Ultrasound Med Biol. 2024 Jul 17:S0301-5629(24)00259-X. doi: 10.1016/j.ultrasmedbio.2024.06.013. Online ahead of print.

ABSTRACT

OBJECTIVE: To investigate the safety and efficacy of high-intensity focused ultrasound (HIFU) ablation combined with pharmacogenomic-guided chemotherapy in treating patients with advanced pancreatic cancer (PC).

METHODS: Thirty-one patients with unresectable PC (stage III 17, stage IV 14) were enrolled in this study. The patients were divided into group A (pharmacogenomic-guided chemotherapy following HIFU treatment, n = 13) and group B (traditional chemotherapy following HIFU treatment, n = 18). Contrast-enhanced computed tomography and magnetic resonance imaging were used to evaluate tumor response. Pain intensity was assessed using the numerical rating scale. The Kaplan-Meier method and log-rank test were used to analyze survival.

RESULTS: The mean pain intensity score in 18 patients decreased from 6.6 ± 2.2 before HIFU to 3.3 ± 1.0 after HIFU (p = 0.000). The mean duration of pain relief was 5.2 ± 3.2 mo in group A and 2.4 ± 1.3 mo in group B (p = 0.026). There was no significant difference of the non-perfused volume ratio (83.5% ± 22.3% in group A and 85.3% ± 16.8% in group B) between the two groups. The median survival time was 14 mo in group A and 5 mo in group B. The 6 and 12-mo survival rates were 74.1% and 59.3% in group A, and 32.4% and 19.4% in group B, respectively. The difference in survival between the two groups was significant (p = 0.04). No severe complications (≥grade 3) related to HIFU were observed. Bone marrow depression was the main adverse reaction related to chemotherapy, with grade 3 bone marrow depression observed 2 (15.4%) patients in group A and 7 (38.9%) patients in group B.

CONCLUSION: HIFU combined with pharmacogenomic-guided chemotherapy is safe and effective in treating patients with advanced PC. It provides better clinical outcomes in pain relief, quality of life and survival benefits for patients with advanced PC compared to HIFU combined with traditional chemotherapy. This combined approach may have the potential to become an important supplement to the treatment of advanced PC.

PMID:39025741 | DOI:10.1016/j.ultrasmedbio.2024.06.013

Cureus. 2024 Jun 17;16(6):e62543. doi: 10.7759/cureus.62543. eCollection 2024 Jun.

ABSTRACT

Infection control remains a significant burden for healthcare systems. The irrational use of antibiotics in the fight against microbial diseases has led to the fast development of antimicrobial resistance. Considering how the latter can adversely influence the effectiveness of modern treatments and the way medicine is practiced, we should revise the events that led to the establishment of the general principles of antisepsis and pay special tribute to the people who contributed to their formation, bearing in mind that they remain unmodified to a great extent until today. Without Semmelweis' conceptualization of the idea of direct transmission of sepsis, Pasteur's emblematic figure that helped promote the idea even further, and Lister's methodology structuring, the scientific community would have significantly delayed winning the battle against germs.

PMID:39022474 | PMC:PMC11254094 | DOI:10.7759/cureus.62543

JHEP Rep. 2024 Apr 6;6(7):101092. doi: 10.1016/j.jhepr.2024.101092. eCollection 2024 Jul.

ABSTRACT

BACKGROUND & AIMS: It has been postulated that carriers of PNPLA3 I148M (CG [Ile/Met] or GG [Met/Met]) develop metabolic dysfunction-associated steatotic liver disease (MASLD) in the absence of insulin resistance or metabolic syndrome. However, the relationship between insulin resistance and MASLD according to the PNPLA3 allele has not been carefully assessed.

METHODS: A total of 204 participants were recruited and underwent PNPLA3 genotyping, an oral glucose tolerance test, liver proton magnetic resonance spectroscopy and percutaneous liver biopsy if diagnosed with MASLD. A subgroup of patients (n = 55) had an euglycemic hyperinsulinemic clamp with glucose tracer infusion.

