CNS Neurosci Ther. 2025 Feb;31(2):e70253. doi: 10.1111/cns.70253.

ABSTRACT

BACKGROUND: Berberine (BBR) has been reported to mitigate epileptic seizures. However, the potential mechanism of its anti-seizure effect remains uncharacterized.

AIMS: This study aimed to investigate the protective effect of BBR on acute epileptic seizures induced by kainic acid (KA) in mice and further explore its mechanism of action in the aspect of analysis of gut microbiota.

MATERIALS AND METHODS: The protective effect of BBR against acute epileptic seizures was assessed via Racine score and Nissl training. Alterations of gut microbiota and metabolites in seizure mice after BBR treatment were analyzed through 16S sequencing and lipidomics, respectively.

RESULTS: Our results showed that the BBR remarkably alleviated acute epileptic seizures and hippocampal neuron damage in KA-induced mice. The analysis of gut microbiota indicated that BBR reduced the acute epileptic seizures in KA-induced mice by increasing the abundance of Bacteroidetes and Alloprevotella, regulating short-chain fatty acids (SCFAs). Results of lipidomics also identified 21 candidate metabolites in the colon and hippocampus possibly involved in the protective effect of BBR against acute seizures.

CONCLUSION: These findings suggest that BBR exerts neuroprotection against KA-induced epileptic seizures through remodeling gut microbiota-associated lipid metabolism in the colon and hippocampus. BBR may serve as a valuable candidate drug for curing patients with epilepsy.

PMID:39915895 | DOI:10.1111/cns.70253

Nat Commun. 2025 Feb 6;16(1):1418. doi: 10.1038/s41467-025-56642-y.

ABSTRACT

Constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are closely related nuclear receptors with overlapping regulatory functions in xenobiotic clearance but distinct roles in endobiotic metabolism. Car activation has been demonstrated to ameliorate hypercholesterolemia by regulating cholesterol metabolism and bile acid elimination, whereas PXR activation is associated with hypercholesterolemia and liver steatosis. Here we show a human CAR agonist/PXR antagonist, MI-883, which effectively regulates genes related to xenobiotic metabolism and cholesterol/bile acid homeostasis by leveraging CAR and PXR interactions in gene regulation. Through comprehensive analyses utilizing lipidomics, bile acid metabolomics, and transcriptomics in humanized PXR-CAR-CYP3A4/3A7 mice fed high-fat and high-cholesterol diets, we demonstrate that MI-883 significantly reduces plasma cholesterol levels and enhances fecal bile acid excretion. This work paves the way for the development of ligands targeting multiple xenobiotic nuclear receptors. Such ligands hold the potential for precise modulation of liver metabolism, offering new therapeutic strategies for metabolic disorders.

PMID:39915454 | DOI:10.1038/s41467-025-56642-y

Pediatr Transplant. 2025 Mar;29(2):e70045. doi: 10.1111/petr.70045.

NO ABSTRACT

PMID:39915226 | DOI:10.1111/petr.70045

Biomed Pharmacother. 2025 Feb 4;184:117873. doi: 10.1016/j.biopha.2025.117873. Online ahead of print.

ABSTRACT

One of the principal challenges in managing hypertension is suboptimal medication adherence, which can result in up to 50 % of patients experiencing pseudo-resistant hypertension and inadequate blood pressure control. The intricate nature of antihypertensive regimens, the high cost of therapy, the prevalence of numerous adverse effects and the therapeutic inertia commonly lead to inconsistent drug use and premature discontinuation of treatment. Consequently, nonadherence significantly elevates the risk of cardiovascular events. Drug concentrations in the patient's serum or urine (also known as therapeutic drug monitoring, or TDM) and blood pressure measurements following supervised medication ingestion are two techniques for assessing treatment adherence. In alignment with guideline from the Food and Drug Administration (FDA) and European Medicines Agency (EMA), this study aims to design, develop, and validate a single UHPLC method for the plasma quantification of five antihypertensive drugs within the calcium channel blocker class: amlodipine, nifedipine, barnidipine, lercanidipine and lacidipine.

