Current medicinal chemistry最新文献

The molecular mechanisms and causes of primary sclerosis cholangitis (PSC) post-liver transplantation are still unclear. PSC is a progressive cholestatic hepatobiliary disease that happens in about 25% of patients post-liver transplantation and requires re-- transplantation. Nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase or Nox) is a family of transmembrane proteins whose main function is producing reactive oxygen species (ROS). ROS generation as a result of NADPH oxidase activity of Kupffer cells and polymorphonuclear leukocytes has been implicated in the pathogenesis of ischemia-reperfusion injuries after liver transplantation, and is related to intraand/ or extrahepatic non-anastomotic biliary stenosis or PSC. In addition, Nox-derived ROS upregulates several molecular pathways to induce hepatocyte apoptosis and hepatic stellate cell (HSC) activation to promote hepatobiliary fibrogenesis. Understanding the multiple molecular aspects of Nox in the development of PSC post-transplantation may help identify new drugs to prevent this disorder.

Introduction: Endothelial dysfunction (ED) results from impaired vascular endothelial cell function, disrupting key processes such as hemostasis, vascular tone regulation, vasculogenesis, angiogenesis, and inflammation. These processes are mediated by a complex signaling network involving hormones, cytokines, and chemokines. ED is recognized as a major contributor to the onset and progression of several micro- and macrovascular diseases, including diabetes. Our previous study demonstrated that the polyphenol Rosolic acid (RA) protects against ER stress-induced ED in vitro by activating nuclear factor erythroid 2-related factor 2 (Nrf2). Additionally, RA enhanced the proliferation and survival of pancreatic β-cells in a co-culture model with endothelial cells under ER stress conditions.

Methods: In this study, we investigated RA's protective effects against diabetes-induced ED using high-fat diet (HFD)-fed and streptozotocin-induced type-2 diabetic rat models. We evaluated RA's impact on vascular function and metabolic parameters in these models.

Results: RA significantly mitigated diabetes-induced ED in the aortic tissues of HFDfed diabetic Wistar rats. RA treatment improved glucose tolerance and reduced hyperlipidemia, showing efficacy comparable to the anti-diabetic drug Gliclazide. Moreover, RA elevated Nrf2 levels and its downstream target genes in aortic tissues while reducing ED markers such as ICAM-1, VCAM-1, and endothelin-1.

Conclusion: These findings highlight RA as a promising therapeutic agent for diabetes and its associated vascular complications, with potential for broader clinical applications.

In most advanced cancers, standard medical treatments are generally employed. With the emergence of Antibody-Drug Conjugates (ADCs), more optimal therapeutic methods have become available for treating tumors. ADC is composed of a monoclonal antibody that targets a specific antigen and a cytotoxic payload, which conjugates via the synthetic linkers. Therefore, ADC combines the accurate targeting of monoclonal antibodies with the potent efficacy of cytotoxic chemotherapy drugs while circumventing systemic toxicity. Besides, the epidermal growth factor receptor (EGFR) family, expressing differently between tumors and normal tissues, is one of the most frequently targeted antigens for ADC therapy, which mainly encompasses EGFR1/ErbB1, human epidermal growth factor receptor 2/ epidermal growth factor receptor 2 (HER2/ErbB2), HER3/ErbB3, and HER4/ErbB4. In contrast to other targets, HER3 stands out as a promising one, closely associated with the pathogenesis of treatment resistance in several cancers. Moreover, solid tumors, which are more prevalent than hematological malignancies, present a vast field of opportunities for the development of HER3-targeting ADCs. However, research on HER3-targeting ADCs treating solid tumors remains insufficient. Therefore, it is imperative for researchers to gather more clinical trial data and continue to elucidate the efficacy and safety of HER3-ADCs in solid tumors. This review summarizes recent advances and future potentials, aiming to provide insights into targeted therapy. We hope that this review will provide useful information to physicians in the field.

Introduction: Internal or external stress can induce cellular senescence, which reduces cell division. These metabolically active cells contribute to medication resistance. We examined the potential for edaravone (Eda) to cause apoptosis in dasatinib (Das)-induced senescent gastric adenocarcinoma cells (AGS). Our goal was to develop a new stomach cancer treatment.

Method: All Eda doses evaluated were nontoxic to cells. Das decreased AGS cell survival in a dose-dependent manner. The study found that Das (5-10 μM) and Eda (100 μM) caused cell senescence in AGS cells. This was shown by increased β-galactosidase enzyme activity and reactive oxygen species levels and decreased telomerase enzyme activity. These are the biggest signs of aging.

