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BACKGROUND: Despite endothelial dysfunction being an initial step in the development of hypertension and associated cardiovascular/renal injuries, effective therapeutic strategies to prevent endothelial dysfunction are still lacking. GPR183 (G protein-coupled receptor 183), a recently identified G protein-coupled receptor for oxysterols and hydroxylated metabolites of cholesterol, has pleiotropic roles in lipid metabolism and immune responses. However, the role of GPR183 in the regulation of endothelial function remains unknown. METHODS: Endothelial-specific GPR183 knockout mice were generated and used to examine the role of GPR183 in endothelial senescence by establishing 2 independent hypertension models: desoxycorticosterone acetate/salt-induced and Ang II (angiotensin II)-induced hypertensive mice. Echocardiography, transmission electron microscopy, blood pressure measurement, vasorelaxation response experiments, flow cytometry analysis, and chromatin immunoprecipitation analysis were performed in this study. RESULTS: Endothelial GPR183 was significantly induced in hypertensive mice, which was further confirmed in renal biopsies from subjects with hypertensive nephropathy. Endothelial-specific deficiency of GPR183 markedly alleviated cardiovascular and renal injuries in hypertensive mice. Moreover, we found that GPR183 regulated endothelial senescence in both hypertensive mice and aged mice. Mechanistically, GPR183 disrupted circadian signaling by inhibiting PER1 (period 1) expression, thereby facilitating endothelial senescence and dysfunction through the cAMP/PKA (protein kinase A)/CREB (cAMP-response element binding protein) signaling pathway. Importantly, pharmacological inhibition of the oxysterol-GPR183 axis by NIBR189 or clotrimazole ameliorated endothelial senescence and cardiovascular/renal injuries in hypertensive mice. CONCLUSIONS: This study discovers a previously unrecognized role of GPR183 in promoting endothelial senescence. Pharmacological targeting of GPR183 may be an innovative therapeutic strategy for hypertension and its associated complications.
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BACKGROUND: Data on pyogenic liver abscess (PLA) of children in China have been limited. We aimed to summarize the clinical feather, microbiological characteristics, management, and outcome of PLA in children. METHOD: We retrospectively reviewed PLA cases from January 2008 to June 2023 at Beijing Children's Hospital. Clinical characteristics, pathogens and management were analyzed. RESULTS: We diagnosed 57 PLA patients in our center. The median onset age was 4.5 years and the male-to-female ratio was 1.6:1. The median diagnostic time was nine days and the median length of stay was 22 days. Twenty-eight patients (49.1%) had predisposing factors, around 71.4% of the patients had malignant hematology and primary immunodeficiency disease. Patients with underlying factors were more likely to have extrahepatic organ involvement (p = 0.024), anemia (p < 0.001), single abscess (p = 0.042), unilateral involvement (p = 0.039), and small size of the abscess (p = 0.008). Twenty-four patients (42.1%) had extrahepatic organ involvement. Pathogens were identified in 17 patients (29.8%), the most common pathogens were Klebsiella pneumoniae and Staphylococcus aureus. The positive rate of metagenomic next-generation sequencing (mNGS) was 87.5% (7/8). On multivariable analysis, the extrahepatic organ involved (p = 0.029) and hepatomegaly (p = 0.025) were two independent factors associated with poor outcomes. CONCLUSIONS: PLA is usually seen in children with predisposing factors. Malignant hematology and primary immunodeficiency disease were the most common underlying diseases. Extrahepatic organ involvement and hepatomegaly are associated with poor prognosis. Increased use of mNGS could be beneficial for identifying pathogens.
