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.

DsbA-L: A Promising Therapeutic Target for Metabolic Diseases.

The increasing incidence of metabolic diseases, including obesity and diabetes, is a serious social public problem. Therefore, there is an urgent need to find effective prevention and treatment measures for these diseases. DsbA-L is a protein that is widely expressed in many tissues and is closely related to metabolism. Emerging evidence shows that DsbA-L plays an important role in antioxidative stress, promoting the synthesis and secretion of adiponectin and maintaining mitochondrial homeostasis, and the abnormalities of these functions are also closely related to the occurrence and development of metabolic diseases. Here, we reviewed the tissue expression patterns and regulatory factors of DsbA-L, summarized its biological functions and the current research progress of DsbA-L in metabolic diseases, and found that DsbA-L may be a promising target for metabolic diseases.

PACS-2 deficiency aggravates tubular injury in diabetic kidney disease by inhibiting ER-phagy.

Autophagy of endoplasmic reticulum (ER-phagy) selectively removes damaged ER through autophagy-lysosome pathway, acting as an adaptive mechanism to alleviate ER stress and restore ER homeostasis. However, the role and precise mechanism of ER-phagy in tubular injury of diabetic kidney disease (DKD) remain obscure. In the present study, we demonstrated that ER-phagy of renal tubular cells was severely impaired in streptozocin (STZ)-induced diabetic mice, with a decreased expression of phosphofurin acidic cluster sorting protein 2 (PACS-2), a membrane trafficking protein which was involved in autophagy, and a reduction of family with sequence similarity 134 member B (FAM134B), one ER-phagy receptor. These changes were further aggravated in mice with proximal tubule specific knockout of Pacs-2 gene. In vitro, transfection of HK-2 cells with PACS-2 overexpression plasmid partially improved the impairment of ER-phagy and the reduction of FAM134B, both of which were induced in high glucose ambience; while the effect was blocked by FAM134B siRNA. Mechanistically, PACS-2 interacted with and promoted the nuclear translocation of transcription factor EB (TFEB), which was reported to activate the expression of FAM134B. Collectively, these data unveiled that PACS-2 deficiency aggravates renal tubular injury in DKD via inhibiting ER-phagy through TFEB/FAM134B pathway.

The Potential Role of Cardiokines in Heart and Kidney Diseases.

As the engine that maintains blood circulation, the heart is also an endocrine organ that regulates the function of distant target organs by secreting a series of cardiokines. As endocrine factors, cardiokines play an indispensable role in maintaining the homeostasis of the heart and other organs. Here, we summarize some of the cardiokines that have been defined thus far and explore their roles in heart and kidney diseases. Finally, we propose that cardiokines may be a potential therapeutic target for kidney diseases.

Current emerging novel therapies for Alzheimer's disease and the future prospects of magneto-mechanical force therapy.

Alzheimer's disease (AD) is the most common neurodegenerative disease among the elderly, and the morbidity increases with the aging population aggravation. The clinical symptoms of AD mainly include cognitive impairment and memory loss, which undoubtedly bring a huge burden to families and society. Currently, the drugs in clinical use only improve the symptoms of AD but do not cure or prevent the progression of the disease. Therefore, it is urgent for us to develop novel therapeutic strategies for effective AD treatment. To provide a better theoretical basis for exploring novel therapeutic strategies in future AD treatment, this review introduces the recent AD treatment technologies from three aspects, including nanoparticle (NP) based drug therapy, biological therapy and physical therapy. The nanoparticle-mediated therapeutic approaches at the nanomaterial-neural interface and biological system are described in detail, and in particular the magneto-regulated strategies by magnetic field actuating magnetic nanoparticles are highlighted. Promising application of magneto-mechanical force regulated strategy in future AD treatment is also addressed, which offer possibilities for the remote manipulation in a precise manner. In the future, it may be possible for physicians to realize a remote, precise and effective therapy for AD using magneto-mechanical force regulated technology based on the combination of magnetic nanoparticles and an external magnetic field.

Molecular mechanism of Hedyotis Diffusae Herba in the treatment of lupus nephritis based on network pharmacology.

