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Nitrogen, oxygen, and sulphur heterocycles as potent anti-inflammatory agents: Insight into the synthetic routes
No full text[[abstract]]Nitrogen, oxygen, and sulfur-containing heterocyclic compounds are broadly established as key scaffolds with potential chemical and biological properties. Benzimidazole, indole, benzoxazole, benzothiazole, pyrazole, and thiophene analogs are significant heterocyclic motifs that bear almost all pharmacological activities. Anti-inflammatory activity is one of the most commonly associated biological activities with these heterocycles and thus has attracted the interest of researchers to synthesize and study them in-depth. The present review highlights mainly the various synthetic methodologies utilized to prepare these diverse heterocycles and their associated pharmacological properties limited to anti-inflammatory activities. Further, this review will provide a comprehensive idea of the methodologies used to prepare biologically active nitrogen, oxygen, and sulfur-bearing heterocycles and possibly invoke new thoughts in the search for rational designs for developing more promising anti-inflammatory agents
3-Monothiopomalidomide, a new immunomodulatory imide drug (IMiD), blunts inflammation and mitigates ischemic stroke in the rat
No full text[[abstract]]An overactive neuroinflammatory response is often evident in the elderly and is a significant contributor to brain tissue damage following acute ischemic stroke. Such an inflammatory response is largely mediated by microglial cells and peripheral blood mononuclear cells (PBMCs). Classical anti-inflammatory agents have not proved clinically effective in mitigating the impact of ischemic stroke but have highlighted targets for new drug development, in particular excessive proinflammatory cytokine release. The immunomodulatory imide drug (IMiD) class has shown potential in reducing neuroinflammation and switching microglial phenotypic expression away from a proinflammatory to a regenerative anti-inflammatory one. 3-Monothiopomalidomide (3-MP), a new IMiD, has a brain/plasma concentration ratio of 0.5 to 0.6, an oral bioavailability of 38.5%, and a monophasic disappearance of half-life 3.2 h following oral administration. 3-MP pretreatment mitigates lipopolysaccharide (LPS)-induced inflammation in cellular human PBMCs and, in rat studies, 3-MP pretreatment lowers proinflammatory cytokine levels in the conditioned media and in plasma and the brain, respectively. Administered systemically to rats challenged with middle cerebral artery occlusion (MCAo) and reperfusion, 3-MP post-MCAo treatment reduced infarction volume; improved body asymmetry, a behavioral measure of stroke impact; and lowered inflammation. In summary, 3-MP exerted neuroprotective effects via anti-inflammatory actions against MCAo-induced ischemic injury and represents a therapeutic that warrants further investigation as a treatment for brain damage and related disorders associated with excessive inflammation
Frailty associated with cardiovascular mortality in hemodialysis patients
No full text[[abstract]]Background: Cardiovascular disease is the leading cause of mortality among hemodialysis patients. Frailty, characterized by diminished physiological reserve, is increasingly recognized as an important risk factor for adverse outcomes in this population. Objectives: This study aimed to investigate the role of frailty in cardiovascular mortality among patients undergoing maintenance hemodialysis. Methods: This prospective cohort study enrolled 1,136 hemodialysis patients from 12 centers in Hsinchu, Taiwan. Baseline data on demographics, comorbidities, dialysis-related factors, and laboratory results were collected. Frailty was assessed using modified Fried frailty criteria, and the patients were followed for a median of 1,187 days. Cardiovascular death was the primary outcome, with a particular emphasis on sudden cardiac death. Cox proportional hazards models were used to analyze the data. Results: Of the 1,136 participants, 34.3% were classified as frail. The frail patients had significantly higher rates of cardiovascular death [25% vs. 12%, hazard ratio (HR) = 2.34, p <0.001] and sudden cardiac death (16% vs. 6%, HR = 3.12, p < 0.001) compared to the non-frail patients. Multivariate analysis confirmed frailty as an independent predictor of cardiovascular death (HR = 1.62, 95% confidence interval 1.20, 2.19, p = 0.002). The association between frailty and sudden cardiac death was more pronounced than that between frailty and non-sudden cardiac death. Conclusions: Frailty was a strong predictor of cardiovascular mortality, and particularly sudden cardiac death, in the enrolled hemodialysis patients. These findings underscore the importance of frailty assessments and targeted interventions to reduce cardiovascular risk in this vulnerable group. Further research is needed to elucidate the mechanisms linking frailty with cardiovascular outcomes and to develop effective management strategies
