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1.
J Med Chem ; 64(8): 4588-4611, 2021 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-33792311

RESUMO

The inhibition of glutaminase 1 (GLS1) represents a potential treatment of malignant tumors. Structural analysis led to the design of a novel series of macrocyclic GLS1 allosteric inhibitors. Through extensive structure-activity relationship studies, a promising candidate molecule 13b (LL202) was identified with robust GLS1 inhibitory activity (IC50 = 6 nM) and high GLS1 binding affinity (SPR, Kd = 24 nM; ITC, Kd = 37 nM). The X-ray crystal structure of the 13b-GLS1 complex was resolved, revealing a unique binding mode and providing a novel structural scaffold for GLS1 allosteric inhibitors. Importantly, 13b clearly adjusted the cellular metabolites and induced an increase in the ROS level by blocking glutamine metabolism. Furthermore, 13b exhibited a similar in vivo antitumor activity as CB839. This study adds to the growing body of evidence that macrocyclization provides an alternative and complementary approach for the design of small-molecule inhibitors, with the potential to improve the binding affinity to the targets.

2.
Hepatol Int ; 2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33826043

RESUMO

PURPOSE: This study aimed to assess efficacy and safety of anlotinib as a first- or second-line treatment for advanced or metastatic hepatocellular carcinoma (aHCC) and to identify the predictive plasma cytokines on efficacy of anlotinib. METHODS: It was a phase II clinical study. Patients with aHCC were recruited from October 2016 to April 2019 and divided into two cohorts according to previous tyrosine kinase inhibitors (TKIs) therapy. Those without or with prior TKIs were in Cohort 1 or 2, respectively. All patients took anlotinib (12 mg/day, Day1-14, 3 weeks per cycle). The primary endpoint was 12-week progression-free survival (PFS) rate. Relationship between the series plasma cytokine level and the efficacy of anlotinib was analyzed. RESULTS: Enrolled 26 patients in Cohort 1 and 24 in Cohort 2. In Cohort 1, the 12-week PFS rate was 80.8% [95% confidence interval (CI); 59.8%-91.5%] and median time to progression (TTP) was 5.9 months (95% CI 4.8-6.9). In Cohort 2, the 12-week PFS rate and median TTP was 72.5% (95% CI 48.7%-86.6%) and 4.6 months (95% CI 2.7-10.0), respectively. The median TTP on patients with a baseline plasma level of CXCL1 (C-X-C motif chemokine ligand 1) less than 7.6 ng/µl was significantly longer in both cohorts. The most common grade 3-5 adverse events were hypertension (8%), diarrhea (8%) and hand-foot syndrome (6%). CONCLUSION: Anlotinib showed promising efficacy and safety as a first- or second-line treatment with a continuous TKIs treatment strategy in aHCC. The plasma CXCL1 might be a predictor for the efficacy of anlotinib.

3.
Ann Palliat Med ; 2021 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-33832313

RESUMO

BACKGROUND: It is necessary to identify valuable predictors of primary lymph node metastasis and prognosis for patients with synchronous colorectal cancer liver metastases (CRLM) with simultaneous resection of colorectal cancer (CRC) and liver metastases. This study constructed nomograms especially incorporating preoperative testing markers to predict primary lymph node metastases and prognosis in CRLM patients. METHODS: By the highest Youden index (sensitivity + 1-specificity), the optimal cut-off values of testing markers for postoperative major complications and lymph node metastasis were identified. Multivariate regression analysis was used to reveal independent predictors for primary lymph node metastasis, postoperative major complications and progression-free survival (PFS). Nomograms based on independent predictors were constructed, and the discrimination and calibration were evaluated. RESULTS: A nomogram predicting primary lymph node metastasis was based on four risky independent predictors: American Society of Anesthesiologists (ASA) score 3-4, preoperative albumin (ALB) <41.15 g/ L, poor differentiation and multiple liver metastases. The performance of the model was acceptable in predicting lymph node metastasis, with an area under the receiver operating characteristic curve (AUROC) of 0.655 (95% CI: 0.591-0.739). Calibration curves and the Hosmer-Lemeshow test revealed desirable model calibration (chi-square: 13.26, P=0.815). In the multivariate analysis, preoperative lactate dehydrogenase (LDH) ≥202.5 U/L [odds ratio (OR) =2.084, 95% confidence interval (CI): 1.039-4.181, P=0.039] and operation time ≥350.5 min (OR =2.848, 95% CI: 1.418-5.723, P=0.003) were independently associated with the presence of postoperative major complications. A nomogram predicting PFS was constructed based on poor differentiation, positive lymph node metastasis, bilobar liver distribution and R0 resection with good discrimination (C-index: 0.656±0.021) and calibration. CONCLUSIONS: This study established predictive nomograms specifically incorporating preoperative ALB and LDH levels for the prediction of primary lymph node metastasis and prognosis in synchronous CRLM patients with simultaneous resection, which have favourable discrimination and calibration to make individualized predictions.

