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Chronic prostatitis-induced excessive inflammation and oxidative stress (OS) damage substantially affect men's quality of life. However, its treatment remains a major clinical challenge. Therefore, the identification of drugs that can decrease chronic prostatitis and oxidative stress targets is urgent and essential. CXCR4 is a classic chemokine receptor that is crucially associated with the occurrence and development of inflammation. This investigation aimed to elucidate how CXCR4 affects prostatitis regression and progression. The effect of CXCR4 on chronic prostatitis was evaluated by HE staining, immunohistochemistry, immunofluorescence, PCR, and TUNEL analyses. Furthermore, CXCR4 influence on metabolism was also evaluated by monitoring body weight, body temperature, food intake, and LC/MS. Additionally, chromatin immunoprecipitation, Western blot, and double luciferase reporter gene assays were carried out to elucidate the mechanism by which CXCR4 modulates Fads2 transcription by PPARγ. Lastly, ROS, DHE, mito-tracker, and ATP were utilized to validate the α-linolenic acid's protective effect against OS in prostate epithelial cells. It was revealed that the inhibition of CXCR4 can effectively alleviate prostatitis in mice. Furthermore, downregulating CXCR4 expression can markedly reduce the inflammatory cell infiltration in mouse prostates, decrease the elevated levels of DNA damage markers,MDA and 4-HNE, and mitigate apoptosis of prostatic epithelial cells. Moreover, treatment of CXCR4 knockdown mice with a PPARγ inhibitor revealed different degrees of changes in the above phenotypes. Mechanistically, the PPARγ protein translocates to the nucleus and serves as a transcription factor to regulate Fads2 expression, thereby altering PUFA metabolism. Additionally, in vitro experiments indicated that α-linolenic acid can effectively alleviate OS damage and RWPE-1 cell apoptosis by protecting mitochondrial function and enhancing the antioxidant capacity of prostatic epithelial cells. In conclusion, reducing the levels of CXCR4 can alleviate inflammation and OS damage in chronic prostatitis.
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Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a urinary disorder that affects youthful to middle-aged men most frequently. It has been revealed that Th17/Treg imbalance is a crucial factor in the pathophysiological mechanisms behind this disease. However, this imbalance's mechanisms are unknown. In the experimental autoimmune prostatitis (EAP) mouse model, the NLRP3 inflammasome was turned on, IL-1ß levels went up. Moreover, there exists a discernible positive association between the upsurge in IL-1ß and the perturbation of Th17/Treg equilibrium. Additionally, we have revealed that IL-1ß plays a vital role in promoting the differentiation of Naïve CD4+ T cells into the Th17 cells and enhances the conversion of Treg cells into Th17 cells. Further studies revealed that IL-1ß promotes STAT3 phosphorylation, which is what causes Treg cells to become Th17 cells. All data strongly suggest that the NLRP3 inflammatory influence Th17 cell development and the conversion of Treg cells into Th17 cells through IL-1ß, disrupting the Th17/Treg balance and exacerbating EAP inflammation. In this article, we provide new theories for the pathogenesis of CP/CPPS and propose new prevention and therapy methods.
