Rapid green analytical methodology for simultaneous monitoring of nitrosamines and semi-volatile organic compounds in water and human urine samples.

Nitrosamines and semi-volatile organic compounds (SVOCs) are carcinogenic contaminants in water and biological matrices. Conventional analytical methods often struggle to detect trace concentrations due to poor extraction efficacies. This study presents a novel, low-cost, in-syringe-assisted fast extraction cum cleanup technique coupled with GC-FID for monitoring four nitrosamines and two SVOCs in drinking water and human urine samples to measure the contamination and exposure levels. This extraction protocol combines a novel green in-syringe liquid-liquid extraction step using dimethyl carbonate as the green extraction solvent, coupled with a semi-automated solid-phase extraction cleanup process. Then, the final extractant is analyzed using gas chromatography-flame ionization detection (GC-FID) for monitoring. The method demonstrated excellent linearity (R2 > 0.998) between 1.5 and 500 ng mL⁻1 for all six target compounds. Detection limits ranged from 1.0 to 2.0 ng mL⁻1. Extraction recoveries were between 87 and 105% for both urine samples and water samples. Intra-day and inter-day precision were below 9% RSD. The blue applicability grade index evaluation scored 70.0, indicating good practical applicability. The developed analytical protocol offers a sensitive, accurate, low-cost, rapid, and environmentally friendly method for simultaneously quantifying multiple nitrosamines and SVOCs in environmental and human samples. Its performance characteristics and sustainability metrics suggest the potential for broad application in monitoring and exposure studies.

Decoding the molecular symphony: interactions between the m6A and p53 signaling pathways in cancer.

The p53 tumor suppressor gene governs a multitude of complex cellular processes that are essential for anti-cancer function and whose dysregulation leads to aberrant gene transcription, activation of oncogenic signaling and cancer development. Although mutations can occur at any point in the genetic sequence, missense mutations comprise the majority of observed p53 mutations in cancers regardless of whether the mutation is germline or somatic. One biological process involved in both mutant and wild-type p53 signaling is the N 6-methyladenosine (m6A) epitranscriptomic network, a type of post-transcriptional modification involved in over half of all eukaryotic mRNAs. Recently, a significant number of findings have demonstrated unique interactions between p53 and the m6A epitranscriptomic network in a variety of cancer types, shedding light on a previously uncharacterized connection that causes significant dysregulation. Cross-talk between wild-type or mutant p53 and the m6A readers, writers and erasers has been shown to impact cellular function and induce cancer formation by influencing various cancer hallmarks. Here, this review aims to summarize the complex interplay between the m6A epitranscriptome and p53 signaling pathway, highlighting its effects on tumorigenesis and other hallmarks of cancer, as well as identifying its therapeutic implications for the future.

Assessment of Eye Care Apps for Children and Adolescents Based on the Mobile App Rating Scale: Content Analysis and Quality Assessment.

BACKGROUND: In China, the current situation of myopia among children and adolescents is very serious. Prevention and control of myopia are inhibited by the lack of medical resources and the low awareness about eye care. Nevertheless, mobile apps provide an effective means to solve these problems. Since the health app market in China is still immature, it has become particularly important to conduct a study to assess the quality of eye-care apps to facilitate the development of better eye-care service strategies. OBJECTIVE: This study aimed to evaluate the quality, functionality, medical evidence, and professional background of eye-care apps targeting children and adolescents in the Chinese app stores. METHODS: A systematic search on iOS and Android app stores was performed to identify eye-care apps for children and adolescents. The general characteristics, development context, and functional features of the apps were described. Quality assessment of the apps was completed by 2 independent researchers using the Mobile App Rating Scale. RESULTS: This study included 29 apps, of which 17 (59%) were developed by commercial organizations and 12 (41%) had a design with relevant scientific basis. The main built-in functions of these apps include self-testing (18/29, 62%), eye exercises (16/29, 55%), and eye-care education (16/29, 55%). The mean overall quality of eye-care apps was 3.49 (SD 0.33), with a score ranging from 2.89 to 4.39. The overall Mobile App Rating Scale score exhibited a significant positive correlation with the subscale scores (r=0.81-0.91; P<.001). In addition, although most apps provided basic eye-care features, there are some deficiencies. For example, only a few apps were developed with the participation of medical organizations or professional ophthalmologists, and most of the apps were updated infrequently, failing to provide the latest eye-care information and technology in a timely manner. CONCLUSIONS: In general, the quality of eye-care apps for children and teenagers in Chinese app stores is good. These apps fulfill users' needs for eye-care services to a certain extent, but they still suffer from insufficient medical background, low user engagement, and untimely updates. In order to further improve the effectiveness of eye-care apps, cooperation with medical institutions and professional ophthalmologists should be strengthened to enhance the scientific and authoritative nature of the apps. At the same time, interactive features and regular updates should be added to enhance user participation and the continuity of the apps. This study provides a reference for future development or improvement of eye-care apps, which can help promote myopia prevention and control.