4.
Ann Palliat Med ; 2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33832316

RESUMO

BACKGROUND: This study aimed to investigate the predictive significance of preoperative red cell volume distribution width (RDW) level for prognosis and to establish nomograms incorporating preoperative blood markers to predict postoperative complications and survival in patients with colorectal liver metastases (CRLM). METHODS: This retrospective study included 380 enrolled CRLM patients who underwent hepatic resection. Predictors of postoperative complications were explored using binary logistic regression analysis. Covariates associated with overall survival (OS) and progression-free survival (PFS) were evaluated through univariate and multivariate Cox regression analyses. Only variables that reached statistical significance at P<0.1 in the univariate analysis were allowed to enter the multivariate analyses. The independent predictors that retained in the final multivariate model were incorporated into nomograms. RESULTS: The optimal cut-off point of preoperative RDW-CV was 16%, and elevated RDW-CV was significantly associated with better prognosis (mPFS: 5.0 vs. 8.9 months, P=0.007; mOS: 59.0 vs. 42.0 months, P=0.041). The optimal cut-off point of preoperative RDW-SD was 43.9 fl, and elevated RDWSD was significantly associated with worse prognosis (mPFS: 8.0 vs. 13.0 months, P<0.001; mOS:36.8 vs. 70.2 months, P=0.001). A nomogram predicting postoperative complications was constructed based on preoperative gamma-glutamyl transpeptidase (GGT) ≥34.5 U/L, preoperative RDW-CV ≥14.1%, and intraoperative blood loss ≥200.0 mL, with AUROC of 0.658. The calibration curves and HosmerLemeshow test revealed desirable model calibration (chi-square: 3.99, P=0.91). A nomogram predicting PFS was constructed based on preoperative GGT ≥31.0 U/L, preoperative D-dimer ≥0.251 mg/L, preoperative RDW-CV <16.0%, preoperative RDW-SD ≥43.9 fl, positive lymph node metastasis, bilobar liver distribution, and R0 resection with good discrimination (C-index: 0.676±0.016) and calibration. A nomogram for the prediction of OS was constructed with favorable discrimination (C-index: 0.700±0.021) and calibration. Significant differences in PFS and OS were shown among patients stratified into three different risk groups (P<0.001) based on the nomograms. CONCLUSIONS: This study first revealed the relationship between preoperative RDW-SD, RDW-CV, and prognosis in patients with CRLM. It also established nomograms especially considering preoperative blood markers to predict postoperative complications, PFS, and OS, which facilitated physicians to determine the optimal clinical management strategies.

5.
Eur J Med Chem ; 218: 113394, 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33813153

RESUMO

Herein, we describe the design, synthesis, and structure-activity relationships of a series of imidazopyrrolopyridines derivatives that selectively inhibit Janus kinase 2 (JAK2). These screening cascades revealed that 6k was a preferred compound, with IC50 values of 10 nM for JAK2. Moreover, 6k was a selective JAK2 inhibitor with 19-fold, >30-fold and >30-fold selectivity over JAK1, JAK3 and TYK2 respectively. In cytokine-stimulated cell-based assays, 6k exhibited a higher JAK2 selectivity over JAK1 isoforms. Indeed, at a dose of 20 mg/kg compound 6k, pSTAT3 and pSTAT5 expression was reduced to levels comparable to those of control animals untreated with GM-CSF. Additionally, 6k showed a relatively good bioavailability (F = 38%), a suitable half-life time (T1/2 = 1.9 h), a satisfactory metabolic stability, suggesting that 6k might be a promising inhibitor of JAK2 for further development research for the treatment of MPNs.

