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The risk of chronic inflammatory diseases has been linked to exposure to polycyclic aromatic hydrocarbons (PAHs). However, limited data are available regarding their impact on periodontitis. This study aims to explore the association between PAHs and periodontitis while also evaluating the potential modifying effects of healthy lifestyles. We included 17,031 participants from the US National Health and Nutrition Examination Survey (NHANES, 2001-2004 and 2009-2014). A meta-analysis-based environment-wide association study (EWAS) was adopted to identify environmental chemicals for the mean probing pocket depth (PPD) and the mean attachment loss (AL). PAHs were further evaluated concerning the cross-sectional association with Mod/Sev periodontitis using multivariable logistic regression models. Moreover, healthy lifestyle scores were estimated to assess their modifying effect on the PAH-periodontitis association. EWAS analysis identified several urinary PAH metabolites as significant risk factors for the mean PPD and AL (false discovery rate <0.05, Q > 0.05). Periodontitis severity was positively associated with eight individual and total PAH concentrations. Stratifying the participants in terms of healthy lifestyle scores did not reveal any association in the healthy group. Moreover, the association weakened in never-smokers and individuals with sufficient physical activity and normal weight. PAH exposure was a risk factor for periodontitis. A healthier lifestyle was observed to offset the risk potentials of PAHs for periodontitis. Smoking cessation, physical activity, and weight loss might be recommended as a healthy lifestyle strategy for ameliorating PAH-related periodontitis.
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Evidence shows that tropomodulin 1 (TMOD1) is a powerful diagnostic marker in the progression of several cancer types. However, the regulatory mechanism of TMOD1 in tumor progression is still unclear. Here, we showed that TMOD1 was highly expressed in acute myeloid leukemia (AML) specimens, and TMOD1-silencing inhibited cell proliferation by inducing autophagy in AML THP-1 and MOLM-13 cells. Mechanistically, the C-terminal region of TMOD1 directly bound to KPNA2, and TMOD1-overexpression promoted KPNA2 ubiquitylation and reduced KPNA2 levels. In contrast, TMOD1-silencing increased KPNA2 levels and facilitated the nuclear transfer of KPNA2, then subsequently induced autophagy and inhibited cell proliferation by increasing the nucleocytoplasmic transport of p53 and AMPK activation. KPNA2/p53 inhibitors attenuated autophagy induced by silencing TMOD1 in AML cells. Silencing TMOD1 also inhibited tumor growth by elevating KPNA2-mediated autophagy in nude mice bearing MOLM-13 xenografts. Collectively, our data demonstrated that TMOD1 could be a novel therapeutic target for AML treatment.
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Autofagia , Proliferação de Células , Leucemia Mieloide Aguda , Camundongos Nus , Tropomodulina , alfa Carioferinas , Humanos , Animais , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , alfa Carioferinas/genética , alfa Carioferinas/metabolismo , Tropomodulina/genética , Tropomodulina/metabolismo , Linhagem Celular Tumoral , Camundongos , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/genética , Camundongos Endogâmicos BALB C , Masculino , Inativação Gênica , Feminino , Células THP-1RESUMO
BACKGROUND: This study compared the differences of microvesicles (MVs) and microvesicles-delivering Smad7 (Smad7-MVs) on macrophage M1 polarization and fibroblast differentiation in a model of Peyronie's disease (PD). METHODS: Overexpression of Smad7 in rat BMSCs was obtained by pCMV5-Smad7 transfection. MVs were collected from rat BMSCs using ultracentrifugation. In cells, 100 µg/mL of MVs or Smad7-MVs were used to treat the 100 ng/mL of lipopolysaccharide (LPS)-induced RAW264.7 cells or 10 ng/mL of recombinant transforming growth factor-ß1 (TGF-ß1)-induced fibroblasts. The pro-inflammatory cytokines and markers of M1 macrophages were measured in RAW264.7 cells, and the migration and markers of fibroblast differentiation were measured in fibroblasts. In rats, 50 µg of MVs or Smad7-MVs were used to treat the TGF-ß1-induced animals. The pathology of tunica albuginea (TA), the markers of M1 macrophages and fibroblast differentiation in the TA were measured. RESULTS: The MVs or Smad7-MVs treatment suppressed the LPS-induced macrophage M1 polarization and TGF-ß1-induced fibroblast differentiation. Moreover, the Smad7-MVs treatment decreased the fibroblast differentiation compared with the MVs treatment. In the TGF-ß1-induced TA of rats, MVs or Smad7-MVs treatment ameliorated the TA fibrosis by suppressing the macrophage M1 polarization and fibroblast differentiation. There was no significance on the M1-polarized macrophages between the MVs treatment and the Smad7-MVs treatment. Meanwhile, the Smad7-MVs treatment had an edge in terms of suppressing the fibroblast differentiation in the TGF-ß1-induced PD model compared with the MVs treatment. CONCLUSIONS: This study demonstrated that Smad7-MVs treatment had advantages over MVs treatment in suppressing of fibroblast differentiation in a model of PD.
