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Ferroptosis has emerged as a potential mechanism for enhancing the efficacy of chemotherapy in cancer treatment. By suppressing nuclear factor erythroid 2-related factor 2 (Nrf2), cancer cells may lose their ability to counteract the oxidative stress induced by chemotherapy, thereby becoming more susceptible to ferroptosis. In this study, we investigate the potential of penexanthone A (PXA), a xanthone dimer component derived from the endophytic fungus Diaporthe goulteri, obtained from mangrove plant Acanthus ilicifolius, to enhance the therapeutic effect of cisplatin (CDDP) on colorectal cancer (CRC) by inhibiting Nrf2. The present study reported that PXA significantly improved the ability of CDDP to inhibit the activity of and induce apoptosis in CRC cells. Moreover, PXA was found to increase the level of oxidative stress and DNA damage caused by CDDP. In addition, the overexpression of Nrf2 reversed the DNA damage and ferroptosis induced by the combination of PXA and CDDP. In vivo experiments using zebrafish xenograft models demonstrated that PXA enhanced the therapeutic effect of CDDP on CRC. These studies suggest that PXA enhanced the sensitivity of CRC to CDDP and induce ferroptosis by targeting Nrf2 inhibition, indicating that PXA might serve as a novel anticancer drug in combination chemotherapy.
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Antineoplásicos , Neoplasias Colorrectales , Ferroptosis , Factor 2 Relacionado con NF-E2 , Xantonas , Pez Cebra , Factor 2 Relacionado con NF-E2/metabolismo , Humanos , Ferroptosis/efectos de los fármacos , Animales , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Xantonas/farmacología , Antineoplásicos/farmacología , Línea Celular Tumoral , Cisplatino/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto , Estrés Oxidativo/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Apoptosis/efectos de los fármacosRESUMEN
The maintenance of hematopoietic stem cell (HSC) functional integrity is essential for effective hematopoietic regeneration when suffering from injuries. Studies have shown that the innate immune pathways play crucial roles in the stress response of HSCs, whereas how to precisely modulate these pathways is not well characterized. Here, we identify the E3 ubiquitin ligase tripartite motif-containing 47 (Trim47) as a negative regulator of the mitochondrial antiviral-signaling protein (MAVS)-mediated innate immune pathway in HSCs. We find that Trim47 is predominantly enriched in HSCs, and its deficiency impairs the function and survival of HSCs after exposure to 5-flurouracil (5-FU) and irradiation (IR). Mechanistically, Trim47 impedes the excessive activation of the innate immune signaling and inflammatory response via K48-linked ubiquitination and degradation of MAVS. Collectively, our findings demonstrate a role of Trim47 in preventing stress-induced hematopoietic failure and thus provide a promising avenue for treatment of related diseases in the clinic.
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Proteínas Adaptadoras Transductoras de Señales , Células Madre Hematopoyéticas , Inmunidad Innata , Ratones Endogámicos C57BL , Transducción de Señal , Ubiquitina-Proteína Ligasas , Ubiquitinación , Animales , Células Madre Hematopoyéticas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Ratones , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ratones Noqueados , Humanos , Fluorouracilo/farmacología , Estrés Fisiológico , Proteínas de Motivos Tripartitos/metabolismo , Proteínas de Motivos Tripartitos/genética , Células HEK293RESUMEN
Pillar-layered metal-organic frameworks (PLMOFs) are promising gas adsorbents due to their high designability. In this work, high CO2 storage capacity as well as controllable C2H2/CO2 separation ability are acquired by rationally manipulating the interlayer stacking in pillar-layered MOF materials. The rational construction of pillar-layered MOFs started from the 2D Ni-BTC-pyridine layer, an isomorphic structure of pioneering MOF-1 reported in 1995. The replacement of terminal pyridine groups by bridging pyrazine linkers under optimized solvothermal conditions led to three 3D PLMOFs with different stacking types between adjacent Ni-BTC layers, named PLMOF 1 (ABAB stacking), PLMOF 2 (AABB stacking), and PLMOF 3 (AAAA stacking). Regulated by the layer arrangements, CO2 and C2H2 adsorption capacities (273 K and 1 bar) of PLMOFs 1-3 vary from 173.0/153.3, 185.0/162.4, to 203.5/159.5 cm3 g-1, respectively, which surpass the values of most MOF adsorbents. Dynamic breakthrough experiments further indicate that PLMOFs 1-3 have controllable C2H2/CO2 separation performance, which can successfully overcome the C2H2/CO2 separation challenge. Specially, PLMOFs 1-3 can remove trace CO2 (3%) from the C2H2/CO2 mixture and produce high-purity ethylene (99.9%) in one step with the C2H2 productivities of 1.68, 2.45, and 3.30 mmol g-1, respectively. GCMC simulations indicate that the superior CO2 adsorption and unique C2H2/CO2 separation performance are mainly ascribed to different degrees of CO2 agglomeration in the ultramicropores of these PLMOFs.
