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Gasdermins, a family of five pore-forming proteins (GSDMA-GSDME) in humans expressed predominantly in the skin, mucosa and immune sentinel cells, are key executioners of inflammatory cell death (pyroptosis), which recruits immune cells to infection sites and promotes protective immunity1,2. Pore formation is triggered by gasdermin cleavage1,2. Although the proteases that activate GSDMB, C, D and E have been identified, how GSDMA-the dominant gasdermin in the skin-is activated, remains unknown. Streptococcus pyogenes, also known as group A Streptococcus (GAS), is a major skin pathogen that causes substantial morbidity and mortality worldwide3. Here we show that the GAS cysteine protease SpeB virulence factor triggers keratinocyte pyroptosis by cleaving GSDMA after Gln246, unleashing an active N-terminal fragment that triggers pyroptosis. Gsdma1 genetic deficiency blunts mouse immune responses to GAS, resulting in uncontrolled bacterial dissemination and death. GSDMA acts as both a sensor and substrate of GAS SpeB and as an effector to trigger pyroptosis, adding a simple one-molecule mechanism for host recognition and control of virulence of a dangerous microbial pathogen.
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Exotoxinas , Piroptosis , Animales , Proteínas Bacterianas/metabolismo , Exotoxinas/genética , Exotoxinas/metabolismo , Ratones , Streptococcus pyogenesRESUMEN
Toll-like receptor 4 (TLR4) sensing of lipopolysaccharide (LPS), the most potent pathogen-associated molecular pattern of gram-negative bacteria, activates NF-κB and Irf3, which induces inflammatory cytokines and interferons that trigger an intense inflammatory response, which is critical for host defense but can also cause serious inflammatory pathology, including sepsis. Although TLR4 inhibition is an attractive therapeutic approach for suppressing overexuberant inflammatory signaling, previously identified TLR4 antagonists have not shown any clinical benefit. Here, we identify disulfiram (DSF), an FDA-approved drug for alcoholism, as a specific inhibitor of TLR4-mediated inflammatory signaling. TLR4 cell surface expression, LPS sensing, dimerization and signaling depend on TLR4 binding to MD-2. DSF and other cysteine-reactive drugs, previously shown to block LPS-triggered inflammatory cell death (pyroptosis), inhibit TLR4 signaling by covalently modifying Cys133 of MD-2, a key conserved residue that mediates TLR4 sensing and signaling. DSF blocks LPS-triggered inflammatory cytokine, chemokine, and interferon production by macrophages in vitro. In the aggressive N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease (PD) in which TLR4 plays an important role, DSF markedly suppresses neuroinflammation and dopaminergic neuron loss, and restores motor function. Our findings identify a role for DSF in curbing TLR4-mediated inflammation and suggest that DSF and other drugs that target MD-2 might be useful for treating PD and other diseases in which inflammation contributes importantly to pathogenesis.
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Alcoholismo , Disulfiram , Animales , Ratones , Receptor Toll-Like 4 , Lipopolisacáridos , Transducción de Señal , CitocinasRESUMEN
Amplification of chromosome 7p11 (7p11) is the most common alteration in primary glioblastoma (GBM), resulting in gains of epidermal growth factor receptor (EGFR) copy number in 50 to 60% of GBM tumors. However, treatment strategies targeting EGFR have thus far failed in clinical trials, and the underlying mechanism remains largely unclear. We here demonstrate that EGFR amplification at the 7p11 locus frequently encompasses its neighboring genes and identifies SEC61G as a critical regulator facilitating GBM immune evasion and tumor growth. We found that SEC61G is always coamplified with EGFR and is highly expressed in GBM. As an essential subunit of the SEC61 translocon complex, SEC61G promotes translocation of newly translated immune checkpoint ligands (ICLs, including PD-L1, PVR, and PD-L2) into the endoplasmic reticulum and promotes their glycosylation, stabilization, and membrane presentation. Depletion of SEC61G promotes the infiltration and cytolytic activity of CD8+ T cells and thus inhibits GBM occurrence. Further, SEC61G inhibition augments the therapeutic efficiency of EGFR tyrosine kinase inhibitors in mice. Our study demonstrates a critical role of SEC61G in GBM immune evasion, which provides a compelling rationale for combination therapy of EGFR-amplified GBMs.
