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Defects in the mitochondrial tRNA genes cause a group of highly clinically and genetically heterogeneous disorders, which poses a challenge for clinical identification and genetic diagnosis. Here, we present a pre-school boy with a novel MT-TD variant m.7560T>C at the heteroplasmy level of 76.53% in blood, 93.34% in urine sediments, and absent in the healthy mother's blood and urine. Besides convulsions, brain magnetic resonance imaging abnormalities and high plasma lactate, the boy presented with the prominent extra-neurologic phenotype including steroid-resistant nephrotic syndrome associated with focal segmental glomerulosclerosis characterized by abnormal mitochondria in podocytes, cortical blindness, and pancreatitis. To our knowledge, this is the unique case with MT-TD m.7560T>C-related multi-organ impairments, which expands the phenotypic and mutational spectrum of primary mitochondrial diseases.
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Primary coenzyme Q10 deficiency-1, caused by COQ2 disease-causing variants, is an autosomal recessive disorder, and genetic testing is the gold standard for diagnosing this condition. A Chinese boy with steroid-resistant nephrotic syndrome, focal segmental glomerulosclerosis, and progressive kidney insufficiency was included in the study. Electron microscopy revealed the glomerular basement membrane with irregular thickness and lamellation with diffuse effacement of foot processes in the podocytes, and swollen mitochondria with abnormal cristae in the podocytes. Coenzyme Q10 supplementation started about 3 weeks after the onset of mild kidney dysfunction did not improve the proband's kidney outcome. Proband-only whole-exome sequencing and Sanger sequencing revealed two heteroallelic COQ2 variants: a maternally inherited novel variant c.1013G > A[p.(Gly338Glu)] in exon 6 and a variant of unknown origin c.1159C > T[p.(Arg387*)] in exon 7. Subsequent long-read sequencing demonstrated these two variants were located on different alleles. Our report extends the phenotypic and genotypic spectrum of COQ2 glomerulopathy.
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Membrana Basal Glomerular , Glomeruloesclerosis Focal y Segmentaria , Síndrome Nefrótico , Ubiquinona , Humanos , Masculino , Síndrome Nefrótico/genética , Glomeruloesclerosis Focal y Segmentaria/genética , Glomeruloesclerosis Focal y Segmentaria/patología , Membrana Basal Glomerular/ultraestructura , Membrana Basal Glomerular/patología , Ubiquinona/análogos & derivados , Ubiquinona/deficiencia , Fenotipo , Predisposición Genética a la Enfermedad , Ataxia/genética , Secuenciación del Exoma , Debilidad Muscular/genética , Biopsia , Mutación , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/patología , Transferasas Alquil y ArilRESUMEN
Triple-negative breast cancer (TNBC) is the most aggressive and lethal clinical subtype and lacks effective targeted therapies at present. Isobavachalcone (IBC), the main active component of Psoralea corylifolia L., has potential anticancer effects. Herein, we identified IBC as a natural sirtuin 2 (SIRT2) inhibitor and characterized the potential mechanisms underlying the inhibition of TNBC. Molecular dynamics analysis, enzyme activity assay, and cellular thermal shift assay were performed to evaluate the combination of IBC and SIRT2. The therapeutic effects, mechanism, and safety of IBC were analyzed in vitro and in vivo using cellular and xenograft models. IBC effectively inhibited SIRT2 enzyme activity with an IC50 value of 0.84 ± 0.22 µM by forming hydrogen bonds with VAL233 and ALA135 within its catalytic domain. In the cellular environment, IBC bound to and stabilized SIRT2, consequently inhibiting cellular proliferation and migration, and inducing apoptosis and cell cycle arrest by disrupting the SIRT2/α-tubulin interaction and inhibiting the downstream Snail/MMP and STAT3/c-Myc pathways. In the in vivo model, 30 mg/kg IBC markedly inhibited tumor growth by targeting the SIRT2/α-tubulin interaction. Furthermore, IBC exerted its effects by inducing apoptosis in tumor tissues and was well-tolerated. IBC alleviated TNBC by targeting SIRT2 and triggering the reactive oxygen species ROS/ß-catenin/CDK2 axis. It is a promising natural lead compound for future development of SIRT2-targeting drugs.
