RESUMO
CD4+ T cells are central to various immune responses, but the molecular programs that drive and maintain CD4+ T cell immunity are not entirely clear. Here we identify a stem-like program that governs the CD4+ T cell response in transplantation models. Single-cell-transcriptomic analysis revealed that naive alloantigen-specific CD4+ T cells develop into TCF1hi effector precursor (TEP) cells and TCF1-CXCR6+ effectors in transplant recipients. The TCF1-CXCR6+CD4+ effectors lose proliferation capacity and do not reject allografts upon adoptive transfer into secondary hosts. By contrast, the TCF1hiCD4+ TEP cells have dual features of self-renewal and effector differentiation potential, and allograft rejection depends on continuous replenishment of TCF1-CXCR6+ effectors from TCF1hiCD4+ TEP cells. Mechanistically, TCF1 sustains the CD4+ TEP cell population, whereas the transcription factor IRF4 and the glycolytic enzyme LDHA govern the effector differentiation potential of CD4+ TEP cells. Deletion of IRF4 or LDHA in T cells induces transplant acceptance. These findings unravel a stem-like program that controls the self-renewal capacity and effector differentiation potential of CD4+ TEP cells and have implications for T cell-related immunotherapies.
Assuntos
Regulação da Expressão Gênica , Linfócitos T Reguladores , Diferenciação CelularRESUMO
Cancer arises from the growth and division of uncontrolled erroneous cells. Programmed cell death (PCD), or regulated cell death (RCD), includes natural processes that eliminate damaged or abnormal cells. Dysregulation of PCD is a hallmark of cancer, as cancer cells often evade cell death and continue to proliferate. Exosomes nanoscale extracellular vesicles secreted by different types of cells carrying a variety of molecules, including nucleic acids, proteins, and lipids, to have indispensable role in the communication between cells, and can influence various cellular processes, including PCD. Exosomes have been shown to modulate PCD in cancer cells by transferring pro- or antideath molecules to neighboring cells. Additionally, exosomes can facilitate the spread of PCD to surrounding cancer cells, making them promising in the treatment of various cancers. The exosomes' diagnostic potential in cancer is also an active area of research. Exosomes can be isolated from a wide range of bodily fluids and tissues, such as blood and urine, and can provide a noninvasive way to monitor cancer progression and treatment response. Furthermore, exosomes have also been employed as a delivery system for therapeutic agents. By engineering exosomes to carry drugs or other therapeutic molecules, they can be targeted specifically to cancer cells, reducing toxicity to healthy tissues. Here, we discussed exosomes in the diagnosis and prevention of cancers, tumor immunotherapy, and drug delivery, as well as in different types of PCD.
Assuntos
Exossomos , Vesículas Extracelulares , Neoplasias , Humanos , Exossomos/metabolismo , Exossomos/patologia , Neoplasias/tratamento farmacológico , Vesículas Extracelulares/patologia , ApoptoseRESUMO
CD4+ T cells orchestrate immune responses and destruction of allogeneic organ transplants, but how this process is regulated on a transcriptional level remains unclear. Here, we demonstrated that interferon regulatory factor 4 (IRF4) was a key transcriptional determinant controlling T cell responses during transplantation. IRF4 deletion in mice resulted in progressive establishment of CD4+ T cell dysfunction and long-term allograft survival. Mechanistically, IRF4 repressed PD-1, Helios, and other molecules associated with T cell dysfunction. In the absence of IRF4, chromatin accessibility and binding of Helios at PD-1 cis-regulatory elements were increased, resulting in enhanced PD-1 expression and CD4+ T cell dysfunction. The dysfunctional state of Irf4-deficient T cells was initially reversible by PD-1 ligand blockade, but it progressively developed into an irreversible state. Hence, IRF4 controls a core regulatory circuit of CD4+ T cell dysfunction, and targeting IRF4 represents a potential therapeutic strategy for achieving transplant acceptance.