Phosphoproteomics-directed manipulation reveals SEC22B as a hepatocellular signaling node governing metabolic actions of glucagon.

The peptide hormone glucagon is a fundamental metabolic regulator that is also being considered as a pharmacotherapeutic option for obesity and type 2 diabetes. Despite this, we know very little regarding how glucagon exerts its pleiotropic metabolic actions. Given that the liver is a chief site of action, we performed in situ time-resolved liver phosphoproteomics to reveal glucagon signaling nodes. Through pathway analysis of the thousands of phosphopeptides identified, we reveal "membrane trafficking" as a dominant signature with the vesicle trafficking protein SEC22 Homolog B (SEC22B) S137 phosphorylation being a top hit. Hepatocyte-specific loss- and gain-of-function experiments reveal that SEC22B was a key regulator of glycogen, lipid and amino acid metabolism, with SEC22B-S137 phosphorylation playing a major role in glucagon action. Mechanistically, we identify several protein binding partners of SEC22B affected by glucagon, some of which were differentially enriched with SEC22B-S137 phosphorylation. In summary, we demonstrate that phosphorylation of SEC22B is a hepatocellular signaling node mediating the metabolic actions of glucagon and provide a rich resource for future investigations on the biology of glucagon action.

Rational design of untranslated regions to enhance gene expression.

How to improve gene expression by optimizing mRNA structures is a crucial question for various medical and biotechnological applications. Previous efforts focus largely on investigation of the 5' UTR hairpin structures. In this study, we present a rational strategy that enhances mRNA stability and translation by engineering both the 5' and 3' UTR sequences. We have successfully demonstrated this strategy using green fluorescent protein (GFP) as a model in Escherichia coli and across different expression vectors. We further validated it with luciferase and Plasmodium falciparum lactate dehydrogenase (PfLDH). To elucidate the underlying mechanism, we have quantitatively analyzed both protein, mRNA levels and half-life time. We have identified several key aspects of UTRs that significantly influence mRNA stability and protein expression in our system: (1) The optimal length of the single-stranded spacer between the stabilizer hairpin and ribosome binding site (RBS) in the 5' UTR is 25-30 nucleotide (nt) long. An optimal 32% GC content in the spacer yielded the highest levels of GFP protein production. (2) The insertion of a homodimerdizable, G-quadruplex structure containing RNA aptamer, "Corn", in the 3' UTR markedly increased the protein expression. Our findings indicated that the carefully engineered 5' UTR and 3' UTR significantly boosted gene expression. Specifically, the inclusion of 5×Corn in the 3' UTR appeared to facilitate the local aggregation of mRNA, leading to the formation of mRNA condensates. Aside from shedding light on the regulation of mRNA stability and expression, this study is expected to substantially increase biological protein production.

[AI-HIP system for prosthesis size, global femoral offset and osteotomy in total hip arthroplasty].

