Drug Saf. 2025 Jun 14. doi: 10.1007/s40264-025-01571-4. Online ahead of print.

ABSTRACT

BACKGROUND: Adverse drug events (ADEs) are events occurring after the administration of a drug. Several authorities are involved in capturing these ADEs to improve pharmacovigilance. These ADEs are reported directly to healthcare professionals or via the telephone, online, or e-mail and are crucial for maintaining drug safety.

OBJECTIVE: Patient-reported adverse drug events (ADEs) are collected using various tools, though not much is known with regard to the comparability of these different methodologies. It is known that telephone-based surveys result in a higher report rate, although it is not known if this has an effect on the type of ADEs that are reported. In this prospective study, we aimed to investigate if there are differences in the number, type, and severity of ADEs reported via telephone and online in an event monitoring setting.

METHODS: Patients included in Dutch community pharmacies were asked whether they experienced any ADEs via telephone and online (Lareb Intensive Monitoring) surveys as part of the PREPARE study. The PREPARE study was a multicenter study, researching the effect of genotype-guided dosing on the incidence of clinically relevant adverse drug reactions. With the paired data acquired in the PREPARE study, we investigated differences in the number, type, and severity of the reported ADEs.

RESULTS: Patients (N = 525) completed both the telephone and online surveys. Of the 525 patients who completed both surveys, 326 reported ADEs via telephone and 239 online. A visual comparison showed a similar distribution in the type of ADEs among the methods except for less commonly reported types of ADEs and cardiac disorders. The perceived severity of ADEs were proportionally reported as more severe during the telephone survey versus the online survey.

CONCLUSIONS: Our study showed a clear difference in the number of ADEs reported during telephone and online monitoring. Additionally, the differences in the type of ADEs and the severity distribution of both tools shows that the tools are not exchangeable (CT.gov identifier: NCT03093818).

PMID:40517185 | DOI:10.1007/s40264-025-01571-4

Cancer Lett. 2025 Jun 12:217865. doi: 10.1016/j.canlet.2025.217865. Online ahead of print.

ABSTRACT

Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by its lack of estrogen, progesterone, and HER2 receptors, leading to limited treatment options and poor prognosis. This review synthesizes current research on the tumor microenvironment (TME) and immune cell crosstalk in TNBC to identify emerging therapeutic opportunities. The TME in TNBC is a complex ecosystem comprising immune cells, fibroblasts, and extracellular matrix components, which significantly influence tumor growth and metastasis. Single-cell RNA sequencing reveals T-cell heterogeneity and identifies prognostic genes. Regulatory T cells (Tregs) play a key role in immunosuppression, with thymidine kinase-1 (TK1) identified as a potential therapeutic target. MUC1-C and CXCL9 modulate the TME, impacting T-cell depletion and macrophage differentiation. Spatial analysis highlights the importance of cell-to-cell interactions in predicting recurrence. Epithelial-mesenchymal transition (EMT) and thermogenesis also influence the TME, while epigenetic modifications, such as HDAC inhibition, can induce pyroptosis and enhance immune cell recruitment. Integrating genomic information with TME analysis is crucial for developing personalized treatments, considering racial disparities in immune infiltration. Emerging therapies targeting immune checkpoints, modulating Treg activity, and inducing pyroptosis hold promise for improving TNBC patient outcomes. Future research should focus on multi-omics data, spatial transcriptomics, and patient-derived models to refine therapeutic interventions.

PMID:40516902 | DOI:10.1016/j.canlet.2025.217865

Pharmacogenomics J. 2025 Jun 13;25(4):16. doi: 10.1038/s41397-025-00375-0.

NO ABSTRACT

PMID:40514366 | DOI:10.1038/s41397-025-00375-0

J Immunother Cancer. 2025 Jun 12;13(6):e011611. doi: 10.1136/jitc-2025-011611.

ABSTRACT

BACKGROUND: Chronic stress is known to promote cancer progression, in part by modulating immune responses through the β2-adrenergic receptor (ADRB2). Inhibiting ADRB2 with β-blockers has demonstrated potential in boosting the effectiveness of immune checkpoint inhibitors across a spectrum of cancers, yet the precise mechanisms remain to be fully elucidated.