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Chalconas , Sirtuina 2 , Neoplasias de la Mama Triple Negativas , Humanos , Sirtuina 2/farmacología , Línea Celular Tumoral , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Tubulina (Proteína)/farmacología , Tubulina (Proteína)/uso terapéutico , Proliferación Celular , ApoptosisRESUMEN
BACKGROUND: Late-onset oligomeganephronia (OMN) is a rare chronic kidney disease and has no quantitative criteria for diagnosis yet. The current study aimed to explore its clinicopathological features by histomorphometric analysis. METHODS: We retrospectively re-reviewed all patients with enlarged and sparse glomeruli by light microscopy at Peking University First Hospital from 2012 to 2021, excluding those with any factor known to contribute to similar changes. Age- and sex-matched patients with thin basement membrane nephropathy were selected as control to establish the cut-off values for glomerulomegaly and rarity. Late-onset OMN cases were then confirmed and the clinicopathological characteristics were summarized. RESULTS: Mean diameter and density of cortical glomeruli in control was 156.53 ± 27.50 µm and 4.07 ± 0.63 /mm2, giving a lower limit of 211.53 µm for glomerulomegaly and an upper of 2.81 /mm2 for rarity. Seven adults of three females and four males were finally diagnosed as late-onset OMN with a mean age of 26.57 years. They showed mild to moderate proteinuria and/or renal dysfunction at biopsy with the mean proteinuria, serum creatinine (Scr) level, and estimated glomerular filtration rate of 0.50 g/d (0.10-0.95 g/d), 140.9 µmol/L (95.1-227.1 µmol/L), and 58.7 mL/min/1.73m2 (21.3-98.0 mL/min/1.73m2), respectively. Four patients (57.1%) had normal Scr at diagnosis. Six patients with available data showed renal tubular injury with increased urinary microalbumin in all, elevated N-acetyl-ß-glucosaminidase in two, and elevated α1 microglobulin in five. Kidney size was normal or slightly reduced. The mean density and glomerular diameter of the seven cases was 0.86 mm2 (0.55-1.41 /mm2) and 229.73 µm (211.88-260.66 µm). Segmental glomerular sclerosis was observed in six (85.7%) with four (66.7%) of perihilar type. Proximal tubule dilation was observed in all, focal to diffuse, lining with enlarged epithelial cells. The mean foot process width was 634.02 nm, wider than 472.54 nm of the control (P = 0.0002). CONCLUSION: Late-onset OMN should be considered a special entity with relatively slow clinical progress characterized by hypertrophy of the sparsely distributed nephron.
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Glomeruloesclerosis Focal y Segmentaria , Insuficiencia Renal Crónica , Masculino , Adulto , Femenino , Humanos , Estudios Retrospectivos , Riñón/patología , Glomeruloesclerosis Focal y Segmentaria/patología , ProteinuriaRESUMEN
Salvia miltiorrhiza Bunge (Danshen) has been widely used to treat cancer and cardiovascular diseases in Chinese traditional medicine. Here, we found that Neoprzewaquinone A (NEO), an active component of S. miltiorrhiza, selectively inhibits PIM1. We showed that NEO potently inhibits PIM1 kinase at nanomolar concentrations and significantly suppresses the growth, migration, and Epithelial-Mesenchymal Transition (EMT) in the triple-negative breast cancer cell line, MDA-MB-231 in vitro. Molecular docking simulations revealed that NEO enters the PIM1 pocket, thereby triggering multiple interaction effects. Western blot analysis revealed that both NEO and SGI-1776 (a specific PIM1 inhibitor), inhibited ROCK2/STAT3 signaling in MDA-MB-231 cells, indicating that PIM1 kinase modulates cell migration and EMT via ROCK2 signaling. Recent studies indicated that ROCK2 plays a key role in smooth muscle contraction, and that ROCK2 inhibitors effectively control the symptoms of high intraocular pressure (IOP) in glaucoma patients. Here, we showed that NEO and SGI-1776 significantly reduce IOP in normal rabbits and relax pre-restrained thoracic aortic rings in rats. Taken together, our findings indicated that NEO inhibits TNBC cell migration and relaxes smooth muscles mainly by targeting PIM1 and inhibiting ROCK2/STAT3 signaling, and that PIM1 may be an effective target for IOP and other circulatory diseases.
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Enfermedades Cardiovasculares , Neoplasias de la Mama Triple Negativas , Humanos , Ratas , Animales , Conejos , Simulación del Acoplamiento Molecular , Línea Celular Tumoral , Relajación Muscular , Transición Epitelial-Mesenquimal , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/metabolismo , Movimiento Celular , Proliferación Celular , Proteínas Proto-Oncogénicas c-pim-1/metabolismo , Factor de Transcripción STAT3/metabolismo , Quinasas Asociadas a rho/metabolismoRESUMEN
BACKGROUND: Peripartum depression in and after pregnancy are common, reported by 11.9% of women worldwide, and the proportion was even higher during the outbreak of coronavirus disease 2019 (COVID-19). We aimed to investigate the prevalence and risk factors of peripartum depression under the influence of COVID-19 in China. METHODS: Using a cross-sectional design, 2026 pregnant and postpartum women residing in Beijing, Wuhan, and Lanzhou of China were recruited from February 28 to April 9, 2020. The Patient Health Questionnaire-9 was used to assess their depressive symptoms. The women were divided into four subgroups based on pregnancy stage, and a binary logistic regression analysis was conducted on each subgroup. RESULTS: Under the influence of COVID-19, the prevalence rate of peripartum depression among Chinese women was 9.7%. It was 13.6, 10.8, 7.9 and 7.3% in the first, second, third trimester and puerperium, respectively. Regression analysis showed that the influence of current pregnancy status on movement (Mild vs. No, aORs were 3.89, P < 0.001, 2.92, P = 0.003, 1.58, P = 0.150 in the three trimesters, respectively; Severe vs. No, aORs were 13.00, 20.45, 5.38 in the three trimesters, respectively, all P < 0.05), and worries and fears about childbirth (aORs were 2.46, 2.96, 2.50 in the three trimesters, respectively, all P < 0.05) were associated with depression throughout pregnancy. CONCLUSIONS: The prevalence rate of peripartum depression during the COVID-19 outbreak in China was not higher than usual. The influence of current pregnancy status on movement, as well as worries and fears about childbirth were independent risk factors for peripartum depression throughout pregnancy during COVID-19. The stage of pregnancy should be considered when implementing interventions.
