Unpacking the environmental quality through the effects of natural resources, renewable energy consumption, banking development and industrial value addition: An empirical evidence from BRICS countries.

This study explores the association between natural resources rent, industrial value addition, banking development, renewable energy consumption, total reserves and environmental quality in the dynamic context of BRICS nations from 1995 to 2019. BRICS economies are responsible for global greenhouse gas emissions and confront pressing environmental challenges, including biodiversity loss and pollution. For the dependent variable, the environmental quality, the study constructed a composite index using PCA for all environmental indicators where interdependencies among variables are prevalent. Besides this, the study incorporates two interaction terms to determine the indirect influence of natural resource rent and banking development on environmental quality through the mediating role of industrial value addition. By applying the CS-ARDL technique, the outcomes of the study reveal that natural resources rent, industrial value addition, and total reserves positively influence ENQ, indicating the adverse consequences of industrial sectors on environmental quality and continued environmental degradation due to resource-intensive industrial production, underscoring the urgency of sustainable resource management. In contrast, banking development and renewable energy consumption negatively influence ENQ, signifying the positive role of developed banking sectors in supporting eco-friendly projects and enhancing environmental quality. This study offers valuable insights for policy interventions to foster a more sustainable future.

Luteolin promotes neuronogenesis in hippocampus of chronic unpredictable mild stress rats and primary hippocampus of fetal rats.

OBJECTIVE: To investigate the effects of luteolin on chronic unpredictable mild stress (CUMS)-induced depressive rats and corticosterone (CORT)-induced depressive primary hippocampal neurons, and to elucidate the mechanism behind the action. METHODS: The antidepressant mechanism of luteolin was studied by using CUMS rat model and primary hippocampal neurons in fetal rats. In vivo, novelty suppressed feeding, open-field and sucrose preference tests as well as Morris water maze were evaluated. The content of brain derived neurotrophic factor (BDNF), 5-hydroxytryptamine (5-HT), norepinephrine (NE), and dopamine (DA) in serum were detected by enzyme-linked immunosorbent assay. The mechanisms of luteolin were explored based on neurotrophin and hippocampal neurogenesis, and proliferation. Survival of the septo-temporal axis in hippocampus was assayed using the 5-bromo-2-deoxyuridine (BrdU), the expression of BDNF, neurotrophin-3 (NT-3), and nerve growth factor (NGF) in hippocampus dentate gyrus region were measured by Western-blotting. In vitro, BDNF, NT-3, tropomyosin receptor kinase B (TrkB), and phosphorylated cyclic adenosine monophosphate responsive element binding protein (p-CREB) were detected through the high content analysis (HCA) to investigate neurotrophin and apoptosis. RESULTS: Induction of CUMS in rats induced depressive symptoms, while luteolin significantly enhanced sucrose consumption, decreased feeding latency, increased locomotor activity, escape latency, distance of target quadrant and regulated the content of depressive-like biomarkers. Histology analysis revealed that luteolin increased the abundance of new born neurons that had been labeled with BrdU, BrdU + neuronal nuclear antigen, and BrdU + doublecortin in septo-temporal axis of S2 (mid-septal) and T3 (mid-temporal). Moreover, expression of BDNF, NT-3, and NGF increased significantly in the septo-temporal axis of S2 and T3. HCA showed increased expression of BDNF, NT-3, TrkB and p-CREB in primary hippocampal neurons. CONCLUSION: The results provided direct evidence that luteolin has an antidepressant effect and could effectively promote the regeneration of the septotemporal axis nerve and hippocampal neuronutrition, which suggested that the antidepressant effect of luteolin may be related to hippocampal neurogenesis.

Association between GLIM-diagnosed malnutrition and quality of life in older patients with cancer.

