Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 11.410
Filtrar
1.
JACS Au ; 4(2): 816-827, 2024 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-38425893

RESUMO

Peptide drugs offer distinct advantages in therapeutics; however, their limited stability and membrane penetration abilities hinder their widespread application. One strategy to overcome these challenges is the hydrocarbon peptide stapling technique, which addresses issues such as poor conformational stability, weak proteolytic resistance, and limited membrane permeability. Nonetheless, while peptide stapling has successfully stabilized α-helical peptides, it has shown limited applicability for most ß-sheet peptide motifs. In this study, we present the design of a novel double-stapled peptide capable of simultaneously stabilizing both α-helix and ß-sheet structures. Our designed double-stapled peptide, named DSARTC, specifically targets the androgen receptor (AR) DNA binding domain and MDM2 as E3 ligase. Serving as a peptide-based PROTAC (proteolysis-targeting chimera), DSARTC exhibits the ability to degrade both the full-length AR and AR-V7. Molecular dynamics simulations and circular dichroism analysis validate the successful constraint of both secondary structures, demonstrating that DSARTC is a "first-in-class" heterogeneous-conformational double-stapled peptide drug candidate. Compared to its linear counterpart, DSARTC displays enhanced stability and an improved cell penetration ability. In an enzalutamide-resistant prostate cancer animal model, DSARTC effectively inhibits tumor growth and reduces the levels of both AR and AR-V7 proteins. These results highlight the potential of DSARTC as a more potent and specific peptide PROTAC for AR-V7. Furthermore, our findings provide a promising strategy for expanding the design of staple peptide-based PROTAC drugs, targeting a wide range of "undruggable" transcription factors.

2.
Front Immunol ; 15: 1285813, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38426091

RESUMO

Background: Vulnerable plaque was associated with recurrent cardiovascular events. This study was designed to explore predictive biomarkers of vulnerable plaque in patients with coronary artery disease. Methods: To reveal the phenotype-associated cell type in the development of vulnerable plaque and to identify hub gene for pathological process, we combined single-cell RNA and bulk RNA sequencing datasets of human atherosclerotic plaques using Single-Cell Identification of Subpopulations with Bulk Sample Phenotype Correlation (Scissor) and Weighted gene co-expression network analysis (WGCNA). We also validated our results in an independent cohort of patients by using intravascular ultrasound during coronary angiography. Results: Macrophages were found to be strongly correlated with plaque vulnerability while vascular smooth muscle cell (VSMC), fibrochondrocyte (FC) and intermediate cell state (ICS) clusters were negatively associated with unstable plaque. Weighted gene co-expression network analysis showed that Secreted Phosphoprotein 1 (SPP1) in the turquoise module was highly correlated with both the gene module and the clinical traits. In a total of 593 patients, serum levels of SPP1 were significantly higher in patients with vulnerable plaques than those with stable plaque (113.21 [73.65 - 147.70] ng/ml versus 71.08 [20.64 - 135.68] ng/ml; P < 0.001). Adjusted multivariate regression analysis revealed that serum SPP1 was an independent determinant of the presence of vulnerable plaque. Receiver operating characteristic curve analysis indicated that the area under the curve was 0.737 (95% CI 0.697 - 0.773; P < 0.001) for adding serum SPP1 in predicting of vulnerable plaques. Conclusion: Elevated serum SPP1 levels confer an increased risk for plaque vulnerability in patients with coronary artery disease.

3.
ACS Sens ; 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38427378

RESUMO

Managing diabetes is a chronic challenge today, requiring monitoring and timely insulin injections to maintain stable blood glucose levels. Traditional clinical testing relies on fingertip or venous blood collection, which has facilitated the emergence of continuous glucose monitoring (CGM) technology to address data limitations. Continuous glucose monitoring technology is recognized for tracking long-term blood glucose fluctuations, and its development, particularly in wearable devices, has given rise to compact and portable continuous glucose monitoring devices, which facilitates the measurement of blood glucose and adjustment of medication. This review introduces the development of wearable CGM-based technologies, including noninvasive methods using body fluids and invasive methods using implantable electrodes. The advantages and disadvantages of these approaches are discussed as well as the use of microneedle arrays in minimally invasive CGM. Microneedle arrays allow for painless transdermal puncture and are expected to facilitate the development of wearable CGM devices. Finally, we discuss the challenges and opportunities and look forward to the biomedical applications and future directions of wearable CGM-based technologies in biological research.