PMID:39913972 | DOI:10.1016/j.biopha.2025.117873

Med Oncol. 2025 Feb 6;42(3):67. doi: 10.1007/s12032-025-02611-w.

ABSTRACT

Currently, there is a growing concern surrounding the treatment of cancer, a formidable disease. Pharmacogenomics and personalized medicine have emerged as significant areas of interest in cancer management. The efficacy of many cancer drugs is hindered by resistance mechanisms, particularly P-glycoprotein (P-gp) efflux, leading to reduced therapeutic outcomes. Efforts have intensified to inhibit P-gp efflux, thereby enhancing the effectiveness of resistant drugs. P-gp, a member of the ATP-binding cassette (ABC) superfamily, specifically the multidrug resistance (MDR)/transporter associated with antigen processing (TAP) sub-family B, member 1, utilizes energy derived from ATP hydrolysis to drive efflux. This review focuses on genetic polymorphisms associated with P-gp efflux and explores various novel pharmaceutical strategies to address this challenge. These strategies encompass SEDDS/SNEDDS, liposomes, immunoliposomes, solid lipid nanoparticles, lipid core nanocapsules, microemulsions, dendrimers, hydrogels, polymer-drug conjugates, and polymeric nanoparticles. The article aims to elucidate the interplay between pharmacogenomics, P-gp-mediated drug resistance in cancer, and formulation strategies to improve cancer therapy by tailoring formulations to genetically susceptible patients.

PMID:39913003 | DOI:10.1007/s12032-025-02611-w

J Palliat Med. 2025 Feb 6. doi: 10.1089/jpm.2025.0038. Online ahead of print.

NO ABSTRACT

PMID:39911035 | DOI:10.1089/jpm.2025.0038

Cancer Epidemiol Biomarkers Prev. 2025 Feb 6;34(2):221-223. doi: 10.1158/1055-9965.EPI-24-1617.

ABSTRACT

The selective estrogen receptor modulator tamoxifen is a mainstay of endocrine breast cancer therapy. However, the clinical response rates of tamoxifen are inferior to those of aromatase inhibitors, which may be partially explained by variable drug exposure due to the pharmacogenetics of the drug-metabolizing enzyme cytochrome P450 (CYP) 2D6. Clinical trials investigating the association between CYP2D6 impairment and tamoxifen outcomes have yielded conflicting results. The results of a comprehensive meta-analysis of 33 single-center tamoxifen trials reported here address this inconsistency by adjusting for two biases that may affect the validity of previous association studies: allele coverage of CYP2D6 genotyping and loss of heterozygosity of the CYP2D6 locus in tumor-derived DNA. After adjustment for bias, meta-analyses show significantly reduced study heterogeneity and a higher risk of recurrence or death in patients with impaired CYP2D6 metabolism compared with those with normal activity. These data may support the use of pharmacogenetics-guided tamoxifen therapy to improve outcomes in patients with CYP2D6-compromised breast cancer. Prospective studies should be considered. See related article by MacLehose et al., p. 224.

PMID:39910985 | DOI:10.1158/1055-9965.EPI-24-1617

Clin Transl Sci. 2025 Feb;18(2):e70138. doi: 10.1111/cts.70138.

ABSTRACT

To plan future steps for the implementation and regulation of pharmacogenetic testing, any issue in the management of pharmacogenetic information by regulatory bodies must be identified. In this paper, an analysis of pharmacogenetic information in the summary of product characteristics (SmCPs) of drugs approved by Italian Drug Agency (AIFA) was conducted. Among 4214 SmCPs of 1063 active ingredients, 53.2% (n = 2240) included pharmacogenetic information in at least one section, most frequently for drugs in the Anatomical Therapeutic Chemical category "Antineoplastic and immunomodulatory agents". To contextualize these data in the international scenario, a pharmacogenetic level of actionability, based on AIFA SmCPs, was assigned to 608 drug/gene pairs included in FDA's "Table of Pharmacogenomic Biomarkers in Drug Labels", according to PharmGKB (The Pharmacogenomics Knowledge Base). Approximately 67% of drug/gene pairs were deemed classifiable: Based on SmCPs phrasing, for half of them the genetic testing was cataloged as "required" or "recommended" (mainly tumor somatic variants), whereas 40% as "actionable" (mostly PK/PD-related germline variants). The comparison with other regulatory agencies highlighted a discordance in the assigned pharmacogenetic levels of actionability ranging from 1% to 14%. This discrepancy may also point out the need to rethink the language used in AIFA-approved SmCPs to clarify whether a pharmacogenetic test is necessary or not and for which subjects it has been recommended. For the first time, a detailed evaluation and comparative analysis of the pharmacogenetic information on Italian SmCPs was presented, placing it in an international context and laying the groundwork for rethinking pharmacogenetic indications in AIFA-approved SmCPs.