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Neoplasias Encefálicas , Glioblastoma , Animales , Ratones , Glioblastoma/patología , Linfocitos T CD8-positivos/metabolismo , Receptores ErbB/metabolismo , Línea Celular Tumoral , Neoplasias Encefálicas/patologíaRESUMEN
Patients with bladder cancer (BCa) frequently acquires resistance to platinum-based chemotherapy, particularly cisplatin. This study centered on the mechanism of cisplatin resistance in BCa and highlighted the pivotal role of lactylation in driving this phenomenon. Utilizing single-cell RNA sequencing, we delineated the single-cell landscape of Bca, pinpointing a distinctive subset of BCa cells that exhibit marked resistance to cisplatin with association with glycolysis metabolism. Notably, we observed that H3 lysine 18 lactylation (H3K18la) plays a crucial role in activating the transcription of target genes by enriching in their promoter regions. Targeted inhibition of H3K18la effectively restored cisplatin sensitivity in these cisplatin-resistant epithelial cells. Furthermore, H3K18la-driven key transcription factors YBX1 and YY1 promote cisplatin resistance in BCa. These findings enhance our understanding of the mechanisms underlying cisplatin resistance, offering valuable insights for identifying novel intervention targets to overcome drug resistance in Bca.
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Cisplatino , Neoplasias de la Vejiga Urinaria , Humanos , Cisplatino/farmacología , Cisplatino/uso terapéutico , Histonas/genética , Histonas/metabolismo , Análisis de Expresión Génica de una Sola Célula , Resistencia a Antineoplásicos/genética , Línea Celular Tumoral , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/metabolismoRESUMEN
Protein kinase C epsilon (PKCε) belongs to a family of serine/threonine kinases that control cell proliferation, differentiation and survival. Aberrant PKCε activation and overexpression is a frequent feature of numerous cancers. However, its role in regulation of lipid metabolism in cancer cells remains elusive. Here we report a novel function of PKCε in regulating of prostate cancer cell proliferation by modulation of PKM2-mediated de novo lipogenesis. We show that PKCε promotes de novo lipogenesis and tumor cell proliferation via upregulation of lipogenic enzymes and lipid contents in prostate cancer cells. Mechanistically, PKCε interacts with NABD (1-388) domain of C-terminal deletion on pyruvate kinase isoform M2 (PKM2) and enhances the Tyr105 phosphorylation of PKM2, leading to its nuclear localization. Moreover, forced expression of mutant Tyr105 (Y105F) or PKM2 inhibition suppressed de novo lipogenesis and cell proliferation induced by overexpression of PKCε in prostate cancer cells. In a murine tumor model, inhibitor of PKM2 antagonizes lipogenic enzymes expression and prostate cancer growth induced by overexpression of PKCε in vivo. These data indicate that PKCε is a critical regulator of de novo lipogenesis, which may represent a potential therapeutic target for the treatment of prostate cancer.
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Neoplasias de la Próstata , Proteína Quinasa C-epsilon , Animales , Humanos , Masculino , Ratones , Línea Celular Tumoral , Lipogénesis/genética , Fosforilación/fisiología , Neoplasias de la Próstata/metabolismo , Isoformas de Proteínas/metabolismo , Proteína Quinasa C-epsilon/genética , Proteína Quinasa C-epsilon/metabolismo , Piruvato Quinasa/genética , Piruvato Quinasa/metabolismoRESUMEN
Bladder cancer is one of the most common malignancies in the world. Cisplatin is one of the most potent and widely used anticancer drugs and has been employed in several malignancies. Cisplatin-based combination chemotherapies have become important adjuvant therapies for bladder cancer patients. Cisplatin-based treatment often results in the development of chemoresistance, leading to therapeutic failure and limiting its application and effectiveness in bladder cancer. To develop improved and more effective cancer therapy, research has been conducted to elucidate the underlying mechanism of cisplatin resistance. Epigenetic modifications have been demonstrated involved in drug resistance to chemotherapy, and epigenetic biomarkers, such as urine tumor DNA methylation assay, have been applied in patients screening or monitoring. Here, we provide a systematic description of epigenetic mechanisms, including DNA methylation, noncoding RNA regulation, m6A modification and posttranslational modifications, related to cisplatin resistance in bladder cancer.
