Current Topics in Medicinal Chemistry - Online First

Prostate cancer is among the most prominent malignant tumors in the male population, characterized by growing morbidity, a high fatality rate, and currently limited therapeutic options, necessitating the urgent development of novel clinical medications. The objective of the current study was to examine the therapeutic potential of zingerone in prostate cancer cells.

In this study, we investigated the underlying mechanism by which zingerone exerts its anticancer effects in prostate cancer cells. We conducted various in vitro and in silico experiments to determine the therapeutic efficacy and mechanism of action of zingerone.

Cytotoxicity analysis of zingerone revealed its substantial cytotoxic impact and ability to elevate lactose dehydrogenase levels in DU145 cells. Using the MTT assay, we determined that a concentration of 24.84 μM zingerone in DU145 cells grown for 24 h resulted in an IC50 value. Zingerone effectively induced apoptosis by increasing the levels of cytochrome c and caspase in DU145 cells. Regarding the identification of signs of ferroptosis, evidence has been shown for the presence of heightened mitochondrial ROS, disrupted mitochondrial membrane potential, increased levels of glutathione (GSH) and malondialdehyde (MDA), and reduced expression of SCL7A11 and GPX4.

Importantly, our study confirms that zingerone triggered both apoptosis and ferroptosis in DU145 cells by downregulating SLC7A11 and GPX4 expression.

This study provides evidence that makes zingerone a potent therapeutic agent for prostate cancer.

This study aimed to explore the mechanisms by which interleukin-10 (IL-10) influences tumorigenesis through T regulatory cells (Treg) regulation.

Environmental factors, such as IL-10, significantly shape the immune microenvironment and tumor progression, yet the regulatory pathways remain unclear.

1) To elucidate the regulatory mechanism of IL-10 on Treg cells through in vitro assays; 2) To elaborate whether Nrp-1/PDX1 knockout affects tumorigenesis via in vivo assays.

CD4+ T cells were isolated from the healthy mice's spleen and induced to differentiate into Treg cells. Then, after being treated with IL-10 and mouse melanoma cell supernatant (CM), the expression levels of Nrp-1 and FoxP3 in Treg cells were examined via qRT-PCR and Western blotting. The ratio of Treg cells was measured by flow cytometry. The interaction between Nrp-1 and PDX1 proteins was detected through GST pull-down assay, Co-IP, Western blotting and immunofluorescence staining. STAT3 luciferase activity was detected, and the expression levels of JAK1 and STAT1 proteins were detected by Western blotting. Furthermore, the B16-bearing melanoma mice and Nrp-1/PDX1 knockout mice model were established to verify the effects of Nrp-1 and PDX1 on Treg formation and tumor development.

The results demonstrated that IL-10 promoted Nrp-1 expression in Treg cells via the JAK-STAT3 signaling pathway. Nrp-1 could combine with PDX1 to form a complex, facilitating PDX1-mediated activation of FoxP3 and Treg production. In melanoma xenograft models, targeting Nrp-1 and PDX1 using shRNAs or antibodies significantly reduced Treg levels and inhibited tumor growth. Collectively, IL-10 promotes Treg formation and tumorigenesis via regulating Nrp-1/PDX1/FoxP3 axis.

This study was the first to identify the interaction between Nrp-1 and PDX1, leading to PDX1 ubiquitination, which enhanced FoxP3 expression and Treg function in the tumor microenvironment. These novel insights highlighted the Nrp-1/PDX1/FoxP3 axis as a critical regulator of Treg-mediated tumorigenesis, offering potential targets for cancer therapy.

These findings highlight the interplay between environmental influences and immune regulation, providing novel insights into Treg-mediated tumorigenesis and suggesting potential strategies for targeted therapy.

Schizophrenia is a heterogeneous chronic brain disorder driven by multiple pathophysiological processes. While dopaminergic theories dominate current therapies, emerging evidence highlights glutamatergic dysregulation, particularly N-methyl-D-aspartate receptor (NMDAR) hypofunction, as a key mechanism alongside dopaminergic, serotonergic, and neurodevelopmental pathways. This article synthesizes mechanistic insights, focusing on neurotransmitter disruptions, oxidative stress, neuroinflammation, and Wnt signaling, to elucidate the clinical diversity of schizophrenia and identify biomarkers for precise diagnostics and therapeutics.

A comprehensive literature search was conducted using Web of Science, Scopus, Google Scholar, and PubMed, with keywords including “schizophrenia,” “psychosis,” “pathophysiology,” “mechanism,” and “biomarker.” Studies were selected to explore NMDAR hypofunction, glutamatergic dysregulation, and associated signaling pathways, integrating preclinical and human data to map circuit-based interactions and biomarker profiles.

We present a novel circuit-based model of schizophrenia pathophysiology, centered on NMDAR hypofunction and glutamatergic dysregulation, integrating dopaminergic, GABAergic, and inflammatory pathways. Key biomarkers, including inflammatory (e.g., high-sensitivity C-reactive protein [hs-CRP], interleukin-6 [IL-6]), neurochemical (e.g., brain-derived neurotrophic factor [BDNF]), and functional (e.g., mismatch negativity [MMN]), are categorized by symptomatic domains and clinical stages, providing diagnostic and prognostic insights.

The findings underscore NMDAR hypofunction’s role in driving schizophrenia’s symptomatic spectrum, though its interplay with other pathways highlights the disorder’s complexity. Neuronal loss, although not universal, is context-specific (e.g., hippocampal interneurons), complementing functional biomarkers such as MMN. Limitations include the need for robust human validation of biomarkers and broader exploration of non-glutamatergic mechanisms.