RESULTS: As expected, patients with the CG/GG genotype had worse intrahepatic triglyceride content and worse liver histology. However, regardless of PNPLA3 genotype, patients with a diagnosis of MASLD had severe whole-body insulin resistance (Matsuda index, an estimation of insulin resistance in glucose metabolic pathways) and fasting and postprandial adipose tissue insulin resistance (Adipo-IR index and free fatty acid suppression during the oral glucose tolerance test, respectively, as measures of insulin resistance in lipolytic metabolic pathways) compared to patients without MASLD. Moreover, for the same amount of liver fat accumulation, insulin resistance was similar in patients with genotypes CC vs. CG/GG. In multiple regression analyses, A1c and Adipo-IR were associated with the presence of MASLD and advanced liver fibrosis, independently of PNPLA3 genotype.

CONCLUSIONS: PNPLA3 variant carriers with MASLD are equally insulin resistant as non-carriers with MASLD at the level of the liver, muscle, and adipose tissue. This calls for reframing "PNPLA3 MASLD" as an insulin-resistant condition associated with increased hepatic susceptibility to metabolic insults, such as obesity or diabetes, wherein early identification and aggressive intervention are warranted to reverse metabolic dysfunction and prevent disease progression.

IMPACT AND IMPLICATIONS: It has been proposed that the PNPLA3 G allele is associated with the presence of metabolic dysfunction-associated steatotic liver disease (MASLD) in the absence of insulin resistance. However, our results suggest that regardless of PNPLA3 alleles, the presence of insulin resistance is necessary for the development of MASLD. This calls for reframing patients with "PNPLA3 MASLD" not as insulin sensitive, but on the contrary, as an insulin-resistant population with increased hepatic susceptibility to metabolic insults, such as obesity or diabetes.

PMID:39022386 | PMC:PMC11252529 | DOI:10.1016/j.jhepr.2024.101092

CNS Neurosci Ther. 2024 Jul;30(7):e14850. doi: 10.1111/cns.14850.

ABSTRACT

INTRODUCTION: Glioma is the most frequent and lethal form of primary brain tumor. The molecular mechanism of oncogenesis and progression of glioma still remains unclear, rendering the therapeutic effect of conventional radiotherapy, chemotherapy, and surgical resection insufficient. In this study, we sought to explore the function of HEC1 (highly expressed in cancer 1) in glioma; a component of the NDC80 complex in glioma is crucial in the regulation of kinetochore.

METHODS: Bulk RNA and scRNA-seq analyses were used to infer HEC1 function, and in vitro experiments validated its function.

RESULTS: HEC1 overexpression was observed in glioma and was indicative of poor prognosis and malignant clinical features, which was confirmed in human glioma tissues. High HEC1 expression was correlated with more active cell cycle, DNA-associated activities, and the formation of immunosuppressive tumor microenvironment, including interaction with immune cells, and correlated strongly with infiltrating immune cells and enhanced expression of immune checkpoints. In vitro experiments and RNA-seq further confirmed the role of HEC1 in promoting cell proliferation, and the expression of DNA replication and repair pathways in glioma. Coculture assay confirmed that HEC1 promotes microglial migration and the transformation of M1 phenotype macrophage to M2 phenotype.

CONCLUSION: Altogether, these findings demonstrate that HEC1 may be a potential prognostic marker and an immunotherapeutic target in glioma.

PMID:39021287 | DOI:10.1111/cns.14850

Int J Sports Physiol Perform. 2024 Jul 17:1-7. doi: 10.1123/ijspp.2023-0205. Online ahead of print.

ABSTRACT

PURPOSE: This study aimed to determine whether the initial levels of aerobic fitness and hematological variables in young female road cyclists are related to their athletic performance development during their careers.

METHODS: Results of graded exercise tests on a cycle ergometer and total hemoglobin mass (tHb-mass) measurements were analyzed in 34 female road cyclists (age 18.6 [1.9] y). Among them, 2 groups were distinguished based on their competitive performance (Union Cycliste Internationale world ranking) over the following 8 years. Areas under the curve in receiver-operating-characteristic curves were calculated as indicators of elite-performance prediction.