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BACKGROUND: The relationship between variation in serum uric acid (SUA) levels and brain health is largely unknown. This study aimed to examine the associations of long-term variability in SUA levels with neuroimaging metrics and cognitive function. METHODS: This study recruited 1111 participants aged 25-83 years from a multicenter, community-based cohort study. The SUA concentrations were measured every two years from 2006 to 2018. We measured the intraindividual SUA variability, including the direction and magnitude of change by calculating the slope value. The associations of SUA variability with neuroimaging markers (brain macrostructural volume, microstructural integrity, white matter hyperintensity, and the presence of cerebral small vessel disease) and cognitive function were examined using generalized linear models. Mediation analyses were performed to assess whether neuroimaging markers mediate the relationship between SUA variation and cognitive function. RESULTS: Compared with the stable group, subjects with increased or decreased SUA levels were all featured by smaller brain white matter volume (beta = - 0.25, 95% confidence interval [CI] - 0.39 to - 0.11 and beta = - 0.15, 95% CI - 0.29 to - 0.02). Participants with progressively increased SUA exhibited widespread disrupted microstructural integrity, featured by lower global fractional anisotropy (beta = - 0.24, 95% CI - 0.38 to - 0.10), higher mean diffusivity (beta = 0.16, 95% CI 0.04 to 0.28) and radial diffusivity (beta = 0.19, 95% CI 0.06 to 0.31). Elevated SUA was also associated with cognitive decline (beta = - 0.18, 95% CI - 0.32 to - 0.04). White matter atrophy and impaired brain microstructural integrity mediated the impact of SUA increase on cognitive decline. CONCLUSIONS: It is the magnitude of SUA variation rather than the direction that plays a critical negative role in brain health, especially for participants with hyperuricemia. Smaller brain white matter volume and impaired microstructural integrity mediate the relationship between increased SUA level and cognitive function decline. Long-term stability of SUA level is recommended for maintaining brain health and preventing cognitive decline.
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Disfunción Cognitiva , Neuroimagen , Ácido Úrico , Humanos , Anciano , Masculino , Disfunción Cognitiva/sangre , Femenino , Persona de Mediana Edad , Anciano de 80 o más Años , Ácido Úrico/sangre , Neuroimagen/métodos , Estudios de Cohortes , Adulto , Encéfalo/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patologíaRESUMEN
This study aimed to determine the function of angiopoietin-related protein 4 (ANGPTL4) and bone morphogenetic protein 7 (BMP7) on hepatocellular carcinoma (HCC). Overexpressing plasmids were cotransfected into HepG2 cells to determine the interaction between ANGPTL4 and BMP7. The effect of ANGPTL4 on the stability of BMP7 is examined by detecting the expression and ubiquitination levels. In vitro and in vivo experiments of knocking down ANGPTL4 while overexpressing BMP7 were performed to investigate whether the effects of ANGPTL4 on HCC proliferation, migration, and downstream signaling pathways were dependent on BMP7. ANGPTL4 is able to interact with BMP7, and knockdown of ANGPTL4 increased BMP7 expression and ubiquitination. Overexpression of BMP7 reversed the inhibition of HCC proliferation and migration as well as the decrease in the expression levels of Smad1/5/8 and MAPK14 caused by knockdown of ANGPTL4. ANGPTL4 promotes the proliferation and migration of HCC by inhibiting the ubiquitination degradation of BMP7 and the Smad/MAPK pathway, providing a novel mechanism and a potential therapeutic target for the treatment of HCC.
