Current pharmaceutical design最新文献

Purpose: This study aimed to explore whether Galangin (Gal) could improve cerebral Ischemia- reperfusion (I/R) injury by regulating astrocytes, and clarify its potential molecular mechanism.

Methods: An I/R injury model of rats was established using the Middle Cerebral Artery Occlusion/Reperfusion (MCAO/R) method, followed by the administration of Gal (25, 50, 100 mg/kg) via gavage for 14 consecutive days. Besides, astrocytes were isolated from the rats to construct an Oxygen-Glucose Deprivation/Re-oxygenation (OGD/R) cell model, with treatments of Gal or the Ras homolog gene family member A (RhoA)/Rho-associated Coiled-coil containing protein Kinase (ROCK) inhibitor Y-27632. Subsequently, the severity of nerve injury was assessed using the modified Neurological Severity Score (mNSS) test; behavioral disorders in I/R rats were observed through the open field and ladder-climbing tests. Pathological damages and neuron survival in the peri-infarct zone were examined by hematoxylin and eosin staining and NeuN staining, respectively. Additionally, immunofluorescence staining was employed to determine astrocyte polarization and TUNEL staining was carried out to measure the level of cell apoptosis; also, western blot was performed to detect the expression of proteins related to the RhoA/ROCK/LIM domain Kinase (LIMK) pathway.

Results: Gal significantly ameliorated the neurological and motor dysfunctions caused by I/R in rats, reduced pathological damage in the peri-infarct zone, and promoted neuronal survival. Additionally, Gal increased the number of A2 astrocytes, while it decreased the number of A1 astrocytes. In vitro experiments revealed that the effect of Gal was consistent with that of Y-27632. Additionally, Gal significantly enhanced the survival of OGD/R cells, increased the number of A2 astrocytes, and inhibited the expression of proteins associated with the RhoA/ROCK pathway.

Conclusion: Gal could reduce the level of apoptosis, promote the polarization of A2 astrocytes, and improve cerebral I/R injury, and its mechanism may be related to the inhibition of the RhoA/ROCK pathway.

Nanoparticles, defined as particles ranging from 1 to 100 nanometers in size, are revolutionizing the approach to combating bacterial infections amid a backdrop of escalating antibiotic resistance. Bacterial infections remain a formidable global health challenge, causing millions of deaths annually and encompassing a spectrum from common illnesses like Strep throat to severe diseases such as tuberculosis and pneumonia. The misuse of antibiotics has precipitated the rise of resistant strains like methicillin-resistant Staphylococcus aureus (MRSA), multidrug-resistant Mycobacterium tuberculosis (MDR-TB), and carbapenem-resistant Enterobacteriaceae (CRE), underscoring the critical need for innovative therapeutic strategies. Nanotechnology offers a promising avenue in this crisis. Nanoparticles possess unique physical and chemical properties that distinguish them from traditional antibiotics. Their high surface area to volume ratio, ability to be functionalized with various molecules, and distinctive optical, electronic, and magnetic characteristics enable them to exert potent antibacterial effects. Mechanisms include physical disruption of bacterial membranes, generation of Reactive Oxygen Species (ROS), and release of metal ions that disrupt bacterial metabolism. Moreover, nanoparticles penetrate biofilms and bacterial cell walls more effectively than conventional antibiotics and can be precisely targeted to minimize off-target effects. Crucially, nanoparticles mitigate the development of bacterial resistance by leveraging multiple simultaneous mechanisms of action, which make it challenging for bacteria to adapt through single genetic mutations. As research advances, nanotechnology holds immense promise in transforming antibacterial treatments, offering effective solutions that address current infections and combat antibiotic resistance globally. This review provides a comprehensive overview of nanoparticle applications in antibacterial therapies, highlighting their mechanisms, advantages over antibiotics, and future directions in healthcare innovation.