BACKGROUND: Older patients with cancer have a higher risk for malnutrition and impaired quality of life (QoL). The present study aimed to investigate the relationship between malnutrition diagnosed according to the Global Leadership Initiative Malnutrition (GLIM) criteria and QoL across various tumor types, and to evaluate the combined prognostic value of malnutrition and QoL in predicting survival among older patients with cancer. METHODS: This multicenter, observational cohort study included 5310 older patients with cancer and 2184 with malnutrition (moderate stage, n = 1023; severe stage, n = 1161). An empirical cumulative distribution curve was performed to illustrate the correlation between malnutrition and QoL. The primary objective was to investigate the association between malnutrition and QoL using logistic regression analysis. Survival analyses were performed to assess the combined prognostic value of malnutrition and QoL. RESULTS: The median age of the patients (66.9% male, 33.1% female) was 70 years (interquartile range [IQR] 67-74 years) years. The median QoL score was highest in patients without malnutrition (91.88 [IQR 84.44-97.44]), followed by those with moderate (86.15 [IQR 76.18-93.85) and severe (82.31 [IQR 69.87-91.11]) malnutrition. Logistics regression revealed that the risk for developing impaired QoL increased 1.98 (95% confidence interval [CI] 1.64-2.38; P < 0.001) and 2.33 (95% CI 1.93-2.81; P < 0.001) times in patients with moderate and severe malnutrition, respectively. Kaplan-Meier curves showed that QoL in combination with GLIM criteria demonstrated a significant discriminative performance for survival and served as an independent prognostic factor among older patients with cancer, especially for lung and gastric cancers. CONCLUSIONS: Malnutrition diagnosed according to the GLIM criteria was a predictor of impaired QoL. Additionally, the combination of QoL and malnutrition demonstrated utility for predicting survival outcomes in older patients with cancer.

Effect of Cold Versus Hot Snare Polypectomy on Colon Postpolypectomy Bleeding in Patients with End-Stage Renal Disease: A Retrospective Cohort Study.

BACKGROUND: Patients with end-stage renal disease (ESRD) who undergo polypectomy may experience postpolypectomy bleeding. To reduce the risk of delayed postpolypectomy bleeding among the general population, cold snare polypectomy (CSP) is recommended for removing colon polyps smaller than 1 cm. Nevertheless, only few studies have examined the effect of CSP on patients with ESRD. METHODS: We retrospectively analyzed the data of patients with ESRD who underwent colonoscopic polypectomy for polyps larger than 5 mm at a Taiwanese university hospital from January 2014 to January 2023. The main outcome was delayed postpolypectomy bleeding within 30 days. Multivariate analysis was conducted to adjust for major confounders. RESULTS: A total of 557 patients with ESRD underwent colonoscopic polypectomy during the study period: 201 underwent CSP and 356 underwent hot snare polypectomy (HSP). Delayed postpolypectomy bleeding occurred in 27 patients (4.8%). The rate of delayed postpolypectomy bleeding was lower in patients with ESRD who underwent CSP than in those who underwent HSP (1.9% vs. 6.4%, P = 0.022). The percentage of patients who did not experience postpolypectomy bleeding within 30 days after CSP remained lower than that observed after HSP (P = 0.019, log-rank test). Multivariate analysis demonstrated immediate postpolypectomy bleeding and HSP to be independent risk factors for delayed postpolypectomy bleeding. A nomogram prognostic model was used to predict the potential of delayed postpolypectomy bleeding within 30 days in patients with ESRD. CONCLUSIONS: Compared with HSP, CSP is more effective in mitigating the risk of delayed postpolypectomy bleeding in patients with ESRD.

Regioselective Alkynylation and Alkenylation at the More Hindered C-B Bond of 1,2-Bis(Boronic) Esters.

Selective transformations at the more sterically hindered sites of organic molecules represent a frontier in the ability to precisely modify molecules. The lack of effective synthetic methods stands in stark contrast to the large number of encumbered sites encountered in molecules of interest. Here, we demonstrate that 1,2-bis(boronates) undergo selective alkynylation and alkenylation at the more sterically hindered C-B bond. Our preliminary mechanistic studies disclosed that this reaction can proceed through two convergent pathways involving direct coupling of sterically encumbered site versus 1,2-boron migratory coupling. Notably, this method facilitated convenient access to alkenyl and alkynyl boron products, which can be diversified by an array of transformations.