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Antineoplásicos , Neoplasias de la Vejiga Urinaria , Humanos , Cisplatino/farmacología , Cisplatino/uso terapéutico , Resistencia a Antineoplásicos/genética , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patología , Epigénesis Genética , Metilación , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/uso terapéuticoRESUMEN
Phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in the first step of the serine synthesis pathway (SSP), is overexpressed in multiple types of cancers. The androgen receptor inhibitor enzalutamide (Enza) is the primary therapeutic drug for patients with castration-resistant prostate cancer (CRPC). However, most patients eventually develop resistance to Enza. The association of SSP with Enza resistance remains unclear. In this study, we found that high expression of PHGDH was associated with Enza resistance in CRPC cells. Moreover, increased expression of PHGDH led to ferroptosis resistance by maintaining redox homeostasis in Enza-resistant CRPC cells. Knockdown of PHGDH caused significant GSH reduction, induced lipid peroxides (LipROS) increase and significant cell death, resulting in inhibiting growth of Enza-resistant CRPC cells and sensitizing Enza-resistant CRPC cells to enzalutamide treatment both in vitro and in vivo. We also found that overexpression of PHGDH promoted cell growth and Enza resistance in CRPC cells. Furthermore, pharmacological inhibition of PHGDH by NCT-503 effectively inhibited cell growth, induced ferroptosis, and overcame enzalutamide resistance in Enza-resistant CRPC cells both in vitro and in vivo. Mechanically, NCT-503 triggered ferroptosis by decreasing GSH/GSSG levels and increasing LipROS production as well as suppressing SLC7A11 expression through activation of the p53 signaling pathway. Moreover, stimulating ferroptosis by ferroptosis inducers (FINs) or NCT-503 synergistically sensitized Enza-resistant CRPC cells to enzalutamide. The synergistic effects of NCT-503 and enzalutamide were verified in a xenograft nude mouse model. NCT-503 in combination with enzalutamide effectively restricted the growth of Enza-resistant CRPC xenografts in vivo. Overall, our study highlights the essential roles of increased PHGDH in mediating enzalutamide resistance in CRPC. Therefore, the combination of ferroptosis inducer and targeted inhibition of PHGDH could be a potential therapeutic strategy for overcoming enzalutamide resistance in CRPC.
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Protein kinase D (PKD) has been linked to inflammatory responses in various pathologic conditions; however, its role in inflammation-induced dermal fibrosis has not been evaluated. In this study, we aimed to investigate the roles and mechanisms of protein kinase D2 (PKD2) in inflammation-induced dermal fibrosis and evaluate the therapeutic potential of PKD inhibitors in this disease. Using homozygous kinase-dead PKD2 knock-in (KI) mice, we examined whether genetic ablation or pharmacologic inhibition of PKD2 activity affected dermal inflammation and fibrosis in a bleomycin (BLM)-induced skin fibrosis model. Our data showed that dermal thickness and collagen fibers were significantly reduced in BLM-treated PKD2 KI mice compared with that in wild-type mice, and so was the expression of α-smooth muscle actin and collagens and the mRNA levels of transforming growth factor-ß1 and interleukin-6 in the KI mice. Corroboratively, pharmacologic inhibition of PKD by CRT0066101 also significantly blocked BLM-induced dermal fibrosis and reduced α-smooth muscle actin, collagen, and interleukin-6 expression. Further analyses indicated that loss of PKD2 activity significantly blocked BLM-induced infiltration of monocytes/macrophages and neutrophils in the dermis. Moreover, using bone marrow-derived macrophages, we demonstrated that PKD activity was required for cytokine production and migration of macrophages. We have further identified Akt as a major downstream target of PKD2 in the early inflammatory phase of the fibrotic process. Taken together, our findings indicate that PKD2 promotes dermal fibrosis via regulating immune cell infiltration, cytokine production, and downstream activation of Akt in lesional skin, and targeted inhibition of PKD2 may benefit the treatment of this condition.
