Medicine in Drug Discovery最新文献

This study examined the effect of aspirin on olfactory discrimination and neurogenesis in experimental aging mice. The results from the buried food test (BFT) and odour preference test (OPT) indicated that aspirin treatment enhanced the olfactory functions in the experimental animals. The immunohistochemical assessment revealed increased amounts of doublecortin (DCX)-positive immature neurons and bromodeoxyuridine (BrdU)/neuronal nuclei (NeuN) double-positive new neurons in the olfactory bulb (OB) of aspirin-treated animals compared to the control group. Besides, aspirin treatment resulted in a decreased number of ionized calcium-binding adaptor molecule (Iba)-1 positive microglia, a main cellular element of neuroinflammation in the brain compared to the control group. In addition, the increased activities of key antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) in OB of the aspirin-treated mice were evident. Acetylcholinesterase (AChE) is a key enzyme that hydrolyses acetylcholine (ACh), an important neurotransmitter, involved in cognition, and olfaction. While the enhanced activity of AChE has been linked to the severity of dementia and OB defects, the biochemical assessments indicated reduced activity of AChE in OB-derived homogenates of the aspirin-treated experimental animals than that of the control group. Taken together, this study validates the proneurogenic, cholinergic, and anti-neuroinflammatory properties of aspirin in the OB which can be considered in boosting neural regeneration and management of olfactory deficits in aging and various disorders.

Diabetes, a chronic disease significantly affects peoples’ health and quality of life. It is a major contributor of severe health complications, such as blindness, kidney failure, heart attacks, strokes, and lower limb amputations. Autophagy is a complex cellular process regulated by specific genes. It is responsible for degrading intracellular proteins and organelles within lysosomes, a process which is crucial for maintaining internal cellular balance and clearing damaged or obsolete cellular components. In the context of diabetes, autophagy plays a key role in maintaining blood glucose homeostasis, particularly through the regulation of insulin secretion and sensitivity. Additionally, autophagy aids in preserving the survival and function of pancreatic beta (β)-cells by eliminating harmful proteins within these cells, which is vital for the prevention and treatment of diabetes. Despite the key role autophagy plays in these aspects, its exact mechanisms and effects in diabetes are still complex and not fully understood. Therefore, further research is needed to deeply explore the specific mechanisms and potential therapeutic applications of autophagy in diabetes. This review explores autophagy's classification, mechanisms, role in diabetic pathogenesis and complications, and its potential in treatment strategies of disease.

Atherosclerosis, a highly prevalent cardiovascular disease, has significantly contributed to morbidity and mortality worldwide. Despite the availability of various treatment options in clinical practice, complete reversal of the atherosclerotic pathological process remains challenging. Traditional anti-arteriosclerosis drugs often suffer from poor solubility, limited targeting ability and obvious adverse effects. Additionally, novel therapeutics such as genetic and protein-based drugs inherently suffer from instability issues, thereby compromising their actual curative efficacy and impeding further clinical application. Recently, nanomedicine-based drug delivery strategies have emerged as promising approaches for treating atherosclerosis due to their ability to specifically transport various drugs to target cells, microstructures and specific molecules within lesion sites. These advanced features enhance drug properties and bioavailability while minimizing off-target effects. Moreover, numerous studies have demonstrated that nanomedicine not only inhibits plaque progression but also reduces lesional areas and eventually reverses atherosclerosis. The utilization of nanomedicine is considered an important therapeutic tactic for further mitigating residual risks associated with atherosclerosis. This review provides a comprehensive overview of emerging nanomedicine-based strategies for targeted delivery of anti-atherosclerosis drugs, elucidating their distinct mechanisms and highlighting their remarkable efficacy in combating atherosclerosis. Additionally, critical challenges and future perspectives associated with the development and application of anti-arteriosclerosis nanomedicine are thoroughly discussed.

Purpose

The increasing resistance to onychomycosis treatment globally is a major concern as it results in treatment failures. This research aimed to investigate the effectiveness of incorporating nanostructured lipid carriers (NLCs) in a gel formulation for treating mild to moderate Candida-associated onychomycosis using Zataria multiflora (Zt) essential oils.

Methods

The characteristics of Zataria multiflora-loaded nanostructured lipid carriers (Zt-NLCs) were validated using a carbopol gel (1 % w/w). In vitro tests were conducted using CLSI M60 standards to evaluate the susceptibility of ten commonly encountered dermatophyte species to antifungal agents. A clinical study was conducted involving 40 volunteers randomly assigned to two groups: one receiving the Zt-NLCs gel and the other receiving a placebo, using a double-blind, placebo-controlled design. The objective was to assess clinical manifestations and mycological findings after topical application for 2 and 4 weeks. The causative agents' species were identified using a PCR-RFLP method.

Results

The preparation of Zt-NLCs gel resulted in a uniform suspension of spherical nanoparticles with favourable characteristics and no cytotoxic effects. Zt-NLCs demonstrated significant inhibitory effects on fungal growth and effectively improved clinical and mycological criteria in comparison to the placebo group (p < 0.005), even after 2 weeks of treatment. The C. albicans complex was recognized as the predominant species isolated from the patients using PCR-RFLP.

Conclusion

The administration of Zt-NLCs gel for two weeks showed significant efficacy in disease management, as reported by both dermatologists and mycologists and therefore shows its potential use as a treatment against Candidal onychomycosis.