4.
Front Plant Sci ; 15: 1305599, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38362444

RESUMO

All living organisms must develop mechanisms to cope with and adapt to new environments. The transition of plants from aquatic to terrestrial environment provided new opportunities for them to exploit additional resources but made them vulnerable to harsh and ever-changing conditions. As such, the transmembrane receptor-like kinases (RLKs) have been extensively duplicated and expanded in land plants, increasing the number of RLKs in the advanced angiosperms, thus becoming one of the largest protein families in eukaryotes. The basic structure of the RLKs consists of a variable extracellular domain (ECD), a transmembrane domain (TM), and a conserved kinase domain (KD). Their variable ECDs can perceive various kinds of ligands that activate the conserved KD through a series of auto- and trans-phosphorylation events, allowing the KDs to keep the conserved kinase activities as a molecular switch that stabilizes their intracellular signaling cascades, possibly maintaining cellular homeostasis as their advantages in different environmental conditions. The RLK signaling mechanisms may require a coreceptor and other interactors, which ultimately leads to the control of various functions of growth and development, fertilization, and immunity. Therefore, the identification of new signaling mechanisms might offer a unique insight into the regulatory mechanism of RLKs in plant development and adaptations. Here, we give an overview update of recent advances in RLKs and their signaling mechanisms.

5.
Forensic Sci Int ; 356: 111961, 2024 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-38377671

RESUMO

With the increasing importance of X-chromosome (Chr-X) genotyping in kinship identification, the exploitation of X chromosome genetic marker multiplex kits is increasing. The Human X-InDels amplification kit is a novel developed system which contained 38 X-chromosomal Insertion/deletion markers (X-InDels) and Amelogenin. Herein, we investigated the genetic diversity of the 38 X-InDels in the Tibetan ethnic minority (n = 792) from seven regions and evaluated the application potential of this novel panel. The rs16368 was the least variable locus, whereas the most polymorphic locus was the rs59605609 in Tibetan population. We confirmed three linkage groups with the haplotype diversities ranged from 0.5032 to 0.5976. The overall combined power of discrimination (PD) in males and females were 0.999999999582066 and 0.999999999999993, respectively. And the overall combined mean exclusion chance (MEC) values were not lower than 0.999125526990159. In addition, we explored the genetic relationships among the Tibetans in seven different regions via series of population comparison analyses, finding that the genetic relationship between the Ngari Tibetan and Chamdo Tibetan was the farthest, which was consistent with geographical distribution.

6.
Ecotoxicol Environ Saf ; 273: 116079, 2024 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-38377778

RESUMO

Nicotine, an addictive component of cigarettes, causes cognitive defects, particularly when exposure occurs early in life. However, the exact mechanism through which nicotine causes toxicity and alters synaptic plasticity is still not fully understood. The aim of the current study is to examine how non-coding developmental regulatory RNA impacts the hippocampus of mice offspring whose mothers were exposed to nicotine. Female C57BL/6J mice were given nicotine water from one week before pregnancy until end of lactation. Hippocampal tissue from offspring at 20 days post-birth was used for LncRNA and mRNA microarray analysis. Differential expression of LncRNAs and mRNAs associated with neuronal development were screened and validated, and the CeRNA pathway mediating neuronal synaptic plasticity GM13530/miR-7119-3p/mef2c was predicted using LncBase Predicted v.2. Using protein immunoblotting, Golgi staining and behavioral tests, our findings revealed that nicotine exposure in offspring mice increased hippocampal NMDAR receptor, activated receptor-dependent calcium channels, enhanced the formation of NMDAR/nNOS/PSD95 ternary complexes, increased NO synthesis, mediated p38 activation, induced neuronal excitability toxicity. Furthermore, an epigenetic CeRNA regulatory mechanism was identified, which suppresses Mef2c-mediated synaptic plasticity and leads to modifications in the learning and social behavior of the offspring during adolescence. This study uncovers the way in which maternal nicotine exposure results in neurotoxicity in offspring.