Considering the multifaceted nature of the disorder, our emphasis on the NMDAR hypofunction model can help explain many of the synergies involved among the seemingly independent dysregulated events.

Zika virus (ZIKV), a flavivirus primarily transmitted by Aedes aegypti, became a major global health concern during the 2015–2016 outbreak, particularly in Brazil. Its association with congenital malformations and neurological disorders underscores the urgent need for effective therapeutic interventions. This review explores molecular targets for ZIKV treatment within the Brazilian context.

A systematic search was conducted using PubMed, ScienceDirect, and Scopus for studies published between 2004 and 2024. Inclusion criteria focused on studies identifying druggable molecular targets related to viral replication, immune evasion, or host-virus interactions. Key search terms included “Zika virus,” “molecular targets,” “Brazil,” “antiviral,” and “drug discovery.”

The review identified several critical viral proteins, NS1, NS3, NS5, and the envelope protein, as potential drug targets. Host cellular factors essential for viral survival were also highlighted. Technologies such as high-throughput screening, molecular docking, and structural genomics contributed significantly to the identification and validation of these targets.

Although promising targets have been identified, therapeutic development is hindered by the genetic variability of ZIKV and its antigenic similarity to other flaviviruses, notably the dengue virus. These challenges complicate the specificity and efficacy of drugs. Nevertheless, Brazil has made strides in research infrastructure and collaborations to tackle these obstacles.

This review synthesizes current knowledge on ZIKV molecular targets and ongoing drug discovery efforts. The findings support the strategic development of antivirals and emphasize the necessity for sustained investment in research to mitigate future ZIKV outbreaks in Brazil and globally.

Obesity, a widespread health condition marked by excessive body fat, markedly elevates the risk of chronic diseases and has emerged as a major global health issue. Chrysin, a flavonoid with promising health benefits, exhibits potent antioxidant and anti-inflammatory properties. This study seeks to examine the impact of chitosan chrysin nanoparticles (Chrysin-CSNPS) on obesity induced by a high-fat diet (HFD) in male rats.

Rats were fed a high-fat diet for 4 weeks to induce obesity, followed by a 4-week treatment period. Thirty rats were allocated into five groups (six rats per group): control (dist. water, orally), HFD control (dist. water, orally), HFD + chrysin (500 mg/kg, orally), HFD + chitosan-NP (60 mg/kg, orally), and HFD + Chrysin-CSNPS (60 mg/kg, orally).

In silico studies revealed that chrysin has a binding energy value of −8.8 kcal/mol to fat mass and obesity-associated (FTO) protein. Also, Chrysin is identified as an inhibitor of several cytochrome P450 enzymes, specifically CYP1A2, CYP2D6, and CYP3A4. Albumin, high-density lipoprotein cholesterol, glutathione, and nitric oxide levels rose, whereas glucose, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, creatinine, urea, total cholesterol, triglycerides, malondialdehyde, and nitric oxide levels fell upon Chrysin-CSNPS treatment. The histological examination revealed a significant enhancement in the structures of the liver and kidneys.

These findings suggest that chrysin could potentially inhibit FTO activity, thereby contributing to a reduction in obesity-related phenotypes. The compound that satisfied Lipinski’s criteria was selected for toxicity prediction.

Chrysin-CSNPS have hypolipidemic properties and an antioxidant role, reducing HFD consequences in the liver and kidney.

This study aims to elucidate the mechanisms underlying Dementia using bioinformatics analysis and machine learning algorithms, to identify novel therapeutic targets for its clinical management.

Gene expression datasets related to dementia were sourced from the GEO database. Differentially expressed genes (DEGs) were identified using R, and key module genes were determined through the Weighted Gene Co-expression Network Analysis (WGCNA) method. Oligodendrocyte (OL) related targets were retrieved from the GeneCards database. The intersecting genes from DEGs, WGCNA, and OL were analyzed using Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes. Subsequently, three machine learning algorithms were employed to pinpoint core genes associated with OL in dementia. The CIBERSORT algorithm was used to evaluate the abundance of 22 immune cell types and their correlation with Dementia-related immune infiltration. Validation was carried out via quantitative reverse transcription polymerase chain reaction (RT-qPCR).

Through bioinformatics and machine learning techniques, six core OL genes associated with Dementia were identified, notably C1QA, CD163, and TGFB2, which showed elevated expression in Dementia. Immune cell infiltration analysis indicated that several immune cell types may contribute to Dementia's pathogenesis, and RT-qPCR results corroborated the bioinformatics findings.

The discovered genes may contribute to dementia pathogenesis through oligodendrocyte dysfunction and neuroimmune interactions. Notably, TGFB2 and complement-related genes (C1QA, CD163) suggest involvement in both myelination defects and neuroinflammation, highlighting their therapeutic potential.

The six feature genes: TGFB2, C1QA, CD163, ACTG1, WIF1, and OPALIN are significantly linked to Dementia.

Colorectal cancer (CRC) remains a significant global health challenge due to its high incidence and mortality rates. The disease's complexity and heterogeneity impede early diagnosis and effective treatment. The study aims to investigate the role of Tetraspanin 11 (TSPAN11) in CRC, exploring its potential as a prognostic biomarker and immunotherapy target through bioinformatics analysis and experimental validation.

