Current Topics in Medicinal Chemistry - Online First

This study explores the unbinding dynamics of alpha-ketoglutarate (AKG) from wild-type and mutant IDH1/IDH2 enzymes through steered molecular dynamics (SMD) simulations, examining how mutations influence binding, stability and enzymatic behaviour.

Isocitrate dehydrogenase (IDH) enzymes are essential for cellular metabolism, catalyzing the conversion of isocitrate to AKG in the tricarboxylic acid cycle. Mutations in IDH1 and IDH2 lead to the aberrant accumulation of the oncometabolite 2-hydroxyglutarate (2-HG), disrupting normal metabolic processes and contributing to tumorigenesis.

SMD simulations were employed to investigate AKG unbinding from both wild-type and mutant IDH1/IDH2. External forces were applied to quantify rupture forces and assess differences in stability among enzyme variants.

Wild-type IDH1 exhibited strong and stable AKG interactions, reflected by higher rupture forces and a greater number of hydrogen bonds, consistent with its normal catalytic function. In contrast, the R132H mutation in IDH1 weakened AKG binding, facilitating dissociation and potentially promoting 2-HG formation. Among IDH2 variants, the R140Q mutant demonstrated lower binding stability compared to R172K, while the wild-type enzyme maintained stronger interactions.

Mutations in IDH1 and IDH2 disrupt AKG binding and alter the stability, which may contribute to the pathological accumulation of 2-HG. These findings provide molecular insights into the oncogenic effects of IDH mutations and may aid in the development of targeted therapeutic strategies to inhibit mutant enzyme activity in cancer.

Diabetic nephropathy is a common microvascular complication that affects 20-40% of individuals with diabetes worldwide. This study aimed to evaluate the therapeutic potential of amla fruit against streptozotocin-induced diabetic nephropathy using animal models.

The male Wistar rats procured for the study were divided into four groups randomly, G1 (negative control group), G2 (positive control group), G3 (rats receiving amla powder at 5% of their diet), and G4 (rats receiving amla powder at 7% of their diet). Diabetic nephropathy (DN) was induced using streptozotocin at a dose of 65 mg/kg. High-performance liquid chromatography (HPLC) was used to quantify the bioactive constituents of amla. Physical, glycemic, oxidative, inflammatory, and renal biomarkers were assessed periodically.

HPLC analysis confirmed the presence of high levels of vitamin C, gallic acid, and quercetin in amla. Amla supplementation significantly improved body weight, controlled kidney hypertrophy, reduced blood glucose levels, enhanced antioxidant enzyme activity such as superoxide dismutase (SOD) and catalase (CAT), and suppressed inflammatory cytokines. Renal function markers, including serum creatinine, blood urea nitrogen (BUN), and urine albumin, were significantly improved in the amla-treated groups. The 5% amla diet showed slightly superior effects compared to the 7% amla diet, although the differences were not statistically significant.

The findings suggested that amla mitigates DN progression by targeting key pathological pathways, particularly oxidative stress and inflammation. Its bioactive compounds appear to modulate glucose homeostasis, restore antioxidant defence, and reduce inflammatory responses. The findings also suggested a potential non-linear dose-response relationship, indicating 5% as a more effective dietary inclusion.

Conclusively, amla fruit effectively alleviated streptozotocin-induced diabetic nephropathy in rats by controlling oxidative stress, inflammation, and hyperglycemia.

The development of secondary brain injury following intracerebral hemorrhage (ICH) involves multiple pathophysiological processes. Da-cheng-qi decoction (DCQD) has a long history of effectiveness in treating ICH and exhibits a variety of pharmacological effects. However, the phytochemicals and targets of DCQD targeting the pathophysiological processes of ICH still require further elucidation. This study aims to investigate the mechanism and key phytochemicals of DCQD in treating ICH based on the pathophysiological processes.