OBJECTIVE: To explore planning effect of AI-HIP assisted surgical planning system in primary unilateral total hip arthroplasty (THA) and its influence on clinical outcomes. METHODS: A retrospective analysis was conducted on clinical data of 36 patients who underwent their first unilateral THA from March 2022 to November 2022 and continuously used AI-HIP system (AI-HIP group), including 16 males and 20 females, aged from 43 to 81 years old with an average of (62.2±10.9) years old. According to the matching principle, 36 patients who were planned by the traditional template method at the same period were selected as the control group, including 16 males and 20 females, aged from 40 to 80 years old with an average of (60.9±12.1) years old. The accuracy between two groups of prostheses were compared, as well as the combined eccentricity difference between preoperative planning and postoperative practice, lower limb length difference, osteotomy height from the upper edge of the lesser trochanter and top shoulder distance to evaluate planning effect. Harris score and visual analogue scale (VAS) were used to evaluate clinical efficacy. RESULTS: Both groups were followed up for 12 to 18 months with an average of (14.5±2.1) months. The complete accuracy and approximate accuracy of acetabular cup and femoral stalk prosthesis in AI-HIP group were 72.2%, 100%, 58.3%, 88.9%, respectively, which were better than 44.4%, 83.3%, 33.3%, 66.7% in control group (P<0.05). There was no statistical significance in planning of femoral head prosthesis size (P>0.05). The actual combined eccentricity difference and combined eccentricity difference (practical-planning) in AI-HIP group were 1.0(0.2, 2.4) mm and 1.1(-2.1, 3.2) mm, respectively;which were better than 3.0 (1.4, 4.9) mm and 3.5 (-1.6, 6.5) mm in control group (P<0.05). There was no significant difference between two groups in actual osteotomy height of the upper margin of the lesser trochanter (P>0.05). In AI-HIP group, the actual difference of lower extremity length after surgery, the difference of lower extremity length (practical-planning), osteotomy height from the upper margin of lesser trochanter (practical-planning), actual topshoulder distance after surgery, and topshoulder distance (practical-planning) were 1.5 (0.2, 2.8), 1.1 (-0.3, 2.2), 2.1(-2.3, 4.1), (15.3±4.1), 2.2(-4.8, 0.3) mm, respectively;which were better than control group of 2.6(1.3, 4.1), 2.5 (0.3, 3.8), 5.8(-2.4, 7.7), (13.0±4.3), -5.7(-9.4, -2.2) mm(P<0.05). At final follow-up, there were no significant differences in Harris scores of pain, function, deformity, total scores and VAS between two groups (P>0.05). The range of motion score was 4.8±0.6 in AI-HIP group, which was higher than that in control group (4.4±0.8)(P<0.05). CONCLUSION: Compared with traditional template planning, AI-HIP assisted surgical planning system has good accuracy in predicting the prosthetic size of the acetabular cup and femoral stalk, restoring joint eccentricity, planning lower limb length, osteotomy height and top shoulder distance on the first unilateral THA, and the clinical follow-up effect is satisfactory.

Electroacupuncture inhibits TLR4/NF-κB signaling in the dorsal root ganglion of rats with spared nerve injury.

OBJECTIVE: Neuropathic pain can be provoked by high mobility group box 1 (HMGB1) activation of toll-like receptor (TLR)4/nuclear factor (NF)-κB signaling in the dorsal root ganglion (DRG). Electroacupuncture (EA) has been reported to effectively alleviate neuropathic pain with few side effects, but its precise mechanism of action remains unknown. The aim of this study was to explore whether 2 Hz EA stimulation suppresses TLR4/NF-κB signaling in the DRG following spared nerve injury (SNI) in a rat model. METHODS: In this experiment, SNI rats were given 2 Hz EA once every other day for a total of 21 days. Paw withdrawal threshold (PWT) was measured to assess SNI-induced mechanical hypersensitivity, and western blotting and immunofluorescence staining were used to determine the levels of pain-related signaling molecules and pro-inflammatory mediators in the DRG. RESULTS: SNI up-regulated HMGB1, TLR4, myeloid differentiation factor-88 adaptor protein (MyD88) and NF-κB p65 protein expression in the DRG. In addition, immunofluorescence staining demonstrated that SNI induced higher levels of TLR4 and MyD88 in the DRG. We also demonstrated co-localization of TLR4 and MyD88 with both calcitonin gene-related peptide (CGRP) and isolectin GS-IB4 in the DRG of SNI rats, respectively. Meanwhile, 2 Hz EA stimulation effectively reversed the elevations of HMGB1, TLR4, MyD88 and NF-κB p65 induced by SNI in the DRG, which was coupled with amelioration of SNI-induced mechanical hypersensitivity. CONCLUSIONS: The results of this study suggested that inhibition of the TLR4/NF-κB signaling pathway in the DRG by 2 Hz EA might be exploited as a therapeutic option for neuropathic pain.