Development of Novel Indazolyl-Acyl Hydrazones as Antioxidant and Anticancer Agents that Target VEGFR-2 in Human Breast Cancer Cells.

The increased expression of VEGFR-2 in a variety of cancer cells promotes a cascade of cellular responses that improve cell survival, growth, and proliferation. Heterocycles are common structural elements in medicinal chemistry and commercially available medications that target several biological pathways and induce cell death in cancer cells. Herein, the evaluation of indazolyl-acyl hydrazones as antioxidant and anticancer agents is reported. Compounds 4e and 4j showed inhibitory activity in free radical scavenging assays (DPPH and FRPA). The titled compounds were employed in cell viability studies using MCF-7 cells, and it was observed that compounds 4f and 4j exhibited IC50 values 15.83 µM and 5.72 µM, respectively. In silico docking revealed the favorable binding energies of -7.30 kcal/mol and -8.04 kcal/mol for these compounds towards Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2), respectively. In conclusion, compounds with antioxidant activity and that target VEGFR-2 in breast cancer cells are reported.

Safety and effectiveness assessment of endovascular recanalization for non-acute middle cerebral artery occlusion.

BACKGROUND: Endovascular treatment for patients with symptomatic nonacute middle cerebral artery occlusion remains clinically challenging, and proof of a beneficial effect on functional outcome is lacking. We aim to evaluate the effectiveness and safety of endovascular recanalization for patients with symptomatic nonacute middle cerebral artery occlusion. METHODS: Ninety-eight patients with symptomatic atherosclerotic nonacute middle cerebral artery occlusion were divided into drug treatment groups (42) and endovascular treatment groups (56). The rate of recanalization, peri-procedural complications, and follow-up results were evaluated. RESULTS: Among the 56 patients who received endovascular treatment, 53 (94.6%) achieved successful recanalization. The rate of peri-procedural complications was 7.1% (4/56), and the death rate was 1.8% (1/56). Any stroke within 90 days was 7.1% (4/56). Among the 42 patients in drug treatment group, any stroke within 90 days was 19.0% (8/42), death rate was 0. CONCLUSION: Among patients with symptomatic nonacute middle cerebral artery occlusion with a short length of occlusion and a moderate-to-good collateral circulation, endovascular treatment seems to be safe. And endovascular treatment could reduce the recurrence rate of stroke.

Development of Piperazine- and Oxazine-Linked Pyrimidines as p65 Subunit Binders of NF-κB in Human Breast Cancer Cells.

Nuclear factor kappa B (NF-κB) is a potential therapeutic target in breast cancer. In the current study, a new class of oxazine- and piperazine-linked pyrimidines was developed as inhibitors of NF-κB, overcoming the complexity of the oxazine structure found in nature and enabling synthesis under laboratory conditions. Among the series of synthesized and tested oxazine-pyrimidine and piperazine-pyrimidine derivatives, compounds 3a and 5b inhibited breast cancer cell (MCF-7) viability with an IC50 value of 9.17 and 6.29 µM, respectively. In silico docking studies showed that the pyrimidine ring of 3a and the 4-methoxybenzyl thiol group of 5b could strongly bind the p65 subunit of NF-κB, with the binding energies -9.32 and -7.32 kcal mol-1. Furthermore, compounds 3a and 5b inhibited NF-κB in MCF-7 breast cancer cells. In conclusion, we herein report newer structures that target NF-κB in BC cells.

Electrochemical Synthesis of New Isoxazoles and Triazoles Tethered with Thiouracil Base as Inhibitors of Histone Deacetylases in Human Breast Cancer Cells.