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Absceso Piógeno Hepático , Humanos , Absceso Piógeno Hepático/microbiología , Absceso Piógeno Hepático/epidemiología , Masculino , Femenino , Estudios Retrospectivos , Preescolar , Niño , Lactante , Beijing/epidemiología , Adolescente , Klebsiella pneumoniae/aislamiento & purificación , Antibacterianos/uso terapéutico , Factores de Riesgo , Staphylococcus aureus/aislamiento & purificaciónRESUMEN
Seaweed waste, abundant and rich in plant-stimulating properties, has the potential to be transformed into valuable soil amendments through proper composting and utilization management. Given its low carbon-to-nitrogen ratio, co-composting seaweed with carbon-rich cornstarch dregs is an effective strategy. However, the potential application of co-composting largely depends on the efficiency of the composting and the quality of the product. This study explores the effects of adding 10 % corn stalk biochar to a co-composting system of seaweed and cornstarch dregs, alongside varying buffering capacities of phosphates (KH2PO4 and K2HPO4·3H2O-KH2PO4) and MgO, on the degradation efficiency of organic matter, nitrogen transformation, and humification. The results indicate that the addition of biochar and salts enhances the oxygen utilization rate (OUR) and cellulase activity during the thermophilic phase. Additionally, X-ray diffraction (XRD) and parallel factor analysis (PARAFAC) demonstrate more intense solubilization and transformation of proteinaceous substances, along with cellulose degradation. These processes are crucial for enhancing organic matter degradation and humification, significantly boosting degradation (with an increase of 28.6 % to 33.8 %) and humification levels (HA/FA increased by 37.1 % to 49.6 %). Specifically, groups with high buffering capacity significantly promote the formation of NO3--N and NH4+-N, and a higher degree of humification, creating an optimal environment for significantly improving nitrogen retention (increased by 4.80 %). Additionally, this treatment retains and slightly enhances the plant-stimulating properties of seaweed. These findings underscore the potential of integrating biochar with specific ratios of phosphates and MgO to enhance composting efficiency and product quality while preserving the plant-stimulating effects of seaweed.
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Carbón Orgánico , Compostaje , Óxido de Magnesio , Nitrógeno , Fosfatos , Algas Marinas , Algas Marinas/química , Carbón Orgánico/química , Óxido de Magnesio/química , Compostaje/métodos , Zea mays , Almidón/química , Sustancias Húmicas/análisis , Suelo/químicaRESUMEN
Tumor organoids have emerged as a crucial preclinical model for multiple cancer research. Their high establishment rates, stability, and ability to replicate key biological features of original tumor cells in vivo render them invaluable for exploring tumor molecular mechanisms, discovering potential anti-tumor drugs, and predicting clinical drug efficacy. Here, we review the establishment of tumor organoid models and provide an extensive overview of organoid culturing strategies. We also emphasize the significance of integrating cellular components of the tumor microenvironment and physicochemical factors in the organoid culturing system, highlighting the importance of artificial intelligence technology in advancing organoid construction. Moreover, we summarize recent advancements in utilizing organoid systems for novel anti-cancer drug screening and discuss promising trends for enhancing advanced organoids in next-generation disease modeling.
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Neoplasias , Organoides , Microambiente Tumoral , Organoides/efectos de los fármacos , Organoides/patología , Humanos , Neoplasias/patología , Neoplasias/tratamiento farmacológico , Animales , Inteligencia Artificial , Ensayos de Selección de Medicamentos Antitumorales/métodos , Antineoplásicos/farmacologíaRESUMEN
BACKGROUND: Group A streptococcal(GAS) meningitis is a severe disease with a high case fatality rate. In the era of increasing GAS meningitis, our understanding about this disease is limited. PURPOSE: To gain a better understanding about GAS meningitis. METHODS: Five new cases with GAS meningitis were reported. GAS meningitis related literatures were searched for systematic review in PUBMED and EMBASE. Case reports and case series on paediatric cases were included. Information on demographics, risk factors, symptoms, treatments, outcomes, and emm types of GAS was summarized. RESULTS: Totally 263 cases were included. Among 100 individuals, 9.9% (8/81) had prior varicella, 11.1% (9/81) had anatomical factors, and 53.2% (42/79) had extracranial infections. Soft tissue infections were common among infants (10/29, 34.5%), while ear/sinus infections were more prevalent in children ≥ 3 years (21/42, 50.0%). The overall case fatality rate (CFR) was 16.2% (12/74). High risk of death was found in patients with shock or systemic complications, young children(< 3 years) and cases related to hematogenic spread. The predominate cause of death was shock(6/8). Among the 163 patients included in case series studies, ear/sinus infections ranged from 21.4 to 62.5%, while STSS/shock ranged from 12.5 to 35.7%, and the CFR ranged from 5.9 to 42.9%. CONCLUSIONS: A history of varicella, soft tissue infections, parameningeal infections and CSF leaks are important clinical clues to GAS in children with meningitis. Young children and hematogenic spread related cases need to be closely monitored for shock due to the high risk of death.