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Bleomicina , Proteína Quinasa D2 , Esclerodermia Sistémica , Animales , Ratones , Actinas/genética , Actinas/metabolismo , Bleomicina/toxicidad , Colágeno/metabolismo , Modelos Animales de Enfermedad , Fibrosis , Inflamación/metabolismo , Interleucina-6 , Proteína Quinasa D2/genética , Proteínas Serina-Treonina Quinasas , Proteínas Proto-Oncogénicas c-aktRESUMEN
PURPOSE: Deficiency of adenosine deaminase 2 (DADA2), an autosomal recessive autoinflammatory disorder caused by biallelic loss-of-function variants in adenosine deaminase 2 (ADA2), has not been systemically investigated in Chinese population yet. We aim to further characterize DADA2 cases in China. METHODS: A retrospective analysis of patients with DADA2 identified through whole exome sequencing (WES) at seventeen rheumatology centers across China was conducted. Clinical characteristics, laboratory findings, genotype, and treatment response were analyzed. RESULTS: Thirty patients with DADA2 were enrolled between January 2015 and December 2021. Adenosine deaminase 2 enzymatic activity was low in all tested cases to confirm pathogenicity. Median age of disease presentation was 4.3 years and the median age at diagnosis was 7.8 years. All but one patient presented during childhood and two subjects died from complications of their disease. The patients most commonly presented with systemic inflammation (92.9%), vasculitis (86.7%), and hypogammaglobinemia (73.3%) while one patient presented with bone marrow failure (BMF) with variable cytopenia. Twenty-three (76.7%) patients were treated with TNF inhibitors (TNFi), while two (6.7%) underwent hematopoietic stem cell transplantation (HSCT). They all achieved clinical remission. A total of thirty-nine ADA2 causative variants were identified, six of which were novel. CONCLUSION: To establish early diagnosis and improve clinical outcomes, genetic screening and/or testing of ADA2 enzymatic activity should be performed in patients with suspected clinical features. TNFi is considered as first line treatment for those with vascular phenotypes. HSCT may be beneficial for those with hematological disease or in those who are refractory to TNFi.
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Adenosina Desaminasa , Péptidos y Proteínas de Señalización Intercelular , Humanos , Adenosina Desaminasa/genética , Péptidos y Proteínas de Señalización Intercelular/genética , Estudios de Cohortes , Estudios Retrospectivos , MutaciónRESUMEN
BACKGROUND: Myocardial injury is a major complication of sepsis and a key factor affecting prognosis. Therefore, early and accurate diagnosis and timely management of sepsis-induced cardiomyopathy (SICM) are of great significance for the prevention and treatment of sepsis. The gut microbiota has been shown to be closely associated with sepsis or myocardial injury, but the association between the gut microbiota and SICM is not fully understood. This study aimed to explore the link between gut microbiota composition and SICM. METHODS: A case-control and single-center study of clinical features and gut microbiota profiles by Metagenome and Virome was conducted in SICM patients (n = 15) and sepsis-uninduced cardiomyopathy patients (SNICM, n = 16). RESULTS: Compared with SNICM patients, SICM patients showed significant myocardial injury and higher 28-day mortality, SOFA scores, lactate levels, and infection levels on admission. Meanwhile, differences in the composition of gut bacteria, archaea, fungi, and viruses were analyzed between the two groups. Differential gut bacteria or viruses were found to have a good predictive effect on SICM. Furthermore, gut bacteria and viruses that differed between the two groups were strongly related. The abundance of Cronobacter and Cronobacter phage was higher in the SICM group than in the SNICM group, and the receiver operating characteristic curve showed that Cronobacter and Cronobacter phage both had a good predictive effect on SICM. CONCLUSIONS: SICM patients may have specific gut microbiota signatures, and Cronobacter and Cronobacter phages have a good ability to identify and diagnose SICM.
