Pharmacogenomics. 2024 Oct 23:1-12. doi: 10.1080/14622416.2024.2411939. Online ahead of print.

ABSTRACT

This study aims to use machine learning model to predict laboratory aspirin resistance (AR) in Chinese stroke patients by incorporating patient characteristics and single nucleotide polymorphisms of GP1BA and LTC4S. 2405 patients were analyzed to measure the Mutation frequency of GP1BA rs6065 and LTC4S rs730012. 112 patients with first-stroke arteriostenosis were prospectively enrolled to establish machine learning model. GP1BA rs6065 mutation frequency is 5.26% and LTC4S rs730012 is 14.78%. GP1BA rs6065 CT patients have more sensitivity to aspirin than CC genotype. Simple linear regression identified significant associations with age, smoking, HDL and GP1BA rs6065. Random forest (RF) and extreme gradient boosting (XGBoost) demonstrated predictive capabilities for AR. Findings suggest pre-identifying GP1BA rs6065 could optimize aspirin treatment, enabling personalized care and future research avenues.

PMID:39440554 | DOI:10.1080/14622416.2024.2411939

Front Pharmacol. 2024 Oct 8;15:1424683. doi: 10.3389/fphar.2024.1424683. eCollection 2024.

ABSTRACT

Hypertension is a common risk factor for cardiovascular disease. Pharmacogenomics, as a tool for personalized healthcare, helps in determining the optimal drug treatment based on the genome of individual patient. This study reports a 49-year-old male with acute cerebral infarction, pulmonary infection, extremely high-risk hypertension (grade3), type 2 diabetes, hyperhomocysteinemia, hyperlipidemia, and fatty liver. The patient initially received conventional systemic treatment but continued to have severe hypertension (159/85 mmHg). To better control blood pressure, a pharmacogenomic test was performed, and results showed that the SNP genotype of rs4961 (ADD1) suggests poor efficacy with certain antihypertensive drugs. The genotype of rs4149601 (NEDD4L) indicates better efficacy with hydrochlorothiazide, while the CYP3A5*3 genotype indicates a slow metabolism of calcium channel blockers, suggesting that amlodipine may be more effective than nifedipine. By replacing nifedipine with amlodipine and increasing the dosage of hydrochlorothiazide, the patient's systolic blood pressure was stabilized, although diastolic blood pressure remained suboptimal (131/91 mmHg). Despite low potassium levels, the patient was not sensitive to spironolactone (141/91 mmHg) but achieved exhibited well-controlled blood pressure (129/90 mmHg) with hydrochlorothiazide, consistent with pharmacogenomics recommendations. In summary, pharmacogenomics testing identified genetic variations influencing the patient's response to specific drugs, guiding their selection and administration. This approach can lead to better blood pressure control and reduce the risk of adverse drug events, highlighting the potential of personalized drugs in managing hypertension through pharmacogenomics.

PMID:39439888 | PMC:PMC11493640 | DOI:10.3389/fphar.2024.1424683

Farm Comunitarios. 2024 Sep 17;16(4):61-82. doi: 10.33620/FC.2173-9218.(2024).27. eCollection 2024 Oct 15.

ABSTRACT

Regulatory agencies such as the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) recognize pharmacogenetics as a key tool in their pharmacological guidelines for pharmaceutical counseling. In this context, community pharmacies play a crucial role in addressing this healthcare need, which could lead to a significant improvement in patients' quality of life by preventing ineffective or contraindicated treatments.In this work, we conducted a systematic review of the available scientific evidence regarding druggene interactions relevant to community pharmacy. We identified the main genes and polymorphisms associated with treatment response and adverse effects in primary care. Finally, we propose a model for implementing pharmacogenetic services in community pharmacies.

PMID:39439868 | PMC:PMC11491914 | DOI:10.33620/FC.2173-9218.(2024).27

Arch Med Sci. 2024 Aug 26;20(4):1328-1333. doi: 10.5114/aoms/192273. eCollection 2024.

ABSTRACT

INTRODUCTION: The present study concerns a connection of the Q192RPON1 polymorphism with atherosclerosis requiring percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) in the Polish population.