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Meningitis Bacterianas , Infecciones Estreptocócicas , Streptococcus pyogenes , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Antibacterianos/uso terapéutico , Meningitis Bacterianas/tratamiento farmacológico , Meningitis Bacterianas/microbiología , Meningitis Bacterianas/mortalidad , Factores de Riesgo , Infecciones Estreptocócicas/tratamiento farmacológico , Infecciones Estreptocócicas/microbiología , Infecciones Estreptocócicas/mortalidadRESUMEN
Colorectal cancer (CRC) stands as a prevalent malignancy globally. A pivotal event in CRC pathogenesis involves the loss-of-function mutation in the APC gene, leading to the formation of benign polyps. Despite the well-established role of APC, the contribution of CUL4B to CRC initiation in the pre-tumorous stage remains poorly understood. In this investigation, we generated a murine model by crossing ApcMin/+ mice with Cul4bΔIEC mice to achieve specific deletion of Cul4b in the gut epithelium against an ApcMin/+ background. By employing histological methods, RNA-sequencing (RNA-seq), and flow cytometry, we assessed alterations and characterized the immune microenvironment. Our results unveiled that CUL4B deficiency in gut epithelium expedited ApcMin/+ adenoma formation. Notably, CUL4B in adenomas restrained the accumulation of tumor-infiltrating myeloid-derived suppressor cells (MDSCs). In vivo inhibition of MDSCs significantly delayed the growth of CUL4B deleted ApcMin/+ adenomas. Furthermore, the addition of MDSCs to in vitro cultured ApcMin/+; Cul4bΔIEC adenoma organoids mitigated their alterations. Mechanistically, CUL4B directly interacted with the promoter of Csf3, the gene encoding granulocyte-colony stimulating factor (G-CSF) by coordinating with PRC2. Inhibiting CUL4B epigenetically activated the expression of G-CSF, promoting the recruitment of MDSCs. These findings offer novel insights into the tumor suppressor-like roles of CUL4B in regulating ApcMin/+ adenomas, suggesting a potential therapeutic strategy for CRC initiation and progression in the context of activated Wnt signaling.
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Adenoma , Proteínas Cullin , Modelos Animales de Enfermedad , Células Supresoras de Origen Mieloide , Animales , Proteínas Cullin/genética , Proteínas Cullin/metabolismo , Ratones , Células Supresoras de Origen Mieloide/metabolismo , Células Supresoras de Origen Mieloide/patología , Adenoma/patología , Adenoma/genética , Adenoma/metabolismo , Proteína de la Poliposis Adenomatosa del Colon/genética , Humanos , Microambiente Tumoral/genética , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/etiología , Eliminación de Gen , Mucosa Intestinal/patología , Mucosa Intestinal/metabolismoRESUMEN
CUL4B, a crucial scaffolding protein in the largest E3 ubiquitin ligase complex CRL4B, is involved in a broad range of physiological and pathological processes. While previous research has shown that CUL4B participates in maintaining intestinal homeostasis and function, its involvement in facilitating intestinal recovery following ionizing radiation (IR) damage has not been fully elucidated. Here, we utilized in vivo and in vitro models to decipher the role of CUL4B in intestinal repair after IR-injury. Our findings demonstrated that prior to radiation exposure, CUL4B inhibited the ubiquitination modification of PSME3, which led to the accumulation of PSME3 and subsequent negative regulation of p53-mediated apoptosis. In contrast, after radiation, CUL4B dissociated from PSME3 and translocated into the nucleus at phosphorylated histones H2A (γH2AX) foci, thereby impeding DNA damage repair and augmenting p53-mediated apoptosis through inhibition of BRCA1 phosphorylation and RAD51. Our study elucidated the dynamic role of CUL4B in the repair of radiation-induced intestinal damage and uncovered novel molecular mechanisms underlying the repair process, suggesting a potential therapeutic strategy of intestinal damage after radiation therapy for cancers.