RESULTS: Initial graded exercise test variables (peak power, peak oxygen uptake, and power at 4 mmol/L blood lactate) were not significantly different in elite (n = 13) versus nonelite (n = 21) riders. In contrast, elite riders had higher tHb-mass expressed either in absolute measures (664 [75] vs 596 [59] g, P = .006) or normalized to body mass (11.2 [0.8] vs 10.3 [0.7] g/kg, P = .001) and fat-free mass (14.4 [0.9] vs 13.1 [0.9] g/kg, P < .001). Absolute and relative erythrocyte volumes were significantly higher in elite subjects (P ranged from < .001 to .006). Of all the variables analyzed, the relative tHb-mass had the highest predictive ability to reach the elite level (area under the curve ranged from .82 to .85).

CONCLUSION: Measurement of tHb-mass can be a helpful tool in talent detection to identify young female road cyclists with the potential to reach the elite level in the future.

PMID:39019447 | DOI:10.1123/ijspp.2023-0205

Pediatr Infect Dis J. 2024 Aug 1;43(8):789-794. doi: 10.1097/INF.0000000000004366. Epub 2024 May 17.

ABSTRACT

INTRODUCTION: Dolutegravir (DTG) dispersible tablet (DTG-DT) is a pediatric-friendly formulation. We aimed to describe the pharmacokinetics and virologic responses of generic DTG-DT in children weighing <20 kg.

METHODS: Children living with HIV-1 and <7 years of age weighing 6 to <20 kg were eligible. A generic 10-mg scored DTG-DT was administered to children using 3 weight bands (WB): WB1 (6 to <10 kg), WB2 (10 to <14 kg) and WB3 (14 to <20 kg), at doses of 20 mg (higher than World Health Organization recommendation of 15 mg), 20 mg and 25 mg, respectively. Steady-state intensive pharmacokinetics (PK) was performed in fasting condition with blood sampling at predose and 1, 2, 3, 4, 6 and 24 hours postdose. DTG PK parameters were estimated using a noncompartmental analysis, and DTG trough concentrations (C 24 ) and 24-hour area under the concentration-time curve were calculated. Comparisons were made with ODYSSEY and IMPAACT 2019. And 90% effective concentration of 0.32 mg/L was used as a reference individual DTG C 24 concentration.

RESULTS: From August 2021 to March 2023, 29 Thai children with a median (interquartile range) age of 3.2 (1.5-4.8) years were enrolled; 8 in WB1, 9 in WB2 and 12 in WB3. All children were treatment experienced and 59% had HIV RNA <200 copies/mL. Overall geometric mean (coefficient of variation percentage) DTG C 24 was 1.0 (46%) mg/L [WB1, 0.9 (53%); WB2, 0.9 (27%); WB3, 1.2 (51%)]. Geometric mean (coefficient of variation percentage) 24-hour area under the concentration-time curve was 83.2 (24%) mg h/L [WB1, 84.3 (31%); WB2, 76.9 (16%); WB3, 87.6 (25%)]. At weeks 24 and 48, 90% and 92% of participants had plasma HIV RNA <200 copies/mL.

CONCLUSIONS: Generic DTG-DT provided adequate drug exposure in children weighing 6 to <20 kg. The exploratory dose of DTG 20 mg for children weighing 6 to <10 kg showed similar PK parameters to World Health Organization doses in the other WB.

PMID:39018516 | DOI:10.1097/INF.0000000000004366

Basic Clin Pharmacol Toxicol. 2024 Jul 16. doi: 10.1111/bcpt.14046. Online ahead of print.