METHODS: A total of 282 individuals who underwent coronary angiography took part in this study. The polymorphism was determined with the PCR-RFLP method.

RESULTS: The odds ratio for atherosclerosis in carriers of the 192RR genotype was 2.50 (p = 0.002). The median HDL-C concentration was significantly lower in the study group than the control group (p = 0.02).

CONCLUSIONS: The presence of the 192RR genotype and 192R allele are indicative of at least a two-fold increased risk of atherosclerosis requiring PCI or CABG in the Polish population.

PMID:39439706 | PMC:PMC11493066 | DOI:10.5114/aoms/192273

NPJ Biofilms Microbiomes. 2024 Oct 23;10(1):112. doi: 10.1038/s41522-024-00566-w.

ABSTRACT

Bile acids (BAs) exert a profound influence on the body's pathophysiology by intricately shaping the composition of gut bacteria. However, the complex interplay between BAs and gut microbiota has impeded a systematic exploration of their impact on intestinal bacteria. Initially, we investigated the effects of 21 BAs on the growth of 65 gut bacterial strains in vitro. Subsequently, we examined the impact of BAs on the overall composition of intestinal bacteria, both in vivo and in vitro. The results unveiled distinct effects of various BAs on different intestinal strains and their diverse impacts on the composition of gut bacteria. Mechanistically, the inhibition of intestinal strains by BAs occurs through the accumulation of these acids within the strains. The intracellular accumulation of deoxycholic acid (DCA) significantly influenced the growth of intestinal bacteria by impacting ribosome transcription and amino-acid metabolism. The metabolomic analysis underscores the pronounced impact of DCA on amino-acid profiles in both in vivo and in vitro settings. This study not only elucidates the effects of BAs on a diverse range of bacterial strains and their role in shaping the gut microbiota but also reveals underlying mechanisms essential for understanding and maintaining a healthy gut microbiota.

PMID:39438471 | DOI:10.1038/s41522-024-00566-w

Mol Genet Genomic Med. 2024 Oct;12(10):e70018. doi: 10.1002/mgg3.70018.

ABSTRACT

BACKGROUND: This systematic review aims to highlight the scope of pharmacogenomics research within global Indigenous populations. This review also explores the barriers and facilitators of pharmacogenomics research within this population.

METHODOLOGY: A systematic review of literature was conducted to identify and present an understanding of current empirical evidence demonstrating the conduct of genomics or pharmacogenomics research within global Indigenous populations (PROSPERO registration: CRD42021257226). Using key search terms, relevant databases were searched for articles published between January 2010 and July 2022. Screening, data extraction, and analysis was conducted using well-defined inclusion criteria. Quality assessment and risk of bias appraisal was conducted using the mixed methods appraisal tool. Indigenous community engagement and participation in genomics research was assessed using the social-ecological framework.

RESULTS: From the 427 articles identified, 77 articles met inclusion criteria and underwent full-text screening. Of these, 30 articles were included in the final review, with 16 being quantitative and 14 either qualitative or mixed methods studies. Most studies were conducted with native Indigenous populations from the United States of America (36%). Content analysis revealed that studies either explored genetic variations associated with disease in Indigenous populations (23%) or markers for drug metabolism (30%) or were designed to understand perspectives of genomics research within this population (47%). Perspectives included the exploration of the role of participants in research, benefits or outcomes achieved from participation in genomics research, and levels of Indigenous engagement and participation in genomics research.

CONCLUSIONS: This review highlights a growing gap in Indigenous genomics research globally. It presents several important considerations from Indigenous participants, identifying how researchers can co-create culturally safe and inclusive design, implementation, analysis, and subsequent outcomes of genomics research involving Indigenous people. Indigenous governance, self-determination and leadership is essential, with researchers required to be responsive to such fundamental partnerships for research to progress.

PMID:39435544 | DOI:10.1002/mgg3.70018

Health Sci Rep. 2024 Oct 20;7(10):e70139. doi: 10.1002/hsr2.70139. eCollection 2024 Oct.

