Design, synthesis and biological evaluation of Nrf2 modulators for the treatment of glioblastoma multiforme.

Glioblastoma multiforme (GBM) is a prevalent primary brain tumor. However, no specific therapeutic drug has been developed for it. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a crucial transcription factor involved in the cellular response to oxidative stress. Numerous studies have demonstrated that Nrf2 plays a pivotal role in GBM angiogenesis, and inhibiting Nrf2 can significantly enhance patient prognosis. Using virtual screening technology, we examined our in-house library and identified pinosylvin as a potential compound with high activity. Pinosylvin exhibited robust hydrogen bond and Π-Π interaction with Nrf2. Cell experiments revealed that pinosylvin effectively reduced the proliferation of U87 tumor cells by regulating Nrf2 and demonstrated greater inhibitory activity than temozolomide. Consequently, we believe that this study will offer valuable guidance for the future development of highly efficient therapeutic drugs for GBM.

Design and synthesis of ERα agonists: Effectively reduce lipid accumulation.

In recent years, the incidence of non-alcoholic fatty liver disease (NAFLD) has been increasing worldwide. Hepatic lipid deposition is a major feature of NAFLD, and insulin resistance is one of the most important causes of lipid deposition. Insulin resistance results in the disruption of lipid metabolism homeostasis characterized by increased lipogenesis and decreased lipolysis. Estrogen receptor α (ERα) has been widely reported to be closely related to lipid metabolism. Activating ERa may be a promising strategy to improve lipid metabolism. Here, we used computer-aided drug design technology to discover a highly active compound, YRL-03, which can effectively reduce lipid accumulation. Cellular experimental results showed that YRL-03 could effectively reduce lipid accumulation by targeting ERα, thereby achieving alleviation of insulin resistance. We believe this study provides meaningful guidance for future molecular development of drugs to prevent and treat NAFLD.

ß-Hydroxybutyrate against Cisplatin-Induced acute kidney injury via inhibiting NLRP3 inflammasome and oxidative stress.

Cisplatin, as a commonly used anticancer drug, can easily lead to acute kidney injury (AKI), and has received more and more attention in clinical practice. ß-hydroxybutyric acid (BHB) is a metabolite in the body and acts as an inhibitor of oxidative stress and NLRP3 inflammasome, reducing inflammatory responses and apoptosis. However, the role of BHB in cisplatin-induced AKI is currently not fully elucidated. In this study, C57BL/6 male mice were randomly divided into normal control group, cisplatin-induced AKI group and AKI with BHB treatment group. Compared to the control, cisplatin-treated mice exhibited high level of serum creatinine, blood urea nitrogen and severe tubular injury, which accompanied with significantly increased expression level of NLRP3, IL-1ß, IL-18, BAX, cleaved-caspase 3, as well as aggravated oxidative stress and renal tubular cell apoptosis. However, these changes were significantly improved in that of BHB treatment. In vitro, our study showed that the expression of cleaved-caspase3, IL-1ß and IL-18 were significantly increased in human proximal tubular epithelial cell line (HK-2) treated with cisplatin compared with the control group, while decreased in cells treated with BHB. Furthermore, a significantly increased expression of cGAS and STING in HK-2 cells treated with cisplatin were found, whereas notably decreased in cells treated with BHB. This data indicates that BHB protects against cisplatin-induced AKI and renal tubular damage mediated by NLRP3 inflammasome and cGAS-STING pathway.

A Glimpse of Inflammation and Anti-Inflammation Therapy in Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is a common complication of diabetes mellitus and a major cause of end-stage kidney disease (ESKD). The pathogenesis of DKD is very complex and not completely understood. Recently, accumulated evidence from in vitro and in vivo studies has demonstrated that inflammation plays an important role in the pathogenesis and the development of DKD. It has been well known that a variety of pro-inflammatory cytokines and related signaling pathways are involved in the procession of DKD. Additionally, some anti-hyperglycemic agents and mineralocorticoid receptor antagonists (MRAs) that are effective in alleviating the progression of DKD have anti-inflammatory properties, which might have beneficial effects on delaying the progression of DKD. However, there is currently a lack of systematic overviews. In this review, we focus on the novel pro-inflammatory signaling pathways in the development of DKD, including the nuclear factor kappa B (NF-κB) signaling pathway, toll-like receptors (TLRs) and myeloid differentiation primary response 88 (TLRs/MyD88) signaling pathway, adenosine 5'-monophosphate-activated protein kinase (AMPK) signaling pathways, inflammasome activation, mitochondrial DNA (mtDNA) release as well as hypoxia-inducible factor-1(HIF-1) signaling pathway. We also discuss the related anti-inflammation mechanisms of metformin, finerenone, sodium-dependent glucose transporters 2 (SGLT2) inhibitors, Dipeptidyl peptidase-4 (DPP-4) inhibitors, Glucagon-like peptide-1 (GLP-1) receptor agonist and traditional Chinese medicines (TCM).