ABSTRACT

Ramipril is an angiotensin-converting enzyme inhibitor used for hypertension and heart failure management. To date, scarce literature is available on pharmacogenetic associations affecting ramipril. The goal of this study was to investigate the effect of 120 genetic variants in 34 pharmacogenes (i.e., genes encoding for enzymes like CYPs or UGTs and transporters like ABC or SLC) on ramipril pharmacokinetic variability and adverse drug reaction (ADR) incidence. Twenty-nine healthy volunteers who had participated in a single-dose bioequivalence clinical trial of two formulations of ramipril were recruited. A univariate and multivariate analysis searching for associations between genetic variants and ramipril pharmacokinetics was performed. SLCO1B1 and ABCG2 genotype-informed phenotypes strongly predicted ramipril exposure. Volunteers with the SLCO1B1 decreased function (DF) phenotype presented around 1.7-fold higher dose/weight-corrected area under the curve (AUC/DW) than volunteers with the normal function (NF) phenotype (univariate p-value [puv] < 0.001, multivariate p-value [pmv] < 0.001, β = 0.533, R2 = 0.648). Similarly, volunteers with ABCG2 DF + poor function (PF) phenotypes presented around 1.6-fold higher AUC/DW than those with the NF phenotype (puv = 0.011, pmv < 0.001, β = 0.259, R2 = 0.648). Our results suggest that SLCO1B1 and ABCG2 are important transporters to ramipril pharmacokinetics, and their genetic variation strongly alters its pharmacokinetics. Further studies are required to confirm these associations and their clinical relevance.

PMID:39011815 | DOI:10.1111/bcpt.14046

Inflamm Bowel Dis. 2024 Jul 16:izae126. doi: 10.1093/ibd/izae126. Online ahead of print.

ABSTRACT

BACKGROUND: Thiopurine drugs are effective treatment options in inflammatory bowel disease and other conditions but discontinued in some patients due to toxicity.

METHODS: We investigated thiopurine-induced toxicity in a pediatric inflammatory bowel disease cohort by utilizing exome sequencing data across a panel of 46 genes, including TPMT and NUDT15.

RESULTS: The cohort included 487 patients with a median age of 13.1 years. Of the 396 patients exposed to thiopurines, myelosuppression was observed in 11%, gastroenterological intolerance in 11%, hepatotoxicity in 4.5%, pancreatitis in 1.8%, and "other" adverse effects in 2.8%. TPMT (thiopurine S-methyltransferase) enzyme activity was normal in 87.4%, intermediate 12.3%, and deficient in 0.2%; 26% of patients with intermediate activity developed toxicity to thiopurines. Routinely genotyped TPMT alleles associated with defective enzyme activity were identified in 28 (7%) patients: TPMT*3A in 4.5%, *3B in 1%, and *3C in 1.5%. Of these, only 6 (21%) patients developed toxic responses. Three rare TPMT alleles (*3D, *39, and *40) not assessed on routine genotyping were identified in 3 patients, who all developed toxic responses. The missense variant p.R139C (NUDT15*3 allele) was identified in 4 patients (azathioprine 1.6 mg/kg/d), but only 1 developed toxicity. One patient with an in-frame deletion variant p.G13del in NUDT15 developed myelosuppression at low doses. Per-gene deleteriousness score GenePy identified a significant association for toxicity in the AOX1 and DHFR genes.

CONCLUSIONS: A significant association for toxicity was observed in the AOX1 and DHFR genes in individuals negative for the TPMT and NUDT15 variants. Patients harboring the NUDT15*3 allele, which is associated with myelosuppression, did not show an increased risk of toxicity.

PMID:39011784 | DOI:10.1093/ibd/izae126

Caspian J Intern Med. 2024 Summer;15(3):499-508. doi: 10.22088/cjim.15.3.499.

ABSTRACT

BACKGROUND: Allelic variants of genes encoding enzymes of the esterase system (CES1) and P-glycoprotein (ABCB1) can change the metabolism and pharmacokinetics of dabigatran. Therefore, they act as determining factors in the development of side effects, especially bleeding. We analyzed the genotype-phenotype relationship of ABCB1 (rs1045642, rs4148738, rs2032582, and rs1128503) and CES1 (rs8192935, rs71647871, and rs2244613) polymorphisms in patients with atrial fibrillation who had been treated with dabigatran.

METHODS: A total of 150 patients were recruited for this study. TaqMan technology was used for SNP genotyping.

RESULTS: Patients with the rs2244613 GG genotype had a lower concentration (55.27 ± 34.22 ng/ml) compared to those with the TT genotype (63.33 ± 52.25 ng/ml) (additive model, P = 0.000). Individuals with the rs8192935 AA genotype had a lower concentration (52.72 ± 30.45 ng/ml) compared to those with the GG genotype (79.78 ± 57 ng/ml) (additive model, P = 0.001). The APTT values among the different genotypes of the ABCB1 SNPs, rs4148738 and rs1045642, were significantly different (P = 0.035 and P = 0.024, respectively).