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COVID-19/psicología , Depresión/epidemiología , Periodo Periparto/psicología , China/epidemiología , Estudios Transversales , Femenino , Humanos , Cuestionario de Salud del Paciente , Periodo Posparto/psicología , Embarazo , Trimestres del Embarazo/psicología , Prevalencia , Factores de Riesgo , SARS-CoV-2RESUMEN
Ibrutinib has potential therapeutic or protective effects against viral- and bacterial-induced acute lung injury (ALI), likely by modulating the Bruton tyrosine kinase (BTK) signaling pathway. However, ibrutinib has multi-target effects. Moreover, immunity and inflammation targets in ALI treatment are poorly defined. We investigated whether the BTK-, FLT3-, and EGFR-related signaling pathways mediated the protective effects of ibrutinib on ALI. The intratracheal administration of poly I:C or LPS after ibrutinib administration in mice was performed by gavage. The pathological conditions of the lungs were assessed by micro-CT and HE staining. The levels of neutrophils, lymphocytes, and related inflammatory factors in the lungs were evaluated by ELISA, flow cytometry, immunohistochemistry, and immunofluorescence. Finally, the expression of proteins associated with the BTK-, FLT3-, and EGFR-related signaling pathways were evaluated by Western blotting. Ibrutinib (10 mg/kg) protected against poly I:C-induced (5 mg/kg) and LPS-induced (5 mg/kg) lung inflammation. The wet/dry weight ratio (W/D) and total proteins in the bronchoalveolar lavage fluid (BALF) were markedly reduced after ibrutinib (10 mg/kg) treatment, relative to the poly I:C- and LPS-treated groups. The levels of ALI indicators (NFκB, IL-1ß, IL-6, TNF-α, IFN-γ, neutrophils, and lymphocytes) were significantly reduced after treatment. Accordingly, ibrutinib inhibited the poly I:C- and LPS-induced BTK-, FLT3-, and EGFR-related pathway activations. Ibrutinib inhibited poly I:C- and LPS-induced acute lung injury, and this may be due to its ability to suppress the BTK-, FLT3-, and EGFR-related signaling pathways. Therefore, ibrutinib is a potential protective agent for regulating immunity and inflammation in poly I:C- and LPS-induced ALI.
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Lesión Pulmonar Aguda , Lipopolisacáridos , Animales , Ratones , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/metabolismo , Agammaglobulinemia Tirosina Quinasa/metabolismo , Líquido del Lavado Bronquioalveolar , Receptores ErbB/metabolismo , Inflamación/patología , Pulmón/patología , FN-kappa B/metabolismo , Poli I/metabolismo , Poli I/farmacología , Poli I/uso terapéuticoRESUMEN
BACKGROUND: Concerning viral pneumonia, few large-scale comparative studies have been published describing non-HIV immunocompromised and immunocompetent patients, but the epidemiological characteristics of different viruses or underlying diseases in immunocompromised hosts are lacking. METHODS: We retrospectively recruited patients hospitalised with viral pneumonia from six academic hospitals in China between August 2016 and December 2019. We measured the prevalence of comorbidities, coinfections, nosocomial infections, and in-hospital mortalities. RESULTS: Of the 806 patients, 370 were immunocompromised and 436 were immunocompetent. The disease severity and in-hospital mortality of immunocompromised patients were higher than those of immunocompetent patients. During the influenza season, an increased number of cases of influenza virus (IFV) infection were found in the immunocompromised group, followed by cases of cytomegalovirus (CMV) and respiratory syncytial virus (RSV) infection. During the non-influenza season, CMV was the main virus detected in the immunocompromised group, while RSV, adenovirus (AdV), parainfluenza virus (PIV), and rhinovirus (HRV) were the main viruses detected in the immunocompetent group. Pneumonia caused by Pneumocystis jirovecii (22.4%), Aspergillus spp. (14.1%), and bacteria (13.8%) were the most frequently observed coinfections in immunocompromised patients but not in immunocompetent patients (Aspergillus spp. [10.8%], bacteria [7.1%], and Mycoplasma spp. [5.3%]). CMV infection and infection with two-or-more viruses were associated with a higher in-hospital mortality rate than non-IFV infection. However, patients with IFV and non-IFV infection in immunocompromised patients had similar disease severity and prognosis. CONCLUSIONS: Immunocompromised patients have a high frequency of coinfections, and a higher mortality rate was observed among those infected with CMV and two-or-more viruses. In addition, patients with IFV and non-IFV infection in immunocompromised patients had similar same disease severity and prognosis. The type of viral infection varied with seasons.