METHODS: In vivo and in vitro experiments were performed to evaluate the role of ADRB2 in melanoma models, including its effects on T cells. RNA sequencing analysis highlighted the importance of the transcription factor SRY-related HMG-box 10 (SOX10), which transcriptionally regulates programmed death-ligand 1 (PD-L1). This regulatory role was further validated using luciferase reporter assays and chromatin immunoprecipitation-PCR assays. Mechanistic studies focused on ADRB2 signaling through protein kinase A (PKA) and its downstream target SOX10. To investigate SOX10's role in mediating the effects of ADRB2, knockdown and overexpression experiments were conducted. Additionally, similar studies in colorectal cancer (CRC) models confirmed the conserved function of the ADRB2-SOX10-PD-L1 axis.

RESULTS: This study explores the role of ADRB2 in regulating tumor PD-L1 expression and T cell functionality, offering insights for cancer immunotherapy. Clinical data revealed that patients with melanoma with high ADRB2 expression responded better to programmed cell death protein 1 inhibitors. In melanoma models, ADRB2 inhibition reduced PD-L1 expression, enhanced T cell infiltration, and promoted antitumor immunity, while ADRB2 activation had the opposite effect. Mechanistically, ADRB2 signaling through PKA upregulated SOX10, which transcriptionally modulates PD-L1. SOX10 knockdown replicated the effects of ADRB2 inhibition, while SOX10 overexpression reversed them. Similar findings in CRC models confirmed the conserved role of the ADRB2-SOX10-PD-L1 axis. Targeting ADRB2 and SOX10 may enhance immune checkpoint inhibitor efficacy in cancer treatment.

CONCLUSIONS: These findings underscore the potential of ADRB2 and SOX10 as therapeutic targets for mitigating stress-induced immunosuppression and for augmenting the effectiveness of immunotherapies in a variety of cancer types.

PMID:40514069 | DOI:10.1136/jitc-2025-011611

Neurochem Int. 2025 Jun 11:106007. doi: 10.1016/j.neuint.2025.106007. Online ahead of print.

ABSTRACT

DNA methylation and hydroxymethylation patterns at the 5th carbon of cytosine (5mC and 5hmC) in CpG dinucleotides tightly regulate gene transcription in normal physiology, aging, and associated diseases, including ischemic stroke. Resilience to ischemic brain injury depends on the interplay of diverse neural and non-neural cell types, whose gene expression and identity are predominantly regulated by brain-enriched epigenetic mechanisms, particularly the dynamics of 5mC and 5hmC in response to changing transcriptional demands under ischemic stress. In this review, we discussed the role of 5mC and 5hmC in aging and the pathophysiology of stroke. Given the high degree of inter-individual variability in stroke studies and its multifactorial etiology, we emphasize the need for personalized, temporally controlled, epigenome-based therapies to improve stroke outcomes.

PMID:40513956 | DOI:10.1016/j.neuint.2025.106007

Prog Neuropsychopharmacol Biol Psychiatry. 2025 Jun 11:111428. doi: 10.1016/j.pnpbp.2025.111428. Online ahead of print.

ABSTRACT

BACKGROUND: Obsessive-compulsive disorder (OCD) is a common neuropsychiatric disorder with a strong genetic component. Previous studies have suggested a role for the dopamine receptor genes in OCD with the dopamine D3 receptor (DRD3) gene being relatively overlooked. There is neurobiological evidence that D3 may be involved in the striatal-cortical circuits that affect compulsive behaviour and anxiety. Thus, we investigated genetic variants of DRD3 in association with OCD and serotonin reuptake inhibitor (SRI) response.

METHODS: We examined nine polymorphisms across DRD3 in 318 individuals with OCD (comprised of 129 small nuclear families, and 196 independent singleton cases) compared to 196 healthy controls matched for age, gender, and ethnicity using the family-based association test (FBAT) and case-control analysis respectively. Quantitative analyses were performed with age at onset (AAO) and Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) severity scores.