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Apoptosis , Proteínas Cullin , Intestinos , Regeneración , Proteína p53 Supresora de Tumor , Animales , Humanos , Ratones , Apoptosis/efectos de la radiación , Proteína BRCA1/metabolismo , Proteína BRCA1/genética , Proteínas Cullin/metabolismo , Proteínas Cullin/genética , Daño del ADN , Reparación del ADN , Histonas/metabolismo , Intestinos/efectos de la radiación , Intestinos/patología , Ratones Endogámicos C57BL , Fosforilación/efectos de la radiación , Recombinasa Rad51/metabolismo , Radiación Ionizante , Regeneración/efectos de la radiación , Proteína p53 Supresora de Tumor/metabolismo , UbiquitinaciónRESUMEN
Objective: To investigate the effects of task-oriented biomechanical sensors-balance training on lower limb motor function and gait balance function in stroke patients with hemiplegia. Methods: Researchers divided 106 stroke patients with hemiplegia into observation and control groups. All received essential rehabilitation training treatment. The observation group's rehabilitation consisted of task-oriented biomechanical sensors-balance training. The modified Ashworth Scale score, FuGL-Meyer Motor Function Scale score, and other indicators measured the results of the two groups. Results: The Berg balance scale score and FuGL-Meyer Motor Function Scale score in the observation group were higher than in the control group (P < .05). The modified Ashworth Scale score of the triceps calf muscle in the observation group was significantly lower than that in the control group (P < .05). The observation group's step length, step frequency, maximum angle of hip extension, and knee flexion exceeded those of the control group. In contrast, the maximum angle of knee extension was smaller than those in the control group (P < .05). Conclusion: Basic rehabilitation training combined with task-oriented biomechanical perception-balance training can improve the lower limb motor function of stroke patients with hemiplegia.
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Although hyperhomocysteinemia (hHcys) has been recognized as an important independent risk factor in the progression of end-stage renal disease and the development of cardiovascular complications related to end-stage renal disease, the mechanisms triggering pathogenic actions of hHcys are not fully understood. The present study was mainly designed to investigate the role of HDACs in renal injury induced by hHcys. Firstly, we identified the expression patterns of HDACs and found that, among zinc-dependent HDACs, HDAC9 was preferentially upregulated in the kidney from mice with hHcys. Deficiency or pharmacological inhibition of HDAC9 ameliorated renal injury in mice with hHcys. Moreover, podocyte-specific deletion of HDAC9 significantly attenuated podocyte injury and proteinuria. In vitro, gene silencing of HDAC9 attenuated podocyte injury by inhibiting apoptosis, reducing oxidative stress and maintaining the expressions of podocyte slit diaphragm proteins. Mechanically, we proved for the first time that HDAC9 reduced the acetylation level of H3K9 in the promoter of Klotho, then inhibited gene transcription of Klotho, finally aggravating podocyte injury in hHcys. In conclusion, our results indicated that targeting of HDAC9 might be an attractive therapeutic strategy for the treatment of renal injury induced by hHcys.
