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Cell Death & Disease May 2024Signal transducer and activator of transcription 3 (STAT3) is frequently overexpressed in patients with acute myeloid leukemia (AML). STAT3 exists in two distinct...
Signal transducer and activator of transcription 3 (STAT3) is frequently overexpressed in patients with acute myeloid leukemia (AML). STAT3 exists in two distinct alternatively spliced isoforms, the full-length isoform STAT3α and the C-terminally truncated isoform STAT3β. While STAT3α is predominantly described as an oncogenic driver, STAT3β has been suggested to act as a tumor suppressor. To elucidate the role of STAT3β in AML, we established a mouse model of STAT3β-deficient, MLL-AF9-driven AML. STAT3β deficiency significantly shortened survival of leukemic mice confirming its role as a tumor suppressor. Furthermore, RNA sequencing revealed enhanced STAT1 expression and interferon (IFN) signaling upon loss of STAT3β. Accordingly, STAT3β-deficient leukemia cells displayed enhanced sensitivity to blockade of IFN signaling through both an IFNAR1 blocking antibody and the JAK1/2 inhibitor Ruxolitinib. Analysis of human AML patient samples confirmed that elevated expression of IFN-inducible genes correlated with poor overall survival and low STAT3β expression. Together, our data corroborate the tumor suppressive role of STAT3β in a mouse model in vivo. Moreover, they provide evidence that its tumor suppressive function is linked to repression of the STAT1-mediated IFN response. These findings suggest that the STAT3β/α mRNA ratio is a significant prognostic marker in AML and holds crucial information for targeted treatment approaches. Patients displaying a low STAT3β/α mRNA ratio and unfavorable prognosis could benefit from therapeutic interventions directed at STAT1/IFN signaling.
Topics: Animals; Leukemia, Myeloid, Acute; Humans; STAT3 Transcription Factor; Mice; Signal Transduction; Interferons; STAT1 Transcription Factor; Mice, Inbred C57BL; Receptor, Interferon alpha-beta; Cell Line, Tumor; Nitriles; Pyrazoles; Pyrimidines
PubMed: 38806478
DOI: 10.1038/s41419-024-06749-9 -
Cell Death & Disease May 2024Epithelial-to-mesenchymal transition (EMT) is one of the main causes of peritoneal fibrosis. However, the pathophysiological mechanisms of EMT, specifically its...
Epithelial-to-mesenchymal transition (EMT) is one of the main causes of peritoneal fibrosis. However, the pathophysiological mechanisms of EMT, specifically its relationship with autophagy, are still unknown. This study aimed to evaluate the role of autophagy in transforming growth factor-beta 1 (TGF-β1)-induced EMT in human peritoneal mesothelial cells (HPMCs). Primary cultured HPMCs were treated with TGF-β1 (2 and 5 ng/mL) and changes in autophagy markers and the relationship between autophagy and EMT were evaluated. We also identified changes in EMT- and autophagy-related signaling pathways after autophagy and NADPH oxidase 4 (NOX4) inhibition. TGF-β1 increased the generation of NOX4 and reactive oxygen species (ROS) in HPMCs, resulting in mitochondrial damage. Treatment with GKT137831 (20 μM), a NOX1/4 inhibitor, reduced ROS in the mitochondria of HPMC cells and reduced TGF-β1-induced mitochondrial damage. Additionally, the indirect inhibition of autophagy by GKT137831 (20 μM) downregulated TGF-β1-induced EMT, whereas direct inhibition of autophagy using 3-methyladenine (3-MA) (2 mM) or autophagy-related gene 5 (ATG5) gene silencing decreased the TGF-β1-induced EMT in HPMCs. The suppressor of mothers against decapentaplegic 2/3 (Smad2/3), autophagy-related phosphoinositide 3-kinase (PI3K) class III, and protein kinase B (Akt) pathways, and mitogen-activated protein kinase (MAPK) signaling pathways, such as extracellular signal-regulated kinase (ERK) and P38, were involved in TGF-β1-induced EMT. Autophagy and NOX4 inhibition suppressed the activation of these signaling pathways. Direct inhibition of autophagy and its indirect inhibition through the reduction of mitochondrial damage by upstream NOX4 inhibition reduced EMT in HPMCs. These results suggest that autophagy could serve as a therapeutic target for the prevention of peritoneal fibrosis in patients undergoing peritoneal dialysis.