RESULTS: Nominally significant biased transmission of alleles in polymorphic sites rs2399504, rs7611535, rs1394016, Ser9Gly, rs167770, and rs2087017 was observed with FBAT. The rs2399504, rs7611535, rs1394016, Ser9Gly, and rs167770 polymorphisms were associated with AAO but not with Y-BOCS scores using FBAT. Five polymorphisms (rs2399504, rs7611535, rs1394016, Ser9Gly, and rs167770) showed a trend in case-control analyses for allele/genotype distributions. Haplotype analyses of the polymorphisms using Haploview revealed several combinations of markers associated with OCD. Nominally positive association between rs167770 and rs11721264 and sertraline response remained significant after correction for multiple testing.

CONCLUSION: This is the first report to our knowledge of involvement of DRD3 in OCD, which requires further research.

PMID:40513807 | DOI:10.1016/j.pnpbp.2025.111428

Gene. 2025 Jun 11:149631. doi: 10.1016/j.gene.2025.149631. Online ahead of print.

ABSTRACT

To investigate the association of KEAP1 rs1048290, rs9676881 and NFE2L2 rs6706649, rs6721961, rs35652124 polymorphisms with glycemic control and development of late complications in patients with type 2 diabetes mellitus (T2DM), a total of 316 T2DM patients were included in the retrospective genetic association study. Genotyping was performed using competitive allele-specific PCR. Data on HbA1c levels as a measure of glycemic control, and information on late complications, including ischemic heart disease, retinopathy, and nephropathy, was obtained from the medical records. Logistic regression analysis was used to assess the association between selected genetic polymorphisms and patients outcomes. Significant associations were observed between KEAP1 rs9676881 (p < 0.001) and NFE2L2 rs6721961 (p = 0.006) polymorphisms and elevated HbA1c levels. Additionally, NFE2L2 rs35652124 polymorphism was linked to a nominally higher risk of late complications, including ischemic heart disease (p = 0.036), retinopathy (p = 0.032), and nephropathy (p = 0.026). Results indicate that polymorphisms in the KEAP1 and NFE2L2 genes may influence glycemic control and the development of late complications in T2DM patients. These findings provide valuable insights into the genetic factors underlying T2DM progression and its complications in European populations, highlighting the potential role of genetic markers in optimizing personalized treatment strategies.

PMID:40513688 | DOI:10.1016/j.gene.2025.149631

Eur J Cancer. 2025 Jun 3;225:115534. doi: 10.1016/j.ejca.2025.115534. Online ahead of print.

ABSTRACT

IMPORTANCE AND BACKGROUND: In high-grade serous ovarian cancer (HGSOC) bevacizumab (bev)/olaparib (ola) maintenance was approved for patients with homologous recombination DNA repair deficiency (HRD+) tumors. Although different methods exist to score genomic instability, DNA quality, tumor cell content, and costs may impair our ability to identify patients that will benefit from treatment.

PATIENTS AND METHOD: We analyzed BRCA1 and RAD51C methylation as an HRD determination tool in patients newly diagnosed of HGSOC (n = 519) based on data from the PAOLA-1/ENGOT-ov25 trial phase III prospective trial. Methylation was analyzed using quantitative methylation specific PCR, correlated to HRD scores, PFS and OS.

RESULTS: 67 (12.9 %) were BRCA1 and 25 (4.8 %) were RAD51C methylated. Of the 81 samples with a failed HRD score, 13 were methylated. Methylated samples were HRD+ (mean score [95 % CI]; 65.9 [62.7-69.1] and 53.3 [48.0-58.6]) and almost mutually exclusive of BRCA1&2 mutations. A significant PFS1 benefit independently of methylation ratios was observed in patients with methylated tumors with bev-ola maintenance compared to bev alone (HR=0.49, 95 % CI 0.29-0.83, P = 0.008). An OS benefit was shown for patients defined as "all-HRD" (including methylation) (HR=0.59, 95 % CI 0.41-0.86, P = 0.007).

