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1.
Gene ; 808: 145996, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34634440

RESUMO

Russula griseocarnosa is a well-known ectomycorrhizal mushroom, which is mainly distributed in the Southern China. Although several scholars have attempted to isolate and cultivate fungal strains, no accurate method for culture of artificial fruiting bodies has been presented owing to difficulties associated with mycelium growth on artificial media. Herein, we sequenced R. griseocarnosa genome using the second- and third-generation sequencing technologies, followed by de novo assembly of high-throughput sequencing reads, and GeneMark-ES, BLAST, CAZy, and other databases were utilized for functional gene annotation. We also constructed a phylogenetic tree using different species of fungi, and also conducted comparative genomics analysis of R. griseocarnosa against its four representative species. In addition, we evaluated the accuracy of one already sequenced genome of R. griseocarnosa based on the internal transcribed spacer (ITS) sequencing of that type of species. The assembly process resulted in identification of 230 scaffolds with a total genome size of 50.67 Mbp. The gene prediction showed that R. griseocarnosa genome included 14,229 coding sequences (CDs). In addition, 470 RNAs were predicted with 155 transfer RNAs (tRNAs), 49 ribosomal RNAs (rRNAs), 41 small noncoding RNAs (sRNAs), 42 small nuclear RNAs (snRNAs), and 183 microRNAs (miRNAs). The predicted protein sequences of R. griseocarnosa were analyzed to indicate the existence of carbohydrate-active enzymes (CAZymes), and the results revealed that 153 genes encoded CAZymes, which were distributed in 58 CAZyme families. These enzymes included 78 glycoside hydrolases (GHs), 34 glycosyl transferases (GTs), 30 auxiliary activities (AAs), 2 carbohydrate esterases (CEs), 8 carbohydrate-binding modules (CBMs), and only one polysaccharide lyase (PL). Compared with other fungi, R. griseocarnosa had fewer CAZymes, and the number and distribution of CAZymes were similar to other mycorrhizal fungi, such as Tricholoma matsutake and Suillus luteus. Well-defined effector proteins that were associated with mycorrhiza-induced small-secreted proteins (MiSSPs) were not found in R. griseocarnosa, which indicated that there may be some special effector proteins to interact with host plants in R. griseocarnosa. The genome of R. griseocarnosa may provide new insights into the energy metabolism of ectomycorrhizal (ECM) fungi, a reference to study ecosystem and evolutionary diversification of R. griseocarnosa, as well as promoting the study of artificial domestication.

2.
J Med Chem ; 64(22): 16711-16730, 2021 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-34748333

RESUMO

Inhibiting PARP-1/2 offered an important arsenal for cancer treatments via interfering with DNA repair of cancer cells. Novel PARP-1/2 inhibitors were designed by capitalizing on methyl- or ethyl-substituted piperizine ring to capture the characteristics of adenine-ribose binding site (AD site), and their unique binding features were revealed by the cocrystal structures of compounds 4 and 6 in PARP-1. The investigation on structure-activity relationship resulted in compounds 24 and 32 with high enzymatic potency, binding selectivity, and significantly longer residence time for PARP-1 over PARP-2 (compound 24, PARP-1: IC50 = 0.51 nM, PARP-2: IC50 = 23.11 nM; compound 32, PARP-1: IC50 = 1.31 nM, PARP-2: IC50 = 15.63 nM). Furthermore, compound 24 was determined to be an attractive candidate molecule, which possessed an acceptable pharmacokinetic profile and produced remarkable antitumor activity in both breast cancer xenograft model and glioblastoma orthotopic model in mice, either alone or in combination treatment.

3.
Phytochemistry ; 194: 113020, 2021 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-34837764

RESUMO

(+)/(-)-Diobolignans A-F, six pairs of enantiomeric obovatol dimeric neolignans, were isolated from the bark of Magnolia officinalis var. biloba. (+)/(-)-Diobolignans A to C possessed a dioxane ring between the benzene ring and the propyl side chain, while (+)/(-)-diobolignans D to F possessed a furan ring. Meanwhile, (+)/(-)-diobolignans B and C, as well as (+)/(-)-diobolignans E and F, were two epimeric pairs of enantiomers, respectively. Their structures were determined by extensive analyses of HRESIMS, UV, IR, NMR and electronic circular dichroism (ECD) calculations. The bioassay showed (+)-diobolignan A displayed cytotoxic activities against human cancer cell lines HGC27 and HT29 with the IC50 values of 9.43 and 9.45 µM, respectively. In addition, (-)-diobolignan A and (±)-diobolignan E showed neuroprotective effect on glutamic acid-induced cellular damage in SK-N-SH cell.

