues and cell lines compared with those in noncancerous tissues and cell lines. We observed that LncHOXA10 was significantly upregulated in gastric cancer tissues and cell lines, whereas RAR-ß showed the opposite trend. Subsequently, loss and gain of LncHOXA10 cell lines were constructed to determine whether LncHOXA10 plays a role in gastric tumorigenesis. The results showed that LncHOXA10 promoted the proliferation, migration, and invasion of cells, whereas apoptosis was markedly inhibited. Subsequently, mechanistic investigations revealed that LncHOXA10 can repress RAR-ß expression and that all-trans retinoic acid (ATRA) can rescue the expression of RAR-ß. Finally, we showed that ATRA can reverse the pro-cancerous function of LncHOXA10. We showed that LncHOXA10 may be a prognostic and therapeutic factor of gastric cancer by negatively regulating RAR-ß. Furthermore, ATRA can inhibit the role of LncHOXA10 in gastric tumorigenesis.

9.
Bioorg Med Chem Lett ; 30(23): 127521, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32882417

RESUMO

In order to rapidly develop C6 and C8 SAR of our reported tricyclic sulfone series of RORγt inverse agonists, a late-stage bromination was employed. Although not regioselective, the bromination protocol allowed us to explore new substitution patterns/vectors that otherwise would have to be incorporated at the very beginning of the synthesis. Based on the SAR obtained from this exercise, compound 15 bearing a C8 fluorine was developed as a very potent and selective RORγt inverse agonist. This analog's in vitro profile, pharmacokinetic (PK) data and efficacy in an IL-23 induced mouse acanthosis model will be discussed.

10.
Bioorg Med Chem Lett ; 30(17): 127392, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32738966

RESUMO

A novel series of cis-3,4-diphenylpyrrolidines were designed as RORγt inverse agonists based on the binding conformation of previously reported bicyclic sulfonamide 1. Preliminary synthesis and structure-activity relationship (SAR) study established (3S,4S)-3-methyl-3-(4-fluorophenyl)-4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxyprop-2-yl)phenyl)pyrrolidine as the most effective scaffold. Subsequent SAR optimization led to identification of a piperidinyl carboxamide 31, which was potent against RORγt (EC50 of 61 nM in an inverse agonist assay), selective relative to RORα, RORß, LXRα and LXRß, and stable in human and mouse liver microsomes. Furthermore, compound 31 exhibited considerably lower PXR Ymax (46%) and emerged as a promising lead. The binding mode of the diphenylpyrrolidine series was established with an X-ray co-crystal structure of 10A/RORγt.

11.
Front Oncol ; 10: 1327, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32850421

RESUMO

Human papillomavirus (HPV) 16 E6 has been proved to increase the radiosensitivity and lead to the EGFR overexpression in cervical cancer cells. In this study, to investigate the inhibition of nimotuzumab-mediated EGFR blockade combined with radiotherapy, we established a C33A cervical squamous cell line overexpressed HPV16-E6 and a nude mouse model bearing these cell lines. The CCK-8 assay was used to detect the effects of various treatments on the proliferation of C33A cells. Flow cytometry was used to detect the rates of apoptosis and cell cycle arrest. Gene transcription and protein expression were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot, respectively. Immunohistochemical staining was used to evaluate protein expression in tumor tissue. We revealed that E6-overexpressing C33A cells grew faster and were more sensitive to radiotherapy than control cells in vitro and in vivo. The expression levels of EGFR, as well as those of downstream signaling molecules AKT and ERK 1/2, were significantly upregulated in C33A cells that overexpressed E6. We observed that nimotuzumab combined with radiotherapy could enhance the inhibition of C33A cell growth induced by E6, both in vitro and in vivo. We also observed enhanced effect after combination on G2/M cell cycle arrest and apoptosis in E6-overexpressing C33A cells. Furthermore, the combined therapy of nimotuzumab and radiation remarkably reduced the protein expression levels of EGFR, AKT, ERK 1/2 in vitro, and in vivo. In conclusion, HPV16 E6 expression is positively correlated with levels of EGFR, AKT, and ERK 1/2 protein expression. The combined treatment with nimotuzumab and radiotherapy to enhance radiosensitivity in E6-positive cervical squamous cell carcinoma was related to enhanced G2/M cell cycle arrest and caspase-related apoptosis.