Involvement of BRD4 in alcoholic liver injury: Autophagy modulation via regulation of the SIRT1/Beclin1 axis.

Alcoholic liver disease (ALD) caused by chronic alcohol abuse involves complex processes from steatosis to fibrosis, cirrhosis, and hepatocellular carcinoma, posing a global health issue. Bromodomain protein 4 (BRD4) typically serves as a "reader" modulating the functions of transcription factors involved in various biological processes and disease progression. However, the specific mechanisms underlying alcoholic liver injury remain unclear. Here, we detected aberrant BRD4 expression in the alcohol-induced ALD mouse model of chronic and binge ethanol feeding developed by the National Institute on Alcohol Abuse and Alcoholism (NIAAA model), consistent with the in vitro results in Aml-12 mouse hepatocytes. Blocking and inhibiting BRD4 restored the impaired autophagic flux and lysosomal functions in alcohol-treated Aml-12 cells, whereas BRD4 overexpression reduced the expression levels of autophagy marker and lysosomal genes. Furthermore, mouse BRD4 knockdown, mediated by a short hairpin RNA carried by the adeno-associated virus serotype 8, significantly attenuated the alcohol-induced hepatocyte damage, including lipid deposition and inflammatory cell infiltration. Mechanistically, BRD4 overexpression in alcoholic liver injury inhibited the expression of sirtuin (SIRT)-1 in Aml-12 cells. Chromatin immunoprecipitation and dual-luciferase reporter assays revealed that BRD4 functions as a transcription factor and suppressor, actively binding to the SIRT1 promoter region and inhibiting its transcription. SIRT1 activated autophagy, which was suppressed in alcoholic liver injury via Beclin1 deacetylation. In conclusion, our study revealed that BRD4 negatively regulated the SIRT1/Beclin1 axis and that its deficiency alleviated alcohol-induced liver injury in mice, thus providing a new strategy for ALD treatment.

Navigating therapeutic challenges in VEXAS syndrome: exploring IL-6 and JAK inhibitors at the forefront.

VEXAS syndrome, an uncommon yet severe autoimmune disorder stemming from a mutation in the UBA1 gene, is the focus of this paper. The overview encompasses its discovery, epidemiological traits, genetic underpinnings, and clinical presentations. Delving into whether distinct genotypes yield varied clinical phenotypes in VEXAS patients, and the consequent adjustment of treatment strategies based on genotypic and clinical profiles necessitates thorough exploration within the clinical realm. Additionally, the current therapeutic landscape and future outlook are examined, with particular attention to the potential therapeutic roles of IL-6 inhibitors and JAK inhibitors, alongside an elucidation of prevailing limitations and avenues for further research. This study contributes essential theoretical groundwork and clinical insights for both diagnosing and managing VEXAS syndrome.

Penicipyrrolizidinones A-C, three pyrrolizidinone alkaloids with unprecedented skeletons from the mangrove-derived fungus Penicillium sp. DM27.

Three previously undescribed pyrrolizidinone alkaloids, penicipyrrolizidinones A and B (1 and 2), possessing an unprecedented 2-methyl-2-(oct-6-enoyl)pyrrolizidin-3-one skeleton, and penicipyrrolizidinone C (3), featuring a rare 1-alkenyl-2-methyl-pyrrolizidin-3,7-dione skeleton, together with four known pyrrolidine derivatives (4-7) were isolated from the mangrove-derived fungus Penicillium sp. DM27. Their structures were elucidated through comprehensive spectroscopic analysis, theoretical calculations of ECD spectra, and the modified Mosher's method. A plausible biosynthetic pathway for penicipyrrolizidinones A-C (1-3) was proposed. Compounds 4 and 5 exhibited moderate cytotoxicity against B16-F10 melanoma cells with IC50 values of 10.5 µM and 15.5 µM, respectively.