4.
Ann Transl Med ; 9(18): 1482, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34734034

RESUMO

Background: Recent evidence has emerged concerning hypoglycemia following the application of glucagon-like peptide-1 receptor agonists (GLP-1RAs). Nevertheless, few real-world investigations have been performed to determine the clinical characteristics, onset, and outcomes of hypoglycemia associated with different GLP-1RAs. This study aimed to compare and assess the relationship between various GLP-1RAs and hypoglycemia in a large population based on updated data from the Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: Bayesian and disproportionality analyses were applied to data mining in order to investigate suspected cases of hypoglycemia following various GLP-1RAs using the FAERS data between January 2004 and September 2020. We also evaluated the onset time, fatality risks, and hospitalization proportions of GLP-1RA-related hypoglycemia. Results: We identified 1,164 GLP-1RA-associated hypoglycemia cases, which seemed to affect more middle-aged patients than elderly ones. Also, females were more affected than males. Lixisenatide demonstrated a stronger association with hypoglycemia compared to other GLP-1RAs, according to the highest reporting odds ratio (ROR) (28.03, 95% confidence interval =15.92, 49.32), empirical Bayes geometric mean [26.00, 95% confidence interval (CI): 16.20], and proportional reporting ratio (PRR) (26.01, χ2=313.37). The median time to hypoglycemia onset was 5 days (interquartile range, 0-67.75 days) following GLP-1RA treatment. In general, GLP-1RA-associated hypoglycemia resulted in fatality and hospitalization proportions of 3.53% and 56.08%, respectively. Conclusions: By analyzing the FAERS data, we outlined the association between hypoglycemia and different GLP-1RAs in greater detail in terms of clinical features, onset, and outcomes. Among all six GLP-1RAs, lixisenatide demonstrated the strongest association with hypoglycemia while no relationship between albiglutide and hypoglycemia was observed. Attention should be given to GLP-1RAs when used in patients with high risks of hypoglycemia.

5.
Water Res ; 205: 117694, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34607085

RESUMO

Free Nitrous Acid (FNA) pre-treatment is a promising technology demonstrated effective in improving waste activated sludge degradability and anaerobic digestion (AD) performance. Pre-treatment conditions including FNA concentration and treatment duration determine operational and capital cost of full-scale implementation, which have not been studied in long-term experiments. The knowledge of FNA pre-treatment conditions improving the AD performance is urgently required to determine suitable conditions for the technology implementation. In this work, five different FNA concentrations (2.2, 4.4, 7.2, 12 mgN/L and nitrite only without pH adjustment) and three treatment durations (8, 24 and 48 h) were studied in four lab-scale semi-continuous AD reactors for over 300 days. FNA pre-treatment was shown under all tested conditions effective in enhancing AD performances, while its effectiveness and resulted benefits varied substantially amongst different pre-treatment conditions. The long-term experiment demonstrated that the methane production, sludge reduction and digested sludge viscosity of AD are positively correlated with the FNA concentration and durations, until an optimal condition is reached, which was identified in this work to be FNA concentration of 7.2 mgN/L and treatment duration of 24 h. Microbial community changes supported the apparent observation of enhanced sludge degradation at elevating FNA concentrations applied during pre-treatment. The short-term sludge solubilization results were inconsistent with the long-term AD performance, which was potentially caused by inhibitions from stringent FNA pre-treatment conditions applied (FNA = 12 mgN/L with 24-hour treatment & FNA = 7.2 mgN/L with 48-hour treatment). Overall, results suggested FNA pre-treatment at the optimized condition is highly beneficial to WWTPs and competitive with other pre-treatment technologies, e.g., thermal hydrolysis pre-treatment. This work comprehensively evaluated the key design parameters of FNA pre-treatment process, reached a major milestone in the development and applications of FNA technologies.