The effective and prompt treatment of wounds remains a significant challenge in clinical settings. Consequently, recent investigations have led to the development of a novel wound dressing production designed to expedite the process of wound healing with minimal adverse complications. Chitosan, identified as a natural biopolymer, emerges as an appealing option for fabricating environmentally friendly dressings due to its biologically degradable, nonpoisonous, and inherent antimicrobial properties. Concurrently, graphene oxide has garnered attention from researchers as an economical, biocompatible material with non-toxic attributes for applications in wound healing. Chitosan (CS) has been extensively studied in agglutination owing to its advantageous properties, such as Non-toxicity biological compatibility, degradability, and facilitation of collagen precipitation. Nonetheless, its limited Medium mechanical and antibacterial strength characteristics impede its widespread clinical application. In addressing these shortcomings, numerous researchers have embraced nanotechnology, specifically incorporating Metal nanoparticles (MNPs), to enhance the mechanical power and targeted germicide features of chitosan multistructures, yielding hopeful outcomes. Additionally, chitosan is a decreasing factor for MNPs, contributing to reduced cytotoxicity. Consequently, the combination of CS with MNPs manifests antibacterial function, superior mechanical power, and anti-inflammatory features, holding significant potential to expedite wound healing. This study delves into Based on chitosan graphene materials in the context of wound healing.

In recent years, immunotherapy, namely immune checkpoint inhibitor therapy, has significantly transformed the approach to treating various forms of cancer. Simultaneously, the adoption of clinical oncology has been sluggish due to the exorbitant expense of therapy, the adverse effects experienced by patients, and the inconsistency in treatment response among individuals. As a reaction, individualized methods utilizing predictive biomarkers have arisen as novel strategies for categorizing patients to achieve successful immunotherapy. Recently, the identification and examination of circulating tumor cells (CTCs) have gained attention as predictive indicators for the treatment of cancer patients undergoing chemotherapy and for personalized targeted therapy. CTCs have been found to exhibit immunological checkpoints in several types of solid tumors, which has contributed to our understanding of managing cancer immunotherapy. Circulating tumor cells (CTCs) present in the bloodstream have a crucial function in the formation of metastases. Nevertheless, the practical usefulness of existing CTC tests is mostly restricted by methodological limitations.

Aims: To improve the understanding of pharmacokinetic/pharmacodynamic (PK/PD) profiles of apixaban, supporting personalised drug prescriptions for future patients.

Background: Genetic as well as nongenetic factors can affect the predictable PK and PD characteristics of apixaban.

Objective: Establish a integrated popPK/PD model that adjusts for critical genetic variant.

Methods: The integrated PK/PD models was characterized on the basis of PK (apixaban blood concentration) and PD (prothrombin time (PT), activated partial thromboplastin time (APTT), and anti-FXa activity) data from 181 healthy Chinese volunteers. Other investigated covariate variables included: Meaningful intrinsic and extraneous determinants, correlated markers (ABCG2, F13A1, C3, etc.). A total of 2877 PK concentration observations were included in the modeling dataset.

Results: The PK model of apixaban is adopted by single compartment model with first-order oral absorption. The estimated values of total clearance rate (CL/F), apparent distribution volume (V/F), and absorption rate constant (KA) in the final model are 3.37 l/h, 28.2 l, and 0.781 l/h, respectively. The PK model includes significance covariates such as FOOD, RBC, WT, and gene (ABCG2). The PD model of apixaban is adopted by a linear direct effect model with additive error, which was used to describe the relationship between markers such as APTT, PT, anti-FXa, versus plasma concentration. PK simulation within the modelled dose range is similar to clinical real date, while PD simulation results also show that the simulated exposure parameters is within the range of the literature.

Conclusion: We established a comprehensive PK/PD model and used it to simulate markers level such as APTT, PT, and anti-FXa of apixaban. Individual predictive values with a dose of 2.5 mg are basically within the expected recommended range.

Objective: This study aimed to preliminary explore the molecular mechanisms of Houttuynia cordata Thunb. (H. cordata; Saururaceae) in treating non-small cell lung cancer (NSCLC), with the goal of screening drug potential targets for clinical drug development.

Methods: This study employed a multi-omics and multi-source data integration approach to identify potential therapeutic targets of H. cordata against NSCLC from the TCMSP database, GEO database, BioGPS database, Metascape database, and others. Meanwhile, target localization was performed, and its possible mechanisms of action were predicted. Furthermore, dynamics simulations and molecular docking were used for verification. Multiomics analysis was used to confirm the selected key genes' efficacy in treating NSCLC.

Results: A total of 31 potential therapeutic targets, 8 key genes, and 5 core components of H. cordata against NSCLC were screened out. These potential therapeutic targets played a therapeutic role mainly by regulating lipid and atherosclerosis, the TNF signaling pathway, the IL-17 signaling pathway, and others. Molecular docking indicated a stable combination between MMP9 and quercetin. Finally, through multi-omics analysis, it was found that the expression of some key genes was closely related not only to the progression and prognosis of NSCLC but also to the level of immune infiltration.