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Hiperhomocisteinemia , Fallo Renal Crónico , Podocitos , Animales , Ratones , Represión Epigenética , Histona Desacetilasas/genética , Histona Desacetilasas/metabolismo , Hiperhomocisteinemia/genética , Hiperhomocisteinemia/complicaciones , Hiperhomocisteinemia/metabolismo , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/genética , Fallo Renal Crónico/metabolismo , Podocitos/patologíaRESUMEN
Mitochondria dysfunction contributes to acute liver injuries, and mitochondrial regulators, such as PGC-1α and MCJ, affect liver regeneration. Therefore, identification of mitochondrial modulators may pave the way for developing therapeutic strategies. Here, ZHX2 is identified as a mitochondrial regulator during acute liver injury. ZHX2 both transcriptionally inhibits expression of several mitochondrial electron transport chain genes and decreases PGC-1α stability, leading to reduction of mitochondrial mass and OXPHOS. Loss of Zhx2 promotes liver recovery by increasing mitochondrial OXPHOS in mice with partial hepatectomy or CCl4-induced liver injury, and inhibition of PGC-1α or electron transport chain abolishes these effects. Notably, ZHX2 expression is higher in liver tissues from patients with drug-induced liver injury and is negatively correlated with mitochondrial mass marker TOM20. Delivery of shRNA targeting Zhx2 effectively protects mice from CCl4-induced liver injury. Together, our data clarify ZHX2 as a negative regulator of mitochondrial OXPHOS and a potential target for developing strategies for improving liver recovery after acute injuries.
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Enfermedad Hepática Crónica Inducida por Sustancias y Drogas , Fosforilación Oxidativa , Humanos , Ratones , Animales , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas/metabolismo , Mitocondrias/metabolismo , Hepatectomía , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Factores de Transcripción/metabolismo , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismoRESUMEN
Hepatitis B virus (HBV) capsid assembly modulators (CAMs) represent a promising therapeutic approach for the treatment of HBV infection. In this study, we designed and synthesized five series of benzamide derivatives based on a multisite-binding strategy at the tolerant region and diversity modification in the solvent-exposed region. Among them, thioureidobenzamide compound 17i exhibited significantly increased anti-HBV activity in HepAD38 (EC50 = 0.012 µM) and HBV-infected HLCZ01 cells (EC50 = 0.033 µM). Moreover, 17i displayed a better inhibitory effect on the assembly of HBV capsid protein compared with NVR 3-778 and a inhibitory effect similar to the clinical drug GLS4. In addition, 17i showed moderate metabolic stability in human microsomes, had excellent oral bioavailability in Sprague-Dawley (SD) rats, and inhibited HBV replication in the HBV carrier mice model, which could be considered as a promising candidate drug for further development.
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Virus de la Hepatitis B , Hepatitis B , Animales , Ratones , Ratas , Humanos , Proteínas de la Cápside/metabolismo , Cápside , Replicación Viral , Antivirales/química , Ratas Sprague-Dawley , Hepatitis B/tratamiento farmacológicoRESUMEN
Plasmodium falciparum (Pf) parasite development in liver represents the initial step of the life-cycle in the human host after a Pf-infected mosquito bite. While an attractive stage for life-cycle interruption, understanding of parasite-hepatocyte interaction is inadequate due to limitations of existing in vitro models. We explore the suitability of hepatocyte organoids (HepOrgs) for Pf-development and show that these cells permitted parasite invasion, differentiation and maturation of different Pf strains. Single-cell messenger RNA sequencing (scRNAseq) of Pf-infected HepOrg cells has identified 80 Pf-transcripts upregulated on day 5 post-infection. Transcriptional profile changes are found involving distinct metabolic pathways in hepatocytes with Scavenger Receptor B1 (SR-B1) transcripts highly upregulated. A novel functional involvement in schizont maturation is confirmed in fresh primary hepatocytes. Thus, HepOrgs provide a strong foundation for a versatile in vitro model for Pf liver-stages accommodating basic biological studies and accelerated clinical development of novel tools for malaria control.
