Aspects of molecular medicine最新文献

Background

Methods

Results

Conclusions

Cardiovascular disease is estimated to be responsible for one-third of all global deaths annually. It occurs mostly due to hyperlipidemia, a condition where excessive cholesterol deposits in blood vessels. A favorable target for treating hyperlipidemia involves the crucial role of inhibition of a specific enzyme known as 3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase). The primary goal of this present study is to identify potential HMG-CoA reductase inhibitors containing tetracyclic triterpene nucleus derived from mushrooms. A library of 86 myco-constituents bearing a tetracyclic triterpene scaffold was prepared and screened to identify potential HMG-CoA reductase inhibitors targeting proteins 1HW8 and 1HW9. For this purpose, molecular docking, ADME prediction, and molecular dynamics (MD) simulation studies were performed on this in-house prepared database. The virtual screening results exhibited M_02(c) as the best hit with promising SP Glide scores compared to standard statin drugs. In order to assess the stability and interactions, a 100 ns MD simulation was performed. Further, M_02(c) was also analysed for MMGBSA binding energy to access and validate the thermodynamic stability of the protein-ligand complex. The results of this study revealed that M_02(c) is a promising hit molecule and may emerge as a potent HMG-CoA reductase inhibitor in preventing and treating hyperlipidemia.

Background

Unnecessary antibiotic avoidance due to allergy fears has adverse cost and health implications however, the problem is difficult to resolve because patient and provider-related factors leading to avoidance are multifactorial. We use qualitative research methods to explore patient perspectives of antibiotic allergy and testing to reach the heart of the problem.

Objective

To reveal factors leading patients to report antibiotic allergy, and determine what education is required to prevent the cycle of erroneous allergy reporting.

Methods

The 29 patients were a sample of convenience recruited from a tertiary public hospital in Western Australia between March 2020 until August 2020; 18 were inpatients and 11 outpatients, with a median age of 64.2 years, and 15 (55%) were female. Semi-structured interviews assessed patients’ understanding and knowledge of three topics: (1) antibiotic allergy, (2) antibiotic allergy testing, and (3) outcomes of testing. Interview transcripts underwent thematic analysis by two researchers, independently.

Results

Three main, overlapping themes emerged as influential across topics: (1) Severity of the Index Reaction, (2) Trust in family and health care providers, and (3) Health literacy. Patients were largely unaware of the benefits of confirmatory testing, and the detrimental health consequences of unnecessary avoidance. Patients displayed trust in health care providers’ expertise and assumed that medical records were accurate to prevent prescribing errors.

Conclusions

The findings provide evidence for an effective patient education strategy and highlight failures among hospital and primary health providers to recognise the potential harm of unverified antibiotic allergy. Healthcare professionals are influential at multiple steps of a patient's healthcare journey and addressing unconfirmed antibiotic allergy should be taken at each opportunity.

Mosquito-borne diseases such as dengue, yellow fever, chikungunya, Zika, malaria, Japanese encephalitis, West Nile fever, and elephantiasis pose significant public health threats globally. Dengue virus (DENV), transmitted primarily by Aedes mosquitoes, infects millions annually, particularly in tropical and subtropical regions. The virus, belonging to the Flaviviridae family, comprises four serotypes (DENV-I to DENV-IV) with distinct structural and non-structural proteins. Transmission occurs through mosquito bites, predominantly by Aedes aegypti and Aedes albopictus. In 2022, India reported 223,251 dengue cases with 308 fatalities, underscoring the urgent need for effective control strategies beyond synthetic drugs due to their costs and adverse effects. Plant-derived compounds have emerged as promising alternatives due to their biological origin, safety profile, and diverse pharmacological activities, including antiviral properties. This review focuses on the application of molecular docking techniques to evaluate the interaction between plant-derived phytochemicals and key dengue viral proteins, particularly NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5. Phytochemicals such as apigenin, hesperidin, kaempferol, and myricetin demonstrated significant binding affinity and potential inhibition of crucial viral enzymes, highlighting their therapeutic promise. Studies on compounds from medicinal plants like Tanacetum parthenium, Silybum marianum, Cyamopsis tetragonoloba, and Astragalus spp. further support the efficacy of plant-based therapies against dengue. The findings underscore the potential of phytochemicals to inhibit viral replication and protein activity, offering a novel avenue for developing antiviral treatments. Molecular docking simulations provided insights into the molecular interactions between phytochemicals and viral proteins, guiding future research and drug development efforts. This comprehensive review consolidates current knowledge on plant-based antivirals against dengue, emphasizing their role in integrated vector management and public health strategies.