Topics: Humans; Epithelial-Mesenchymal Transition; Transforming Growth Factor beta1; Autophagy; Oxidative Stress; Reactive Oxygen Species; NADPH Oxidase 4; Signal Transduction; Epithelial Cells; Mitochondria; Peritoneum; Pyrazolones; Pyridones
PubMed: 38806451
DOI: 10.1038/s41419-024-06753-z -
Journal of the American Chemical Society Jun 2024Utopia Point Bayesian Optimization (UPBO) was used to identify reaction conditions that are highly selective for the formation of N1 and N2-methyl-3-aryl pyrazole...
Utopia Point Bayesian Optimization (UPBO) was used to identify reaction conditions that are highly selective for the formation of N1 and N2-methyl-3-aryl pyrazole constitutional isomers. UPBO was used to explore a wide chemical space and identify basic reaction conditions for a typically acid-catalyzed Knorr pyrazole condensation. These studies revealed that selectivity in the reaction stems from a condition-dependent equilibrium of intermediates prior to dehydration. For the N2-methyl isomer reaction pathway, a hemiaminal intermediate was found to form reversibly under the reaction conditions, enabling a highly selective synthesis of the N2 isomer upon dehydrative workup. UPBO was able to successfully optimize conversion and selectivity simultaneously with search spaces of >1 million potential variable combinations without the need for high-performance computational resources.
PubMed: 38804885
DOI: 10.1021/jacs.4c01616 -
Psychopharmacology Jul 2024Zuranolone, a newly FDA-approved synthetic neurosteroid, shows promise in treating depression. (Meta-Analysis)
Meta-Analysis Review
RATIONALE
Zuranolone, a newly FDA-approved synthetic neurosteroid, shows promise in treating depression.
OBJECTIVES
Our aim is to evaluate Zuranolone's efficacy and safety in treating depression.
METHODS
Five databases were searched until September 2023 for relevant randomized clinical trials evaluating the efficacy and safety of zuranolone. The potential risk of bias in the included trials was evaluated by the Cochrane Risk of Bias II guideline Data were extracted and pooled using Review Manager Software (RevMan 5.3).
RESULTS
An analysis of eight studies highlights Zuranolone's efficacy in treating depression compared to placebo across most of the outcomes. Notably, the 30mg and 50mg doses demonstrated significant improvements in reducing HAM-D scores by over 50% within a 15-day follow-up (RR) of 1.46 (95% CI [1.27, 1.68], p < 0.0001) and 1.14 (95% CI [1.01, 1.3], p = 0.04). Additionally, the HAM-D ≤ 7% score analysis revealed significant enhancements with the 30mg dose over both 15-day (RR = 1.82, 95% CI [1.44, 2.31], p < 0.0001) and 45-day (RR = 1.43, 95% CI [1.16, 1.77], p = 0.0008) durations. Adverse Events Drug Discontinuation demonstrated no overall significant difference (OR = 1.33, 95% CI: [0.79, 2.23], p = 0.282). Further, specific adverse events, such as headache, showed no significant overall difference between Zuranolone and placebo (OR = 1.11, 95% CI: [0.84, 1.47], p = 0.47), with dose-dependent analysis revealing less headache in the 30 mg group.
CONCLUSION
Zuranolone demonstrates favorable tolerability and safety, particularly at 30mg and 50mg doses after 15 days, suggesting its potential and effective treatment for depression.
Topics: Humans; Randomized Controlled Trials as Topic; Antidepressive Agents; Depression; Dose-Response Relationship, Drug; Treatment Outcome; Pregnanolone; Pyrazoles
PubMed: 38802705
DOI: 10.1007/s00213-024-06611-y -
Frontiers in Chemistry 2024
PubMed: 38800579
DOI: 10.3389/fchem.2024.1421449 -
The International Journal of... Jul 2024Elevated levels of prostaglandin E have been implicated in the pathophysiology of various diseases. Anti-inflammatory drugs that act through the inhibition of...