Urinary sediment CCL5 messenger RNA as a potential prognostic biomarker of diabetic nephropathy.

BACKGROUND: Urinary sediment messenger RNAs (mRNAs) have been shown as novel biomarkers of kidney disease. We aimed to identify targeted urinary mRNAs in diabetic nephropathy (DN) based on bioinformatics analysis and clinical validation. METHODS: Microarray studies of DN were searched in the GEO database and Nephroseq platform. Gene modules negatively correlated with estimated glomerular filtration rate (eGFR) were identified by informatics methods. Hub genes were screened within the selected modules. In validation cohorts, a quantitative polymerase chain reaction assay was used to compare the expression levels of candidate mRNAs. Patients with renal biopsy-confirmed DN were then followed up for a median time of 21 months. End-stage renal disease (ESRD) was defined as the primary endpoint. Multivariate Cox proportional hazards regression was developed to evaluate the prognostic values of candidate mRNAs. RESULTS: Bioinformatics analysis revealed four chemokines (CCL5, CXCL1, CXLC6 and CXCL12) as candidate mRNAs negatively correlated with eGFR, of which CCL5 and CXCL1 mRNA levels were upregulated in the urinary sediment of patients with DN. In addition, urinary sediment mRNA of CXCL1 was negatively correlated with eGFR (r = -0.2275, P = 0.0301) and CCL5 level was negatively correlated with eGFR (r = -0.4388, P < 0.0001) and positively correlated with urinary albumin:creatinine ratio (r = 0.2693, P = 0.0098); also, CCL5 and CXCL1 were upregulated in patients with severe renal interstitial fibrosis. Urinary sediment CCL5 mRNA was an independent predictor of ESRD [hazard ratio 1.350 (95% confidence interval 1.045-1.745)]. CONCLUSIONS: Urinary sediment CCL5 and CXCL1 mRNAs were upregulated in DN patients and associated with a decline in renal function and degree of renal interstitial fibrosis. Urinary sediment CCL5 mRNA could be used as a potential prognostic biomarker of DN.

Effects of HIF-1α on renal fibrosis in cisplatin-induced chronic kidney disease.

Cisplatin (Cis) can cause chronic kidney disease (CKD) and promote renal fibrosis, but the underlying mechanism is not fully understood. Hypoxia inducible factor-1α (HIF-1α) can promote renal fibrosis in some kidney diseases, but its role in Cis-induced CKD is still unknown. Notch-1 is a recognized molecule that promotes renal fibrosis under pathological circumstances, and evidence shows that HIF-1α and Notch-1 are closely related to each other. In the present study, mice with HIF-1α gene knockout in proximal tubular cells (PTCs) (PT-HIF-1α-KO) were generated and treated with Cis to induce CKD. A human proximal tubular cell line (HK-2) and primary mouse PTCs were used for in vitro studies. The results showed that HIF-1α was increased in the kidneys of Cis-treated wild-type mice, accompanied by elevated Notch-1, Notch-1 intracellular domain (N1ICD), Hes-1 and renal fibrosis. However, these alterations were partially reversed in PT-HIF-1α-KO mice. Similar results were observed in HK-2 cells and primary mouse PTCs. In addition, treating the cells with Cis induced a marked interaction of HIF-1α and N1ICD. Further inhibiting Notch-1 significantly reduced cellular fibrogenesis but did not affect HIF-1α expression. The data suggested that HIF-1α could promote renal fibrosis in Cis-induced CKD by activating Notch-1 both transcriptionally and post-transcriptionally and that HIF-1α may serve as a potential therapeutic target for Cis-induced CKD.

