Current Medicinal Chemistry - Volume 31, Issue 35, 2024

Curcumin is a naturally polyphenolic compound used for hepatoprotective, thrombosuppressive, neuroprotective, cardioprotective, antineoplastic, antiproliferative, hypoglycemic, and antiarthritic effects. Kidney disease is a major public health problem associated with severe clinical complications worldwide. The protective effects of curcumin against nephrotoxicity have been evaluated in several experimental models. In this review, we discussed how curcumin exerts its protective effect against renal toxicity and also illustrated the mechanisms of action such as anti-inflammatory, antioxidant, regulating cell death, and anti-fibrotic. This provides new perspectives and directions for the clinical guidance and molecular mechanisms for the treatment of renal diseases by curcumin.

Background: The receptor tyrosine kinase EphA2 plays a role in many diseases, like cancer, cataracts, and osteoporosis. Interestingly, it has also been linked to viral infections. Objective: Herein, current literature has been reviewed to clarify EphA2 functions in viral infections and explore its potential role as a target in antiviral drug discovery strategies. Methods: Research and review articles along with preprints connecting EphA2 to different viruses have been searched through PubMed and the web. Structures of complexes between EphA2 domains and viral proteins have been retrieved from the PDB database. Results: EphA2 assumes a key role in Kaposi’s sarcoma-associated herpesvirus (KSHV) and Epstein Barr virus (EBV) infections by directly binding, through its ligand binding domain, viral glycoproteins. For human cytomegalovirus (HCMV), the role of EphA2 in maintaining virus latency state, through cooperation with specific viral proteins, has also been speculated. In certain cells, with high EphA2 expression levels, following ligand stimulation, receptor activation might contribute to severe symptoms accompanying a few viral infections, including lung injuries often related to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Conclusion: Since EphA2 works as a host receptor for certain viruses, it might be worth more deeply investigating known compounds targeting its extracellular ligand binding domain as antiviral therapeutics. Due to EphA2's function in inflammation, its possible correlation with SARS-CoV-2 cannot be excluded, but more experimental studies are needed in this case to undoubtedly attribute the role of this receptor in viral infections.

Background: Neurodegenerative diseases are among the diseases that cause the foremost burden on the health system of the world. The diseases are multifaceted and difficult to treat because of their complex pathophysiology, which includes protein aggregation, neurotransmitter breakdown, metal dysregulation, oxidative stress, neuroinflammation, excitotoxicity, etc. None of the currently available therapies has been found to be significant in producing desired responses without any major side effects; besides, they only give symptomatic relief otherwise indicated off-episode relief. Targeting various pathways, namely choline esterase, monoamine oxidase B, cannabinoid system, metal chelation, β-secretase, oxidative stress, etc., may lead to neurodegeneration. By substituting various functional moieties over the coumarin nucleus, researchers are trying to produce safer and more effective neuroprotective agents. Objectives: This study aimed to review the current literature to produce compounds with lower side effects using coumarin as a pharmacophore. Methods: In this review, we have attempted to compile various synthetic strategies that have been used to produce coumarin and various substitutional strategies used to produce neuroprotective agents from the coumarin pharmacophore. Moreover, structure-activity relationships of substituting coumarin scaffold at various positions, which could be instrumental in designing new compounds, were also discussed. Results: The literature review suggested that coumarins and their derivatives can act as neuroprotective agents following various mechanisms. Conclusion: Various studies have demonstrated the neuroprotective activity of coumarin due to an oxaheterocyclic loop, which allows binding with a broad array of proteins, thus motivating researchers to explore its potential as a lead against various neurodegenerative diseases.

Nucleosides containing carboranes are one of the most important boron delivery agents for boron neutron capture therapy, BNCT, which are good substrates of hTK1. The development of several nucleosides containing carboranes at early stages led to the discovery of the first generation of 3CTAs by incorporating a hydrocarbon spacer between the thymidine scaffold and carborane cluster and attaching dihydroxylpropyl group on the second carbon (C2) atom of the carborane cluster (e.g., N5 and N5-2OH). Phosphorylation rate, tumor cellular uptake, and retention have been evaluated in parallel to change the length of the tether arm of spacers in these compounds. Many attempts were reported and discussed to overcome the disadvantage of the first generation of 3CTAs by a) incorporating modified spacers between thymidine and carborane clusters, such as ethyleneoxide, polyhydroxyl, triazole, and tetrazole units, b) attaching hydrophilic groups at C2 of the carborane cluster, c) transforming lipophilic closo-carboranes to hydrophilic nidocarborane. The previous modifications represented the second generation of 3CTAs to improve the hydrogen bond formation with the hTK1 active site. Moreover, amino acid prodrugs were developed to enhance biological and physicochemical properties. The structure-activity relationship (SAR) of carboranyl thymidine analogues led to the roadmap for the development of the 3^rd generation of the 3CTAs for BNCT.

