Current topics in medicinal chemistry最新文献

Background: 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.

Method: 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.

Results: 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.

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

Introduction: 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.

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

Results: 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.

Discussion: 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.

Conclusion: 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.

Precision medicine's quick development has transformed the way cancer is treated, and because small-molecule kinase inhibitors can specifically block the abnormal signaling pathways that cause tumor growth and progression, they are now a key component of targeted therapy. This review explores the most recent advancements in kinase inhibitor design and optimization, with a focus on novel drug scaffolds, improved structure-activity relationships (SARs), and molecular modification techniques meant to improve target selectivity, potency, and pharmacokinetic profiles. Emerging strategies to combat resistance mechanisms are heavily emphasized, such as the use of dual-target inhibitors that block parallel signaling cascades, allosteric modulators that bind to non-ATP sites, and combination therapies that work in concert to increase efficacy while reducing resistance. A thorough summary of the kinase inhibitors that are now FDA-approved for use in treating different forms of cancer is also included in the review, along with information on their safety profiles, clinical effectiveness, and changing indications of usage. Additionally, it examines encouraging results from preclinical research and ongoing clinical studies assessing nextgeneration kinase inhibitors, which have the potential to further customize cancer treatment. In order to improve patient outcomes, address therapeutic resistance, and broaden the therapeutic scope of kinase-targeted interventions in oncology, the review concludes by highlighting future research directions, such as drug repurposing, computational drug discovery, and advanced precision oncology approaches.

Small Ubiquitin-like Modifier 1 Pseudogene 3 (SUMO1P3) is a novel long non-coding RNA (lncRNA) located at the 1q23.2 locus of the human chromosome. Recent evidence indicates that SUMO1P3 is aberrantly upregulated in nine types of human cancer and functions as an oncogene. Elevated SUMO1P3 expression is strongly associated with unfavorable clinicopathological features and poor prognosis in eight cancer types. Mechanistically, SUMO1P3 functions as a miRNA sponge, an epigenetic regulator, and directly interacting with proteins. It activates key signaling pathways, such as the Wnt/β-catenin and AKT pathways, and regulates Epithelial- Mesenchymal Transition (EMT), which facilitates cancer progression and therapy resistance. Due to its diverse functional roles, SUMO1P3 emerges as a promising diagnostic and prognostic biomarker, as well as a potential therapeutic target in precision oncology. This review provides a comprehensive summary of current research on SUMO1P3, highlighting its regulatory mechanisms, biological functions, and clinical significance in cancer biology.

Various drugs face limitations in their solubility parameters which limits their total oral bioavailability, and such drugs are also categorized under the biopharmaceutical classification system (BCS) Class II. To modulate such limitations there were various novel drug delivery systems (DDS) designed including lipid-based DDS such as liposomes, niosomes, nanostructured lipid carriers (NLCs), nanoemulsion, self-nanoemulsifying DDS (SNEDDS) but the most effective and easily prepared DDS is nano-cocrystals (NCs). This study aims to give a clear emphasis on the NCs, their development and various advantages related to their usage as DDS. NCs are developed to modify the characteristics of dynamic drug adjustments with enhanced dissolvability, disintegration, and bioavailability compared to their naive form. Due to their high surface-to-volume ratio and co-crystal structure, easily converted in the nanosized range, they can further enhance these qualities. Even though NCs have been the subject of numerous studies, drug NC research is still in its early stages. In this review, many methods for organizing NCs have been discussed. A detailed understanding of NCs will be provided by a thorough examination of a few scientific methods and representations. The purpose of this analysis is to provide direction for the development of novel NCs with pharmaceutical industry economic value and proven as an effective approach for enhancement of drug aqueous solubility and ultimately resulted in the modulation of total oral bioavailability of the drug. NCs will be the modern DDS from the futuristic point of view due to their easy development and better physiochemical properties.

Introduction: 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.

Objective: 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 ischemiareperfusion in rats.

Methods: 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.

Results: 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.

Discussion: 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.

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

Microfluidics-based polymers are transforming drug delivery systems for liver cancer treatment as they enable precise synthesis of nano- and microparticles suitable for targeted therapy. The manufacture of programmable nanoparticles and tunable sizes is made possible by microfluidic platforms, which are essential for improving the effectiveness of medication administration. A wide range of therapeutic chemicals, including hydrophobic medications like doxorubicin, can be encapsulated in these systems to target liver cancers while reducing systemic toxicity effectively. It has also been demonstrated that combining natural hydrogels and droplet microfluidics can create multicellular tumor spheroids that resemble the tumor microenvironment more closely. This methodology improves screening and drug efficacy research and offers a strong foundation for assessing treatment outcomes. This research also explores novel uses of microfluidic technologies to develop intelligent drug delivery devices that respond to particular stimuli and release medication at the tumor site. It also investigated how artificial cell assemblies made with microfluidics can open new possibilities for individualized cancer treatment. To sum up, microfluidic-based polymers offer advanced tools for developing tailored and efficient drug delivery systems that can enhance patient outcomes, and represent a significant advancement in the treatment of liver cancer. The review paper discusses challenges in liver cancer treatment, including high drug clearance rates, low concentrations, and multidrug resistance. It suggests microfluidic technology can improve drug delivery systems by creating controlled particles and responding to tumor conditions. This could revolutionize liver cancer therapies, enabling better drug testing and treatment prediction, as well as designing tailored therapies.

Aim: 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.

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Introduction: 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.

Methods: 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 was induced using streptozotocin at a dose of 65 mg/kg. High-Performance Liquid Chromatography (HPLC) analysis quantified the bioactive constituents of amla. Physical, glycemic, oxidative, inflammatory, and renal biomarkers were assessed periodically.

Results: 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.

Discussion: 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.

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

Introduction: 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.

Methods: 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.

Result: 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.

Discussion: Polysaccharide-derived biomaterials, including chitosan, alginate, and cellulose, facilitate wound healing by maintaining moisture, promoting cell migration, and exhibiting antimicrobial properties. However, challenges such as weak mechanical strength and rapid degradation limit their clinical use. Recent advancements in composite hydrogels, nanomaterials, and 3Dprinted 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.

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