Aims: To determine the bioactive components of Hedyotis Diffusae Herba (HDH) and the targets in treating lupus nephritis (LN), and so as to elucidate the protective mechanism of HDH against LN. Methods and results: An aggregate of 147 drug targets and 162 LN targets were obtained from online databases, with 23 overlapped targets being determined as potential therapeutic targets of HDH against LN. Through centrality analysis, TNF, VEGFA and JUN were screened as core targets. And the bindings of TNF with stigmasterol, TNF with quercetin, and VEGFA with quercetin were further validated by molecular docking. By conducting Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses for drug targets, disease targets and the shared targets, TNF signaling pathway, Toll-like receptor signaling pathway, NF-kappa B signaling pathway and HIF-1 signaling pathway, etc., were found in all these three lists, indicating the potential mechanism of HDH in the treatment of LN. Conclusion: HDH may ameliorate the renal injury in LN by targeting multi-targets and multi-pathways, including TNF signaling pathway, NF-kappa B signaling pathway, HIF-1 signaling pathway and so on, which provided novel insights into further researches of the drug discovery in LN.

Overview of the development of HBV small molecule inhibitors.

Like tuberculosis and Acquired Immune Deficiency Syndrome (AIDS), hepatitis B is a globally recognized major public health threat. Although there are many small-molecule drugs for the treatment of hepatitis B, the approved drugs cannot eradicate the pathogenic culprit covalently closed circular DNA in patients, so the patients need long-term medication to control HBV amplification. Driven by a high unmet medical need, many pharmaceutical companies and research institutions have been engaged in the development of anti-HBV drugs to achieve a functional cure for chronic hepatitis B as soon as possible. This review summarizes the pathogenesis of hepatitis B virus and the research progress in the development of anti-HBV small molecule drugs, and introduces the cccDNA formation and transcription inhibitors and core inhibitors in detail, especially emphasizes the role of chinese herbal medicine in the treatment of chronic hepatitis B. Furthermore, this review proposes three potential strategies for cccDNA eradication in the future. We believe this review will provide meaningful guidance to achieve a functional cure for viral hepatitis B in the future.

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.

Bone-kidney axis: A potential therapeutic target for diabetic nephropathy.

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD). However, its pathogenesis remains unclear, and effective prevention and treatment strategies are lacking. Recently, organ-to-organ communication has become a new focus of studies on pathogenesis. Various organs or tissues (the liver, muscle and adipose tissue) secrete a series of proteins or peptides to regulate the homeostasis of distal organs in an endocrine manner. Bone, an important part of the body, can also secrete bone-derived proteins or peptides that act on distal organs. As an organ with high metabolism, the kidney is responsible for signal and material exchange with other organs at any time through circulation. In this review, we briefly discussed bone composition and changes in bone structure and function in DN and summarized the current status of bone-derived proteins and their role in the progression of DN. We speculated that the "bone-kidney axis" is a potential target for early diagnosis and treatment of DN.

Lipid droplet - mitochondria coupling: A novel lipid metabolism regulatory hub in diabetic nephropathy.

Diabetic nephropathy (DN) involves serious lipid metabolism disorder, and renal ectopic lipid deposition aggravates DN progression. However, the molecular mechanism of renal lipid deposition in DN remains unclear. Lipid droplets (LDs) are lipid pools in cells that change dynamically in response to the cellular energy needs. The LDs and mitochondria are connected through a part of the mitochondria known as the peridroplet mitochondria (PDM). In this review, we summarize the definition, detection methods, and function of the PDM. Finally, we discuss the research status of PDM in DN and the possibility of its use as a therapeutic target.

Myokines: Novel therapeutic targets for diabetic nephropathy.

With the increasing incidence of diabetic nephropathy (DN), there is an urgent need to find effective DN preventive and therapeutic modalities. It is widely believed that effective exercise is good for health. However, the beneficial role of exercise in kidney disease, especially in DN, and the underlying molecular mechanisms have rarely been reported. Muscle is not only an important motor organ but also an important endocrine organ, secreting a group of proteins called "myokines" into the blood circulation. Circulating myokines then move to various target organs to play different biological roles. In this review, we summarize the currently known myokines and the progress in research relating them to DN and discuss its potential as a therapeutic target for DN.