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Bacteriófagos , Cardiomiopatías , Microbioma Gastrointestinal , Sepsis , Humanos , Estudios de Casos y Controles , Disbiosis/complicaciones , Cardiomiopatías/etiología , Bacterias/genética , Sepsis/complicacionesRESUMEN
Climate projections foresee intense precipitation and long-term drought events is increasing with consequent rapid changes in surface water bodies in a short period. In areas with drastic hydrological changes, achieving accurate and rapid mapping of these phenomena in combination with hydrologic variability characteristics is a key of effective emergency management and disaster risk reduction plans. This study presents an automatic method for mapping drought and flood hazards, particularly in regions with significant hydrological changes. We use Sentinel-1/2 and Landsat data to extract surface water and classify permanent and seasonal water bodies in historical periods, which serve as the basis for identifying flood or drought areas. The water extraction method combines index-based analysis for optical data and the region-Otsu method for radar data, ensuring accurate identification of water. The effectiveness of this approach is demonstrated through comparisons with existing products in Poyang Lake (China), the Po River Plain (Italy), and the Indus River Plain (Pakistan). Findings show a high similarity between the two, and our results can provide more specific details. Our method is particularly well-suited for areas with fluctuating hydrological conditions, can also map quickly without optical data. By effectively identifying areas affected by drought and flood hazards while mitigating errors from natural hydrological dynamics, this methodology contributes valuable insights to enhance emergency management and disaster risk reduction plans.
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Inundaciones , Agua , Ríos , Lagos , ChinaRESUMEN
BACKGROUND: Preoperative anemia is an established risk factor for morbidity and mortality after surgery. Men and women have different hemoglobin concentrations and are at different risks of postoperative complications. However, sex-stratified analysis on the association between preoperative hemoglobin and outcomes after noncardiac surgery has been limited in previous studies. METHODS: This was a retrospective cohort study of adult patients undergoing elective major noncardiac surgery in a large academic hospital. The primary outcome was a collapsed composite of postoperative mortality or cardiovascular, renal, pulmonary, and infectious complications during hospitalization. Sex-specific univariable associations between preoperative hemoglobin and the composite outcome were visualized using moving-average and cubic-spline smoothing plots. Multivariable regression models adjusting for patient demographics, comorbidities, medication uses, laboratory tests, and anesthesia/surgery features were used to estimate confounder-adjusted associations. Restricted cubic spline and piecewise linear functions were used to assess the possible nonlinear relationships between preoperative hemoglobin and the outcomes. The interaction between patient sex and hemoglobin on outcomes was assessed using a likelihood-ratio test. RESULTS: We included 22,550 patients, with 6.7% (622 of 9268) of women and 9.7% (1293 of 13,282) of men developing the primary outcome. Lower preoperative hemoglobin was associated with a higher incidence of the primary composite outcome in both men and women. Nonlinearity for the association was not statistically significant in either women ( P = .539) or men ( P = .165). The multivariable-adjusted odds ratios per 1 g/dL increase in hemoglobin were 0.93 (95% confidence interval [CI], 0.87-0.98; P = .013) for women and 0.94 (95% CI, 0.90-0.97; P < .001) for men, with no interaction by sex ( Pinteraction = .923). No hemoglobin thresholds were confirmed at which the associations with the primary outcome changed significantly. CONCLUSIONS: Low preoperative hemoglobin was associated with a higher risk of complications or mortality after elective noncardiac surgery in both men and women. No differences in the strength of associations between sexes were found. Further studies are needed to assess whether these associations are linear or there are sex-specific thresholds of preoperative hemoglobin concentrations below which postoperative risks begin to increase.