Pan-cancer patient data were obtained from The Cancer Genome Atlas (TCGA) and the GSE71187 dataset, including 672 CRC tissues and 51 adjacent normal tissues. Differential expression analysis, Kaplan-Meier survival analysis, gene set enrichment analysis (GSEA), and immune infiltration assessment were performed. TSPAN11 expression was validated in CRC cell lines using quantitative reverse transcription PCR (qRT-PCR).

TSPAN11 was significantly downregulated in CRC tissues compared to normal tissues (p < 0.001), with lower expression associated with poorer overall survival (OS; p = 0.011) and disease-specific survival (DSS; p = 0.038). Multivariate analysis identified TSPAN11 as an independent prognostic factor (p = 0.045). TSPAN11 expression was linked to key pathways such as ECM receptor interaction and TGF-β signaling, and correlated with immune infiltration, immune checkpoint genes, tumor mutational burden (TMB), microsatellite instability (MSI), and drug sensitivity.

The findings suggest that TSPAN11 may influence CRC progression through multiple biological pathways and immune-related mechanisms. Its downregulation is associated with poorer prognosis and immune evasion, highlighting its potential as a biomarker and therapeutic target. However, validation in larger cohorts and elucidation of underlying mechanisms are needed to confirm these results and translate them into clinical practice.

TSPAN11 may serve as a promising prognostic biomarker and immunotherapy target in CRC. Its associations with clinical outcomes, immune features, and drug sensitivity underscore its potential for improving CRC diagnosis and treatment strategies.

Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder affecting 70-75% of women. This condition is frequently linked with large and dysfunctional ovaries, high levels of androgens, and insulin resistance. A variety of conventional treatments, including metformin, oral contraceptives, and anti-androgen agents, have been used to treat PCOS and its complications, but they have been linked to several negative side effects, including hyperkalemia, weight gain, cardiovascular and hepatic toxicity, vitamin B12 and folic acid deficiency. As a result, there is growing interest in natural methods as complementary or alternative approaches to mitigate these side effects. According to several studies, traditionally used Natural oils (NOs) from various sources have been utilized to identify their ameliorating characteristics against PCOS. The paper aims to study pre-clinical investigations and clinical studies of NOs from different sources against PCOS and gives a comprehensive overview of controlling PCOS. Also, it highlights and tabulates the prominent bioactive phytoconstituents from the reported NOs and their mechanism of action.

For this review purpose, the authors have gone through a vast number of scientific literature from different scientific databases like Google Scholar, ScienceDirect, Web of Science, and PubMed.

Mentha spicata L., Foeniculum vulgare Mill., Linum usitatissimum L., Nigella sativa L., Bambusa bambos (L.) Voss, Thuja occidentalis L., Syzygium aromaticum L., Pimpinella anisum L., Rosa canina L., Cocos nucifera L., Oenothera biennis L., Corylus avellana L., and fish oil have been reported to have anti-PCOS activity by maintaining body weight, testosterone, LH, FSH levels, and improving ovarian cysts.

NOs derived from plant and animal sources show promise in treating PCOS by balancing hormone levels, enhancing ovarian morphology, and alleviating metabolic symptoms. However, significant clinical trials and molecular research are required to evaluate their therapeutic potential, identify suitable dosages, investigate their precise mechanisms of action, and ensure long-term safety and efficacy in PCOS management.

Further research is needed to understand the molecular mechanisms of NOs responsible for anti-PCOS activity. Studies are needed to concentrate on their mechanisms of action, routes of impact, safe dosage, and potential side effects to ensure their efficacy and safety in treating PCOS.

Current trends in peptide synthesis protocols have emerged as the most attractive domain in the field of pharma and medicine. Since most of the peptide/peptidomimetic-based molecules serve as potential candidates for many diseases, as they are bioavailable molecules.

We present the synthesis of bioactive peptides through TAGGING approach with the help of TAG-OH as a linker to the N^α-protected amino acid.

FRDEHKK and NKDRG are two peptides that possess antioxidant and antiproliferative activity, and their in-silico investigations reveal that they exhibit anticancer properties when bound to the AXL kinase and EGFR proteins.

This TAG method enables the easy isolation of peptides at each step as solids, and all the impurities were washed off by simple filtration. The method allows a bulk-scale preparation of the peptides without any difficulty, and hence the protocol is highly efficient for the production of peptides of therapeutic importance.

The two peptides FRDEHKK and NKDRG were isolated as fine solids with 82% and 85% yield and were characterized by NMR and MASS spectroscopy. In-silico studies reveal FRDEHKK and NKDRG peptides exhibit good affinity towards EGFR and AXL kinase.

Skin cutaneous melanoma (SKCM) is a life-threatening malignancy, and pyroptosis-mediated inflammatory response is associated with SKCM progression. We aimed to uncover the underlying pathogenesis of SKCM based on pyroptosis features.

The single-cell and bulk RNA-seq data and clinical information of SKCM patients were downloaded from the TCGA and GEO databases, and the REACTOME_PYROPTOSIS.v2024.1.Hs.gmt from the MSigDB database was used for Gene Set Enrichment Analysis (GSEA). Differentially expressed gene (DEG) analysis was performed utilizing the “limma” R package, and the “GSVA” R package was used for the analysis of pyroptosis pathway activation. In addition, scRNA-seq analysis and cell communication analysis were carried out by employing the “Seurat” R package and “CellChat” R package, respectively. Gene expression was measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR), while cell counting kit-8 (CCK-8), wound healing, and Transwell assays were carried out to assess cell proliferation, migration, and invasion, respectively.

