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BACKGROUND: Sirolimus is increasingly utilized in treating diseases associated with mTOR pathway overactivation. Despite its potential, the lack of evidence regarding its long-term safety across all age groups, particularly in pediatric patients, has limited its further application. This study aims to assess the long-term safety of sirolimus, with a specific focus on its impact on growth patterns in pediatric patients. METHODS: This pooled analysis inlcudes two prospective cohort studies spanning 10 years, including 1,738 participants (aged 5 days to 69 years) diagnosed with tuberous sclerosis and/or lymphangioleiomyomatosis. All participants were mTOR inhibitor-naive and received 1 mg/m²/day of sirolimus, with dose adjustments during a two-week titration period to maintain trough blood concentrations between 5 and 10 ng/ml (maximum dose 2 mg). Indicators of physical growth, hematopoietic, liver, renal function, and blood lipid levels were all primary outcomes and were analyzed. The adverse events and related management were also recorded. RESULTS: Sirolimus administration did not lead to deviations from normal growth ranges, but higher doses exhibited a positive association with Z-scores exceeding 2 SD in height, weight, and BMI. Transient elevations in red blood cell and white blood cell counts, along with hyperlipidemia, were primarily observed within the first year of treatment. Other measured parameters remained largely unchanged, displaying only weak correlations with drug use. Stomatitis is the most common adverse event (920/1738, 52.9%). In adult females, menstrual disorders were observed in 48.5% (112/217). CONCLUSIONS: Sirolimus's long-term administration is not associated with adverse effects on children's physical growth pattern, nor significant alterations in hematopoietic, liver, renal function, or lipid levels. A potential dose-dependent influence on growth merits further exploration. TRIAL REGISTRATION: Pediatric patients: Chinese clinical trial registry, No. ChiCTR-OOB-15,006,535. Adult patients: ClinicalTrials, No. NCT03193892.
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Sirolimo , Humanos , Sirolimo/efeitos adversos , Sirolimo/uso terapêutico , Criança , Feminino , Adolescente , Pré-Escolar , Adulto , Masculino , Lactente , Adulto Jovem , Pessoa de Meia-Idade , Recém-Nascido , Idoso , Esclerose Tuberosa/tratamento farmacológico , Linfangioleiomiomatose/tratamento farmacológico , Estudos ProspectivosRESUMO
BACKGROUND: Gastric signet ring cell carcinoma (GSRC) represents a specific subtype of gastric cancer renowned for its contentious epidemiological features, treatment principles, and prognostic factors. AIM: To investigate the epidemiology of GSRC and establish an improved model for predicting the prognosis of patients with locally advanced GSRC (LAGSRC) after surgery. METHODS: The annual rates of GSRC incidence and mortality, covering the years 1975 to 2019, were extracted from the Surveillance, Epidemiology, and End Results (SEER) database to explore the temporal trends in both disease incidence and mortality rates using Joinpoint software. The clinical data of 3793 postoperative LAGSRC patients were collected from the SEER database for the analysis of survival rates. The Cox regression model was used to explore the independent prognostic factors for overall survival (OS). The risk factors extracted were used to establish a prognostic nomogram. RESULTS: The overall incidence of GSRC increased dramatically between 1975 and 1998, followed by a significant downward trend in incidence after 1998. In recent years, there has been a similarly optimistic trend in GSRC mortality rates. The trend in GSRC showed discrepancies based on age and sex. Receiver operating characteristic curves, calibration curves, and decision curve analysis for 1-year, 3-year, and 5-year OS demonstrated the high discriminative ability and clinical utility of this nomogram. The area under the curve indicated that the performance of the new model outperformed that of the pathological staging system. CONCLUSION: The model we established can aid clinicians in the early prognostication of LAGSRC patients, resulting in improved clinical outcomes by modifying management strategies and patient health care.