Results: This combination therapy also upregulated the expression of cell-senescence genes p53, p16, p21, and p38. This resulted in increased expression of inflammation genes such as TNF-α, IL-1β, and IL-6.

Conclusion: The scratch assay showed that this combination medication down-regulated the cell migration-regulating MMP2 gene. Both Das and Eda decreased AGS cell proliferation, suggesting treatment with Eda may prevent metastasis.

Osteoporosis, a metabolic disorder distinguished by decreased bone density and degradation of bone tissue microarchitecture, is a silent disease that evolves without any clinical symptoms or signs. An individual may not be aware of osteoporosis until a fracture occurs. The lifetime risk of osteoporosis is estimated to be between 10 and 20%. The disease can have intrinsic causes, like genetic predisposition, aging, and lack of sex hormones. However, it can also occur secondary to calcium and vitamin D deficiencies due to the influence of various factors. With a global increase in osteoporotic fractures, there is a need for macro-level and micro-level interventions to prevent and treat osteoporosis and its complications. This review highlights the crucial role of various biomolecules in diagnosing and managing osteoporosis and emphasizes the importance of further research in the field.

Background: The interplay between dietary habits and the development of Diverticular Disease (DD) has long been a subject of vibrant debate.

Objective: Utilizing Mendelian Randomization (MR), this study aims to meticulously examine the causal dynamics at play.

Methods: The foundation for the Genome-Wide Association Studies (GWAS) on DD was established using a dataset from the FinnGen consortium, encompassing 33,619 patients and 329,381 control participants. Data on 18 dietary habits and DD for the validation cohort were procured from the UK Biobank. An MR analysis was executed to delve into the causal relationship between dietary habits and DD, adhering to a rigorous Bonferroni correction threshold of 3.00E-03. Our main analysis method was the Inverse Variance Weighted (IVW) approach. To improve the accuracy and reliability of our study, we also conducted heterogeneity analysis, tests for horizontal pleiotropy, outlier identification, and "leave-one-out" sensitivity analysis.

Results: Our analysis unearthed a potential causal association between the consumption of dried fruits and a lower risk of developing DD (IVW: odds ratio (OR) 0.372, 95% confidence interval (CI) 0.272 - 0.509, p = 5.79E-10), a finding that was corroborated in the validation cohort (IVW: OR 0.975, 95% CI 0.961 - 0.990, p = 1.04E-03). Conversely, our results do not substantiate a causal link between the consumption of alcohol, dietary fiber, and red meat and the risk of DD.

Conclusion: Our detailed MR analyses show that eating dried fruit lowers the risk of DD, providing strong support for prevention and treatment approaches for DD.

The melanoma incidence has been increasing over the past three decades, with a disproportionately high fraction of in situ tumors. The diagnosis of melanoma at its earliest stages can be challenging. The detectability of tumor melanocytes in the dermis is of key importance for distinguishing in situ from invasive melanomas. In this review, a total of 475 melanomas diagnosed as in situ tumors by hematoxylin and eosin staining were analyzed. This diagnosis was confirmed for 68% of cases, but 15% of in situ melanomas were reassessed as invasive lesions using immunohistochemistry. The cases were upstaged by Melan-A/Mart-1, S-100, and SOX-10 with frequencies of 14.6%, 11.7%, and 10.8%, respectively. Whereas, the diagnosis of in situ melanoma was confirmed by SOX-10, Melan-A/Mart-1, and S-100 in 81.4%, 63.8%, and 59.1% of cases, respectively. Moreover, the analysis of immunohistochemical detectability of melanocyte markers in different types of dermal cells was carried out for 574 various skin lesions. The stainings of S-100, SOX-10, MITF, and PRAME in fibroblasts and histiocytes, as well as Melan-A/Mart-1, HMB-45, and MITF in melanophages, were noted. The diagnosis of in situ melanoma based on hematoxylin and eosin staining is confirmed by immunohistochemistry in most cases. However, some in situ tumors become reassessed as invasive malignancies. Although none of the currently used melanocyte markers is absolutely specific, simultaneous analysis of nuclear SOX-10 and cytoplasmic Melan-A/Mart-1 stainings can support the diagnosis. However, immunohistochemistry remains an auxiliary tool, and the results should be analyzed in association with the cytomorphological features.

Introduction: This work provides preclinical in vitro studies of an innovative antimicrobial agent named pyridosept, belonging to the quaternary bis-ammonium salts and synthesized on the base of pyridoxine. Since the wide spread of pathogens with tolerance to both antibiotics and antiseptics challenges the development of new antimicrobials providing high efficiency against fungi and microorganisms with multiple resistance.