DEGs analysis detected no significant pyroptosis-related DEGs. Analysis of the expression of two representative pyroptosis genes (GZMA and GSDMB) revealed that GZMA was significantly upregulated in the SKCM tissues, but the expression of GSDMB was downregulated. The pyroptosis pathway was not activated in the tumor group. In addition, we observed that high expression of GZMA and GSDMB was closely associated with a favorable outcome in SKCM. The two genes were downregulated in SKCM cells, while the overexpression of GZMA significantly impaired the proliferation, migration, and invasion ability of SKCM cells. Nine main cell subpopulations were identified, and GZMA was specifically overexpressed in CD8+ T cells. Gene function analysis revealed that specific genes of CD8+ T cells were enriched in cell death-related and inflammation activation pathways. Cell communication demonstrated that CD8+ T cells interacted with melanocytes through the CD99-CD99 and HLA-C-KIR2DL3 ligand-receptor pairs.

Based on the pyroptosis features in SKCM, this study found that blocking GZMA protein in CD8+ T cells within melanocytes may be the potential underlying pathogenesis for tumor immune escape in cancer.

CAs serve as crucial enzymes involved in a variety of physiological processes, including brain metabolism and cognitive function. hCA VII, a brain-associated isoform, plays an important role in modulating cerebral metabolism. Activating hCA VII may provide therapeutic benefits in Alzheimer's disease and other neurodegenerative or age-related illnesses. This study proposes to add to the growing interest in CAAs by developing innovative drugs with selective activation characteristics that target brain-associated CA isoforms.

A series of 4-arylazo-3,5-diamino-1H-pyrazoles have been produced by reacting aniline and aniline derivatives with a malononitrile solution at 0-5 °C, resulting in compounds 1(a-m). Then, arylazo malononitrile compounds were added with hydrazine monohydrate to obtain 4-arylazo-3,5-diamino-1H-pyrazole derivatives 2(a-m). The activity of the synthesized compounds was examined on human CA isoforms I, II, IV, and VII to determine activation potency and selectivity.

The synthesized compounds demonstrated a wide spectrum of strong micromolar activation on human CA isoforms, with particularly encouraging results for hCA VII. The discovered activators showed a high selectivity profile for the brain-associated hCA VII isoform, indicating their potential use in neurological methods of therapy.

Among the most compelling findings of this study is the unprecedented potency of several synthesized derivatives, particularly 2i and 2m, in selectively activating hCA VII far beyond the benchmark histamine, positioning them as promising pharmacological candidates for addressing CA-related neurological disorders.

The research successfully discovered potent and selective CAAs with specific activity against hCA VII, a key enzyme in brain metabolism. These outcomes offer novel possibilities for developing medicinal products for neurological disorders and provide critical molecules for further study into CAAs. Furthermore, the study advances our understanding of enzyme activation kinetics and gives significant insights into the future of enzyme-based treatment research.

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.

Polysaccharide-derived biomaterials have emerged as promising candidates for wound healing applications due to their biocompatibility, biodegradability, and ability to mimic the extracellular matrix. These materials play a crucial role in maintaining a moist wound environment, promoting cell proliferation, and exhibiting anti-microbial properties, making them suitable alternatives to traditional wound dressings.

A systematic literature review was conducted using reputable databases including ScienceDirect, PubMed, Scopus, and Google Scholar. Relevant studies were identified, screened, and analyzed to ensure comprehensive coverage of the topic.

Wound healing is aided by essential polysaccharides such as chitosan, alginate, cellulose, and carrageenan, which help to retain moisture, promote cell proliferation, and prevent infections.

Polysaccharide-derived biomaterials, including chitosan, alginate, and cellulose, facilitate wound healing by maintaining moisture, promoting cell migration, and exhibiting anti-microbial properties. However, challenges such as weak mechanical strength and rapid degradation limit their clinical use. Recent advancements in composite hydrogels, nanomaterials, and 3D-printed scaffolds have improved stability, drug release, and anti-microbial efficacy. Further research is required to enhance their mechanical properties and long-term applicability for clinical wound care solutions.

Biomaterials developed from polysaccharides have the potential to revolutionize wound healing by providing biocompatible, adaptable solutions that promote enhanced tissue regeneration and infection control.

The goal of this study is to provide a comprehensive review of physicochemical and pharmacological properties, including pharmacokinetics and pharmacodynamics parameters, with an overview of preclinical and clinical trial data, chemistry, and multiple routes of synthesis, bioanalytical methods, and patents of the API: Vadadustat

A review was conducted by compiling data from Science Direct, PubMed, Drug Bank, WIPO patent, Clinicaltrialgov, Wolters Kluwer, and many others to enhance understanding of the topic

The FDA approved Vadadustat on March 27, 2024, for treating anemia in adults with CKD on dialysis. Vadadustat effectively increased hemoglobin levels in both non-dialysis and dialysis-dependent CKD patients. It showed comparable efficacy to traditional erythropoiesis-stimulating agents (ESAs) like darbepoetin alfa. Multiple clinical trials, including Phase 2 and Phase 3 studies, demonstrated Vadadustat’s potential as an effective treatment for anemia in CKD patients.

Vadadustat, as an oral HIF-PH inhibitor, offers significant advantages in the treatment of anemia in CKD. Its oral route of administration improves patient compliance, and its efficacy is comparable to ESAs. Clinical and preclinical data support its safety and therapeutic potential, although long-term cardiovascular effects remain under observation.