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The extensive use of herbicide metamifop (MET) in rice fields for weeds control will inevitably lead to its entering into water environments and threaten the aquatic organisms. Previous researches have demonstrated that sublethal exposure of MET significantly affected zebrafish development. Yet the long-term toxicological impacts of MET on aquatic life remains unknown. Herein, we investigated the potential effects of MET (5 and 50 µg/L) on zebrafish during an entire life cycle. Since the expression level of male sex differentiation-related gene dmrt1 and sex hormone synthesis-related gene cyp19a1b were significantly changed after 50 µg/L MET exposure for only 7 days, indicators related to sex differentiation and reproductive system were further investigated. Results showed that the transcript of dmrt1 was inhibited, estradiol content increased and testosterone content decreased in zebrafish of both sexes after MET exposure at 45, 60 and 120 dpf. Histopathological sections showed that the proportions of mature germ cells in the gonads of male and female zebrafish (120 dpf) were significantly decreased. Moreover, males had elevated vitellogenin content while females did not after MET exposure; MET induced feminization in zebrafish, with the proportion of females significantly increased by 19.6% while that of males significantly decreased by 13.2% at 120 dpf. These results suggested that MET interfered with the expression levels of gonad development related-genes, disrupted sex hormone balance, and affected sex differentiation and reproductive system of female and male zebrafish, implying it might have potential endocrine disrupting effects after long-term exposure.
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Diferenciação Sexual , Vitelogeninas , Poluentes Químicos da Água , Peixe-Zebra , Animais , Diferenciação Sexual/efeitos dos fármacos , Masculino , Feminino , Poluentes Químicos da Água/toxicidade , Vitelogeninas/metabolismo , Vitelogeninas/genética , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo , Herbicidas/toxicidade , Aromatase/genética , Aromatase/metabolismo , Estradiol , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Testosterona , Gônadas/efeitos dos fármacos , Reprodução/efeitos dos fármacosRESUMO
Multidrug resistance (MDR) is frequently induced after long-term exposure to reduce the therapeutic effect of chemotherapeutic drugs, which is always associated with the overexpression of efflux proteins, such as P-glycoprotein (P-gp). Nano-delivery technology can be used as an efficient strategy to overcome tumor MDR. In this study, mesoporous silica nanoparticles (MSNs) were synthesized and linked with a disulfide bond and then coated with lipid bilayers. The functionalized shell/core delivery systems (HT-LMSNs-SS@DOX) were developed by loading drugs inside the pores of MSNs and conjugating with D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) and hyaluronic acid (HA) on the outer lipid surface. HT-LMSNs-SS and other carriers were characterized and assessed in terms of various characteristics. HT-LMSNs-SS@DOX exhibited a dual pH/reduction responsive drug release. The results also showed that modified LMSNs had good dispersity, biocompatibility, and drug-loading capacity. In vitro experiment results demonstrated that HT-LMSNs-SS were internalized by cells and mainly by clathrin-mediated endocytosis, with higher uptake efficiency than other carriers. Furthermore, HT-LMSNs-SS@DOX could effectively inhibit the expression of P-gp, increase the apoptosis ratios of MCF-7/ADR cells, and arrest cell cycle at the G0/G1 phase, with enhanced ability to induce excessive reactive oxygen species (ROS) production in cells. In tumor-bearing model mice, HT-LMSNs-SS@DOX similarly exhibited the highest inhibition activity against tumor growth, with good biosafety, among all of the treatment groups. Therefore, the nano-delivery systems developed herein achieve enhanced efficacy towards resistant tumors through targeted delivery and redox-responsive drug release, with broad application prospects.
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Doxorrubicina , Resistencia a Medicamentos Antineoplásicos , Bicamadas Lipídicas , Nanopartículas , Oxirredução , Dióxido de Silício , Dióxido de Silício/química , Humanos , Animais , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Nanopartículas/química , Camundongos , Doxorrubicina/farmacologia , Doxorrubicina/química , Doxorrubicina/administração & dosagem , Bicamadas Lipídicas/química , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Sistemas de Liberação de Medicamentos , Apoptose/efeitos dos fármacos , Porosidade , Feminino , Células MCF-7 , Ensaios Antitumorais Modelo de Xenoenxerto , Linhagem Celular Tumoral , Ácido Hialurônico/química , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Camundongos NusRESUMO
The mammary gland is a dynamic organ that undergoes significant changes at multiple stages of postnatal development. Although the roles of systemic hormones and microenvironmental cues in mammary homeostasis have been extensively studied, the influence of neural signals, particularly those from the sympathetic nervous system, remains poorly understood. Here, using a mouse mammary gland model, we delved into the regulatory role of sympathetic nervous signaling in the context of mammary stem cells and mammary development. Our findings revealed that depletion of sympathetic nerve signals results in defective mammary development during puberty, adulthood, and pregnancy, accompanied by a reduction in mammary stem cell number. Through in vitro three-dimensional culture and in vivo transplantation analyses, we demonstrated that the absence of sympathetic nerve signals hinders mammary stem cell self-renewal and regeneration, while activation of sympathetic nervous signaling promotes these capacities. Mechanistically, sympathetic nerve signals orchestrate mammary stem cell activity and mammary development through the ERK signaling pathway. Collectively, our study unveils the crucial roles of sympathetic nerve signals in sustaining mammary development and regulating mammary stem cell activity, offering a novel perspective on the involvement of the nervous system in modulating adult stem cell function and organ development.