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto , Transplante de Coração , Fatores Reguladores de Interferon/imunologia , Animais , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Diferenciação Celular , Movimento Celular , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/imunologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Rejeição de Enxerto/genética , Rejeição de Enxerto/mortalidade , Rejeição de Enxerto/patologia , Granzimas/genética , Granzimas/imunologia , Fatores Reguladores de Interferon/deficiência , Fatores Reguladores de Interferon/genética , Interferon gama/genética , Interferon gama/imunologia , Interleucina-17/genética , Interleucina-17/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Citotóxicas Formadoras de Poros/genética , Proteínas Citotóxicas Formadoras de Poros/imunologia , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Transdução de Sinais , Análise de Sobrevida , Fatores de Transcrição/genética , Fatores de Transcrição/imunologia , Transplante HomólogoRESUMO
Bacterial RecJ exhibits 5'â3' exonuclease activity that is specific to ssDNA; however, archaeal RecJs show 5' or 3' exonuclease activity. The hyperthermophilic archaea Methanocaldococcus jannaschii encodes the 5'-exonuclease MjRecJ1 and the 3'-exonuclease MjRecJ2. In addition to nuclease activity, archaeal RecJ interacts with GINS, a structural subcomplex of the replicative DNA helicase complex. However, MjRecJ1 and MjRecJ2 do not interact with MjGINS. Here, we report the structural basis for the inability of the MjRecJ2 homologous dimer to interact with MjGINS and its efficient 3' hydrolysis polarity for short dinucleotides. Based on the crystal structure of MjRecJ2, we propose that the interaction surface of the MjRecJ2 dimer overlaps the potential interaction surface for MjGINS and blocks the formation of the MjRecJ2-GINS complex. Exposing the interaction surface of the MjRecJ2 dimer restores its interaction with MjGINS. The cocrystal structures of MjRecJ2 with substrate dideoxynucleotides or product dCMP/CMP show that MjRecJ2 has a short substrate binding patch, which is perpendicular to the longer patch of bacterial RecJ. Our results provide new insights into the function and diversification of archaeal RecJ/Cdc45 proteins.
Assuntos
Proteínas Arqueais , Proteínas Arqueais/química , Proteínas Arqueais/metabolismo , Proteínas Arqueais/genética , Cristalografia por Raios X , Methanocaldococcus/enzimologia , Methanocaldococcus/metabolismo , Ligação Proteica , Multimerização Proteica , DNA Helicases/metabolismo , DNA Helicases/química , DNA Helicases/genética , Modelos Moleculares , Exodesoxirribonucleases/metabolismo , Exodesoxirribonucleases/química , Exodesoxirribonucleases/genéticaRESUMO
T helper 17 (Th17) cells are prominently featured in multiple autoimmune diseases, but the regulatory mechanisms that control Th17 cell responses are poorly defined. Here we found that stimulation of OX40 triggered a robust chromatin remodeling response and produced a "closed" chromatin structure at interleukin-17 (IL-17) locus to inhibit Th17 cell function. OX40 activated the NF-κB family member RelB, and RelB recruited the histone methyltransferases G9a and SETDB1 to the Il17 locus to deposit "repressive" chromatin marks at H3K9 sites, and consequently repressing IL-17 expression. Unlike its transcriptional activities, RelB acted independently of both p52 and p50 in the suppression of IL-17. In an experimental autoimmune encephalomyelitis (EAE) disease model, we found that OX40 stimulation inhibited IL-17 and reduced EAE. Conversely, RelB-deficient CD4(+) T cells showed enhanced IL-17 induction and exacerbated the disease. Our data uncover a mechanism in the control of Th17 cells that might have important clinic implications.