Identification and biological evaluation of a novel CLK4 inhibitor targeting alternative splicing in pancreatic cancer using structure-based virtual screening
No full text[[abstract]]Pancreatic cancer is an aggressive malignancy with a poor prognosis and limited treatment options. Cdc-like kinase 4 (CLK4), a kinase that regulates alternative splicing by phosphorylating spliceosome components, is implicated in aberrant splicing events driving pancreatic cancer progression. In this study, we established a computational model that integrates pharmacological interactions of CLK4 inhibitors with an improved hit rate. Through this model, we identified a novel CLK4 inhibitor, compound 150441, with a 50% inhibitory concentration (IC50) value of 21.4 nm. Structure-activity relationship analysis was performed to investigate key interactions and functional groups. Kinase profiling revealed that compound 150441 is selective for CLK4. Subsequent in vitro assays demonstrated that this inhibitor effectively suppressed cell growth and viability of pancreatic cancer cells. In addition, it inhibited the phosphorylation of key splicing factors, including serine- and arginine-rich splicing factor (SRSF) 4 and SRSF6. Cell cycle analysis further indicated that the compound induced G2/M arrest, leading to apoptosis. RNA-seq analysis revealed that the compound induced significant changes in alternative splicing and key biological pathways, including RNA processing, DNA replication, DNA damage, and mitosis. These findings suggest that compound 150441 has promising potential for further development as a novel pancreatic cancer treatment
Identification of PTGR2 inhibitors as a new therapeutic strategy for diabetes and obesity
No full text[[abstract]]Peroxisome proliferator-activated receptor γ (PPARγ) is a master transcriptional regulator of systemic insulin sensitivity and energy balance. The anti-diabetic drug thiazolidinediones (TZDs) are potent synthetic PPARγ ligands with undesirable side effects, including obesity, fluid retention, and osteoporosis. 15-keto prostaglandin E2 (15-keto-PGE2) is an endogenous PPARγ ligand metabolized by prostaglandin reductase 2 (PTGR2). Here, we confirmed that 15-keto-PGE2 binds to and activates PPARγ via covalent binding. In patients with type 2 diabetes and obese mice, serum 15-keto-PGE2 levels were decreased. Administration of 15-keto-PGE2 improves glucose homeostasis and prevented diet-induced obesity in mice. Either genetic inhibition of PTGR2 or PTGR2 inhibitor BPRPT0245 protected mice from diet-induced obesity, insulin resistance, and hepatic steatosis without causing fluid retention and osteoporosis. In conclusion, inhibition of PTGR2 is a new therapeutic approach to treat diabetes and obesity through increasing endogenous PPARγ ligands while avoiding side effects including increased adiposity, fluid retention, and osteoporosis
[[alternative]]Adenoviral vector-based vaccine against enterovirus infection
No full text[[abstract]]本發明關於一種重組腺病毒載體，可用於產生免疫力以對抗腸病毒感染。於一具體實施例中，本發明之重組腺病毒載體包含一表現卡匣，其編碼腸病毒之P1蛋白及3CD蛋白酶。於另一具體實施例中，本發明重組腺病毒載體包含一表現卡匣，其編碼腸病毒之3C蛋白酶或3CD蛋白酶。本發明亦關於一種疫苗組合物，包含所述之重組腺病毒載體。本發明提供一種使用該重組腺病毒載體及疫苗組合物以誘發個體產生免疫反應，對抗腸病毒感染的方法。進一步提供一種產生腸病毒之類病毒顆粒之方法，係藉由表現本文所述之腺病毒載體於哺乳動物細胞中
The way of nephropathy development in T2DM with different risk factors: TaiWan P4P Data analysiS (TWPDS)
No full text[[abstract]]Background: Type 2 diabetes mellitus (T2DM) and its complications have contributed to the global burden of mortality and disability. Kidney failure is responsible for around 10% of T2DM deaths. However, there has been scarce research on how diabetic nephropathy progresses through its stages. Aim: We aimed to investigate the development and progres- sion of nephropathy in T2DM patients in Taiwan. Method: Real-world data of patients with T2DM from Taiwan’s pay-for-performance-diabetes mellitus (P4P-DM) program during 2010–2021 were queried. Results: Data of 719,921 patients were analyzed. The mean age was 59.6 ± 13.1 years, and 54.1% were males. The 5-year cumulative incidence of chronic kidney disease (CKD) progression from estimated glomerular filtration rate [eGFR] ≥ 90 mL/min/1.73 m2 to eGFR 60–89 mL/min/1.73 m2 was 21.5%, while 32.7% progressed from normal (urine albumin-creatinine ratio [UACR] 300 or UPCR > 1000 mg/gm) to dialysis reached 16.0% (Figure 1). Conclusion: T2DM patients in Taiwan were more likely to have albuminuria before a decline in eGFR occurred. Compared to individuals with stage 3b CKD, those with macroalbuminuria had nearly three times the likelihood of progressing to dialysis within 5 years. The findings suggest that albuminuria could serve as an early and better indicator in comparison with eGFR for diabetic nephropathy. Incorporating routine screening for UACR in clinical practice will be pivotal for the early detection and management of diabetic nephropathy and ultimately improve outcomes and quality of life for patients with T2DM
Novel approach to anti-tumour and anti-SARS-COV-2 drugs by modulating sialylation of N-glycans