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Enfermedades Autoinmunes , Modelos Animales de Enfermedad , Interleucina-1beta , Proteína con Dominio Pirina 3 de la Familia NLR , Prostatitis , Linfocitos T Reguladores , Células Th17 , Animales , Masculino , Prostatitis/inmunología , Prostatitis/metabolismo , Prostatitis/patología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Interleucina-1beta/metabolismo , Células Th17/inmunología , Células Th17/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Ratones , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/metabolismo , Factor de Transcripción STAT3/metabolismo , Inflamasomas/metabolismo , Diferenciación Celular , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is very common worldwide, and alcohol consumption is a notable contributing factor. Researches have shown that gut microbiota can be influenced by alcohol consumption and is an important mediator in regulating Th17 cell immunity. However, it is still unclear the exact mechanism by which alcohol exacerbates the CP/CPPS and the role of gut microbiota in this process. METHOD: We first constructed the most-commonly used animal model for CP/CPPS, the experimental autoimmune prostatitis (EAP) model, through immunoassay. Based on this, mice were divided into EAP group and alcohol-consuming EAP group. By 16S rRNA sequencing and non-targeted metabolomics analysis, differential gut microbiota and their metabolites between the two groups were identified. Subsequently, metabolomics detection targeting cholesterols was carried out to identify the exact difference in cholesterol. Furthermore, multiple methods such as flow cytometry and immunohistochemistry were used to detect the differentiation status of Th17 cells and severity of prostatitis treated with 27-hydroxycholesterol (the differential cholesterol) and its upstream regulatory factor-sterol regulatory element-binding protein 2 (SREBP2). Lastly, fecal transplantation was conducted to preliminary study on whether alcohol intake exacerbates EAP in immune receptor mice. RESULTS: Alcohol intake increased the proportion of Th17 cells and levels of related inflammatory factors. It also led to an altered gut bacterial richness and increased gut permeability. Further metabolomic analysis showed that there were significant differences in a variety of metabolites between EAP and alcohol-fed EAP mice. Metabolic pathway enrichment analysis showed that the pathways related to cholesterol synthesis and metabolism were significantly enriched, which was subsequently confirmed by detecting the expression of metabolic enzymes. By targeting cholesterol synthesis, 27-hydroxycholesterol was significantly increased in alcohol-fed EAP mice. Subsequent mechanistic research showed that supplementation with 27-hydroxycholesterol could aggravate EAP and promote Th17 cell differentiation both in vivo and in vitro, which is regulated by SREBP2. In addition, we observed that fecal transplantation from mice with alcohol intake aggravated EAP in immunized recipient mice fed a normal diet. CONCLUSION: Our study is the first to show that alcohol intake promotes Th17 cell differentiation and exacerbates EAP through microbiota-derived cholesterol biosynthesis.
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Consumo de Bebidas Alcohólicas , Enfermedades Autoinmunes , Diferenciación Celular , Colesterol , Modelos Animales de Enfermedad , Microbioma Gastrointestinal , Ratones Endogámicos C57BL , Prostatitis , Células Th17 , Animales , Masculino , Células Th17/inmunología , Prostatitis/inmunología , Prostatitis/microbiología , Prostatitis/metabolismo , Prostatitis/inducido químicamente , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/inmunología , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/inducido químicamente , Ratones , Diferenciación Celular/efectos de los fármacos , Consumo de Bebidas Alcohólicas/efectos adversos , Colesterol/metabolismo , Proteína 2 de Unión a Elementos Reguladores de Esteroles/metabolismo , Proteína 2 de Unión a Elementos Reguladores de Esteroles/genéticaRESUMEN
CONTEXT: N6-methyladenosine (m6A) of RNA is involved in the progression of non-small cell lung cancer (NSCLC). OBJECTIVE: This study investigated the role of METTL14 in NSCLC and the mechanism. MATERIALS AND METHODS: Expression levels were assessed by quantitative real-time PCR and ELISA assays. Cells viability was assessed by cell counting kit-8. M6A methylation was analysed by methylated RNA immunoprecipitation (MeRIP), RIP, luciferase assay, and mRNA stability assay. RESULTS: The results showed that METTL14 was highly expressed in NSCLC tissues and cell lines. Knockdown of METTL14 inhibited the cell viability while induced ferroptosis of NSCLC cells. Mechanistically, METTL14 interacts with GPX4, mediates m6A modification of GPX4, enhances its mRNA stability, and upregulates its expression. In addition, IGF2BP1 recognises the m6A-methylated GPX4 and mediates the elevated mRNA stability. Moreover, GPX4 reversed the effects of METTL14 depletion. DISCUSSION AND CONCLUSION: The METTL14/GPX4 axis promotes NSCLC progression by inhibiting cell ferroptosis through the recognition of m6A modification mediated by IGF2BP1.