ABSTRACT

BACKGROUND AND AIM: Among the cardiovascular diseases (CVDs), heart failure, hypertension, and myocardial infarction are associated with the greatest number of disability-adjusted life years due to lifestyle changes and the failure of therapeutic approaches, especially the one-size-fits-all interventions. As a result, there has been advances in defining genetic variants responsible for different responses to cardiovascular drugs such as antiplatelets, anticoagulants, statins, and beta-blockers, which has led to their usage in guiding treatment plans. This study comprehensively reviews the current state-of-the-art potential of pharmacogenomics in dramatically altering CVD treatment. It stresses the applicability of pharmacogenomic technology, the threats associated with its adoption in the clinical setting, and proffers relevant solutions.

METHODS: Literature search strategies were used to retrieve articles from various databases: PubMed, Google Scholar, and EBSCOhost. Articles with information relevant to pharmacogenomics, DNA variants, cardiovascular diseases, sequencing techniques, and drug responses were reviewed and analyzed.

RESULTS: DNA-based technologies such as next generation sequencing, whole genome sequencing, whole exome sequencing, and targeted segment sequencing can identify variants in the human genome. This has played a substantial role in identifying different genetic variants governing the poor response and adverse effects associated with cardiovascular drugs. Thus, this has reduced patients' number of emergency visits and hospitalization.

CONCLUSION: Despite the emergence of pharmacogenomics, its implementation has been threatened by factors including patient compliance and a low adoption rate by clinicians. Education and training programs targeting both healthcare professionals and patients should be established to increase the acceptance and application of the emerging pharmacogenomic technologies in reducing the burden of CVDs.

PMID:39435035 | PMC:PMC11491551 | DOI:10.1002/hsr2.70139

BMC Gastroenterol. 2024 Oct 22;24(1):374. doi: 10.1186/s12876-024-03456-9.

ABSTRACT

BACKGROUND: Hepatitis B virus (HBV) infection is a public health concern in resource limited settings like Ghana. Over the past decades, it is noted that the natural course of HBV in persons infected are taking a worse turn leading to liver cirrhosis and cancer. The outcome of HBV infection is influenced by viral and host factors including genetics. Cytokine variations affect virus survival and progression and may even influence associated complications. Cytokines such as tumor necrosis factor alpha (TNF-α), interleukins (IL-4, IL-6, IL-8, IL-10, IL-18), interferon gamma (IFN)-γ, and tumor growth factor-beta (TGF-β) have key roles in HBV infection and modulation. In this study, polymorphisms occurring in five cytokines were analysed to understand how they can influence prognosis of HBV infection.

METHODS: The study is a single centre cross-sectional study involving 227 participants made up of HBV infected participants and HBV-negative controls. Recruitment was from March 2021 to April 2022. Blood samples were taken for full blood count, HBV antigen profile, liver function tests, HBV DNA quantification and cytokine genotyping. FIB score was calculated using available tools. Statistical analysis was undertaken with p < 0.05 set as statistically significant.

RESULTS: The 20-39-year-old group formed majority of the HBV infected participants with 60% of all participants being classified as healthy HBsAg carriers. IL2 rs1479920 GG carriers ((1258.93; 0.00-5011.87) IU/mL had reduced HBV DNA in comparison to IL2 rs1479920 AA ((5011.87; 2113.49-5956.62) /AG (3548.13; 0.00-6309.57) IU/mL carriers. TNF-α rs1800629 AA carriers (1258.93; 0.00-3981.07) IU/mL had a reduction in HBV DNA levels in comparison to TNF-α rs1800629 GG carriers (1584.89; 0.00-5011.87) IU/mL. The results of univariate (OR = 0.08, 0.00-0.93; p = 0.043) and multivariate (OR = 0.02, 0.00-0.67; p = 0.029) analysis, showed that carrying TNF-α rs1800629 AA genotype reduce susceptibility to high FIB score compared with GG genotypes. In univariate analysis, subjects aged 20-39 years (OR = 5.00, 1.13-6.10; p = 0.034) and 40-59 years (OR = 41.99, 3.74-47.21; p = 0.0002) were more susceptible to high FIB score compared to subjects aged 1-19 years. Being female (OR = 2.42, 1.03-5.71; p = 0.043) in the univariate models showed higher odds of having high levels of HBV DNA in the multivariate model. There was a reduced likelihood of herbal medicine usage influencing HBV DNA levels significantly (OR = 0.29, 0.10-0.86; p = 0.025).