MAMs Protect Against Ectopic Fat Deposition and Lipid-Related Kidney Damage in DN Patients.

Ectopic fat deposition (EFD) in the kidney plays a key role in the development of diabetic nephropathy (DN). Mitochondria-associated ER membranes (MAMs) are structures that connect to the endoplasmic reticulum (ER) and are involved in lipid metabolism. However, there are few studies on MAMs in the field of kidney disease, and the relationship between EFD and MAMs in DN is still unclear. In this study, increased EFD in the kidneys of DN patients was observed, and analysis showed that the degree of EFD was positively correlated with renal damage. Then, the MAMs were quantified by an in situ proximity ligation assay (PLA). The MAMs in the kidneys were found to gradually decrease through the different stages of DN, while the expression of ADRP (a marker of lipid droplets) and tubulointerstitial damage increased. Moreover, correlation analysis showed that the MAMs were negatively correlated with serum lipid levels, the EFD in the kidney and renal damage. Finally, we observed decreased expression of MAM-control proteins (DsbA-L, PACS-2, and MFN-2) in different stages of DN and they were associated with lipid deposition and renal damage. These data showed that the destruction of MAMs in DN might be the cause of EFD and interstitial damage in the kidney.

Mitophagy: A Novel Therapeutic Target for Treating DN.

Diabetic nephropathy (DN) is a common microvascular complication of diabetes and one of the leading causes of end-stage renal disease. Tubular damage is an early change and characteristic of DN, and mitochondrial dysfunction plays an important role in the development of DN. Therefore, the timely removal of damaged mitochondria in tubular cells is an effective treatment strategy for DN. Mitophagy is a type of selective autophagy that ensures the timely elimination of damaged mitochondria to protect cells from oxidative stress. In this review, we summarize our understanding of mitochondrial dysfunction and dynamic disorders in tubular cells in DN and the molecular mechanism of mitophagy. Finally, the role of mitophagy in DN and its feasibility as a therapeutic target for DN are discussed.

Aristolochic acid induces renal fibrosis by arresting proximal tubular cells in G2/M phase mediated by HIF-1α.

Renal tubulointerstitial fibrosis (TIF) is a common pathological feature of aristolochic acid (AA) nephropathy (AAN). G2/M arrest of proximal tubular cells (PTCs) is implicated in renal fibrosis of AAN, but the upstream regulatory molecule remains unknown. Hypoxia inducible factor-1α (HIF-1α) promotes renal fibrosis in kidney disease, but the role of HIF-1α in AAN is unclear. Evidence shows that HIF-1α and p21, a known inducer of cellular G2/M arrest, are closely related to each other. To investigate the role of HIF-1α in renal fibrosis of AAN and its effects on p21 expression and PTCs G2/M arrest, mice with HIF-1α gene knockout PTCs (PT-HIF-1α-KO) were generated, and AAN was induced by AA. In vitro tests were conducted on the human PTCs line HK-2 and primary mouse PTCs. HIF-1α and p21 expression, fibrogenesis, and G2/M arrest of PTCs were determined. Results showed that HIF-1α was upregulated in the kidneys of wild-type (WT) AAN mice, accompanied by p21 upregulation, PTCs G2/M arrest and renal fibrosis, and these alterations were reversed in PT-HIF-1α-KO AAN mice. Similar results were observed in HK-2 cells and were further confirmed in primary PTCs from PT-HIF-1α-KO and WT mice. Inhibiting p21 in HK-2 cells and primary PTCs did not change the expression of HIF-1α, but G2/M arrest and fibrogenesis were reduced. These data indicate that HIF-1α plays a key role in renal fibrosis in AAN by inducing PTCs G2/M arrest modulated through p21. HIF-1α may serve as a potential therapeutic target for AAN.

Manganese(ii)-catalysed dehydrogenative annulation involving C-C bond formation: highly regioselective synthesis of quinolines.

An inexpensive nontoxic manganese(ii)-catalysed dehydrogenative annulation was developed for C-C bond formation. The reaction showed high selectivity and efficiency across a broad substrate scope. Remarkably simple conditions and the ability to conduct gram-scale synthesis underscore this method's utility. To demonstrate the potential of this approach, we tested the drug effects of compound 3n, which showed activity for blocking vascular development. The results of this study will be important for the treatment of eye diseases and tumors caused by vascular proliferation.