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Chronic prostatitis is one of the most common urologic diseases that troubles young men, with unclear etiology and ineffective treatment approach. Pyroptosis is a novel model of cell death, and its roles in chronic prostatitis are unknown. In this study, P2X7R, NEK7, and GSDMD-NT expression levels were detected in prostate tissues from benign prostate hyperplasia (BPH) patients and experiment autoimmune prostatitis (EAP) mice. P2X7R agonist, antagonist, NLRP3 inhibitor, and disulfiram were used to explore the roles of the P2X7R-NEK7-NLRP3 axis in prostate epithelial cell pyroptosis and chronic prostatitis development. We found that P2X7R, NEK7, and GSDMD-NT were highly expressed in the prostate epithelial cells of BPH patients with prostatic inflammation and EAP mice. Activation of P2X7R exacerbated prostatic inflammation and increased NLRP3 inflammasome component expressions and T helper 17 (Th17) cell proportion. Moreover, P2X7R-mediated potassium efflux promoted NEK7-NLRP3 interaction, and NLRP3 assembly and activation, which caused GSDMD-NT-mediated prostate epithelial cell pyroptosis to exacerbate EAP development. Disulfiram could effectively improve EAP by inhibiting GSDMD-NT-mediated prostate epithelial cell pyroptosis. In conclusion, the P2X7R-NEK7-NLRP3 axis could promote GSDMD-NT-mediated prostate epithelial cell pyroptosis and chronic prostatitis development, and disulfiram may be an effective drug to treat chronic prostatitis.
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Células Epiteliales , Quinasas Relacionadas con NIMA , Proteína con Dominio Pirina 3 de la Familia NLR , Proteínas de Unión a Fosfato , Próstata , Prostatitis , Piroptosis , Animales , Humanos , Masculino , Ratones , Enfermedades Autoinmunes/metabolismo , Células Epiteliales/metabolismo , Gasderminas , Ratones Endogámicos C57BL , Quinasas Relacionadas con NIMA/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteínas de Unión a Fosfato/metabolismo , Proteínas de Unión a Poli-ADP-Ribosa/metabolismo , Próstata/metabolismo , Prostatitis/metabolismo , Piroptosis/efectos de los fármacos , Receptores Purinérgicos P2X7/metabolismoRESUMEN
Lung adenocarcinoma (LUAD) is the most common histologic subtype of lung cancer. Angiogenesis plays a pivotal role in LUAD progression via supplying oxygen and nutrients for cancer cells. Non-coding miR-1293, a significantly up-regulated miRNA in LUAD tissues, can be potentially used as a novel biomarker for predicting the prognosis of LUAD patients. However, little information is available about the function of miR-1293 in LUAD progression especially cancer-induced angiogenesis. Herein, we found that miR-1293 knockdown could obviously attenuate LUAD-induced angiogenesis in vitro and down-regulate two most important pro-angiogenic cytokines VEGF-A and bFGF expression and secretion. Indeed, miR-1293 abrogation inactivated the angiogenesis-promoting ERK1/2 signaling characterized by decreased ERK1/2 phosphorylation and translocation from nucleus to cytoplasm. Next we found that miR-1293 knockdown reactivated the endogenous ERK1/2 pathway inhibitor Spry4 expression and Spry4 perturbance with specific siRNA transfection abolished the inhibition of ERK1/2 pathway and LUAD-induced angiogenesis by miR-1293 knockdown. Finally, with in vivo assay, we found obvious Spry4 up-regulation and VEGF-A, bFGF, ERK1/2 phosphorylation, micro-vessel density marker CD31 expression down-regulation in vivo, respectively. Collectively, these results indicated that miR-1293 knockdown could significantly attenuate LUAD angiogenesis via Spry4-mediated ERK1/2 signaling inhibition, which might be helpful for uncovering more functions of miR-1293 in LUAD and providing experimental basis for possible LUAD therapeutic strategy targeting miR-1293.