PMID:39910906 | DOI:10.1111/cts.70138

J Exp Clin Cancer Res. 2025 Feb 5;44(1):40. doi: 10.1186/s13046-025-03306-w.

ABSTRACT

BACKGROUND: Despite the high response rate to PD-1 blockade therapy in metastatic melanoma (MM) patients, a significant proportion of patients do not respond. Identifying biomarkers to predict patient response is crucial, ideally through non-invasive methods such as liquid biopsy.

METHODS: Soluble forms of PD1, PD-L1, LAG-3, CTLA-4, CD4, CD73, and CD74 were quantified using ELISA assay in plasma of a cohort of 110 MM patients, at baseline, to investigate possible correlations with clinical outcomes. A clinical risk prediction model was applied and validated in pilot studies.

RESULTS: No biomarker showed statistically significant differences between responders and non-responders. However, high number of significant correlations were observed among certain biomarkers in non-responders. Through univariate and multivariate Cox analyses, we identified sPD-L1, sCTLA-4, sCD73, and sCD74 as independent biomarkers predicting progression-free survival and overall survival. According to ROC analysis we discovered that, except for sCD73, values of sPD-L1, sCTLA-4, and sCD74 lower than the cut-off predicted lower disease progression and reduced mortality. A comprehensive risk score for predicting progression-free survival was developed by incorporating the values ​​of the two identified independent factors, sCTLA-4 and sCD74, which significantly improved the accuracy of outcome prediction. Pilot validations highlighted the potential use of the risk score in treatment-naive individuals and long responders.

CONCLUSION: In summary, risk score based on circulating sCTLA-4 and sCD74 reflects the response to immune checkpoint inhibitor (ICI) therapy in MM patients. If confirmed, through further validation, these findings could assist in recommending therapy to patients likely to experience a long-lasting response.

PMID:39910579 | DOI:10.1186/s13046-025-03306-w

Br J Pharmacol. 2025 Feb 5. doi: 10.1111/bph.17449. Online ahead of print.

ABSTRACT

BACKGROUND AND PURPOSE: Non-adherence to atorvastatin treatment is relatively common and partly due to statin-related myotoxicities (SRMs). The risk of developing SRM is dose- and concentration-dependent, highlighting the importance of atorvastatin pharmacokinetics. This study explored the inter-individual variabilities in expression of the atorvastatin transporter gene contributing to modulation of atorvastatin within the muscle cell.

EXPERIMENTAL APPROACH: mRNA levels of efflux and influx transporters were measured and modulated with siRNAs to evaluate effects on intracellular accumulation of atorvastatin in primary cultures of differentiated myotubes from 12 human volunteers.

KEY RESULTS: All genes assessed were expressed with a high inter-individual variability. In differentiated myotubes, efflux transporters were expressed at higher levels than the influx carriers. When considering efflux and influx transporters separately, ABCC1 and SLCO2B1 are the most highly expressed efflux and influx transporters. Suppression of ABCC1, ABCC4 and/or ABCG2 mRNA levels with siRNA significantly increased intracellular accumulation of atorvastatin in differentiated myotubes. Interestingly, the siRNA targeting ABCG2 had a moderate effect on intracellular accumulation of atorvastatin in a volunteer expressing the ABCG2 variant rs2231142 (c.421C>A, p.Gln141Lys). This hypothesis was further validated in a HEK recombinant model overexpressing ABCG2 either wild-type (421C) or variant (421A). Reduction of SLCO1B1 and SLCO2B1 mRNA levels significantly modified intracellular accumulation of atorvastatin in only some volunteers, depending on the expression levels of transporters.