12.
Bioorg Med Chem Lett ; 30(19): 127466, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32763309

RESUMO

RORγt is the master regulator of the IL-23/IL-17 axis, a pathway that is clinically validated for the treatment of various immunological disorders. Over the last few years, our group has reported different chemotypes that potently act as inverse agonists of RORγt. One of them, the tricyclic pyrrolidine chemotype, has demonstrated biologic-like preclinical efficacy and has led to our clinical candidate BMS-986251. In this letter, we discuss the invention of an annulation reaction which enabled the synthesis of a tricyclic exocyclic amide chemotype and the identification of compounds with RORγt inverse agonist activity. Preliminary structure activity relationships are disclosed.

13.
Bioorg Med Chem Lett ; 30(19): 127441, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32736080

RESUMO

In an effort to discover oral inverse agonists of RORγt to treat inflammatory diseases, a new 2,6-difluorobenzyl ether series of cyclopentyl sulfones were found to be surprisingly more potent than the corresponding alcohol derivatives. When combined with a more optimized phenyl ((R)-3-phenylpyrrolidin-3-yl)sulfone template, the 2,6-difluorobenzyl ethers yielded a set of very potent RORγt inverse agonists (e.g., compound 26, RORγt Gal4 EC50 11 nM) that are highly selective against PXR, LXRα and LXRß. After optimizing for stability in human and mouse liver microsomes, compounds 29 and 38 were evaluated in vivo and found to have good oral bioavailability (56% and 101%, respectively) in mice. X-ray co-crystal structure of compound 27 in RORγt revealed that the bulky benzyl ether group causes helix 11 of the protein to partially uncoil to create a new, enlarged binding site, which nicely accommodates the benzyl ether moiety, leading to net potency gain.

14.
ACS Med Chem Lett ; 11(6): 1221-1227, 2020 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-32551004

RESUMO

Novel tricyclic analogues were designed, synthesized, and evaluated as RORγt inverse agonists. Several of these compounds were potent in an IL-17 human whole blood assay and exhibited excellent oral bioavailability in mouse pharmacokinetic studies. This led to the identification of compound 5, which displayed dose-dependent inhibition of IL-17F production in a mouse IL-2/IL-23 stimulated pharmacodynamic model. In addition, compound 5 was studied in mouse acanthosis and imiquimod-induced models of skin inflammation, where it demonstrated robust efficacy comparable to a positive control. As a result of this excellent overall profile, compound 5 (BMS-986251) was selected as a clinically viable developmental candidate.

15.
Eur J Immunol ; 50(9): 1400-1411, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32388860

RESUMO

Inflammatory bowel diseases (IBD) are chronic conditions that result from uncontrolled intestinal inflammation. Pathogenic Th17 cells, characterized by production of IL-17A in the absence of IL-10, are thought to contribute to this inflammation, but in humans, antibody-mediated blockade of IL-17A is an ineffective IBD therapy whereas IL-23 blockade is effective. Here, we investigated the effects of pharmacological inhibition of RORC2, the Th17 cell lineage-defining transcription factor, on in vivo-differentiated human Th17 cells and Th17-like Tregs (Th17-Tregs). BMS-336, a small molecule RORC2 inverse agonist, inhibited expression of RORC2-regulated genes in peripheral Th17 cells (CD4+ CD25- CD127+ CXCR3- CCR4+ CCR6+ ) in a dose-dependent manner, with similar inhibitory effects on laminar propria mononuclear cells from IBD and non-IBD subjects. Exposure of peripheral Th17-Tregs (CD4+ CD25hi CD127lo CXCR3- CCR4+ CCR6+ ) to BMS-336 also inhibited IL-17A production and prevented inflammatory cytokine-induced destabilization, as evidenced by preserved FOXP3 expression and epigenetic status of the Treg-specific demethylation region. In parallel, RORC2 inhibition increased the production of IL-10 in Th17-Tregs, resulting in enhanced suppression of inflammatory cytokines from myeloid cells. Thus, via its ability to simultaneously inhibit Th17 cells and enhance the stability and function of Th17-Tregs, pharmacological inhibition of RORC2 is a promising approach to suppress inflammation and promote immune regulation in IBD.