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Adenocarcinoma del Pulmón , Técnicas de Silenciamiento del Gen , Neoplasias Pulmonares , Sistema de Señalización de MAP Quinasas , MicroARNs , Neovascularización Patológica , Regulación hacia Arriba , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Neovascularización Patológica/metabolismo , Neovascularización Patológica/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Animales , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/metabolismo , Sistema de Señalización de MAP Quinasas/fisiología , Sistema de Señalización de MAP Quinasas/genética , Ratones , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones Desnudos , Masculino , Ratones Endogámicos BALB C , Células A549 , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Femenino , AngiogénesisRESUMEN
BACKGROUND: Chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS) leads to severe discomfort in males and loss of sperm quality. Current therapeutic options have failed to achieve satisfactory results. Sodium butyrate (NaB) plays a beneficial role in reducing inflammation, increasing antioxidant capacities, and improving organ dysfunction; additionally NaB has good safety prospects and great potential for clinical application. The purpose of the current research was to study the effect of NaB on CP/CPPS and the underlying mechanisms using a mouse model of experimental autoimmune prostatitis (EAP) mice. METHODS: The EAP mouse model was successfully established by subcutaneously injecting a mixture of prostate antigen and complete Freund's adjuvant. Then, EAP mice received daily intraperitoneal injections of NaB (100, 200, or 400 mg/kg/day) for 16 days, from Days 26 to 42. We then explored anti-inflammatory potential mechanisms of NaB by studying the effects of Nrf2 inhibitor ML385 and HO-1 inhibitor zinc protoporphyrin on prostate inflammation and pelvic pain using this model. On Day 42, hematoxylin-eosin staining and dihydroethidium staining were used to evaluate the histological changes and oxidative stress levels of prostate tissues. Chronic pelvic pain was assessed by applying Von Frey filaments to the lower abdomen. The levels of inflammation-related cytokines, such as interleukin (IL)-1ß, IL-6, and tumor necrosis factor were detected by enzyme-linked immunosorbent assay. The regulation of Nrf2/HO-1 signaling pathway and the expression of NLRP3 inflammasome-related protein in EAP mice were detected by western blot analysis assay. RESULTS: Compared with the EAP group, chronic pain development, histological manifestations, and cytokine levels showed that NaB reduced the severity of EAP. NaB treatment could inhibit NLRP3 inflammasome activation. Mechanism studies showed that NaB intervention could alleviate oxidative stress in EAP mice through Nrf2/HO-1 signal pathway. Nrf2/HO-1 pathway inhibitors can inhibit NaB -mediated oxidative stress. The inhibitory effect of NaB on the activation of NLRP3 inflammasome and anti-inflammatory effect can also be blocked by Nrf2/HO-1 pathway. CONCLUSIONS: NaB treatment can alleviates prostatic inflammation and pelvic pain associated with EAP by inhibiting oxidative stress and NLRP3 inflammasome activation via the Nrf2/HO-1 pathway. NaB has the potential as an effective agent in the treatment of EAP.
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Ácido Butírico , Prostatitis , Animales , Masculino , Antiinflamatorios/uso terapéutico , Ácido Butírico/uso terapéutico , Dolor Crónico/tratamiento farmacológico , Citocinas/metabolismo , Modelos Animales de Enfermedad , Inflamasomas/metabolismo , Inflamación , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/uso terapéutico , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Estrés Oxidativo , Dolor Pélvico/tratamiento farmacológico , Prostatitis/patologíaRESUMEN
BACKGROUND: Carbonic anhydrase 4 (CA4) is a member of a large family of zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide and was found to have low expression in non-small cell lung cancer (NSCLC). However, the specific role of CA4 in NSCLC and the underlying mechanisms remain unknown. METHODS: The bioinformatic analysis on lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) datasets downloaded from The Cancer Genome Atlas (TCGA) database was performed. We found that CA4 expression was lower in tumors than that in normal tissues, which were verified by Real-time PCR. Lower CA4 levels were significantly associated with higher T stages in LUAD and LUSC cohorts. Multivariate analysis showed that CA4 is an independent prognostic factor for NSCLC. Furthermore, the expression of CA4 also correlated with immune infiltration and drug sensitivity. RESULTS: Ectopic expression of CA4 decreased NSCLC cell proliferation in vitro by CCK-8 assay. CA4 caused G0/G1 cell cycle arrest by cell experiments. Mechanistic studies found that CA affects the cell cycle and inhibits cell proliferation by downregulating the expression of CDK2. CONCLUSION: The present findings highlight the role of CA4 in NSCLC and identify CA4 as a potential novel diagnostic and prognostic biomarker for the treatment of NSCLC.
