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Interleukin-1 receptor-associated kinase 4 (IRAK4) is a pivotal enzyme in the Toll-like receptor (TLR)/MYD88 dependent signaling pathway, which is highly activated in rheumatoid arthritis tissues and activated B cell-like diffuse large B-cell lymphoma (ABC-DLBCL). Inflammatory responses followed by IRAK4 activation promote B-cell proliferation and aggressiveness of lymphoma. Moreover, proviral integration site for Moloney murine leukemia virus 1 (PIM1) functions as an anti-apoptotic kinase in propagation of ABC-DLBCL with ibrutinib resistance. We developed a dual IRAK4/PIM1 inhibitor KIC-0101 that potently suppresses the NF- κ B pathway and proinflammatory cytokine induction in vitro and in vivo . In rheumatoid arthritis mouse models, treatment with KIC-0101 significantly ameliorated cartilage damage and inflammation. KIC-0101 inhibited the nuclear translocation of NF- κ B and activation of JAK/STAT pathway in ABC-DLBCLs. In addition, KIC-0101 exhibited an anti-tumor effect on ibrutinib-resistant cells by synergistic dual suppression of TLR/MYD88-mediated NF- κ B pathway and PIM1 kinase. Our results suggest that KIC-0101 is a promising drug candidate for autoimmune diseases and ibrutinib-resistant B-cell lymphomas., Competing Interests: The authors declare no conflicts of interest., (© 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Two series of 2-substituted benzimidazole conjugated 1,3,4-oxadiazole derivatives were designed, synthesized and evaluated for their cytotoxic activities against the three human cancer cell lines (cervical cancer (HeLa), breast cancer (MCF-7) and lung cancer (A549)). As the results 14 compounds demonstrated consistent to stronger cytotoxicities compared to the control 5-fluorouracil (5-FU) towards the tested cell lines including 4c (HeLa); 4b, 4e, 4h, 7i-j, 7m-n, 7s (MCF-7); 7b (MCF-7, A549); 7h (HeLa, MCF-7); and 4d, 4i, 7c (HeLa, MCF-7, A549), with the IC 50 ranging from 2.7 to 38 µM. Notably, compound 4b illustrated almost 5-fold activity against the MCF-7 while 4d, 4i were 9- and 8-fold (HeLa), 4.5- and 13-fold (MCF-7), 4.7- and 4-fold (A549) increase in activity compared to 5-FU, respectively, and were found as lead compounds. These findings suggest that compounds 4b, 4d and 4i merit further characterization and can serve as promising scaffolds in the discovery of new potent anticancer agents.

Objective: To evaluate the association between suicidal behaviors and binge drinking among Brazilian adolescents., Methods: A cross-sectional study was conducted with 2,476 students 14 to 19 years of age from 26 public high schools in the city of Olinda, Brazil. Data collection occurred between March and June 2018 through the self-administered Youth Risk Behavior Survey. Descriptive analysis and Poisson regression (p < 0.05, 95%CI) were performed., Results: The prevalence of suicidal ideation, planning and attempt in the previous 12 months was 23.7%, 17.4% and 13.5%, respectively. Suicidal ideation was associated with binge drinking one to two days (PR:1.053, 95%CI:1.011-1.096) and ≥ three days in the previous 30 days (PR:1.069, 95%CI:1.016-1.125), sadness/hopelessness in the previous 12 months (PR:1.313, 95%CI:1.267-1.360), a report of family physical aggression in the previous 12 months (PR:1.111, 95%CI:1.068-1.155), the female sex (PR:1.082, 95%CI:1.049-1.115) and a non-nuclear family (PR:1.037, 95%CI:1.004-1.071). Suicidal planning was associated with sadness/hopelessness in the previous 12 months (PR:1.257, 95%CI:1.214-1.302), report of family physical aggression in the previous 12 months (PR:1.110, 95%CI:1.065-1.156) and the female sex (PR:1.072, 95%CI:1.041-1.104). Suicide attempt was associated with binge drinking ≥ three days in the previous 30 days (PR:1.062, 95%CI:1.008-1.119), sadness/hopelessness in the previous 12 months (PR:1.202, 95%CI:1.161-1.244), report of family physical aggression in the previous 12 months (PR:1.105, 95%CI:1.060-1.153) and the female sex (PR:1.064, 95%CI:1.034-1.095). The Catholic (PR:0.938, 95%CI:0.899-0.979; PR:0.925, 95%CI:0.888-0.9865; PR:0.937, 95%CI:0.899-0.977) and Evangelical (PR:0.956, 95%CI:0.922-0.992; PR:0.954, 95%CI:0.919-0.991) religions acted as a possible protective factor against suicidal behaviors., Conclusions: Suicidal ideation and attempt were associated with binge drinking.