CONCLUSION: Our research demonstrates that the CES1 polymorphisms, rs8192935 and rs2244613, are associated with the pharmacodynamics and pharmacokinetics of dabigatran in the Kazakh subpopulation.

PMID:39011438 | PMC:PMC11246689 | DOI:10.22088/cjim.15.3.499

Indian J Hematol Blood Transfus. 2024 Jul;40(3):517-521. doi: 10.1007/s12288-023-01726-2. Epub 2024 Feb 24.

ABSTRACT

Increased bleeding tendency is a common and challenging complication of warfarin therapy which results in extensive pharmacogenomic studies in order to develop a personalized dosing approach and minimize the risk of related side effects. Here we aimed to explore the potential role of NQO1 gene expression in warfarin response in a group of Iranian patients. We also evaluated the NQO1 promoter methylation and its association with mRNA expression. A total of 87 patients on warfarin therapy including 34 cases with drug-induced bleeding events and 53 matched controls without bleedings were included in the study. The expression of NQO1 was examined by real-time q-PCR and the methylation status of its promoter region was analyzed using methyQESD technique. There was a significant association between the reduced NQO1 gene expression and susceptibility to bleeding before (OR = 1.92, 95% CI = 1.23-3.00, p = 0.004) and following adjustment for hypertriglyceridemia (OR = 2.22, 95% CI = 1.33-3.69, p = 0.002). Furthermore, a medium negative correlation was observed between NQO1 expression and its promoter methylation (r = - 0.382, p = 0.001). The lower expression of NQO1 which partly arises from increased methylation of promoter region, may predispose warfarin treated patients to bleeding events.

PMID:39011266 | PMC:PMC11246350 | DOI:10.1007/s12288-023-01726-2

medRxiv [Preprint]. 2024 Jul 5:2024.07.03.24309466. doi: 10.1101/2024.07.03.24309466.

ABSTRACT

The major anxiety disorders (ANX; including generalized anxiety disorder, panic disorder, and phobias) are highly prevalent, often onset early, persist throughout life, and cause substantial global disability. Although distinct in their clinical presentations, they likely represent differential expressions of a dysregulated threat-response system. Here we present a genome-wide association meta-analysis comprising 122,341 European ancestry ANX cases and 729,881 controls. We identified 58 independent genome-wide significant ANX risk variants and 66 genes with robust biological support. In an independent sample of 1,175,012 self-report ANX cases and 1,956,379 controls, 51 of the 58 associated variants were replicated. As predicted by twin studies, we found substantial genetic correlation between ANX and depression, neuroticism, and other internalizing phenotypes. Follow-up analyses demonstrated enrichment in all major brain regions and highlighted GABAergic signaling as one potential mechanism underlying ANX genetic risk. These results advance our understanding of the genetic architecture of ANX and prioritize genes for functional follow-up studies.

PMID:39006447 | PMC:PMC11245051 | DOI:10.1101/2024.07.03.24309466

Sci Rep. 2024 Jul 15;14(1):16290. doi: 10.1038/s41598-024-66809-0.

ABSTRACT

Bictegravir, a key second-generation integrase strand transfer inhibitor in the treatment of HIV, is subject to active efflux transport mediated by ABCB1 (P-glycoprotein). Several coding variants of ABCB1 have been described and associated with variable effects on substrate drugs pharmacokinetics. Here, we investigated the effect of the four most common coding ABCB1 single nucleotide polymorphisms (i.e., c.1199G > A, c.1236C > T, c.2677G > T and c.3435C > T) on the intracellular accumulation of bictegravir. Using a previously validated HEK293 recombinant cell line model, we found decreased bictegravir intracellular concentrations in cell lines overexpressing ABCB1 as compared to control cell lines, in line with the known role of ABCB1 in bictegravir transport. However, we were unable to demonstrate any significant difference in bictegravir intracellular accumulation when comparing HEK293 cells overexpressing the wild type (1236C-2677G-3435C, 1199G) or the variant (1236C-2677G-3435T, 1236T-2677T-3435T or 1199A) proteins. These findings suggest that the ABCB1 c.1199G > A and c.1236C > T-c.2677G > T-c.3435C > T variants have no or at least limited impact on the active transport of bictegravir by ABCB1.