CONCLUSION AND IMPLICATIONS: Silencing ABCC1, ABCC4 or ABCG2 expression alters accumulation of atorvastatin in myotubes, whereas the effect of silencing influx transporters depends on the expression of these transporters.

PMID:39909477 | DOI:10.1111/bph.17449

Pharmacol Ther. 2025 Feb 4;267:108805. doi: 10.1016/j.pharmthera.2025.108805. Online ahead of print.

ABSTRACT

The interactions of drugs with the host's immune cells determine the drug's efficacy and adverse effects in patients. Nonsteroidal Anti-Inflammatory Drugs (NSAID), such as corticosteroids, NSAIDs, and immunosuppressants, affect the immune cells and alter the immune response. Molecularly, drugs can interact with immune cells via cell surface receptors, changing the antigen presentation by modifying the co-stimulatory molecules and interacting with the signaling pathways of T cells, B cells, Natural killer (NK) cells, mast cells, basophils, and macrophages. Immunotoxicity, resulting from drug-induced changes in redox status, generation of Reactive Oxygen Species (ROS)/Reactive Nitrogen Species (RNS), and alterations in antioxidant enzymes within immune cells, leads to immunodeficiency. This, in turn, causes allergic reactions, autoimmune diseases, and cytokine release syndrome (CRS). The treatment options should include the evaluation of immune status and utilization of the concept of pharmacogenomics to minimize the chances of immunotoxicity. Many strategies in redox, like targeting the redox pathway or using redox-active agents, are available for the modulation of the immune system and developing drugs. Case studies highlight significant drug-immune cell interactions and patient outcomes, underscoring the importance of understanding these complexities. The future direction focuses on the drugs to deliver antiviral therapy, new approaches to immunomodulation, and modern technologies for increasing antidote effects with reduced toxicity. In conclusion, in-depth knowledge of the interaction between drugs and immune cells is critical to protect the patient from the adverse effects of the drug and improve therapeutic outcomes of the treatment process. This review focuses on the multifaceted interactions of drugs and their consequences at the cellular levels of immune cells.

PMID:39908660 | DOI:10.1016/j.pharmthera.2025.108805

Cancer Res. 2025 Feb 4. doi: 10.1158/0008-5472.CAN-24-2289. Online ahead of print.

ABSTRACT

Non-coding RNA transcribed from active enhancers, known as enhancer RNA (eRNA), is a critical element in gene regulation with a highly specific expression pattern in the regulatory networks of tumor-infiltrating cells. Therefore, eRNA signatures could potentially be applied to represent anti-tumor immune cells and to improve cancer immunotherapy. Herein, we identified thousands of eRNAs that were significantly correlated with infiltrating immune cell abundance in more than 10,000 patient samples across a variety of cancer types. The expression of these eRNAs was mediated by transcription factors with high expression in anti-tumor immune cells, as identified through single-cell assays. An eRNA immunotherapy signature (eRIS) developed using the anti-tumor eRNAs was highly associated with the objective response rate (ORR) of immunotherapy and was elevated in patients who benefited from immune checkpoint blockade (ICB) treatment. In comparison with a signature based on protein-coding genes, the eRIS was more effective in predicting the response to immunotherapy. Integration of the eRIS with pharmacogenomic data revealed hundreds of anti-cancer drugs that have the potential to enhance immunotherapy efficacy. Finally, treatment of a mouse model of IDH mutant glioma with the histone deacetylase inhibitor vorinostat improved the effects of anti-PD-1 immunotherapy through increased abundance of infiltrating immune cells. Taken together, this study developed an eRIS with demonstrated efficacy in predicting immunotherapy response and used the eRIS to identify a series of effective combination drugs, thus highlighting the clinical utility of the eRIS in immunotherapy enhancement.