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Malaria Falciparum , Malaria , Humanos , Plasmodium falciparum/genética , Hígado/metabolismo , Hepatocitos/metabolismo , Malaria/parasitología , Organoides/metabolismo , Malaria Falciparum/parasitologíaRESUMEN
Oxidative stress plays a central role in the pathophysiology of acute kidney injury (AKI). Although RNA is one of the most vulnerable cell components to oxidative damage, it is unclear whether RNA oxidation is involved in the pathogenesis of AKI. In this study, we found that the level of RNA oxidation was significantly enhanced in kidneys of patients with acute tubular necrosis (ATN) and in the renal tubular epithelial cells (TECs) of mice with AKI, and oxidized RNA overload resulted in TEC injury. We further identified interferon-stimulated gene 20 (ISG20) as a novel regulator of RNA oxidation in AKI. Tubule-specific deficiency of ISG20 significantly aggravated renal injury and RNA oxidation in the ischemia/reperfusion-induced AKI mouse model and ISG20 restricted RNA oxidation in an exoribonuclease activity-dependent manner. Importantly, overexpression of ISG20 protected against oxidized RNA overproduction and renal ischemia/reperfusion injury in mice and ameliorated subsequent protein aggresome accumulation, endoplasmic reticulum stress, and unfolded protein response. Thus, our findings provide direct evidence that RNA oxidation contributes to the pathogenesis of AKI and that ISG20 importantly participates in the degradation of oxidized RNA, suggesting that targeting ISG20-handled RNA oxidation may be an innovative therapeutic strategy for AKI.
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Lesión Renal Aguda , Daño por Reperfusión , Animales , Humanos , Ratones , Lesión Renal Aguda/genética , Lesión Renal Aguda/terapia , Apoptosis , Exorribonucleasas/genética , Exorribonucleasas/metabolismo , Interferones/metabolismo , Isquemia/metabolismo , Riñón/metabolismo , Daño por Reperfusión/genética , Daño por Reperfusión/complicaciones , Daño por Reperfusión/metabolismo , ARN/metabolismoRESUMEN
Chemotherapy is a common strategy to treat cancer. However, acquired resistance and metastasis are the major obstacles to successful treatment. Anastasis is a process by which cells survive executioner caspase activation when facing apoptotic stress. Here we demonstrate that colorectal cancer cells can undergo anastasis after transient exposure to chemotherapeutic drugs. Using a lineage tracing system to label and isolate cells that have experienced executioner caspase activation in response to drug treatment, we show that anastasis grants colorectal cancer cells enhanced migration, metastasis, and chemoresistance. Mechanistically, treatment with chemotherapeutic drugs induces upregulated expression of cIAP2 and activation of NFκB, which are required for cells to survive executioner caspase activation. The elevated cIAP2/NFκB signaling persists in anastatic cancer cells to promote migration and chemoresistance. Our study unveils that cIAP2/NFκB-dependent anastasis promotes acquired resistance and metastasis after chemotherapy.
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Reversión de Muerte Celular , Neoplasias Colorrectales , Humanos , Resistencia a Antineoplásicos , FN-kappa B , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , CaspasasRESUMEN
Cancer relapse and metastasis are major obstacles for effective treatment. One important mechanism to eliminate cancer cells is to induce apoptosis. Activation of executioner caspases is the key step in apoptosis and was considered "a point of no return". However, in recent years, accumulating evidence has demonstrated that cells can survive executioner caspase activation in response to apoptotic stimuli through a process named anastasis. Here we show that breast cancer cells that have survived through anastasis (anastatic cells) after exposure to chemotherapeutic drugs acquire enhanced proliferation and migration. Mechanistically, cadherin 12 (CDH12) is persistently upregulated in anastatic cells and promotes breast cancer malignancy via activation of ERK and CREB. Moreover, we demonstrate that executioner caspase activation induced by chemotherapeutic drugs results in loss of DNA methylation and repressive histone modifications in the CDH12 promoter region, leading to increased CDH12 expression. Our work unveils the mechanism underlying anastasis-induced enhancement in breast cancer malignancy, offering new therapeutic targets for preventing post-chemotherapy cancer relapse and metastasis.
