Current Pharmaceutical Design - Volume 28, Issue 23, 2022

Gliomas are the most common and malignant primary tumors of the central nervous system (CNS). Glioblastomas are the most malignant and aggressive form of primary brain tumors and account for the majority of brain tumor-related deaths. The current standard treatment for gliomas is surgical resection supplemented by postoperative chemotherapy. Platinum drugs are a class of chemotherapeutic drugs that affect the cell cycle, and the main site of action is the DNA of cells, which are common chemotherapeutic drugs in clinical practice. Chemotherapy with platinum drugs such as cisplatin, carboplatin, oxaliplatin, or a combination thereof is used to treat a variety of tumors. However, the results of gliomas chemotherapy are unsatisfactory, and resistance to platinum drugs is one of the important reasons. The resistance of gliomas to platinum drugs is the result of a combination of influencing factors. Decreased intracellular drug concentration, enhanced function of cell processing active products, enhanced repair ability of cellular DNA damage, and blockage of related apoptosis pathways play an important role in it. It is known that the pathogenic properties of glioma cells and the response of glioma towards platinum-based drugs are strongly influenced by non-coding RNAs, particularly, by microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). miRNAs and lncRNAs control drug sensitivity and the development of tumor resistance towards platinum drugs. This mini-review summarizes the resistance mechanisms of gliomas to platinum drugs, as well as molecules and therapies that can improve the sensitivity of gliomas to platinum drugs.

Background: For the nanoparticulate system and the transportation of cellular elements for the fabrication of microelectronic devices, self-assembled nanoclusters arrange the components into an organized structure. Nanoclusters reduce transcytosis and increase endocytosis in intestinal mucin to strengthen the retrograde pathway that helps for delivery of actives to the Golgi apparatus. Objectives: This review article focuses on the self-assembled nanoclusters for cellular transportation, applications of self-assembled structures in the delivery of essential elements like using a peptide in targeted and stimuli-responsive drug delivery systems, and self-assembly of tocopherol nanoclusters that promote vitamin E delivery across the endothelial barrier. Methods: Current innovation in the self-assembly of peptides includes the formation of nanostructures like vesicles, fibers, and rod-coil in various applications of wound healing, tissue engineering, atherosclerosis treatment, sensing heavy metals from biological and environmental samples, and advanced drug delivery. Results: Self-assembled biodegradable nanoclusters are used as biomimetic structures for a synergistic effect. For temperature-triggered drug release nanoclusters, modifications in preparation methods, such as the inclusion of a copolymer, are made. Conclusion: Green synthesis of nanoclusters, nanocluster-based biosensors, and artificial intelligence are future concepts in the manufacturing and prevention of toxicity in humans.

Background: Nanosponge, as a carrier for the skin delivery system for drugs, plays a vital role. It not only serves to administer the drug to the targeted layer of skin but also increases the drug retention and deposition on the skin. Objective: In this review, we aim to highlight the effects of several processes and formulation variables prompting the characteristics of various nanosponges for the delivery of drugs into/ across the skin. Methods: In the present review article, the overall introduction of nanosponges, their preparation, characteristic features, advantages, disadvantages, and factors affecting their preparation, are covered. Furthermore, an elaborative description of nanosponges for skin delivery and its toxicological perspective with some referential examples of nanosponge drugs has also been deliberated here. Results: Factors associated with the formation of nanosponges can directly or indirectly affect its efficacy in the skin delivery of drugs. These nanoforms are efficient in delivering the drugs which possess lower aqueous solubility, therefore, the aqueous solubility of drugs possessing a narrow therapeutic window can easily be enhanced. It also helps in achieving targeted drug delivery, controlled release of drugs, increases bioavailability, reduces drug toxicity, decreases drug degradation, and many more. Conclusion: Nanosponges have been identified as potential drug delivery carriers into as well as across skin. Delivery of biologics such as vaccines, enzymes, peptides, proteins, and antibodies, is also gaining attention in the recent past.

In the developed world, cancer is the most common cause of death. Among the 36 human genes of the RAS family, KRAS, NRAS, and HRAS play a prominent role in human cancer. KRAS belongs to the Ras superfamily of proteins and is a small GTPase signal transduction protein. Among the RAS isoform, KRAS is the dominant mutant that induces approximately 86% of the RAS mutations. The most frequently mutated KRAS isoform is KRAS4B. About 90% of pancreatic cancer, 30-40% of colon cancer, and 15 to 20% of lung cancers are caused by mutations KRAS4B isoform. Liver cancer, bladder cancer, breast cancer, and myeloid leukaemia are also caused by mutations in KRAS but are rare. The FDA has recently approved sotorasib for the treatement of KRASG12C-mutated advanced non-small cell lung cancer (NSCLC) patients. However, no FDAapproved drugs are available for other KRAS-driven cancer. As the KRAS proteins lack a druggable pocket accessible to the chemical inhibitors, the cancer-causing mutant proteins are almost identical to their essential wild-type counterparts. Therefore, they are considered undruggable. The new insights into the structure and function of RAS have changed this understanding and encouraged the development of many drug candidates. This review provides information about the different strategies for targeting KRAS, a challenging drug target that might be valuable for the scientific community.