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Diferenciação Celular , Micropartículas Derivadas de Células , Modelos Animais de Doenças , Fibroblastos , Macrófagos , Induração Peniana , Proteína Smad7 , Fator de Crescimento Transformador beta1 , Animais , Induração Peniana/metabolismo , Induração Peniana/tratamento farmacológico , Diferenciação Celular/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/efeitos dos fármacos , Ratos , Masculino , Proteína Smad7/metabolismo , Proteína Smad7/genética , Camundongos , Micropartículas Derivadas de Células/metabolismo , Células RAW 264.7 , Fator de Crescimento Transformador beta1/metabolismo , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Ratos Sprague-Dawley , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/citologiaRESUMO
BACKGROUND: Radical inguinal lymph node dissection (rILND) is the most available treatment to cure penile cancer (PC) with limited inguinal-confined disease. However, guidelines regarding acceptable boundaries of rILND are controversial, and consensus is lacking. The authors aimed to standardize the surgical boundaries of rILND with definite pathological evidence and explore the distribution pattern of inguinal lymph nodes (ILNs) in PC. METHODS: A total of 414 PC patients from two centers who underwent rILND were enrolled. The ILN distribution was divided into seven zones anatomically for pathological examination. Student's t test and Kaplan-Meier survival analysis were used. RESULTS: ILNs displayed a funnel-shaped distribution with high density in superior regions. ILNs and metastatic nodes are present anywhere within the radical boundaries. Positive ILNs were mainly concentrated in zone I (51.7%) and zone II (41.3%), but there were 8.7% and 12.3% in inferior zones V and VI, respectively, and 7.1% in the deep ILNs. More importantly, a single positive ILN and first-station positive zone was detected in all seven regions. Single positive ILNs were located in zones I through VI in 40.4%, 23.6%, 6.7%, 18.0%, 4.5%, and 1.1%, respectively, and 5.6% presented deep ILN metastasis directly. CONCLUSIONS: The authors established a detailed ILN distribution map and displayed lymphatic drainage patterns with definite pathological evidence using a large cohort of PC patients. Single positive ILNs and first-station metastatic zones were observed in any region, even directly with deep ILN metastasis. Only rILND can ensure tumor-free resection without the omission of positive nodes.
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Canal Inguinal , Excisão de Linfonodo , Linfonodos , Metástase Linfática , Neoplasias Penianas , Humanos , Masculino , Neoplasias Penianas/cirurgia , Neoplasias Penianas/patologia , Excisão de Linfonodo/métodos , Estudos Retrospectivos , Pessoa de Meia-Idade , Idoso , Canal Inguinal/cirurgia , Canal Inguinal/patologia , Linfonodos/patologia , Linfonodos/cirurgia , Adulto , Estudos de CoortesRESUMO
Focal segmental glomerulosclerosis (FSGS) is a leading kidney disease, clinically associated with proteinuria and progressive renal failure. The occurrence of this disease is partly related to gene mutations. We describe a single affected family member who presented with FSGS. We used high-throughput sequencing, sanger sequencing to identify the pathogenic mutations, and a systems genetics analysis in the BXD mice was conducted to explore the genetic regulatory mechanisms of pathogenic genes in the development of FSGS. We identified high urinary protein (++++) and creatinine levels (149 µmol/L) in a 29-year-old male diagnosed with a 5-year history of grade 2 hypertension. Histopathology of the kidney biopsy showed stromal hyperplasia at the glomerular segmental sclerosis and endothelial cell vacuolation degeneration. Whole-exome sequencing followed by Sanger sequencing revealed a heterozygous missense mutation (c.643C > T) in exon 2 of TRPC6, leading to the substitution of arginine with tryptophan at position 215 (p.Arg215Trp). Systems genetics analysis of the 53 BXD mice kidney transcriptomes identified Pygm as the upstream regulator of Trpc6. Those two genes are jointly involved in the regulation of FSGS mainly via Wnt and Hippo signaling pathways. We present a novel variant in the TRPC6 gene that causes FSGS. Moreover, our data suggested TRPC6 works with PYGM, as well as Wnt and Hippo signaling pathways to regulate renal function, which could guide future clinical prevention and targeted treatment for FSGS outcomes.