This review examines therapeutic, pharmacological, analytical, and regulatory aspects related to Vadadustat.

The limitations of conventional drug delivery methods, such as systemic side effects and poor absorption, highlight the need for safer and more effective alternatives. Polysaccharides, due to their biocompatible, biodegradable, and mucoadhesive properties, have shown promise in formulations for the oral cavity, particularly in localized delivery systems and tissue regeneration. This study aims to conduct a bibliometric analysis to characterize the scientific output on the use of polysaccharides in the oral cavity, identifying trends, international collaborations, and research gaps.

A Web of Science search was conducted in January 2025 using keywords related to polysaccharides and mucosal adhesion. The analysis included original articles published in English between 2015 and 2024. Bibliometric data and study characteristics were extracted and analyzed, focusing on study types, formulation types, and international collaborations.

The analysis included 66 articles with 1144 citations. In vitro studies were predominant, while clinical trials were lacking. Chitosan and alginate emerged as the most commonly used polysaccharides, with gels and hydrogels being the most prevalent formulations. International collaborations involved 28 countries, with China, Brazil, and Italy standing out in terms of scientific production.

The results highlight important advancements in the use of polysaccharides for oral cavity formulations, particularly in gels and hydrogels. However, the predominance of in vitro studies and the lack of clinical trials suggest limitations for translating these findings into clinical practice. The strong performance of countries such as China, Brazil, Italy, Spain, and Norway underscores the relevance of international collaborations and the global potential of this topic.

The increasing scientific output reflects the growing interest in the use of polysaccharides for oral health applications. Despite these advancements, critical gaps remain, such as the lack of clinical studies. Future research should prioritize translational studies, personalized therapies, and the sustainable development of biomaterials.

Cancer remains a devastating global health burden. Despite the identification of numerous biological targets, effective therapeutic agents remain limited. As a highly promising novel target, the role of Discoid Domain Receptors (DDRs) in pan-cancer biology is still poorly characterized. Thus, this study aims to elucidate the regulatory mechanisms and diagnostic potential of DDR1 across different cancer types.

Herein, we used UCSC, SangerBox, GEPIA, GSCA, and GeneMANIA online databases to analyze the expression and role of DDR1 in pan-cancer.

The expression levels of DDR1 showed significant differences in some tumour T, N, and M stages. Importantly, DDR1 expression was associated with clinical prognosis in five cancers. In addition, DDR1 was inversely correlated with most immune checkpoint pathways, immunomodulatory genes, and immune cell infiltration in a few cancers. Furthermore, in most cancers, DDR1 promotes cancer progression by promoting apoptosis, inhibiting cell cycle and EMT, activating hormone AR activity, activating PI3K/AKT pathway, RASMAPK pathway, and RTK pathway. Finally, we also found that the DDR1 gene was positively associated with stemness scores in most tumors.

Our findings demonstrate that DDR1 exhibits diagnostic utility and holds promising translational potential as a therapeutic target across multiple cancer types.

Many metabolic diseases, such as Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD), are largely caused by obesity, a complicated ailment characterized by excessive fat buildup. By 2030, obesity is expected to have increased in prevalence, affecting over 1 billion people worldwide. MASLD, formerly known as NAFLD, is a broad category of liver illnesses caused by metabolic dysfunction and frequently linked to obesity. Drugs are available for obesity, but long-term use causes serious adverse effects, as reported. Currently, there are no FDA-approved therapies for MASLD. Interest in marine animals and their metabolites for their potential as therapeutics is growing, given the shortcomings of traditional medicines. This review emphasizes different marine species and metabolites, and macromolecules and tabulates all the pre-clinical studies targeting obesity and MASLD.

For this review, the authors have gone through a vast number of article sources from different scientific databases like PubMed, Google Scholar and ScienceDirect.

Algae, fungi, and bacteria found in the ocean are abundant in bioactive chemicals that have anti-obesity and anti-MASLD properties. A variety of studies have reported the anti-obesity and anti-MASLD effects of marine species such as Spirulina platensis, Chlorella vulgaris, Caulerpa okamurae, and bioactive macromolecules like dieckol, fucosterol, fucoxanthin, sodium alginate and paramylon.

These marine-derived substances have a variety of pharmacological characteristics, including lipid-modulating, anti-adipogenic, antioxidant, and anti-inflammatory activities. These qualities are crucial for treating the underlying mechanisms that underlie obesity and MASLD. These marine species may be useful as natural supplements or therapeutic agents in the management and treatment of metabolic diseases associated with obesity. Some of these bioactive phytoconstituents have been identified for their potential against obesity and MASLD; however, more investigation is necessary to identify the precise bioactive substances causing these advantageous effects and assess their safety and effectiveness in clinical trials.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer. M1 macrophages exhibit dual roles in the tumor microenvironment (TME), but the specific mechanisms underlying their involvement in HCC remain unclear.

M1-polarized macrophages were differentiated from THP-1 monocytes employing Phorbol 12-Myristate 13-Acetate (PMA) and lipopolysaccharide (LPS). Then, macrophage activity was determined based on Mean Fluorescence Intensity (MFI), and their metabolic capacity was assessed according to extracellular acidification rate (ECAR) and Oxygen Consumption Rate (OCR). Quantitative Real-Time PCR (qRT-PCR) was performed to assess the expression of polarization-related genes.