CONCLUSION: In conclusion, variations in IL2 rs1479920 GG and IL2 rs1479921 AA could offer protective effects by reducing HBV DNA. TNF-α rs179924CT may also cause elevation in HBV DNA levels whiles TNF-α -308A/G, showed a potential protective effect on liver scarring in HBV infected participants. It is therefore important to take a further look at such variations for understanding of HBV modulation in the Ghanaian population.

PMID:39434005 | DOI:10.1186/s12876-024-03456-9

PLoS One. 2024 Oct 21;19(10):e0311810. doi: 10.1371/journal.pone.0311810. eCollection 2024.

ABSTRACT

There is an urgent need for better biomarkers for the detection of early-stage breast cancer. Utilizing untargeted metabolomics and lipidomics in conjunction with advanced data mining approaches for metabolism-centric biomarker discovery and validation may enhance the identification and validation of novel biomarkers for breast cancer screening. In this study, we employed a multimodal omics approach to identify and validate potential biomarkers capable of differentiating between patients with breast cancer and those with benign tumors. Our findings indicated that ether-linked phosphatidylcholine exhibited a significant difference between invasive ductal carcinoma and benign tumors, including cases with inconsistent mammography results. We observed alterations in numerous lipid species, including sphingomyelin, triacylglycerol, and free fatty acids, in the breast cancer group. Furthermore, we identified several dysregulated hydrophilic metabolites in breast cancer, such as glutamate, glycochenodeoxycholate, and dimethyluric acid. Through robust multivariate receiver operating characteristic analysis utilizing machine learning models, either linear support vector machines or random forest models, we successfully distinguished between cancerous and benign cases with promising outcomes. These results emphasize the potential of metabolic biomarkers to complement other criteria in breast cancer screening. Future studies are essential to further validate the metabolic biomarkers identified in our study and to develop assays for clinical applications.

PMID:39432469 | DOI:10.1371/journal.pone.0311810

Int J Adolesc Med Health. 2024 Oct 22. doi: 10.1515/ijamh-2024-0099. Online ahead of print.

ABSTRACT

OBJECTIVE: The objective of the current study was to compare the level of sensitivity of body mass index (BMI) or waist-height ratio (WHtR) in identifying physically determinable adiposity levels that are considered to be landmarks for commencing intervention to prevent more sinister cardio-metabolic risks among schizophrenia patients receiving olanzapine.

METHODS: The study was a descriptive crossectional one among patients with schizophrenia recieving olanzapine and healthy volunteers as controls. Key measurement of anthropological parameters were compared between the population.

RESULTS: Our findings revealed significantly higher rates of abnormal body mass index (BMI) (X2=17.06, p=0.000036; OR=4.58, CI=2.16-9.74) and abnormal waist-height ratio (WHtR) (X2=35.57, p=2.46E-9; OR=6.37, CI=3.39-12.00) among the schizophrenia patients compared to the healthy volunteers. Notably, BMI identified 43.3 % of the schizophrenia patients as having concerning weight changes, whereas WHtR identified 64.7 %, indicating that WHtR is a more sensitive measure. This discrepancy means that an additional 21.4 % of schizophrenia patients would benefit from weight management guidance based on WHtR rather than BMI.

CONCLUSION: Our results underscore the critical importance of WHtR in assessing adiposity among schizophrenia patients treated with olanzapine, highlighting its value as a tool for monitoring and managing cardiometabolic risks in this population.

PMID:39432346 | DOI:10.1515/ijamh-2024-0099

Breast Cancer Res Treat. 2024 Oct 21. doi: 10.1007/s10549-024-07519-z. Online ahead of print.

ABSTRACT

PURPOSE: In tamoxifen-treated individuals, reduced-function genetic variants in the CYP2D6 gene or inhibition of the enzyme result in low circulating endoxifen concentrations. We assessed the impact of reduced CYP2D6 activity and circulating endoxifen concentrations on breast cancer outcomes.