6.
Free Radic Biol Med ; 167: 205-217, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33713839

RESUMO

Cancer cells prefers to rely on aerobic glycolysis than pyruvate oxidation to meet the high demand of energy for rapidly proliferation. Peroxisome proliferator-activated receptors (PPARs) are a kind of important ligand-inducible transcription factors and play crucial roles in glucose and lipid metabolism. Careful designing of novel agonists for PPARs, may show improvement with the side effects and also increase the therapeutic value for cancer and other metabolic disorder diseases. Compared with normal human liver cells, lower expression or acitivity of PPARs is observed in hepatocellular carcinoma (HCC). In this study, we show that oroxyloside (OAG) is a new dual agonist of PPARγ/ɑ, and inhibits cell proliferation of HCC based on metabolic switch. Via both PPAR-dependent and PPAR-independent regulations on glycolipid metabolic enzymes, OAG shuts down the catabolism of glucose and promotes fatty acids oxidation to generate acetyl-CoA for TCA cycle and oxidative phosphorylation. The metabolic switch induced by OAG results in a marked increase of reactive oxygen species (ROS) levels, leading to rapid dephosphorylation of RB and cell-cycle arrest in G1 phase. Pyruvate dehydrogenase kinase 4 (PDK4) and ß-Oxidation are required for the suppression of cell cycle progression by OAG. Together, our findings provide a new drug candidate and a viable therapeutic strategy for HCC based on metabolic reprogram.

7.
Eur J Med Chem ; 217: 113376, 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-33756125

RESUMO

Prostate cancer (PCa) is one of the most common malignancies affecting men worldwide. Androgen receptor (AR) has been a target of PCa treatment for nearly six decades. AR antagonists/degraders can effectively treat PCa caused by increased AR overexpression. However, all approved AR antagonists have similar chemical structures and exhibit the same mode of action on the protein. Although initially effective, resistance to these AR antagonists usually develops. Therefore, this calls for the identification of novel chemical structures of AR antagonists to overcome the resistance. Herein, we employed the synergetic combination of virtual and experimental screening to identify a flavonoid compound which not only effectively inhibits AR transcriptional activity, but also induces the degradation of the protein. Based on this compound, we designed and synthesized a series of derivatives. We discovered that the most potent compound 10e could effectively inhibit AR transcriptional activity, and possessed a profound ability to cause degradation of both full length- and ARv7 truncated forms of human AR. Notably, 10e efficiently inhibited the growth of ARv7 dependent prostate cancer cell-lines, which are completely resistant to all current anti-androgens. Compound 10e also showed strong antitumor activity in the LNCaP (androgen dependent prostate cancer cell line) in vivo xenograft model. These results provide a foundation for the development of a new class of AR antagonists.

8.
BMC Surg ; 21(1): 105, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33648470

RESUMO

BACKGROUND: Recent studies suggest red blood cell distribution width (RDW) was a prognostic factor in various types of cancer patients, although the results are controversial. The objective of this study was to investigate the significance of RDW in patients with intrahepatic cholangiocarcinoma (ICC) after radical resection. METHOD: The relationship between the preoperative serum RDW value and clinic pathological characteristics was analyzed in 157 ICC patients between January 2012 and June 2018 who underwent curative resection. X-tile software was used to determine 40.2 fl, 12.6% as the optimal cut-off value for RDW-SD and RDW-CV respectively. 153 patients were classified into the low RDW-SD (≤ 40.2, n = 53) group and the high RDW-SD (> 40.2, n = 104) group, low RDW-CV (≤ 12.6, n = 94) group and the high RDW-CV (> 12.6, n = 63). Based on the RDW-SD combined with RDW-CV (SCC), classified into SCC = 0, 1 and 2 group. Kaplan-Meier survival analysis and Cox proportional hazard models were used to examine the effect of RDW on survival. RESULTS: Kaplan-Meier curve analysis showed that Patients with RDW-SD > 40.2 were significantly associated with better OS (P = 0.004, median OS: 68.0 months versus 17.0 months). Patients with RDW-CV > 12.6 were significantly associated with better OS (p = 0.030, median OS: not reach versus 22.0 months). Compared with a SCC = 0 or SCC = 1, SCC = 2 was significantly associated with better OS (p < 0.001, median OS: not reach versus 33.0 months versus 16, respectively). In the multivariate analysis, RDW-SD > 40.2 fl (HR = 0.446, 95% CI: 0.262-0.760, p = 0.003), RDW-CV > 12.6% (HR = 0.425, 95%CI: 0.230-0.783, p = 0.006), SCC = 2 (HR = 0.270, 95%CI: 0.133-0.549, p < 0.001) were associated with favorable OS. The multivariate analysis showed RDW-SD, RDW-CV and SCC level were not independent prognostic factors for DFS. CONCLUSIONS: Preoperative low levels of RDW are associated with poor survival in ICC after curative resection. This provides a new way for predicting the prognosis of ICC patients and more targeted intervention measures.