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Diabetic kidney disease (DKD) is the most prevalent chronic kidney disease. Macrophage infiltration in the kidney is critical for the progression of DKD. However, the underlying mechanism is far from clear. Cullin 4B (CUL4B) is the scaffold protein in CUL4B-RING E3 ligase complexes. Previous studies have shown that depletion of CUL4B in macrophages aggravates lipopolysaccharide-induced peritonitis and septic shock. In this study, using two mouse models for DKD, we demonstrate that myeloid deficiency of CUL4B alleviates diabetes-induced renal injury and fibrosis. In vivo and in vitro analyses reveal that loss of CUL4B suppresses migration, adhesion, and renal infiltration of macrophages. Mechanistically, we show that high glucose upregulates CUL4B in macrophages. CUL4B represses expression of miR-194-5p, which leads to elevated integrin α9 (ITGA9), promoting migration and adhesion. Our study suggests the CUL4B/miR-194-5p/ITGA9 axis as an important regulator for macrophage infiltration in diabetic kidneys.
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Diabetes Mellitus , Nefropatías Diabéticas , MicroARNs , Animales , Ratones , Proteínas Cullin/genética , Proteínas Cullin/metabolismo , Diabetes Mellitus/metabolismo , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/metabolismo , Cadenas alfa de Integrinas/metabolismo , Macrófagos/metabolismo , MicroARNs/genética , MicroARNs/metabolismoRESUMEN
Animal models and static cultures of intestinal epithelial cells are commonly used platforms for exploring mercury ion (Hg(II)) transport. However, they cannot reliably simulate the human intestinal microenvironment and monitor cellular physiology in situ; thus, the mechanism of Hg(II) transport in the human intestine is still unclear. Here, a gut-on-a-chip integrated with transepithelial electrical resistance (TEER) sensors and electrochemical sensors is proposed for dynamically simulating the formation of the physical intestinal barrier and monitoring the transport and absorption of Hg(II) in situ. The cellular microenvironment was recreated by applying fluid shear stress (0.02 dyne/cm2) and cyclic mechanical strain (1%, 0.15 Hz). Hg(II) absorption and physical damage to cells were simultaneously monitored by electrochemical and TEER sensors when intestinal epithelial cells were exposed to different concentrations of Hg(II) mixed in culture medium. Hg(II) absorption increased by 23.59% when tensile strain increased from 1% to 5%, and the corresponding expression of Piezo1 and DMT1 on the cell surface was upregulated.
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Hypertensive nephropathy (HTN) ranks as the second-leading cause of end-stage renal disease (ESRD). Accumulating evidence suggests that persistent hypertension injures tubular cells, leading to tubulointerstitial fibrosis (TIF), which is involved in the pathogenesis of HTN. G protein-coupled receptors (GPCRs) are implicated in many important pathological and physiological processes and act as important drug targets. In this study, we explored the intrarenal mechanisms underlying hypertension-associated TIF, and particularly, the potential role of GPR97, a member of the adhesion GPCR subfamily, in TIF. A deoxycorticosterone acetate (DOCA)/salt-induced hypertensive mouse model was used. We revealed a significantly upregulated expression of GPR97 in the kidneys, especially in renal tubules, of the hypertensive mice and 10 patients with biopsy-proven hypertensive kidney injury. GPR97-/- mice showed markedly elevated blood pressure, which was comparable to that of wild-type mice following DOCA/salt treatment, but dramatically ameliorated renal injury and TIF. In NRK-52E cells, we demonstrated that knockdown of GPR97 suppressed the activation of TGF-ß signaling by disturbing small GTPase RhoA-mediated cytoskeletal reorganization, thus inhibiting clathrin-mediated endocytosis of TGF-ß receptors and subsequent Smad activation. Collectively, this study demonstrates that GPR97 contributes to hypertension-associated TIF at least in part by facilitating TGF-ß signaling, suggesting that GPR97 is a pivotal intrarenal factor for TIF progression under hypertensive conditions, and therapeutic strategies targeting GPR97 may improve the outcomes of patients with HTN.