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Plasma membrane H+-ATPases (PMAs) play an important role in the pathogenicity of pathogenic fungi. Lipid droplets are important storage sites for neutral lipids in fungal conidia and hyphae and can be used by plant pathogenic fungi for infection. However, the relationship between plasma membrane H+-ATPase, lipid droplets and virulence remains unclear. Here, we characterized a plasma membrane H+-ATPase, CsPMA2, that plays a key role in lipid droplet formation, appresorial development and virulence in C. siamense. Deletion of CsPMA2 impaired C. siamense conidial size, conidial germination, appressorial development and virulence but did not affect hyphal growth. ΔCsPMA2 increased the sensitivity of C. siamense to phytic acid and oxalic acid. CsPMA2 was localized to lipids on the plasma membrane and intracellular membrane. Deletion of CsPMA2 significantly inhibited the accumulation of lipid droplets and significantly affected the contents of some species of lipids, including 12 species with decreased lipid contents and 3 species with increased lipid contents. Furthermore, low pH can inhibit CsPMA2 expression and lipid droplet accumulation. Overall, our data revealed that the plasma membrane H+-ATPase CsPMA2 is involved in the regulation of lipid droplet formation and affects appressorial development and virulence in C. siamense.
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Colletotrichum , Gotículas Lipídicas , Virulência , Gotículas Lipídicas/metabolismo , Proteínas Fúngicas/metabolismo , Lipídeos , Membrana Celular/metabolismo , ATPases Translocadoras de Prótons/genética , ATPases Translocadoras de Prótons/metabolismoRESUMO
BACKGROUND: Penile metastases are extremely rare events, originating primarily from primary pelvic tumours of the prostate, bladder, and gastrointestinal tract. The underlying mechanism of bladder cancer metastasis to the penis remains unclear. Metastasis to the penis is usually considered a late manifestation of systemic spread. Therefore, the prognosis of patients with penile metastasis remains poor and their survival period is short. Therefore, reporting this rare case will help to better understand the characteristics, diagnosis, and treatment processes of the disease, with the aim of improving the accuracy and efficiency of diagnosis and treatment. CASE DESCRIPTION: A 65-year-old male received transurethral resection of a bladder tumor. One year later, he underwent radical cystectomy because of the recurrence and progression of bladder cancer. Postoperative pathology demonstrated that the stage of bladder cancer was T3N0M0. One year later, he discovered a penile mass that gradually grew and became hard, accompanied by urinary retention, but without other clinical symptoms. The patient underwent a complete penectomy. Histopathology and immunohistochemistry results demonstrated the tumour's origin as a bladder urothelial carcinoma. The patient received systemic chemotherapy after surgery, but died 7 months later. CONCLUSIONS: Although penile metastasis of bladder cancer typically indicates an advanced stage of the malignant tumour and poor prognosis, we recommend that male patients with a history of bladder cancer should undergo a regular clinical examination of the penis to rapidly detect the disease and receive early treatment. In this case, despite treatment measures such as systemic chemotherapy and penectomy, the patient's prognosis remained poor.