CONCLUSIONS: This study confirms the feasibility and clinical value of BRCA1/RAD51C methylation for predicting response to ola-bev maintenance in newly diagnosed HGSOC. Assessment of methylation in parallel to mutation testing allowed the identification of nearly 85 % of HRD+ samples at low costs. This study suggests that methylation testing could be easily implemented to optimize the selection of patients that benefit from olaparib+bevacizumab maintenance.

PMID:40513287 | DOI:10.1016/j.ejca.2025.115534

Pharmacogenet Genomics. 2025 Jun 13. doi: 10.1097/FPC.0000000000000572. Online ahead of print.

ABSTRACT

INTRODUCTION: Praziquantel (PZQ) is commonly used to treat schistosomiasis; however, there is considerable interindividual variability in its efficacy, partly because of genetic variation. Data on this relationship is scarce across Africa - where schistosomiasis is prevalent. This study aimed to investigate the pharmacokinetic/pharmacodynamic and pharmacogenetic relationship between PZQ and its metabolites in a Zimbabwean population infected with Schistosoma haematobium by leveraging dried blood spots (DBS) and mass spectrometry (MS).

METHODS: DBS were obtained from 38 Zimbabwean participants on PZQ treatment at four-time points (0.5, 1.5, 2.5, and 4 h). We compared two extraction methods for recovering PZQ and its metabolites from the DBS cards and performed MS analysis to determine the concentrations. A random forest model was used to determine whether CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 known variants were predictive of PZQ efficacy. The relationships between PZQ/metabolite concentration, metabolite ratio, and drug exposure with genotype were determined using a one-way analysis of variance.

RESULTS: An acetonitrile and water (4 : 1) mixture was determined to be optimal for recovering PZQ and its metabolites from the DBS cards. Subsequent MS analysis identified PZQ and six metabolite compounds - including phase 1 metabolites (-2H)-O-PZQ, O2-PZQ, and 4-OH-PZQ. Pooled MS sampling was comparable to individual MS sampling for determining pharmacokinetic profiles at the 2.5 and 4-h time points. The (-2H)-O-PZQ and O2-PZQ metabolites had significantly higher concentrations in participants with CYP2C9*1/*9 and *9/*9 versus those with CYP2C9*1/*1. CYP1A2 rs2069514-A (formerly *1C) and rs762551-A (CYP1A2*30; formerly *1F) were observed to alter PZQ pharmacokinetic profiles; however, differences in analyte concentrations across the corresponding genotypes were NS.

CONCLUSION: We show that low-cost microsampling using DBS and MS is feasible for detecting and quantifying PZQ and its metabolites. Furthermore, our pharmacogenetics analysis elucidates the impact of known cytochrome P450 variants on PZQ drug response in an African setting.

PMID:40512603 | DOI:10.1097/FPC.0000000000000572

J Am Assoc Nurse Pract. 2025 Jun 13. doi: 10.1097/JXX.0000000000001158. Online ahead of print.

ABSTRACT

Treatment-resistant depression (TRD) is a persistent challenge in psychiatry, affecting approximately 30% of patients with major depressive disorder. Defined by the failure to achieve remission after two adequate trials of antidepressants at therapeutic doses, TRD significantly impairs quality of life, heightens suicide risk, and increases health care utilization and economic burden. Current treatment paradigms rely heavily on trial and error, often leading to delayed symptom relief and exposure to unnecessary side effects. This underscores the urgent need for personalized approaches to care. Pharmacogenomic testing has emerged as a transformative tool in addressing the complexities of TRD. By analyzing genetic polymorphisms, such as those in cytochrome P450 enzymes, serotonin transporter, and methylenetetrahydrofolate reductase, pharmacogenomics offers insights into drug metabolism, receptor sensitivity, and neurotransmitter synthesis. This precision approach enables clinicians to optimize antidepressant selection, dosing, and augmentation strategies, minimizing adverse effects and enhancing therapeutic outcomes. This case series highlights the clinical utility of pharmacogenomic testing in managing TRD. Three diverse cases illustrate how genetic insights guided tailored interventions, leading to significant improvements in depressive symptoms, enhanced adherence, and overall patient satisfaction. The findings underscore pharmacogenomics' potential to shift psychiatry from trial and error to precision medicine, improving outcomes for patients with complex treatment histories. Despite challenges, such as cost, accessibility, and the need for clinician training, integrating pharmacogenomics into routine practice represents a promising avenue for advancing the management of TRD and enhancing the quality of psychiatric care.