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Adenocarcinoma del Pulmón , Carcinoma de Pulmón de Células no Pequeñas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Humanos , Adenocarcinoma del Pulmón/genética , Biomarcadores , Anhidrasa Carbónica IV , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , PronósticoRESUMEN
Objective: Low-intensity shockwave therapy (LiST) has been applied in the clinical treatment of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), but few studies have focused on the prediction of its therapeutic effect before treatment. Methods: Seventy-five CP/CPPS patients from our institute between July 2020 and May 2021 were enrolled and received 3 Hz, 0.25 mJ/mm2 LiST once a week over the course of four weeks. The scores of the NIH-CPSI, IPSS questionnaire and demographic features before treatment were recorded. The plasma before LiST treatment was also collected, while liquid chromatography-tandem mass spectrometry was used to detect the metabolites. Least absolute shrinkage and selection operator (LASSO) regression analysis was employed to identify the prediction metabolites and generate the metabolism score. Receiver operating characteristic curves and calibration curves were drawn to assess the prediction accuracy of the nomogram. Results: Twelve metabolites were identified at incomparable levels before and after LiST treatment. The metabolism score generated by LASSO analysis presented a perfect prediction value (AUC: 0.848, 95% CI: 0.719-0.940) in the training cohort and further increased to 0.892 (95% CI: 0.802-0.983) on the nomogram, which accompanied with the NIH-CPSI scores and age. Similar results of the metabolism score (AUC: 0.732, 95% CI: 0.516-0.889) and total nomogram (AUC: 0.968, 95% CI: 0.909-1.000) were obtained in the testing cohort. Further enrichment of the 12 metabolites indicated that the glycine and serine metabolism pathway was involved in the LiST treatment. Conclusion: We used our system to accurately and quantitatively measure plasma metabolites and establish a predictive model to identify suitable patients for LiST treatment.
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Dolor Crónico , Enfermedades de los Genitales Femeninos , Prostatitis , Enfermedades Vasculares , Enfermedad Crónica , Dolor Crónico/complicaciones , Femenino , Humanos , Masculino , Nomogramas , Dolor Pélvico/complicaciones , Dolor Pélvico/diagnóstico , Dolor Pélvico/terapia , Prostatitis/complicaciones , Síndrome , Enfermedades Vasculares/complicacionesRESUMEN
Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a very common urological disorder and has been gradually regarded as an immune-mediated disease. Multiple studies have indicated that the gut microflora plays a pivotal part in immune homeostasis and autoimmune disorder development. However, whether the gut microflora affects the CP/CPPS, and the underlying mechanism behind them remain unclear. Here, we built an experimental autoimmune prostatitis (EAP) mouse model by subcutaneous immunity and identified that its Th17/Treg frequency was imbalanced. Using fecal 16s rRNA sequencing and untargeted/targeted metabolomics, we discovered that the diversity and relative abundance of gut microflora and their metabolites were obviously different between the control and the EAP group. Propionic acid, a kind of short-chain fatty acid (SCFA), was decreased in EAP mice compared to that in controls, and supplementation with propionic acid reduced susceptibility to EAP and corrected the imbalance of Th17/Treg cell differentiation in vivo and in vitro. Furthermore, SCFA receptor G-protein-coupled receptor 43 and intracellular histone deacetylase 6 regulated by propionic acid in Th17 and Treg cells were also evaluated. Lastly, we observed that fecal transplantation from EAP mice induced the decrease of Treg cell frequency in recipient mice. Our data showed that gut dysbiosis contributed to a Th17/Treg differentiation imbalance in EAP via the decrease of metabolite propionic acid and provided valuable immunological groundwork for further intervention in immunologic derangement of CP/CPPS by targeting propionic acid.
