Development of 9-cinnamyl-9H-purine derivatives as potent anticancer agents through inactivation of NF-κb/p65 and p-STAT1 signaling pathways: Discovery of a new template for adenosine receptor.

Based on the structure of resveratrol and curcumin, a novel 9-cinnamyl-9H-purine structure was designed and synthesized to avoid a pan-assay interference compound (PAINS) related to invalid metabolic pancreas activity (IMPS). In a previous study, it exhibited anti-inflammatory activities by disrupting the TLR4-MyD88 protein interaction, leading to the suppression of the NF-κB signaling pathway. In this study, further structure-activity relationship studies were conducted to evaluate 9-cinnamyl-9H-purine derivatives for their potential anticancer activities, as NF-κB inhibition is known to reduce tumor growth and increase cancer cell death.

Sex differences in bladder cancer: understanding biological and clinical implications.

Bladder cancer (BC) remains a significant global health concern, with substantial sex and racial disparities in incidence, progression, and outcomes. BC is the sixth most common cancer among males and the seventeenth most common among females worldwide. Over 90% of BC cases are urothelial carcinoma (UC) with high degrees of pathological heterogeneity.

G Protein-Coupled Estrogen Receptor-Mediated Anti-Inflammatory and Mucosal Healing Activity of a Trimethylpyridinol Analogue in Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is characterized by abnormal immune responses, including elevated proinflammatory cytokines, such as tumor necrosis factor-α (TNFα) and interleukin-6 (IL-6) in the gastrointestinal (GI) tract. This study presents the synthesis and anti-inflammatory evaluation of 2,4,5-trimethylpyridin-3-ol analogues, which exhibit dual inhibition of TNFα- and IL-6-induced inflammation. Analysis using methods, including 3D shape-based target identification, modeling, and docking, identified G protein-coupled estrogen receptor 1 (GPER) as the molecular target for the most effective analogue, -, which exhibits remarkable efficacy in ameliorating inflammation and restoring colonic mucosal integrity.

siRNA treatment targeting integrin α11 overexpressed via EZH2-driven axis inhibits drug-resistant breast cancer progression.

Background: Breast cancer, the most prevalent cancer in women worldwide, faces treatment challenges due to drug resistance, posing a serious threat to patient survival. The present study aimed to identify the key molecules that drive drug resistance and aggressiveness in breast cancer cells and validate them as therapeutic targets.

Methods: Transcriptome microarray and analysis using PANTHER pathway and StemChecker were performed to identify the most significantly expressed genes in tamoxifen-resistant and adriamycin-resistant MCF-7 breast cancer cells.

Is it double chambered left ventricle? Unveiling the mirage using cardiac magnetic resonance imaging.

Double chambered left ventricle (DCLV) is an uncommon congenital heart condition typically identified incidentally, with the majority of patients showing no symptoms and experiencing a benign course. It is crucial to differentiate DCLV from other abnormalities like diverticulum or aneurysm, which can have significant clinical implications. Due to the limited available data, our understanding of the natural progression, prognosis, complications, and treatment options for this rare condition is poorly defined.

Role of 3D transoesophageal echocardiography in correct diagnosis of congenital isolated double orifice mitral valve in a young adult misdiagnosed as rheumatic heart disease.

Double orifice mitral valve (DOMV) is an extremely rare congenital anomaly of the mitral valve (MV) wherein the MV orifice divides into two separate orifices by an accessory fibrous band.Isolated DOMV is a rarity and is often discovered incidentally. It may be associated with other congenital conditions wherein it is identified in early childhood.

Induction of promyelocytic leukemia zinc finger protein by miR-200c-3p restores sensitivity to anti-androgen therapy in androgen-refractory prostate cancer and inhibits the cancer progression via down-regulation of integrin α3β4.

Purpose: Androgen-refractory prostate cancer (ARPC) is one of the aggressive human cancers with metastatic capacity and resistance to androgen deprivation therapy (ADT). The present study investigated the genes responsible for ARPC progression and ADT resistance, and their regulatory mechanisms.

Methods: Transcriptome analysis, co-immunoprecipitation, confocal microscopy, and FACS analysis were performed to determine differentially-expressed genes, integrin α3β4 heterodimer, and cancer stem cell (CSC) population.

Antitumor effect of 3-(quinolin-2-ylmethylene)-4,6-dimethyl-5-hydroxy-7-azaoxindole down-regulating the Gas6-Axl axis.