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Carcinoma de Células de Transição , Neoplasias Penianas , Neoplasias da Bexiga Urinária , Idoso , Humanos , Masculino , Carcinoma de Células de Transição/cirurgia , Neoplasias Penianas/diagnóstico , Pênis/patologia , Prognóstico , Neoplasias da Bexiga Urinária/cirurgia , Neoplasias da Bexiga Urinária/patologia , Metástase NeoplásicaRESUMO
Amplification of amino acids synthesis is reported to promote tumorigenesis. The serine/glycine biosynthesis pathway is a reversible conversion of serine and glycine catalyzed by cytoplasmic serine hydroxymethyltransferase (SHMT)1 and mitochondrial SHMT2; however, the role of SHTM1 in renal cell carcinoma (RCC) is still unclear. We found that low SHMT1 expression is correlated with poor survival of RCC patients. The in vitro study showed that overexpression of SHMT1 suppressed RCC proliferation and migration. In the mouse tumor model, SHMT1 significantly retarded RCC tumor growth. Furthermore, by gene network analysis, we found several SHMT1-related genes, among which homeobox D8 (HOXD8) was identified as the SHMT1 regulator. Knockdown of HOXD8 decreased SHMT1 expression, resulting in faster RCC growth, and rescued the SHMT1 overexpression-induced cell migration defects. Additionally, ChIP assay found the binding site of HOXD8 to SHMT1 promoter was at the -456~-254 bp region. Taken together, SHMT1 functions as a tumor suppressor in RCC. The transcription factor HOXD8 can promote SHMT1 expression and suppress RCC cell proliferation and migration, which provides new mechanisms of SHMT1 in RCC tumor growth and might be used as a potential therapeutic target candidate for clinical treatment.
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Carcinoma de Células Renais , Neoplasias Renais , Animais , Humanos , Camundongos , Carcinoma de Células Renais/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Glicina , Glicina Hidroximetiltransferase/genética , Glicina Hidroximetiltransferase/química , Glicina Hidroximetiltransferase/metabolismo , Proteínas de Homeodomínio/genética , Neoplasias Renais/genética , Serina/metabolismo , Fatores de TranscriçãoRESUMO
Prostate cancer (PCa) has a certain degree of heritability, and metastasis occurs as cancer progresses. However, its underlying mechanism remains largely unknown. We sequenced four cases of cancer without metastasis, four metastatic cancer, and four benign hyperplasia tissues as controls. A total of 1839 damaging mutations were identified. Pathway analysis, gene clustering, and weighted gene co-expression network analysis were employed to find characteristics associated with metastasis. Chr19 had the most mutation density and 1p36 had the highest mutation frequency across the genome. These mutations occurred in 1630 genes, including the most frequently mutated genes TTN and PLEC, and dozens of metastasis-related genes, such as FOXA1, NCOA1, CD34, and BRCA2. Ras signalling and arachidonic acid metabolism were uniquely enriched in metastatic cancer. Gene programmes 10 and 11 showed the signatures indicating the occurrence of metastasis better. A module (135 genes) was specifically associated with metastasis. Of them, 67.41% reoccurred in program 10, with 26 genes further retained as the signature genes related to PCa metastasis, including AGR3, RAPH1, SOX14, DPEP1, and UBL4A. Our study provides new molecular perspectives on PCa metastasis. The signature genes and pathways could be served as potential therapeutic targets for metastasis or cancer progression.
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Neoplasias da Próstata , Masculino , Humanos , RNA-Seq , Neoplasias da Próstata/patologia , Perfilação da Expressão Gênica , Mutação , Sequência de Bases , Regulação Neoplásica da Expressão Gênica , Fatores de Transcrição SOXB2/genética , Fatores de Transcrição SOXB2/metabolismoRESUMO
Introduction: In addition to many cellular processes, Ca2+ is also involved in tumor initiation, progression, angiogenesis, and metastasis. The development of new tools for single-cell Ca2+ measurement could open a new avenue for cancer therapy. Methods: The all-solid-state calcium ion-selective microelectrode (Ca2+-ISµE) based on carbon fiber modified with PEDOT (PSS) as solid-contact was developed in this work, and the characteristics of the Ca2+-ISµE have also been investigated. Results: The Ca2+-ISµE exhibits a stable Nernstian response in CaCl2 solutions in the active range of 1.0 × 10-8 - 3.1 × 10-3 M with a low detection limit of 8.9 × 10-9 M. The Ca2+-ISµE can be connected to a patch clamp to fabricate a single-cell analysis platform for in vivo calcium monitoring of a single renal carcinoma cell. The calcium signal decreased significantly (8.6 ± 3.2 mV, n = 3) with severe fluctuations of 5.9 ± 1.8 mV when the concentration of K+ in the tumor microenvironment is up to 20 mM. Discussion: The results indicate a severe cell response of a single renal carcinoma cell under high K+ stimuli. The detection system could also be used for single-cell analysis of other ions by changing different ion-selective membranes with high temporal resolution.