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Proteína 4 Similar a la Angiopoyetina , Proteína Morfogenética Ósea 7 , Carcinoma Hepatocelular , Movimiento Celular , Proliferación Celular , Neoplasias Hepáticas , Ubiquitinación , Humanos , Proliferación Celular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Células Hep G2 , Proteína 4 Similar a la Angiopoyetina/metabolismo , Proteína 4 Similar a la Angiopoyetina/genética , Movimiento Celular/genética , Proteína Morfogenética Ósea 7/metabolismo , Proteína Morfogenética Ósea 7/genética , Animales , Proteínas Smad/metabolismo , Proteínas Smad/genética , Ratones , Sistema de Señalización de MAP Quinasas , Transducción de Señal , Ratones Desnudos , Regulación Neoplásica de la Expresión GénicaRESUMEN
BACKGROUND: To systematically describe clinical characteristics and investigate factors associated with COVID-19-related infection, hospital admission, and IgG4-related disease relapse in IgG4-RD patients. METHODS: Physician-reported IgG4-RD patients were included in this retrospective study. Using multivariable logistic regression analysis to determine factors for primary outcome (COVID-19-related IgG4-RD relapse) and secondary outcome (COVID-19-related infection and hospital admission). Covariates included age, sex, body mass index, smoking status, comorbidities, IgG4-RD clinical features, and treatment strategies. RESULTS: Among 649 patients, 530 had a diagnosis of COVID-19, 25 had COVID-19-related hospital admission, and 69 had COVID-19-related IgG4-RD relapse. Independent factors associated with COVID-19 infection were age (OR, 0.98; 95% CI, 0.96-1.00), body mass index (1.10, 1.03-1.18), and tofacitinib (0.34, 0.14-0.79). Further analysis indicated that age (1.10, 1.03-1.16), coronary heart disease (24.38, 3.33-178.33), COVID-19-related dyspnea (7.11, 1.85-27.34), pulmonary infection (73.63, 16.22-4615.34), and methotrexate (17.15, 1.93-157.79) were associated with a higher risk of COVID-19-related hospital admission. Importantly, age (0.93, 0.89-0.98), male sex (0.16, 0.03-0.80), ever/current smoking (19.23, 3.78-97.80), COVID-19-related headache (2.98, 1.09-8.17) and psychiatric symptoms (3.12, 1.07-9.10), disease activity before COVID-19 (1.89, 1.02-3.51), number of involved organs (1.38, 1.08-1.76), glucocorticoid dosage (1.08, 1.03-1.13), and methotrexate (5.56, 1.40-22.08) were strong factors for COVID-19-related IgG4-RD relapse. CONCLUSIONS: Our data add to evidence that smoking and disease-specific factors (disease activity, number of involved organs, and specific medications) were risk factors of COVID-19-related IgG4-RD relapse. The results highlight the importance of adequate disease control with b/tsDMARDs, preferably without using methotrexate and increasing glucocorticoid dosages in the COVID-19 era. Key Points ⢠COVID-19-related infection or hospital admission were associated with known general factors (age, body mass index, specific comorbidities and methotrexate) among IgG4-RD patients. ⢠Smoking and disease-specific factors (disease activity, number of involved organs and specific medications) were associated with higher odds of COVID-19-related IgG4-RD relapse. ⢠The results highlight the importance of adequate disease control with b/tsDMARDs, preferably without using methotrexate or increasing glucocorticoid dosages.
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COVID-19 , Hospitalización , Enfermedad Relacionada con Inmunoglobulina G4 , Humanos , COVID-19/epidemiología , COVID-19/inmunología , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Enfermedad Relacionada con Inmunoglobulina G4/epidemiología , Enfermedad Relacionada con Inmunoglobulina G4/tratamiento farmacológico , Anciano , Hospitalización/estadística & datos numéricos , Adulto , Recurrencia , SARS-CoV-2 , Comorbilidad , Factores de Riesgo , Factores de EdadRESUMEN
Highly active catalysts with salt and acid/alkali resistance are desired in peroxymonosulfate (PMS) activation processes and marine environment applications. F- and Cl-doped graphene (F-GN and Cl-GN) were prepared via electronegative and atom radius adjustment for tetracycline hydrochloride (TCH) pollution removal to satisfy these requirements. The introduction of special F and Cl functionalities into graphene exhibits superior electron transfer properties for PMS activation, considering the experimental and density functional theory (DFT) calculation results. The TCH degradation efficiency reached up to 80% under various pH and salt disturbance conditions with F-GN and Cl-GN. Cl-GN exhibited an activity superior to F-GN due to the higher electron polarization effect of C atoms adjacent to Cl atoms. The presence of more positive charged C sites in Cl-GN (around Cl doping) is more favorable for PMS attachment and sequence radical generation than F-GN. In addition, the main active species functionalized during reaction included ·OH and SO4-·, and the stability of F-GN and Cl-GN was confirmed to be over 60% by recycle test. Final research results provide an effective strategy for designing and preparing PMS activators resistant to salt, acid, and alkali, thereby expanding their application potential.