PATIENTS AND METHODS: Patients with locally advanced or stage IV hormone receptor-positive breast cancer were enrolled in this single arm phase II trial and received open label tamoxifen 20 mg PO daily. The primary objective was to assess CYP2D6 poor metabolizer (PM) vs intermediate and normal metabolizer status (IM + NM) with progression-free survival (PFS). CYP2D6 phenotype was determined from whole blood samples (Roche Amplichip), and secondary endpoint evaluated endoxifen concentrations determined from 3 month post registration plasma samples (Quest Diagnostics).

RESULTS: From September 2010 to June 2013, 113 of planned 204 patients were registered to the trial and began protocol treatment. Accrual to the trial closed early due to lower-than-expected rate of CYP2D6 poor metabolizers. Median age was 62, 86% (97/113) were white, 33% (30/113) Hispanic, 83% (92/113) postmenopausal. Samples were evaluable for CYP2D6 in 75% (85/113) of patients (2/85 PM, 27/85 IM, and 56/85 NM). Median PFS for PM and IM + NM was 12.9 months and 6.9 months, respectively. Median PFS was 11.1 and 13.8 months respectively for patients with low (≤ 15.5) and high (> 15.5) endoxifen concentrations (ng/ml).

CONCLUSION: We did not observe significant associations between CYP2D6 metabolizer status or endoxifen with PFS. Small sample sizes and barriers to adequate samples in this trial prohibited determination of relationship between these markers and PFS.

TRIAL ID: NCT01124695 (registered May 14, 2010).

PMID:39432161 | DOI:10.1007/s10549-024-07519-z

Am Heart J Plus. 2024 Oct 1;46:100469. doi: 10.1016/j.ahjo.2024.100469. eCollection 2024 Oct.

NO ABSTRACT

PMID:39431118 | PMC:PMC11490664 | DOI:10.1016/j.ahjo.2024.100469

EClinicalMedicine. 2024 Oct 8;76:102835. doi: 10.1016/j.eclinm.2024.102835. eCollection 2024 Oct.

ABSTRACT

BACKGROUND: Guidelines recommend low-dose colchicine for secondary prevention in cardiovascular disease, but uncertainty remains concerning its efficacy for stroke, efficacy in key subgroups and about uncommon but serious safety outcomes.

METHODS: In this trial-level meta-analysis, we searched bibliographic databases and trial registries form inception to May 16, 2024. We included randomised trials of colchicine for secondary prevention of ischaemic stroke and major adverse cardiovascular events (MACE: ischaemic stroke, myocardial infarction, coronary revascularisation, or cardiovascular death). Secondary outcomes were serious safety outcomes and mortality. A fixed-effect inverse-variance model was used to generate a pooled estimate of relative risk (RR) with 95% confidence intervals (CI). This study is registered with PROSPERO, CRD42024540320.

FINDINGS: Six trials involving 14,934 patients with prior stroke or coronary disease were included. In all patients, colchicine compared with placebo or no colchicine reduced the risk for ischaemic stroke by 27% (132 [1.8%] events versus 186 [2.5%] events, RR 0.73 [95% CI 0.58-0.90]) and MACE by 27% (505 [6.8%] events versus 693 [9.4%] events, with RR 0.73 [0.65-0.81]). Efficacy was consistent in key subgroups (females versus males, age below versus above 70, with versus without diabetes, statin versus non-statin users). Colchicine was not associated with an increase in serious safety outcomes: hospitalisation for pneumonia (109 [1.5%] versus 106 [1.5%], RR 0.99 [0.76-1.30]), cancer (247 [3.5%] versus 255 [3.6%], RR 0.97 [0.82-1.15]), and gastro-intestinal events (153 [2.1%] versus 135 [1.9%]), RR 1.15 [0.91-1.44]. There was no difference in all-cause death (201 [2.7%] versus 181 [2.4%], RR 1.09 [0.89-1.33]), cardiovascular death (70 [0.9%] versus 80 [1.1%], RR 0.89 [0.65-1.23]), or non-cardiovascular death (131 [1.8%] versus 101 [1.4%], RR 1.26 [0.98-1.64]).

INTERPRETATION: In patients with prior stroke or coronary disease, colchicine reduced ischaemic stroke and MACE, with consistent treatment effect in key subgroups, and did not increase serious safety events or death.