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BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapy for hematologic malignancies and non-malignant disorders, such as aplastic anemia, fanconi anemia, and certain immune deficiencies. Post-transplantation kidney injury is a common complication and involves a wide spectrum of structural abnormalities, including glomerular (MSPGN, mesangial proliferative glomerulonephritis; FSGS, focal segmental glomerulosclerosis; MPGN, membranoproliferative glomerulonephritis; MCD, minimal change disease), vascular (TMA, thrombotic microangiopathy), and/or tubulointerstitial (TIN, tubulointerstitial nephritis; ATI, acute tubular injury). Renal biopsy is the gold-standard examination for defining multiple etiologies of kidney impairment. Although kidney injury following HSCT has been studied, little is known about the effects of allo-HSCT on renal pathology in pediatric patients. METHODS: We retrospectively analyzed renal biopsy specimens from children with kidney injury after allo-HSCT and correlated results with clinical data in the last 10 years. RESULTS: Among 25 children (18 males and 7 females), three patients had proteinuria indicating nephrotic syndrome (24-hour urinary total protein/weight > 50 mg/kg/d), nine patients had severely reduced estimated glomerular filtration rate (eGFR < 30 ml/min/1.73 m2) and four patients received kidney replacement therapy (KRT). The main pathologies identified from kidney biopsies were MSPGN (n = 12), FSGS (n = 12), MPGN (n = 5), TMA (n = 4), MCD (n = 3), diffuse glomerular fibrosis (DGF, n = 2), ATI and TIN, in isolation or combined with other pathologies. The median follow-up time was 16.5 (0.5 ~ 68.0) months. Three patients died of recurrent malignancy and/or severe infection, one child developed to end-stage renal disease (ESRD), six patients (24%) had elevated serum creatinine (SCr > 100µmol/l) and nine patients (36%) still had proteinuria. CONCLUSIONS: This study evaluates histomorphologic findings from kidney biopsies of pediatric recipients following allo-HSCT. Detailed evaluation of renal biopsy samples is helpful to elucidate the nature of renal insult, and may potentially identify treatable disease processes.
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Glomerulonefritis Membranoproliferativa , Glomerulonefritis Membranosa , Glomeruloesclerosis Focal y Segmentaria , Trasplante de Células Madre Hematopoyéticas , Enfermedades Renales , Niño , Femenino , Humanos , Masculino , Biopsia/efectos adversos , Glomerulonefritis Membranoproliferativa/complicaciones , Glomerulonefritis Membranoproliferativa/patología , Glomerulonefritis Membranosa/complicaciones , Glomerulonefritis Membranosa/patología , Glomeruloesclerosis Focal y Segmentaria/complicaciones , Glomeruloesclerosis Focal y Segmentaria/patología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Riñón/patología , Proteinuria/complicaciones , Estudios RetrospectivosRESUMEN
Atopic dermatitis (AD) is a kind of chronic skin disease with inflammatory infiltration, characterized by skin barrier dysfunction, immune response dysregulation, and skin dysbiosis. Thymic stromal lymphopoietin (TSLP) acts as a regulator of immune response, positively associated with AD deterioration. Mainly secreted by keratinocytes, TSLP interacts with multiple immune cells (including dendritic cells, T cells, and mast cells), following induction of Th2-oriented immune response during the pathogenesis of AD. This article primarily focuses on the TSLP biological function, the relationship between TSLP and different cell populations, and the AD treatments targeting TSLP.