Assuntos
Montagem e Desmontagem da Cromatina , Encefalomielite Autoimune Experimental/imunologia , Interleucina-17/metabolismo , Esclerose Múltipla/imunologia , Receptores OX40/metabolismo , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Animais , Células Cultivadas , Regulação para Baixo , Fatores de Transcrição Forkhead/metabolismo , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/metabolismo , Humanos , Interleucina-17/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores OX40/genética , Transdução de Sinais , Fator de Transcrição RelB/genética , Fator de Transcrição RelB/metabolismoRESUMO
White matter of the human brain is influenced by common genetic variations and shaped by neural activity-dependent experiences. Variations in microstructure of cerebral white matter across individuals and even across fiber tracts might underlie differences in cognitive capacity and vulnerabilities to mental disorders. The frontoparietal and cingulo-opercular networks of the brain constitute the central system supporting cognitive functions, and functional connectivity of these networks has been used to distinguish individuals known as "functional fingerprinting." The frontal aslant tract (FAT) that passes through the two networks has been implicated in executive functions. However, whether FAT can be used as a "structural fingerprint" to distinguish individuals and predict an individual's cognitive function and dysfunction is unknown. Here we investigated the fingerprinting property of FAT microstructural profiles using three independent diffusion MRI datasets with repeated scans on human participants including both females and males. We found that diffusion and geometric profiles of FAT can be used to distinguish individuals with a high accuracy. Next, we demonstrated that fractional anisotropy in different FAT segments predicted distinct cognitive functions, including working memory, inhibitory control, and relational reasoning. Finally, we assessed the contribution of altered FAT microstructural profiles to cognitive dysfunction in unmedicated patients with obsessive-compulsive disorders. We found that the altered microstructure in FAT was associated with the severity of obsessive-compulsive symptoms. Collectively, our findings suggest that the microstructural profiles of FAT can identify individuals with a high accuracy and may serve as an imaging marker for predicting an individual's cognitive capacity and disease severity.SIGNIFICANCE STATEMENT The frontoparietal network and cingulo-opercular network of the brain constitute a dual-network architecture for human cognitive functions, and functional connectivity of these two networks can be used as a "functional fingerprint" to distinguish individuals. However, the structural underpinnings of these networks subserving individual heterogeneities in their functional connectivity and cognitive ability remain unknown. We show here that the frontal aslant tract (FAT) that passes through the two networks distinguishes individuals with a high accuracy. Further, we demonstrate that the diffusion profiles of FAT predict distinct cognitive functions in healthy subjects and are associated with the clinical symptoms in patients with obsessive-compulsive disorders. Our findings suggest that the FAT may serve as a unique structural fingerprint underlying individual cognitive capability.
Assuntos
Encéfalo , Transtorno Obsessivo-Compulsivo , Masculino , Feminino , Humanos , Imagem de Difusão por Ressonância Magnética , Cognição , Função Executiva , Transtorno Obsessivo-Compulsivo/diagnóstico , Imageamento por Ressonância MagnéticaRESUMO
BACKGROUND: The effect of computer-aided polyp detection (CADe) on adenoma detection rate (ADR) among endoscopists-in-training remains unknown. METHODS: We performed a single-blind, parallel-group, randomized controlled trial in Hong Kong between April 2021 and July 2022 (NCT04838951). Eligible subjects undergoing screening/surveillance/diagnostic colonoscopies were randomized 1:1 to receive colonoscopies with CADe (ENDO-AID[OIP-1]) or not (control) during withdrawal. Procedures were performed by endoscopists-in-training with <500 procedures and <3 years' experience. Randomization was stratified by patient age, sex, and endoscopist experience (beginner vs intermediate level, <200 vs 200-500 procedures). Image enhancement and distal attachment devices were disallowed. Subjects with incomplete colonoscopies or inadequate bowel preparation were excluded. Treatment allocation was blinded to outcome assessors. The primary outcome was ADR. Secondary outcomes were ADR for different adenoma sizes and locations, mean number of adenomas, and non-neoplastic resection rate. RESULTS: A total of 386 and 380 subjects were randomized to CADe and control groups, respectively. The overall ADR was significantly higher in the CADe group than in the control group (57.5% vs 44.5%; adjusted relative risk, 1.41; 95% CI, 1.17-1.72; P < .001). The ADRs for <5 mm (40.4% vs 25.0%) and 5- to 10-mm adenomas (36.8% vs 29.2%) were higher in the CADe group. The ADRs were higher in the CADe group in both the right colon (42.0% vs 30.8%) and left colon (34.5% vs 27.6%), but there was no significant difference in advanced ADR. The ADRs were higher in the CADe group among beginner (60.0% vs 41.9%) and intermediate-level (56.5% vs 45.5%) endoscopists. Mean number of adenomas (1.48 vs 0.86) and non-neoplastic resection rate (52.1% vs 35.0%) were higher in the CADe group. CONCLUSIONS: Among endoscopists-in-training, the use of CADe during colonoscopies was associated with increased overall ADR. (ClinicalTrials.gov, Number: NCT04838951).