PMID:40512564 | DOI:10.1097/JXX.0000000000001158

Naunyn Schmiedebergs Arch Pharmacol. 2025 Jun 13. doi: 10.1007/s00210-025-04364-9. Online ahead of print.

NO ABSTRACT

PMID:40512217 | DOI:10.1007/s00210-025-04364-9

J Pharm Bioallied Sci. 2025 May;17(Suppl 1):S55-S58. doi: 10.4103/jpbs.jpbs_568_25. Epub 2025 Apr 29.

ABSTRACT

Drug-induced liver injury (DILI) stands as the worldwide medical problem that causes substantial portions of both acute liver failure incidents and necessary liver transplants and fatalities. The liver functions as the main detoxifying organ of the body therefore, it becomes easily susceptible to destructive effects from the medicine components as well as other substances such as herbal supplements. DILI produces diverse liver damage that extends from unnoticed enzyme level elevations through the acute liver failure detection points. The purpose of this review assessment is to deliver an extensive breakdown of DILI pathogenic elements alongside diagnostic hurdles and present rule-of-the-art clinical practices. Researchers analyze three major pathophysiological mechanisms-oxidative stress, along with mitochondrial dysfunction and immune-mediated damage-for liver damage formation. The article explains diagnostic tools for DILI alongside establishing biomarkers and employment of liver biopsy for diagnosis. This discussion explores detailed information about the three management options that consist of drug withdrawal and supportive care together with liver transplantation. The discovery of genetic DILI susceptibilities combined with pharmacogenomic applications in clinical care leads to promising patient-specific treatments for better clinical achievements.

PMID:40511247 | PMC:PMC12156578 | DOI:10.4103/jpbs.jpbs_568_25

Clin Neuropsychopharmacol Ther. 2021;12:12-17. doi: 10.5234/cnpt.12.12. Epub 2021 Aug 31.

ABSTRACT

Novel interventions are needed to manage treatment-resistant depression (TRD), defined as patients who do not respond to two or more antidepressant trials of adequate dose and duration. We report on a 28-year-old female with TRD with nonresponse to several adequate trials of antidepressants who experienced full symptomatic remission after participating in the heated hatha yoga (HY) arm of a randomized controlled trial (RCT) for depression. Patients, including the one of interest, were randomized to 8 weeks of at least twice weekly HY or an 8-week waitlist followed by 8 weeks of HY. HY incorporates yoga plus heat through a series of standardized poses performed in a heated room (105° F). The 30-item Inventory of Depressive Symptoms, Clinician-Rated (IDS-C30) and 28-item Hamilton Depression Rating Scale (HAM-D28) were assessed at key time points throughout the study. The patient attended 16 classes over 8 weeks. Her baseline IDS-C30 score of 42 decreased to 26 following 2 weeks of HY, and continued declining throughout the intervention, with a final score of 6 (remission) after 8 weeks. HAM-D28 scores decreased from 26 at baseline to 4 (remission) after 8 weeks. At the 1-month follow-up, the patient's scores remained stable at 4 on IDS-C30 and 7 on HAM-D28, respectively. HY may serve as a potential intervention for TRD in patients who have not previously responded to conventional antidepressants. The rigorousness of the intervention must be considered regarding recommendations for use in the general population.

PMID:40510918 | PMC:PMC12160573 | DOI:10.5234/cnpt.12.12

Front Genet. 2025 May 29;16:1574325. doi: 10.3389/fgene.2025.1574325. eCollection 2025.

ABSTRACT

INTRODUCTION: Pharmacogenomic (PGx) testing improves drug efficacy and reduces risk of toxicity for commonly prescribed medications, with most pharmacogenomic studies largely focused on individuals of European descent to date. The impact of pharmacogenomic testing in a racially diverse population is still emerging, especially for Admixed American patients.

