Current Topics in Medicinal Chemistry - Online First

This study aims to establish a novel, straightforward, and reliable UPLC-MS method for determining the stability and impurity profile of Nirogacestat under various stress conditions, in accordance with ICH guidelines. The stability of Nirogacestat was investigated under various stress conditions, including acid/base hydrolysis, oxidation (H2O2​), photolysis, reduction, and thermal degradation. This research addresses the need for a validated, stability-indicating method that performs reliably across key analytical parameters, thereby contributing to pharmaceutical quality assurance.

Stress testing was performed by exposing Nirogacestat to various degradation conditions, including acid (0.1 and 1N HCl), base (NaOH), oxidative (30% H2O2), thermal (105°C), photolytic, and reductive environments. The mobile phase consisted of acetonitrile and 0.1% triethylamine/formic acid, adjusted to pH 2.5 in a 30:70 (v/v) ratio. Chromatographic separation was achieved using an Acquity UPLC BEH Shield RP-18 column (50 × 1.0 mm, 1.7 µm), with a flow rate of 0.5 mL/min and detection at 251 nm. Linearity was evaluated over a concentration range of 0.25 to 1.5 µg/mL. Validation studies assessed parameters such as selectivity, linearity, accuracy, precision, robustness, and solution stability.

The method demonstrated excellent linearity (r² = 0.999), with peak area directly proportional to concentration within the studied range. All validation parameters were within acceptable limits. Forced degradation studies revealed distinct degradation products under each stress condition. Notably, alkaline degradation resulted in the least degradation, while acid, peroxide, photolytic, thermal, and reductive conditions produced a variety of degradation products. These were effectively separated from Nirogacestat using the developed method. The relative retention times for Nirogacestat and its impurities remained consistent, and mass spectrometry confirmed the identities of the degradation products.

The validated UPLC-MS method exhibited high sensitivity, selectivity, and robustness in detecting Nirogacestat and its impurities. It effectively distinguishes degradation products even within complex matrices and fully complies with ICH guidelines for analytical method validation. The degradation profile of Nirogacestat under various stress conditions provides critical insights into its stability behavior, which is essential for formulation development and regulatory compliance. The successful separation and identification of degradation products further underscore the method’s applicability as a stability-indicating assay.

The developed UPLC-MS method is the first validated stability-indicating technique for Nirogacestat, offering comprehensive impurity profiling. It is precise, accurate, linear, and robust, making it highly suitable for routine quality control and regulatory submission. This method enables the reliable detection of degradation products, thereby enhancing the safety and efficacy profile of Nirogacestat in pharmaceutical preparations.

To explore the molecular mechanism of α7 nicotinic acetylcholine receptor (α7nAChR) mediated by Formononetin (FMN) in inhibiting macrophage inflammatory polarization and stabilizing atherosclerotic plaque.

SiRNA α7nAChR was transfected into THP-1-induced M0 cells and treated with FMN. Oil Red O staining was used to evaluate macrophage lipid deposition. RT-qPCR was used to detect α7nAChR, COX-2, IL-1β, IL-6, HO-1, and SHIP1 expression in M1 and M2 macrophages. Western blot was used to detect α7nAChR, iNOS, CD206, CD68, p-JAK2, and p-STAT3 protein expression in M1 and M2 macrophages.

Compared with the control group, FMN-mediated α7nAChR reduced lipid deposition in M1 and M2 macrophages. RT-qPCR results showed that FMN intervention significantly downregulated COX-2 and IL-1β expression in M1 (P < 0.05). α7nAChR expression significantly reduced COX-2, IL-6, and IL-1β expression in M2 (P < 0.05) and significantly increased HO-1 and SHIP1 expression (P < 0.05). FMN-mediated α7nAChR significantly decreased the expression of iNOS, CD68, p-JAK2, and p-STAT3 in M1 and M2 macrophages and significantly increased the expression of CD206 protein by Western blot (P < 0.05).

This study, for the first time, elucidated the mechanism of FMN regulating macrophage polarization through the α7nAChR/JAK2/STAT3 axis, providing new experimental evidence for the role of the cholinergic anti-inflammatory pathway in cardiovascular diseases. However, there are some limitations, such as the limited applicability of the THP-1 cell line, the need to strengthen the dose correlation study, the bioavailability and solubility limiting clinical translation, and the lack of human toxicological data.

FMN effectively modulates macrophage polarization through inhibition of the JAK/STAT signaling pathway while promoting α7nAChR expression.

Crohn's disease (CD) is a complex inflammatory bowel disorder with incompletely understood mechanisms. This study aimed to identify novel biomarkers and elucidate macrophage-related pathogenesis in CD.