PMID:39009738 | DOI:10.1038/s41598-024-66809-0

JCO Oncol Pract. 2024 Jul 15:OP2400366. doi: 10.1200/OP.24.00366. Online ahead of print.

ABSTRACT

Oncologists use molecular prediction/pharmacogenomics to improve Rx of cancer. Voltaire now wrong.

PMID:39008788 | DOI:10.1200/OP.24.00366

EClinicalMedicine. 2024 Jun 21;73:102679. doi: 10.1016/j.eclinm.2024.102679. eCollection 2024 Jul.

ABSTRACT

BACKGROUND: Sézary syndrome is an extremely rare and fatal cutaneous T-cell lymphoma (CTCL). Mogamulizumab, an anti-CCR4 monoclonal antibody, has recently been associated with increased progression-free survival in a randomized clinical trial in CTCL. We aimed to evaluate OS and prognostic factors in Sézary syndrome, including treatment with mogamulizumab, in a real-life setting.

METHODS: Data from patients with Sézary (ISCL/EORTC stage IV) and pre-Sézary (stage IIIB) syndrome diagnosed from 2000 to 2020 were obtained from 24 centers in Europe. Age, disease stage, plasma lactate dehydrogenases levels, blood eosinophilia at diagnosis, large-cell transformation and treatment received were analyzed in a multivariable Cox proportional hazard ratio model. This study has been registered in ClinicalTrials (SURPASSe01 study: NCT05206045).

FINDINGS: Three hundred and thirty-nine patients were included (58% men, median age at diagnosis of 70 years, Q1-Q3, 61-79): 33 pre-Sézary (9.7% of 339), 296 Sézary syndrome (87.3%), of whom 10 (2.9%) had large-cell transformation. One hundred and ten patients received mogamulizumab. Median follow-up was 58 months (95% confidence interval [CI], 53-68). OS was 46.5% (95% CI, 40.6%-53.3%) at 5 years. Multivariable analysis showed that age ≥ 80 versus <50 (HR: 4.9, 95% CI, 2.1-11.2, p = 0.001), and large-cell transformation (HR: 2.8, 95% CI, 1.6-5.1, p = 0.001) were independent and significant factors associated with reduced OS. Mogamulizumab treatment was significantly associated with decreased mortality (HR: 0.34, 95% CI, 0.15-0.80, p = 0.013).

INTERPRETATION: Treatment with mogamulizumab was significantly and independently associated with decreased mortality in Sézary syndrome.

FUNDING: French Society of Dermatology, Swiss National Science Foundation (IZLIZ3_200253/1) and SKINTEGRITY.CH collaborative research program.

PMID:39007062 | PMC:PMC11245986 | DOI:10.1016/j.eclinm.2024.102679

Clin Transl Sci. 2024 Jul;17(7):e13884. doi: 10.1111/cts.13884.

ABSTRACT

Sofosbuvir/Velpatasvir (SOF/VEL) is a combination drug used for chronic hepatitis C (HCV) infection. However, limited information exists regarding the pharmacokinetics of SOF/VEL and its metabolites in hemodialysis patients. We conducted a prospective investigation of the pharmacokinetic parameters of SOF/VEL after a single dose of SOF/VEL (400/100 mg) on days with and without dialysis in 12 Thai hemodialysis patients with chronic HCV infection, who had been undergoing hemodialysis for a duration of 0.5-20 years. Blood samples were collected before dose (0) and 0.5, 1.0, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 8.0, and 12.0 h after dose. Dialysate samples were also collected before dose (0) and 1.0, 2.0, 3.0, and 4.0 h after dose. Plasma and dialysate samples were quantified for SOF and its metabolite, GS-331007, and VEL concentrations using a fully validated LCMS technique. In addition, a preliminary efficacy study was conducted using the proposed SOF/VEL dose reduction regimen in all patients. No differences in SOF/VEL PK parameters between on- and off-dialysis studies. On the contrary, GS-331007 exhibited a 30% reduction in the area under the plasma concentration-time curve from time 0 to 24 h (AUC0-24h) on dialysis days compared with non-dialysis days (AUC0-24h ratio 0.68 vs. 1.04, respectively). The dialysis clearance of SOF and GS-331007 was 9.35 (8.72-15.11) and 8.89 (8.52-14.07) mL/min, respectively. Subsequently, an alternate-day regimen of SOF/VEL (400/100 mg) was administered for 12 weeks, resulting in an undetectable plasma HCV viral load without side effects. Further clinical studies are warranted to validate the efficacy and safety of our proposed dose reduction regimen.