In this study, a new series of 3-arylidene-4,6-dimethyl-5-hydroxy-7-azaoxindole compounds with a wide range of functional groups were designed, synthesized, and evaluated for their antitumor activity. Among the 35 compounds, compound 6-15, with a quinoline moiety, showed cytotoxic IC values superior to those of sunitinib against the seven cancer cell lines (MCF-7, MDA-MB-231, HT-29, DU145, U937, A549, and PANC-1). However, its inhibitory activity against receptor tyrosine kinases (VEGFR2, PDGFRβ, c-KIT, FGFR1, FLT3, CSF1R, EGFR, Axl, and Axl mutant) was 100 -3000-fold weaker than that of sunitinib.

Megakaryocyte-Derived IL-8 Acts as a Paracrine Factor for Prostate Cancer Aggressiveness through CXCR2 Activation and Antagonistic AR Downregulation.

Prostate cancer is the fifth leading cause of cancer-related mortality in men, primarily because of treatment resistance, recurrence, and metastasis. In the present study, we investigated the role of paracrine interleukin-8 (IL-8) in the antagonistic expression of IL-8 and androgen receptor (AR), and the contribution of IL-8 to prostate cancer aggressiveness. In hormone-responsive LNCaP cells that do not express IL-8, recombinant IL-8 treatment significantly increased expressions of IL-8, CXC chemokine receptor 2 (CXCR2), matrix metalloproteinase (MMP)-2/9, Snail, and vimentin.

Synchronous Primary Adenocarcinoma of Distal Common Bile Duct and Gall bladder.

Synchronous primary cancer of the gall bladder and distal common bile duct is rare. There are only few case reports and case series available of these synchronous cancers. Management of this tumor is individualized in these case reports and series based upon the presentation.

Antitumor activity of a pexidartinib bioisostere inhibiting CSF1 production and CSF1R kinase activity in human hepatocellular carcinoma.

Macrophage colony-stimulating factor (M-CSF, also known as CSF1) in tumor tissues stimulates tumor growth and tumor-induced angiogenesis through an autocrine and paracrine action on CSF1 receptor (CSF1R). In the present study, novel bioisosteres of pexidartinib (1) were synthesized and evaluated their inhibitory activities against CSF1R kinase and tumor growth. Among newly synthesized bioisosteres, compound 3 showed the highest inhibition (95.

6-Amino-2,4,5-trimethylpyridin-3-ol and 2-amino-4,6-dimethylpyrimidin-5-ol derivatives as selective fibroblast growth factor receptor 4 inhibitors: design, synthesis, molecular docking, and anti-hepatocellular carcinoma efficacy evaluation.

A novel series of aminotrimethylpyridinol and aminodimethylpyrimidinol derivatives were designed and synthesised for FGFR4 inhibitors. Structure-activity relationship on the FGFR4 inhibitory activity of the new compounds was clearly elucidated by an intensive molecular docking study. Anti-cancer activity of the compounds was evaluated using hepatocellular carcinoma (HCC) cell lines and a chick chorioallantoic membrane (CAM) tumour model.

TPH1 and 5-HT Receptor Overexpression Leading to Gemcitabine-Resistance Requires Non-Canonical Permissive Action of EZH2 in Pancreatic Ductal Adenocarcinoma.

In the present study, we investigated the regulatory mechanisms underlying overexpression of EZH2, tryptophan hydroxylase 1 (TPH1), and 5-HT, in relation to gemcitabine resistance and CSC survival in PDAC cells. In aggressive PANC-1 and MIA PaCa-2 cells, knock-down (KD) of EZH2, TPH1, or HTR7 induced a decrease in CSCs and recovery from gemcitabine resistance, while preconditioning of less aggressive Capan-1 cells with 5-HT induced gemcitabine resistance with increased expression of EZH2, TPH1, and 5-HT. Such effects of the gene KD and 5-HT treatment were mediated through PI3K/Akt and JAK2/STAT3 signaling pathways.

Novel Pyridine Bioisostere of Cabozantinib as a Potent -Met Kinase Inhibitor: Synthesis and Anti-Tumor Activity against Hepatocellular Carcinoma.

Two novel bioisosteres of cabozantinib, and , were designed and synthesized. The benzene ring in the center of the cabozantinib structure was replaced by trimethylpyridine () and pyridine (), respectively. Surprisingly, the two compounds showed extremely contrasting mesenchymal-epithelial transition factor (-Met) inhibitory activities at 1 μM concentration (4% inhibition of vs.