Overlooked Trace Molecules in Organic Aerosol Revealed by Gas Chromatography-Orbitrap Mass Spectrometry.

Molecular characterization of organic aerosol (OA) is crucial for understanding its sources and atmospheric processes. However, the chemical components of OA remain not well constrained. This study used gas chromatography-Orbitrap mass spectrometry (GC-Orbitrap MS) and GC-Quadrupole MS (GC-qMS) to investigate the organic composition in PM2.5 from Xi'an, Northwest China. GC-Orbitrap MS identified 335 organic tracers, including overlooked isomers and low-concentration molecules, approximately 1.6 times more than GC-qMS. The "molecular corridor" assessment shows the superior capability of GC-Orbitrap MS in identifying an expansive range of compounds with higher volatility and oxidation states, such as furanoses/pyranoses, di/hydroxy/ketonic acids, di/poly alcohols, aldehydes/ketones, and amines/amides. Seasonal variations in OA composition reflect diverse sources: increased di/poly alcohols in winter are derived from indoor emissions, furanoses/pyranoses and heterocyclics in spring and summer might be from biogenic emissions and secondary formation, and amides in autumn are probably from biomass burning. Integrating partial least squares discriminant analysis (PLS-DA) and potential source contribution function (PSCF) models, the source similarities and differences are further elucidated, highlighting the role of local emissions and transport from southern cities. This study offers new insights into the OA composition aided by the high mass resolution and sensitivity of GC-Orbitrap MS.

Nanoporous Aramid Nanofiber Separators with High Modulus and Thermal Stability for Safe Lithium-Ion Batteries.

Developing high-safety separators is a promising strategy to prevent thermal runaway in lithium-ion batteries (LIBs), which stems from the low melting temperatures and inadequate modulus of commercial polyolefin separators. However, achieving high modulus and thermal stability, along with uniform nanopores in these separators, poses significant challenges. Herein, the study presents ultrathin nanoporous aramid nanofiber (ANF) separators with high modulus and excellent thermal stability, enhancing the safety of LIBs. These separators are produced using a microfluidic-based continuous printing strategy, where the flow thickness can be meticulously controlled at the micrometer scale. This method allows for the continuous fabrication of nanoporous ANF separators with thicknesses ranging from 1.6 ± 0.1 µm to 2.7 ± 0.1 µm. Thanks to the double-side solvent diffusion, the separators exhibit controllably uniform pore sizes with a narrow distribution, spanning from 40 ± 5 nm to 105 ± 9 nm, and a high modulus of 3.3 ± 0.5 GPa. These nanoporous ANF separators effectively inhibit lithium dendrite formation, resulting in a high-capacity retention rate for the LIBs (80% after 240 cycles). Most notably, their robust structural and mechanical stability at elevated temperatures significantly enhances LIB safety under transient thermal abuse conditions, thus addressing critical safety concerns associated with LIBs.

Synergistic Mitochondrial Genotoxicity of Carbon Dots and Arsenate in Earthworms Eisenia fetida across Generations: The Critical Role of Binding.

The escalating utilization of carbon dots (CDs) in agriculture raises ecological concerns. However, their combined toxicity with arsenic remains poorly understood. Herein, we investigated the combined mitochondrial genotoxicity of CDs and arsenate at environmentally relevant concentrations across successive earthworm generations. Iron-doped CDs (CDs-Fe) strongly bound to arsenate and arsenite, while nitrogen-doped CDs (CDs-N) exhibited weaker binding. Both CDs enhanced arsenate bioaccumulation without affecting its biotransformation, with most arsenate being reduced to arsenite. CDs-Fe generated significantly more reactive oxygen species than did CDs-N, causing stronger mitochondrial DNA (mtDNA) damage. Arsenate further exacerbated the oxidative mtDNA damage induced by CDs-N, as evidenced by increased reactive oxygen species, elevated 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-OHdG) levels, and a higher correlation between 8-OHdG and mtDNA damage. This was due to arsenic inhibiting the antioxidant enzyme catalase. This exacerbation was negligible with CDs-Fe because their strong binding with arsenic prevented catalase inhibition. Maternal mitochondrial DNA damage was inherited by filial earthworms, which experienced significant weight loss in coexposure groups coupled with mtDNA toxicity. This study reveals the synergistic genotoxicity of CDs and arsenate, suggesting that CDs could disrupt the arsenic biogeochemical cycle, increase arsenate risk to terrestrial animals, and influence ecosystem stability and health through multigenerational impacts.