We used the UHPLC-MS/MS method to identify the main phytochemicals of DCQD and evaluate their pharmacological and toxicological parameters. We obtained and systematically analyzed the action targets of the main phytochemicals of DCQD and screened the targets related to ICH key pathophysiological processes and the corresponding phytochemicals. The results of molecular docking, molecular dynamic simulations, the GEO database and in vitro validation experiments confirmed the results of network pharmacology.

The 20 main phytochemicals of DCQD interact with a total of 186 targets, with 75 targets specifically associated with the treatment of ICH identified through pathophysiological processes. Among them, chrysophanol 1-glucoside, aloe emodin, emodin, hesperidin, tangeritin, rhein and physcion were recognized as the potential phytochemicals of DCQD for the treatment of ICH. Neuroinflammation is a crucial factor in the development of secondary brain injury following ICH. Further analysis results suggest that targeting ferroptosis is one of the mechanisms by which DCQD regulates the pathophysiology processes of ICH to improve ICH. In vitro cell experiment results have demonstrated the regulatory effect of naringin on TNF-α and Cox2. In addition, the phytochemicals in DCQD also contribute to enhancement of cognitive function impaired by ICH.

This study contributes to a better understanding of the underlying mechanisms behind DCQD's medicinal effects in treating ICH, offering insights into potential lead compounds for the development of anti-ICH drugs.

Long noncoding RNAs are essential regulators in numerous biological processes and have been linked to various diseases including cancer. Despite their initial classification as transcriptional byproducts lncRNAs have been shown to modulate chromatin structure transcription RNA processing protein translation and intranuclear transport. LINC-PINT a lncRNA induced by P53 is particularly noteworthy for its role in tumor suppression across multiple cancers

By utilizing the PubMed database and applying inclusion criteria based on relevance literature quality and data availability we conducted a comprehensive analysis of 128 studies to provide an overview of the functions of LINC-PINT and its mechanisms of action in cancers

LINC-PINT was confirmed to function as a tumor suppressor factor in many cancers such as triple-negative breast cancer non-small cell lung cancer gastric cancer glioma melanoma osteosarcoma laryngeal squamous cell carcinoma esophageal cancer colorectal cancer nasopharyngeal carcinoma retinoblastoma ovarian cancer thyroid cancer hepatocellular carcinoma and pancreatic cancer by promoting apoptosis and senescence inhibiting proliferation migration invasion drug resistance cell stemness EMT radioresistance and DNA damage repair

LINC-PINT serves as a tumor suppressor with its ability to sponge miRNAs regulate epigenetic modulation DNA damage repair etc. Despite the promising findings the complex and tissue-specific functions of LINC-PINT along with the need for further clinical validation underscore the importance of continued research to fully understand its mechanisms and potential as a therapeutic target

LINC-PINT is a potential target in cancer progression and treatment

Diabetes affects over 537 million people, with 20% developing chronic wounds. These wounds are made worse by inflammation, stress, immune problems, and poor blood vessel growth. Plants like Aloe barbadensis, Nigella sativa, and Moringa oleifera contain compounds that help heal wounds by reducing inflammation, stress, and boosting tissue growth.

This review explains why diabetic wounds heal slowly, focusing on factors like ROS, NO, and immune problems. It also looks at natural compounds that help healing and how traditional medicines can work with modern treatments for better wound care.

A systematic literature review was conducted using Scopus, Elsevier, PubMed, ScienceDirect, and Web of Science for studies published between 2000 and 2024. Inclusion criteria comprised clinical trials, preclinical studies, and ethnopharmacological research related to diabetic wound healing, pathophysiology, herbal medicine, active constituents, and mechanisms of action. Studies lacking diabetic wound specificity or methodological clarity were excluded. PRISMA guidelines were followed for study selection and synthesis.

Numerous studies demonstrated that traditional medicines enhance diabetic wound healing by regulating cytokine levels, promoting macrophage polarization, reducing oxidative damage, and remodelling the extracellular matrix. Flavonoids and polyphenols notably improved angiogenesis and tissue repair, while alkaloids and saponins exhibited antimicrobial and anti-inflammatory effects.