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Studies showed that SARS-CoV-2 can directly target the kidney and induce renal damage. As the cell surface receptor for SARS-CoV-2 infection, the angiotensin-converting enzyme 2 (ACE2) plays a pivotal role for renal physiology and function. Thus, it is important to understand ACE2 through which pathway influences the pathogenesis of renal damage induced by COVID-19. In this study, we first performed an eQTL mapping for Ace2 in kidney tissues in 53 BXD mice strains. Results demonstrated that Ace2 is highly expressed and strongly controlled by a genetic locus on chromosome 16 in the kidney, with six genes (Dnase1, Vasn, Usp7, Abat, Mgrn1, and Rbfox1) dominated as the upstream modulator, as they are highly correlated with Ace2 expression. Gene co-expression analysis showed that Ace2 co-variates are significantly involved in the renin-angiotensin system (RAS) pathway which acts as a reno-protector. Importantly, we also found that Ace2 is positively correlated with Pdgf family members, particularly Pdgfc, which showed the most association among the 76 investigated growth factors. Mammalian Phenotype Ontology enrichment indicated that the cognate transcripts for both Ace2 and Pdgfc were mainly involved in regulating renal physiology and morphology. Among which, Cd44, Egfr, Met, Smad3, and Stat3 were identified as hub genes through protein-protein interaction analysis. Finally, in aligning with our systems genetics findings, we found ACE2, pdgf family members, and RAS genes decreased significantly in the CAKI-1 kidney cancer cells treated with S protein and receptor binding domain structural protein. Collectively, our data suggested that ACE2 work with RAS, PDGFC, as well as their cognate hub genes to regulate renal function, which could guide for future clinical prevention and targeted treatment for COVID-19-induced renal damage outcomes. KEY MESSAGES: ⢠Ace2 is highly expressed and strongly controlled by a genetic locus on chromosome 16 in the kidney. ⢠Ace2 co-variates are enriched in the RAS pathway. ⢠Ace2 is strongly correlated with the growth factor Pdgfc. ⢠Ace2 and Pdgfc co-expressed genes involved in the regulation of renal physiology and morphology. ⢠SARS-CoV-2 spike glycoprotein induces down-regulation of Ace2, RAS, and Pdgfc.
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COVID-19 , Animais , Camundongos , COVID-19/metabolismo , SARS-CoV-2/metabolismo , Enzima de Conversão de Angiotensina 2/genética , Peptidil Dipeptidase A/genética , Rim/metabolismo , Mamíferos/metabolismo , Ubiquitina-Proteína Ligases , Proteínas de Membrana/metabolismo , Proteínas Reguladoras de Apoptose/metabolismoRESUMO
Due to their broad functional plasticity, myeloid cells contribute to both liver injury and recovery during acetaminophen overdose-induced acute liver injury (APAP-ALI). A comprehensive understanding of cellular diversity and intercellular crosstalk is essential to elucidate the mechanisms and to develop therapeutic strategies for APAP-ALI treatment. Here, we identified the function of IFN-I in the myeloid compartment during APAP-ALI. Utilizing single-cell RNA sequencing, we characterized the cellular atlas and dynamic progression of liver CD11b+ cells post APAP-ALI in WT and STAT2 T403A mice, which was further validated by immunofluorescence staining, bulk RNA-seq, and functional experiments in vitro and in vivo. We identified IFN-I-dependent transcriptional programs in a three-way communication pathway that involved IFN-I synthesis in intermediate restorative macrophages, leading to CSF-1 production in aging neutrophils that ultimately enabled Trem2+ restorative macrophage maturation, contributing to efficient liver repair. Overall, we uncovered the heterogeneity of hepatic myeloid cells in APAP-ALI at single-cell resolution and the therapeutic potential of IFN-I in the treatment of APAP-ALI.