No full text[[abstract]]Variations in cell surface sialylation are known to play an important role in tumour cell invasion and metastasis. Modifications of sialylation in vivo are mediated by several glycoprotein-and glycolipid-specific sialytransferases (STs). At present, few selective STs inhibitors with a cell-permeable property have been documented. In addition. observations of sialylated glycans, specifically glycolipids. facilitate viral entry of SARS-CoV-2 are confirmed and validated. Thus, the discovery of anti-SARS-Co-2 agents that can target specific ST isozymes in vivo, is essential for the development of effective chemical therapeutics to prevent viral infection. To address the scarcity of novel STs inhibitors, we now report the synthesis and biological evaluation of new and novel bishomolithocholic acid derivatives with promising therapeutic potential against breast cancer growth and SARS-CoV-2 infection. Among the series, SPP-037 preferentially inhibited the activity of ST6GAL1 (sialylation of N-glycan) with an IC50 value of 3.6 µM over ST3GAL1 (IC50>500µM; sialyation of O-glycan)). In vitro cell-based assays revealed that SPP-037 suppressed MDA-MB-231cell migration and HUVEC tube formation. Moreover, administration of SPP-037 to tumour-bearing mice resulted in reduced tumour growth, thereby highlighting its anticancer activity. Furthermore, we validated that SARS-CoV-2 upregulates ST6GAL1 expression and sialylation using RT-qPCR analysis, immunohistochemistry and immunofluorescence imaging assays. It was found that treatment of A549-hACE2 cells with SPP-037 attenuated cellular sialylation, substantially decreasing SARS-CoV-2 infections. Our results underscore the feasibility of ST6GAL1 inhibition as an ingenious therapeutic intervention to suppress SARS-CoV-2 infectivity
An enzymatic-independent function of palmitoyl hydrolase in cohesin loading onto chromosome
No full text[[abstract]]Sister chromatid cohesion is mediated by a conserved multiprotein complex called cohesin. The loading of cohesin onto chromosomes involves the RSC (remodels the structure of chromatin) chromatin remodeling complex. Here, we demonstrate that the fission yeast Phi1, a palmitoyl hydrolase inactive protein 1, serves to bridge the interaction between cohesin and the RSC complex. Phi1 interacts with Rad21 in cohesin and Snf21, the RSC complex ATPase, to promote chromosome loading of cohesin. The identified characteristic features of Phi1 are conserved in the human homologues Apt1 and Apt2, which interact with Rad21 and Brg1, the human homologue of Snf21, in an enzymatic-independent manner. Intriguingly, the cohesin-Apt1-Brg1 complex is upregulated in C4-2B prostate cancer cells, and co-depletion of Apt1 and Apt2 by small interfering RNA triggers mitotic catastrophe in these cells. In addition, Apt1 nuclear localization is associated with poor clinical outcomes in prostate cancer. These results suggest a pro-survival function against mitotic stress for the complex
Reduced taurine synthesis underlies morphine-promoted lung metastasis of triple-negative breast cancer
No full text[[abstract]]Background: The mechanisms underlying the progression and metastasis of triple-negative breast cancer (TNBC) in the context of extended morphine exposure remain poorly understood. Morphine consumption has been a pressing issue in many countries. While the physiological impact of extended morphine use is multifaceted, cancer patients with a history of extended morphine usage often have a poor prognosis. Methods: In this study, we investigated the impact of extended morphine treatment on the transcriptional profiles of TNBC. To this end, mice were administered morphine intraperitoneally for 14 days, followed by the implantation of EO771 cells, which are triple-negative breast cancer cells, into their mammary fat pad. After primary tumors were removed on the 38th day, a subset of mice was continuously given saline or morphine until the 68th day. Tumor size, organ metastasis, and tumor RNA expression were analyzed. Results: Our findings showed that extended exposure to morphine led to an increase in lung metastasis in the mouse model of triple-negative breast cancer. We analyzed RNA sequencing on tumors to compare their transcriptional profiles with or without metastasis. Through pathway analysis, we specifically examined the novel impact of morphine on the downregulation of taurine/hypotaurine biosynthesis. Given that morphine, droperidol (a dopamine receptor antagonist), and naloxone (an opioid receptor antagonist) might act through either opioid receptors or dopamine receptors, we further demonstrated that taurine mitigated EO771 cell invasion induced by morphine but not by droperidol or naloxone treatment. Additionally, morphine treatment markedly decreased the expression of GAD1, one of the enzymes essential for taurine biosynthesis, whereas droperidol and naloxone did not. Conclusions: The findings of morphine-induced reduction in GAD1 levels and the inhibition of invasion by taurine treatment suggest that taurine could serve as a potential supplement for triple-negative breast cancer patients who require morphine as part of their treatment regimen or due to their circumstances