Assuntos
Ácido Nitroso , Eliminação de Resíduos Líquidos , Anaerobiose , Reatores Biológicos , Metano , Esgotos
6.
Front Pharmacol ; 12: 741697, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34658878

RESUMO

PURPOSE: To investigate the efficacy and mechanism of compound 23, a PI3K/HDAC dual-target inhibitor, on hematologic tumor cells in vitro and in vivo. Methods: The MTS Kit was used to study the antiproliferative effects in vitro. Western blot was used to analyze the involved signaling pathways. Flow cytometry was used to analyze apoptosis and the cell cycle. The antiproliferative effects were evaluated in vivo using EL4 and A20 xenograft models. The CCLE database was used to analyze gene expression. RESULTS: Compound 23 significantly inhibited the proliferation of hematologic tumors; it simultaneously regulated PI3K/HDAC pathways and induced apoptosis and G1-phase arrest in EL4, NB4, and A20 cells in vitro. When tested in vivo, compound 23 significantly inhibited the proliferation of EL4 and A20. The expression levels of ErbB2 and ErbB3 decreased in hematologic tumors compared with it in solid tumors. CONCLUSION: Compound 23 modulates the PI3K/HDAC pathway, which results in significant inhibition of hematologic tumor proliferation in vivo and in vitro. The differential levels of ERBB2 and ERBB3 might be related to the difference in the effect of compound 23 on hematologic tumors and solid tumors.

7.
Front Oncol ; 11: 708195, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34604047

RESUMO

Background and Objective: Although anti-programmed cell death protein 1 (PD-1) antibodies have exerted remarkable anticancer activity in non-small cell lung cancer (NSCLC), it remains a challenge to identify patients who can benefit from these treatments. Immune-related adverse events (irAEs) may be associated with improved clinical outcomes after immune checkpoint inhibition. However, no conclusive evidence of this correlation has been summarized in patients with NSCLC receiving PD-1 inhibitors. We performed a systematic review and meta-analysis to evaluate the association between irAEs induced by anti-PD-1 antibodies and clinical outcomes in patients with NSCLC. Methods: Various databases were searched from their inception to January 9, 2021, followed by screening of eligible studies. Hazard ratios were used for the pooled analysis of overall survival (OS) and progression-free survival (PFS), while odds ratios (ORs) were utilized to pool objective response rates (ORRs) and disease control rates (DCRs). A random-effects model was applied to all analyses. Results: A total of 26 cohorts, including 8,452 patients with NSCLC receiving anti-PD-1 antibodies, were enrolled in the study. Significantly improved OS (HR: 0.51; 95% CI: 0.44-0.60; P < 0.01) and PFS (HR: 0.50; 95% CI: 0.43-0.58; P < 0.01) were found to be correlated with irAEs. In addition, patients with NSCLC who developed irAEs after PD-1 inhibition demonstrated better responses to therapies, confirmed by pooled ORs of ORRs (OR: 3.41; 95% CI: 2.66-4.35; P < 0.01) and DCRs (OR: 4.08; 95% CI: 2.30-7.24; P < 0.01). Furthermore, subgroup analysis suggested that both skin and endocrine irAEs are closely correlated with a reduced risk of death, whereas pulmonary irAEs showed no association with longer OS. Conclusions: In patients with NSCLC treated with anti-PD-1 therapies, the presence of irAEs was strongly correlated with better survival and response, suggesting its potential role as a predictive biomarker for outcomes after PD-1 inhibition.

8.
J Med Chem ; 64(22): 16626-16640, 2021 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-34676759

RESUMO

Increasing evidence shows that the CXC chemokine receptor 2 (CXCR2) signaling pathway is essentially implicated in the recruitment of myeloid-derived suppressor cells (MDSCs) to the tumor microenvironment and leads to MDSC-mediated immune suppression. Therefore, CXCR2 has recently emerged as a promising drug target for cancer immunotherapy. In this paper, benzocyclic sulfone derivatives were designed as potent CXCR2 antagonists. Structure-activity relationship studies resulted in two lead compounds 9b and 11h, which demonstrated double-digit nanomolar potencies against CXCR2 and significantly inhibited neutrophil infiltration into the air pouch in an in vivo setting. More importantly, 9b and 11h dose-dependently inhibited the tumor growth through oral administration in the Pan02 mouse model. Further cytometry and immunohistochemical analyses revealed that 9b and 11h could reduce the infiltration of neutrophils and MDSCs and enhance the infiltration of CD3+ T lymphocytes into the Pan02 tumor tissues, shedding light on their mechanisms of action in cancer immunotherapy.