Assuntos
Neoplasias dos Ductos Biliares , Ductos Biliares Intra-Hepáticos , Colangiocarcinoma , Neoplasias dos Ductos Biliares/cirurgia , Ductos Biliares Intra-Hepáticos/cirurgia , Colangiocarcinoma/cirurgia , Índices de Eritrócitos , Humanos , Prognóstico , Análise de Sobrevida
9.
Exp Biol Med (Maywood) ; : 1535370221990322, 2021 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-33554647

RESUMO

Cancer-associated sarcopenia is a complex metabolic syndrome marked by muscle mass wasting. Muscle wasting is a serious complication that is a primary contributor to cancer-related mortality. The underlying molecular mechanisms of cancer-associated sarcopenia have not been completely described to date. In general, evidence shows that the main pathophysiological alterations in sarcopenia are associated with the degradation of cellular components, an exceptional inflammatory secretome and mitochondrial dysfunction. Importantly, we highlight the prospect that several miRNAs carried by tumor-derived exosomes that have shown the ability to promote inflammatory secretion, activate catabolism, and even participate in the regulation of cellular degradation pathways can be delivered to and exert effects on muscle cells. In this review, we aim to describe the current knowledge about the functions of exosomal miRNAs in the induction of cancer-associated muscle wasting and propose potential treatment strategies.

10.
Br J Pharmacol ; 178(7): 1524-1540, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33474722

RESUMO

BACKGROUND AND PURPOSE: Disturbed flow induces endothelial dysfunction and contributes to uneven distribution of atherosclerotic plaque. Emerging evidence suggests that harmine, a natural constituent of extracts of Peganum harmala, has potent beneficial activities. Here, we investigated if harmine has an atheroprotective role under disturbed flow and the underlying mechanism. EXPERIMENTAL APPROACH: Mice of ApoE-/- , LDLR-/- , and endothelial cell (EC)-specific overexpression of yes-associated protein (YAP) in ApoE-/- background were fed with a Western diet and given harmine for 4 weeks. Atherosclerotic lesion size, cellular composition, and expression of inflammatory genes in the aortic roots were assessed. HUVECs were treated with oscillatory shear stress (OSS) and harmine and also used for proteomic analysis. KEY RESULTS: Harmine retarded atherogenesis in both ApoE-/- and LDLR-/- mice by inhibiting the endothelial inflammatory response. Mechanistically, harmine blocked OSS-induced YAP nuclear translocation and EC activation by reducing phosphorylation of YAP at Y357. Overexpression of endothelial YAP blunted the beneficial effects of harmine in mice. Proteomic study revealed that protein tyrosine phosphatase non-receptor type 14 (PTPN14) could bind to YAP. Moreover, harmine increased PTPN14 expression by stabilizing its protein level and inhibiting its degradation in proteasomes. PTPN14 knockdown blocked the effects of harmine on YAPY357 and EC activation. Finally, overexpression of PTPN14 mimicked the effects of harmine and ameliorated atherosclerosis, and knockdown of PTPN14 blunted the atheroprotective effects of harmine and accelerated atherosclerosis, in a partial ligation mouse model. CONCLUSION AND IMPLICATIONS: Harmine alleviated OSS-induced EC activation via a PTPN14/YAPY357 pathway and had a potent atheroprotective role.