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Acetaminofen , Doença Hepática Induzida por Substâncias e Drogas , Animais , Camundongos , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Fígado/metabolismo , Neutrófilos/metabolismo , Macrófagos , Camundongos Endogâmicos C57BL , Glicoproteínas de Membrana/metabolismo , Receptores Imunológicos/metabolismoRESUMO
BACKGROUND: Globally, the burden of endometrial endometrioid carcinoma (EEC) increases annually. However, the histological grade of EEC remains unelucidated. We developed a novel model for predicting lymph node metastasis (LNM) in patients with endometrioid carcinoma (EC), which has not been well established. METHODS: A total of 344 patients with EEC were classified into training (n = 226) and validation (n = 118) cohorts. To develop a nomogram to predict LNM, independent predictors were defined using univariate and multivariate regression analyses. The calibration curve, area under the decision curve analysis (DCA), and receiver operating characteristic curve were used to evaluate the performance of the nomogram. RESULTS: Independent predictors of LNM in EC were identified in the univariate analysis, including mitosis; microcystic, elongated, and fragmented patterns; lymphovascular invasion (LVI); necrosis; and high-grade pattern. Mitosis, LVI, and high-grade pattern remained independent predictors of LNM in multivariate analysis. An LNM nomogram that was constructed by incorporating the five predictors showed reliable discrimination and calibration. DCA showed that the LNM nomogram scoring system had significant clinical application value. In addition, a high nomogram score (score > 150) was a significant prognosticator for survival in both LNM-positive and LNM-negative ECs. CONCLUSIONS: Our novel predictive model for LNM in patients with EC has the potential to assist surgeons in making optimal treatment decisions.
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Carcinoma Endometrioide , Feminino , Humanos , Carcinoma Endometrioide/patologia , Metástase Linfática/patologia , Nomogramas , Análise Multivariada , Invasividade Neoplásica/patologia , Linfonodos/patologiaRESUMO
The RPW8s (Resistance to Powdery Mildew 8) are atypical broad-spectrum resistance genes that provide resistance to the powdery mildew fungi. Powdery mildew of rubber tree is one of the serious fungal diseases that affect tree growth and latex production. However, the RPW8 homologs in rubber tree and their role of resistance to powdery mildew remain unclear. In this study, four RPW8 genes, HbRPW8-a, b, c, d, were identified in rubber tree, and phylogenetic analysis showed that HbRPW8-a was clustered with AtRPW8.1 and AtRPW8.2 of Arabidopsis. The HbRPW8-a protein was localized on the plasma membrane and its expression in rubber tree was significantly induced upon powdery mildew infection. Transient expression of HbRPW8-a in tobacco leaves induced plant immune responses, including the accumulation of reactive oxygen species and the deposition of callose in plant cells, which was similar to that induced by AtRPW8.2. Consistently, overexpression of HbRPW8-a in Arabidopsis thaliana enhanced plant resistance to Erysiphe cichoracearum UCSC1 and Pseudomonas syringae pv. tomato DC30000 (PstDC3000). Moreover, such HbRPW8-a mediated resistance to powdery mildew was in a salicylic acid (SA) dependent manner. Taken together, we demonstrated a new RPW8 member in rubber tree, HbRPW8-a, which could potentially contribute the resistance to powdery mildew.
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Proteínas de Arabidopsis , Arabidopsis , Ascomicetos , Hevea , Arabidopsis/metabolismo , Hevea/genética , Hevea/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Expressão Ectópica do Gene , Filogenia , Espécies Reativas de Oxigênio/metabolismo , Látex/metabolismo , Doenças das Plantas/microbiologia , Ascomicetos/fisiologia , Erysiphe , Ácido Salicílico/metabolismo , Nicotiana/metabolismo , Resistência à Doença/genéticaRESUMO
Non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH) has become the leading cause of liver disease worldwide. NASH, an advanced form of NAFL, can be progressive and more susceptible to developing cirrhosis and hepatocellular carcinoma. Currently, lifestyle interventions are the most essential and effective strategies for preventing and controlling NAFL without the development of fibrosis. While there are still limited appropriate drugs specifically to treat NAFL/NASH, growing progress is being seen in elucidating the pathogenesis and identifying therapeutic targets. In this review, we discussed recent developments in etiology and prospective therapeutic targets, as well as pharmacological candidates in pre/clinical trials and patents, with a focus on diabetes, hepatic lipid metabolism, inflammation, and fibrosis. Importantly, growing evidence elucidates that the disruption of the gut-liver axis and microbe-derived metabolites drive the pathogenesis of NAFL/NASH. Extracellular vesicles (EVs) act as a signaling mediator, resulting in lipid accumulation, macrophage and hepatic stellate cell activation, further promoting inflammation and liver fibrosis progression during the development of NAFL/NASH. Targeting gut microbiota or EVs may serve as new strategies for the treatment of NAFL/NASH. Finally, other mechanisms, such as cell therapy and genetic approaches, also have enormous therapeutic potential. Incorporating drugs with different mechanisms and personalized medicine may improve the efficacy to better benefit patients with NAFL/NASH.