9.
Cell Rep ; 36(12): 109706, 2021 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-34551291

RESUMO

The serine synthesis pathway (SSP) involving metabolic enzymes phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), and phosphoserine phosphatase (PSPH) drives intracellular serine biosynthesis and is indispensable for cancer cells to grow in serine-limiting environments. However, how SSP is regulated is not well understood. Here, we report that activating transcription factor 3 (ATF3) is crucial for transcriptional activation of SSP upon serine deprivation. ATF3 is rapidly induced by serine deprivation via a mechanism dependent on ATF4, which in turn binds to ATF4 and increases the stability of this master regulator of SSP. ATF3 also binds to the enhancers/promoters of PHGDH, PSAT1, and PSPH and recruits p300 to promote expression of these SSP genes. As a result, loss of ATF3 expression impairs serine biosynthesis and the growth of cancer cells in the serine-deprived medium or in mice fed with a serine/glycine-free diet. Interestingly, ATF3 expression positively correlates with PHGDH expression in a subset of TCGA cancer samples.

10.
Water Res ; 205: 117671, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34555740

RESUMO

In this study, a Spiral Symmetry Stream Anaerobic Bioreactor (SSSAB) was adopted for treating actual saline heparin sodium pharmaceutical wastewater (HSPW). After adaptation, under the influent COD of 8731 mg/L, OLR of 6.98 kg COD/(m³â€¢d) and salinity of 3.57 wt%, the COD removal reached up to 82%. This value is much higher than the reported for the other reactors at similar salinity. Benzenes are the major organic compounds in HSPW. The main rate-limiting steps are the degradations of phenol and p-cresol. In addition, the degradation pathways of typical benzenes in HSPW were analyzed. After adaptation, the soluble salt content in the granular sludge increased, and the bacterial extracellular polymers (EPS), especially tightly-bound EPS also significantly increased. 16S rRNA analysis revealed that the microbial community in the anaerobic granular sludge (AGS) had become adapted to the HSPW treatment since Mesotoga (12.4%), Anaerophaga (9.0%), Oceanotoga (6.1%) and Aminobacterium (4.1%) increased from previously below 1.0% values. The relative abundance of Methanosarcina in the upper layer of the reactor (68.7%) is significantly higher than that at the bottom (3.8%). This proves the superiority of the SSSAB structure. Finally, a model for salt-tolerant microorganisms is given, which proposes a mechanism for this study and provides reference for other anaerobic biological treatments of high-salt containing wastewater.


Assuntos
Preparações Farmacêuticas , Águas Residuárias , Anaerobiose , Reatores Biológicos , Heparina , RNA Ribossômico 16S/genética , Rios , Tolerância ao Sal , Eliminação de Resíduos Líquidos
11.
Biomed Chromatogr ; : e5223, 2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34350591

RESUMO

The effective fraction of coumarin glycosides from Hydrangea paniculata Sieb (HP) has been under development for the treatment of chronic kidney disease for years. Skimmin and apiosylskimmin are the main coumarin glycosides of HP, and the major metabolites in rats are 7-hydroxycoumarin (7-HC) and 7-hydroxycoumarin glucuronide (7-HCG). In this study, a sensitive and reliable liquid chromatography-Orbitrap mass spectrometry method was developed for the simultaneous determination of skimmin, apiosylskimmin, 7-HC and 7-HCG in rat plasma. The chromatographic separation was performed on a Zobax SB C18 column (2.1 × 100 mm, 3.5 µm) at a flow rate of 0.3 ml/min with a gradient mobile phase of water and acetonitrile containing 0.2% formic acid. Skimmin, apiosylskimmin and 7-HCG were detected in targeted-selected-ion-monitoring mode at positive ions m/z of 325.0911, 457.1331 and 339.0703, respectively. 7-HC and the internal standard were detected in parallel-reaction-monitoring mode at m/z 163.0387 → 119.0492 and 260.1641 → 116.1071 to overcome the carryover of 7-HC. Linearity was obtained for the analytes within the ranges 20-2,000 ng/ml for skimmin, 5-500 ng/ml for apiosylskimmin and 7-HC and 100-10,000 ng/ml for 7-HCG. Validation parameters were all in line with the criteria of international guidance. The method has been applied to the pharmacokinetic study of HP in rats.