Quorum-sensing is a communication mechanism between bacteria with the ability to activate signaling pathways in the bacterium and in the host cells. Pseudomonas aeruginosa is a pathogen with high clinical relevance due to its vast virulence factors repertory and wide antibiotic resistance mechanisms. Due to this, it has become a pathogen of interest for developing new antimicrobial agents in recent years. P. aeruginosa has three major QS systems that regulate a wide gene range linked with virulence factors, metabolic regulation, and environment adaption. Consequently, inhibiting this communication mechanism would be a strategy to prevent the pathologic progression of the infections caused by this bacterium. In this review, we aim to overview the current studies about the signaling mechanisms of the QS system of P. aeruginosa and its effects on this bacterium and the host.

The application of the CRISPR-associated nuclease 9 (Cas9) system in tumor studies has led to the discovery of several new treatment strategies for colorectal cancer (CRC), including the recognition of novel target genes, the construction of animal mass models, and the identification of genes related to chemotherapy resistance. CRISPR/Cas9 can be applied to genome therapy for CRC, particularly regarding molecular-targeted medicines and suppressors. This review summarizes some aspects of using CRISPR/- Cas9 in treating CRC. Further in-depth and systematic research is required to fully realize the potential of CRISPR/Cas9 in CRC treatment and integrate it into clinical practice.

miRNAs are crucial regulators in a variety of physiological and pathological processes, while their regulation mechanisms were usually described as negatively regulating gene expression by targeting the 3’-untranslated region(3’-UTR) of target gene miRNAs through seed sequence in tremendous studies. However, recent evidence indicated the existence of non-canonical mechanisms mediated by binding other molecules besides mRNAs. Additionally, accumulating evidence showed that functions of intracellular and intercellular miRNAs exhibited spatiotemporal patterns. Considering that detailed knowledge of the miRNA regulating mechanism is essential for understanding the roles and further clinical applications associated with their dysfunction and dysregulation, which is complicated and not fully clarified. Based on that, we summarized the recently reported regulation mechanisms of miRNAs, including recognitions, patterns of actions, and chemical modifications. And we also highlight the novel findings of miRNAs in atherosclerosis progression researches to provide new insights for non-coding RNA-based therapy in intractable diseases.

As a transitional metal, copper plays a crucial role in maintaining the normal physiological activities of mammals. The intracellular copper concentration is meticulously regulated to maintain extremely low levels through homeostatic regulation. Excessive accumulation of free copper in cells can have deleterious effects, as observed in conditions such as Wilson’s disease. Moreover, data accumulated over the past few decades have revealed a crucial role of copper imbalance in tumorigenesis, progression and metastasis. Recently, cuproptosis, also known as copper-induced cell death, has been proposed as a novel form of cell death. This discovery offers new prospects for treating copperrelated diseases and provides a promising avenue for developing copper-responsive therapies, particularly in cancer treatment. We present a comprehensive overview of the Yin– Yang equilibrium in copper metabolism, particularly emphasising its pathophysiological alterations and their relevance to copper-related diseases and malignancies.

Background: Currently, there is no accounted-for consensus and practical standard when counseling diet modification for kidney transplant recipients (KTRs). There are many differences between transplant centers regarding what KTRs are needed to follow a diet, what dietary factors and supplements are allowed, and how long KTRs should follow a modified diet. Relatively few scatter data are available for dietary factors in KTRs. Thus, we aimed to systematically review the literature on the purported dietary factors for kidney function. Methods: A systematic literature search was performed between February and March 2022 and updated in February 2023 using PubMed, Scopus, Web of Science, and Google Scholar. We included human observational and interventional studies that evaluated a dietary factor on kidney function and graft survival in KTRs. Data were extracted, and the risk of bias was assessed using established tools relevant to the study design. Results: Of the 5341 citations retrieved, seven prospective cohorts, five cross-sectional, seventeen randomized, and ten non-randomized clinical trials were included that evaluated seven purported dietary factors. Almost half of the studies (n = 22; 56%) were classified as having a low degree of bias and sufficient support. Twenty-one studies (54%) reported a positive effect on KTRs. DASH and Mediterranean diets decreased graft failure, low-sodium diet reduced blood pressure, and antioxidants improved creatinine, GFR, and graft function. Of these, only twelve studies (31%) were at low risk of bias. Conclusion: Some dietary factors, including DASH, Mediterranean, moderate protein, and low-- sodium diet, as well as antioxidants, may be associated with improved survival and kidney function in KTRs. However, more research is needed.