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Peripheral blood mononuclear cell (PBMC) are recognized as a conveniently collected reprogramming resource. Several methods are available in academia to reprogram PBMC into induced pluripotent stem cells (iPSC). In this research, we reprogrammed PBMC of different genders by using non-integrative non-viral liposome electrotransfer containing the reprogramming factors OCT4, SOX2, KLF4, and c-MYC. The three obtained iPSC cell lines were karyotypically normal and showed significant tritiated differentiation potential in vitro and in vivo. Our study provided an efficient procedure for reprogramming PBMC into iPSC and obtained three well-functioning iPSC, that may contribute to advance personalized cell therapy in the future.
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Células-Tronco Pluripotentes Induzidas , Fator 4 Semelhante a Kruppel , Leucócitos Mononucleares , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/metabolismo , Masculino , Feminino , Diferenciação Celular , Reprogramação Celular , Linhagem Celular , AnimaisRESUMO
Background: Wheat (Tritium aestivum L.) production is critical for global food security. In recent years, due to climate change and the prolonged growing period of rice varieties, the delayed sowing of wheat has resulted in a loss of grain yield in the area of the middle and lower reaches of the Yangtze River. It is of great significance to screen for natural germplasm resources of wheat that are resistant to late sowing and to explore genetic loci that stably control grain size and yield. Methods: A collection of 327 wheat accessions from diverse sources were subjected to genome-wide association studies using genotyping-by-sequencing. Field trials were conducted under normal, delayed, and seriously delayed sowing conditions for grain length, width, and thousand-grain weight at two sites. Additionally, the additive main effects and multiplicative interaction (AMMI) model was applied to evaluate the stability of thousand-grain weight of 327 accessions across multiple sowing dates. Results: Four wheat germplasm resources have been screened, demonstrating higher stability of thousand-grain weight. A total of 43, 35, and 39 significant MTAs were determined across all chromosomes except for 4D under the three sowing dates, respectively. A total of 10.31% of MTAs that stably affect wheat grain size could be repeatedly identified in at least two sowing dates, with PVE ranging from 0.03% to 38.06%. Among these, six were for GL, three for GW, and one for TGW. There were three novel and stable loci (4A_598189950, 4B_307707920, 2D_622241054) located in conserved regions of the genome, which provide excellent genetic resources for pyramid breeding strategies of superior loci. Our findings offer a theoretical basis for cultivar improvement and marker-assisted selection in wheat breeding practices.
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Estudo de Associação Genômica Ampla , Locos de Características Quantitativas , Fenótipo , Triticum/genética , Melhoramento Vegetal , Grão Comestível/genéticaRESUMO
High-throughput whole genome sequencing (WGS) is clinically used in finding single nucleotide variants and small indels. Several bioinformatics tools are developed to call short tandem repeats (STRs) copy numbers from WGS data, such as ExpansionHunter denovo, GangSTR and HipSTR. However, expansion disorders are rare and it is hard to find candidate expansions in single patient sequencing data with ~ 800,000 STRs calls. In this paper I describe a snakemake pipeline for genome-wide STRs Annotation and Score (STRAS) using a Random Forest (RF) model to predict pathogenicity. The predictor was validated by benchmark data from Clinvar and PUBMED. True positive rate was 93.8%. True negative rate was 98.0%.Precision was 98.6% and recall rate was 93.8%. F1-score was 0.961. Sensitivity was 93.8% and specificity was 99.6%. These results showed STRAS could be a useful tool for clinical researchers to find STR loci of interest and filter out neutral STRs. STRAS is freely available at https://github.com/fancheyu5/STRAS .