PMID:39004798 | DOI:10.1111/cts.13884

Nat Commun. 2024 Jul 14;15(1):5919. doi: 10.1038/s41467-024-50198-z.

ABSTRACT

Pregnane X receptor (PXR) has been reported to regulate glycolipid metabolism. The dysfunction of intestinal barrier contributes to metabolic disorders. However, the role of intestinal PXR in metabolic diseases remains largely unknown. Here, we show that activation of PXR by tributyl citrate (TBC), an intestinal-selective PXR agonist, improves high fat diet (HFD)-induced obesity. The metabolic benefit of intestinal PXR activation is associated with upregulation of β-1,3 galactosyltransferase 5 (B3galt5). Our results reveal that B3galt5 mainly expresses in the intestine and is a direct PXR transcriptional target. B3galt5 knockout exacerbates HFD-induced obesity, insulin resistance and inflammation. Mechanistically, B3galt5 is essential to maintain the integrity of intestinal mucus barrier. B3galt5 ablation impairs the O-glycosylation of mucin2, destabilizes the mucus layer, and increases intestinal permeability. Furthermore, B3galt5 deficiency abolishes the beneficial effect of intestinal PXR activation on metabolic disorders. Our results suggest the intestinal-selective PXR activation regulates B3galt5 expression and maintains metabolic homeostasis, making it a potential therapeutic strategy in obesity.

PMID:39004626 | DOI:10.1038/s41467-024-50198-z

Chem Res Toxicol. 2024 Jul 13. doi: 10.1021/acs.chemrestox.4c00109. Online ahead of print.

ABSTRACT

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (commonly known as NNK) is one of the most prevalent and potent pulmonary carcinogens in tobacco products that increases the human lung cancer risk. Kava has the potential to reduce NNK and tobacco smoke-induced lung cancer risk by enhancing urinary excretion of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL, the major metabolite of NNK) and thus reducing NNK-induced DNA damage. In this study, we quantified N-glucuronidated NNAL (NNAL-N-gluc), O-glucuronidated NNAL (NNAL-O-gluc), and free NNAL in the urine samples collected before and after 1-week kava dietary supplementation. The results showed that kava increased both NNAL-N-glucuronidation and O-glucuronidation. Since NNAL-N-glucuronidation is dominantly catalyzed by UGT2B10, its representative single-nucleotide polymorphisms (SNPs) were analyzed among the clinical trial participants. Individuals with any of the four analyzed SNPs appear to have a reduced basal capacity in NNAL-N-glucuronidation. Among these individuals, kava also resulted in a smaller extent of increases in NNAL-N-glucuronidation, suggesting that participants with those UGT2B10 SNPs may not benefit as much from kava with respect to enhancing NNAL-N-glucuronidation. In summary, our results provide further evidence that kava enhances NNAL urinary detoxification via an increase in both N-glucuronidation and O-glucuronidation. UGT2B10 genetic status has not only the potential to predict the basal capacity of the participants in NNAL-N-glucuronidation but also potentially the extent of kava benefits.

PMID:39001862 | DOI:10.1021/acs.chemrestox.4c00109

Int J Mol Sci. 2024 Jun 25;25(13):6948. doi: 10.3390/ijms25136948.