7.
Arab J Gastroenterol ; 2024 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-38378357

RESUMO

BACKGROUND AND STUDY AIMS: Metabolic dysfunction-associated fatty liver disease (MAFLD) has become the most common cause of chronic liver disease worldwide. Diet plays a critical role in the prevention and treatment of MAFLD. Our hypothesis was that the intake of some macronutrients, vitamins, or mineral elements is associated with MAFLD. PATIENTS AND METHODS: Patients with MAFLD can be diagnosed based on the evidence of hepatic steatosis and if they meet any of the three additional criteria of overweight/obesity, diabetes mellitus, or metabolic dysregulation. Diets were recorded using photographs and diaries of meals for seven consecutive days. The consumed dietary composition was compared with the recommended intake according to the China Food Composition Tables (Standard Edition) version 2019 and the Chinese Dietary Reference Intakes version 2013, and its association with MAFLD was assessed by logistical regression analyses. RESULTS: A total of 229 MAFLD patients and 148 healthy controls were included in this study. MAFLD patients, compared with that by non-MAFLD participants, consumed more polyunsaturated fatty acids (PUFAs) (p < 0.001), vitamin E (p < 0.001), and iron (p = 0.008). The intake of PUFAs (OR = 1.070, 95 % CI: 1.017-1.127, p = 0.009) and vitamin E (OR = 1.100, 95 % CI: 1.018-1.190, p = 0.016) was positively associated with MAFLD. In addition, the percentages of individuals who consumed PUFAs (p = 0.006), vitamin E (p < 0.001), or iron (p = 0.046) above the recommended intake were higher among the individuals with MAFLD. Daily intake of PUFAs > 11 % (OR = 2.328, 95 % CI: 1.290-4.201, p = 0.005) and vitamin E > 14 mg (OR = 2.189, 95 % CI: 1.153-4.158, p = 0.017) was positively correlated with MAFLD. CONCLUSIONS: Patients with MAFLD consumed more PUFAs, vitamin E, and iron in their daily diet. Excessive consumption of PUFAs and vitamin E might be independent risk factors for the incidence of MAFLD.

9.
J Atten Disord ; : 10870547241233207, 2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-38379197

RESUMO

OBJECTIVE: The study involved 17 children with Autism Spectrum Disorder (ASD), 21 with ADHD, 30 with both (ASD + ADHD), and 28 typically developing children (TD). METHODS: The amplitude of low-frequency fluctuations (ALFF) was measured as a regional brain function index. Intrinsic functional connectivity (iFC) was also analyzed using the region of interest (ROI) identified in ALFF analysis. Statistical analysis was done via one-way ANCOVA, Gaussian random field (GRF) theory, and post-hoc pair-wise comparisons. RESULTS: The ASD + ADHD group showed increased ALFF in the left middle frontal gyrus (MFG.L) compared to the TD group. In terms of global brain function, the ASD group displayed underconnectivity in specific regions compared to the ASD + ADHD and TD groups. CONCLUSION: The findings contribute to understanding the neural mechanisms underlying ASD + ADHD.

10.
J Clin Nurs ; 2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-38379345

RESUMO

AIMS AND OBJECTIVES: The aim of this study was to explore the association between transition shocks and professional identity and the mediating roles of self-efficacy and resilience among Chinese novice nurses. BACKGROUND: Novice nurses experience transition shock when they start their careers, which might lead to decreased professional identity and ultimately turnover. By contrast, self-efficacy and resilience are excellent psychological resources that may be associated with higher professional identity. It is unclear how transition shock affects professional identity by influencing these two internal resources. DESIGN: A cross-sectional survey. METHODS: The STROBE guidelines were followed to report this study. Convenience sampling was used to recruit participants, and 252 novice nurses completed the Transition Shock of Novice Nurses Scale, the Professional Identity Assessment Scale, the General Self-Efficacy Scale and the Connor-Davidson Resilience Scale between April 2022 and May 2022. Influencing factors were primarily identified using independent-sample t-tests and a one-way ANOVA. Structural equation modelling was used to detect the mediating effects of self-efficacy and resilience. RESULTS: Differences in novice nurses' levels of professional identity were found across age groups, hospitals and departments. Transition shock was negatively related to professional identity. Self-efficacy and resilience mediated the complete chain relationship between transition shock and professional identity. CONCLUSION: To our knowledge, this study is the first to explore the mediating effect of self-efficacy and resilience on transition shock and professional identity. Higher transition shock may lead to lower professional identity by reducing self-efficacy and resilience. RELEVANCE TO CLINICAL PRACTICE: Nursing managers ought to emphasise the significant role of psychological resources in the work adaptation process of novice nurses. It may be more effective to improve professional identity and maintain the stability of the health care system. PATIENT OR PUBLIC CONTRIBUTION: Nursing administrators working at seven preselected hospitals actively assisted us in the process of collecting self-report questionnaires from novice nurses, such as by booking appointments and providing access for questionnaire administration. In addition, the participants were actively involved in the data collection process.