Histone deacetylases (HDACs) are an attractive drug target for the treatment of human breast cancer (BC), and therefore, HDAC inhibitors (HDACis) are being used in preclinical and clinical studies. The need to understand the scope of the mode of action of HDACis, as well as the report of the co-crystal structure of HDAC6/SS-208 at the catalytic site, provoked us to develop an isoxazole-based lead structure called 4-(2-(((1-(3,4-dichlorophenyl)-1H-1,2,3-triazol-4-yl)methyl)thio) pyrimidin-4-yl) morpholine (5h) and 1-(2-(((3-(p-tolyl) isoxazol-5-yl)methyl)thio) pyrimidin-4-yl) piperidin-4-one (6l) that targets HDACs in human BC cells. We found that the compound 5h or 6l could inhibit the proliferation of BC cells with an IC50 value of 8.754 and 11.71 µM, respectively. Our detailed in silico analysis showed that 5h or 6l compounds could target HDAC in MCF-7 cells. In conclusion, we identified a new structure bearing triazole, isoxazole, and thiouracil moiety, which could target HDAC in MCF-7 cells and serve as a base to make new drugs against cancer.

Population Frequency of Undiagnosed Fabry Disease in the General Population.

Introduction: Fabry disease is an X-linked disorder that results from pathogenic GLA variants and can now be treated. Most studies of its population frequency have examined only males or attendees at kidney failure or cardiac clinics. This study determined the prevalence of undiagnosed Fabry disease from predicted pathogenic GLA variants in the general population. Methods: The Genome Aggregation Database (gnomAD) was examined for predicted pathogenic GLA variants based on variant rarity (≤5), and transcript effect in 4 computational tools (CADD >20, PP2 >0.95, SIFT <0.05, Mutation Taster - Disease-causing) and amino acid conservation in vertebrates in a Clustal. Results: Predicted pathogenic variants in GLA occurred in 1 in 3225 of the gnomAD population and 1 in 3478 of its control subset. Predicted pathogenic variants were more common in women than expected (3.1:1), which is consistent with men being excluded from gnomAD because of Fabry complications. Predicted pathogenic variants were not found in members of this cohort with South Asian, Ashkenazim, or Finnish ancestries. Variants identified as pathogenic in the Fabry database were found in 1 in 2651 individuals of the gnomAD database and pathogenic variants from ClinVar in 1 in 4420. Discussion: The population frequency of 1 in 3225 for undiagnosed men and women with Fabry disease still represents an underestimate because our pathogenicity criteria were rigorous, the cohort did not include already-diagnosed individuals, and whole exome sequencing does not detect intronic variants and large deletions. This study confirms that Fabry disease is more common than previously recognized and still underdiagnosed especially in women.

Ir-Catalyzed Enantioselective Synthesis of gem-Diborylalkenes Enabled by 1,2-Boron Shift.

Asymmetric cross-couplings based on 1,2-carbon migration from B-ate complexes have been developed efficiently to access valuable organoboronates. However, enantioselective reactions triggered by 1,2-boron shift have remained to be unaddressed synthetic challenge. Here, Ir-catalyzed asymmetric allylic alkylation enabled by 1,2-boron shift was developed. In this reaction, we disclosed that excellent enantioselectivities were achieved through an interesting dynamic kinetic resolution (DKR) process of allylic carbonates at the elevated temperature. Notably, the highly valuable (bis-boryl)alkenes have enabled an array of diversifications to access versatile molecules. Extensive experimental and computational studies were conducted to elucidate the reaction mechanism of DKR process and clarify the origin of excellent enantioselectivities.

Methyl-Thiol-Bridged Oxadiazole and Triazole Heterocycles as Inhibitors of NF-κB in Chronic Myelogenous Leukemia Cells.

Nuclear factor kappa beta (NF-κB) is a transcriptional factor that plays a crucial role in regulating cancer cell proliferation. Therefore, the inhibition of NF-κB activity by small molecules may be beneficial in cancer therapy. In this report, methyl-thiol-bridged oxadiazole and triazole heterocycles were synthesized via click chemistry and it was observed that the lead structure, 2-(((1-(3,4-dichlorophenyl)-1H-1,2,3-triazol-4-yl)methyl)thio)-5-(4-methoxybenzyl)-1,3,4-oxadiazole (4c), reduced the viability of MCF-7 cells with an IC50 value of 7.4 µM. Compound 4c also caused concentration-dependent loss of cell viability in chronic myelogenous leukemia (CML) cells. Furthermore, compound 4c inhibited the activation of NF-κB in human CML cells as observed by nuclear translocation and DNA binding assays. Functionally, compound 4c produced PARP cleavage and also suppressed expression of Bcl-2/xl, MMP-9, COX-2, survivin, as well as VEGF, resulting in apoptosis of CML cells. Moreover, ChIP assay showed that compound 4c decreased the binding of COX-2 to the p65 gene promoter. Detailed in silico analysis also indicated that compound 4c targeted NF-κB in CML cells. In conclusion, a novel structure bearing both triazole and oxadiazole moieties has been identified that can target NF-κB in CML cells and may constitute a potential novel drug candidate.