Assuntos
Adenoma , Pólipos do Colo , Neoplasias Colorretais , Pólipos , Humanos , Neoplasias Colorretais/diagnóstico , Método Simples-Cego , Colonoscopia/métodos , Adenoma/diagnóstico , Computadores , Pólipos do Colo/diagnósticoRESUMO
Achieving accurate detection of different speciations of heavy metal ions (HMIs) in an aqueous solution is an urgent problem due to the different bioavailabilities and physiological toxicity. Herein, we nominated a novel strategy to detect HCrO4- and Cr(OH)2+ at a trace level via the electrochemical sensitive surface constructed by Co3O4-rGO modified with amino and carboxyl groups, which revealed that the interactions between distinct functional groups and different oxygen-containing groups of target ions are conducive to the susceptible and anti-interference detection. The detection sensitivities of 19.46 counts µg-1 L for HCrO4- and 13.44 counts µg-1 L for Cr(OH)2+ were obtained under optimal conditions, while the limits of detection were 0.10 and 0.12 µg L-1, respectively. Satisfactory anti-interference and actual water sample analysis results were obtained. A series of advanced optical techniques like X-ray photoelectron spectroscopy, X-ray absorption near-edge structure technology, and density functional theory calculations under an electric field demonstrated that chemical interactions between groups contribute more to the fixation of target ions than electrical attraction alone. The presence of oxygen-containing groups distinct from simple ionic forms was a critical factor in the selectivity and anti-interference detection. Furthermore, the valence cycle of Co(II)/(III) synergistically boosted the detection performance. This research provides a promising tactic from the microscopic perspective of groups' interactions to accomplish the precise speciation analysis of HMIs in the water environment.
RESUMO
LiMn1-yFeyPO4 (LMFP) is a significant and cost-effective cathode material for Li-ion batteries, with a higher working voltage than LiFePO4 (LFP) and improved safety features compared to layered oxide cathodes. However, its commercial application faces challenges due to a need for a synthesis process to overcome the low Li-ion diffusion kinetics and complex phase transitions. Herein, a solid-state synthesis process using LFP and nano LiMn0.7Fe0.3PO4 (MF73) is proposed. The larger LFP acts as a structural framework fused with nano-MF73, preserving the morphology and high performance of LFP. These results demonstrate that the solid-state reaction occurs quickly, even at a low sintering temperature of 500 °C, and completes at 700 °C. However, contrary to the expectations, the larger LFP particles disappeared and fused into the nano-MF73 particles, revealing that Fe ions diffuse more easily than Mn ions in the olivine framework. This discovery provides valuable insights into understanding ion diffusion in LMFP. Notably, the obtained LMFP can still deliver an initial capacity of 142.3 mAh g-1, and the phase separation during the electrochemical process is significantly suppressed, resulting in good cycling stability (91.1% capacity retention after 300 cycles). These findings offer a promising approach for synthesizing LMFP with improved performance and stability.
RESUMO
Plastics serve as an essential foundation in contemporary society. Nevertheless, meeting the rigorous performance demands in advanced applications and addressing their end-of-life disposal are two critical challenges that persist. Here, an innovative and facile method is introduced for the design and scalable production of polycarbonate, a key engineering plastic, simultaneously achieving high performance and closed-loop chemical recyclability. The bisphenol framework of polycarbonate is strategically adjusted from the low-bond-dissociation-energy bisphenol A to high-bond-dissociation-energy 4,4'-dihydroxydiphenyl, in combination with the incorporation of polysiloxane segments. As expected, the enhanced bond dissociation energy endows the polycarbonate with an extremely high glow-wire flammability index surpassing 1025 °C, a 0.8 mm UL-94 V-0 rating, a high LOI value of 39.2%, and more than 50% reduction of heat and smoke release. Furthermore, the π-π stacking interactions within biphenyl structures resulted in a significant enhancement of mechanical strength by as more as 37.7%, and also played a positive role in achieving a lower dielectric constant. Significantly, the copolymer exhibited outstanding closed-loop chemical recyclability, allowing for facile depolymerization into bisphenol monomers and the repolymerized copolymer retains its high heat and fire resistance. This work provides a novel insight in the design of high-performance and closed-loop chemical recyclable polymeric materials.