Synthesis and anti-hepatocellular carcinoma activity of aminopyridinol-sorafenib hybrids.

Sorafenib is recommended as the primary therapeutic drug for patients with hepatocellular carcinoma. To discover a new compound that avoids low response rates and toxic side effects that occur in sorafenib therapy, we designed and synthesized new hybrid compounds of sorafenib and 2,4,5-trimethylpyridin-3-ols. Compound was selected as the best of 24 hybrids that inhibit each of the four Raf kinases.

Synthesis and activity of N-(5-hydroxy-3,4,6-trimethylpyridin-2-yl)acetamide analogues as anticolitis agents via dual inhibition of TNF-α- and IL-6-induced cell adhesions.

Tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) are the critical pro-inflammatory cytokines involved in the pathogenesis of inflammatory bowel disease (IBD). Inhibition of these cytokines and related signaling pathways has been a target for the development of IBD therapeutics. In the current study, 6-acetamido-2,4,5-trimethylpyridin-3-ol (1) and various analogues with the amido scaffold were synthesized and examined for their inhibitory activities in in vitro and in vivo IBD models.

Synthesis and anticancer evaluation of 6-azacyclonol-2,4,6-trimethylpyridin-3-ol derivatives: M3 muscarinic acetylcholine receptor-mediated anticancer activity of a cyclohexyl derivative in androgen-refractory prostate cancer.

We recently reported 2,4,5-trimethylpyridin-3-ol with C(6)-azacyclonol, whose code name is BJ-1207, showing a promising anticancer activity by inhibiting NOX-derived ROS in A549 human lung cancer cells. The present study was focused on structural modification of the azacyclonol moiety of BJ-1207 to find a compound with better anticancer activity. Ten new compounds (3A-3J) were prepared and evaluated their inhibitory actions against proliferation of eighteen cancer cell lines as a primary screening.

Inhibition of colitis by ring-modified analogues of 6-acetamido-2,4,5-trimethylpyridin-3-ol.

6-Aminopyridin-3-ol scaffold has shown an excellent anti-inflammatory bowel disease activity. Various analogues with the scaffold were synthesized in pursuit of the diversity of side chains tethering on the C(6)-position. Structure-activity relationship among the analogues was investigated to understand the effects of the side chains and their linkers on their anti-inflammatory activities.

Potent Inhibitory Effect of BJ-3105, a 6-Alkoxypyridin-3-ol Derivative, on Murine Colitis Is Mediated by Activating AMPK and Inhibiting NOX.

Inflammatory bowel disease (IBD) is a chronic relapsing inflammation in the gastrointestinal tract. Biological therapeutics and orally available small molecules like tofacitinib (a JAK inhibitor) have been developed to treat IBD, but half of the patients treated with these drugs fail to achieve sustained remission. In the present study, we compared the therapeutic effects of BJ-3105 (a 6-alkoxypyridin-3-ol derivative) and tofacitinib in IBD.

Antitumor activity of BJ-1207, a 6-amino-2,4,5-trimethylpyridin-3-ol derivative, in human lung cancer.

Enhanced expression of NADPH oxidase (NOX) and the subsequent production of reactive oxygen species (ROS) are associated with lung cancer. In the present study, fifty 6-amino-2,4,5-trimethylpyridin-3-ol derivatives were screened for anticancer activity by targeting NOX2-derived ROS. The compounds suppressed ROS production and decreased cancer cell viability (R = 0.

Biofilm Production and Antimicrobial Resistance among Uropathogens in Pediatric Cases: a Hospital Based Study.

Background: The study was designed to provide account of etiological agents of urinary tract infection in pediatric patients and the antimicrobial resistance pattern plus biofilm producing profile of the isolates.

Methods: The prospective study was conducted in Alka Hospital, Nepal with 353 clean catch urine samples from children. It was obtained during July 2014 to January 2015 which were first cultured by semi-quantitative method, followed by antimicrobial susceptibility testing and biofilm production assay on Congo red agar.

The role of propranolol as a radiosensitizer in gastric cancer treatment.

Purpose: The National Comprehensive Cancer Network guidelines indicate that radiotherapy in gastric cancer shows limited effectiveness at reducing the growth of gastric cancer. Therefore, enhancing the sensitivity and effect of radiotherapy with propranolol, a β-adrenoceptor antagonist, could reduce tumor growth. The role of propranolol as a radiosensitizer has not been adequately studied; therefore, the purpose of the present study is to evaluate the effect of propranolol as a radiosensitizer against gastric cancer in vivo.