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Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Fibrose , Humanos , Inflamação , Cirrose Hepática , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Transdução de Sinais/genéticaRESUMO
OBJECTIVE: Peyronie's disease (PD) is a fibrotic disorder of the penis, but effective treatments are lacking. Here, we observed the effects of rat-derived bone marrow mesenchymal stem cells (BMSCs) injection in the active phase and chronic phase in a rat model of PD, and the possible mechanism was analysed with fibroblasts derived from rat penile tunica albuginea (TA). METHODS: Thirty-two male Sprague-Dawley rats were divided into four groups. In sham group, the rats were injected with 50 µL of vehicle. In the PD group, the rats were injected with 50 µg TGF-ß1. In the PD + BMSCs early treatment group, the rats were injected with 50 µg TGF-ß1 and injected with 1 × 106 BMSCs after 1 day. In the PD + BMSCs late treatment group, the rats were injected with 50 µg TGF-ß1 and injected with 1 × 106 BMSCs after 28 days. Twenty-seven days after the last injection, the erectile function of the rats was measured, and then, penile fibrosis was analysed by histology and western blot. In vitro, fibroblasts derived from rat penile TA were used to identify a possible antifibrotic mechanism of BMSCs, and a Smad7 expression vector was used as a positive control. Fibroblasts were pretreated with the Smad7 expression vector or BMSCs for 48 h and then activated with 10 ng/mL TGF-ß1 for 24 h. Cells viability was assessed, and Smad7, collagen 3, elastase-2B and osteopontin expression levels were analysed by immunofluorescence and western blot. Furthermore, fibroblasts were transfected with Smad7 siRNA or scramble control to observe whether the effects of BMSCs could be offset. RESULTS: Erectile function obviously improved, and fibrosis of penile TA was prevented after BMSCs treatment compared with that in the rats with PD. Furthermore, the effects of BMSCs treatment in the active phase were better than those in the chronic phase. After cocultured with BMSCs, cell viability was not affected, Smad7 expression was upregulated, and collagen 3, elastase-2B and osteopontin levels were decreased in the TGF-ß1-treated fibroblasts. After transfection with Smad7 siRNA, the antifibrotic effects of BMSCs were offset. CONCLUSIONS: The antifibrotic effects of BMSCs treatment in the active phase of the PD rat model were better than those in the chronic phase. A possible mechanism of BMSCs treatment was related to increased Smad7 expression, suggesting a possible effective and safe procedure for the treatment of PD.
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Disfunção Erétil , Células-Tronco Mesenquimais , Induração Peniana , Animais , Células da Medula Óssea/metabolismo , Modelos Animais de Doenças , Disfunção Erétil/terapia , Fibrose , Humanos , Masculino , Células-Tronco Mesenquimais/metabolismo , Osteopontina/metabolismo , Elastase Pancreática , Induração Peniana/patologia , Induração Peniana/terapia , RNA Interferente Pequeno , Ratos , Ratos Sprague-Dawley , Proteína Smad7/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismoRESUMO
Curcumin is an anti-inflammatory and neuroprotective compound in turmeric. It is a potential ligand of the aryl hydrocarbon receptor (AhR) that mediates anti-inflammatory signaling. However, the AhR-mediated anti-inflammatory effect of curcumin within the brain remains unclear. We investigated the role of AhR on the curcumin effect in inflammatory astrogliosis. Curcumin attenuated lipopolysaccharide (LPS)-induced proinflammatory IL-6 and TNF-α gene expression in primary cultured rat astrocytes. When AhR was knocked down, LPS-induced IL-6 and TNF-α were increased and curcumin-decreased activation of the inflammation mediator NF-κB p65 by LPS was abolished. Although LPS increased AhR and its target gene CYP1B1, curcumin further enhanced LPS-induced CYP1B1 and indoleamine 2,3-dioxygenase (IDO), which metabolizes tryptophan to AhR ligands kynurenine (KYN) and kynurenic acid (KYNA). Potential interactions between curcumin and human AhR analyzed by molecular modeling of ligand-receptor docking. We identified a new ligand binding site on AhR different from the classical 2,3,7,8-tetrachlorodibenzo-p-dioxin site. Curcumin docked onto the classical binding site, whereas KYN and KYNA occupied the novel one. Moreover, curcumin and KYNA collaboratively bound onto AhR during molecular docking, potentially resulting in synergistic effects influencing AhR activation. Curcumin may enhance the inflammation-induced IDO/KYN axis and allosterically regulate endogenous ligand binding to AhR, facilitating AhR activation to regulate inflammatory astrogliosis.