11.
Acta Diabetol ; 2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38383671

RESUMO

AIMS: Inflammation is central to the pathogenesis of metabolic syndrome (MetS). Leukocyte cell-derived chemotaxin 2 (LECT2) is constitutively secreted in response to inflammatory stimuli and oxidative stress contributing to tissue or systemic inflammation. We explored the relationship between LECT2 levels and MetS severity in humans and mice. METHODS: Serum LECT2 levels were measured in 210 participants with MetS and 114 without MetS (non-MetS). LECT2 expression in the liver and adipose tissue was also examined in mice fed a high-fat diet (HFD) and genetically obese (ob/ob) mice. RESULTS: Serum LECT2 levels were significantly higher in MetS participants than in non-MetS participants (7.47[3.36-17.14] vs. 3.74[2.61-5.82], P < 0.001). Particularly, serum LECT2 levels were significantly elevated in participants with hypertension, central obesity, diabetes mellitus (DM), hyperglycaemia, elevated triglyceride (TG) levels, and reduced high-density lipoprotein cholesterol (HDL-C) levels compared to those in participants without these conditions. Pearson's correlation analysis showed that serum LECT2 levels were positively associated with conventional risk factors in all patients. Moreover, LECT2 was positively associated with the number of MetS components (r = 0.355, P < 0.001), indicating that higher serum LECT2 levels reflected MetS severity. Multivariate regression analysis revealed that a one standard deviation increase in LECT2 was associated with an odds ratio of 1.52 (1.01-2.29, P = 0.044) for MetS prevalence after adjusting for age, sex, body mass index, waist circumference, smoking status, white blood cell count, fasting blood glucose, TG, total cholesterol, HDL-C, blood urea nitrogen, and alanine aminotransferase. Receiver operating characteristic curve analysis confirmed the strong predictive ability of serum LECT2 levels for MetS. The optimum serum LECT2 cut-off value was 9.05. The area under the curve was 0.73 (95% confidence interval 0.68-0.78, P < 0.001), with a sensitivity and specificity of 45.71% and 95.61%, respectively. Additionally, LECT2 expression levels were higher at baseline and dramatically enhanced in metabolic organs (e.g. the liver) and adipose tissue in HFD-induced obese mice and ob/ob mice. CONCLUSIONS: Increased LECT2 levels were significantly and independently associated with the presence and severity of MetS, indicating that LECT2 could be used as a novel biomarker and clinical predictor of MetS.

12.
Allergy ; 2024 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-38372149

RESUMO

Tight junction (TJ) proteins establish a physical barrier between epithelial cells, playing a crucial role in maintaining tissue homeostasis by safeguarding host tissues against pathogens, allergens, antigens, irritants, etc. Recently, an increasing number of studies have demonstrated that abnormal expression of TJs plays an essential role in the development and progression of inflammatory airway diseases, including chronic obstructive pulmonary disease, asthma, allergic rhinitis, and chronic rhinosinusitis (CRS) with or without nasal polyps. Among them, CRS with nasal polyps is a prevalent chronic inflammatory disease that affects the nasal cavity and paranasal sinuses, leading to a poor prognosis and significantly impacting patients' quality of life. Its pathogenesis primarily involves dysfunction of the nasal epithelial barrier, impaired mucociliary clearance, disordered immune response, and excessive tissue remodeling. Numerous studies have elucidated the pivotal role of TJs in both the pathogenesis and response to traditional therapies in CRS. We therefore to review and discuss potential factors contributing to impair and repair of TJs in the nasal epithelium based on their structure, function, and formation process.