Small-molecule drugs development for Alzheimer's disease.

Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative brain disorder with no effective therapeutic drugs currently. The complicated pathophysiology of AD is not well understood, although beta-amyloid (Aß) cascade and hyperphosphorylated tau protein were regarded as the two main causes of AD. Other mechanisms, such as oxidative stress, deficiency of central cholinergic neurotransmitters, mitochondrial dysfunction, and inflammation, were also proposed and studied as targets in AD. This review aims to summarize the small-molecule drugs that were developed based on the pathogenesis and gives a deeper understanding of the AD. We hope that it could help scientists find new and better treatments to gradually conquer the problems related to AD in future.

Using network pharmacology to explore the mechanism of Danggui-Shaoyao-San in the treatment of diabetic kidney disease.

Danggui-Shaoyao-San (DSS) is one of traditional Chinese medicine, which recently was found to play a protective role in diabetic kidney disease (DKD). However, the pharmacological mechanisms of DSS remain obscure. This study would explore the molecular mechanisms and bioactive ingredients of DSS in the treatment of DKD through network pharmacology. The potential target genes of DKD were obtained through OMIM database, the DigSee database and the DisGeNET database. DSS-related targets were acquired from the BATMAN-TCM database and the STITCH database. The common targets of DSS and DKD were selected for analysis in the STRING database, and the results were imported into Cytoscape to construct a protein-protein interaction network. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment analysis and Gene Ontology (GO) enrichment analysis were carried out to further explore the mechanisms of DSS in treating DKD. Molecular docking was conducted to identify the potential interactions between the compounds and the hub genes. Finally, 162 therapeutic targets of DKD and 550 target genes of DSS were obtained from our screening process. Among this, 28 common targets were considered potential therapeutic targets of DSS for treating DKD. Hub signaling pathways including HIF-1 signaling pathway, TNF signaling pathway, AMPK signaling pathway, mTOR signaling pathway, and PI3K-Akt signaling pathway may be involved in the treatment of DKD using DSS. Furthermore, TNF and PPARG, and poricoic acid C and stigmasterol were identified as hub genes and main active components in this network, respectively. In this study, DSS appears to treat DKD by multi-targets and multi-pathways such as inflammatory, oxidative stress, autophagy and fibrosis, which provided a novel perspective for further research of DSS for the treatment of DKD.

PACS-2 deficiency in tubular cells aggravates lipid-related kidney injury in diabetic kidney disease.

BACKGROUND: Lipid accumulation in tubular cells plays a key role in diabetic kidney disease (DKD). Targeting lipid metabolism disorders has clinical value in delaying the progression of DKD, but the precise mechanism by which molecules mediate lipid-related kidney injury remains unclear. Phosphofurin acidic cluster sorting protein 2 (PACS-2) is a multifunctional sorting protein that plays a role in lipid metabolism. This study determined the role of PACS-2 in lipid-related kidney injury in DKD. METHODS: Diabetes was induced by a high-fat diet combined with intraperitoneal injections of streptozotocin (HFD/STZ) in proximal tubule-specific knockout of Pacs-2 mice (PT-Pacs-2-/- mice) and the control mice (Pacs-2fl/fl mice). Transcriptomic analysis was performed between Pacs-2fl/fl mice and PT-Pacs-2-/- mice. RESULTS: Diabetic PT-Pacs-2-/- mice developed more severe tubule injury and proteinuria compared to diabetic Pacs-2fl/fl mice, which accompanied with increasing lipid synthesis, uptake and decreasing cholesterol efflux as well as lipid accumulation in tubules of the kidney. Furthermore, transcriptome analysis showed that the mRNA level of sterol O-acyltransferase 1 (Soat1) was up-regulated in the kidney of control PT-Pacs-2-/- mice. Transfection of HK2 cells with PACS-2 siRNA under high glucose plus palmitic acid (HGPA) condition aggravated lipid deposition and increased the expression of SOAT1 and sterol regulatory element-binding proteins (SREBPs), while the effect was blocked partially in that of co-transfection of SOAT1 siRNA. CONCLUSIONS: PACS-2 has a protective role against lipid-related kidney injury in DKD through SOAT1/SREBPs signaling.