Using gene expression data (GSE17928522) from the Gene Expression Omnibus (GEO) database, we compared 1135 CD patients with 180 healthy controls to identify altered gene expression profiles. Immune infiltration analysis was conducted to evaluate changes in immune cell subpopulations. Weighted Gene Co-expression Network Analysis (WGCNA) was employed to construct gene co-expression networks and identify macrophage-associated modules. Mendelian randomization was used to validate the causal role of macrophages. For ex vivo validation, immunohistochemical staining of GBP4 protein expression was performed in colonic tissue samples from 6 CD patients (with ileal or colonic lesions). Non-lesional tissues from the same patients served as intra-individual controls to minimize inter-patient variability.

Our analysis revealed significant changes in immune cell subpopulations, particularly macrophages, within the CD microenvironment. A macrophage-associated module was identified, with GBP4 emerging as a critical gene. Immunohistochemical staining confirmed differential expression of GBP4 in CD tissue samples compared to controls.

This multi-modal study establishes GBP4 as a novel macrophage-associated biomarker for CD, supported by causal Mendelian randomization and immunohistochemical validation. The integration of WGCNA and genetic evidence strengthens the role of macrophage dysregulation in CD pathogenesis. Limitations include population bias in genomic data and small validation cohorts, but the consistency across methodologies underscores GBP4's potential as a therapeutic target.

Our findings highlight GBP4 as a novel potential biomarker and therapeutic target in CD, providing insights into the immune-mediated mechanisms underlying the disease. These results contribute to a better understanding of CD pathogenesis and may lead to new therapeutic strategies.

At present, malignant tumors are still under development with an increasing trend, and their prevention, treatment, and prognosis are also difficult. The INHBA gene, also known as inhibin β, has a wide range of roles to play in this context. Through studies, several researchers have confirmed that an abnormal expression of the INHBA gene affects the development and prognosis of several malignant tumors (cervical, colorectal, breast, gastric, etc.). This study aims to investigate the relationship between INHBA and the occurrence, development, treatment, and prognosis of malignant tumors.

This review, which involved scanning of pertinent literature, describes and evaluates recent research on the biological functions and mechanisms of INHBA in malignancies.

An aberrant expression of INHBA can lead to a variety of tumors, including cervical, esophageal, breast, colorectal, squamous cell, bladder, nasopharyngeal, gastric, and ovarian cancers.

INHBA, as a protein-coding gene, can affect the development of various tumors and the prognosis of tumor patients, suggesting that INHBA can be a target for tumor therapy. However, the research on targeted therapy is still immature and has certain safety risks.

Research findings indicate that the INHBA gene plays a role in both carcinogenesis and prognosis. As such, it may have the potential utility as a biomarker or therapeutic target in the treatment of malignant tumors.

During cerebral ischemia, brain tissue is damaged in two successive stages: ischemia and reperfusion (I/R). In the ischemic phase, brain tissue undergoes energy failure due to an impaired circulatory system (cerebrovascular), resulting in oxygen and glucose deprivation and consequent brain damage.

The study aimed to determine the effect of a two-week administration of naringin on caspase-3, IL-17, and NF-κB levels in cerebellar tissue in experimental focal brain ischemia-reperfusion in rats.

The research was conducted on 10- to 12-week-old Wistar-type rats obtained from the Selcuk University Experimental Animals Research and Application Center. Experimental brain ischemia-reperfusion in rats was performed under general anesthesia (carotid arteries were exposed to ischemia for 30 minutes). Experimental groups were formed as follows. 1) Control group, 2) Sham, 3) Sham + vehicle, 4) Ischemia-reperfusion, 5) Ischemia-reperfusion + Naringin supplemented group for two weeks (100mg/kg). At the end of the experiments, the levels of IL-17, caspase-3, and NF-κB were determined in the cerebellum tissue of the animals under general anesthesia. First of all, blood was drawn from the heart, and the animals were killed by cervical dislocation.

Experimental brain ischemia-reperfusion significantly increased caspase-3, IL-17, and NF-κB levels in the brain tissue of rats. In contrast, naringin supplementation for 2 weeks significantly suppressed the ischemia-reperfusion-induced inflammatory process.

The findings obtained from our research generally showed that, as a result of focal brain ischemia-reperfusion in rats, the levels of NF-κB, a key molecule involved in inflammatory pathways, as well as the pro-inflammatory cytokine IL-17 and caspase-3, an indicator of apoptosis, increased significantly in cerebellar tissue. However, intragastric naringin supplementation for two weeks following ischemia-reperfusion led to significant improvements in the adverse effects caused by the ischemic injury.

The study's results demonstrate that naringin treatment effectively mitigates inflammatory activation in the cerebellum following brain ischemia-reperfusion in rats.