Method: This work presents in vitro studies of pyridosept, such as antibacterial and anti-fungal activities (determination of minimal inhibitory concentration and quantitative suspension test method), as well as antibacterial activity of metal surface test, sporicidal and spermicidal activities, formation of resistance (to bacteria and fungi), Skin-PAMPA(study of membrane transdermal permeability), mutagenicity assays (in Ames test and OS-chromotest), cytotoxicity (MTT-assay) and comet assay in human skin fibroblasts.

Results: Pyridosept demonstrates advantageous antibacterial and antifungal activity in both suspension and metal surface tests; it has anti-SARS-CoV-2, spermicidal and sporicidal activities (comparable to chlorhexidine digluconate). On the other hand, it demonstrates a low frequency of bacterial resistance development (no more than 2-4-fold in-crease of the MIC in 30 passages, with MIC values fluctuating within 1-8 μg/ml for Gram-positive bacteria and 4-32 μg/ml for Gram-negative bacteria) and membrane transdermal permeability (Skin-PAMPA, 500-fold less compared to progesterone). While cytotoxicity (in MTT- and comet assay) of pyridosept is comparable with those for bezalkonium chloride and chlorhexidine, our results suggest that pyridosept represents an advantageous structure for the design of new antiseptics.

Conclusion: The information obtained during the studies demonstrated that pyridosept has a good efficacy and safety profile, which allows us to consider it as a potential anti-septic and disinfectant, for which it is necessary to conduct additional in vivo studies.

Background: The precise function of DDX59 Antisense RNA 1 (DDX59- AS1) in lung adenocarcinoma (LUAD) has yet to be fully elucidated.

Objective: This study uses bioinformatics analysis and experimental validation to investigate the association between DDX59-AS1 and LUAD.

Methods: This study uses statistical analysis and database interrogation to investigate the potential association between DDX59-AS1 expression and various clinical characteristics, prognostic factors, regulatory networks, and immune infiltration in LUAD. The quantification of DDX59-AS1 expression in LUAD cell lines is conducted through the use of quantitative real-time polymerase chain reaction (qRT-PCR).

Results: DDX59-AS1 showed significantly elevated levels of expression in patients with LUAD. High levels of DDX59-AS1 expression were found to be significantly associated with poorer overall survival (OS) in patients with LUAD (p = 0.024). Furthermore, an independent correlation was observed between high DDX59-AS1 expression (p = 0.037) and OS in LUAD patients. DDX59-AS1 was found to be involved in various pathways, including glutathione metabolism, proteasome function, and the cytosolic DNA sensing pathway, among others. A significant correlation was observed between the expression levels of DDX59-AS1 and immune cell infiltration in the context of LUAD. Notably, elevated expression of DDX59-AS1 was observed in LUAD cell lines compared to the non-cancerous Beas-2B cell line.

Conclusion: A significant correlation was observed between elevated DDX59-AS1 expression in patients with LUAD and adverse prognosis, alongside increased immune infiltration. These results indicate that DDX59-AS1 may function as a prognostic marker for LUAD and a potential predictor of immunotherapy response.

Curcumin, a natural polyphenolic compound found in turmeric, has garnered increasing research interest due to its potential health benefits, particularly in the context of the rising global prevalence of metabolic syndrome (MetS). With MetS affecting a significant portion of the global population and serving as a precursor to chronic diseases, such as type 2 diabetes and cardiovascular diseases, identifying effective, accessible, and safe interventions has become a critical public health priority. This review explores curcumin's role in regulating gut microbiota composition, enhancing intestinal barrier function, and reducing inflammation, which can collectively improve key components of MetS, such as hyperglycemia, dyslipidemia, obesity, and hypertension. Supplementation with curcumin has shown promising results in improving metabolic health by promoting the production of short-chain fatty acids (SCFAs), such as butyric and propionic acids. These effects may protect against dyslipidemia and reduce the risk of chronic conditions. Furthermore, curcumin has demonstrated potential in reducing hypertension through various mechanisms, including inflammation reduction, modulation of lipopolysaccharide (LPS) production, activation of G-protein-coupled receptor 43 (GPR43), and increased levels of SCFAs. Given the significant public health implications of MetS, understanding curcumin's impact on gut microbiota presents an opportunity for developing novel therapeutic strategies that address this urgent health challenge. Despite its promise, further research is necessary to fully comprehend the underlying mechanisms involved. Additionally, determining the optimal dosage and duration of curcumin supplementation for achieving its effects on metabolic syndrome is crucial for future therapeutic applications. This review highlights curcumin's potential as a natural compound with multifaceted health benefits, particularly in the context of metabolic syndrome and its associated complications, emphasizing the pressing need for clinical studies to validate findings and inform evidence-based therapeutic applications.