13.
ACS Biomater Sci Eng ; 2024 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-38372216

RESUMO

Atherosclerosis management heavily relies on the suppression of the inflammatory response of macrophages. Colchicine's potent anti-inflammatory properties make it a promising candidate for secondary prevention against cardiovascular disease. However, its high toxicity and numerous adverse effects limit its clinical use. To address this, there is an urgent need for specific drug delivery systems to boost the level of accumulation of colchicine within atherosclerotic plaques. In this study, the cluster of differentiation-44 receptor was verified to be overexpressed in inflammatory macrophages within plaques both in vitro and in vivo. Subsequently, a Prussian blue-based nanomedical loading system with hyaluronic acid (HA) coating was constructed, and its effects were observed on the atherosclerosis regression. Colchicine and Cy5.5 were encapsulated within Prussian blue nanoparticles through self-assembly, followed by conjugation with hyaluronic acid to create col@PBNP@HA. The formulated col@PBNP@HA displayed a cubic shape and scattered distribution. Importantly, col@PBNP@HA demonstrated specific cellular uptake into lipopolysaccharide-stimulated macrophages. In vitro experiments showed that col@PBNP@HA more effectively inhibited expression of inflammatory factors and scavenged reactive oxygen species compared with the control group, which were treated with colchicine. Furthermore, col@PBNP@HA exhibited its specific and higher accumulation in aortic plaque analysis via fluorescence imaging of aortas. After 4 weeks, administration of col@PBNP@HA resulted in significant atherosclerosis regression in the mice model, with therapeutic effects superior to those of free colchicine. Similar to colchicine, col@PBNP@HA inhibited the secretion of inflammation factors and scavenged ROS through the regulation of the toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (Myd88)/nuclear factor kappa-B (NF-κB) and peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) signaling pathway. In summary, col@PBNP@HA demonstrated specific targeting ability to inflammatory plaques and exerted beneficial effects on atherosclerosis regression through TLR4/Myd88/NF-κB and PGC-1α modulation.

14.
J Cancer ; 15(6): 1603-1612, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38370374

RESUMO

Background: METTL3 accelerates m6A modification to influence cancer progression including non-small cell lung cancer (NSCLC). To illustrate the role and underlying mechanism of METTL3 mediated miR-196a upregulation in NSCLC. Method: The global level of m6A modification was detected by qPCR, western blot and immumohistochemical staining. The TCGA, GEPIA, CPTAC and TIMER databases were used to explore the expression change of METTL3, miR-196a and GAS7 in NSCLC patients. Kaplan-Meier analysis was performed to analyze the prognostic value of miR-196a. NSCLC cells overexpressed or knockdown miR-196a were constructed and used for CCK8, colony formation assay, western blot and immunofluorescence in vitro. The effect of miR-196a on tumor growth was investigated in vivo. Result: We found that METTL3 mediated miR-196a were notably enhancive in NSCLC tissues and in NSCLC cells, which is markedly positively related with the serious TNM stage, the large tumor size, the distant metastasis, and the poor prognosis in patients of NSCLC. Further investigation showed that up-regulated miR-196a promoted cell viability and cell autophagy, while down-regulation of miR-196a revealed opposite results in H1299 and A549 cells. In terms of mechanism, we found that miR-196a interacted with GAS7. In addition, GAS7 expression in NSCLC patients may be positively related with the infiltration of immune cell subsets in tumor microenvironment (TME). Conclusion: The axis of METTL3-miR-196a-GAS7 might be a target for molecular targeted therapy, a potential and novel diagnostic marker for NSCLC patients.