RESUMO
The mechanisms that regulate the T(H)9 subset of helper T cells and diseases mediated by T(H)9 cells remain poorly defined. Here we found that the costimulatory receptor OX40 was a powerful inducer of T(H)9 cells in vitro and T(H)9 cell-dependent airway inflammation in vivo. In polarizing conditions based on transforming growth factor-ß (TGF-ß), ligation of OX40 inhibited the production of induced regulatory T cells and the T(H)17 subset of helper T cells and diverted CD4(+)Foxp3(-) T cells to a T(H)9 phenotype. Mechanistically, OX40 activated the ubiquitin ligase TRAF6, which triggered induction of the kinase NIK in CD4(+) T cells and the noncanonical transcription factor NF-κB pathway; this subsequently led to the generation of T(H)9 cells. Thus, our study identifies a previously unknown mechanism for the induction of T(H)9 cells and may have important clinical implications in allergic inflammation.
Assuntos
Ligante OX40/metabolismo , Receptores OX40/metabolismo , Sistema Respiratório/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Antígenos CD4/biossíntese , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Interleucina-9/biossíntese , Interleucina-9/metabolismo , Camundongos , NF-kappa B/metabolismo , Ligante OX40/imunologia , Proteínas Serina-Treonina Quinases/biossíntese , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/imunologia , Proteínas Proto-Oncogênicas/metabolismo , Receptores OX40/imunologia , Transdução de Sinais/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Fator 6 Associado a Receptor de TNF/biossíntese , Fator 6 Associado a Receptor de TNF/metabolismo , Transativadores/imunologia , Transativadores/metabolismo , Fator de Crescimento Transformador beta/imunologia , Fator de Crescimento Transformador beta/metabolismo , Quinase Induzida por NF-kappaBRESUMO
OBJECTIVE: To assess the efficacy and safety of FDA-approved KRASG12C inhibitors in patients with KRASG12C-mutated solid tumors. METHODS: We searched PubMed, EMBASE, Cochrane Library, and major international conferences for clinical trials published in English up to March 6, 2023. Clinical trials investigating sotorasib or adagrasib and reporting the clinical outcomes of the objective response rate (ORR), disease control rate (DCR), or incidence rate of grade ≥ 3 adverse events (AEs) were eligible. The primary endpoint was the ORR. Secondary endpoints included the DCR, incidence rate of grade ≥ 3 AEs, and odds ratio (OR) of the ORR between patients with or without co-mutation. The Random-effects model was applied for the outcomes of interest. RESULTS: 18 studies with 1224 patients were included in this meta-analysis. The pooled ORR, DCR, and incidence rate of grade ≥ 3 AEs were 31 % (95 % CI, 25-37 %), 86 % (95 % CI, 82-89 %), and 29 % (95 % CI, 23-36 %), respectively. KRASG12C-mutated NSCLC patients with a co-mutation of KEAP1 exhibited a worse ORR than those with wild-type KEAP1 (OR: 0.35, 95 % CI: 0.16-0.77). CONCLUSIONS: This study provided a comprehensive understanding of the efficacy and safety of KRASG12C inhibitors in treating solid tumors and identified KEAP1 mutation as a potential predictive biomarker of inferior response in patients treated with KRASG12C inhibitors. These findings may assist in the design of future clinical trials for identifying populations that may benefit from KRASG12C inhibitor treatment.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch , Proteínas Proto-Oncogênicas p21(ras) , Fator 2 Relacionado a NF-E2 , MutaçãoRESUMO
The genera Rhodobaca and Roseinatronobacter are phylogenetically related genera within the family Paracoccaceae. Species of these genera were described using 16S rRNA gene-based phylogeny and phenotypic characteristics. However, the 16S rRNA gene identity and phylogeny reveal the controversy of the taxonomic status of these two genera. In this work, we examined the taxonomic positions of members of both genera using 16S rRNA gene phylogeny, phylogenomic analysis and further validated using overall genome-related indexes, including digital DNA-DNA hybridization, average nucleotide identity, average amino acid identity and percentage of conserved proteins. Based on phylogenetic and phylogenomic results, the current four species of the two genera clustered tightly into one clade with high bootstrap values, suggesting that the genus Rhodobaca should be merged with Roseinatronobacter. In addition, a novel species isolated from a soda soil sample collected from Anda City, PR China, and designated as HJB301T was also described. Phenotypic, chemotaxonomic, genomic and phylogenetic properties suggested that strain HJB301T (=CCTCC AB 2021113T=KCTC 82977T) represents a novel species of the genus Roseinatronobacter, for which the name Roseinatronobacter alkalisoli sp. nov. is proposed.