METHODS: In this study, we assessed the frequency of actionable PGx variants by analyzing anonymized exome sequencing data of a racially diverse cohort of 1777 pediatric patients, collected for routine clinical genetic diagnosis at Children's Hospital Los Angeles (CHLA). Utilizing exome data, we used the Illumina DRAGEN germline pipeline v4.2, to determine the predicted phenotypes of 25 pharmacogenes including HLA-A and HLA-B, including CPIC Level A genes and genes recommended for PGx testing by the U.S. Food and Drug Administration. To assess cross-platform consistency, we compared our results to those generated by PyPGx, a pharmacogenomic genotyping tool developed by the same author as Stargazer. As the distribution of PGx alleles is ancestry specific, we estimated genetic ancestry bioinformatically using the Somalier tool.

RESULTS: Genetic ancestry analysis demonstrated that 62% of our cohort was Admixed American, followed by 23% European, 8% East Asian, 5% African American, and 2% South East Asian. Actionability analysis showed that: 1) 93% of all exome cases had at least one actionable PGx phenotype, 2) one in five cases (22%) had at least three actionable PGx phenotypes, and 3) CYP2B6 (54%) and CYP2D6 (33%) had the highest number of actionable phenotypes. Further analysis revealed notable differences, including higher rates of poor metabolizers for CYP2B6 and variations in CYP2D6 metabolizer statuses, in PGx phenotypes compared to previously collated frequencies in the PharmGKB database, especially within the Admixed American population.

DISCUSSION: In conclusion, our study reinforces the importance of PGx testing, underscores the diversity of PGx variation in ancestral backgrounds, and supports the clinical utility of preemptive PGx testing using exome or genome sequencing approaches.

PMID:40510810 | PMC:PMC12159002 | DOI:10.3389/fgene.2025.1574325

Int J Mol Sci. 2025 Jun 5;26(11):5417. doi: 10.3390/ijms26115417.

ABSTRACT

Anxiety disorders are among the most common psychiatric conditions that significantly impair one's quality of life and place a significant burden on healthcare systems. Conventional treatments have certain restraints, such as potential side effects and limited efficacy. Τhe underlying pathophysiological mechanisms of anxiety are not fully understood. A comprehensive literature search was performed in MEDLINE and Scopus databases for original English-language articles published between January 2014 and December 2024. Study selection, data extraction, and screening were independently carried out by multiple investigators using predefined criteria. Our review aimed to help better comprehend the molecular basis of anxiety, focusing on the hypothalamic-pituitary-adrenal (HPA) axis, serotonergic signaling, and gamma-aminobutyric acid (GABA) neurotransmission. In addition, we addressed the role of epigenetics and pharmacogenomics in personalized treatment. Although novel anxiety treatments are promising, they are predominantly preclinical and highly heterogeneous, which poses a challenge to achieving reliable therapeutic efficacy. Our findings could potentially contribute to the development of new therapeutic interventions. Further research is warranted, especially in human subjects, with an aim to combine genetic and epigenetic profiles to refine treatment approaches and develop innovative therapeutics.

PMID:40508224 | DOI:10.3390/ijms26115417

Int J Mol Sci. 2025 Jun 1;26(11):5338. doi: 10.3390/ijms26115338.

ABSTRACT

Glucagon-like peptide-1 receptor agonists, originally developed for the treatment of metabolic disorders, have recently emerged as promising candidates for the management of substance use disorders. This review synthesizes preclinical, clinical, and translational evidence on the effects of glucagon-like peptide-1 receptor agonists across addiction models involving alcohol, nicotine, psychostimulants, and opioids. In animal studies, glucagon-like peptide-1 receptor agonists consistently reduce drug intake, attenuate dopamine release in reward circuits, and decrease relapse-like behavior. Clinical and observational studies provide preliminary support for these findings, particularly among individuals with comorbid obesity or insulin resistance. However, several translational barriers remain, including limited blood-brain barrier penetration, species differences in pharmacokinetics, and variability in treatment response due to genetic and metabolic factors. Ethical considerations and methodological heterogeneity further complicate clinical translation. Future directions include the development of central nervous system penetrant analogues, personalized medicine approaches incorporating pharmacogenomics, and rigorously designed trials in diverse populations. Glucagon-like peptide-1 receptor agonists may offer a novel therapeutic strategy that addresses both metabolic and neuropsychiatric dimensions of addiction, warranting further investigation to define their role in the evolving landscape of substance use disorder treatment.