16.
Br J Nutr ; 124(3): 330-340, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32234090

RESUMO

Primary liver cancer is the third leading cause of cancer-related death worldwide. Most patients are diagnosed at late stages with poor prognosis; thus, identification of modifiable risk factors for primary prevention of liver cancer is urgently needed. The well-established risk factors of liver cancer include chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV), heavy alcohol consumption, metabolic diseases such as obesity and diabetes, and aflatoxin exposure. However, a large proportion of cancer cases worldwide cannot be explained by current known risk factors. Dietary factors have been suspected as important, but dietary aetiology of liver cancer remains poorly understood. In this review, we summarised and evaluated the observational studies of diet including single nutrients, food and food groups, as well as dietary patterns with the risk of developing liver cancer. Although there are large knowledge gaps between diet and liver cancer risk, current epidemiological evidence supports an important role of diet in liver cancer development. For example, exposure to aflatoxin, heavy alcohol drinking and possibly dairy product (not including yogurt) intake increase, while intake of coffee, fish and tea, light-to-moderate alcohol drinking and several healthy dietary patterns (e.g. Alternative Healthy Eating Index) may decrease liver cancer risk. Future studies with large sample size and accurate diet measurement are warranted and need to consider issues such as the possible aetiological heterogeneity between liver cancer subtypes, the influence of chronic HBV or HCV infection, the high-risk populations (e.g. cirrhosis) and a potential interplay with host gut microbiota or genetic variations.


Assuntos
Dieta Saudável , Dieta/efeitos adversos , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/etiologia , Adulto , Idoso , Inquéritos sobre Dietas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Observacionais como Assunto , Fatores de Risco
17.
Hepatology ; 2020 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-32150756

RESUMO

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is characterized by accumulation of excessive triglycerides (TGs) in hepatocytes. Obesity is a major risk factor for developing fatty liver, although the intracellular molecular basis remains largely unclear. N6 -methyladenosine (m6 A) RNA methylation is the most common internal modification in eukaryotic mRNA. APPROACH AND RESULTS: In the present study, by m6 A sequencing and RNA sequencing, we found that both m6 A enrichment and mRNA expression of lipogenic genes were significantly increased in leptin-receptor-deficient db/db mice. Importantly, our results showed that YT521-B homology domain-containing 2 (Ythdc2), an m6 A reader, was markedly down-regulated in livers of obese mice and NAFLD patients. Suppression of Ythdc2 in livers of lean mice led to TG accumulation, whereas ectopic overexpression of Ythdc2 in livers of obese mice improved liver steatosis and insulin resistance. Mechanistically, we found that Ythdc2 could bind to mRNA of lipogenic genes, including sterol regulatory element-binding protein 1c, fatty acid synthase, stearoyl-CoA desaturase 1, and acetyl-CoA carboxylase 1, to decrease their mRNA stability and inhibit gene expression. CONCLUSIONS: Our findings describe an important role of the m6 A reader, Ythdc2, for regulation of hepatic lipogenesis and TG homeostasis, which might provide a potential target for treating obesity-related NAFLD.

18.
J Med Chem ; 62(21): 9931-9946, 2019 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-31638797

RESUMO

RORγt is an important nuclear receptor that regulates the production of several pro-inflammatory cytokines such as IL-17 and IL-22. As a result, RORγt has been identified as a potential target for the treatment of various immunological disorders such as psoriasis, psoriatic arthritis, and inflammatory bowel diseases. Structure and computer-assisted drug design led to the identification of a novel series of tricyclic RORγt inverse agonists with significantly improved in vitro activity in the reporter (Gal4) and human whole blood assays compared to our previous chemotype. Through careful structure activity relationship, several potent and selective RORγt inverse agonists have been identified. Pharmacokinetic studies allowed the identification of the lead molecule 32 with a low peak-to-trough ratio. This molecule showed excellent activity in an IL-2/IL-23-induced mouse pharmacodynamic study and demonstrated biologic-like efficacy in an IL-23-induced preclinical model of psoriasis.