As the most abundant protein in the blood, albumin binds and transports hydrophilic, hydrophobic, and lipophilic molecules required for the growth and development of cells and tissues. Due to the surface location of charged groups and the inner hydrophobic site, it transports proteins, peptides, amino acids, fatty acids, nutrients, and other biomolecules. It is a multi-domain protein involved in various functions of the blood, including the contribution to oncotic pressure. Because of its unique sequence and structure, albumin can be efficiently utilized to develop drug delivery systems against various diseases, including cancer. As a protein, rich in both negative and positive charges on the surface, it attracts great attention in the drug delivery discipline. Inner hydrophobic sites were proven to be an efficient location for delivering hydrophobic and lipophilic drugs. Albumin binding domains, widely distributed among receptors and matricellular molecules, ease its penetration into cells. A high ratio of cysteine provides stability to the molecule and causes thiol-disulfide interactions, which play an essential role in drug release. In this work, we highlighted several points of albumin nature as a drug-carrying molecule regarding biochemical and physical properties: self-assembling, formation of covalent bonds, formation of in situ albumin corona, etc. Research publications were searched in the NCBI database by various keywords related to sections/subsections to review the related topic. Tens of research works have been dedicated to enhancing the therapeutic efficacy of anticancer drugs using albumin in the last two decades and contributed to clarifying the mechanistic action of albumin. We discussed its mechanisms of action in drug delivery in the first section. In another section, we reviewed the enhanced antitumor/anticancer efficacies of those fabricated DDSs in terms of albumin contribution. The results of in vitro and in vivo experiments were merged into that section consisting of subsections of DDSs of individual anticancer means. Clinical trials of three drugs were reviewed as a separate section. The approaches used to enhance the efficacy of albumin-based DDSs were reviewed in the last section. The final section is devoted to strategies that could significantly improve albumin efficacy in cancer drug delivery.

CHK1 plays a crucial role in cancer biology as it modulates cell cycle checkpoint activation and DNA repair. Furthermore, a number of other cellular functions of CHK1 are also gradually discovered. Based on these biological functions, CHK1 has been regarded as a potential target for cancer therapy, but regrettably no CHK1 inhibitors have been marketed up to now. The incorporation of effective biomarkers or combined combinations is expected to promote the development process of CHK1 inhibitors. This paper reviews the latest research progress on the functions and inhibitors of CHK1.

The colonic microbiota, comprising 500 species and 40 trillion bacteria, is influenced by various factors, such as diet, habits, and constitution, which impact human health and disease. This paper discusses the significance of colonic microbiota in human health and explores various in vitro colonic microbiota culture models to evaluate the effects of functional ingredients on gut microbiota. Traditional evaluation methods involve animal experiments and human intervention studies. However, ethical and practical challenges remain. This study introduces the Kobe University Human Intestinal Microbiota Model (KUHIMM) as an innovative in vitro culture system. This study details the operational methods and distinctive features of the KUHIMM, highlighting its capacity to accurately reproduce the diversity of the colonic microbiota and the metabolites in individual human donors. Various applications of the KUHIMM have been presented, ranging from the assessment of dietary fibers and probiotics to drugs and herbal medicines. The ability of the model to predict health effects and its sensitivity in evaluating different drugs make it a valuable tool for research and development. This study acknowledges its limitations, including the absence of an absorption system for metabolites, but anticipates the increasing importance of in vitro gut microbiota culture systems in advancing the understanding of human health and expediting the development of effective interventions.

Psoriasis is a chronic autoimmune disorder that has a major effect on the quality of life for millions of people throughout the world. The pathogenesis of psoriasis has revealed intricate molecular networks and signaling pathways, opening new avenues for precision medicine. Psoriasis treatments include topical therapy, phototherapy, systemic therapies, and biologics, but achieving optimal outcomes is difficult. Despite advancements in understanding the causes of psoriasis and the development of various treatments, optimizing therapeutic outcomes remains challenging. Managing psoriasis poses challenges in terms of drug delivery and evaluation models. Novel drug delivery systems capable of navigating complex skin barriers and delivering therapeutics precisely to target cells are crucial for advancing treatment options. This article provides an inclusive overview of psoriasis, highlighting recent discoveries and potential therapeutic targets. The article emphasizes the importance of combining different modalities, such as synthetic and herbal agents, with biologics to improve efficacy. Nanocarriers show promise for targeted drug delivery in psoriasis, as they can encapsulate antipsoriatic drugs, biologics, and gene therapies, providing enhanced stability, improved tissue penetration, and precise cellular targeting. These advancements in drug delivery systems have the potential to revolutionize psoriasis treatment by maximizing efficacy while minimizing side effects. The article also discusses the commercial outcomes in psoriasis formulations, including patents related to treatment and ongoing clinical trials, which provide valuable insights into the evolving landscape of psoriasis therapeutics. These insights contribute to the evolving field of psoriasis therapeutics and offer hope for improved outcomes for patients suffering from psoriasis.

Calix[n]arene is a class of macrocyclic compounds and has been investigated to improve the physicochemical properties of water insoluble molecules. In this work, a complex of morin hydrate (MH) drug was prepared using p-sulfocalix[4]arene (SC[4]A) as complexing agent to increase its water solubility, dissolution rate and stability. Solvent evaporation methanol was used to prepare the inclusion complex (MH-SC[4]A) between pure MH and SC[4]A and analysed by FTIR, NMR, UV, DLS, TEM, and DSC techniques. Concentration-dependent solubility study showed 22 folds enhancement of MH at 8 mM concentration of SC[4]A. The in vitro anticancer efficacy of MH against A549 cells was increased after complex formation. AO/EtBr staining study showed the more apoptosis mediated anticancer activity than native MH. Molecular geometry, stabilizing interactions, release behaviour and full-unwinding pathway of the complex were characterized by the computed Potential of Mean Force (PMF) using extended umbrella sampling. The combined computational and experimental data confirmed that our designed MH-SC[4]A complex could be utilized as a promising drug delivery carrier for hydrophobic MH.