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Biologia Computacional , Genoma Humano , Repetições de Microssatélites , Anotação de Sequência Molecular , Software , Humanos , Repetições de Microssatélites/genética , Anotação de Sequência Molecular/métodos , Biologia Computacional/métodos , Sequenciamento Completo do Genoma/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
The whole-grain, hulled Tartary buckwheat flour (HTBF) with outstanding bioactive functions was prepared, and the effects of partial substitution ratios (0, 30%, 51% and 70%) of wheat flour with HTBF on the characteristics of TB noodles (TBNs) were investigated, mainly including the cooking characteristics, sensory analysis, internal structure, bioactive components, and in vitro starch digestibility. With an increasing replacement level of HTBF, the water absorption index of the noodles decreased, whereas the cooking loss increased. A sensory analysis indicated that there were no off-flavors in all TBN samples. The scanning electron microscope images presented that the wheat noodles, 30% TBNs and 70% TBNs had dense and uniform cross sections. Meanwhile, the deepest color, V-type complexes, and lowest crystallinity (13.26%) could be observed in the 70% TBNs. A HTBF substitution increased the rutin content and the total phenolic and flavonoid contents in the TBNs, and higher values were found in the 70% TBNs. Furthermore, the lowest rapidly digestible starch content (16%) and highest resistant starch content (66%) were obtained in the 70% TBNs. Results demonstrated that HTBF could be successfully applied to make TBNs, and a 70% substitution level was suggested. This study provides consumers with a good option in the realm of special noodle-type products.
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KEY MESSAGE: SNP-based and InDel-based GWAS on multi-environment data identified genomic regions associated with barley grain size. Barley yield and quality are greatly influenced by grain size. Improving barley grain size in breeding programs requires knowledge of genetic loci and alleles in germplasm resources. In this study, a collection of 334 worldwide two-rowed barley accessions with extensive genetic diversity was evaluated for grain size including grain length (GL), grain width (GW), and thousand-grain weight (TGW) across six independent field trials. Significant differences were observed in genotype and environments for all measured traits. SNP- and InDel-based GWAS were applied to dissect the genetic architecture of grain size with an SLAF-seq strategy. Two approaches using the FarmCPU model revealed 38 significant marker-trait associations (MTAs) with PVE ranging from 0.01% to 20.68%. Among these MTAs, five were on genomic regions where no previously reported QTL for grain size. Superior alleles of TGW-associated SNP233060 and GL-associated InDel11006 exhibited significantly higher levels of phenotype. The significant MTAs could be used in marker-assisted selection breeding.
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Hordeum , Hordeum/genética , Estudo de Associação Genômica Ampla , Melhoramento Vegetal , Alelos , Grão Comestível/genéticaRESUMO
Strobilurin fungicides (SFs) are commonly used in agriculture worldwide and frequently detected in aquatic environments. High toxicity of SFs to aquatic organisms has caused great concerns. To explore whether vitamin E (VE) can relieve the toxicity caused by pyraclostrobin (PY), zebrafish were exposed to PY with or without VE supplementation. When co-exposure with VE (20 µM), the 96 h-LC50 values of PY to zebrafish embryos, adult, and the 24 h-LC50 value of PY to larvae increased from 43.94, 58.36 and 38.16 µg/L to 64.72, 108.62 and 72.78 µg/L, respectively, indicating that VE significantly decreased the toxicity of PY to zebrafish at different life stages. In addition, VE alleviated the deformity symptoms (pericardial edema and brain damage), reduced speed and movement distance, and decreased heart rate caused by 40 µg/L PY in zebrafish larvae. Co-exposure of PY with VE significantly reduced PY-caused larval oxidative stress and immunotoxicity via increasing the activities of superoxide dismutase, catalase and level of glutathione, as well as reducing the malondialdehyde production and the expression levels of Nrf2, Ucp2, IL-8, IFN and CXCL-C1C. Meanwhile, the expression levels of gria4a and cacng4b genes, which were inhibited by PY, were significantly up-regulated after co-exposure of PY with VE. Moreover, co-exposure with VE significantly reversed the increased mitochondrial DNA copies and reduced ATP content caused by PY in larvae, but had no effect on the expression of cox4i1l and activity of complex III that reduced by PY, suggesting VE can partially improve PY-induced mitochondrial dysfunction. In conclusion, the potential mechanisms of VE alleviating PY-induced toxicity may be ascribed to decreasing the oxidative stress level, restoring the functions of heart and nervous system, and improving the immunity and mitochondrial function in zebrafish.