11.
Ultrason Sonochem ; 72: 105458, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33453682

RESUMO

In this study, we investigated the effect of the ultrasound-assisted Maillard reaction on the structural and emulsifying properties of myofibrillar protein (MP) and dextran (DX) conjugates with different molecular weights (40, 70 and 150 kDa). Compared with classical heating, mild and moderate ultrasound-assisted methods (100-200 W) could accelerate the later stage of the Maillard reaction, which increased the degree of graft (DG) and the content of advanced Maillard reaction products (MPRs). Structural analysis revealed conjugates obtained by Maillard reaction induced the loss of ordered secondary structures (α-helix, ß-sheets) and red-shift of maximum emission wavelength of intrinsic fluorescence spectrum. The conjugate containing 40 kDa DX exhibited higher extent of Maillard reaction compared to those containing 70 kDa and 150 kDa DX under various treating methods. Moreover, the ultrasound-assisted Maillard reaction could effectively improve the emulsifying behaviors. 100 W ultrasound-induced conjugates grafted by 70 kDa DX produced the smallest emulsion size with optimum storage stability. Confocal laser scanning microscopy and analytical centrifugal analyzer further confirmed MP grafted by 70 kDa DX with the assistance of 100 W ultrasound field could produce the smallest and most homogeneous MP-base emulsion with no flocculation. Our study demonstrated that mild ultrasound treatment resulted in well-controlled Maillard reaction, and the related glycoconjugate grafted with 70 kDa DX showed the greatest improvements in emulsifying ability and stability. These findings provided a theoretical foundation for the development of emulsion-based foods with excellent characteristics.

12.
Cell Death Dis ; 12(1): 97, 2021 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-33462219

RESUMO

Breast cancer (BC) is the most common malignancy among women. Mesenteric estrogen-dependent adipogenesis gene (MEDAG) was first reported as a novel adipogenic gene, and its involvement and mechanism in visceral adiposity were analyzed. However, the role of MEDAG in BC is unclear. The biological roles and corresponding mechanisms were investigated in vitro and in vivo. We found that MEDAG was highly expressed in BC samples and that a high MEDAG expression was correlated with clinicopathological characteristics and poor survival in BC patients. MEDAG knockdown inhibited cell proliferation, invasion, and migration; triggered epithelial-to-mesenchymal transition (EMT); and enhanced epirubicin sensitivity in vitro. The opposite results were observed in MEDAG-overexpressing cells. The inhibition of MEDAG suppressed tumor growth and metastasis in vivo. Mechanistically, MEDAG knockdown led to decreased phosphorylation levels of AKT, increased levels of p-AMPK, and reduced levels of p-mTOR, while the overexpression of MEDAG had the opposite effects. Moreover, the activation of p-AKT and inhibition of p-AMPK restored the effect of MEDAG on EMT and chemosensitivity in BC cell lines, indicating that MEDAG functions as an oncogene by regulating the AKT/AMPK/mTOR pathway. MEDAG regulates BC progression and EMT via the AKT/AMPK/mTOR pathway and reduces chemosensitivity in BC cells. Therefore, MEDAG is a promising target for BC.

13.
Eur J Med Chem ; 211: 113091, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33338869

RESUMO

Cyclin-dependent kinase 9 (CDK9) is an increasingly important potential cancer treatment target. Nowadays, developing selective CDK9 inhibitors has been extremely challenging as its ATP-binding sites are similar with other CDKs. Here, we report that the CDK9 inhibitor BAY-1143572 is converted into a series of proteolysis targeting chimeras (PROTACs) which leads to several compounds inducing the degradation of CDK9 in acute myeloid leukemia cells at a low nanomolar concentration. In addition, the most potent PROTAC molecule B03 could inhibit cell growth more effectively than warhead alone, with little inhibition of other kinases. This enhanced antiproliferative activity is mediated by a slight increase in kinase inhibitory activity and an increase in the level of apoptosis induction. Moreover, B03 could induce the degradation of CDK9 in vivo. Our work provides evidence that B03 represents a lead for further development and that CDK9 degradation is a potential valuable therapeutic strategy in acute myeloid leukemia.


Assuntos
Quinase 9 Dependente de Ciclina/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proliferação de Células , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Inibidores de Proteínas Quinases/farmacologia
14.
J Mater Chem B ; 2020 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-33289778