Fibre-specific mitochondrial protein abundance is linked to resting and post-training mitochondrial content in the muscle of men.

Analyses of mitochondrial adaptations in human skeletal muscle have mostly used whole-muscle samples, where results may be confounded by the presence of a mixture of type I and II muscle fibres. Using our adapted mass spectrometry-based proteomics workflow, we provide insights into fibre-specific mitochondrial differences in the human skeletal muscle of men before and after training. Our findings challenge previous conclusions regarding the extent of fibre-type-specific remodelling of the mitochondrial proteome and suggest that most baseline differences in mitochondrial protein abundances between fibre types reported by us, and others, might be due to differences in total mitochondrial content or a consequence of adaptations to habitual physical activity (or inactivity). Most training-induced changes in different mitochondrial functional groups, in both fibre types, were no longer significant in our study when normalised to changes in markers of mitochondrial content.

Does patient-specific instrument or robot improve imaging and functional outcomes in unicompartmental knee arthroplasty? A bayesian analysis.

INTRODUCTION: This study conducted a Bayesian network meta-analysis (NMA) to compare the imaging and functional outcomes of patient-specific instrument-assisted unicompartmental knee arthroplasty (P-UKA), robot-assisted unicompartmental knee arthroplasty (R-UKA), and conventional unicompartmental knee arthroplasty (C-UKA). MATERIALS AND METHODS: A comprehensive search was performed on five electronic databases and major orthopedic journals as of September 24, 2023. We included randomized controlled studies featuring at least two interventions of P-UKA, R-UKA, or C-UKA. Primary outcomes encompassed the deviation angle of hip-knee-ankle angle, as well as the coronal and sagittal plane alignment of femoral and tibial components. Secondary outcomes included patient-reported outcome measures (PROM), surgery time, revision rate, and complication rate. Bayesian framework was employed for risk ratio (RR) or mean deviation (MD) analysis, and treatment hierarchy was established based on rank probabilities. RESULTS: This NMA included 871 knees from 12 selected studies. In sagittal plane, R-UKA exhibited a significantly reduced deviation angle of femoral component compared to P-UKA (MD: 4.16, 95% CI: 0.21, 8.07), and of tibial component in comparison to C-UKA (MD: -2.45, 95% CI: -4.20, -0.68). Notably, the surgery time was significantly longer in R-UKA than in C-UKA (MD: 15.98, 95% CI: 3.11, 28.88). However, no significant differences were observed in other outcomes. CONCLUSION: Compared with P-UKA or C-UKA, R-UKA significantly improves the femoral and tibial component alignment in the sagittal plane, although this does not translate into discernible differences in functional outcomes. Comprehensive considerations of economic and learning costs are imperative for the judicious selection of the appropriate procedure.

Regulation of Lead Iodide Crystallization and Distribution for Efficient Perovskite Solar Cells.