12.
Bioresour Technol ; 340: 125702, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34385128

RESUMO

This work aimed to study the treatment of polyvinyl alcohol containing wastewater (PVA-containing wastewater) discharged from textile industry. The batch experiment verified the feasibility of anaerobic treatment and determined that the optimal substrate COD was around 3000 mg/L. The single spiral symmetrical stream anaerobic bioreactor (SSSAB) was used for treating PVA-containing wastewater, which shows the stability of SSSAB and the improvement of biodegradability of wastewater. Finally, two stage SSSABs coupled SBR was proposed. By this scheme, under the influent COD of 3014 mg/L and PVA of 413 mg/L, the COD and PVA removal reached 89.4% and 90.7%, respectively, which were higher than the values obtained by other schemes. Contribution rates of reactors show that each reactor plays an essential role, and SEM images show the unique of microbial flora in each SSSAB. The SSSAB-SSSAB-SBR process can provide an alternative to the chemical methods for treating PVA-containing wastewater.


Assuntos
Álcool de Polivinil , Águas Residuárias , Anaerobiose , Reatores Biológicos , Rios , Eliminação de Resíduos Líquidos
13.
Sci Total Environ ; 801: 149722, 2021 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-34425439

RESUMO

Anaerobic co-digestion (AcoD) has become an important mean for the stabilization and recycling of textile dyeing sludge (TDS). Using the soybean okara byproduct (SOB) as a co-digestion substrate, the effects on AcoD performance and heavy metal stability were studied. The results indicated that the optimal mixing ratio was 1:1 (calculated by total sloid). Under this condition, the SCOD removal efficiency was 64% (that of TDS alone and SOB alone were 47% and 48%, respectively) and the cumulative methane production field was 503 L CH4/kg VS (that of TDS alone and SOB alone were 435 L CH4/kg VS and 408 L CH4/kg VS, respectively). At the same time, the addition of SOB could also enhance the stability of heavy metals (Zn, Cu, Cr and Ni) in TDS. Remarkably, that could increase the steady state content nickel from 47.98% to 57.21%, while anaerobic digestion of TDS caused no increase but a decrease (only 42.13%). According to the risk assessment code analyses, the AcoD of TDS by SOB can significantly reduce the ecotoxicity risk caused by Ni, Zn and Cr.


Assuntos
Metais Pesados , Esgotos , Anaerobiose , Reatores Biológicos , Digestão , Metano , Têxteis
14.
Front Pharmacol ; 12: 677120, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34234673

RESUMO

IMMH-010 is a prodrug of YPD-29B, which is a novel PD-L1 inhibitor. A specific and sensitive LC-MS/MS method with polarity switching was developed and validated for the simultaneous determination of IMMH-010 and YPD-29B in rat plasma, liver, brain, urine and fecal samples. Method validation was investigated to demonstrate the lower limit of quantification linearity, precision and accuracy, matrix effect and recovery, stability and dilution reliability for IMMH-010 and YPD-29B. This validated method was successfully applied to investigate the pharmacokinetics, tissue distribution, and excretion of IMMH-010 and YPD-29B in rats. After oral administration of IMMH-010 maleate to rats, IMMH-010 was rapidly and extensively converted to the active metabolite YPD-29B. The areas under the plasma concentration-time curve (AUC) of IMMH-010 and YPD-29B were proportional to the dose in the range of 10-100 mg/kg. IMMH-010 was primarily distributed in the adrenal gland, lymph nodes, heart, liver and spleen. YPD-29B was mainly observed in the liver, lymph, kidney, and lung. Approximately 28.81% of the IMMH-010 dose was recovered in the urine and feces within 72 h, including unchanged IMMH-010 (7.99%) and YPD-29B (20.82%). The results of this study may be useful as a reference for further development of IMMH-010 and PD-L1 inhibitors. Clinical Trial Registration: [https://clinicaltrials.gov/ct2/show/NCT04343859?term=IMMH-010&draw=2&rank=1], identifier [NCT04343859]."