This study aimed to analyze the demand for health services or professionals by adolescents with individual determinants and contextual variables (school teaching modality and Social Vulnerability Index). Data were collected from March to June 2018, in state public schools in Olinda, Pernambuco, Brazil, through a structured questionnaire with questions from the Youth Risk Behavior Survey (YRBS) and the National School Health Survey (PeNSE). Among the 2,454 adolescents, the proportion of those looking for a health service was higher among women; in adolescents whose mothers had a minimum of nine schooling years; in the physically active; and whose parents did not receive a family aid (Bolsa Família). We observed that the contextual variables did not influence the demand for health services among adolescents. In the third model of the multilevel analysis, which analyzed the individual variables, we observed that only females (OR=1,80), having a mother with schooling greater than or equal to 9 years of study (OR=1,30), not receiving Bolsa Família (OR=1,23), and physically active (OR=1,32) were associated with an increased demand for health services or professionals.

We have synthesized 50 benzimidazole (BMZ) derivatives with 1,2-phenylenediamines and aromatic aldehydes under mild oxidation conditions by using inexpensive, nontoxic inorganic salt sodium metabisulfite in a one-pot condensation reaction and screened their ability to interfere with Zika virus (ZIKV) infection utilizing a cell-based phenotypic assay. Seven BMZs inhibited an African ZIKV strain with a selectivity index (SI=CC 50 /EC 50 ) of 9-37. Structure-activity relationship analysis demonstrated that substitution at the C-2, N-1, and C-5 positions of the BMZ ring were important for anti-ZIKV activity. The hybrid structure of BMZ and naphthalene rings was a structural feature responsible for the high anti-ZIKV activity. Importantly, BMZs inhibited ZIKV in human neural stem cells, a physiologically relevant system considering the severe congenital anomalies, like microcephaly, caused by ZIKV infection. Compound 39 displayed the highest antiviral efficacy against the African ZIKV strain in Huh-7 (SI>37) and neural stem cells (SI=12). Compound 35 possessed the highest activity in Vero cells (SI=115). Together, our data indicate that BMZs derivatives have to be considered for the development of ZIKV therapeutic interventions., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Nuclear factor of activated T cells 5 (NFAT5) has been implicated in the pathogenesis of various human diseases, including cancer and arthritis. However, therapeutic agents inhibiting NFAT5 activity are currently unavailable. To discover NFAT5 inhibitors, a library of >40,000 chemicals was screened for the suppression of nitric oxide, a direct target regulated by NFAT5 activity, through high-throughput screening. We validated the anti-NFAT5 activity of 198 primary hit compounds using an NFAT5-dependent reporter assay and identified the novel NFAT5 suppressor KRN2, 13-(2-fluoro)-benzylberberine, and its derivative KRN5. KRN2 inhibited NFAT5 upregulation in macrophages stimulated with lipopolysaccharide and repressed the formation of NF-κB p65-DNA complexes in the NFAT5 promoter region. Interestingly, KRN2 selectively suppressed the expression of pro-inflammatory genes, including Nos2 and Il6, without hampering high-salt-induced NFAT5 and its target gene expressions. Moreover, KRN2 and KRN5, the latter of which exhibits high oral bioavailability and metabolic stability, ameliorated experimentally induced arthritis in mice without serious adverse effects, decreasing pro-inflammatory cytokine production. Particularly, orally administered KRN5 was stronger in suppressing arthritis than methotrexate, a commonly used anti-rheumatic drug, displaying better potency and safety than its original compound, berberine. Therefore, KRN2 and KRN5 can be potential therapeutic agents in the treatment of chronic arthritis., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)