Assuntos
Desenho de Fármacos , Agonismo Inverso de Drogas , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Pirrolidinas/farmacologia , Animais , Humanos , Células Jurkat , Camundongos , Modelos Moleculares , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/química , Conformação Proteica , Pirrolidinas/química , Pirrolidinas/farmacocinética , Relação Estrutura-Atividade , Distribuição Tecidual
19.
Oncol Lett ; 18(2): 1607-1616, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31423228

RESUMO

Chemotherapy resistance is a major obstacle to the effective treatment of patients with gastric cancer (GC). Mounting evidence has indicated that the dysregulation of microRNAs (miRNAs) is associated with the sensitivity of cancer cells to chemotherapy. However, the mechanisms underlying miRNA-mediated chemoresistance in GC cells remain to be elucidated. The present study aimed to identify functional miRNAs that may regulate the sensitivity of human GC cells to cisplatin (DDP) treatment. miRNA microarray analysis was used to identify differentially expressed miRNAs between the human cisplatin-sensitive GC cell line SGC7901 and the corresponding cisplatin-resistant cell line SGC7901/DDP. miRNA (miR)-362-5p, which is associated with numerous types of tumors, was identified to be downregulated in the SGC7901/DDP cell line. However, the biological role of miR-362-5p in SGC7901/DDP cells remains to be explored. The expression level of miR-362-5p was demonstrated to be reduced in SGC7901/DDP cells compared with SGC7901 cells by reverse transcription-quantitative PCR. Upregulation of miR-362-5p significantly increased cisplatin sensitivity and cisplatin-induced apoptosis, whereas downregulation of miR-362-5p attenuated these effects. Databases predicted that suppressor of zeste 12 protein (SUZ12) may function as a target of miR-362-5p. In addition, the mRNA and protein expression levels of SUZ12 in SGC7901/DDP cells were significantly higher compared with SGC7901 cells and negatively associated with miR-362-5p expression. MTT and western blot analysis assays confirmed that knockdown of SUZ12 enhanced cisplatin sensitivity and decreased NF-κB/p65 protein levels in SGC7901/DDP cells. In addition, upregulation of miR-362-5p in SGC7901/DDP cells decreased the protein expression level of SUZ12, whereas downregulation of miR-362-5p increased the SUZ12 expression level. The results of the present study suggested that dysregulated miR-362-5p may target SUZ12 to promote the development of cisplatin resistance and attenuate cisplatin-induced apoptosis. Therefore, miR-362-5p upregulation combined with cisplatin treatment may serve as a promising therapeutic strategy for patients with cisplatin-resistant GC.

20.
Sci Transl Med ; 11(502)2019 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-31341059

RESUMO

TYK2 is a nonreceptor tyrosine kinase involved in adaptive and innate immune responses. A deactivating coding variant has previously been shown to prevent receptor-stimulated activation of this kinase and provides high protection from several common autoimmune diseases but without immunodeficiency. An agent that recapitulates the phenotype of this deactivating coding variant may therefore represent an important advancement in the treatment of autoimmunity. BMS-986165 is a potent oral agent that similarly blocks receptor-stimulated activation of TYK2 allosterically and with high selectivity and potency afforded through optimized binding to a regulatory domain of the protein. Signaling and functional responses in human TH17, TH1, B cells, and myeloid cells integral to autoimmunity were blocked by BMS-986165, both in vitro and in vivo in a phase 1 clinical trial. BMS-986165 demonstrated robust efficacy, consistent with blockade of multiple autoimmune pathways, in murine models of lupus nephritis and inflammatory bowel disease, supporting its therapeutic potential for multiple immune-mediated diseases.


Assuntos
Autoimunidade/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , TYK2 Quinase/química , Animais , Feminino , Voluntários Saudáveis , Compostos Heterocíclicos/farmacologia , Humanos , Interferon alfa-2/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos SCID , Inibidores de Proteínas Quinases/farmacologia , TYK2 Quinase/antagonistas & inibidores
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