15.
J Immunother Cancer ; 9(7)2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34272308

RESUMO

BACKGROUND: Mesenteric lymph nodes (MLNs) are critical draining lymph nodes of the immune system that accommodate more than half of the body's lymphocytes, suggesting their potential value as a cancer immunotherapy target. Therefore, efficient delivery of immunomodulators to the MLNs holds great potential for activating immune responses and enhancing the efficacy of antitumor immunotherapy. Self-microemulsifying drug delivery systems (SMEDDS) have attracted increasing attention to improving oral bioavailability by taking advantage of the intestinal lymphatic transport pathway. Relatively little focus has been given to the lymphatic transport advantage of SMEDDS for efficient immunomodulators delivery to the MLNs. In the present study, we aimed to change the intestinal lymphatic transport paradigm from increasing bioavailability to delivering high concentrations of immunomodulators to the MLNs. METHODS: Chlorogenic acid (CHA)-encapsulated SMEDDS (CHA-SME) were developed for targeted delivery of CHA to the MLNs. The intestinal lymphatic transport, immunoregulatory effects on immune cells, and overall antitumor immune efficacy of CHA-SME were investigated through in vitro and in vivo experiments. RESULTS: CHA-SME enhanced drug permeation through intestinal epithelial cells and promoted drug accumulation within the MLNs via the lymphatic transport pathway. Furthermore, CHA-SME inhibited tumor growth in subcutaneous and orthotopic glioma models by promoting dendritic cell maturation, priming the naive T cells into effector T cells, and inhibiting the immunosuppressive component. Notably, CHA-SME induced a long-term immune memory effect for immunotherapy. CONCLUSIONS: These findings indicate that CHA-SME have great potential to enhance the immunotherapeutic efficacy of CHA by activating antitumor immune responses.

16.
Eur J Pharmacol ; 907: 174264, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34147476

RESUMO

Dengue fever is a common arbovirus disease, which has been spread to the entire tropical world. At present, effective drugs for the treatment of dengue fever have not yet appeared, and the dengue vaccines studied in various countries have also experienced severe adverse reactions. Thus it is urgent to find new chemicals against dengue virus. Now we found Sirtuins (SIRTs) were increased during dengue virus infection and tenovin-1, a SIRT1/2 inhibitor, showed an impressive antiviral ability in vitro. In BHK-21 cells, tenovin-1 inhibited the replication of DENV2 with an EC50 at 3.41 ± 1.10 µM, also inhibited other three types of dengue viruses with EC50 at 0.97 ± 1.11 µM, 1.81 ± 1.08 µM, 3.81 ± 1.34 µM respectively. Moreover, the cytopathic effect-induced DENV2 was largely improved by tenovin-1 treatment and the release of progeny viruses was inhibited by tenovin-1 treatment. At the same time, the viral protein level and mRNA level were decreased with tenovin-1 treatment after dengue virus infection. From the drug-addition assay, the tenovin-1 played its antiviral after viral infection, which indicated tenovin-1 was not a microbicide. Apart from its antiviral effect, tenovin-1 inhibited the inflammatory response caused by DENV2, reducing the release of inflammatory factors during viral infection. The antiviral effect of tenovin-1 was abrogated with SIRT agonist or SIRT2 knockdown treatment, which indicated the effect of tenovin-1 was on-target. In conclusion, tenovin-1 was proved to be a promising compound against flavivirus infection through SIRT2, which should be pay more attention for further study.

17.
Eur J Med Chem ; 223: 113634, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34147745

RESUMO

Selective inhibition of cyclin-dependent kinase 8 (CDK8) has been recently regarded as a potential approach for cancer therapy. A series of novel CDK8 inhibitors with the pyridine core was identified via scaffold hopping from the known CDK8 inhibitor A-7. The new inhibitors were designed to improve the ligand efficiency so as to enhance drug-likeness. Most of the compounds showed significant inhibition against CDK8/cyclin C, and the most active compounds (5d, 5e and 7') displayed IC50 values of 2.4 nM, 5.0 nM and 7.7 nM, respectively. Preliminary kinase profiling of selected compounds against a panel of kinases from different families indicated that this compound class might selectively inhibit CDK8 as well as its paralog CDK19. Some compounds exhibited cellular activity in both MTT and SRB assays against a variety of tumor cells, including HCT-116, A549, MDA-MB-231, KB, KB-VIN and MCF-7. Further flow cytometry analysis revealed a dose-dependent G2/M phase arrest in MDA-MB-231 cells treated with compounds 6'a, 6'b, 6'j and 6'k. In addition, compound 6'k demonstrated moderate antitumor efficacy in HCT-116 mouse models, although unfavorable pharmacokinetic profiles were suggested by preliminary study in mice. The results provided a new structural prototype for the search of selective CDK8 inhibitors as antitumor agents.