Assuntos
Curcumina , Gliose , Receptores de Hidrocarboneto Arílico , Animais , Curcumina/farmacologia , Gliose/tratamento farmacológico , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Interleucina-6 , Ácido Cinurênico/metabolismo , Cinurenina/metabolismo , Ligantes , Lipopolissacarídeos , Simulação de Acoplamento Molecular , Ratos , Receptores de Hidrocarboneto Arílico/metabolismo , Fator de Necrose Tumoral alfa/genéticaRESUMO
MAIN CONCLUSION: A putative powdery mildew effector can elicit defense responses including reactive oxygen species and callose accumulations in model plants Nicotiana benthamiana and Arabidopsis thaliana and host plant Hevea brasiliensis. Powdery mildew fungi cause severe diseases in many agricultural plants, such as the mildew fungus Erysiphe quercicola infecting the rubber tree (Hevea brasiliensis), causing latex yield losses. However, effectors of E. quercicola were rarely functionally characterized. In this study, we identified a highly specific candidate-secreted effector protein, EqCSEP04187, from E. quercicola. This putative effector is expressed at the late stage but not the early stage during infection. The constitutive expression of EqCSEP04187 in model plants Nicotiana benthamiana and Arabidopsis thaliana elicited defense responses, as did transient expression of EqCSEP04187 in protoplasts of H. brasiliensis. Introducing EqCSEP04187 into another H. brasiliensis-associated fungal pathogen, Colletotrichum gloeosporioides, inhibited H. brasiliensis infection, and infection by E. quercicola was decreased in the A. thaliana eds1 mutant expressing EqCSEP04187. Further analysis suggests that these reductions in infection were the consequences of EqCSEP04187 eliciting defense responses. Our study suggests that this putative effector has elicitor activity that can improve plant resistance.
Assuntos
Ascomicetos , Hevea , Doenças das Plantas , Imunidade Vegetal , Borracha , ÁrvoresRESUMO
OBJECTIVE: To improve the complications of traditional laparoscopic radical cystectomy (LRC), a novel technique of extraperitoneal laparoscopic radical cystectomy (ELRC) with preservation of fertility was described. MATERIALS AND METHODS: Selected patients with bladder cancer were treated with the ELRC technique. The seminal vesicles and the vas deferens were preserved. Patient's perioperative conditions, tumor prognosis, and follow-up data were analyzed retrospectively. RESULTS: We successfully completed ELRC surgery in dozens of patients. The orthotopic ileal neobladder was placed in the extraperitoneal area, completely preserving the peritoneum. The postoperative complications caused by postoperative peritoneal loss were reduced. Moreover, the perioperative period was strictly managed with the concept of enhanced recovery after surgery (ERAS). We described the operation process in detail through a typical case of a child. All patients were free of complication at short-term follow-up, and reported satisfied sexual function with normal erections. CONCLUSION: The ELRC technique has benefits in terms of decreased ileus, reoperation rates, hospital stay, ease of management of urinary leaks, and improves the patient quality of life. ELRC is also an oncologically safe approach with excellent significant functional outcomes in carefully selected transitional cell carcinoma (TCC) or non-TCC patients who expect to maintain sexual function and fertility, especially for young patients. In addition, more patient groups and longer follow-ups are needed to further understand the safety and practicality of the ELRC technology.