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Grafito , Peróxidos , Tetraciclina , Tetraciclina/química , Grafito/química , Catálisis , Peróxidos/químicaRESUMEN
AIMS: The xanthone dimer 12-O-deacetyl-phomoxanthone A (12-ODPXA) was extracted from the secondary metabolites of the endophytic fungus Diaporthe goulteri. The 12-ODPXA compound exhibited anticancer properties in murine lymphoma; however, the anti-ovarian cancer (OC) mechanism has not yet been explored. Therefore, the present study evaluated whether 12-ODPXA reduces OC cell proliferation, metastasis, and invasion by downregulating pyruvate dehydrogenase kinase (PDK)4 expression. METHODS: Cell counting kit-8, colony formation, flow cytometry, wound healing, and transwell assays were performed to examine the effects of 12-ODPXA on OC cell proliferation, apoptosis, migration, and invasion. Transcriptome analysis was used to predict the changes in gene expression. Protein expression was determined using western blotting. Glucose, lactate, and adenosine triphosphate (ATP) test kits were used to measure glucose consumption and lactate and ATP production, respectively. Zebrafish xenograft models were constructed to elucidate the anti-OC effects of 12-ODPXA. RESULTS: The 12-ODPXA compound inhibited OC cell proliferation, migration, invasion, and glycolysis while inducing cell apoptosis via downregulation of PDK4. In vivo experiments showed that 12-ODPXA suppressed tumor growth and migration in zebrafish. CONCLUSION: Our data demonstrate that 12-ODPXA inhibits ovarian tumor growth and metastasis by downregulating PDK4, revealing the underlying mechanisms of action of 12-ODPXA in OC.
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Apoptosis , Movimiento Celular , Proliferación Celular , Regulación hacia Abajo , Neoplasias Ováricas , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora , Xantonas , Pez Cebra , Animales , Femenino , Neoplasias Ováricas/patología , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/metabolismo , Humanos , Xantonas/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Antineoplásicos/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Metástasis de la Neoplasia , Invasividad NeoplásicaRESUMEN
OBJECTIVES: Gout is characterized by hyperuricemia and recurrent inflammatory episodes caused by intra-articular crystal deposition of monosodium urate (MSU). There is a clear relationship between gout and metabolic syndrome. Recent evidence indicates that perforin plays a role in regulating glucose homeostasis and provides protection in diet-induced non-alcoholic steatohepatitis models. However, the impact of perforin on immune inflammation in gout remains unclear. METHODS: We induced acute gout models in both wild-type (WT) mice and Prf1null mice by administering intra-articular injections of MSU crystals. We compared the ankle joint swelling and the histological score between the two groups. Furthermore, we investigated underlying mechanisms through in vitro co-culture experiments involving CD8 T cells and macrophages. RESULTS: In this study, Prf1null mice showed significantly more pronounced ankle swelling with increased inflammatory cell infiltrations compared with WT mice 24 h after local MSU injection. Moreover, MSU-induced Prf1null mice exhibited increased accumulation of CD8 T cells but not NK cells. Perforin-deficient CD8 T cells displayed reduced cytotoxicity towards bone marrow-derived M0 and M1 macrophages and promoted TNF-α secretion from macrophage. CONCLUSIONS: Perforin from CD8 T cells limits joint inflammation in mice with acute gout by downregulating macrophage-mediated inflammation. Key Points ⢠Perforin deficiency increased swelling in the ankle joints of mice upon MSU injection. ⢠Perforin deficiency is associated with increased immune cell recruitment and severe joint damage in gout. ⢠Perforin regulated CD8 T cell accumulation in gout and promoted CD8 T cell cytotoxicity towards M0 and M1 macrophages. ⢠CD8 T cell-derived perforin regulated pro-inflammatory cytokine secretion of macrophage.
