Current pharmaceutical design最新文献

Ulcerative Colitis (UC) known as a sub-category of Inflammatory Bowel Diseases (IBD) is a longterm condition that causes inflammation, irritation, and ulcers in the colon and rectum. Though the precise pathogenesis of UC is not fully understood yet, impaired immune responses and imbalanced intestinal microbiome composition have been regarded as two main key players in colitis pathobiology. As conventional treatments are challenged with limitations and side effects, finding a new therapeutic approach has gained increasing attention. Probiotic bacteria with multifunctional health-promoting properties have been considered novel therapeutic options. There is strong evidence indicating that probiotics exert their therapeutic effects mostly by regulating immune system responses and restoring gut microbiome homeostasis. These results validate the rationale behind the clinical application of probiotics in UC management whether prescribed alone or in combination with conventional therapy. This article explores the pathogenesis of UC, concentrating on the influence of immune dysregulation and intestinal microbiome imbalances. Also, it reviews recent in vitro, in vivo, and clinical studies that have demonstrated the efficacy of Lactobacillus species in decreasing UC symptoms by modifying immune responses, restoring gut microbiota balance, and promoting intestinal barrier function.

Introduction/objective: The current study aims to investigate the blood Hcy levels in patients with CAD and hypertension in Serbia, a country with a high incidence and mortality of both diseases.

Methods: The level of Hcy in the Serbian population was assessed in 123 patients with chronic coronary artery disease (CAD) and hypertension. There were 53 patients with chronic CAD and 70 patients with hypertension (HTA), but without CAD.

Results: The Hcy levels were high in both groups of patients (the mean Hcy level of 16.0 ± 7.0 μmol/L) without a statistical difference between the patients in the CAD (14.9 ± 7.3 μmol/L) and hypertension (16.7 ± 6.7 μmol/L) groups. Hypercholesterolemia was found in 81% of the patients with CAD and 92.0% of the patients with HTA, as a common concern across both clinical conditions. It was also found that not a single conventional risk factor (diabetes, hypertension, the smoking status, the family history of CAD, and hyperlipidemia) may individually influence Hcy levels. By contrast, the low levels of vitamin B12 may be related to the high levels of Hcy.

Conclusion: Given the fact that it is known that various factors interact and influence Hcy levels and associated cardiovascular risks, specific dietary habits, lifestyle and the other Serbia-specific possible factors were done.

Human Immunodeficiency Virus (HIV) has become an epidemic causing Acquired Immunodeficiency Syndrome (AIDS). Highly active antiretroviral therapy (HAART) consists of Nucleoside Reverse Transcriptase Inhibitors (NRTIS), Nucleotide Reverse Transcriptase Inhibitors (NtRTIS), and Non- Nucleoside Reverse Transcriptase Inhibitors (NNRTIS) with HIV Protease Inhibitors (HIV PIs). However, the emergence of resistant strains of NNRTIS necessitates the search for better HIV-1-RT inhibitors.

Methods: In this study, a series of novel imidazoles (SP01-SP30) was designed using molecular docking inside the non-nucleoside inhibitory binding pocket (NNIBP) of the HIV-1-RT (PDB ID-1RT2) using Glide v13.0.137, Autodock Vina, and FlexX v2.1.3. Prime MMGBSA was used to study the free energy of binding of the inhibitors with the target enzyme. Molecular dynamics simulation studies were carried out to discover the dynamic behavior of the protein as well as to unveil the role of the essential amino acids required for the better binding affinity of the inhibitor within the NNIBP of the enzyme. The QikProp software module of Schrodinger and online SwissADME were also used to evaluate the drug-likeliness of these compounds.

Results: The imidazole derivative SP08 is predicted to be the most promising design compound that can be considered for further synthetic exploitations to obtain a molecule with the highest therapeutic index against HIV-1-RT.

Conclusion: The results of the current study demonstrate the robustness of our in-silico drug design strategy that can be used for the discovery of novel HIV-1-RT inhibitors.

Protein engineering alters the polypeptide chain to obtain a novel protein with improved functional properties. This field constantly evolves with advanced in silico tools and techniques to design novel proteins and peptides. Rational incorporating mutations, unnatural amino acids, and post-translational modifications increases the applications of engineered proteins and peptides. It aids in developing drugs with maximum efficacy and minimum side effects. Currently, the engineering of peptides is gaining attention due to their high stability, binding specificity, less immunogenic, and reduced toxicity properties. Engineered peptides are potent candidates for drug development due to their high specificity and low cost of production compared with other biologics, including proteins and antibodies. Therefore, understanding the current perception of designing and engineering peptides with the help of currently available in silico tools is crucial. This review extensively studies various in silico tools available for protein engineering in the prospect of designing peptides as therapeutics, followed by in vitro aspects. Moreover, a discussion on the chemical synthesis and purification of peptides, a case study, and challenges are also incorporated.