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Neumonía Viral , Infecciones del Sistema Respiratorio , Virosis , Humanos , Huésped Inmunocomprometido , Estudios RetrospectivosRESUMEN
BACKGROUND: The toxicity and inefficient delivery of triptolide (TPL) in tumor therapy have greatly limited the clinical application. Thus, we fabricated a CD44-targeting and tumor microenvironment pH/redox-sensitive nanosystem composed of hyaluronic acid-vitamin E succinate and poly (ß-amino esters) (PBAEss) polymers to enhance the TPL-mediated suppression of breast cancer proliferation and lung metastasis. RESULTS: The generated TPL nanoparticles (NPs) had high drug loading efficiency (94.93% ± 2.1%) and a desirable average size (191 nm). Mediated by the PBAEss core, TPL/NPs displayed a pH/redox-dual-stimuli-responsive drug release profile in vitro. Based on the hyaluronic acid coating, TPL/NPs exhibited selective tumor cellular uptake and high tumor tissue accumulation capacity by targeting CD44. Consequently, TPL/NPs induced higher suppression of cell proliferation, blockage of proapoptotic and cell cycle activities, and strong inhibition of cell migration and invasion than that induced by free TPL in MCF-7 and MDA-MB-231 cells. Importantly, TPL/NPs also showed higher efficacy in shrinking tumor size and blocking lung metastasis with decreased systemic toxicity in a 4T1 breast cancer mouse model at an equivalent or lower TPL dosage compared with that of free TPL. Histological immunofluorescence and immunohistochemical analyses in tumor and lung tissue revealed that TPL/NPs induced a high level of apoptosis and suppressed expression of matrix metalloproteinases, which contributed to inhibiting tumor growth and pulmonary metastasis. CONCLUSION: Collectively, our results demonstrate that TPL/NPs, which combine tumor active targeting and pH/redox-responsive drug release with proapoptotic and antimobility effects, represent a promising candidate in halting breast cancer progression and metastasis while minimizing systemic toxicity.
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Neoplasias de la Mama/tratamiento farmacológico , Diterpenos/química , Compuestos Epoxi/química , Receptores de Hialuranos/química , Neoplasias Pulmonares/tratamiento farmacológico , Nanopartículas/química , Fenantrenos/química , Animales , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular , Liberación de Fármacos , Femenino , Humanos , Ácido Hialurónico/farmacología , Concentración de Iones de Hidrógeno , Células MCF-7 , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Oxidación-Reducción , Cicatrización de HeridasRESUMEN
To study the relationship between clinical indexes and the severity of coronavirus disease 2019 (COVID-19), and to explore its role in predicting the severity of COVID-19. Clinical data of 443 patients with COVID-19 admitted to our hospital were retrospectively analyzed, which were divided into nonsevere group (n = 304) and severe group (n = 139) according to their condition. Clinical indicators were compared between different groups. The differences in sex, age, the proportion of patients with combined heart disease, leukocyte, neutrophil-to-lymphocyte ratio (NLR), neutrophil, lymphocyte, platelet, D-dimer, C-reactive protein (CRP), procalcitonin, lactate dehydrogenase, and albumin on admission between the two groups were statistically significant (P < .05). Multivariate logistic regression analysis showed NLR and CRP were independent risk factors for severe COVID-19. Platelets were independent protective factors for severe COVID-19. The receiver operating characteristic (ROC) curve analysis demonstrated area under the curve of NLR, platelet, CRP, and combination was 0.737, 0.634, 0.734, and 0.774, respectively. NLR, CRP, and platelets can effectively assess the severity of COVID-19, among which NLR is the best predictor of severe COVID-19, and the combination of three clinical indicators can further predict severe COVID-19.