ABSTRACT

The lack of specific biological materials and biomarkers limits our knowledge of the mechanisms underlying intrauterine regulation of iron supply to the fetus. Determining the meconium content of proteins commonly used in the laboratory to assess the transport, storage, and distribution of iron in the body may elucidate their roles in fetal development. Ferritin, transferrin, haptoglobin, ceruloplasmin, lactoferrin, myeloperoxidase (MPO), neutrophil gelatinase-associated lipocalin (NGAL), and calprotectin were determined by ELISA in meconium samples obtained from 122 neonates. There were strong correlations between the meconium concentrations of haptoglobin, transferrin, and NGAL (p < 0.05). Meconium concentrations of ferritin were several-fold higher than the concentrations of the other proteins, with the exception of calprotectin whose concentration was approximately three-fold higher than that of ferritin. Meconium ceruloplasmin concentration significantly correlated with the concentrations of MPO, NGAL, lactoferrin, and calprotectin. Correlations between the meconium concentrations of haptoglobin, transferrin, and NGAL may reflect their collaborative involvement in the storage and transport of iron in the intrauterine environment in line with their recognized biological properties. High meconium concentrations of ferritin may provide information about the demand for iron and its utilization by the fetus. The associations between ceruloplasmin and neutrophil proteins may indicate the involvement of ceruloplasmin in the regulation of neutrophil activity in the intrauterine environment.

PMID:39000056 | DOI:10.3390/ijms25136948

Int J Mol Sci. 2024 Jun 21;25(13):6832. doi: 10.3390/ijms25136832.

ABSTRACT

Familial episodic pain syndrome (FEPS) is an early childhood onset disorder of severe episodic limb pain caused mainly by pathogenic variants of SCN11A, SCN10A, and SCN9A, which encode three voltage-gated sodium channels (VGSCs) expressed as key determinants of nociceptor excitability in primary sensory neurons. There may still be many undiagnosed patients with FEPS. A better understanding of the associated pathogenesis, epidemiology, and clinical characteristics is needed to provide appropriate diagnosis and care. For this study, nationwide recruitment of Japanese patients was conducted using provisional clinical diagnostic criteria, followed by genetic testing for SCN11A, SCN10A, and SCN9A. In the cohort of 212 recruited patients, genetic testing revealed that 64 patients (30.2%) harbored pathogenic or likely pathogenic variants of these genes, consisting of 42 (19.8%), 14 (6.60%), and 8 (3.77%) patients with variants of SCN11A, SCN10A, and SCN9A, respectively. Meanwhile, the proportions of patients meeting the tentative clinical criteria were 89.1%, 52.0%, and 54.5% among patients with pathogenic or likely pathogenic variants of each of the three genes, suggesting the validity of these clinical criteria, especially for patients with SCN11A variants. These clinical diagnostic criteria of FEPS will accelerate the recruitment of patients with underlying pathogenic variants who are unexpectedly prevalent in Japan.

PMID:38999942 | DOI:10.3390/ijms25136832

J Clin Med. 2024 Jun 26;13(13):3719. doi: 10.3390/jcm13133719.

ABSTRACT

Background: One factor that may negatively impact male reproductive health is the illegal use of testosterone and anabolic-androgenic steroids. This study aimed to evaluate the prevalence of testosterone use in recreational athletes, as well as factors associated with its use, and to determine the profile of a person using testosterone. Methods: A cross-sectional analysis of data from an anonymous, online questionnaire of men recruited from gyms, randomly selected in Wrocław, Poland, has been performed. The minimal sample size was evaluated with the univariate logistic regression model. The association between testosterone use and other factors was also evaluated with the univariate logistic regression model. Results: A total of 35% of respondents used testosterone. The main purposes of testosterone use were the improvement of training effects and the improvement of body shape. The respondents most likely to use testosterone and other anabolic-androgenic steroids were men aged 26-35, whose earnings were at the level of the middle class or higher, who were married, had children, had training experience of at least 6 months, exercised at least once a week, took part in weightlifting competitions, were managers in a corporation or enterprise, or were self-employed. Most of the people using testosterone had self-treated side effects. Conclusions: The profile of the person most likely to use testosterone corresponds to the characteristics of men in optimal socio-demographic conditions for reproduction. These results indicate that this is a significant social problem that may impact male reproductive health.

PMID:38999285 | DOI:10.3390/jcm13133719