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Linfocitos T CD8-positivos , Modelos Animales de Enfermedad , Gota , Inflamación , Macrófagos , Perforina , Ácido Úrico , Animales , Linfocitos T CD8-positivos/inmunología , Ratones , Macrófagos/metabolismo , Macrófagos/inmunología , Perforina/metabolismo , Gota/inmunología , Gota/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Masculino , Factor de Necrosis Tumoral alfa/metabolismo , Proteínas Citotóxicas Formadoras de PorosRESUMEN
BACKGROUND: Serum uric acid (SUA) is a major cause of cardiovascular and cerebrovascular diseases. Whether and to what extent the excess risk of enlarged perivascular spaces (EPVS) conferred by SUA is unknown. The study was conducted to investigate the association between SUA and EPVS in different brain regions. METHODS: Data are from Multi-modality medical imaging study based on Kailuan study (META-KLS) in this cross-sectional study. Participants were divided into five groups based on SUA levels, and EPVS in basal ganglia (BG), centrum semiovale (CSO) and midbrain (MB) was systematically assessed and divided into Low and High group. Odds ratio (OR) and 95% confidence intervals (95% CIs) for high EPVS outcomes were estimated using multivariable logistic regression analysis. Restricted cubic spline (RCS) was used to further investigate dose-response relationship. RESULTS: A total of 1014 participants aged 25-83 years from 11 centers were enrolled in the study. In the multivariable-adjusted model, SUA, as an independent risk factor, correlated positively with high degree of MB-EPVS (OR, 1.002; 95% CI, 1.000 to 1.004; p = 0.023) in general population. In addition, RCS further demonstrated the linear association between SUA and MB-EPVS (p = 0.072). No association was found between SUA and BG-EPVS or CSO-EPVS. CONCLUSION: SUA was an independent risk factor of MB-EPVS. High SUA levels were more predictive of increased risk occurrence of high degree of MB-EPVS, supporting a linear association between SUA and MB-EPVS and further indicating that SUA may play an important role in cerebral small vessel disease. TRIAL REGISTRATION: The KaiLuan Study and META-KLS were registered online (ChiCTR2000029767 on chictr.org.cn and NCT05453877 on Clinicaltrials.gov, respectively).
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Mesencéfalo , Ácido Úrico , Humanos , Ácido Úrico/sangre , Femenino , Persona de Mediana Edad , Masculino , Estudios Transversales , Anciano , Adulto , Mesencéfalo/diagnóstico por imagen , Mesencéfalo/patología , Anciano de 80 o más Años , Sistema Glinfático/diagnóstico por imagen , Sistema Glinfático/patología , China/epidemiología , Imagen por Resonancia Magnética , Imagen MultimodalRESUMEN
OBJECTIVES: To develop a novel ultrasound scoring system for the major salivary glands in patients with immunoglobulin G4-related sialadenitis (IgG4-RS) and assess its diagnostic value in a multicenter cohort of Chinese patients. METHODS: Twenty clinicians (rheumatologists, stomatologists, and radiologists) participated. The study was conducted in four steps: (1) defining the ultrasonography (US) elements, (2) developing a novel ultrasound scoring system for US of the salivary glands, (3) evaluation of inter- and intra-reader reliabilities using the new ultrasound scoring system, and (4) assessing the diagnostic value of this novel ultrasound scoring system in IgG4-RS patients in a Chinese multicenter cohort. RESULTS: A novel ultrasound scoring system for the salivary glands was developed, with total scores ranging from 0 to 34. The inter- and intra-reader reliabilities of the ultrasound scoring system were excellent (0.972 and 0.940, respectively). A total of 470 people were recruited in this study; 187 patients were diagnosed with IgG4-RS, and the remaining 283 people were diagnosed with non-IgG4-RS. Patients with IgG4-RS had significantly higher US scores than the non-IgG4-RS group (mean US score=16 vs. 4, P < 0.001). The calculated area under the curve (AUC) for the total US score was 0.852 (95% CI: 0.814-0.891). The total US scores≥9 showed a sensitivity of 75.4% and a specificity of 91.9%. Association analysis showed a positive correlation between total US scores and serum IgG4 levels and hypocomplementemia (r=0.221, r=0.349; P = 0.002) and a negative correlation between total US scores and serum C3 and C4 levels (r=-0.210, r=-0.303; P = 0.005, P < 0.001). CONCLUSIONS: A novel semiquantitative ultrasound scoring system for patients with IgG4-RS was developed, with good diagnostic performance. The inter- and intra-reader reliabilities were excellent. US scores were correlated with IgG4, C3, and C4 levels and hypocomplementemia.