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COVID-19/diagnóstico , Diabetes Mellitus/diagnóstico , Cardiopatías/diagnóstico , Hipertensión/diagnóstico , SARS-CoV-2/patogenicidad , Adulto , Anciano , Antivirales/uso terapéutico , Biomarcadores/sangre , Plaquetas/patología , Plaquetas/virología , Proteína C-Reactiva/metabolismo , COVID-19/sangre , COVID-19/fisiopatología , COVID-19/terapia , China , Comorbilidad , Diabetes Mellitus/sangre , Diabetes Mellitus/fisiopatología , Diabetes Mellitus/terapia , Femenino , Productos de Degradación de Fibrina-Fibrinógeno/metabolismo , Cardiopatías/sangre , Cardiopatías/fisiopatología , Cardiopatías/terapia , Humanos , Hipertensión/sangre , Hipertensión/fisiopatología , Hipertensión/terapia , Linfocitos/patología , Linfocitos/virología , Masculino , Persona de Mediana Edad , Neutrófilos/patología , Neutrófilos/virología , Polipéptido alfa Relacionado con Calcitonina/sangre , Curva ROC , Estudios Retrospectivos , Factores de Riesgo , SARS-CoV-2/efectos de los fármacos , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
BACKGROUND: Pediatric native kidney diseases are common worldwide. The pathological diagnosis of kidney lesions is crucial for clinical treatment and prognosis. The aim of the current study was therefore to evaluate the value of electron microscopy (EM) to the final diagnosis of native kidney biopsies in children. METHODS: A retrospective evaluation of 855 pediatric kidney biopsies obtained from the Department of Pediatrics in Peking University First Hospital between November 2010 and December 2017 was performed to assess the contribution of EM to the final diagnosis. RESULTS: The role of EM in the final diagnosis was determined to be crucial in 300 cases (35.1%), important in 280 cases (32.7%), and auxiliary in 275 cases (32.2%). EM is considered most valuable in a large percentage of glomerular diseases, mainly including minimal change disease, early-stage membranous nephropathy, postinfectious glomerulonephritis, Alport syndrome, thin basement membrane nephropathy, and thrombotic microangiopathy. EM also provided helpful diagnostic information in cases of focal segmental glomerulosclerosis, lupus nephritis, IgA nephropathy, and IgA vasculitis (Henoch-Schonlein purpura nephritis). Additionally, EM was crucial in 90.0% of cases of subtle pathological changes observed with light microscopy (LM) and immunofluorescence (IF) and in 69.3% of the IF-negative specimens. Patients with nephrotic syndrome or hematuria also benefit from ultrastructural examination. CONCLUSIONS: The present study demonstrated the crucial or important role of EM in the diagnosis of a majority of native kidney biopsies in children. The application of EM should be integrated together with LM and IF as a routine method of assessing pediatric kidney specimens. Graphical abstract.
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Biopsia/instrumentación , Enfermedades Renales/diagnóstico , Riñón/ultraestructura , Microscopía Electrónica , Adolescente , Biopsia/estadística & datos numéricos , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Enfermedades Renales/epidemiología , Enfermedades Renales/patología , Estudios Longitudinales , Masculino , Estudios RetrospectivosRESUMEN
Osteoarthritis (OA) is attributed to a reduction in chondrocytes within joint cartilage, and research has shown that endoplasmic reticulum (ER) stress and autophagy play important roles in the survival of chondrocytes. However, the relationship between ER stress and autophagy in chondrocytes remains unclear. In this study, we investigated the changes in apoptotic and autophagic activity in chondrocytes under ER stress. Following treatment with tunicamycin, the rate of apoptosis among chondrocytes increased. Western blot analysis showed the levels of unfolded protein response (UPR) related proteins increased, followed by elevated expression of light chain 3B-II (LC3B-II) and Beclin-1. An ultrastructural investigation showed that a large number of pre-autophagosomal structures or autophagosomes formed under tunicamycin treatment. However, the autophagy activity was significantly inhibited in chondrocytes after suppression of GRP78 by siRNA. The apoptosis ratio of chondrocytes pre-treated with 3-methyladenine was much higher than that of normal chondrocytes after exposure to tunicamycin. Our study revealed that the tunicamycin-induced persistent UPR expression led to apoptosis of chondrocytes and activation of autophagy incorporation with GRP78. Blocking autophagy accelerated the apoptosis induced by ER stress, which confirmed the protective function of autophagy in the homeostasis of chondrocytes. These findings advance our understanding of chondrocyte apoptosis and provide potential molecular targets for preventing apoptotic death of chondrocytes.
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Autofagia , Condrocitos/patología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Tunicamicina/farmacología , Adenina/análogos & derivados , Adenina/farmacología , Animales , Apoptosis/efectos de los fármacos , Autofagosomas/efectos de los fármacos , Autofagosomas/metabolismo , Autofagosomas/ultraestructura , Autofagia/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Condrocitos/efectos de los fármacos , Condrocitos/ultraestructura , Chaperón BiP del Retículo Endoplásmico , Proteínas de Choque Térmico/metabolismo , Masculino , ARN Interferente Pequeño/metabolismo , Ratas Sprague-Dawley , Respuesta de Proteína Desplegada/efectos de los fármacosRESUMEN
Cordycepin is the major bioactive component extracted from Cordyceps militaris. In recent years, cordycepin has received increasing attention owing to its multiple pharmacological activities. This study reviews recent researches on the anti-inflammatory effects and the related activities of cordycepin. The results from our review indicate that cordycepin exerts protective effects against inflammatory injury for many diseases including acute lung injury (ALI), asthma, rheumatoid arthritis, Parkinson's disease (PD), hepatitis, atherosclerosis, and atopic dermatitis. Cordycepin regulates the NF-κB, RIP2/Caspase-1, Akt/GSK-3ß/p70S6K, TGF-ß/Smads, and Nrf2/HO-1 signaling pathways among others. Several studies focusing on cordycepin derivatives were reviewed and found to down metabolic velocity of cordycepin and increase its bioavailability. Moreover, cordycepin enhanced immunity, inhibited the proliferation of viral RNA, and suppressed cytokine storms, thereby suggesting its potential to treat COVID-19 and other viral infections. From the collected and reviewed information, this article provides the theoretical basis for the clinical applications of cordycepin and discusses the path for future studies focusing on expanding the medicinal use of cordycepin. Taken together, cordycepin and its analogs show great potential as the next new class of anti-inflammatory agents.