PMID:39903841 | DOI:10.1158/0008-5472.CAN-24-2289

Elife. 2025 Feb 4;13:RP97577. doi: 10.7554/eLife.97577.

ABSTRACT

Progression through the G1 phase of the cell cycle is the most highly regulated step in cellular division. We employed a chemogenetic approach to discover novel cellular networks that regulate cell cycle progression. This approach uncovered functional clusters of genes that altered sensitivity of cells to inhibitors of the G1/S transition. Mutation of components of the Polycomb Repressor Complex 2 rescued proliferation inhibition caused by the CDK4/6 inhibitor palbociclib, but not to inhibitors of S phase or mitosis. In addition to its core catalytic subunits, mutation of the PRC2.1 accessory protein MTF2, but not the PRC2.2 protein JARID2, rendered cells resistant to palbociclib treatment. We found that PRC2.1 (MTF2), but not PRC2.2 (JARID2), was critical for promoting H3K27me3 deposition at CpG islands genome-wide and in promoters. This included the CpG islands in the promoter of the CDK4/6 cyclins CCND1 and CCND2, and loss of MTF2 lead to upregulation of both CCND1 and CCND2. Our results demonstrate a role for PRC2.1, but not PRC2.2, in antagonizing G1 progression in a diversity of cell linages, including chronic myeloid leukemia (CML), breast cancer, and immortalized cell lines.

PMID:39903505 | DOI:10.7554/eLife.97577

Pharmgenomics Pers Med. 2025 Jan 30;18:19-34. doi: 10.2147/PGPM.S490135. eCollection 2025.

ABSTRACT

Pharmacogenomics is the integration of genomics and pharmacology to optimize drug response and reduce side effects. In terms of personalized or individualized medicine, PGx is defined as the identification and analysis of specific genetic variants associated with particular drug treatments for each patient. Under a precision public health (PPH) approach, population-level data are analyzed to generate public health strategies. The objective of this study was to conduct a scoping review of technological tools, examining their evolution, the predominance of high-income countries in their development, and the gaps and needs for genomic data and advances in low- and middle-income countries (LMICs). This review was conducted in accordance with the ScPRISMA guidelines. A search was conducted in PubMed, Web of Science and Embase until January 2024. A total of 40 documents were selected, which revealed the continuous evolution and progressive development of pharmacogenomic tools. The technological tools developed come from high-income countries, particularly the United States, Canada, China, and several European nations, where international collaboration has been essential to maintain and expand these tools, which have evolved to keep pace with the rapid generation of genomic data. This trend shows a scarce development of technological tools for public health precision in LMICs, which evidences the need to increase investment in genomic research infrastructure in this aspect and in the development of capacities to guarantee global accessibility and boost PPH for all populations.

PMID:39902237 | PMC:PMC11789506 | DOI:10.2147/PGPM.S490135

Curr Cardiol Rev. 2025 Jan 31. doi: 10.2174/011573403X334668241227074314. Online ahead of print.

ABSTRACT

Pharmacogenomics has transformed the way we approach the treatment of the most common diseases worldwide, especially cardiovascular. In this article, we highlight the main categories of drugs involved in major cardiovascular diseases (CVD), related genetic variability and their effects on metabolism in each case of contrastive operability. This not only explains disparities in treatment outcomes but also unfolds customised management based on genomic studies to improve efficiency and limit side effects. Genetic variations have been identified that impact the efficacy, safety, and adverse effects of drugs commonly used in the treatment of CVDs, such as Angiotensin converting Enzyme Inhibitor (ACEI), Angiotensin Receptor Blocker (ARBs), calcium channel blockers, antiplatelet agents, diuretics, statins, beta-blockers, and anticoagulants. It discusses the impact of genetic polymorphisms on drug metabolism, efficacy, and adverse reactions, highlighting the importance of genetic testing in optimizing treatment outcomes. Pharmacogenomics holds immense potential for revolutionizing the management of CVDs by enabling personalized medicine approaches tailored to individual genetic profiles. However, challenges such as clinical implementation, cost-effectiveness, and ethical considerations need to be addressed to completely incorporate pharmacogenomic testing into standard clinical practice. Continued research and clinical diligence are required for the utilization of pharmacogenomics to improve therapeutic outcomes and reduce the burden of CVD globally.