Background: Direct oral anticoagulants (DOACs) are the guideline-recommended therapy for some hypercoagulable diseases but are used off-label for left ventricular thrombus (LVT) owing to a paucity of evidence. We performed a meta-analysis to assess the safety and efficacy of DOACs compared with vitamin K antagonists (VKAs) for LVT treatment. Methods: We comprehensively searched PubMed, EMBASE, Cochrane Library, and Web of Science databases for studies that compared DOACs with VKAs for LVT treatment. Outcome indicators included stroke or systemic embolism (SSE), thrombus resolution, bleeding, and death. The Newcastle-Ottawa scale was used to evaluate the quality of included studies. Data were analyzed using Review Manager 5.3, and the meta-analysis is registered at PROSPERO (CRD 42020211376). Results: We included 12 observational studies (n = 2262 patients). SSE was similar for DOACs and VKAs groups (odds ratio (OR) = 1.01, 95% confidence interval (CI) 0.66-1.54, P = 0.95). For thrombus resolution, DOACs were not significantly different to VKAs (OR = 1.15, 95% CI 0.54-2.45, P = 0.71). DOACs and VKAs had a similar bleeding risk (OR = 0.78, 95% CI 0.45-1.35, P = 0.37). DOACs and VKAs groups had a comparable mortality (OR = 0.91, 95% CI 0.50-1.65, P = 0.76). Subgroup analysis showed that post-acute myocardial infarction (AMI) patients using DOACs had a lower risk of SSE (OR = 0.24, 95% CI 0.07-0.87, P = 0.03) and bleeding (OR = 0.38, 95% CI 0.18-0.81, P = 0.01). Conclusion: DOACs and VKAs showed no difference in the safety and efficacy of patients with LVT. DOACs might be superior to VKAs for LVT treatment in post-AMI patients.

Background and Aims: Curcumin is one of the most commonly used indigenous molecules endowed with various shielding functionalities that protect the liver. In the present research, we aimed to investigate the effects of curcumin on metabolic factors and body mass index (BMI) in patients with non-alcoholic fatty liver disease (NAFLD) using a meta-analysis of randomized, controlled trials. Methods: Online databases PubMed, Embase, Web of Science, and Science Direct were searched until April 2021 to identify eligible articles. Fourteen trials were included. Results: The results showed that curcumin consumption can significantly reduce AST (-0.35, (-0.57 to -0.14)), total cholesterol (-0.81, (-1.34 to -0.27)), TG (-0.49, (-0.71 to -0.27)), and FBS (-0.28, (-0.46 to -0.09)) in patients with NAFLD. However, the improvements in ALT (-0.29, (-0.58 to 0.00)), LDL (-0.48, (-0.97 to 0.01)), HDL (0.03, (-0.38 to 0.44)), and BMI (-0.13, (-0.29 to 0.02)) were not statistically significant. Furthermore, the findings revealed that the optimal dose and duration of curcumin consumption for patients with NAFLD is <500 mg/d for less than 10 weeks. Conclusion: The present study suggests that consuming curcumin can improve liver enzymes, lipid profile, FBS, and BMI in patients with NAFLD. Moreover, curcumin supplementation may provide beneficial effects on metabolic biomarkers and body weight if used at the appropriate dose and duration. Further RCTs are required to confirm our findings.

Introduction: A growing body of evidence indicates that repeated alcohol exposure or withdrawal from alcohol can result in persistent molecular and cellular adaptations. One molecular adaptation that occurs is the regulation of gene expression, which is believed to lead to functional alterations that characterize addiction. MicroRNAs (miRs) have been recently identified as master regulators of gene expression through posttranscriptional regulation. The aim of this meta-analytic review was to evaluate the regulatory forms of miRs during alcoholism. Methods: We used several databases such as PubMed, Scopus, and Web of Science without limitations on publication time. All studies were analyzed by Comprehensive Meta-Analysis software. Results and Discussion: Six clinical papers with 243 alcoholic patients and 162 controls were included. In this study, 1680 articles were initially reviewed and eventually, six clinical studies were included in the metaanalysis. The results of the meta-analysis showed that according to the random model, the difference between the upregulation and downregulation of central addiction targets was statistically significant, indicating that most dopamine- or gamma-aminobutyric acid receptor subunit (GABA)-related miRs are upregulated in alcoholics (P: 0.00, CI: 0.149-0.439). Conclusion: This study strongly suggests that dopamine- or GABA-related miRs were mostly upregulated in alcoholism. Our findings revealed that about 9% of miRs were downregulated in alcoholism, including miR- 567, miR-126, miR-1, miR-432, and miR-153. To identify other or specific miRs as potential biomarkers in alcoholics, large-scale studies and more clinical work are required.

Background: Reperfusion Injury Acute ischemic stroke is increasing in people recently and Musk, as a commonly used Traditional Chinese Medicine (TCM), has been suggested as a potential agent against acute ischemic stroke, but the efficacies and underlying mechanisms of it remain unknown. Objective: This study was aimed to test the hypotheses that volatile compounds of musk could attenuate nerve injury and identify the bioactive compounds and potential mechanisms of Musk. Methods: Transient middle cerebral artery occlusion (MCAO) model in vivo in Sprague-Dawley rats (SD rats) was used to test this hypothesis. Collecting ingredients of Musk and their related targets were discerned from the Gas chromatography-olfactory mass spectrometry (GC-O-MS) experiment. Then the potential mechanisms and targets of the compounds were searched by network pharmacology techniques. Finally, the pathway was verified by Western Bolt (WB). Results: First, Musk treatment significantly up-regulated the relative levels of AKT1, PI3KA, and VEGFA in the hippocampus, and improved the sport functions in the post-MCAO ischemic rats in vivo. Next, twenty potential flavor active compounds were recognized by GC-O-MS. A total of 89 key targets including HIF-1, PIK3CA, TNF signaling pathway, and VEGF were identified. AKT1, HIF1A, PIK3CA, and VEGFA were viewed as the most important genes, which were validated by molecular docking simulation. Conclusion: The Volatile compounds of musk can attenuate nerve injury and improving post-cerebral ischemic exercise functions by HIF1A pathways, and the combined data provide novel insight for Musk volatile compounds developed as new drug for improving reperfusion injury in acute ischemic stroke.