Conclusion: Through comprehensive network pharmacology and multi-omics analysis, this study predicts that the core components of H. cordata play a role in treating NSCLC by regulating lipid and atherosclerosis, as well as the TNF signaling pathway. Among them, the anti-NSCLC activity of isoramanone is reported for the first time.

Alzheimer's disease (AD) is a gradual degenerative ailment of the nervous system that is marked by the buildup of amyloid-β plaques and neurofibrillary tangles. This accumulation causes problems with the connections between nerve cells and the loss of these cells. This review paper explores the complex pathophysiology of AD, analyzing the neuronal loss reported in key brain regions like the entorhinal cortex, amygdala, hippocampus, and cortical association areas. The text also examines subcortical nuclei participation, such as the noradrenergic locus coeruleus, serotonergic dorsal raphe, and cholinergic basal nucleus. Also, this review discusses the importance of tau protein hyperphosphorylation, oxidative stress, and metal ion dysregulation in the evolution of AD. Moreover, it explores the cholinergic theory and the influence of the APOE (apolipoprotein E) genotype on the effectiveness of therapy. This article thoroughly summarizes the current knowledge on AD, including its clinical symptoms and possible treatment approaches, by combining several theories and new targets. The study highlights the connection between the degree of tangle development and the severity of dementia, underlining the need for creative methods to tackle the complex difficulties of discovering drugs for AD.

Background: Several previous studies indicated that melatonin supplementation may positively affect glycemic control in patients with diabetes. However, research on the influence of melatonin supplementation on glycemic parameters remains inconclusive. Therefore, this study aimed to assess the impacts of melatonin supplementation on glycemic parameters in type 2 diabetes by conducting a meta-analysis.

Methods: PubMed/Medline, Scopus, and Web of Science were comprehensively searched until July 2024 to find eligible randomized clinical trials (RCTs). The overall effect sizes were estimated by using the randomeffect model and presented as weighted mean differences (WMD) with a 95% confidence interval (CI). Furthermore, the heterogeneity among the included trials was assessed by performing the Cochran Q test and interpreted based on the I² statistic.

Results: Of the 1361 papers, eight eligible RCTs were included in this meta-analysis. Our findings indicated that melatonin supplementation significantly decreased fasting blood glucose (WMD = -12.65 mg/dl; 95% CI: -20.38, -4.92; P = 0.001), insulin (WMD = -2.30 μU/ml; 95% CI: -3.20, -1.40; P < 0.001), hemoglobin A1c (WMD = -0.79 %; 95% CI: -1.28, -0.29; P = 0.002), and HOMA-IR (WMD, -0.83; 95% CI: -1.59 to - 0.07; P = 0.03).

Conclusion: According to the results of the current meta-analysis, persons with type 2 diabetes who supplement with melatonin had improved glycemic control. It looks that supplementing with melatonin at a dose exceeding 6 mg daily for over a period of 12 weeks may be more successful than other forms of intervention. Nevertheless, further research with larger sample sizes is necessary to draw definitive conclusions.

Breast Cancer stands on the second position in the world in being common and women happen to have it with high rate of about five-folds around the world. The causes of occurrence can matter with different humans be it external factors or the internal genetic ones. Breast cancer is primarily driven by mutations in the BRCA1 and BRCA2 susceptibility genes. These BC susceptibility genes encode proteins critical for DNA homologous recombination repair (HRR). Poly (ADP ribose) polymerases (PARP) are the essential enzymes involved in the repairing of the damaged DNA. So the inhibition of these inhibitors can be considered as the promising strategy for targeting cancers with defective damage in the deoxyribonucleic acid. Olaparib and talazoparib are PARP inhibitors (PARPi) are being employed for the monotherapies in case of the deleterious germline HER2-negative and BRCA-mutated breast cancer. The potency of PARP for trapping on DNA and causes cytotoxicity may have difference in the safety and efficacy with the PARPi. The PARPi have been found its place in the all different types of Breast Cancers and have shown potential benefits. The purpose of this review is to provide an update on the oral poly(ADP-ribose) polymerase (PARP)inhibitors for the improvement in the treatment and management of Breast Cancer.