PMID:40508146 | DOI:10.3390/ijms26115338

Int J Mol Sci. 2025 May 29;26(11):5237. doi: 10.3390/ijms26115237.

ABSTRACT

Multiple myeloma is a neoplastic disease characterised by the proliferation of clonal, atypical plasma cells. In cancer cells, the balance between two paths of cell death, necroptosis and apoptosis, is disrupted. The aim of this study was to analyse the occurrence of polymorphisms in genes encoding key proteins for the necroptosis process, i.e., RIPK-1, RIPK-3 and MAPKAPK2. We investigated the potential relations between the occurrence of genetic variability and the clinical course of the disease. We analysed six single-nucleotide polymorphisms in a population of patients with multiple myeloma (n = 205) and healthy volunteers (n = 100): RIPK1 rs2272990, RIPK1 rs9391981, RIPK3 rs724165, RIPK3rs3212243, MAPKAPK2, rs45514798 and MAPKAPK2 rs4073250. We found that genotypes rs9391981 CG, rs724165 CG, rs3212243 GG, and rs4073250 AA were independent predictors of overall survival, while genotype MAPKAPK2 rs4073250 AA was an independent predictor of progression-free survival. MAPKAPK2 rs45514798 AA was associated with polyneuropathy after thalidomide therapy. In conclusion, some of the SNPs tested have potential prognostic value and could be used as marker of survival in patients with multiple myeloma.

PMID:40508046 | DOI:10.3390/ijms26115237

Liver Int. 2025 Jul;45(7):e70163. doi: 10.1111/liv.70163.

ABSTRACT

BACKGROUND AND AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common cause of liver disease and a leading contributor to liver-related morbidity and mortality. Currently, no pharmacological approach has demonstrated consistent and long-lasting benefits across all patients. Therefore, identifying new therapeutic targets remains an urgent clinical need. The hepatic serine protease matriptase-2, encoded by TMPRSS6, inhibits the BMP-SMAD pathway. Interestingly, reduced BMP-SMAD signalling in the liver is frequently associated with altered lipid metabolism in patients. Conversely, inactivation of Tmprss6 has been linked to reduced high-fat diet-induced obesity. Based on these findings, we hypothesize that TMPRSS6 represents a novel and promising target for the treatment of MASLD.

METHODS: Hepatic TMPRSS6 expression was analysed in obese patients with or without MASLD. Adult male mice were fed a MASLD-MASH diet, and once hepatosteatosis was established, they were treated with antisense oligonucleotides targeting Tmprss6 while continuing the dietary regimen for an additional 6 weeks.

RESULTS: The expression of the BMP-SMAD inhibitor TMPRSS6 was increased in people with MASLD and negatively correlated with PPARα signaling, a key regulator of hepatic lipid metabolism. In experimental MASLD, downregulation of hepatocytic Tmprss6 using GalNAc-ASO significantly reduced steatohepatitis and fibrosis and attenuated MASLD-MASH-associated ferroptosis by reshaping hepatic transcription factor activity towards PPARα and SMAD4/SMAD5-driven signalling. Consistently, enhanced BMP-SMAD signalling increased PPARα activity in vivo.

CONCLUSIONS: Our findings reveal a novel functional crosstalk between TMPRSS6 and PPARα. Pharmacological downregulation of Tmprss6 in experimental MASLD mitigates hepatosteatosis, inflammation and fibrosis by enhancing PPARα signalling and attenuating ferroptosis.