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Dolor Crónico , Microbioma Gastrointestinal , Prostatitis , Animales , Diferenciación Celular , Humanos , Masculino , Ratones , Dolor Pélvico/metabolismo , Propionatos/farmacología , ARN Ribosómico 16S , Linfocitos T Reguladores/metabolismoRESUMEN
CD44 partcipates in multiple inflammatory reactions. Here, we aimed to investigate the role of CD44 and the ligand, hyaluronan (HA), on chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) pathogenesis. We found that CD44 was universally expressed in CD4+ lymphocytes in the peripheral blood of CP/CPPS patients. After silencing CD44 expression or delivering 4-methylumbelliferone (4-MU), the pain severity and prostatic inflammation were significantly relieved. In vitro assay found that HA/CD44 was able to regulate T helper 1 (Th1) cells differentiation, the deficiency of which diminished experimental autoimmune prostatitis (EAP) susceptibility. Bioinformatic analysis suggested that after HA or 4-MU treatment, mTOR signaling was significantly altered, and these results were confirmed by subsequent Western blotting assay. Besides, mass spectrometry and co-immunoprecipitation assays found that CD44 was able to interact with Annexin A1 (ANX A1), and this kind of interaction stabilized ANX A1 protein and maintained the activation of Akt/mTOR pathway. Meanwhile, HA-treatment-enhanced prostatic inflammation, Th1 cell differentiation, and Akt/mTOR pathway activation were reversed after silencing the expression of ANX A1 using shANX A1-lentivirus. The present study systematically investigates the functional role of HA/CD44 in CP/CPPS and identifies novel mechanisms for HA/CD44 promoting Th1 cell differentiation. Targeting the HA/CD44/ANX A1/Akt/mTOR signaling represents novel potential therapeutic strategies for patients with CP/CPPS.
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Anexina A1 , Dolor Crónico , Prostatitis , Anexina A1/genética , Anexina A1/metabolismo , Humanos , Receptores de Hialuranos/genética , Receptores de Hialuranos/metabolismo , Ácido Hialurónico , Inflamación , Masculino , Dolor Pélvico/metabolismo , Dolor Pélvico/patología , Prostatitis/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Células TH1/metabolismoRESUMEN
BACKGROUND: Chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS) is an inflammatory immune disease that is characterized by infiltrating inflammatory cells in the prostate and pelvic or by perineal pain. Receptor CXCR3modulates immune and inflammatory responses; however, the effects of CXCR3 antagonist AMG487 in the context of CP/CPPS are unknown. Therefore, we investigated the effect of AMG487 in experimental autoimmune prostatitis (EAP) mice and explored the potential functional mechanisms. METHODS: The EAP model was induced by intradermally injecting a mixture of prostate antigens and complete Freund's adjuvant on Days 0 and 28. To evaluate the effect of AMG487 on EAP mice, treatment with AMG487 and vehicle solution was conducted for the indicated period. Then, procedures were performed, including behavioral test, to evaluate the pain response to stimulation before the mice were killed and a histological assessment to evaluate the inflammation after the mice were killed. Immunofluorescence, flow cytometry, and Western blot assay were used to analyze the functional phenotype and regulation mechanism of AMG487 on T helper type 1 (Th1) cells and macrophages. RESULTS: We found high expression of CXCR3 in human benign prostate tissues with inflammation and EAP mice. The elevated CXCR3 in prostate tissues correlates with the severity of inflammation. CXCR3 antagonist AMG487 treatment ameliorated the inflammatory changes and the pelvic pain of EAP mice. AMG487 inhibits Th1 cell differentiation through the IL-12/STAT4pathway and inhibits pro-inflammatory M1 macrophages through the lipopolysaccharide/NF-κB p65signaling. AMG487 could inhibit the secretion of inflammatory mediators in EAP mice. CONCLUSION: CXCR3 antagonist AMG487 could ameliorate the inflammatory changes and the pelvic pain of EAP mice by diminishing Th1 cell differentiation and inhibiting macrophage M1 phenotypic activation. Thus, the results imply that AMG487 has the potential as an effective therapeutic agent in the prevention and treatment of EAP.