Acid-promoted iron-catalysed dehydrogenative [4 + 2] cycloaddition for the synthesis of quinolines under air.

An acid-promoted iron-catalysed dehydrogenative [4 + 2] cycloaddition reaction was developed for the synthesis of quinolines using air as a terminal oxidant. Acetic acid was the best cocatalyst for the cycloaddition of N-alkyl anilines with alkenes or alkynes under air. Various quinoline derivatives were obtained in satisfactory-to-excellent yields, and no other byproducts besides water were produced in the reaction. The zebrafish model has become an important vertebrate model for evaluating drug effects. We tested the activity of 3n in zebrafish. The test results showed that 1 µg mL-13n treatments resulted in morphological malformation, and 0.01-0.1 µg mL-13n treatments led to potent angiogenic defects in zebrafish embryos. The results of this study will be of great significance for promoting drug research in cardiovascular and cerebrovascular diseases.

[Impact of preoperative dual antiplatelet therapy on perioperative bleeding in patients undergoing off-pump coronary artery bypass grafting].

OBJECTIVE: To evaluate the impact of preoperative dual antiplatelet therapy of aspirin and clopidogrel on perioperative blood loss and blood transfusion requirements. METHODS: A total of 60 patients underwent off-pump coronary artery bypass grafting (OPCABG) performed by the same surgeons. And they were assigned to receive dual antiplatelet therapy of aspirin and clopidogrel (group AC, n = 30) and discontinue antiplatelet therapy more than 5 days before surgery (group control, n = 30). RESULTS: No significant inter-group differences existed in basic clinical characteristics (all P > 0.05). Itraoperative blood loss volume was similar for two groups (637 ± 257 vs 635 ± 196 ml, P = 0.978). No significant inter-group difference existed in 24 h chest drainage volume (522 ± 160 vs 524 ± 204 ml, P = 0.961) or total volume of chest drainage (1044 ± 337 vs 1118 ± 198 ml, P = 0.306). CONCLUSION: Preoperative dual antiplatelet therapy of aspirin and clopidogrel does not increase the total volume of postoperative chest drainage.

[Application of bilateral internal mammary artery in coronary artery bypass grafting].

OBJECTIVE: To evaluate the effects of application of bilateral internal mammary artery grafts in coronary artery by pass grafting (CABG). METHODS: From Jan. 1998 to Mar. 2001, 51 patients with coronary arteriosclerotic cardiopathy, all males, aged 36 - 65 (average 49.9 years), underwent coronary artery bypass grafting with bilateral internal mammary artery grafts. The pathologic change involved three branches of coronary artery in 48 cases and involved the left main trunk in 3 cases. 37 patients had the history of myocardial infarction. Four cases were complicated by left ventricular aneurysm. 47 cases were operated upon on-pump and 4 off-pump. Left ventricular aneurysmectomy was done in 4 patients and coronary endarterectomy in 1 patient. The patterns of anastomosis were as follows: right internal mammary artery (RIMA) to left anterior descending artery (LAD) and left internal mammary artery (LIMA) to obtuse marginal (OM) in 39 cases, LIMA to LAD and RIMA to right coronary artery (RCA) in 9 cases, and LIMA to LAD and RIMA to OM in 3 cases. Gastroepiploic artery and left radical artery were used in other bypass grafting. The average number of grafts used for each case was 3. RESULTS: There were 3 early operative deaths, with an early operative mortality rate of 5.9%. One patient died of low output syndrome due to perioperative myocardial infection, 1 patient died of refractory arrhythmia, and 1 patient died of cerebral accident 40 days after operation. Intraaortic balloon pump was used in 4 cases post-operatively. Mediastinal infection occurred in 2 patients. The patients were followed up for 2 to 39 months (average 15.5 months). During the follow-up, no angina pectoris occurred and ultrasonography showed that the bilateral internal mammary artery grafts were unobstructed in all patients. CONCLUSION: Bilateral internal mammary artery grafts can be applied effectively in CABG with a good short-term effect, especially for young patients.