PMID:39901689 | DOI:10.2174/011573403X334668241227074314

Pharmacol Res Perspect. 2025 Feb;13(1):e70065. doi: 10.1002/prp2.70065.

ABSTRACT

Pharmacogenomics is a field of personalized medicine that aims to tailor drug dosing based on the genetics of an individual. The polymorphic and complex CYP2D6 gene is important to analyze because of its role in the metabolism of approximately a quarter of all drugs. Several bioinformatic tools have been developed to genotype CYP2D6 from short-read sequencing data. Among these, Cyrius, a tool specifically designed for CYP2D6 genotyping, has demonstrated high performance across various datasets. However, Cyrius has not been updated in the past 3 years, during which dozens of new star alleles have been identified and some previously defined ones revised. In this work, we simulated all known CYP2D6 haplotypes to assess the ability of Cyrius to identify them. In that dataset, Cyrius was unable to call or misidentified 50 of 360 samples. Given the importance of providing an up-to-date tool, particularly in clinical settings, we present an upgraded version of the tool, named BCyrius, which includes all the missing star alleles as well as revisions to the previously listed ones. BCyrius successfully identified 100% of the currently defined minor star alleles, higher than Cyrius (85.6%) and the two other tested tools, Aldy and StellarPGx, which identified 92.2% and 87.8%, respectively. BCyrius also demonstrated slightly improved performance on a dataset of real biological samples, resulting in a higher call rate while maintaining similar accuracy with Cyrius. In addition to providing genotyping results, BCyrius also reports the predicted phenotype, along with information for each detected haplotype, including population frequencies.

PMID:39901590 | DOI:10.1002/prp2.70065

Commun Med (Lond). 2025 Feb 3;5(1):34. doi: 10.1038/s43856-025-00745-6.

ABSTRACT

BACKGROUND: Although COVID-19 initially caused great concern about respiratory symptoms, mounting evidence shows that also the pancreas is productively infected by SARS-CoV-2. However, the severity of pancreatic SARS-CoV-2 infection and its pathophysiology is still under debate. Here, we investigate the consequences of SARS-CoV-2 pancreatic infection and the role of the host factor Placenta-associated protein (PLAC8).

METHODS: We analyze plasma levels of pancreatic enzymes and inflammatory markers in a retrospective cohort study of 120 COVID-19 patients distributed in 3 severity-stratified groups. We study the expression of SARS-CoV-2 and PLAC8 in the pancreas of deceased COVID-19 patients as well as in non-infected donors. We perform pseudovirus infection experiments in PLAC8 knock-out PDAC and human beta cell-derived cell lines and validate results with SARS-CoV-2 virus.

RESULTS: We find that analysis of circulating pancreatic enzymes aid the stratification of patients according to COVID-19 severity and predicts outcomes. Interestingly, we find an association between PLAC8 expression and SARS-CoV-2 infection in postmortem analysis of COVID-19 patients both in the pancreas and in other bonafide SARS-CoV-2 target tissues. Functional experiments demonstrate the requirement of PLAC8 in SARS-CoV-2 pancreatic productive infection by pseudovirus and full SARS-CoV-2 infectious virus inoculum from Wuhan-1 and BA.1 strains. Finally, we observe an overlap between PLAC8 and SARS-CoV-2 immunoreactivities in the pancreas of deceased patients.

CONCLUSIONS: Our data indicate the human pancreas as a SARS-CoV-2 target with plausible signs of injury and demonstrate that the host factor PLAC8 is required for SARS-CoV-2 pancreatic infection, thus defining new target opportunities for COVID-19-associated pancreatic pathogenesis.

PMID:39900678 | DOI:10.1038/s43856-025-00745-6

Clin Transl Sci. 2025 Feb;18(2):e70108. doi: 10.1111/cts.70108.