PMID:40501083 | PMC:PMC12159589 | DOI:10.1111/liv.70163

Eur J Med Res. 2025 Jun 12;30(1):477. doi: 10.1186/s40001-025-02738-6.

ABSTRACT

Obesity, clinically defined by pathological adipose tissue accumulation disrupting metabolic homeostasis, has reached pandemic proportions. The World Obesity Atlas 2024 reports over 1.5 billion projected cases by 2035, highlighting its growing threat among pediatric and adult populations globally. While newly approved pharmacotherapies such as glucagon-like peptide-1 receptor agonists (GLP-1 RAs) show efficacy, their clinical utility remains constrained by dose-dependent gastrointestinal complications, underscoring the urgent need for safer alternatives. This therapeutic gap has revitalized interest in natural bioactive compounds, particularly berberine (BBR)-a benzodioxoloquinolizine alkaloid derived from Coptis chinensis and related medicinal plants. Preclinical and clinical studies demonstrate BBR's multimodal anti-obesity mechanisms: (i) adenosine monophosphate-activated protein kinase (AMPK) activation enhancing lipolysis and β-oxidation, (ii) peroxisome proliferator-activated receptor γ (PPAR-γ) suppression inhibiting adipogenesis, (iii) gut microbiota modulation improving metabolic endotoxemia, and (iv) uncoupling protein 1 (UCP1) upregulation promoting adipose browning. Notably, BBR metabolites demonstrate pharmacological activity comparable to or exceeding that of the parent compound. However, BBR's translational applications face biopharmaceutical challenges, including poor intestinal absorption (< 1% bioavailability) due to P-glycoprotein efflux and first-pass metabolism. This comprehensive review critically evaluates recent advances in BBR's anti-obesity pharmacology through three lenses: (1) preclinical and clinical evidence from randomized controlled trials, (2) molecular mechanisms underlying metabolic regulation, and (3) innovative strategies for pharmacokinetic optimization. Given its multi-target efficacy and botanical safety profile, BBR represents a cost-effective adjuvant for obesity management, particularly in resource-limited settings. Future research should prioritize standardized clinical protocols and pharmacogenomic studies to optimize therapeutic outcomes.

PMID:40506769 | DOI:10.1186/s40001-025-02738-6

J Allergy Clin Immunol Glob. 2025 May 8;4(3):100492. doi: 10.1016/j.jacig.2025.100492. eCollection 2025 Aug.

ABSTRACT

BACKGROUND: Earlier studies have demonstrated significant differences in food allergy by race and ethnicity, particularly for seafood and shrimp. Shrimp allergy is particularly interesting given the potential for cross-reactive sensitization from other arthropods.

OBJECTIVES: We characterized risk factors for shrimp allergy and shrimp sensitization.

METHODS: Data from electronic health records were abstracted for food allergies among patients who sought care at a large health system between October 1, 2010, and April 1, 2024. Geocoded addresses were linked to US Census data to identify characteristics associated with shrimp allergy. Non-Hispanic Black participants from the Study of Asthma-Related Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity (SAPPHIRE) were assessed for allergic sensitization using an IgE array, and survey data collected from participants were evaluated for association with shrimp, cockroach, and dust mite sensitization.

RESULTS: Among 2,975,183 health system patients, 4,709 individuals reported shrimp allergy. Compared to White individuals, rates of shrimp allergy were significantly higher in Black, Asian/Pacific Islander, Native American, and Latino individuals. Shrimp allergy was higher with increasing age, female sex, and asthma, and it was inversely related to median household income. Among SAPPHIRE participants, sensitization to shrimp, cockroach, and dust mite was positively associated with total IgE levels and proportion of African ancestry, but inversely associated with head of household level of education.

CONCLUSIONS: Both shrimp allergy and sensitization were associated with sociodemographic factors, suggesting that environmental exposures leading to cross-reactive sensitization may be important risk factors. Nevertheless, sensitization was also associated with ancestry, highlighting the potential importance of group-specific genetic risk factors.

PMID:40502543 | PMC:PMC12155558 | DOI:10.1016/j.jacig.2025.100492