Assuntos
Técnicas de Tipagem Bacteriana , DNA Bacteriano , Genoma Bacteriano , Hibridização de Ácido Nucleico , Filogenia , RNA Ribossômico 16S , Análise de Sequência de DNA , Microbiologia do Solo , RNA Ribossômico 16S/genética , DNA Bacteriano/genética , China , Composição de Bases , Ácidos GraxosRESUMO
AIM: To evaluate the impact of non-alcoholic fatty liver disease (NAFLD) presence and fibrosis risk on adverse outcomes in patients with type 2 diabetes and chronic kidney disease. METHODS: Data were sourced from two longitudinal cohorts: 1172 patients from the National Health and Nutrition Examination Survey (NHANES) and 326 patients from the kidney biopsy cohort at the West China Hospital of Sichuan University. Cox regression estimated hazard ratios (HRs) for NAFLD and liver fibrosis concerning adverse clinical outcomes. Subsequently, a two-sample Mendelian randomization study using genome-wide association study statistics explored NAFLD's potential causal link to cardio-cerebrovascular events. RESULTS: In the NHANES cohort, NAFLD stood as an independent risk factor for various outcomes: overall mortality [HR 1.53 (95% confidence interval, CI 1.21-1.95)], mortality because of cardio-cerebrovascular diseases [HR 1.63 (95% CI 1.12-2.37)], heart disease [HR 1.58 (95% CI 1.00-2.49)], and cerebrovascular disease [HR 3.95 (95% CI 1.48-10.55)]. Notably, advanced liver fibrosis, identified by a fibrosis-4 (FIB-4) score >2.67, exhibited associations with overall mortality, cardio-cerebrovascular disease mortality and heart disease mortality. Within the kidney biopsy cohort, NAFLD correlated with future end-stage kidney disease [ESKD; HR 2.17 (95% CI 1.41-3.34)], while elevated FIB-4 or NAFLD Fibrosis Scores predicted future ESKD, following full adjustment. Liver fibrosis was positively correlated with renal interstitial fibrosis and tubular atrophy in biopsies. Further Mendelian randomization analysis supported a causal relationship between NAFLD and cardio-cerebrovascular events. CONCLUSIONS: In patients with type 2 diabetes and chronic kidney disease, the NAFLD presence and elevated FIB-4 scores link to heightened mortality risk and ESKD susceptibility. Moreover, NAFLD shows a causal relationship with cardio-cerebrovascular events.
RESUMO
P2X7 receptor (P2X7R) plays an important role in modulating inflammation and fibrosis, but information is limited whether Zusanli (ST36) can inhibit inflammation and fibrosis by regulating P2X7R. Isoprenaline at 5 mg/kg was subcutaneously injected to wild-type and P2X7R knockout mice for 7 days, while treatment groups received electroacupuncture (EA) stimulation at ST36 for 7 sessions. Following 7-session treatment, Masson's trichrome staining was performed to assess the fibrosis. Morphology, electrocardiogram, and echocardiography were carried out to evaluate the cardiac function and structure. Western blotting, hematoxylin and eosin staining, immunohistochemistry, and biochemical analysis of inflammatory cytokine and transmission electron microscopy were carried out to characterize the effect of ST36 on inflammation. P2X7R was overexpressed in ISO-treated mice. EA at ST36, but not at non-points, reduced ISO-induced cardiac fibrosis, increases in HW/BW, R+S wave relative to mice in ISO groups. In addition, EA at ST36 downregulated ISO-upregulated P2X7R and NLRP3 in ventricle. Moreover, EA reduced cytokines of IL-1ß, IL-6, and IL-18 in serum, and inhibited foam cell gathering, inflammatory cell infiltration, and autophagy. However, EA at ST36 failed to attenuate the cardiac fibrosis and hypertrophy in P2X7R knockout mice. In conclusion, EA at ST36 attenuated ISO-induced fibrosis possibly via P2X7R.