At present, the power conversion efficiency (PCE) of perovskite solar cells (PSCs) has reached 26.1%. Polycrystalline perovskite films prepared by sequential deposition are often accompanied by excess PbI2. Although excess PbI2 can reduce the internal defects of the perovskites and promote charge transfer, excess PbI2 is unevenly distributed in the perovskites and easily decomposed into the composite center of charge. Therefore, the growth and distribution of PbI2 crystals can be regulated by introducing 4-fluoroaniline (4-FLA) as an additive into the precursor of PbI2. We observe that the presence of an amino group in 4-FLA leads to a reduction in the strength of van der Waals forces between PbI2 layer structures, thereby facilitating the uniform dispersion of excess PbI2 within the perovskites. Additionally, 4-FLA is restricted from being embedded in the PbI2 layer due to the steric hindrance of 4-FLA and the hydrogen bond interaction between nitrogen atoms and PbI2. Therefore, it leads to better dispersion of PbI2, resulting in better passivation and device efficiency. Based on the hydrophobicity of the benzene ring, the modified perovskite film shows excellent hydrophobicity. Ultimately, we achieved 21.63% PCE and 1.16V VOC. This provides an effective strategy for regulating excess PbI2 to achieve efficient and stable PSCs.

The CYP3A inducer dexamethasone affects the pharmacokinetics of sunitinib by accelerating its metabolism in rats.

Sunitinib, a novel anti-tumor small molecule targeting VEGFR, is prescribed for advanced RCC and GISTs. Sunitinib is primarily metabolized by the CYP3A enzyme. It is well-known that dexamethasone serves as a potent inducer of this enzyme system. Nonetheless, the effect of dexamethasone on sunitinib metabolism remains unclear. This study examined the effect of dexamethasone on the pharmacokinetics of sunitinib and its metabolite N-desethyl sunitinib in rats. The plasma levels of both compounds were measured using UHPLC-MS/MS. Pharmacokinetic parameters and metabolite ratio values were calculated. Compare to control group, the low-dose dexamethasone group and high-dose dexamethasone group decreased the AUC(0-t) values of sunitinib by 47 % and 45 %, respectively. Meanwhile, the AUC(0-t) values of N-desethyl sunitinib were increased by 2.2-fold and 2.4-fold in low-dose dexamethasone group and high-dose dexamethasone group, respectively. The CL values for sunitinib were both approximately 45 % higher in the two dexamethasone groups. Remarkably, metabolite ratio values increased over 5-fold in both low-dose dexamethasone group and high-dose dexamethasone group, indicating a significant enhancement of sunitinib metabolism by dexamethasone. Moreover, the total levels of sunitinib and its metabolite are also significantly increased. The impact of interactions on sunitinib metabolism, as observed with CYP3A inducers such as dexamethasone, is a crucial consideration for clinical practice. To optimize the dosage and prevent adverse drug events, therapeutic drug monitoring can be employed to avoid the toxicity from such interactions.

Longitudinal study on metabolic abnormalities and diabetes risk in normal-weight japanese adults.

Background: Diabetes is a significant global health concern, with a growing prevalence in Japan. Individuals with normal body mass index who are metabolically unhealthy exhibit an elevated risk of diabetes onset. Investigating the relationship between Metabolically Unhealthy Normal-weight (MUNW) status and the risk of diabetes in non-diabetic individual is vital for implementing early preventive strategies. Methods: Using data from the NAGALA cohort, This study categorized 8,194 Japanese adults based on the score of metabolic syndrome (MetS) components they possessed. Cox proportional hazards regression models and multivariate logistic regression were used to assess the relationship between MUNW and the risk of developing diabetes, with analyses stratified by age and sex. Results: During an average follow-up of 7.19 years, 123 participants (1.5%) were diagnosed with diabetes. Among the participants, 766 (9.35%) were classified as MUNW, and 157 (1.92%) as having MetS. Compared to those with no MetS components, individuals with 1, 2, and ≥3 MetS components had progressively higher adjusted hazard ratios (HRs) for developing diabetes, at 4.56, 8.79, and 25.16, respectively. Further stratified analysis revealed that men aged ≤40 years had the highest risk of developing diabetes. For men, the adjusted HRs for having 1, 2, and ≥3 MetS components were 5.61, 7.80, and 28.59, respectively, and for participants aged ≤40 years, the HRs were 12.31, 25.57, and 129.82, respectively. Conclusion: The prevalence of MUNW in non-diabetic individuals in Japan is 9.35%. The score of MetS components was positively correlated with the risk of diabetes. Early intervention and lifestyle modifications are crucial, especially for MUNW individuals and notably young Japanese men aged ≤40 years, for the prevention and management of diabetes.