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RATIONALE & OBJECTIVE: Renal arteriolar microangiopathic lesions may occur in immunoglobulin A nephropathy (IgAN), but their role in disease progression remains unclear. We sought to understand the prevalence and character of microangiopathic lesions in IgAN and their role in disease progression. STUDY DESIGN: A retrospective cohort study. SETTING & PARTICIPANTS: In this study, we enrolled a Chinese cohort with 944 adult patients with IgAN who had been followed up for at least 1 year. PREDICTORS: Renal arteriolar microangiopathic lesions. OUTCOMES: Composite kidney end point event defined as a>50% reduction in estimated glomerular filtration rate, end-stage kidney disease, or death. ANALYTICAL APPROACH: All kidney biopsies were independently reviewed by 2 investigators. Renal arteriolar microangiopathic lesions were detected using light microscopy. Multivariable Cox regression analysis was used to test the association between microangiopathic lesions and the outcomes. RESULTS: Overall, 194 (20.6%) patients had renal arteriolar microangiopathic lesions. Patients with microangiopathic lesions presented with higher blood pressures, more severe proteinuria, and lower estimated glomerular filtration rates (all P<0.001) than patients without microangiopathic lesions. After a median follow-up of 4.2 years, 75 (38.7%) patients with microangiopathic lesions and 83 (11.1%) patients without these lesions reached the composite kidney end point (P<0.001). In a multivariable Cox regression model adjusting for clinical and pathologic variables available at the time of biopsy, the presence of microangiopathic lesions was an independent risk factor for kidney failure (HR, 1.95; 95% CI, 1.34-2.83; P<0.001). Renal vascular sclerosis (arterial intimal fibrosis or arteriolar hyalinosis) was not a risk factor for kidney disease progression (P = 0.5). LIMITATIONS: A single Chinese center's experience, retrospective study, most patients were not tested for hemolytic markers (for example, haptoglobin level, lactate dehydrogenase level, and schistocytes). CONCLUSIONS: Renal arteriolar microangiopathic lesions are frequent in IgAN and their presence is independently associated with progression to kidney failure. If confirmed in other patient cohorts, such lesions could be considered for inclusion in formal classification schemes of IgAN.
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Arteriolas/patología , Glomerulonefritis por IGA/patología , Riñón/irrigación sanguínea , Arteria Renal/patología , Adulto , Biopsia , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular , Glomerulonefritis por IGA/fisiopatología , Humanos , Riñón/patología , Masculino , Microscopía Fluorescente , Estudios Retrospectivos , Factores de TiempoRESUMEN
Stress wave-based communication has great potential for succeeding in subsea environments where many conventional methods would otherwise face excessive difficulty, and it can benefit logging well by using the drill string as a conduit for stress wave propagation. To achieve stress wave communication, a new stress wave-based pulse position modulation (PPM) communication system is designed and implemented to transmit data through pipeline structures with the help of piezoceramic transducers. This system consists of both hardware and software components. The hardware is composed of a piezoceramic transducer that can generate powerful stress waves travelling along a pipeline, upon touching, and a PPM signal generator that drives the piezoceramic transducer. Once the transducer is in contact with a pipeline surface, the generator integrated with an amplifier is utilized to excite the piezoceramic transducer with a voltage signal that is modulated to encode the information. The resulting vibrations of the transducer generates stress waves that propagate throughout the pipeline. Meanwhile, piezoceramic sensors mounted on the pipeline convert the stress waves to electric signals and the signal can be demodulated. In order to enable the encoding and decoding of information in the stress wave, a PPM-based communication protocol was integrated into the software system. A verification experiment demonstrates the functionality of the developed system for stress wave communication using piezoceramic transducers and the result shows that the data transmission speed of this new communication system can reach 67 bits per second (bps).
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Calpastatin is an endogenous specific inhibitor of calpain, a calcium-dependent cysteine protease. Here we show that loss-of-function mutations in calpastatin (CAST) are the genetic causes of an autosomal-recessive condition characterized by generalized peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads, which we propose to be given the acronym PLACK syndrome. In affected individuals with PLACK syndrome from three families of different ethnicities, we identified homozygous mutations (c.607dup, c.424A>T, and c.1750delG) in CAST, all of which were predicted to encode truncated proteins (p.Ile203Asnfs∗8, p.Lys142∗, and p.Val584Trpfs∗37). Immunohistochemistry shows that staining of calpastatin is reduced in skin from affected individuals. Transmission electron microscopy revealed widening of intercellular spaces with chromatin condensation and margination in the upper stratum spinosum in lesional skin, suggesting impaired intercellular adhesion as well as keratinocyte apoptosis. A significant increase of apoptotic keratinocytes was also observed in TUNEL assays. In vitro studies utilizing siRNA-mediated CAST knockdown revealed a role for calpastatin in keratinocyte adhesion. In summary, we describe PLACK syndrome, as a clinical entity of defective epidermal adhesion, caused by loss-of-function mutations in CAST.