RESUMO
Small cell lung cancer (SCLC) is a recalcitrant malignancy with dismal prognosis due to rapid relapse after an initial treatment response. More effective treatments for SCLC are desperately needed. Our previous studies showed that cell migration-inducing hyaluronan binding protein (CEMIP) functionally promotes SCLC cell proliferation and metastasis. In this study, we investigated whether and how CEMIP regulates the chemosensitivity of SCLC. Through the GDSC database, we found that CEMIP expression levels were positively correlated with the IC50 values of several commonly used chemotherapeutic drugs in SCLC cells (cisplatin, gemcitabine, 5-fluorouracil and cyclophosphamide). We demonstrated that overexpression or knockdown of CEMIP in SCLC cells resulted in a notable increase or reduction in the IC50 value of cisplatin or etoposide, respectively. We further revealed that CEMIP functions as an adaptor protein in SCLC cells to interact with SRC and YAP through the 1-177 aa domain and 820-1361 aa domain, respectively, allowing the autophosphorylation of Y416 and activation of SRC, thus facilitating the interaction between YAP and activated SRC, and resulting in increased phosphorylation of Y357, protein stability, nuclear accumulation and transcriptional activation of YAP. Overexpressing SRC or YAP counteracted the CEMIP knockdown-mediated increase in the sensitivity of SCLC cells to cisplatin and etoposide. The combination of the SRC inhibitor dasatinib or the YAP inhibitor verteporfin and cisplatin/etoposide (EP regimen) displayed excellent synergistic antitumor effects on SCLC both in vitro and in vivo. This study demonstrated that targeted therapy against the CEMIP/SRC/YAP complex is a potential strategy for SCLC and provides a rationale for the development of future clinical trials with translational prospects.
RESUMO
Cardiac fibrosis is a detrimental pathological process, which constitutes the key factor for adverse cardiac structural remodeling leading to heart failure and other critical conditions. Circular RNAs (circRNAs) have emerged as important regulators of various cardiovascular diseases. It is known that several circRNAs regulate gene expression and pathological processes by binding miRNAs. In this study we investigated whether a novel circRNA, named circNSD1, and miR-429-3p formed an axis that controls cardiac fibrosis. We established a mouse model of myocardial infarction (MI) for in vivo studies and a cellular model of cardiac fibrogenesis in primary cultured mouse cardiac fibroblasts treated with TGF-ß1. We showed that miR-429-3p was markedly downregulated in the cardiac fibrosis models. Through gain- and loss-of-function studies we confirmed miR-429-3p as a negative regulator of cardiac fibrosis. In searching for the upstream regulator of miR-429-3p, we identified circNSD1 that we subsequently demonstrated as an endogenous sponge of miR-429-3p. In MI mice, knockdown of circNSD1 alleviated cardiac fibrosis. Moreover, silence of human circNSD1 suppressed the proliferation and collagen production in human cardiac fibroblasts in vitro. We revealed that circNSD1 directly bound miR-429-3p, thereby upregulating SULF1 expression and activating the Wnt/ß-catenin pathway. Collectively, circNSD1 may be a novel target for the treatment of cardiac fibrosis and associated cardiac disease.
RESUMO
BACKGROUND: With the world's population steadily shifting toward urban living, children's engagement with the natural environment seems to be diminishing. This raises significant concerns about the influence of urban greenspaces on the cardiovascular health of children. OBJECTIVE: To assess the association between urban greenspaces exposure and blood pressure (BP) in Chinese primary schoolchildren. METHODS: This prospective cohort study used data from the Children's growth environment, lifestyle, physical, and mental health development (COHERENCE) project in Guangzhou, China. Participants included 164,853 primary schoolchildren starting from 2016/17 to 2019/20 academic year. We assessed the surrounding greenspaces at home and school by using Sentinel-2 satellite data on the normalized difference vegetation index. Prehypertension and hypertension status were defined with BP above 90th to less than the 95th percentile, at or above the 95th percentile, respectively. The association of surrounding greenness with children's BP levels and risk of prehypertension/hypertension were examined using linear mixed-effects models and Cox proportional hazards model. RESULTS: Among 164,853 eligible children aged 7.21 (0.74) years, 89,190 (54.1%) were boys. Our results showed that average systolic and diastolic BP increased by 0.48 and 0.42 standard deviations, respectively, over the 3-year follow-up. We identified 23,225 new cases of prehypertension and 35,067 of hypertension status. An interquartile range increase both in home-, school- and home-school NDVI100m was significantly associated with a reduction of 0.018-0.037 in BP z-scores and a 2.7%-7.6% lower risk of hypertension. Additionally, family socioeconomic status modified the impact of home-school greenness on BP levels. Air pollution exhibited mediating effects solely in school-greenness-BP associations, while physical activity and children's BMI mainly mediated the relationships between home-greenness and BP. CONCLUSION: The findings of this large cohort study suggest that surrounding greenspaces are associated with lower BP levels and a decreased risk of prehypertension and hypertension in Chinese schoolchildren.