15.
J Environ Manage ; 353: 120233, 2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38330838

RESUMO

Methane (CH4) emissions from manure management on livestock farms are a key source of greenhouse gas emissions in some regions and for some production systems, and the opportunities for mitigation may be significant if emissions can be adequately documented. We investigated a method for estimating CH4 emissions from liquid manure (slurry) that is based on anaerobic incubation of slurry collected from commercial farms. Methane production rates were used to derive a parameter of the Arrhenius temperature response function, lnA', representing the CH4 production potential of the slurry at the time of sampling. Results were used for parameterization of an empirical model to estimate annual emissions with daily time steps, where CH4 emissions from individual sources (barns, outside storage tanks) can be calculated separately. A monitoring program was conducted in four countries, i.e., Denmark, Sweden, Germany and the Netherlands, during a 12-month period where slurry was sampled to represent barn and outside storage on finishing pig and dairy farms. Across the four countries, lnA' was higher in pig slurry compared to cattle slurry (p < 0.01), and higher in slurry from barns compared to outside storage (p < 0.01). In a separate evaluation of the incubation method, in-vitro CH4 production rates were comparable with in-situ emissions. The results indicate that lnA' in barns increases with slurry age, probably due to growth or adaptation of the methanogenic microbial community. Using lnA' values determined experimentally, empirical models with daily time steps were constructed for finishing pig and dairy farms and used for scenario analyses. Annual emissions from pig slurry were predicted to be 2.5 times higher than those from cattle slurry. Changing the frequency of slurry export from the barn on the model pig farm from 40 to 7 d intervals reduced total annual CH4 emissions by 46 %; this effect would be much less on cattle farms with natural ventilation. In a scenario with cattle slurry, the empirical model was compared with the current IPCC methodology. The seasonal dynamics were less pronounced, and annual CH4 emissions were lower than with the current methodology, which calls for further investigations. Country-specific models for individual animal categories and point sources could be a tool for assessing CH4 emissions and mitigation potentials at farm level.


Assuntos
Gases de Efeito Estufa , Esterco , Animais , Suínos , Bovinos , Fazendas , Esterco/análise , Metano/análise , Gases de Efeito Estufa/análise , Temperatura
16.
Case Rep Genet ; 2024: 6319030, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38322183

RESUMO

Chromothripsis is characterized by shattering and subsequent reassembly of chromosomes by DNA repair processes, which can give rise to a variety of congenital abnormalities and cancer. Constitutional chromothripsis is a rare occurrence, reported in children presenting with a wide range of birth defects. We present a case of a female child born with multiple major congenital abnormalities including severe microcephaly, ocular dysgenesis, heart defect, and imperforate anus. Chromosomal microarray and mate pair sequencing identified a complex chromosomal rearrangement involving the terminal end of the long arm of chromosome 2, with two duplications (located at 2p25.3-p25.1 and 2q35-q37.2 regions) and two deletions (located at 2q37.2-q37.3 and 2q37.3 regions) along with structural changes including inverted segments. A review of the literature for complex rearrangements on chromosome 2 revealed overlapping features; however, our patient had a significantly more severe phenotype which resulted in early death at the age of 2 years. Breakpoints analysis did not reveal the involvement of any candidate genes. We concluded that the complexity of the genomic rearrangement and the combined dosage/structural effect of these copy number variants are likely explanations for the severe presentation in our patient.

17.
Am J Hematol ; 2024 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-38343062

RESUMO

Jaktinib, a novel JAK and ACVR1 inhibitor, has exhibited promising results in treating patients with myelofibrosis (MF). ZGJAK002 is a Phase 2 trial aimed to assess the efficacy and safety of jaktinib 100 mg BID (N = 66) and 200 mg QD (N = 52) in JAK inhibitor-naive patients with intermediate- or high-risk MF. We herein present the long-term data with a median follow-up of 30.7 months. At data cutoff, 30.3% of patients in 100 mg BID and 28.8% in 200 mg QD were still continuing their treatment. The 100 mg BID group displayed a numerically higher best spleen response compared with the 200 mg QD group (69.7% vs. 46.2%), with 50.4% from the BID and 51.2% from the QD group maintaining spleen responses over 120 weeks. The 36-month survival rates were 78.2% in BID and 73.6% in QD group. The tolerability of jaktinib remained well, and common grade ≥3 adverse drug reactions included anemia (15.2% vs. 21.2%), thrombocytopenia (15.2% vs. 11.5%), and infectious pneumonia (10.6% vs. 1.9%) in BID and QD groups, respectively. By comparing the two groups, the incidence of adverse events (AEs) were similar, except for drug-related serious AEs (24.2% vs. 9.6%) and AEs leading to treatment discontinuation (15.2% vs. 7.7%), which were higher in BID group. The percentages of AEs resulting in death were comparable, with 6.1% in BID and 5.8% in QD group. These analyses further support the long-term durable efficacy and acceptable safety of jaktinib at 100 mg BID and 200 mg QD doses for treating MF.