The results showed that LPS at a concentration higher than 10 ng/mL significantly affected the viability of macrophages differentiated from THP-1 monocytes but promoted the MFI of CD86. At the same time, LPS treatment notably enhanced the M1 polarization of macrophages, as evidenced by the upregulated expression of markers related to the M1 phenotype. Moreover, the mitochondrial oxidative metabolism of M1 macrophages shifted toward aerobic glycolysis under LPS treatment. When T-cells and HCC cells were co-cultured with M1 macrophages, the reactivity of T cells was enhanced, and the level of Bax (an apoptosis-enhancer) was increased. At the same time, the expression of Bcl-2 (an apoptosis-suppressor) was suppressed.

LPS-induced M1 macrophages exert antitumor effects through metabolic reprogramming and immune modulation, though further mechanistic studies are needed.

M1 macrophages inhibit HCC progression by activating T cells and inducing tumor cell apoptosis, offering novel insights for HCC immunotherapy.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are one of the most widely prescribed medications in the world, yet their applications as anti-inflammatory, analgesic, and anti-pyretic drugs remain principally restricted by their detrimental effects on the gastrointestinal tract (GIT) systems. The prodrug approaches have substantially combated the drawbacks of currently available marketed NSAIDs and also showed increased activity.

In the present study, an extensive literature review on mutual prodrugs of NSAIDs with natural antioxidants has been presented.

Different databases like ScienceDirect, Elsevier, PubMed, Google Scholar, etc. were used for an extensive search of articles related to NSAIDs, prodrug concepts, as well as research based on all of the NSAIDs-prodrug molecules prepared to date.

Recent developments in prodrug design have been explored that utilize naturally occurring antioxidants, including Thymol, Guaiacol, Menthol, Eugenol, Sesamol, Vanillin, and Umbelliferon, for the synthesis of mutual prodrugs by esterification methods. Many studies have shown that these prodrugs have significant stability in acidic pH while hydrolyzing in neutral and alkaline pH environments. This indicates their potential as advantageous therapeutic agents with enhanced safety profiles.

The mutual prodrug strategy offers a chance in medicinal chemistry to enhance the therapeutic and clinical efficiency of a drug that has certain unfavorable qualities that limit its clinical utility. This review enlightens mutual prodrugs of NSAIDs and antioxidants that are less harmful and beneficial to mankind, respectively.

Myocyte enhancer factor 2C (MEF2C) is a pivotal transcription factor that is responsible for maintaining myocyte differentiation. MEF2C is multifunctional, participating in diverse biological processes, including cardiac morphogenesis, angiogenesis, neurogenesis, and cortical development. Emerging evidence has identified MEF2C as a novel oncogene with dual regulatory functions in tumorigenesis. However, the mechanisms by which MEF2C regulates the progression of various malignant tumors are unknown. Therefore, it is crucial to further investigate the multiple signaling pathways under different expression levels of MEF2C. In this review, the expression level of MEF2C in various malignant tumors and its specific pathways are described.

This review systematically summarizes and critically analyzes the current studies on MEF2C’s biological function in malignant tumors by comprehensively searching them in PubMed databases.

MEF2C demonstrates aberrant expression patterns across multiple tumor types, spanning both solid tumors (e.g., glioma, breast cancer, hepatocellular carcinoma) and hematological malignancies (e.g., leukemia). MEF2C orchestrates multiple oncogenic processes, including tumor cell proliferation, migration, and invasion, while also modulating cancer drug resistance and systemic manifestations, like cachexia and apoptosis resistance.

Given its multifaceted roles in tumor initiation, progression, and clinical aspects, MEF2C has the potential to serve as both a diagnostic biomarker and a therapeutic target for various malignancies.

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.

Cancer continues to be a significant public health issue and one of the leading causes of death globally. In this context, developing new, potent, and more specific treatments against this disease is urgent.

A total of 15 benzoxathiolone-thiazolidinones hybrids were synthesized in a 5-step route and tested for their cytotoxicity against five human cancer cell lines: AGP-01 (gastric), SKMEL-103 (melanoma), HCT-116 (colon), CAL27 (tongue), and K562 (leukemia), as well as a non-tumoral cell line MRC-5.

Compounds 3-(6-hydroxy-2-oxobenzo[d][1,3]oxathiol-5-yl)-2-(4-nitrophenyl)thiazolidin-4-one and 2-(2,4-dichlorophenyl)-3-(6-hydroxy-2-oxobenzo[d][1,3]oxathiol-5-yl)thiazolidin-4-one exhibited good activity against the K562 leukemia cell line, with IC50 values of 4.0 μM and 5.3 μM, respectively. Docking studies demonstrated that these compounds likely bind to the BCR-ABL1 kinase, a key protein in the pathogenesis of chronic myeloid leukemia (CML).

The study suggests these benzoxathiolone-thiazolidinone hybrids could be promising lead compounds for developing new anticancer agents targeting leukemia.

Although E. coli is considered a normal human microbiota, it may cause life-threatening infections such as septicemia, urinary tract infections, and enteric infections. Moreover, multidrug-resistant strains are a serious challenge in the clinic due to high mortality rates and the limited number of therapeutic options. Hence, the current study aimed to benefit from pink rose petals as a source of green synthesis of copper nanoparticles (Cu-NPs), to investigate the antibacterial features against multidrug-resistant E. coli, and to measure the cytotoxicity of Cu-NPs.