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Enfermedades Autoinmunes , Dolor Crónico , Prostatitis , Acetamidas , Animales , Diferenciación Celular , Modelos Animales de Enfermedad , Humanos , Inflamación , Macrófagos/patología , Masculino , Ratones , Dolor Pélvico/tratamiento farmacológico , Dolor Pélvico/etiología , Dolor Pélvico/metabolismo , Fenotipo , Prostatitis/patología , Pirimidinonas , Receptores CXCR3/genética , Receptores CXCR3/uso terapéuticoRESUMEN
To identify factors that could influence the treatment outcomes of low-intensity extracorporeal shock wave therapy (Li-ESWT) on chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS)-like symptoms and establish a predictive model based on these factors to precisely screen individuals who might be more suitable for Li-ESWT. This study enrolled 84 patients with CP/CPPS-like symptoms who received Li-ESWT. Patients were divided into an effective group and an ineffective group based on the reduction of their National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI). A nomogram was established based on logistic regression analyses. Then, receiver operating characteristic (ROC) curves, calibration curves and decision curve analysis (DCA) were used to evaluate the nomogram. Univariate and multivariate logistic regression analysis showed that a higher NIH-CPSI score, a habit of holding urine, alcohol consumption, and urination soon after intercourse were independent predictors of Li-ESWT efficacy (p < 0.05). The nomogram constructed based on these four indicators and the added age effectively predicted the probability of Li-ESWT effectiveness for CP/CPPS-like symptoms (0.809 [95% CI: 0.717-0.901]; Hosmer-Lemeshow: p = 0.936). This study established a predictive model for the efficacy of Li-ESWT in treating CP/CPPS-like symptoms patients and help improve the management of CP/CPPS-like symptoms.
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Dolor Crónico , Tratamiento con Ondas de Choque Extracorpóreas , Prostatitis , Enfermedad Crónica , Dolor Crónico/terapia , Tratamiento con Ondas de Choque Extracorpóreas/métodos , Conducta Alimentaria , Humanos , Estilo de Vida , Masculino , Dolor Pélvico/terapia , Prostatitis/terapia , SíndromeRESUMEN
Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a poorly understood disease. Accumulating evidence suggests that autoimmune dysfunction is involved in the development of CP/CPPS. Interleukin-17 (IL-17) is associated with the occurrence and development of several chronic autoimmune inflammatory diseases. However, the molecular mechanisms underlying the role of IL-17 in CP/CPPS are not clear. We confirmed that IL-17 was increased in the prostate tissues of experimental autoimmune prostatitis (EAP) mice. Corresponding to the increase of IL-17, neutrophil infiltration and the levels of CXCL1 and CXCL2 (CXC chemokine ligands 1 and 2) were also increased in the prostate of EAP. Treatment of EAP mice with an IL-17-neutralizing monoclonal antibody (mAb) decreased the number of infiltrated neutrophils and CXCL1 and CXCL2 levels. Depletion of neutrophils using anti-Ly6G antibodies ameliorated the inflammatory changes and hyperalgesia caused by EAP. Fucoidan, a could potent inhibitor of neutrophil migration, also ameliorate the manifestations of EAP. Our findings suggested that IL-17 promoted the production of CXCL1 and CXCL2, which triggered neutrophil chemotaxis to prostate tissues. Fucoidan might be a potential drug for the treatment of EAP via the effective inhibition of neutrophil infiltration.