18.
Free Radic Biol Med ; 214: 69-79, 2024 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-38336100

RESUMO

Cyclooxygenase-2 (COX-2) is an inducible enzyme responsible for prostaglandin synthesis during inflammation and immune responses. Our previous results show that NAD+ level decreased in activated macrophages while nicotinamide mononucleotide (NMN) supplementation suppressed the inflammatory responses via restoring NAD+ level and downregulating COX-2. However, whether NMN downregulates COX-2 in mouse model of inflammation, and its underlying mechanism needs to be further explored. In the present study, we established LPS- and alum-induced inflammation model and demonstrated that NMN suppressed the inflammatory responses in vivo. Quantitative proteomics in mouse peritoneal macrophages identified that NMN activated AhR signaling pathway in activated macrophages. Furthermore, we revealed that NMN supplementation led to IDO1 activation and kynurenine accumulation, which caused AhR nuclear translocation and activation. On the other hand, AhR or IDO1 knockout abolished the effects of NMN on suppressing COX-2 expression and inflammatory responses in macrophages. In summary, our results demonstrated that NMN suppresses inflammatory responses by activating IDO-kynurenine-AhR pathway, and suggested that administration of NMN in early-stage immuno-activation may cause an adverse health effect.

19.
Front Microbiol ; 15: 1337402, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38384265

RESUMO

Introduction: Revealing factors and mechanisms in determining species co-existence are crucial to community ecology, but studies using gut microbiota data are still lacking. Methods: Using gut microbiota data of 556 Brandt's voles from 37 treatments in eight experiments, we examined the relationship of species co-occurrence of gut microbiota in Brandt's voles (Lasiopodomys brandtii) with genetic distance (or genetic relatedness), community diversity, and several environmental variables. Results: We found that the species co-occurrence index (a larger index indicates a higher co-occurrence probability) of gut microbiota in Brandt's voles was negatively associated with the genetic distance between paired ASVs and the number of cohabitating voles in the experimental space (a larger number represents more crowding social stress), but positively with Shannon diversity index, grass diets (representing natural foods), and non-physical contact within an experimental space (representing less stress). Discussion: Our study demonstrated that high diversity, close genetic relatedness, and favorable living conditions would benefit species co-occurrence of gut microbiota in hosts. Our results provide novel insights into factors and mechanisms that shape the community structure and function of gut microbiota and highlight the significance of preserving the biodiversity of gut microbiota.

20.
Front Mol Biosci ; 11: 1297437, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38384498

RESUMO

Atherosclerosis is a complex vascular disorder characterized by the deposition of lipids, inflammatory cascades, and plaque formation in arterial walls. A thorough understanding of its causes and progression is necessary to develop effective diagnostic and therapeutic strategies. Recent breakthroughs in metabolomics have provided valuable insights into the molecular mechanisms and genetic factors involved in atherosclerosis, leading to innovative approaches for preventing and treating the disease. In our study, we analyzed clinical serum samples from both atherosclerosis patients and animal models using laser desorption ionization mass spectrometry. By employing methods such as orthogonal partial least-squares discrimination analysis (OPLS-DA), heatmaps, and volcano plots, we can accurately classify atherosclerosis (AUC = 0.892) and identify key molecules associated with the disease. Specifically, we observed elevated levels of arachidonic acid and its metabolite, leukotriene B4, in atherosclerosis. By inhibiting arachidonic acid and monitoring its downstream metabolites, we discovered the crucial role of this metabolic pathway in regulating atherosclerosis. Metabolomic research provides detailed insights into the metabolic networks involved in atherosclerosis development and reveals the close connection between abnormal metabolism and the disease. These studies offer new possibilities for precise diagnosis, treatment, and monitoring of disease progression, as well as evaluating the effectiveness of therapeutic interventions.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...