Pink rose petals were used as a reducing agent for Cu-NP synthesis, and then XRD, zeta potential, UV-Vis, FTIR, SEM, and DLS analyses were performed to characterize the synthesized NPs. Moreover, the MIC and zone of inhibition values of Cu-NPs were measured and compared to common antibiotics. Additionally, the MTT assay was performed to assess the cytotoxicity.

The green synthesized Cu-NPs were spherical and uniform with a size of ~200 nm. The MIC of Cu-NPs was 1024 μg/ml on the MDR strain of E. coli, representing the antibacterial activity comparable to levofloxacin (p-value>0.05) but less than imipenem and trimethoprim (p-value<0.001). Moreover, the CC50 of synthesized Cu-NPs was 731.2 μg/ml and significantly lower than the studied antibiotics (p-value<0.001).

The findings may suggest Cu-NPs as a promising antibacterial strategy against MDR strains of E. coli, however, further studies are encouraged to clarify the safety of optimized doses.

Genistein, a natural isoflavonoid found predominantly in legumes and soy-based foods, has garnered significant attention due to its multifaceted mechanisms and potential therapeutic applications. Chemically, genistein is a 4',5,7-Trihydroxyisoflavone having a molecular formula of C15H10O5, which enables its interactions with diverse biological targets.

The main objective of this review is to summarize the pharmacological effects of genistein, elucidating its potential mechanisms of action. Furthermore, the review emphasizes genistein's impact on human health when used as a dietary supplement.

The authors have gone through a vast number of article sources from various scientific databases like Google Scholar, PubMed and Web of Science.

Genistein exhibits antioxidant properties by countering free radicals and reducing lipid peroxidation. Genistein's anti-inflammatory effects involve inhibiting proinflammatory pathways and cytokine production. Notably, it shows anticancer potential against various malignancies by promoting apoptosis, inhibiting angiogenesis, and hindering metastasis. Moreover, genistein has antidiabetic properties, enhancing insulin secretion, protecting β-cells, and improving glucose tolerance. Its antiviral and antibacterial actions contribute to inhibiting pathogen growth and viral replication. Genistein accelerates wound healing by minimizing oxidative stress, facilitating re-epithelialization, and suppressing inflammation. Its potential in peptic ulcer treatment is supported by anti-inflammatory and antioxidant effects. Hepatoprotective activities include inhibiting lipid peroxidation, bolstering antioxidant defences, and modulating metabolic enzymes. Furthermore, genistein positively impacts the immune response, influencing cytokine levels, lymphocyte proliferation, and interferon production.

Genistein's multifaceted pharmacological activities render it a promising dietary supplement with implications for diverse health conditions, warranting further comprehensive research to optimize its clinical utility.

The dihydroorotate dehydrogenase (DHODH) enzyme plays a crucial role in the de novo pyrimidine biosynthesis pathway, catalysing the conversion of dihydroorotate to orotate in the cells. This pathway is important for the synthesis of nucleic acids and vital molecules essential for homeostasis, cellular functioning, and survival. So, targeting this enzyme can be an effective approach for the treatment of cancer, arthritis, malaria, viral or microbial infections, and other autoimmune diseases.

In this review, we have highlighted the therapeutic implications of DHODH inhibition in cancer, rheumatoid arthritis and multiple sclerosis through an extensive literature survey from various scientific databases like PubMed, Google Scholar, Science Direct, Embase, clinical trials.gov.in, Google Patents, etc.

We have tried to identify the pharmacophores from synthetic, phytochemical, and microbial origins, effective as DHODH inhibitors. The effect of structural changes on activity has been summarised, providing insights into the efficacy and mechanisms of these inhibitors at the molecular level. Furthermore, this review also presents a comprehensive analysis of clinical trials and patents related to DHODH inhibition to extract the valuable information to be used for clinical drug development in cancer, rheumatoid arthritis, and multiple sclerosis.

By integrating data from synthetic, plant, and microbial sources, along with clinical trial and patent outcomes, this review highlights the diverse role of DHODH. Its inhibition offers a more targeted approach to reduce the proliferation of rapidly dividing cells while sparing normal cells, modulating specific immune responses. But, limiting understanding of resistance mechanisms and potential for toxicity are the current challenges. It offers a roadmap for future research and drug discovery endeavours focused on harnessing the beneficial potential of DHODH inhibition, including the development of novel inhibitors with improved selectivity and pharmacokinetics across a wide array of pathological conditions.

Exploring the correlation between ovarian cancer and aging has great significance for understanding the pathogenesis of ovarian cancer and formulating targeted therapeutic regimens.

This computational study aims to identify and validate key genes in monocyte subtypes related to ovarian cancer and aging, exploring potential causal relationships.

We collected single-cell RNA sequencing data (GSE157007, GSE184880), GWAS data (14,049 samples and 40,941 controls from a European population), and eQTL data of ovarian cancer and aging. Using R software packages like Seurat and singleR, we conducted data integration, quality control, cell classification, and differential gene expression analysis to identify intersecting monocyte subtype genes in ovarian cancer and aging. We employed summary data-based Mendelian randomization (SMR) analysis and Heterogeneity in Dependent Instruments (HEIDI) tests to pinpoint causal genes. Further single-cell functional analyses (gene switching, cell communication, metabolic pathway analysis), Bulk RNA sequencing validation, functional enrichment, and protein-protein interaction (PPI) analyses elucidated these genes' biological roles.