Crosstalk between the liver and kidney in diabetic nephropathy.

Diabetic nephropathy (DN) is a serious complication of diabetes, and its pathogenesis has not been fully elucidated. Recently, communication between organs has gradually become a new focus in the study of diseases pathogenesis, and abnormal interorgan communication has been proven to be involved in the occurrence and progression of many diseases. As an important metabolic organ in the human body, the liver plays an important role in maintaining homeostasis in humans. The liver secretes a series of proteins called hepatokines that affect adjacent and distal organs through paracrine or endocrine signaling pathways. In this review, we summarize some of the hepatokines identified to date and describe their roles in DN to discuss the possibility that the liver-renal axis is potentially useful as a therapeutic target for DN. We summarize the important hepatokines identified thus far and discuss their relationship with DN. We propose for the first time that the "liver-renal axis" is a potential therapeutic target in individuals with DN.

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.

NBMA Promotes Spermatogenesis by Mediating Oct4 Pathway.

Non-obstructive azoospermia is one of the most common causes of male infertility, but there is still no specific treatment drug. Given that the Oct4 (Octamer-binding transcription factor 4) has an important regulatory effect on spermatogenesis, activating it can effectively promote spermatogenesis, so it is of great value to develop Oct4-targeted drug design and elucidating its mechanism of action. Here, we screened out the Oct4-targeted drug molecule NBMA (N-benzyl-4-methoxy-2-(1-(4-(trifluoromethyl)phenyl)vinyl)aniline) by computer-assisted technology, and found that it has a significant promoting effect on spermatogenesis in the established mouse azoospermia model. Subsequently, through transcriptome sequencing and enrichment analysis, real-time fluorescent quantitative PCR (qPCR) and western blot experiments revealed that NBMA promotes the differentiation of spermatogonial stem cells by activating the Oct4 pathway, thereby promoting spermatogenesis. This study proves that NBMA is a molecule with great potential to be developed as a therapeutic drug for azoospermia. It also shows that computer-assisted, chemical and biological multidisciplinary methods play a very important role in innovative drug discovery.

PACS-2 Ameliorates Tubular Injury by Facilitating Endoplasmic Reticulum-Mitochondria Contact and Mitophagy in Diabetic Nephropathy.

Mitochondria-associated endoplasmic reticulum membrane (MAM) may have a role in tubular injury in diabetic nephropathy (DN), but the precise mechanism remains unclear. Here, we demonstrate that the expression of phosphofurin acidic cluster sorting protein 2 (PACS-2), a critical regulator of MAM formation, is significantly decreased in renal tubules of patients with DN, and PACS-2 expression is positively correlated with renal function and negatively correlated with degrees of tubulointerstitial lesions. Conditional deletion of Pacs-2 in proximal tubules (PTs) aggravates albuminuria and tubular injury in a streptozotocin-induced mouse model of diabetes. Mitochondrial fragmentation, MAM disruption, and defective mitophagy accompanied by altered expression of mitochondrial dynamics and mitophagic proteins, including Drp1 and Becn1, are observed in tubules of diabetic mice; these changes are more pronounced in PT-specific Pacs-2 knockout mice. In vitro, overexpression of PACS-2 in HK-2 cells alleviates excessive mitochondrial fission induced by high glucose concentrations through blocking mitochondrial recruitment of DRP1 and subsequently restores MAM integrity and enhances mitophagy. Mechanistically, PACS-2 binds to BECN1 and mediates the relocalization of BECN1 to MAM, where it promotes the formation of mitophagosome. Together, these data highlight an important but previously unrecognized role of PACS-2 in ameliorating tubular injury in DN by facilitating MAM formation and mitophagy.