FUNDING: There was no funding source for this study.

PMID:39431112 | PMC:PMC11490869 | DOI:10.1016/j.eclinm.2024.102835

Transl Lung Cancer Res. 2024 Sep 30;13(9):2212-2221. doi: 10.21037/tlcr-24-263. Epub 2024 Sep 12.

ABSTRACT

BACKGROUND: Pulmonary sarcomatoid carcinomas (PSC) are notorious for their poor prognosis and resistance to chemotherapy. The literature suggests that immunotherapy might be effective against this aggressive tumor. This study aims to evaluate the efficacy of immunotherapy, either alone or combined with chemotherapy, as first-line treatment for PSC patients.

METHODS: In a retrospective, multicentric, real-world study conducted between July 2017 and April 2021, patients with stage III (ineligible for surgery or radio-chemotherapy) or stage IV PSC were enrolled. These patients received their first-line treatment with immunotherapy and were categorized into two groups based on their treatment modality: the immuno-chemotherapy (IO CT) group or the immunotherapy-alone (IO) group.

RESULTS: This study analyzed a population of 34 patients from eight different hospital centers. In this cohort, the objective response rate (ORR) was 56%, median duration of response was 20.5 months, median progression-free survival (PFS) was 5.11 months, and median overall survival (OS) 13.9 months. Demographic characteristics remained consistent among the treatment groups except for the age (54.0- and 71.0-year-old in the IO CT and IO group, respectively, P=0.02). The IO CT group demonstrated an ORR of 64.0%, a median PFS at 8.72 months, and a median OS of 16.08 months, while the IO group displayed respective values of 52.0%, 3.45 months, and 13.11 months.

CONCLUSIONS: This study showed the potential efficacy of immunotherapy as a first-line treatment for PSC. While acknowledging the retrospective nature of the study, our findings suggest a trend favoring the combination of IO CT over IO alone in these patients.

PMID:39430330 | PMC:PMC11484717 | DOI:10.21037/tlcr-24-263

Drug Des Devel Ther. 2024 Oct 15;18:4585-4600. doi: 10.2147/DDDT.S480402. eCollection 2024.

ABSTRACT

BACKGROUND: Anlotinib was approved as a third line therapy for advanced non-small cell lung cancer in China. However, the impact of concurrent administration of various clinical drugs on the drug-drug interaction (DDI) potential of anlotinib remains undetermined. As such, this study aims to evaluate the DDI of anlotinib as a victim by establishing a physiologically based pharmacokinetic (PBPK) model.

METHODS: The PBPK model of anlotinib as a victim drug was constructed and validated in the Simcyp® incorporating parameters derived from in vitro studies, pre-clinical investigations, and clinical research encompassing patients with cancer. Subsequently, plasma exposure of anlotinib in cancer patients was predicted for single- and multi-dose co-administration with typical perpetrators mentioned in Food and Drug Administration (FDA) industrial guidance.

RESULTS: Based on predictions, the CYP3A potent inhibitor ketoconazole demonstrated the most significant DDI with anlotinib, regardless of whether anlotinib is administered as a single dose or multiple doses. Ketoconazole increased the area under the concentration-time curve (AUC) and maximum concentration (Cmax) of single-dose anlotinib to 1.41-fold and 1.08-fold, respectively. In contrast, rifampicin, a potent inducer of CYP3A enzymes, exhibited a relatively higher level of DDI, with AUCR and CmaxR values of 0.44 and 0.79, respectively.

CONCLUSION: Based on the PBPK modeling, there is a low risk of DDI between anlotinib and potent CYP3A/1A2 inhibitors, but caution and enhanced monitoring for adverse reactions are advised. To mitigate the risk of anti-tumor treatment failure, it is recommended to avoid concurrent use of strong CYP3A inducers. In conclusion, our study enhances understanding of anlotinib's interaction with medications, aiding scientists, prescribers, and drug labels in gauging the expected impact of CYP3A/1A2 modulators on anlotinib's pharmacokinetics.

PMID:39429896 | PMC:PMC11490238 | DOI:10.2147/DDDT.S480402

Comput Biol Chem. 2024 Oct 12;113:108249. doi: 10.1016/j.compbiolchem.2024.108249. Online ahead of print.