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Fungicidas Industriais , Poluentes Químicos da Água , Animais , Estrobilurinas/toxicidade , Peixe-Zebra/metabolismo , Vitamina E/metabolismo , Vitamina E/farmacologia , Poluentes Químicos da Água/metabolismo , Estresse Oxidativo , Fungicidas Industriais/metabolismo , Larva , Embrião não MamíferoRESUMO
Neuropeptide FF (NPFF) plays a critical role in various physiological processes through the activation of neuropeptide FF receptor 1 and 2 (NPFFR1 and NPFFR2). Numerous evidence has indicated that NPFF exhibits opposite opioid-modulating effects on opioid-induced analgesia after supraspinal and spinal administrations, while the detailed role of NPFFR1 and NPFFR2 remains unclear. In this study, we employed pharmacological and genetic inhibition of NPFFR to investigate the modulating roles of central NPFFR1 and NPFFR2 in opioid-induced analgesia and hyperalgesia, using a male mouse model of acute fentanyl-induced analgesia and secondary hyperalgesia. Our findings revealed that intrathecal (i.t.) injection of the nonselective NPFFR antagonist RF9 significantly enhanced fentanyl-induced analgesia, whereas intracerebroventricular (i.c.v.) injection did not show the same effect. Moreover, NPFFR2 deficient (npffr2-/-) mice exhibited stronger analgesic responses to fentanyl compared to wild type (WT) or NPFFR1 knockout (npffr1-/-) mice. Intrathecal injection of RF9 in npffr1-/- mice also significantly enhanced fentanyl-induced analgesia. These results indicate a crucial role of spinal NPFFR2 in the enhancement of opioid analgesia. Contrastingly, hyperalgesia induced by fentanyl was markedly reversed in npffr1-/- mice but remained unaffected in npffr2-/- mice. Similarly, i.c.v. injection of the selective NPFFR1 antagonist RF3286 effectively prevented fentanyl-induced hyperalgesia in WT or npffr2-/- mice. Notably, co-administration of i.c.v. RF3286 and i.t. RF9 augmented fentanyl-induced analgesia while reducing hyperalgesia. Collectively, these findings highlight the modulating effects of blocking spinal NPFFR2 and supraspinal NPFFR1 on fentanyl-induced analgesia and hyperalgesia, respectively, which shed a light on understanding the pharmacological function of NPFF system in future studies.
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Analgesia , Hiperalgesia , Camundongos , Masculino , Animais , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Fentanila/farmacologia , Analgésicos Opioides/farmacologia , Dor , Receptores de Neuropeptídeos/genéticaRESUMO
Octupolar molecules possessing a strong two-photon response are vital for numerous advanced applications. However, accurately predicting their two-photon absorption (TPA) spectra requires high-precision quantum chemical calculations, which are computationally expensive due to repeated simulations of molecular excited-state properties. To address this challenge, we introduce a deep learning approach capable of rapidly and accurately forecasting TPA spectra for octupolar molecules. By leveraging the geometric structure as an initial descriptor, we employ a graph neural network to predict the maximum two-photon transition wavelength and cross-section. Our model demonstrates a mean absolute percentage error of less than 4% compared to time-dependent density-functional theory calculations, effectively reproducing experimental observations. Notably, this deep learning technique is nearly 100 000 times faster than comparable quantum calculations, making it an efficient and cost-effective tool for simulating TPA properties of octupolar molecules. Furthermore, this method holds great promise for the high-throughput screening of exceptional TPA materials.