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To investigate the functional differences of angiopoietin-related protein 4 (ANGPTL4) transcripts in hepatocellular carcinoma (HCC) cells. By transfecting ANGPTL4-Transcript 1 and ANGPTL4-Transcript 3 overexpression vectors into HepG2 and Huh7 cell lines with ANGPTL4 knockdown, the effects of overexpression of two transcripts on cell viability, invasion, migration, and apoptosis were analyzed. The expression of two transcripts was compared in human liver cancer tissue, and their effects on tumor development were validated in vivo experiments in mice. Compared with control, the overexpression of ANGPTL4-Transcript 1 had no significant effect on viability, invasion, healing, and apoptosis of HepG2 and Huh7 cells. However, these two cell lines overexpressing ANGPTL4-Transcript 3 showed remarkably enhanced cell viability, invasive and healing ability, and decreased apoptosis ability. Furthermore, the mRNA level of ANGPTL4-Transcript 3 was significantly increased in human HCC tissues and promoted tumor growth compared with Transcript 1. Different transcripts of gene ANGPTL4 have distinct effects on HCC. The abnormally elevated Transcript 3 with the specific ability of promoting HCC proliferation, infiltration, and migration is expected to become a new biological marker and more precise intervention target for HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Animales , Ratones , Neoplasias Hepáticas/patología , Carcinoma Hepatocelular/patología , Proteína 4 Similar a la Angiopoyetina/genética , Proteína 4 Similar a la Angiopoyetina/metabolismo , Línea Celular Tumoral , Movimiento Celular/genética , Apoptosis/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión GénicaRESUMEN
OBJECTIVE: To develop and conduct an initial validation of the Damage Index for IgG4-related disease (IgG4-RD DI). METHODS: A draft of index items for assessing organ damages in patients with IgG4-RD was generated by experts from the Chinese IgG4-RD Consortium (CIC). The preliminary DI was refined using the Delphi method, and a final version was generated by consensus. 40 IgG4-RD cases representing four types of clinical scenarios were then selected, each with two time points of assessment for at least 3 years of follow-up. 48 rheumatologists from 35 hospitals nationwide were invited to evaluate organ damage using the CIC IgG4-RD DI. The intraclass correlation coefficient (ICC) and the Kendall-W coefficient of concordance (KW) were used to assess the inter-rater reliability. The criterion validity of IgG4-RD DI was tested by calculating the sensitivity and specificity of raters. RESULTS: IgG4-RD DI is a cumulative index consisting of 14 domains of organ systems, including a total of 39 items. The IgG4-RD DI was capable of distinguishing stable and increased damage across the active disease subgroup and stable disease subgroup. In terms of scores at baseline and later observations by all raters, overall consistency in scores at baseline and later observations by all raters was satisfactory. ICC at the two time points was 0.69 and 0.70, and the KW was 0.74 and 0.73, respectively. In subgroup analysis, ICC and KW in all subgroups were over 0.55 and 0.61, respectively. The analysis of criterion validity showed a good performance with a sensitivity of 0.86 (95% CI 0.82 to 0.88), a specificity of 0.79 (95% CI 0.76 to 0.82) and an area under the curve of 0.88 (95% CI 0.85 to 0.91). CONCLUSION: The IgG4-RD DI is a useful approach to analyse disease outcomes, and it has good operability and credibility. It is anticipated that the DI will become a useful tool for therapeutic trials and studies of prognosis in patients with IgG4-RD.
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Enfermedad Relacionada con Inmunoglobulina G4 , Humanos , Enfermedad Relacionada con Inmunoglobulina G4/diagnóstico , Consenso , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , China/epidemiologíaRESUMEN
OBJECTIVES: B10 and B10pro cells suppress immune responses via secreting interleukin (IL)-10. However, their regulators and underlying mechanisms, especially in human autoimmune diseases, are elusive. This study aimed to address these questions in rheumatoid arthritis (RA), one of the most common highly disabling autoimmune diseases. METHODS: The frequencies and functions of B10 and B10pro cells in healthy individuals and patients with RA were first analysed. The effects of proinflammatory cytokines, particularly tumour necrosis factor (TNF)-α on the quantity, stability and pathogenic phenotype of these cells, were then assessed in patients with RA before and after anti-TNF therapy. The underlying mechanisms were further investigated by scRNA-seq database reanalysis, transcriptome sequencing, TNF-α-/- and B cell-specific SHIP-1-/- mouse disease model studies. RESULTS: TNF-α was a key determinant for B10 cells. TNF-α elicited the proinflammatory feature of B10 and B10pro cells by downregulating IL-10, and upregulating interferon-γ and IL-17A. In patients with RA, B10 and B10pro cells were impaired with exacerbated proinflammatory phenotype, while anti-TNF therapy potently restored their frequencies and immunosuppressive functions, consistent with the increased B10 cells in TNF-α-/- mice. Mechanistically, TNF-α diminished B10 and B10pro cells by inhibiting their glycolysis and proliferation. TNF-α also regulated the phosphatidylinositol phosphate signalling of B10 and B10pro cells and dampened the expression of SHIP-1, a dominant phosphatidylinositol phosphatase regulator of these cells. CONCLUSIONS: TNF-α provoked the proinflammatory phenotype of B10 and B10pro cells by disturbing SHIP-1 in RA, contributing to the disease development. Reinstating the immunosuppressive property of B10 and B10pro cells might represent novel therapeutic approaches for RA.