ABSTRACT

Cystic fibrosis is an autosomal recessive condition caused by mutations in the CFTR gene, which encodes the CFTR protein. Currently, CF is a life-limiting illness that has a limited cure. The present study aimed to identify top leads against CFTR protein with F508del in comparison with Lumacaftor. In this study, a homology model of the NBD domain of CFTR protein was developed using the available NBD domain crystal structure. The protein model was refined through apo dynamics. Energy-optimized pharmacophore mapping was carried out to identify essential features for CFTR, resulting in a model with a hydrogen-bond donor, two hydrogen-bond acceptors, and three aromatic ring sites. A screening of a compound from the NPASS database using these DAARRR six-point-pharmacophore features led to the identification of potential ligands that could act against CFTR protein. Further studies such as ADME/T, molecular dynamics, MM_GBSA, and DFT were performed to identify the top-hit compound from the NPASS database. The compound Anguibactin (NPC41982) has been identified as a top lead that exhibits higher binding affinity and stability than the reference compound Lumacaftor, suggesting their potential to bind to the active site of the CFTR protein. These compounds could serve as starting points for the development of drug-like molecules for treating cystic fibrosis.

PMID:39427605 | DOI:10.1016/j.compbiolchem.2024.108249

Sci Rep. 2024 Oct 19;14(1):24588. doi: 10.1038/s41598-024-76245-9.

ABSTRACT

Iron is an essential mineral that supports numerous biological functions. Studies have reported associations between iron dysregulation and certain cardiovascular and neurodegenerative diseases, but the direction of influence is not clear. Our goal was to use computational approaches to better understand the role of genetically predicted iron levels on disease risk. We meta-analyzed genome-wide association study summary statistics for serum iron levels from two cohorts and two previous meta-analyses. We then obtained summary statistics from 11 neurodegenerative, cerebrovascular, cardiovascular or lipid traits to assess global and regional genetic correlation between iron levels and these traits. We used two-sample Mendelian randomization (MR) to estimate causal effects. Sex-stratified analyses were also carried out to identify effects potentially differing by sex. Overall, we identified three significant global correlations between iron levels and (i) coronary heart disease, (ii) triglycerides, and (iii) high-density lipoprotein (HDL) cholesterol levels. A total of 194 genomic regions had significant (after correction for multiple testing) local correlations between iron levels and the 11 tested traits. MR analysis revealed two potential causal relationships, between genetically predicted iron levels and (i) total cholesterol or (ii) non-HDL cholesterol. Sex-stratified analyses suggested a potential protective effect of iron levels on Parkinson's disease risk in females, but not in males. Our results will contribute to a better understanding of the genetic basis underlying iron in cardiovascular and neurological health in aging, and to the eventual identification of new preventive interventions or therapeutic avenues for diseases which affect women and men worldwide.

PMID:39427026 | DOI:10.1038/s41598-024-76245-9

Cancer Lett. 2024 Oct 17:217304. doi: 10.1016/j.canlet.2024.217304. Online ahead of print.

ABSTRACT

Small nucleolar RNAs (snoRNAs) are a class of non-coding RNAs primarily known for their role in the chemical modification of other RNAs. Recent studies suggested that snoRNAs may play a broader role in anti-cancer treatments such as targeted therapies and immunotherapies. Despite these insights, the comprehensive landscape of snoRNA associations with drug response and immunotherapy outcomes remains unexplored. In this study, we identified 79,448 and 75,185 associations between snoRNAs and drug response using data from VAEN and CancerRxTissue, respectively. Additionally, we discovered 29,199 associations between snoRNAs and immune checkpoint genes and 47,194 associations between snoRNAs and immune cell infiltrations. Sixteen snoRNAs were significantly correlated with immunotherapy objective response rate (ORR), and 92 snoRNAs showed significantly differential expression between cancers with high and low ORR. Furthermore, we identified 17 snoRNAs with significantly differential expression between cancer types with high and low immune-related adverse event (irAE) reporting odds ratio (ROR). Several snoRNAs, such as SNORD92, and SNORD83B, may represent promising biomarkers or therapeutic targets that needs further investigation. To facilitate further research, we developed a user-friendly portal, Pharmacogenomic and Immune Landscape of SnoRNA (PISNO, https://hanlaboratory.com/PISNO/), enabling researchers to visualize, browse, and download multi-dimensional data. This study highlights the potential of snoRNAs as biomarkers or therapeutic targets, paving the way for more effective and personalized anti-cancer treatments.