Precise application of topical tranexamic acid to enhance endoscopic hemostasis for peptic ulcer bleeding: a randomized controlled study (with video).

BACKGROUND AND AIMS: Peptic ulcer recurrent bleeding occurs in 20% to 30% of patients after standard endoscopic hemostasis, particularly within 4 days after the procedure. The application of additional tranexamic acid (TXA) to the ulcer may enhance hemostasis. This study investigated the effectiveness of TXA powder application on bleeding ulcers during endoscopic hemostasis. METHODS: This study enrolled patients who had peptic ulcer bleeding between March 2022 and February 2023. After undergoing standard endoscopic therapy, the patients were randomly assigned to either the TXA group or the standard group. In the TXA group, an additional 1.25 g of TXA powder was sprayed endoscopically on the ulcer. Both groups then received 3 days of high-dose (8 mg/h) continuous infusion proton pump inhibitor therapy. Second-look endoscopy was conducted on days 3 to 4. The primary end point of early treatment failure was defined as ulcer recurrent bleeding within 4 days or major stigmata of recent hemorrhage on the second-look endoscopy. RESULTS: Sixty patients (30 in each group) with peptic ulcer bleeding and balanced baseline characteristics were randomly assigned to a treatment group. The early treatment failure rate was lower in the TXA group (6.7%) than in the standard group (30%) (P = .042). The freedom from treatment failure periods for 4 and 28 days was significantly longer in the TXA group than in the standard group (P = .023). No adverse events from TXA were recorded. CONCLUSIONS: The precise delivery of topical TXA alongside standard endoscopic hemostasis reduced the early treatment failure rate in patients with bleeding peptic ulcers. (Clinical trial registration number: NCT05248321.).

Discovery of Pyrimidine- and Coumarin-Linked Hybrid Molecules as Inducers of JNK Phosphorylation through ROS Generation in Breast Cancer Cells.

Human epidermal growth factor receptor 2 (HER2)-positive breast cancer exhibits early relapses, poor prognoses, and high recurrence rates. Herein, a JNK-targeting compound has been developed that may be of utility in HER2-positive mammary carcinoma. The design of a pyrimidine-and coumarin-linked structure targeting JNK was explored and the lead structure PC-12 [4-(3-((2-((4-chlorobenzyl)thio) pyrimidin-4-yl)oxy)propoxy)-6-fluoro-2H-chromen-2-one (5d)] was observed to selectively inhibit the proliferation of HER2-positive BC cells. The compound PC-12 exerted DNA damage and induced apoptosis in HER-2 positive BC cells more significantly compared to HER-2 negative BC cells. PC-12 induced PARP cleavage and down-regulated the expression of IAP-1, BCL-2, SURVIVIN, and CYCLIN D1 in BC cells. In silico and theoretical calculations showed that PC-12 could interact with JNK, and in vitro studies demonstrated that it enhanced JNK phosphorylation through ROS generation. Overall, these findings will assist the discovery of new compounds targeting JNK for use in HER2-positive BC cells.

De Novo Design of Imidazopyridine-Tethered Pyrazolines That Target Phosphorylation of STAT3 in Human Breast Cancer Cells.