The dataset included 123,280 cells, revealing differential gene expression in classical monocytes (104 genes), intermediate monocytes (43 genes), and myeloid dendritic cells (39 genes). SMR and HEIDI identified causal relationships for 7 genes in classical monocytes, 3 in intermediate monocytes, and 3 in myeloid dendritic cells with ovarian cancer. Bulk RNA seq validation confirmed six monocyte genes as causal in ovarian cancer and aging. TREM1, SERPINB2, and CD44 were upregulated, while DST was downregulated; SLC11A1 and PNRC1 showed contradictory patterns. Interactions with NK and T cells involved LGALS9 - CD44/45 receptors. Riboflavin metabolism was a common enriched pathway.

This study identified six specific monocyte genes as potential therapeutic targets for ovarian cancer and aging.

Skin cancer is one of the most prevalent cancers globally and is considered a serious public health problem associated with high death rates. The current therapeutic regimes for skin cancer are limited by their low bioavailability, generation of resistance, or adverse side effects. Many fruit extract-based nutraceuticals hold potential as topical treatment methods. Pyrus communis (Pear) fruit extract is a rich source of cholinergic acid, presently used as therapy for various skin diseases. Thus, it qualifies as a promising candidate for skin cancer treatment.

The objective of the study is to evaluate the cytotoxicity of Pyrus communis extract entrapped in ethosomes.

In this study, Pyrus communis fruit extract was formulated in ethosomes using the hot method and optimized using central composite design. The optimized ethosomes were characterized in vitro for particle size distribution, zeta potential, entrapment efficiency, morphology, and particle stability.

Preliminary phytochemical screening results suggest that PCHE contains a significant amount of phenolic compounds compared to other extracts (PCEA and PCAE). The presence of these phenolic compounds contributes to the strong antioxidant and cytotoxic effects of PCHE, which are observed in a dose-dependent manner. Analysis through GC-MS has identified chlorogenic acid, arbutin, ursolic acid, quercetin, and epicatechin are present in PCHE. Based on the initial testing of the extracts, PCHE was chosen for the preparation of ethosomes. The optimized ethosomes were found to have a particle size of 699 nm and a zeta potential of -16.07. Transmission Electron Microscopy illustrated a closed, spherically symmetrical structure of the ethosomes. Additionally, the Franz diffusion cell analysis for percutaneous absorption using egg membrane indicated a steady-state flux of the drug from the ethosomes. The formulation's cytotoxicity potential was assessed using the epidermoid carcinoma cell line (A431) through the MTT assay. The results show that the ethosome formulations exhibit cytotoxic activity better than PCHE extract. 1

In sum, the result of this study clearly points out that Pyrus communis extract entrapped in ethosomes, prepared by hot method, displayed a cytotoxic potential against skin cancer cell lines. This ethosomal formulation can be harnessed for skin cancer therapy through further mechanistic analysis and animal studies.

Colorectal cancer (CRC), the world's third leading cause of death, can be caused by a variety of reasons, one of which is a valine-to-glutamate mutation at position 600 in the BRAF gene. Nonetheless, the prognosis of patients with BRAF mutations remains poor, necessitating additional research in this field.

This work aims to recognize and validate innovative and effective BRAF inhibitor.

A merged-featured ligand-based pharmacophore model was validated and screened against various external databases. The pharmacokinetic and toxicological characteristics of the 102 hits were analyzed, and the appropriate ligands were docked against BRAF protein. The top four protein-ligand complexes with the lowest binding energies were chosen, and their Molecular Dynamic (MD) simulation studies were accomplished.

The finest complex selected has a Root Mean Square Deviation (RMSD) value of 2.229A⁰ and a Radius of Gyration (RoG) value of 25.770A⁰. The LC50 of the best ligand was experimentally calculated to be 102.83 µg/ml. The ligand was found to destroy CRC cells, but it did not affect normal non-cancerous cells much.

This work thus proposes 3-(6,7-dimethoxy-3,4-dihydroisoquinoline-2-carbonyl)-N-(2-methoxyphenyl)benzenesulphonamide as a potential BRAF V600E inhibitor for the CRC treatment.

This study aims to isolate and evaluate the anticancer potential of laccaic acids from lac dye by utilizing polarity-based fractionation and high-performance liquid chromatography (HPLC).

In this study, polarity-based fractionation of lac dye was performed to isolate its constituents. A novel HPLC method was developed for the chromatographic separation of lac dye components, utilizing gradient elution with two solvents: 0.1% (v/v) formic acid in LCMS-grade water (A) and 90:10 acetonitrile HPLC-grade (B) at a flow rate of 0.4 mL/min. This method facilitated the isolation of four key constituents: laccaic acid D, laccaic acid B, laccaic acid C, and laccaic acid A.

The purity of these compounds was confirmed via LCMS methods. The anticancer activity of the isolated constituents was evaluated against the MDA-MB-231 cell line using the MTT assay. Notably, laccaic acid A demonstrated significant anticancer activity with an IC50 value of less than 100 nM, comparable to that of Adriamycin. Further investigations into the apoptotic activity of laccaic acid A were conducted using flow cytometry, revealing that laccaic acid A is a non-necrotic and apoptotic inducer. Additionally, considering that an effective anticancer agent may also exhibit antioxidant, anti-inflammatory, and anti-angiogenesis properties, the isolated laccaic acids were accessed for these biological activities.

The results were promising, indicating that laccaic acids could offer a multifaceted approach to cancer treatment. This study highlights the potential of laccaic acids as valuable candidates for anticancer therapy and warrants further investigation into their mechanisms of action and therapeutic efficacy.