Assuntos
Hipertensão , Pré-Hipertensão , Masculino , Criança , Humanos , Feminino , Pressão Sanguínea , Pré-Hipertensão/epidemiologia , Estudos de Coortes , Estudos Prospectivos , Parques Recreativos , Hipertensão/epidemiologia , China/epidemiologiaRESUMO
A Gram-stain-positive, rod-shaped, non-spore-forming, alkane degrading bacterium, designated DJM-14T, was isolated from oilfield alkali-saline soil in Heilongjiang, Northeast China. On the basis of 16 S rRNA gene sequencing, strain DJM-14T was shown to belong to the genus Nocardioides, and related most closely to Nocardioides terrigena KCTC 19,217T (95.53% 16 S rRNA gene sequence similarity). Strain DJM-14T was observed to grow at 25-35 °C, pH 7.0-11.0, in the presence of 0-6.0% (w/v) NaCl. The predominant respiratory quinone was MK-8 (H4) and LL-diaminopimelic acid was the diagnostic diamino acid in the cell-wall peptidoglycan. The major fatty acids were identified as iso-C16:0 and C18:1 ω9c. It contained diphosphatidylglycerol, phosphatidylglycerol and phosphatidylinositol as the polar lipids. The genome (3,722,608 bp), composed of 24 contigs, had a G + C content of 69.6 mol%. Out of the 3667 predicted genes, 3618 were protein-coding genes, and 49 were ncRNAs. Digital DNA-DNA hybridization (dDDH) estimation and average nucleotide identity (ANI) of strain DJM-14T against genomes of the type strains of related species in the same family ranged between 18.7% and 20.0%; 68.8% and 73.6%, respectively. According to phenotypic, genotypic and phylogenetic data, strain DJM-14T represents a novel species in the genus Nocardioides, for which the name Nocardioides limicola sp. nov. is proposed and the type strain is DJM-14T (= CGMCC 4.7593T, =JCM 33,692T). In addition, novel strains were able to grow with n-alkane (C24-C36) as the sole carbon source. Multiple copies of alkane 1-monooxygenase (alkB) gene, as well as alcohol dehydrogenase gene and aldehyde dehydrogenase gene involved in the alkane assimilation were annotated in the genome of type strain DJM-14T.
Assuntos
Nocardioides , Fosfolipídeos , Fosfolipídeos/química , Nocardioides/genética , Solo , Filogenia , Campos de Petróleo e Gás , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Ácidos Graxos/química , DNA , DNA Bacteriano/genética , Técnicas de Tipagem BacterianaRESUMO
OBJECTIVE: An increasing number of studies shown that inadequate energy intake causes an increase in adverse incidents in chronic kidney disease (CKD) patients on low-protein diets (LPD). The study aimed to investigate the relationship between energy intake and cardiovascular mortality in CKD patients on a LPD. METHODS: This was a cross-sectional study, a total of 4264 CKD patients were enrolled from the NHANES database between 2009 and 2018. Restricted cubic spline plots and Cox regression analysis were used to analyze the association between energy intake and cardiovascular mortality in CKD patients on a LPD. Additionally, a nomogram was constructed to estimate cardiovascular survival in CKD patients on a LPD. RESULTS: Among CKD patients on a LPD in the United States, 90.05% had an energy intake of less than 25 kcal/kg/day, compared to 36.94% in CKD patients on a non-LPD. Energy intake and cardiovascular mortality showed a linear relationship in CKD patients on a LPD, while a 'U-shaped' relationship was observed in CKD patients on a non-LPD. Multifactorial Cox regression models revealed that for Per-standard deviation (Per-SD) decrement in energy intake, the risk of cardiovascular mortality increased by 41% (HR: 1.41, 95% CI: 1.12, 1.77; P = 0.004) in CKD patients on a LPD. The concordance index of the nomogram was 0.79 (95% CI, 0.75, 0.83). CONCLUSION: CKD patients, especially those on a LPD, have significantly inadequate energy intake. Lower energy intake is associated with higher cardiovascular mortality in CKD patients on a LPD.