Increasing evidence suggests that gut microbiota-derived metabolites affect cognitive function, but the underlying molecular mechanisms remain unclear. In this study, mechanisms of cognitive dysfunction that can be targeted by acetic acid and butyric acid were analyzed using literature review, Metascape, Mienturnent, Passonline, and WissADME. We found that acetic acid and butyric acid may regulate important genes (PPARG, CASP3, IL1B, SOD2, and TNF) that protect against cognitive decline. We also found microRNAs (hsa-miR-17-5p and hsa-miR-20a-5p) and transcription factors (RELA and NFKB1) that play a critical role in this protective mechanism. The AGE-RAGE signaling pathway and apoptosis pathways also emerged as crucial to understanding the underlying pathophysiological mechanisms. Our findings are further supported by the physicochemical properties and pharmacokinetic profiles of acetic acid and butyric acid, which demonstrate remarkable intestinal absorption, ability to penetrate the blood-brain barrier, and non-inhibition of CYP450 enzymes. Our study provides further evidence of the therapeutic potential of butyric acid in managing cognitive impairment, including its anti-inflammatory properties, stimulation of insulin synthesis, and regulation of lipid metabolism. We also identified several promising treatments for cognitive impairment, including miRNA sponges, mesalazine, omega-3 fatty acids, pomalidomide, and andrographolide. Focused investigations into the apoptosis and AGE-RAGE signaling pathways, miRNA sponges, promising drugs, and the role of gut microbiota in cognitive function are warranted.

Flavonoids are a group of bioactive compounds widely distributed in edible plants. They have gained special attention given strong scientific evidence supporting their health promoting actions. This review summarizes current knowledge on the biosynthetic pathways of flavonoids in plants, the regulation of those pathways, and the conservation of flavonoids in plant road to becoming a food. Additionally, the main dietary sources of flavonoid, evidence from population and clinical studies, and possible mechanisms involved in the beneficial effects of flavonoids on human health are also discussed.

Background

Type 2 diabetes mellitus (T2D) stands as one of the most prevalent chronic diseases globally, posing substantial health and economic burdens on society. Within the spectrum of T2D, familial cases emerge as a distinct entity characterized by a strong familial clustering of the disease. This phenomenon has long suggested that genetics contributes substantially to T2D susceptibility, motivating extensive research into the genetic determinants of familial T2D.

Methods

We recruited 212 multigenerational Italian families with multiple cases of T2D. The families were genotyped using genomic array (≥ 600k) derived from the UK Biobank Axiom Array platform. Informative markers were tested via Pseudomarker for linkage to and linkage disequilibrium (i.e., linkage joint to association) with T2D across the following models: dominant with complete penetrance (D1), dominant with incomplete penetrance (D2), recessive with complete penetrance (R1), and recessive with incomplete penetrance (R2).

Results

We identified a total of 566 variants reaching genome-wide significant (P < 0.00005) linkage and/or association to/with the risk of T2D in Italian families. Of the 355 genes identified in our study, 341 (96%) are novel and have not been reported with T2D or any of its related phenotypes (i.e., obesity, metabolic syndrome, insulin resistance, polycystic ovary syndrome, and hyperglycemia).

Conclusion

Our study constitutes the first familial T2D-linkage and association study in the Italian population. However, the functional relevance of the novel variants and genes reported in our study remains to be explored.

We analyzed data from human genome-wide association studies (GWASs) to identify genetic variants and biological pathways linked to Alzheimer's disease (AD). Ten AD biomarkers (APOE, NECTIN2, APOC1, APOC1P1, TOMM40, RNU4-67P, KRAS, Y_RNA, THORLNC, LINC01956) were found across studies, including six central genetic variants (MAPT (rs242557-A), GRIN2B (rs74442473-G), APOE (rs438811-T), ANK3 (rs438811-T), BIN1 (rs744373-G), and BDNF (rs7481773-A)). ANK3 (rs438811-T) and GRIN2B (rs74442473-G) were essential hub biomarkers for amyloid plaques, while MAPT (rs242557-A) and BIN1 (rs744373-G) were crucial for neurofibrillary tangles (NFTs). Higher-risk AD biomarkers were associated with increased protein-lipid complex formation, while lower-risk AD biomarkers were correlated with improved synaptic function. Six essential miRNAs (hsa-miR-124–3p, 15a-5p, 16–5p, 204–5p, 520g-3p, 520h) and three transcription factors (ZMAT4, ZBED6, FOXG1) emerged as possible candidates to reveal the genetic differences that lead to amyloid plaques, NFTs, and ultimately AD. These findings serve as a basis for potential AD treatments and offer new avenues for therapeutic approaches to directly target the genetic variations and processes associated with the disease.