ABSTRACT

5-hydroxytryptamine-3 (5-HT3) receptor antagonists including ondansetron, tropisetron, dolasetron, palonosetron, granisetron, and ramosetron are commonly used to prevent and treat nausea and vomiting. Most of these medications are at least partially metabolized via the highly polymorphic CYP2D6 enzyme, resulting in variations of metabolism among individuals. Current (2017) international prescribing guidelines for ondansetron/tropisetron use according to genotype provide recommendations for CYP2D6 ultrarapid metabolizers but not intermediate or poor metabolizers. However, multiple studies have been conducted since this guideline was published. This review evaluated all available evidence of an association between CYP2D6 genotype and 5-HT3 receptor antagonist outcomes, including in patients who are CYP2D6 intermediate/poor metabolizers and pediatric-specific studies. In this review, we confirm that CYP2D6 genotype impacts ondansetron response in a postoperative nausea and vomiting setting, which was supported by a meta-analysis. We also highlight the heterogeneity and limitations of included studies as well as provide future directions for pharmacogenomics research.

PMID:39899439 | DOI:10.1111/cts.70108

Front Nutr. 2025 Jan 17;12:1524125. doi: 10.3389/fnut.2025.1524125. eCollection 2025.

ABSTRACT

Intermittent fasting has been linked to metabolic health by improving lipid profiles, reducing body weight, and increasing insulin sensitivity. However, several randomized clinical trials have shown that intermittent fasting is not more effective than standard daily caloric restriction for short-term weight loss or cardiometabolic improvements in patients with obesity. Observational studies also suggest cardiovascular benefits from extended rather than reduced eating windows, and indicate that long-term intermittent fasting regimens may increase the risk of cardiovascular disease mortality. In this perspective, we discuss evidence that may support potential adverse effects of intermittent fasting on cardiovascular health through the loss of lean mass, circadian misalignment and poor dietary choices associated with reward-based eating. Given the ongoing revolution in obesity pharmacotherapy, we argue that future research should integrate anti-obesity medications with dietary strategies that confer robust benefits to cardiometabolic health, combine exercise regimens, and consider genetic factors to personalize obesity treatment. Comprehensive approaches combining diet, pharmacotherapy, and lifestyle modifications will become crucial for managing obesity and minimizing long-term cardiovascular risk.

PMID:39895836 | PMC:PMC11782017 | DOI:10.3389/fnut.2025.1524125

Biol Pharm Bull. 2025;48(1):86-92. doi: 10.1248/bpb.b24-00684.

ABSTRACT

Vitamin D plays a crucial role in immune system function. Several studies have indicated that genetic variations in the vitamin D receptor (VDR) and vitamin D binding protein (VDBP, encoded by GC gene) increase the risk of developing asthma. However, the effect of these variations on the prognosis and clinical outcomes of asthma remains unclear. This study, involving 152 adult patients with asthma, aimed to assess the influence of VDR and GC polymorphisms on asthma severity and its exacerbation. Gene polymorphisms previously associated with asthma risk were analyzed, and VDR mRNA expression levels were evaluated in peripheral blood mononuclear cells. The AA genotype of the VDR rs2228570 polymorphism was associated with an elevated risk of severe asthma compared to the AG/GG genotype (odds ratio, 3.20; 95% confidence interval [CI], 1.24-8.28). Furthermore, patients with the rs2228570 AA genotype showed an elevated risk of exacerbation during the 1-year follow-up period (hazard ratio, 4.01; 95% CI, 1.75-9.15). VDR mRNA expression was significantly reduced in patients with the AA genotype. Furthermore, the mRNA expression levels of GLCCI1, HDAC2, NR3C1, and NFE2L2, which are associated with steroid response, were reduced in patients with the AA genotype. Our findings indicate that patients with the AA genotype of VDR rs2228570 are more likely to experience severe asthma and exacerbations. This polymorphism has the potential to reduce vitamin D efficacy by altering VDR function and expression, potentially resulting in increased inflammation and reduced steroid responsiveness in patients with asthma.

PMID:39894560 | DOI:10.1248/bpb.b24-00684