RESUMO

Abnormal protein glycosylation is associated with many diseases including cardiovascular disease, diabetes, and cancer. Therefore, selective capturing of glycoproteins under physiological or weak acid conditions (tumor microenvironment) is vital for disease diagnosis and further comprehensive analysis. Here, we propose a strategy of intermolecular B-N bond-based phenylboronic acid affinity to capture glycoproteins under neutral and slightly acidic conditions. Surprisingly, the captured glycoproteins were released in alkaline solution. This is contrary to the traditional phenylboric acid affinity, and we studied this from the perspective of materials, proteins, and incubation conditions. We identified the synergistic effect of intermolecular B-N bond-based phenylboronic acid affinity, electrostatic interaction, and polymer brush structure-based glycoprotein adsorption under slightly acidic conditions. The electrostatic repulsion between Fe3O4@SiO2@poly (2-aminoethyl methacrylate hydrochloride)-4-carboxyphenylboronic acid (Fe3O4@SiO2@PAMA-CPBA) nanoparticles and transferrin (TRF) was far greater than the specific binding between phenylboric acid of CPBA and glycosylation residues of TRF resulting in the release of the captured glycoproteins in alkaline solution. Fe3O4@SiO2@PAMA-CPBA nanoparticles exhibited different selectivity capabilities toward different glycoproteins in multiprotein solutions due to protein interactions. These results may pave a new way for the design of phenylboric acid-based materials towards glycoprotein adsorption in a physiological environment.

15.
Cell Discov ; 6(1): 83, 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33298875

RESUMO

The COVID-19 pandemic has accounted for millions of infections and hundreds of thousand deaths worldwide in a short-time period. The patients demonstrate a great diversity in clinical and laboratory manifestations and disease severity. Nonetheless, little is known about the host genetic contribution to the observed interindividual phenotypic variability. Here, we report the first host genetic study in the Chinese population by deeply sequencing and analyzing 332 COVID-19 patients categorized by varying levels of severity from the Shenzhen Third People's Hospital. Upon a total of 22.2 million genetic variants, we conducted both single-variant and gene-based association tests among five severity groups including asymptomatic, mild, moderate, severe, and critical ill patients after the correction of potential confounding factors. Pedigree analysis suggested a potential monogenic effect of loss of function variants in GOLGA3 and DPP7 for critically ill and asymptomatic disease demonstration. Genome-wide association study suggests the most significant gene locus associated with severity were located in TMEM189-UBE2V1 that involved in the IL-1 signaling pathway. The p.Val197Met missense variant that affects the stability of the TMPRSS2 protein displays a decreasing allele frequency among the severe patients compared to the mild and the general population. We identified that the HLA-A*11:01, B*51:01, and C*14:02 alleles significantly predispose the worst outcome of the patients. This initial genomic study of Chinese patients provides genetic insights into the phenotypic difference among the COVID-19 patient groups and highlighted genes and variants that may help guide targeted efforts in containing the outbreak. Limitations and advantages of the study were also reviewed to guide future international efforts on elucidating the genetic architecture of host-pathogen interaction for COVID-19 and other infectious and complex diseases.

16.
J Med Chem ; 2020 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-33215494

RESUMO

Indoleamine 2,3-dioxygenase 1 (IDO1) has received increasing attention due to its immunosuppressive function in connection with various diseases, including cancer. A recent increase in the understanding of IDO1 has significantly contributed to the discovery of numerous novel inhibitors, but the latest clinical outcomes raised questions and have indicated a future direction of IDO1 inhibition for therapeutic approaches. Herein, we present a comprehensive review of IDO1, discussing the latest advances in understanding the IDO1 structure and mechanism, an overview of recent IDO1 inhibitor discoveries and potential therapeutic applications to provide helpful information for medicinal chemists investigating IDO1 inhibitors.

17.
Exp Cell Res ; : 112387, 2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33220257

RESUMO

Non-muscle myosin IIA (NMIIA) has been reported to be involved in the carcinogenesis and malignant progression of various human tumors. However, the role and potential mechanism of NMIIA in the biological functions and apoptosis in colorectal cancer (CRC) remain elusive. In this study, we found that NMIIA was overexpressed in CRC tissues and significantly associated with poor survival in CRC patients. In addition, NMIIA promoted CRC cell proliferation and invasion via activating the AMPK/mTOR pathway in vitro, and NMIIA knockdown inhibited CRC growth in vivo. Meanwhile, NMIIA knockdown downregulated the CSCs markers (CD44 and CD133) expression in CRC cells. Furthermore, AMPK/mTOR pathway activation effectively reversed the NMIIA knockdown-induced inhibition of proliferation, invasion and stemness in CRC cells. Finally, NMIIA protects CRC cells from 5-FU-induced apoptosis and proliferation inhibition through the AMPK/mTOR pathway. Taken together, these results indicate that NMIIA plays a pivotal role in CRC growth and progression by regulating AMPK/mTOR pathway activation, and it may act as a novel therapeutic target prognostic factor in CRC.