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Dermatitis Atópica , Linfopoyetina del Estroma Tímico , Humanos , Citocinas , Queratinocitos , Piel/patologíaRESUMEN
The single sample calibration laser-induced breakdown spectroscopy (SSC-LIBS) is quite suitable for the fields where the standard sample is hard to obtain, including space exploration, geology, archaeology, and jewelry identification. But in practice, the self-absorption effect of plasma destroys the linear relationship of spectral intensity and element concentration based on the Lomakin-Scherbe formula which is the guarantee of the high accuracy of the SSC-LIBS. Thus, the self-absorption effect limits the quantitative accuracy of SSC-LIBS greatly. In this work, an improved SSC-LIBS with self-absorption correction (SSC-LIBS with SAC) is proposed for the promotion of quantitative accuracy of SSC-LIBS. The SSC-LIBS with SAC can correct the intensity ratio of spectral lines in the calculation of SSC-LIBS through relative self-absorption coefficient K without complicated preparatory information. The alloy samples and pressed ore samples were used to verify the effect of the SSC-LIBS with SAC. Compared with SSC-LIBS, for alloy samples, the average RMSEP and average ARE of SSC-LIBS with SAC decreased from 0.83 wt.% and 13.75% to 0.40 wt.% and 4.06%, respectively. For the pressed ore samples, the average RMSEP and average ARE of SSC-LIBS with SAC decreased from 4.77 wt.% and 90.48% to 2.34 wt.% and 14.60%. The experimental result indicates that SSC-LIBS with SAC has a great improvement of quantitative accuracy and better universality compared with traditional SSC-LIBS, which is a mighty promotion of the wide application of SSC-LIBS.
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Having healthy adipose tissue is essential for metabolic health, as excessive adipose tissue in the body can cause its dysregulation and driving chronic metabolic diseases. Protein kinase D1 (PKD1) is considered to be a key kinase in signal transduction, which regulates multiple cellular functions, but its physiological functions in adipose are still not fully understood. This study aimed at elucidating the function of adipocyte PKD1 on lipogenesis. From RNA-Sequencing data, we found that the fatty acid biosynthesis pathway in white adipose tissue lacking PKD1 was significantly affected. Critical rate-limiting enzymes for de novo lipogenesis in adipocytes, such as FASN, ACCα, and SCD1, were significantly repressed after deleting PKD1 in vivo and in vitro. Further studies revealed that blockade of PKD1 significantly increased phosphorylation of SREBP1c at serine 372 site. Co-immunoprecipitation analysis showed that PKD1 interacts with SREBP1c in vitro and in vivo. Importantly, overexpression of SREBP1c reversed the inhibition of FASN and ACCα expression caused by PKD1 silencing. Together, adipocyte PKD1 promotes de novo lipogenesis via SREBP1c-dependent manner in visceral white adipose tissue and might provide a new target for the development of anti-obesity therapies.
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Tejido Adiposo/crecimiento & desarrollo , Lipogénesis/genética , Proteína Quinasa C/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Tejido Adiposo/metabolismo , Animales , Silenciador del Gen , Ratones , Ratones Noqueados , Especificidad de Órganos/genética , Transducción de Señal/genéticaRESUMEN
BACKGROUND: Evidence suggests a potential relationship between gut microbiota and chronic postoperative pain (CPP). This study aimed to explore the predictive and preventive potential of preoperative gut microbiota in CPP in breast cancer survivors. METHODS: In the clinical experiments, we designed a nested case-control study to compared preoperative gut microbiota of breast cancer survivors with and without CPP using 16s rRNA sequencing. The primary outcome was clinically meaningful pain in or around the operative area 3 months after surgery. Logistic prediction models based on previously identified risk factors for CPP in breast cancer survivors were tested with and without differential bacteria to evaluate the model's potential for improvement with the addition of gut microbiota information. In the animal experiments, preoperative fecal microbiota was transplanted from patients with and without CPP to mice, and a spared nerve injury (SNI) model was used to mimic neuropathic pain in CPP. Mechanical hyperalgesia and the expression of markers of spinal microglia and peroxisome proliferator-activated receptor-γ (PPAR-γ) were assessed. RESULTS: Sixty-six CPP patients and 66 matched controls were analyzed. Preoperative gut microbiota composition was significantly different in the 2 groups at phylus, family, and genera levels. The discrimination of the clinical prediction model (determined by area under the receiver operating characteristic curve) improved by 0.039 and 0.099 after the involvement of differential gut microbiota at the family and genus levels, respectively. After fecal microbiota transplantation (FMT), "CPP microbiota" recipient mice exhibited significantly increased mechanical hyperalgesia and decreased expression of Ppar-γ and arginase-1 (Arg-1) in the spinal cord. CONCLUSIONS: Preoperative gut microbiota has the potential to predict and prevent the development of CPP and plays a causal role in its development via the PPAR-γ-microglia pathway in the spinal cord. Thus, it could be targeted to develop a prevention strategy for CPP in breast cancer survivors.