Traditional medicinal plants, through their diverse bioactive constituents, offer significant therapeutic potential for diabetic wound care. By targeting key molecular pathways involved in immune regulation and tissue repair, they present a viable adjunct to conventional therapies, potentially improving clinical outcomes in diabetic wound management.

The link between telomere length and Colorectal Cancer (CRC) risk and survival has been established. This study aims to investigate Telomere Maintenance-related Genes (TMGs) for predicting immunotherapy response and prognosis in CRC patients.

In this study, gene expression data and clinical information of CRC patients were obtained from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, and TMG-related scores were calculated for the samples. Subsequently, Weighted Gene Co-Expression Network Analysis (WGCNA) was used to identify gene modules that were highly correlated with the TMG score and intersected with differentially expressed genes to screen for potential functionally relevant candidate genes. The key genes significantly associated with prognosis were further analyzed using Cox regression analysis, from which the key genes were identified, and a risk score model was constructed. Finally, the survival prediction ability of the model was evaluated across multiple cohorts, and differences in immune cell infiltration characteristics and drug sensitivity were analyzed within different risk groups.

A higher TMG score was noticed in CRC, and the TMG score was negatively correlated with the StromalScore, ImmuneScore, and ESTIMATEScore. Gene modules significantly associated with the TMG score were identified using WGCNA. Two key genes, CDC25C and USP39, which were closely associated with prognosis, were screened through differential expression analysis, and a risk score model was constructed. The model showed good survival prediction in both TCGA and GSE17537 independent cohorts. The scores of activated CD4 T cells, Type 17 T helper cells, Type 2 T helper cells, and neutrophils in high-risk patients were lower, while that of macrophages was higher in high-risk patients. Additionally, a negative correlation was observed between the risk score and the IC50 values of most drugs, as well as the enriched pathways of patients at high risk, which included epithelial-mesenchymal transition, angiogenesis, and myogenesis.

This study unveiled a TMG-related signature that predicts prognosis and immunotherapy in CRC. Based on the 2 prognostically relevant genes CDC25C and USP39, a reliable risk score model was established for the prognostic prediction, and the correlation between the drug sensitivity and the risk score was also explored.

This study reveals the significant value of TMGs in CRC prognostic assessment and immunotherapy response prediction, providing a new molecular basis for the development of individualized treatment strategies.

Exosomes, which are vesicles that are naturally derived and contain a biomolecular payload, are promising vehicles for melanoma therapy because of their biocompatibility, targeting capabilities, and stability. This review emphasizes their capacity to circumvent the constraints of conventional treatments.

We carried out a comprehensive search of PubMed, ScienceDirect, and Google Scholar for peer-reviewed articles published between 2015 and 2024 utilizing terms such as “exosomes,” “melanoma,” and “chemotherapy.” Studies on exosome characterization or non-melanoma malignancies were excluded from the inclusion criteria, which centered on exosome-based therapeutics.

Drugs delivered via exosomes, such as small interfering RNA (siRNA) and chemotherapeutics, demonstrated enhanced tumor accumulation, achieving 2.5 times greater bioavailability and resulting in a tumor reduction of 60 to 90% when compared to their free counterparts. Surface modifications, such as cRGD peptides, have been shown to enhance targeting capabilities, whereas exosome-mediated photodynamic therapy has been effective in augmenting reactive oxygen species generation and promoting apoptosis.

Exosomes tackle significant challenges such as drug resistance and systemic toxicity; however, they encounter obstacles related to scalability and immunogenicity. Their dual function in tumor advancement and treatment highlights the necessity for standardized protocols.

Exosome-based therapies signify a groundbreaking advancement in the treatment of melanoma. Future endeavors should refine engineering methodologies, enhance production capabilities, and substantiate effectiveness through rigorous clinical trials.