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Artritis Reumatoide , Enfermedades Autoinmunes , Linfocitos B Reguladores , Factor de Necrosis Tumoral alfa , Animales , Humanos , Ratones , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/metabolismo , Enfermedades Autoinmunes/metabolismo , Linfocitos B Reguladores/metabolismo , Fenotipo , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatasas/genética , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatasas/metabolismo , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND: Hepatocellular carcinoma (HCC) is a malignant tumor that impacts individuals worldwide and is particularly prevalent in Asia. Angiopoietin-like protein 4 (ANGPTL4) plays an important role in regulating glucose and lipid metabolism in mouse liver. We sought to explore the effects of the ANGPTL4 gene on cell viability, migration, invasive capacity, and apoptosis of HCC cells. METHODS: The expression of ANGPTL4 in HCC and paracancerous tissues was determined by immunohistochemistry and immunofluorescence assays. The ANGPTL4 knockdown cells were established by shRNA transfection. The effect of ANGPTL4 knockdown on HepG2 and Huh7 cells was determined by Cell Count Kit-8 (CCK-8), wound healing and transwell assays. Cell apoptosis was determined by flow cytometry. RESULTS: The ANGPTL4 expression was dramatically enhanced in HCC tissues than in paracancerous tissues (p < 0.001). HCC cell lines HepG2 and Huh7 with knockdown of ANGPTL4 gene showed lower cell viability, migration, and invasion ability while inducing higher apoptosis levels than the control group (p < 0.001). CONCLUSIONS: High expression of ANGPTL4 is closely related to HCC. Knockdown of ANGPTL4 significantly inhibits the proliferation of HCC cells. This study provides a rationale for the ANGPTL4 gene, a molecular marker of HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Animales , Ratones , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Proteína 4 Similar a la Angiopoyetina/genética , Proteína 4 Similar a la Angiopoyetina/metabolismo , Línea Celular Tumoral , Apoptosis/genética , Proliferación Celular/genética , Movimiento Celular/genética , Regulación Neoplásica de la Expresión GénicaRESUMEN
OBJECTIVE: The purpose of this research was to ascertain the effectiveness of the newly established criteria for classifying IgG4-related disease (IgG4-RD), as applied to a large Chinese cohort in real-world clinical settings. METHODS: Patient data were procured from the digital health records of 4 prominent academic hospitals. The criterion standard for identifying IgG4-RD patients was from a seasoned rheumatologist. The control group consisted of individuals with other ailments such as cancer, other forms of pancreatitis, infectious diseases, and illnesses that mimic IgG4-RD. RESULTS: A total of 605 IgG4-RD patients and 760 mimickers were available for analysis. The 2019 EULAR/ACR criteria have a sensitivity of 69.1% and a specificity of 90.9% in this large Chinese cohort. IgG4-RD had a greater proportion of males (55.89% vs 36.25%, p < 0.001), an older average age at diagnosis (54.91 ± 13.44 vs 48.91 ± 15.71, p < 0.001), more pancreatic (29.59% vs 6.12%, p < 0.001) and salivary gland (63.30% vs 27.50%, p < 0.001) involvement, and a larger number of organ involvement (3.431 ± 2.054 vs 2.062 ± 1.748, p < 0.001) compared with mimickers. CONCLUSIONS: The 2019 EULAR/ACR criteria are effective in classifying IgG4-RD in Chinese patients, demonstrating high specificity and moderate sensitivity.