Implementing lifestyle interventions as a primary prevention strategy is a cost-effective approach to reducing the occurrence of cancer, which is a significant contributor to illness and death globally. Recent advanced studies have uncovered the crucial role of nutrients in safeguarding women's health and preventing disorders. Genistein is an abundant isoflavonoid found in soybeans. Genistein functions as a chemotherapeutic drug against various forms of cancer, primarily by modifying apoptosis, the cell cycle, and angiogenesis and suppressing metastasis. Furthermore, Genistein has demonstrated diverse outcomes in women, contingent upon their physiological characteristics, such as being in the early or postmenopausal stages. The primary categories of gynecologic cancers are cervical, ovarian, uterine, vaginal, and vulvar cancers. Understanding the precise mechanism by which Genistein acts on ovarian cancer could contribute to the advancement of anti-breast cancer treatments, particularly in situations where no specific targeted therapies are currently known or accessible. Additional investigation into the molecular action of Genistein has the potential to facilitate the development of a plant-derived cancer medication that has fewer harmful effects. This research could also help overcome drug resistance and prevent the occurrence of ovarian cancers.

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Background: Vascular endothelial dysfunction is the initial factor involved in cardiovascular injury in patients with diabetes. Retinoic acid is involved in improving vascular complications in patients with diabetes, but its protective mechanism is still unclear. This study aimed to evaluate the effect and mechanism of All-Trans Retinoic Acid (ATRA) on endothelial dysfunction induced by diabetes.

Methods: In the present study, streptozotocin (STZ)-induced diabetic rats and high glucose (HG)-induced human umbilical vein endothelial cells (HUVECs) were observed, and the effects of ATRA on HG-induced endothelial dysfunction and ferroptosis were evaluated.

Results: ATRA treatment improved impaired vasorelaxation in diabetic aortas in an endothelium-dependent manner, and this effect was accompanied by an increase in the NO concentration and eNOS expression. Ferroptosis, characterized by lipid peroxidation and iron overload induced by HG, was improved by ATRA administration, and a ferroptosis inhibitor (ferrostatin-1, Fer-1) improved endothelial function to a similar extent as ATRA. In addition, the inactivation of phosphoinositol-3-kinase (PI3K)/protein kinases B (AKT) and Yes-Associated Protein (YAP) nuclear localization induced by HG were reversed by ATRA administration. Vascular ring relaxation experiments showed that PI3K/AKT activation and YAP inhibition had similar effects on ferroptosis and endothelial function. However, the vasodilative effect of retinoic acid was affected by PI3K/AKT inhibition, and the inhibitory effects of ATRA on ferroptosis and the improvement of endothelial function were dependent on the retinoic acid receptor.

Conclusion: ATRA could improve vascular endothelial dysfunction by inhibiting PI3K/AKT/YAP-mediated ferroptosis induced by HG, which provides a new idea for the treatment of vascular lesions in diabetes.

Inflammation is a universal response of mammalian tissue to harm, comprising reactions to injuries, pathogens, and foreign particles. Liver inflammation is commonly associated with hepatocyte necrosis and apoptosis. These forms of liver cell injury initiate a sequence of events independent of the etiological basis for the inflammation and can result in hepatic disorders. It is also common for liver cancer. This review fundamentally focuses on the molecular pathways involved in hepatic inflammation. This review aims to explore the molecular pathways involved in hepatic inflammation, focusing on arachidonic acid, NF-κB, MAPK, PI3K/Akt, and JAK/STAT pathways. It investigates active compounds in herbal plants and their pharmacological characteristics. The review proposes a unique therapeutic blueprint for managing hepatic inflammation and diseases by modifying these pathways with herbal remedies.

Drug Delivery Systems (DDS) have been developed to address the challenges associated with traditional drug delivery methods. These DDS aim to improve drug administration, enhance patient compliance, reduce side effects, and optimize target therapy. To achieve these goals, it is crucial to design DDS with optimal performance characteristics. The final properties of a DDS are determined by several factors that go into formulating a pharmaceutical preparation. Thus, optimizing these factors can lead to the ideal DDS formulation. Artificial Neural Networks (ANN) are computational models that mimic the function of biological neurons and neural networks and perform mathematical operations on inputs to generate outputs. ANN is widely used in medical sciences for modeling disease diagnosis and treatment, dose adjustment in combination therapy, medical education, and other fields. In the pharmaceutical sciences, ANN has gained significant attention for designing and optimizing pharmaceutical formulations. This article reviews the use of ANN in the design and optimization of pharmaceutical formulations, specifically DDS. Since DDS is highly diverse, different factors are examined for each type of DDS. These factors are considered independent and dependent parameters for each ANN model, and various examples are provided. By utilizing ANN, it is possible to establish the relationship between the formulation factors and the resulting DDS characteristics, ultimately leading to the development of optimized DDS.