Discovery of novel natural-product-derived mutant isocitrate dehydrogenases 1 inhibitors: Structure-based virtual screening, biological evaluation and structure-activity relationship study.

Mutations in IDH1 are commonly observed across various cancers, causing the conversion of α-KG to 2-HG. Elevated levels of 2-HG disrupt histone and DNA demethylation processes, promoting tumor development. Consequently, there is substantial interest in developing small molecule inhibitors targeting the mutant enzymes. Herein, we report a structure-based high-throughput virtual screening strategy using a natural products library, followed by hit-to-lead optimization. Through this process, we discover a potent compound, named 11s, which exhibited significant inhibition to IDH1 R132H and IDH1 R132C with IC50 values of 124.4 and 95.7 nM, respectively. Furthermore, 11s effectively reduced 2-HG formation, with EC50 values of 182 nM in U87 R132H cell, and 84 nM in HT-1080 cell. In addition, 11s significantly reduced U87 R132H and HT-1080 cell proliferation with GC50 values of 3.48 and 1.38 µM, respectively. PK-PD experiments further confirmed that compound 11s significantly decreased 2-HG formation in an HT-1080 xenograft mouse model, resulting in notable suppression of tumor growth without apparent loss in body weight.

Predictive value of arterial blood lactate/serum albumin ratio for myocardial injury in elderly patients with severe community-acquired pneumonia.

ABSTRACT: To investigate the predictive value of arterial blood lactate (Lac)/serum albumin (Alb) ratio (Lac/Alb) on myocardial injury in elderly patients with severe community-acquired pneumonia (SCAP).Seventy-two elderly SCAP patients hospitalized in the intensive care unit (ICU) of the emergency department of Hebei General Hospital from March 2020 to March 2021 were included, and the general data and arterial blood Lac and serum Alb levels were collected, and Lac/Alb values were calculated. The patients were divided into myocardial injury group (n = 25) and nonmyocardial injury group (n = 47) according to whether the myocardial injury occurred during their ICU stay, and the predictive value of Lac/Alb on myocardial injury in elderly patients with SCAP was assessed using receiver operating characteristic curve and area under the curve.There were no statistically significant differences in age and gender between the 2 groups (both P > .05), and there were no statistical differences in oxygenation index, procalcitonin, C-reactive protein, lymphocyte count, and Alb levels between the 2 groups (all P > .05). Neutrophil count, neutrophil\lymphocyte ratio, serum creatinine, Lac, and Lac/Alb levels were significantly higher in patients in the myocardial injury group than in the nonmyocardial injury group [13.90 (11.07,19.67) × 109/L vs 10.79 (8.16,14.23) × 109/L, 26.48 (20.07,31.88) vs 17.79 (9.85,27.23), 135.71 (81.50,284.75) µmol/L vs 76.30 (60.30,140.30) µmol/L, 3.0 (2.2,4.5) mmol/L vs 2.1 (1.6,3.1) mmol/L, 1.34 (0.88,2.16) vs 0.78 (0.60,1.12), all P < .05]. Patients in the myocardial injury group had a significantly higher mortality rate in the ICU than in the nonmyocardial injury group (72.0% vs 36.2%, P < .01). Neutrophils, neutrophil/lymphocyte ratio, serum creatinine, Lac, and Lac/Alb showed a weak positive correlation with myocardial injury in patients (all P < .05). The area under the curve of Lac/Alb for predicting myocardial injury in elderly patients with SCAP was 0.737 (95% confidence interval 0.620-0.834), and the sensitivity and specificity of the prediction with 1.21 as the cutoff value were 60.00% and 78.72%, respectively.Lac/Alb has an excellent predictive value for myocardial injury in elderly SCAP patients.

Regulation of Blood Glucose Using Islets Encapsulated in a Melanin-Modified Immune-Shielding Hydrogel.

Islet transplantation is currently a promising treatment for type 1 diabetes mellitus. However, the foreign body reaction and retrieval difficulty often lead to transplantation failure and hinder the clinical application. To address these two challenges, we propose a balanced charged sodium alginate-polyethyleneimine-melanin (SA-PEI-Melanin) threadlike hydrogel with immune shielding and retrievable properties. The attractiveness of this study lies in that the introduction of melanin can stimulate insulin secretion, especially under near-infrared (NIR) irradiation. After demonstrating a good immune-shielding effect, we performed an in vivo transplantation experiment. The results showed that the blood glucose level in the SA-PEI-Melanin group was stably controlled below the diabetic blood glucose criterion, and this blood glucose level could be further adjusted after NIR irradiation. In addition, the evaluation after retrieving the SA-PEI-Melanin hydrogel indicated that the islets still maintained a normal physiological function, further proving its excellent immunological protection. This study provides a new approach for the accurate regulation of blood glucose in patients with type 1 diabetes mellitus and contributes to developing a promising transplant system to reconcile real-time and precise light-defined insulin secretion regulation.

SOX11 and FAK participate in the stretch­induced mechanical injury to alveolar type 2 epithelial cells.