Assuntos
Antineoplásicos/uso terapêutico , Quinase 8 Dependente de Ciclina/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinase 8 Dependente de Ciclina/metabolismo , Desenho de Fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Piridinas/síntese química , Piridinas/metabolismo , Piridinas/farmacocinética , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Pharmacol Res ; 170: 105721, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34116207

RESUMO

Dengue virus (DENV) is the most prevalent arthropod-borne viral disease of humans and has a major impact on global public health. There is no clinically approved drugs for DENV infection. Since intracellular VEGFR2 is increased in DENV infected patients, we thus hypothesized that VEGFR2 participated DENV proliferation and its inhibitors could be served as antivirals against DENV. Actually our results showed that VEGFR2 was induced by DENV infection. Also the agonist of VEGFR2, VEGF-A, promoted DENV proliferation. Therefore, we screened the inhibitors of VEGFR2 and found that brivanib alaninate (brivanib) showed the best anti-DENV ability with the lowest cellular cytotoxicity. Mechanically, our results indicated VEGFR2 directly interacted with PTP1B to dephosphorylate AMPK to provide lipid environment for viral replication. However, this effect could be inhibited by brivanib, which significantly reversed the reduction of AMPK phosphorylation caused by DENV infection, thus improving the cellular lipid environment. Moreover, the antiviral effect of brivanib could be reversed by AMPK inhibitor, Compound C. In addition, oral administration of brivianib (20-50 mg/kg/day) clearly improved the survival rate of DENV2 infection, and this effect was abolished in accompanied with Compound C (10mg/kg/day). Collectively, our study disclosed the mechanism of VEGFR2 in DENV2 and evaluated the antiviral ability of brivanib, which deserved more attention for clinical usage in DENV infection.

19.
Animal Model Exp Med ; 4(2): 138-150, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34179721

RESUMO

Programmed cell death protein 1 (PD-1) /programmed cell death ligand 1 (PD-L1) blockade is an important therapeutic strategy for melanoma, despite its low clinical response. It is important to identify genes and pathways that may reflect the clinical outcomes of this therapy in patients. We analyzed clinical dataset GSE96619, which contains clinical information from five melanoma patients before and after anti-PD-1 therapy (five pairs of data). We identified 704 DEGs using these five pairs of data, and then the number of DEGs was narrowed down to 286 in patients who responded to treatment. Next, we performed KEGG pathway enrichment and constructed a DEG-associated protein-protein interaction network. Smooth muscle actin 2 (ACTA2) and tyrosine kinase growth factor receptor (KDR) were identified as the hub genes, which were significantly downregulated in the tumor tissue of the two patients who responded to treatment. To confirm our analysis, we demonstrated similar expression tendency to the clinical data for the two hub genes in a B16F10 subcutaneous xenograft model. This study demonstrates that ACTA2 and KDR are valuable responsive markers for PD-1/PD-L1 blockade therapy.


Assuntos
Antígeno B7-H1 , Melanoma , Actinas/genética , Apoptose , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Humanos , Ligantes , Melanoma/tratamento farmacológico , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular
20.
Acta Pharmacol Sin ; 2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-33990764

RESUMO

Renal fibrosis contributes to progressive damage to renal structure and function. It is a common pathological process as chronic kidney disease develops into kidney failure, irrespective of diverse etiologies, and eventually leads to death. However, there are no effective drugs for renal fibrosis treatment at present. Lipid aggregation in the kidney and consequent lipotoxicity always accompany chronic kidney disease and fibrosis. Numerous studies have revealed that restoring the defective fatty acid oxidation in the kidney cells can mitigate renal fibrosis. Thus, it is an important strategy to reverse the dysfunctional lipid metabolism in the kidney, by targeting critical regulators of lipid metabolism. In this review, we highlight the potential "druggability" of lipid metabolism to ameliorate renal fibrosis and provide current pre-clinical evidence, exemplified by some representative druggable targets and several other metabolic regulators with anti-renal fibrosis roles. Then, we introduce the preliminary progress of noncoding RNAs as promising anti-renal fibrosis drug targets from the perspective of lipid metabolism. Finally, we discuss the prospects and deficiencies of drug targeting lipid reprogramming in the kidney.

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