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Neoplasias de la Mama , Supervivientes de Cáncer , Microbioma Gastrointestinal , Animales , Neoplasias de la Mama/cirugía , Estudios de Casos y Controles , Femenino , Humanos , Hiperalgesia , Ratones , Modelos Estadísticos , Dolor Postoperatorio/diagnóstico , Dolor Postoperatorio/etiología , Dolor Postoperatorio/prevención & control , Receptores Activados del Proliferador del Peroxisoma , Pronóstico , ARN Ribosómico 16S/genéticaRESUMEN
The on-demand release of antibacterial components due to pH variations caused by acidogenic/cariogenic bacteria is a possible design for smart antibacterial restorative materials. This study aimed to fabricate pH-responsive Zn2+-releasing glass particles and evaluate their solubilities, ion-releasing characteristics, and antibacterial properties in vitro. Three kinds of silicate-based glass particles containing different molar ratios of Zn (PG-1: 25.3; PG-2: 34.6; PG-3: 42.7 mol%) were fabricated. Each particle was immersed in a pH-adjusted medium, and the solubility and concentration of the released ions were determined. To evaluate the antibacterial effect, Streptococcus mutans was cultured in the pH-adjusted medium in the presence of each particle, and the bacterial number was counted. The solubility and concentration of Zn2+ released in the medium increased with a decrease in medium pH. PG-3 with a greater content of Zn demonstrated higher concentrations of released Zn2+ compared with PG-1 and PG-2. PG-2 exhibited bactericidal effects at pH 5.1, whereas PG-3 demonstrated bactericidal effects at pH values of 5.1 and 6.1, indicating that PG-3 was effective at inhibiting S. mutans even under slightly acidic conditions. The glass particle with 42.7 mol% Zn may be useful for developing smart antibacterial restoratives that contribute to the prevention of diseases such as caries on root surfaces with lower acid resistance.
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Vidrio , Streptococcus mutans , Antibacterianos/farmacología , Antibacterianos/química , Iones , Concentración de Iones de Hidrógeno , Zinc/farmacologíaRESUMEN
Epithelial regeneration is essential for homeostasis and mucosal barrier repair. In this study, we aimed to define the effect of IL-10 on mucosal healing. Intestinal stem cells (ISCs) cultures and mice were treated with recombinant mice IL-10 (rmIL-10). The level of cell proliferation, differentiation, death and related signaling pathways for self-renewal of ISCs were measured in vitro and in vivo. It was uncovered that rmIL-10 increased the size and death, but reduced the total number of organoids. In addition, rmIL-10 depleted Lgr5+ ISCs and reduced epithelial proliferation, but enhanced the differentiation of epithelial cells and expanded numbers of transit-amplifying (TA) cells. These changes are related to the decrease of Wnt and Notch signals in vivo and in vitro. Meanwhile, increased expression of Paneth cells and decreased expression of enteroendocrine cells and goblet cells were induced by rmIL-10. Thus, our data indicate that IL-10 reduces the survival of Lgr5+ ISCs and proliferation of epithelial cells by inhibiting Notch and Wnt signaling, but promotes enhanced the differentiation of epithelial cells and expanded numbers of TA cells. Therefore, IL-10 acts as an anti-inflammatory factor, but may damage intestinal mucosa repair and maybe a potential target for the treatment of intestinal injury.