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Viral infections present significant challenges to human health, underscoring the importance of understanding the immune response for effective therapeutic strategies. Immune cell activation leads to dynamic changes in gene expression. Numerous studies have demonstrated the crucial role of long noncoding RNAs (lncRNAs) in immune activation and disease processes, including viral infections. This review provides a comprehensive overview of lncRNAs expressed in immune cells, including CD8 T cells, CD4 T cells, B cells, monocytes, macrophages, dendritic cells, and granulocytes, during both acute and chronic viral infections. LncRNA-mediated gene regulation encompasses various mechanisms, including the modulation of viral replication, the establishment of latency, activation of interferon pathways and other critical signaling pathways, regulation of immune exhaustion and aging, and control of cytokine and chemokine production, as well as the modulation of interferon-stimulated genes. By highlighting specific lncRNAs in different immune cell types, this review enhances our understanding of immune responses to viral infections from a lncRNA perspective and suggests potential avenues for exploring lncRNAs as therapeutic targets against viral diseases.
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RNA Longo não Codificante , Viroses , Humanos , RNA Longo não Codificante/genética , Imunidade Inata , Viroses/genética , Interferons , CitocinasRESUMO
The cyclic peptide c[d-Lys2, Asp5]-DN-9 has recently been identified as a multifunctional opioid/neuropeptide FF receptor agonist, displaying potent analgesic activity with reduced side effects. This study utilized Tyr-c[d-Lys-Gly-Phe-Asp]-d-Pro-NH2 (0), a cyclic hexapeptide derived from the opioid pharmacophore of c[d-Lys2, Asp5]-DN-9, as a chemical template. We designed, synthesized, and characterized 22 analogs of 0 with a single amino acid substitution to investigate its structure-activity relationship. Most of these cyclic hexapeptide analogs exhibited multifunctional activity at µ and δ opioid receptors (MOR and DOR, respectively) and produced antinociceptive effects following subcutaneous administration. The lead compound analog 15 showed potent agonistic activities at the MOR, κ opioid receptor (KOR), and DOR in vitro and produced a strong and long-lasting analgesic effect through peripheral MOR and KOR in the tail-flick test. Further biological evaluation identified that analog 15 did not cause significant side effects such as tolerance, withdrawal, or reward liability.
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Analgésicos Opioides , Analgésicos , Analgésicos Opioides/uso terapêutico , Relação Estrutura-Atividade , Analgésicos/farmacologia , Receptores Opioides kappa/metabolismo , Peptídeos Cíclicos/química , Receptores Opioides mu/agonistasRESUMO
BACKGROUND: Sickle cell disease (SCD) is a common inherited blood disorder among African Americans (AA), with premature mortality which has been associated with prolongation of the heart rate-corrected QT interval (QTc), a known risk factor for sudden cardiac death. Although numerous genetic variants have been identified as contributors to QT interval prolongation in the general population, their impact on SCD patients remains unclear. This study used an unweighted polygenic risk score (PRS) to validate the previously identified associations between SNPs and QTc interval in SCD patients, and to explore possible interactions with other factors that prolong QTc interval in AA individuals with SCD. METHODS: In SCD patients, candidate genetic variants associated with the QTc interval were genotyped. To identify any risk SNPs that may be correlated with QTc interval prolongation, linear regression was employed, and an unweighted PRS was subsequently constructed. The effect of PRS on the QTc interval was evaluated using linear regression, while stratification analysis was used to assess the influence of serum alanine transaminase (ALT), a biomarker for liver disease, on the PRS effect. We also evaluated the PRS with the two subcomponents of QTc, the QRS and JTc intervals. RESULTS: Out of 26 candidate SNPs, five risk SNPs were identified for QTc duration under the recessive model. For every unit increase in PRS, the QTc interval prolonged by 4.0 ms (95% CI: [2.0, 6.1]; p-value: <0.001) in the additive model and 9.4 ms in the recessive model (95% CI: [4.6, 14.1]; p-value: <0.001). Serum ALT showed a modification effect on PRS-QTc prolongation under the recessive model. In the normal ALT group, each PRS unit increased QTc interval by 11.7 ms (95% CI: [6.3, 17.1]; p-value: 2.60E-5), whereas this effect was not observed in the elevated ALT group (0.9 ms; 95% CI: [-7.0, 8.8]; p-value: 0.823). CONCLUSION: Several candidate genetic variants are associated with QTc interval prolongation in SCD patients, and serum ALT acts as a modifying factor. The association of a CPS1 gene variant in both QTc and JTc duration adds to NOS1AP as evidence of involvement of the urea cycle and nitric oxide metabolism in cardiac repolarization in SCD. Larger replication studies are needed to confirm these findings and elucidate the underlying mechanisms.