PMID:39426663 | DOI:10.1016/j.canlet.2024.217304

J Ethnopharmacol. 2024 Oct 17:118942. doi: 10.1016/j.jep.2024.118942. Online ahead of print.

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: The use of lavender as sleep aid or hypnotic agent can be traced back as early as ancient Romans and Greeks. Yet, objective experimental data on whether and how lavender enhances sleep duration or/and sleep quality remain lacking.

AIM OF THE STUDY: We aimed to characterize the sleep-wake regulating effects of lavender in the mouse and to demonstrate the brain targets and neural circuits involved.

MATERIALS AND METHODS: A self-made precise odor delivery system combined with chronic polysomnographic recordings was employed to assess the sleep-wake effects of inhalation with lavender essential oil (LEO, extracted from lavender) and its different constituents during the light and dark phases in free-moving C57BL/6J mice. Neuroviral labeling, in situ hybridization and pharmacogenetics were combined to identify the neural circuits and targets involved. Finally, an insomniac model of DL-4-Chlorophenylalanine (PCPA)-treated mice was established to examine the sleep-inducing potential of LEO.

RESULTS: We found that inhalation of LEO with a concentration at 25.0% during the light (inactive) phase significantly shortened the latency to non-rapid eye movement (NREM) sleep, increased the total amount of NREM sleep at the expense of wakefulness (W), and enhanced cortical EEG slow wave activities, notably delta power spectra density. We further identified linalool, d-limonene, 1,8-cineole, linalyl acetate and terpinene-4-ol as the major effective sleep-promoting monomer components. Importantly, we found that LEO no longer produced any of the above sleep-promoting effect following either nasal injection of zinc sulfate which interrupts the olfactory pathway, or pharmacogenetics silencing of central amygdala GABAergic neurons. Finally, LEO reestablished NREM sleep with short latency in PCPA-treated insomniac mice, effects comparable with those induced by a potent sedative diazepam.

CONCLUSIONS: We have characterized the quantitative and qualitative sleep-promoting effects of LEO and its effective components via the olfactory pathway and central amygdala GABA neuronal targets. The hypnotic property of LEO is reinforced by its ability to restore sleep in insomnia. Our study thus establishes a neurobiological basis for aromatherapy of sleep disorders using lavender.

PMID:39426576 | DOI:10.1016/j.jep.2024.118942

Sci Rep. 2024 Oct 18;14(1):24512. doi: 10.1038/s41598-024-75514-x.

ABSTRACT

While Coronavirus disease 2019 (COVID-19) vaccines have proven to be both effective and generally safe, rare but severe adverse events following immunization (AEFIs) are described. Autoantibodies to platelet factor-4 are associated with catastrophic thrombotic AEFIs, but comprehensive investigations of other autoantibodies are lacking. We aimed to detect and describe autoantibodies targeting coagulation-related proteins in a population-wide cohort (SWEDEGENE) including AEFIs attributed to COVID-19 vaccines in Sweden. Subjects were recruited from December 2020 to October 2022 and were stratified based on diagnosis and COVID-19 exposure. Screening was carried out in two phases, with a multiplex bead-based assay in the first subset (until September 2021) and with targeted assays for the second (until October 2022). Positivity was defined based on absolute, relative, and biological/technical thresholds. Patients with coagulation-related AEFIs were older and the Vaxzevria vaccine was overrepresented in this group. Two cases had antiphospholipid antibodies but none had PF4 antibodies. We identified six positives for protein S autoantibodies. Protein S concentrations were negatively correlated with autoantibody response in patients with immunoreactivity and functional analysis revealed low protein S activity in three subjects. Our population-wide analysis reveals cases with autoantibodies against protein S which possibly underlie coagulopathic AEFIs.

PMID:39424883 | DOI:10.1038/s41598-024-75514-x