Elevated levels of prostaglandin E have been implicated in the pathophysiology of various diseases. Anti-inflammatory drugs that act through the inhibition of cyclooxygenase enzymatic activity, thereby leading to the suppression of prostaglandin E, are often associated with several side effects due to their non-specific inhibition of cyclooxygenase enzymes. Consequently, the targeted suppression of prostaglandin E production with innovative molecules and/or mechanisms emerges as a compelling therapeutic strategy for the treatment of inflammatory-related diseases. Therefore, in this study, a systematic analysis of 28 pyrazole derivatives was conducted to explore their potential mechanisms for reducing prostaglandin E levels. In this context, the evaluation of these derivatives extended to examining their capacity to reduce prostaglandin Ein vitro in human whole blood, inhibit cyclooxygenase-1 and cyclooxygenase-2 enzymes, modulate cyclooxygenase-2 expression, and suppress oxidative burst in human leukocytes. The results enabled the establishment of significant structure-activity relationships, elucidating key determinants for their activities. In particular, the 4-styryl group on the pyrazole moiety and the presence of chloro substitutions were identified as key determinants. Pyrazole 8 demonstrated the capacity to reduce prostaglandin E levels by downregulating cyclooxygenase-2 expression, and pyrazole-1,2,3-triazole 18 emerged as a dual-acting agent, inhibiting human leukocytes' oxidative burst and cyclooxygenase-2 activity. Furthermore, pyrazole 26 demonstrated effective reduction of prostaglandin E levels through selective cyclooxygenase-1 inhibition. These results underscore the multifaceted anti-inflammatory potential of pyrazoles, providing new insights into the substitutions and structural frameworks that are beneficial for the studied activity.
Topics: Humans; Pyrazoles; Dinoprostone; Respiratory Burst; Leukocytes; Cyclooxygenase 2; Cyclooxygenase 1; Anti-Inflammatory Agents; Structure-Activity Relationship; Cyclooxygenase Inhibitors
PubMed: 38797495
DOI: 10.1016/j.biocel.2024.106599 -
Scientific Reports May 2024Hercynite magnetic nanoparticles were produced through the co-precipitation of ferrous and aluminum cations. The surface of hercynite was respectively coated with...
Hercynite magnetic nanoparticles were produced through the co-precipitation of ferrous and aluminum cations. The surface of hercynite was respectively coated with silica, 2,4,6-trichloro-1,3,5-triazine, and 1H-pyrazole-3,5-dicarboxylic acid to provide a suitable substrate for Pd(II) loading, furnishing Pd@Her-TCT-PDA. Subsequently, the introduced Pd(II) was reduced to Pd(0) using NaBH. FT-IR, EDS, XRD, TGA, TEM and SEM images were the characteristic methods to prove the success of catalyst synthesis. The SEM image illustrated the particles with a nanosize of 25-50 nm and TEM image confirmed the presence of Pd nanoparticles with sizes lower than 2 nm. EDS elemental analysis of the catalyst proved the existence of Pd, Fe, and Al atoms along with the C, O, N, and Si atoms belong to the heterocyclic moieties. VSM analysis clarified a considerable drop in the magnetic properties of the hercynite core of the final catalyst due to its modified surface. TGA curve demonstrated that Pd@Her-TCT-PDA contains 20% organic content, attributed to the anchored heterocyclic ligands. Finally, Pd@Her-TCT-PDA was employed along with NaBH as a catalytic system to reduce completely the nitro group of aromatic compounds to their corresponding amines. The recyclability tests showed low drop in the catalytic activity of Pd@Her-TCT-PDA after third run with negligible leaching of Pd NPs.
PubMed: 38796550
DOI: 10.1038/s41598-024-62226-5 -
RMD Open May 2024Obesity and age are strongly linked to severe COVID-19 pneumonia where immunomodulatory agents including Janus kinase inhibitors have shown benefits but the efficacy of... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Obesity and age are strongly linked to severe COVID-19 pneumonia where immunomodulatory agents including Janus kinase inhibitors have shown benefits but the efficacy of such therapy in viral pneumonia is not well understood. We evaluated the impact of obesity and age on survival following baricitinib therapy for severe COVID-19.
METHODS
A post hoc analysis of the COV-BARRIER multicentre double-blind randomised study of baricitinib versus placebo (PBO) with an assessment of 28-day mortality was performed. All-cause mortality by day 28 was evaluated in a Cox regression analysis (adjusted to age) in three different groups according to body mass index (BMI) (<25 kg/m, 25-30 kg/m and >30 kg/m) and age <65 years and ≥65 years.