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.

This study aims to discover and design β-5 tubulin-specific covalent inhibitors for non-small cell lung cancer (NSCLC) that can minimize hematotoxicity, a major side effect of current microtubule-targeting agents (MTAs).

Current microtubule-targeting drugs cause toxicities such as hematotoxicity and multidrug resistance (MDR). The colchicine binding site in β-5 has Cys-239, whereas β-1 has Ser-239, allowing selective inhibition based on the reactivity differences for covalent reactions.

β-5 and β-1 tubulin models were developed, and covalent docking and virtual screening were conducted to identify selective inhibitors targeting the β-5 tubulin colchicine binding site. Twenty hits were selected, and a comparative study was carried out between β-5 and β-1 to evaluate the selectivity and binding potential of the inhibitors.

Among the 20 identified hits, four compounds demonstrated selective inhibition of β-5 tubulin, exhibiting stronger binding affinity for β-5 over β-1 tubulin. Molecular dynamics studies further confirmed their stability and enhanced binding, highlighting their potential as promising candidates for further drug development.

The study identified four novel β-5 tubulin-specific covalent inhibitors that may act as potential therapeutic agents for NSCLC, with the possibility of reduced hematotoxicity. These findings suggest that selective inhibition could help minimize side effects, addressing a critical need in cancer treatment.

Clear cell renal cell carcinoma (ccRCC) is the most prevalent of renal cancers, with a 5-year survival rate of less than 10% for metastatic cases. The most efficient current strategies to treat ccRCC in advanced settings slightly increase progression-free survival. Chimeric antigen receptor T cells (CAR T cells) targeting carbonic anhydrase IX (CAIX) have reemerged as a promising alternative to ccRCC treatment based on recent preclinical data. CAIX and cyclooxygenase-2 (COX-2) are key players in tumor progression across various malignancies, overexpressed in 95% and 50% of ccRCC cases, respectively.

This study employed in silico analysis to examine the expression of CAIX and COX-2 in ccRCC cell lines. The effects of celecoxib, anti-CAIX monoclonal antibodies, and anti-CAIX CAR T cells were evaluated using immunofluorescence microscopy and flow cytometry techniques.

Herein, we show a positive correlation between CAIX and COX-2 expression in ccRCC cell lines in vitro and in silico. Notably, COX-2 blockade with celecoxib led to a significant downregulation of CAIX expression in ccRCC cell lines. This effect is retroactive since treatment of these ccRCC cells with two different anti-CAIX monoclonal antibodies (mAbs) resulted in the downregulation of COX-2 expression. The association of celecoxib with anti-CAIX CAR T cell therapy impaired their cytotoxic potential over ccRCC in vitro, depending on CAIX cellular density.

These findings suggest a regulatory interaction between CAIX and COX-2 levels, indicating that COX-2 inhibitors may diminish the efficacy of CAIX-targeted therapies and should be avoided in combination treatments.

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by the impaired utilization of glucose, insulin resistance, or reduced insulin production. Although conventional pharmacologic agents like metformin, sulfonylureas, and thiazolidinediones are effective in regulating elevated blood glucose levels, they are often associated with some adverse effects, such as weight gain and liver problems.

The present review summarizes the possibility of using phytochemicals as safer alternatives for the management of DM by modulation of molecular receptors.

Several studies have reported that certain antioxidant phytochemicals exhibit inhibitory effects on key signaling pathways involved in glucose metabolism and insulin sensitivity under in vitro conditions. Therefore, this review will focus on the therapeutic potential of phytochemicals in modulating molecular targets, such as PPARs, GPR119, free fatty acid (FFA) receptors, glucocorticoid receptors, and others. For this purpose, a systematic and extensive literature search was carried out to obtain relevant data, focusing on the prospect of phytochemicals in modulating molecular receptors for diabetes mellitus (DM) management. Electronic databases, including PubMed, Scopus, ScienceDirect, and Google Scholar, were accessed for articles up to March 2025.

Curcumin, resveratrol, and quercetin are bioactive molecules that increase the sensitivity of the body to insulin and protect the pancreatic β-cells from oxidative stress. Natural agents, such as garlic, green tea, and blackcurrants, possess an antidiabetic action by inhibiting enzymes, such as α-glucosidase, and increasing the uptake of glucose. The co-administration of synthetic drugs along with natural agents has a synergistic effect in improving glycemic control with fewer side effects. Examples include resveratrol with metformin or curcumin with thiazolidinediones.

The findings of this review should be validated at the clinical level in future research studies, including toxicity profiling and formulation optimization, to maximize the therapeutic potential of phytochemicals in the management of DM.