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Proteínas de Unión al Calcio/genética , Queilitis/genética , Queratosis/genética , Mutación , Enfermedades de la Uña/genética , Enfermedades de la Piel/genética , Adulto , Apoptosis/genética , Proteínas de Unión al Calcio/metabolismo , Adhesión Celular/genética , Epidermis/metabolismo , Femenino , Homocigoto , Humanos , Etiquetado Corte-Fin in Situ , Queratinocitos , Masculino , Persona de Mediana Edad , Linaje , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Piel/patologíaRESUMEN
OBJECTIVE: More recent studies suggested that defects in autophagy contribute to the pathogenesis of SLE, especially in adaptive immunity. Occurrence and progression of lupus nephritis (LN) is the end result of complex interactions between regulation of immune responses and pathological process by renal resident cells, but there is still a lot of missing information for an establishment on the role of autophagy in pathogenesis of LN and as a therapy target. METHODS: Systemic and organ-specific aetiologies of autophagy were first evaluated by autophagy protein quantification in tissue homogenates in MRL lpr/lpr lupus prone and female C57BL mice. Analysis of gene expression was also adopted in human blood and urine sediments. Then, some key mediators of the disease, including complement inactivated serum, IgG from patients with LN (IgG-LN) and interferon (IFN)-α were chosen to induce podocyte autophagy. Podocyte injuries including apoptosis, podocin derangement, albumin filtration and wound healing were monitored simultaneously with autophagy steady-state and flux. RESULTS: Elevated LC3B in kidney homogenates and increased autophagosomes in podocyte from MRL lpr/lpr were observed. In humans, mRNA levels of some key autophagy genes were increased in blood and urinary sediments, and podocyte autophagosomes were observed in renal biopsies from patients with LN. Complement inactivated serum, IgG-LN and IFN-α could induce podocyte autophagy in a time-dependent and dosage-dependent manner, and by reactive oxygen species production and mTORC1 inhibition, respectively. Autophagy inhibition aggravated podocyte damage whereas its inducer relieved the injury. CONCLUSION: Podocyte autophagy is activated in lupus-prone mice and patients with lupus nephritis. Increased autophagy is cytoprotective against antibody and interferon-α induced podocyte injury.
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Autofagia/fisiología , Nefritis Lúpica/patología , Podocitos/patología , Animales , Autoanticuerpos/inmunología , Femenino , Humanos , Interferón-alfa/inmunología , Nefritis Lúpica/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos MRL lprRESUMEN
BACKGROUND/AIMS: The molecules involved in nephrotic syndrome (NS) have not been fully clarified. Mitochondrial fission proteins are found to be involved in podocyte injury in vitro. Increased glomerular expression of mitochondrial fission proteins was found in adriamycin nephropathy in our previous study. Whether or not mitochondrial fission proteins are involved in podocyte injury in NS is not clear. This study explored the glomerular expression and possible pathological significance of mitochondrial fission-associated proteins, including dynamin-related protein 1 (Drp1) and mitochondrial fission protein 1 (Fis1), in children with NS. METHODS: Eighteen children with primary NS, including 6 with minimal change disease, 6 with focal segmental glomerulosclerosis, 6 with membranous nephropathy, 6 children with isolated haematuria and 3 normal controls were included. The glomerular expression of Drp1, phospho-Drp1 (Ser616) and Fis1, urinary protein measurements, and podocyte mitochondrial density under electron microscopy were investigated and compared. RESULTS: Glomerular expression of Drp1, phospho-Drp1 (Ser616) and Fis1 was mainly increased in children with NS with membranous nephropathy. No relationship was found between glomerular expression of Drp1, phospho-Drp1 (Ser616) and Fis1 and podocyte mitochondrial density or urinary protein measurements. CONCLUSION: Glomerular overproduction of Drp1, phospho-Drp1 (Ser 616) and Fis1 occurred mainly in children with membranous nephropathy. The pathological significance deserves further investigation.