The aim of the present study was to explore the potential role of SOX11 in the stretch­induced mechanical injury to alveolar type 2 epithelial (AT2) cells. A cell stretch (CS) test was used to induce mechanical injury to primary cultured AT2 cells. Wound healing, adhesion, cell viability assays and flow cytometry were performed to evaluate the migration, adhesion, viability and apoptosis of AT2 cells. Changes in the invasive ability of AT2 cells were detected using a Transwell invasion assay. To further explore the underlying molecular mechanisms, reverse transcription­quantitative PCR and western blot analysis were used to assess the expression levels of SOX11, FAK, Akt, caspase­3/8, p65 and matrix metalloproteinase (MMP)7. Co­immunoprecipitation (Co­IP) and luciferase reporter assays were used to detect the interaction between SOX11 and FAK. CS reduced the invasion, migration and adhesion, and increased the apoptosis of AT2 cells. It also resulted in the downregulation of SOX11 and FAK expression in AT2 cells. The overexpression of SOX11 reversed these changes, whereas the knockdown of SOX11 aggravated the deterioration of the aforementioned biological behaviors and the apoptosis of the AT2 cells following CS. The overexpression of SOX11 upregulated the FAK and Akt expression levels, and downregulated caspase­3/8 expression, whereas the silencing of SOX11 reversed these changes following CS. Furthermore, the effects of SOX11 overexpression were inhibited by FAK antagonism. The results of Co­IP demonstrated that SOX11 and FAK were bound together, and that the expression of FAK was significantly increased in the SOX11 overexpression group. Luciferase assays revealed that the luciferase activity and the mRNA expression of FAK were significantly increased following transfection with pcDNA SOX11 and pGL3 FAK promoter. Co­IP and luciferase assays revealed that SOX11 directly regulated the expression of FAK. On the whole, the present study demonstrates that the downregulated expression of SOX11 and FAK are involved in the stretch­induced mechanical injury to AT2 cells. The overexpression of SOX11 significantly alleviates AT2 cell injury through the upregulation of FAK and Akt, and the inhibition of apoptosis. These findings suggest that the activation of SOX11 and FAK may be potential preventive and therapeutic options for ventilator­induced lung injury.

Enhancement of FAK alleviates ventilator-induced alveolar epithelial cell injury.

Mechanical ventilation induces lung injury by damaging alveolar epithelial cells (AECs), but the pathogenesis remains unknown. Focal adhesion kinase (FAK) is a cytoplasmic protein tyrosine kinase that is involved in cell growth and intracellular signal transduction pathways. This study explored the potential role of FAK in AECs during lung injury induced by mechanical ventilation. High-volume mechanical ventilation (HMV) was used to create a mouse lung injury model, which was validated by analysis of lung weight, bronchoalveolar lavage fluid and histological investigation. The expression of FAK and Akt in AECs were evaluated. In addition, recombinant FAK was administered to mice via the tail vein, and then the extent of lung injury was assessed. Mouse AECs were cultured in vitro, and FAK expression in cells under stretch was investigated. The effects of FAK on cell proliferation, migration and apoptosis were investigated. The results showed that HMV decreased FAK expression in AECs of mice, while FAK supplementation attenuated lung injury, reduced protein levels/cell counts in the bronchoalveolar lavage fluid and decreased histological lung injury and oedema. The protective effect of FAK promoted AEC proliferation and migration and prevented cells from undergoing apoptosis, which restored the integrity of the alveoli through Akt pathway. Therefore, the decrease in FAK expression by HMV is essential for injury to epithelial cells and the disruption of alveolar integrity. FAK supplementation can reduce AEC injury associated with HMV.

Transfection of Sox11 plasmid alleviates ventilator-induced lung injury via Sox11 and FAK.

Background Ventilator-induced lung injury (VILI) is the most common complication in the mechanical ventilation in clinic. The pathogenesis of VILI has not been well understood. The SRY related High Mobility Group box group-F family member 11(Sox11) is a protein associated with lung development. The focal adhesion kinase(FAK) is a cytoplasmic tyrosine kinase and is regulated by Sox11. The present study, therefore, was undertaken to explore the potential role of Sox11 and FAK in VILI. Methods High volume mechanical ventilation(HMV) was used to establish mouse VILI model under anesthesia. The lung injury was evaluated by analyzing the lung weight, bronchoalveolar lavage fluid, histopathological changes and apoptosis of the lung. The Sox11 and FAK expressions in the lung were investigated by real-time qPCR, western blot and immunohistochemistry analysis. Results HMV induced VILI simultaneously companied with decreased expressions of Sox11 and FAK in alveolar epithelial and interstitial cells either in gene and protein levels. Transfection of Sox11 plasmid significantly upregulated expressions of Sox11 and FAK in gene and protein levels in the lung and particularly effectively alleviated VILI. Furthermore, FAK antagonism by PF562271(FAK antagonist) blocked the alleviating effect of Sox11 plasmid transfection on the VILI. Conclusion The dysregulation in the Sox11 and FAK after HMV play an important role in the pathogenesis of VILI, and facilitating the activity of Sox11and FAK might be an effective target and potential option in the prevention and treatment of VILI in clinic.