In breast cancer (BC), STAT3 is hyperactivated. This study explored the design of imidazopyridine-tethered pyrazolines as a de novo drug strategy for inhibiting STAT3 phosphorylation in human BC cells. This involved the synthesis and characterization of two series of compounds namely, 1-(3-(2,6-dimethylimidazo [1,2-a]pyridin-3-yl)-5-(3-nitrophenyl)-4,5-dihydro-1H-pyrazol-1-yl)-2-(4-(substituted)piperazin-1-yl)ethanone and N-substituted-3-(2,6-dimethylimidazo[1,2-a]pyridin-3-yl)-5-(3-nitrophenyl)-4,5-dihydro-1H-pyrazoline-1-carbothioamides. Compound 3f with 2,3-dichlorophenyl substitution was recognized among the tested series as a lead structure that inhibited the viability of MCF-7 cells with an IC50 value of 9.2 µM. A dose- and time-dependent inhibition of STAT3 phosphorylation at Tyr705 and Ser727 was observed in MCF-7 and T47D cells when compound 3f was added in vitro. Calculations using density functional theory showed that the title compounds HOMOs and LUMOs are situated on imidazopyridine-pyrazoline and nitrophenyl rings, respectively. Hence, compound 3f effectively inhibited STAT3 phosphorylation in MCF-7 and T47D cells, indicating that these structures may be an alternative synthon to target STAT3 signaling in BC.

LiMYB108 is involved in floral monoterpene biosynthesis induced by light intensity in Lilium 'Siberia'.

KEY MESSAGE: We find that the MYB family transcription factor, LiMYB108, has a novel function to regulate the floral fragrance affected by light intensity. Floral fragrance determines the commercial value of flowers and is influenced by many environmental factors, especially light intensity. However, the mechanism by which light intensity affects the release of floral fragrance is unclear. Here, we isolated an R2R3-type MYB transcription factor LiMYB108, the expression of which was induced by light intensity and located in the nucleus. Light of 200 and 600 µmol m-1 s-1 significantly increased the expression of LiMYB108, which was consistent with the improving trend of monoterpene synthesis under light. Virus-induced gene silencing (VIGS) of LiMYB108 in Lilium not only significantly inhibited the synthesis of ocimene and linalool, but also decreased the expression of LoTPS1; however, transient overexpression of LiMYB108 exerted opposite effects. Furthermore, yeast one-hybrid assays, dual-luciferase assays, and electrophoretic mobility shift assays (EMSA) demonstrated that LiMYB108 directly activated the expression of LoTPS1 by binding to the MYB binding site (MBS) (CAGTTG). Our findings demonstrate that light intensity triggered the high expression of LiMYB108, and then LiMYB108 as a transcription factor to activate the expression of LoTPS1, thus promoting the synthesis of the ocimene and linalool, which are important components of floral fragrance. These results provide new insights into the effects of light intensity on floral fragrance synthesis.

Nano-Zirconium Dioxide Catalyzed Multicomponent Synthesis of Bioactive Pyranopyrazoles That Target Cyclin Dependent Kinase 1 in Human Breast Cancer Cells.

Small molecules are being used to inhibit cyclin dependent kinase (CDK) enzymes in cancer treatment. There is evidence that CDK is a drug-target for cancer therapy across many tumor types because it catalyzes the transfer of the terminal phosphate of ATP to a protein that acts as a substrate. Herein, the identification of pyranopyrazoles that were CDK inhibitors was attempted, whose synthesis was catalyzed by nano-zirconium dioxide via multicomponent reaction. Additionally, we performed an in-situ analysis of the intermediates of multicomponent reactions, for the first-time, which revealed that nano-zirconium dioxide stimulated the reaction, as estimated by Gibbs free energy calculations of spontaneity. Functionally, the novel pyranopyrazoles were tested for a loss of cell viability using human breast cancer cells (MCF-7). It was observed that compounds 5b and 5f effectively produced loss of viability of MCF-7 cells with IC50 values of 17.83 and 23.79 µM, respectively. In vitro and in silico mode-of-action studies showed that pyranopyrazoles target CDK1 in human breast cancer cells, with lead compounds 5b and 5f having potent IC50 values of 960 nM and 7.16 µM, respectively. Hence, the newly synthesized bioactive pyranopyrazoles could serve as better structures to develop CDK1 inhibitors against human breast cancer cells.