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Acetato de Desoxicorticosterona , Hipertensión Renal , Hipertensión , Ratones , Animales , Acetato de Desoxicorticosterona/efectos adversos , Riñón/patología , Hipertensión Renal/tratamiento farmacológico , Hipertensión Renal/metabolismo , Hipertensión Renal/patología , Hipertensión/tratamiento farmacológico , Factor de Crecimiento Transformador beta/metabolismo , FibrosisRESUMEN
BACKGROUND: Central nervous system candidiasis due to Candida albicans (CNSC) in children is easily misdiagnosed and is associated with poor outcomes and a high mortality rate. There is no big data research or systematic review of CNSC. METHODS: Patients diagnosed as CNSC with positive culture results of Candida albicans in Beijing Children's Hospital affiliated to Capital Medical University from March 2010 to March 2019 were included. Patients receiving immunosuppressive therapy or transplantation, or with malignant tumours were excluded. We analysed the clinical characteristics, follow-up results, drug susceptibility tests and whole-exome sequencing (WES) results. RESULTS: Thirty-three definitive patients were enrolled, including 22 males and 11 females. Twenty-five patients suffered from CNSC when they were less than 1 year old, and a total of 29 patients had high-risk factors. The main clinical manifestations were fever, convulsions, and positive neurological signs. Twenty-two patients had CNS infections alone, and 11 patients had CNS infections combined with invasive infections involving multiple sites. Twenty-seven cases had a positive CSF and/or blood culture at our hospital. All strains were susceptible to fluconazole, and 2 strains had intermediate susceptibility to voriconazole. As for amphotericin B, all the strains were wild type (WT). WES of 16 patients revealed 2 cases with CARD9 mutations, who suffered from recurrent onychomycosis or thrush before. CONCLUSION: CNSC mostly existed in children younger than 1 year old, who all had underlying risk factors. CNSC patients with onset at an older age or with recurrent superficial fungal infections might have primary immunodeficiency.
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Candidiasis , Infecciones Fúngicas del Sistema Nervioso Central , Masculino , Femenino , Humanos , Niño , Lactante , Candida albicans/genética , Antifúngicos/uso terapéutico , Antifúngicos/farmacología , Candidiasis/microbiología , Fluconazol/uso terapéutico , Infecciones Fúngicas del Sistema Nervioso Central/diagnóstico , Infecciones Fúngicas del Sistema Nervioso Central/tratamiento farmacológico , Sistema Nervioso Central , Pruebas de Sensibilidad Microbiana , Farmacorresistencia FúngicaRESUMEN
Lethal intestinal tissue toxicity is a common side effect and a dose-limiting factor in chemoradiotherapy. Chemoradiotherapy can trigger DNA damage and induce P53-dependent apoptosis in LGR5+ intestinal stem cells (ISCs). Gamma-aminobutyric acid (GABA) and its A receptors (GABAAR) are present in the gastrointestinal tract. However, the functioning of the GABAergic system in ISCs is poorly defined. We found that GABAAR α1 (GABRA1) levels increased in the murine intestine after chemoradiotherapy. GABRA1 depletion in LGR5+ ISCs protected the intestine from chemoradiotherapy-induced P53-dependent apoptosis and prolonged animal survival. The administration of bicuculline, a GABAAR antagonist, prevented chemoradiotherapy-induced ISC loss and intestinal damage without reducing the chemoradiosensitivity of tumors. Mechanistically, it was associated with the reduction of reactive oxygen species-induced DNA damage via the L-type voltage-dependent Ca2+ channels. Notably, flumazenil, a GABAAR antagonist approved by the U.S. Food and Drug Administration, rescued human colonic organoids from chemoradiotherapy-induced toxicity. Therefore, flumazenil may be a promising drug for reducing the gastrointestinal side effects of chemoradiotherapy.