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GTP Fosfohidrolasas/metabolismo , Glomerulonefritis Membranosa/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Proteínas Mitocondriales/metabolismo , Adolescente , Niño , Preescolar , Dinaminas , Humanos , Glomérulos Renales/metabolismo , Dinámicas Mitocondriales , Podocitos/metabolismo , Podocitos/ultraestructuraRESUMEN
BACKGROUND: The mechanism of podocyte apoptosis is not fully understood. In addition, the role of the inositol 1,4,5-triphosphate receptor (IP3R)/glucose-regulated protein 75 (Grp75)/voltage-dependent anion channel 1 (VDAC1)/mitochondrial calcium uniporter (MCU) calcium regulation axis, which is located at sites of endoplasmic reticulum (ER) mitochondria coupling, in the mechanism of podocyte apoptosis is unclear. This study aimed to understand the roles of this axis in podocyte apoptosis and explore potential targets for podocyte protection. METHODS: The expression of IP3R, Grp75, VDAC1, and MCU and mitochondrial Ca2+ were analyzed during Adriamycin- or angiotensin II-induced apoptosis in cultured mouse podocytes. The interaction between IP3R, Grp75, and VDAC1 was investigated using co-immunoprecipitation experiments. The effects of IP3R, Grp75, and MCU agonists and antagonists on mitochondrial Ca2+ and apoptosis were investigated in cultured podocytes. The podocyte-protective effects of an MCU inhibitor were further investigated in rats with Adriamycin-induced nephropathy. RESULTS: Increased expression of IP3R, Grp75, VDAC1 and MCU, enhanced interaction among the IP3R-Grp75-VDAC1 complex, mitochondrial Ca2+ overload, and increased active caspase-3 levels were confirmed during Adriamycin- or angiotensin II-induced mouse podocyte apoptosis. Agonists of this axis facilitated mitochondrial Ca2+ overload and podocyte apoptosis, whereas specific antagonists against IP3R, Grp75, or MCU prevented mitochondrial Ca2+ overload and podocyte apoptosis. A specific MCU inhibitor prevented Adriamycin-induced proteinuria and podocyte foot process effacement in rats. CONCLUSIONS: This study identified a novel pathway in which the IP3R-Grp75-VDAC1-MCU calcium regulation axis mediated podocyte apoptosis by facilitating mitochondrial Ca2+ overload. Antagonists that inhibit Ca2+ transfer from ER to mitochondria protected mouse podocytes from apoptosis. An MCU inhibitor protected podocytes and decreased proteinuria in rats with Adriamycin-induced nephropathy. Therefore, antagonists to this pathway have promise as novel podocyte-protective drugs.
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Calcio/fisiología , Doxorrubicina/toxicidad , Enfermedades Renales/metabolismo , Compuestos Macrocíclicos/farmacología , Oxazoles/farmacología , Podocitos/metabolismo , Proteinuria/metabolismo , Adenosilhomocisteinasa/antagonistas & inhibidores , Adenosilhomocisteinasa/biosíntesis , Animales , Antibióticos Antineoplásicos/toxicidad , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Canales de Calcio/biosíntesis , Células Cultivadas , Retículo Endoplásmico/efectos de los fármacos , Retículo Endoplásmico/metabolismo , Proteínas HSP70 de Choque Térmico/antagonistas & inhibidores , Proteínas HSP70 de Choque Térmico/biosíntesis , Enfermedades Renales/inducido químicamente , Enfermedades Renales/tratamiento farmacológico , Compuestos Macrocíclicos/uso terapéutico , Masculino , Proteínas de la Membrana/antagonistas & inhibidores , Proteínas de la Membrana/biosíntesis , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Oxazoles/uso terapéutico , Podocitos/efectos de los fármacos , Proteinuria/tratamiento farmacológico , Ratas , Ratas Sprague-Dawley , Canal Aniónico 1 Dependiente del Voltaje/antagonistas & inhibidores , Canal Aniónico 1 Dependiente del Voltaje/biosíntesisRESUMEN
Keratoderma-hypotrichosis-leukonychia totalis syndrome (KHLS) is an extremely rare, autosomal-dominant disorder characterized by severe skin hyperkeratosis, congenital alopecia and leukonychia totalis. The genetic defect underlying KHLS remained undetermined. By performing whole-exome sequencing in a family with KHLS, we identified a heterozygous mutation (c.23G>T [p.Gly8Val]) in GJA1, which cosegregated with the phenotype in the family. In an additional affected individual, we also found the identical de novo mutation which was absent in his unaffected family members. GJA1 encodes a gap junction protein connexin 43 (Cx43) which is ubiquitously expressed in various organs, including the epidermis and hair follicles. In vitro studies on HEK293 cells expressing Cx43(Gly8Val) found that the protein formed gap junction plaques between adjacent transfected cells, as observed in the wild-type. Dye-transfer experiments by microinjection of Lucifer yellow displayed functional gap junction of the Cx43(Gly8Val) mutant. Using patch clamp and Ca(2+) imaging methods, we observed that the Cx43(Gly8Val) hemichannel had significantly more openings than Cx43(WT), facilitating Ca(2+) influx at resting potential. Such gain-of-function effect might result in cytoplasmic Ca(2+) overload, accelerated apoptosis of keratinocytes and subsequent skin hyperkeratosis. Taken together, our results demonstrated that, with probably enhanced hemichannel activities, a mutation in GJA1 is linked to KHLS without extracutaneous involvement.