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Anemia Falciforme , Síndrome do QT Longo , Humanos , Síndrome do QT Longo/genética , Eletrocardiografia , Morte Súbita Cardíaca/etiologia , Fatores de Risco , Anemia Falciforme/genética , Proteínas Adaptadoras de Transdução de Sinal/genéticaRESUMO
Our previous study reported the multifunctional agonist for opioid and neuropeptide FF receptors DN-9, along with its cyclic peptide analogues c[D-Cys2, Cys5]-DN-9 and c[D-Lys2, Asp5]-DN-9. These analogues demonstrated potent antinociceptive effects with reduced opioid-related side effects. To develop more stable and effective analgesics, we designed, synthesized, and evaluated seven hydrocarbon-stapled cyclic peptides based on DN-9. In vitro calcium mobilization assays revealed that most of the stapled peptides, except 3, displayed multifunctional agonistic activities at opioid and neuropeptide FF receptors. Subcutaneous administration of all stapled peptides resulted in effective and long-lasting antinociceptive activities lasting up to 360 min. Among these stapled peptides, 1a and 1b emerged as the optimized compounds, producing potent central antinociception following subcutaneous, intracerebroventricular, and oral administrations. Additionally, subcutaneous administration of 1a and 1b caused nontolerance antinociception, with limited occurrence of constipation and addiction. Furthermore, 1a was selected as the final optimized compound due to its wider safety window compared to 1b.
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Analgésicos Opioides , Oligopeptídeos , Analgésicos Opioides/efeitos adversos , Oligopeptídeos/química , Analgésicos/química , Peptídeos/química , Receptores de Neuropeptídeos/agonistas , Encéfalo , Receptores Opioides mu/agonistasRESUMO
To evaluate the safety of orange consumption induced by mycotoxins, 'Newhall' navel oranges were artificially inoculated with P. expansum and A. tenuissima, followed by an evaluation of the distribution and migration patterns of corresponding mycotoxins (patulin [PAT], tentoxin [Ten], altenuene [ALT], alternariol monomethyl ether [AME], alternariol [AOH] and tenuazonic acid [TeA]) during orange storage and processing. The concentration of mycotoxins decreased as the increase of distance from the lesion, and mycotoxins could be detected throughout the orange when the lesion extended to 8 mm in diameter. AOH and AME pose the primary source of dietary risk with high concentrations and low thresholds of toxicological concern. Orange juice and pectin processing could remove 43.4-98.7% of mycotoxins, while tangerine peelprocessing might lead to significant enrichment of mycotoxins with the processing factors (PFs) of 2.8-3.5. The findings may offer scientific insights into mitigating the dietary risk of mycotoxin exposure from oranges and their derivatives.
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Citrus sinensis , Micotoxinas , Patulina , Micotoxinas/análise , Alternaria , Ácido Tenuazônico , Lactonas/análise , Contaminação de Alimentos/análiseRESUMO
Dystrophic epidermolysis bullosa pruriginosa (DEB-Pr) is a rare subtype of inherited DEB. In the present study, whole-exome sequencing was conducted on 12 individuals from the same affected family and a rare heterozygous variation was identified in the collagen type VII, α1 (COL7A1) gene, namely c.6859G>A (p.Gly2287Arg). Subsequently, this heterozygous variant was confirmed using Sanger sequencing of individual plasma cell-free DNA (cfDNA) and it was demonstrated for the first time, to the best of our knowledge, that COL7A1 exons can be amplified from plasma cfDNA. Within the large pedigree examined, 14 out of 18 individuals carried the variant, 3 carried the wild type, and one exceptional case, III-9, showed no disease symptoms despite carrying the disease variant. A general association between genotype and phenotype was established. Of note, the mutation landscape indicated that this G2287R variant is primarily reported in Asian countries. In silico structure prediction suggested that the residue resulting from the mutation may affect collagen protein stability. In conclusion, the present study provides evidence for the involvement of the COL7A1 G2287R gene variant in the development of DEB-Pr and highlights the potential utility of cfDNA in genetic disease diagnosis.