RESULTS
In the high BMI group (>25 kg/m), baricitinib therapy showed a significant survival advantage compared with PBO (incidence rate ratio (IRR) for mortality by day 28 0.53 (95% CI 0.32 to 0.87)) and 0.66 (95% CI 0.46 to 0.94) for the respective <65 years and ≥65 years, respectively. The 28-day all-cause-mortality rates for BMI over 30 were 5.62% for baricitinib and 9.22% for PBO (HR=0.6, p<0.05). For BMI under 25 kg/m, irrespective of age, baricitinib therapy conferred no survival advantage (IRR of 1.89 (95% CI 0.49 to 7.28) and 0.95 (95% CI 0.46 to 1.99) for <65 years and ≥65 years, respectively) ((mortality 6.6% baricitinib vs 8.1 in PBO), p>0.05).
CONCLUSION
The efficacy of baricitinib in COVID-19 pneumonia is linked to obesity suggesting that immunomodulatory therapy benefit is associated with obesity-associated inflammation.
Topics: Humans; Purines; Sulfonamides; Azetidines; Obesity; Male; Middle Aged; COVID-19; Pyrazoles; Female; Aged; SARS-CoV-2; Body Mass Index; Double-Blind Method; Janus Kinase Inhibitors; COVID-19 Drug Treatment; Pneumonia, Viral; Treatment Outcome; Betacoronavirus; Coronavirus Infections; Pandemics
PubMed: 38796180
DOI: 10.1136/rmdopen-2023-004045 -
Theriogenology Sep 2024Here, we examined the effects of the BMP signaling pathway inhibitor LDN-193189 on the pluripotency of porcine embryonic stem cells (ESCs) in the absence of feeder cells...
Here, we examined the effects of the BMP signaling pathway inhibitor LDN-193189 on the pluripotency of porcine embryonic stem cells (ESCs) in the absence of feeder cells using molecular and transcriptomic techniques. Additionally, the effects of some extracellular matrix components on porcine ESC pluripotency were evaluated to develop an optimized and sustainable feeder-free culture system for porcine ESCs. Feeder cells were found to play an important role in supporting the pluripotency of porcine ESCs by blocking trophoblast and mesodermal differentiation through the inhibition of the BMP pathway. Additionally, treatment with LDN-193189, an inhibitor of the BMP pathway, maintained the pluripotency and homogeneity of porcine ESCs for an extended period in the absence of feeder cells by stimulating the secretion of chemokines and suppressing differentiation, based on transcriptome analysis. Conclusively, these results suggest that LDN-193189 could be a suitable replacement for feeder cells in the maintenance of porcine ESC pluripotency during culture. Additionally, these findings contribute to the understanding of pluripotency gene networks and comparative embryogenesis.
Topics: Animals; Swine; Embryonic Stem Cells; Signal Transduction; Pyrazoles; Pyrimidines; Bone Morphogenetic Proteins; Pluripotent Stem Cells; Cell Differentiation; Smad Proteins; Feeder Cells; Cell Culture Techniques
PubMed: 38795512
DOI: 10.1016/j.theriogenology.2024.05.027 -
Pharmaceuticals (Basel, Switzerland) May 2024In this innovative research, we aim to reveal pyrazole-based Schiff bases as new multi-target agents. In this context, we re-synthesized three sets of pyrazole-based...
Exploring the Potential Biological Activities of Pyrazole-Based Schiff Bases as Anti-Diabetic, Anti-Alzheimer's, Anti-Inflammatory, and Cytotoxic Agents: Studies with Computational Predictions.
In this innovative research, we aim to reveal pyrazole-based Schiff bases as new multi-target agents. In this context, we re-synthesized three sets of pyrazole-based Schiff bases, -, -, and -, to evaluate their biological applications. The data from biological assays (including antioxidant and scavenging activities, anti-diabetes, anti-Alzheimer's, and anti-inflammatory properties) of the pyrazole-based Schiff bases -, -, and - showed that the six pyrazole-based Schiff bases , , , , , and possess the highest biological properties among the compounds evaluated. The cytotoxicity against lung (A549) and colon (Caco-2) human cancer types, as well as normal lung (WI-38) cell lines, was evaluated. The data from the cytotoxicity investigation demonstrated that the three Schiff bases , , and are active against lung (A549) cells, while the two Schiff bases and exhibited the highest cytotoxicity towards colon (Caco-2) cells. Additionally, the enzymatic activities against caspase-3 and Bcl-2 of the six pyrazole-based Schiff bases , , , , , and were evaluated. Furthermore, we assessed the absorption, distribution, metabolism, and toxicity (ADMT) properties of the more potent pyrazole-based Schiff bases. After modifying the structures of the six pyrazole-based Schiff bases, we plan to further extend the studies in the future.
PubMed: 38794225
DOI: 10.3390/ph17050655