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Enfermedad Relacionada con Inmunoglobulina G4 , Pancreatitis , Humanos , Masculino , Pueblo Asiatico , China , Enfermedad Relacionada con Inmunoglobulina G4/diagnóstico , Pancreatitis/diagnóstico , Glándulas Salivales , FemeninoRESUMEN
Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by progressive memory loss, neurodegeneration, and cognitive decline. Aging is one of the risk factors for AD. Although the mechanisms underlying aging and the incidence rate of AD are unclear, aging and AD share some hallmarks, such as oxidative stress and chronic inflammation. Cannabidiol (CBD), the major non-psychoactive phytocannabinoid extracted from Cannabis sativa, has recently emerged as a potential candidate for delaying aging and a valuable therapeutic tool for the treatment of aging-related neurodegenerative diseases due to its antioxidant and anti-inflammation properties. This article reviews the relevant literature on AD, CBD treatment for AD, cellular senescence, aging, and CBD treatment for aging in recent years. By analyzing these published data, we attempt to explore the complex correlation between cellular senescence, aging, and Alzheimer's disease, clarify the positive feedback effect between the senescence of neurocytes and Alzheimer's disease, and summarize the role and possible molecular mechanisms of CBD in preventing aging and treating AD. These data may provide new ideas on how to effectively prevent and delay aging, and develop effective treatment strategies for age-related diseases such as Alzheimer's disease.
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Enfermedad de Alzheimer , Cannabidiol , Enfermedades Neurodegenerativas , Humanos , Cannabidiol/farmacología , Cannabidiol/uso terapéutico , Enfermedad de Alzheimer/tratamiento farmacológico , EncéfaloRESUMEN
Immunoglobulin G4 (IgG4)-related disease is a chronic fibroinflammatory disease mediated by immune disorders. Given the challenging clinical diagnosis and treatment, knowledge of the pathogenesis of IgG4-related disease is important. The typical elevation of serum IgG4 concentrations and infiltration of IgG4-positive plasma cells in the involved tissues indicate the involvement of B lymphocytes in the pathogenesis of IgG4-related disease. Mass production of autoantibodies reflects abnormal activation of B cells, which causes tissue damage. Circulating plasmablasts are recently discovered markers that correlate with serum IgG4 concentration, the extent of organ involvement and disease activity. B-cell depletion therapy is an emerging curative strategy that can significantly alleviate clinical manifestations and achieve remission in patients with IgG4-related disease. These findings highlight the potential role of B cells in IgG4-related disease. In this review, we discuss the pathogenic impact of B lymphocytes on IgG4-related disease and describe novel therapies targeting B cells.
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Objective: To explore the relationship between physical activity and depression among college students, as well as the mediating role of rumination and anxiety. Methods: A total of 1,292 Chinese college students were investigated by physical activity questionnaire, rumination scale, self-rating anxiety scale (SAS), and depression scale. Results: (1) There was a significant negative correlation between physical activity and depression (r = -0.399, p < 0.01), and the direct path of physical activity on depression was significant (ß = -0.399, t = -13.374, p < 0.01). (2) Physical activity negatively predicted rumination (ß = -0.322, t = -10.440, p < 0.01) and anxiety (ß = -0.222, t = -7.089, p < 0.01). Rumination positively predicted anxiety (ß = 0.283, t = 9.017, p < 0.01) and depression (ß = 0.267, t = 9.046, p < 0.01). Anxiety positively predicted depression (ß = 0.262, t = 8.902, p < 0.01). (3) Rumination and anxiety play a significant mediating role between physical activity and depression. The mediating effect involves three paths: physical activity â rumination â depression (the mediating effect value: -0.076); physical activity â anxiety â depression (the mediating effect value: -0.052). Physical activity â rumination â anxiety â depression (the mediating effect value: -0.021). Conclusion: (1) Physical activity can negatively predict the rumination, anxiety, and depression of college students, which means physical activity can reduce rumination, anxiety, and depression of college students. (2) Physical activity can not only directly affect the depression of college students, but also indirectly affect depression through the independent intermediary role of rumination and anxiety, and the chain mediation of rumination and anxiety.
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Aging is usually considered a key risk factor associated with multiple diseases, such as neurodegenerative diseases, cardiovascular diseases and cancer. Furthermore, the burden of age-related diseases has become a global challenge. It is of great significance to search for drugs to extend lifespan and healthspan. Cannabidiol (CBD), a natural nontoxic phytocannabinoid, has been regarded as a potential candidate drug for antiaging. An increasing number of studies have suggested that CBD could benefit healthy longevity. Herein, we summarized the effect of CBD on aging and analyzed the possible mechanism. All these conclusions may provide a perspective for further study of CBD on aging.