18.
Front Oncol ; 10: 574787, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33178603

RESUMO

Monocarboxylate transporter 1 (MCT1) participates in the transport of lactate to facilitate metabolic reprogramming during tumor progression. Tumor-associated macrophages (TAMs) are also involved in the inflammatory adaptation of the tumor microenvironment (TME). This study aimed to determine the correlation between metabolite changes and the polarization of macrophages in the TME. We demonstrated that the expression of CD163 on macrophages was significantly higher in breast cancer tissues than in normal tissues, especially in the HER2 subtype, although it was not statistically associated with recurrence-free survival (RFS). The presence of MCT1+ and CD163+ macrophages in the invasive margin was significantly correlated with decreased RFS. A significant correlation existed between MCT1 and CD163 expression in the margin, and high infiltration of MCT1+CD163+ macrophages into the margin predicted rapid progression and poor survival outcomes for breast cancer patients. These data suggested that MCT1 at least partially promoted the alternative polarization of macrophages to inhibit antitumor immunity, and blocking this interaction may be a promising method for breast cancer therapy.

19.
Virulence ; 11(1): 1443-1452, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33108255

RESUMO

The diagnosed COVID-19 cases revealed that the incubation periods (IP) varied a lot among patients. However, few studies had emphasized on the different clinical features and prognosis of patients with different IP. A total of 330 patients with laboratory-confirmed COVID-19 were enrolled and classified into immediate onset group(IP<3 days, I group, 57 cases) and late onset group(IP>10 days, L group, 75 cases) based on IP. The difference of clinical characteristics and prognosis of the two groups were compared. There were more patients with fever in I group than in L group(P = 0.003), and counts of all the total lymphocytes, total T lymphocytes, CD4 + and CD8 + T lymphocytes were significantly different between the two groups(all P < 0.01). Besides, patients in L group had more GGOs in CT scan than I group and there were more patients in I group receiving antibiotic treatment than in L group(P < 0.001). For disease aggravation, the median CT scores were comparable between the two groups, but individually, there were more patients with increased CT score during hospitalization in I group than in L group. The aggravation incidence of CT presentation was 21.1% in I group, significantly higher than L group(8.0%, P = 0.042). Multivariable COX models suggested that IP was the only independent factors for CT aggravation. Conclusively, patients with different IP were different in clinical symptoms, laboratory tests, and CT presentations. Shorter IP was associated with the aggravation of lung involvement in CT scan.


Assuntos
Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/patologia , Período de Incubação de Doenças Infecciosas , Pneumonia Viral/epidemiologia , Pneumonia Viral/patologia , Adulto , Betacoronavirus/patogenicidade , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/diagnóstico por imagem , Progressão da Doença , Feminino , Febre/epidemiologia , Febre/patologia , Hospitalização , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/diagnóstico por imagem , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Tomografia Computadorizada por Raios X
20.
J Mater Chem B ; 8(36): 8414-8421, 2020 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-32966536

RESUMO

Due to the number of phosphorylation sites, mono- and multiple-phosphopeptides exhibit significantly different biological effects. Therefore, comprehensive profiles of mono- and multiple-phosphopeptides are vital for the analysis of these biological and pathological processes. However, the most commonly used affinity materials based on metal oxide affinity chromatography (MOAC) show stronger selectivity toward mono-phosphopeptides, thus losing most information on multiple-phosphopeptides. Herein, we report polymer functionalized magnetic nanocomposite microspheres as an ideal platform to efficiently enrich both mono- and multiple-phosphopeptides from complex biological samples. Driven by complementary multiple hydrogen bonding interactions, the composite microspheres exhibited remarkable performance for phosphopeptide enrichment from model proteins and real bio-samples. Excellent selectivity (the molar ratio of nonphosphopeptides/phosphopeptides was 5000 : 1), high enrichment sensitivity (2 fmol) and coverage, as well as high capture rates of multiple-phosphopeptides revealed their great potential in comprehensive phosphoproteomics studies. More importantly, we successfully captured the cancer related phosphopeptides (from the phosphoprotein Stathmin-1) and identified their relevant phosphorylation sites from oral carcinoma patients' saliva and tissue lysate, demonstrating the potential of this material for phosphorylated disease marker detection and discovery.

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