Current pharmaceutical design最新文献

Background: PGK1 and PKM2 are glycolytic enzymes, and their expression is upregulated in cancer cells. STAT3 is a transcription factor implicated in breast cancer progression and chemoresistance. Researchers worldwide continue to explore how targeting genes might lead to more effective anti-breast cancer therapies. The present study aims to synthesize quinazolines containing caffeoyl moiety for developing innovative anticancer agents against the human breast cancer cell line (MCF-7).

Methods: A new quinazoline 2 was synthesized by reacting caffeic acid with 5-amino-phenylpyrazole carboxylate 1 in the presence of PCl3. Compound 2 reacted with NH2NH2.H2O to produce compound 3 through cyclo-condensation. Apoptosis and necrosis as well as inhibition activity compounds 2 and 3 against PGK1, and PKM2 were evaluated. The effect of compounds 2 and 3 on the levels of GSH, GR, SOD, GPx, CAT, MDA, Bax, Bcl-2, caspase-3, P53 and VEGF levels as well as PGK1, PKM2 and STAT3 gene expression were estimated in MCF-7 tumor cells.

Results: The viability of MCF-7 cells was reduced to 22.42% and 45.86% after incubation with compounds 2 and 3 for 48 hours, respectively. The IC50 values for compounds 2 and 3 are 62.05 μg/mL and 16.73 μg/mL. Furthermore, compound 3 exhibited more significant apoptosis and necrosis than compound 2. IC50 values of compound 2 against PGK1, and PKM2 at interval concentration equals 1.04, and 0.32 μM/mL, respectively, after 210 minutes of incubation. Moreover, compound 3 were revealed strong inhibition of PGK1, and PKM2 with IC50 values equals 0.55 and 0.21 μg/mL, respectively after 210 minutes of incubation. Our results proved that the incubation of compounds 2 and 3 with MCF-7 cells increased the levels of apoptotic proteins, elevated MDA, Bax, caspase-3 and P53 levels, depleted GSH, GR, SOD, GPx, CAT, Bcl-2 levels and downregulated the levels of STAT3, PGK1, and PKM2 gene expression significantly. Our In-silico results proved that compound 2 showed a stronger estimated binding affinity with a ΔG of -7.2, -7.5, and - 7.9 kcal/mol., respectively towards PGK1, PKM2 and STAT3 proteins. Also, compound 3 exhibits a strong binding affinity with ΔG of -7.9, -8.5, and - 8.7 kcal/mol., towards PGK1, PKM2 and STAT3 proteins.

Conclusion: The results show that compounds 2 and 3 induce apoptotic activity by blocking the PGK1- PKM2-STAT3 signaling pathway. The present investigation opens exciting possibilities for developing innovative new anticancer quinazolines bearing caffeoyl moiety.

The escalating prevalence of type 2 diabetes (T2DM) has emerged as a global public health dilemma. This ailment is associated with insulin resistance and heightened blood glucose concentrations. Despite the rapid advancements in modern medicine, where a regimen of medications is employed to manage blood glucose effectively, certain treatments manifest significant adverse reactions. Recent studies have elucidated the pivotal role of gallotannins in mitigating inflammation and obesity, potentially reducing the prevalence of obesity-linked T2DM. Gallotannins, defined by their glycosidic cores and galloyl groups, are ubiquitously present in plants, playing diverse biological functions and constituting a significant segment of water-soluble polyphenolic compounds within the heterogeneous tannins group. The structural attributes of gallotannins are instrumental in dictating their myriad biological activities. Owing to their abundance of hydroxyl groups (-OH) and complex macromolecular structure, gallotannins exhibit an array of pro-physiological properties, including antioxidant, anti-inflammatory, antidiabetic, protein-precipitating, and antibacterial effects. Extensive research demonstrates that gallotannins specifically obstruct α-amylase and pancreatic lipase, enhance insulin sensitivity, modulate short-chain fatty acid production, alleviate oxidative stress, exhibit anti-inflammatory properties, and influence the gut microbiota, collectively contributing to their antidiabetic efficacy. This review aims to consolidate and scrutinize the extant literature on gallotannins to furnish essential insights for their potential application in diabetes management.

Background: IgA nephropathy (IgAN) is the most prevalent primary glomerulonephritis globally and has a high propensity to develop into end-stage renal disease (ESRD). Hydroxychloroquine has been proven to reduce proteinuria in IgAN patients, but the precise mechanism remains unclear. Therefore, network pharmacology was used to investigate the mechanism.

Methods: PubChem and SwissADME databases were utilized to acquire the structure of hydroxychloroquine. The SwissTargetPrediction, PharmMapper, DrugBank, TargetNet, and BATMAN-TCM databases were then utilized to obtain the targets. The target genes related to IgAN were then gathered from the databases, which included GeneCards, PHARMGKB, DrugBank, OMIM, and DisGeNET. Common targets were obtained by UniProt. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to define the main molecular mechanisms and pathways. Furthermore, a protein-protein interaction (PPI) network was constructed using the STRING tool, and the core targets were obtained by Cytoscape. Finally, molecular docking between the core targets and hydroxychloroquine was performed.

Results: 167 common target genes were acquired by overlapping. The core targets were TNF, ALB, IL1B, JUN, FOS, SRC, and MMP9. The GO and KEGG results showed the targets to be related to the production of inflammatory cytokines and chemokines and were engaged in the toll-like receptor (TLR) signaling pathway. At the same time, the molecular docking results showed that the core targets all combined with hydroxychloroquine closely.

Conclusion: This study proved that hydroxychloroquine may treat IgAN through the TLR signaling pathway, and the restraint of TNF, TLR, IL1B, and JUN may be essential for the treatment.

Alzheimer's disease (AD) remains one of the hardest neurodegenerative diseases to treat due to its enduring cognitive deterioration and memory loss. Despite extensive research, few viable treatment approaches have been found; these are mostly due to several barriers, such as the disease's complex biology, limited pharmaceutical efficacy, and the BBB. This presentation discusses current strategies for addressing these therapeutic barriers to enhance AD treatment. Innovative drug delivery methods including liposomes, exosomes, and nanoparticles may be able to pass the blood-brain barrier and allow medicine to enter specific brain regions. These innovative strategies of medicine distribution reduce systemic side effects by improving absorption. Moreover, the development of disease-modifying treatments that target tau protein tangles, amyloid-beta plaques, and neuroinflammation offers the chance to influence the course of the illness rather than only treat its symptoms. Furthermore, gene therapy and CRISPR-Cas9 technologies have surfaced as potentially groundbreaking methods for addressing the underlying genetic defects associated with AD. Furthermore, novel approaches to patient care may involve the utilization of existing medications having neuroprotective properties, such as those for diabetes and cardiovascular conditions. Furthermore, biomarker research and personalized medicine have made individualized therapy approaches possible, ensuring that patients receive the best care possible based on their unique genetic and molecular profiles.

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.