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Enfermedades Autoinmunes , Dolor Crónico , Prostatitis , Animales , Quimiocina CXCL1 , Quimiocina CXCL2 , Enfermedad Crónica , Modelos Animales de Enfermedad , Humanos , Interleucina-17 , Masculino , Ratones , Infiltración Neutrófila , Dolor Pélvico , Prostatitis/tratamiento farmacológicoRESUMEN
Background: Chronic nonbacterial prostatitis (CNP) has a high incidence, low cure rate, and unclear pathogenesis. Here, we aimed to systematically identify effective diagnostic and therapeutic targets for CNP. Methods: Prostate tissues were obtained from established mouse models and negative controls and were used for mRNA array sequencing and immunohistochemistry (IHC) staining. Predominant pathways were identified based on pathway enrichment analysis and pharmaceutical experiments. We also investigated the functional role of CXCL12 on CP, a critical factor belonging to the predominant chemotaxis pathway, and employed IHC staining to explore the influence of the CXCL12/CXCR4 axis on the activation of the NF-κB, AKT, and STAT3 signaling pathways. Serum samples derived from both CNP cases and healthy controls were used to determine the secretion level of CXCL12. Results: By employing mRNA array sequencing and immunohistochemistry, we found that CXCR4, CXCL12, CD44, and OFLM4 were highly expressed in the infiltrated inflammatory T cells of the prostate tissues generated from CNP mice, while they were rarely expressed on the epithelial cells. Based on the pathway enrichment results, we applied pathway inhibitors to suppress the activity of these classic pathways. We found that targeting the CXCL12/CXCR4 axis with its specific antagonist AMD3100 remarkably alleviated inflammatory infiltration of the prostate in CNP models. Similar results were obtained when we replaced AMD3100 with adenovirus-associated virus (AAV)-shCxcl12. To clarify the potential mechanisms of how the CXCL12/CXCR4 axis influences the pathogenesis of CNP, we tested the classical downstream pathways. The results suggested that p-Akt, p-STAT3, and p-NF-κB were more highly expressed on the inflammatory cells of the prostate derived from the CNP model and were partly suppressed after applying AMD3100 or delivering AAV-shCxcl12, indicating that the CXCL12/CXCR4 axis potentially functioned through AKT/NF-κB and STAT3 signaling to influence the pathogenesis of CNP. Conclusion: Our study provides potential diagnostic biomarkers and therapeutic targets for CNP.
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REarranged during Transfection (RET) gene fusion is one of the common oncogenic variants in non-small cell lung cancers (NSCLCs). However, few RET fusion-positive cases have partner intergenic-breakpoint fusions, in which the partner breakpoint localizes to intergenic regions. Here, we report a 40-year-old Chinese female non-smoker diagnosed with minimally invasive lung adenocarcinomas (pT1bN0M0, stage IA). Targeted next-generation sequencing revealed a rare form of RET fusion in the cancerous tissue, in which an intergenic fragment upstream multiple inositol-polyphosphate phosphatase 1 gene was fused with the tyrosine kinase domain in RET. The result was validated by fluorescence in situ hybridization. To our knowledge, this novel form of RET fusion in NSCLC is reported for the first time, which expands the alteration spectrum and paves the way for the future development of specific targeted therapies.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Adulto , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Fusión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Hibridación Fluorescente in Situ , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Proteínas de Fusión Oncogénica/genética , Proteínas Proto-Oncogénicas c-ret/genéticaRESUMEN
BACKGROUND: We aimed to systematically identify novel susceptible factors related to the occurrence and development of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS)-like symptoms that were not limited to lifestyles or dietary habits in Chinese population. METHODS: We recruited participants from three centers (Shanghai [northeast], Hefei [east], and Lanzhou [northwest]) from August 2020 to June 2021. Demographics, lifestyles, dietary habits, past medical history, and national institutes of health-chronic prostatitis symptom index (NIH-CPSI) were collected from the individuals via optimized questionnaires. Logistic regression analysis and multivariate adjustment models were used to calculate the odds ratio (OR) and 95% confidence interval (95% CI) to assess the association between these variables and CP/CPPS-like symptoms. RESULTS: A total of 1851 participants were enrolled in this study (764 cases and 1087 controls). Age distributions differed between groups (median, range: 32, 18-74 vs. 29, 18-70, p < 0.001). After adjustment, physicochemical occupational hazards were identified significantly related to CP/CPPS-like symptom occurrence and development (ORoccurrence : 1.389, 95% CI: 1.031-1.870, p < 0.001; ORdevelopment : 2.222, 95% CI: 1.464-3.372, p < 0.001); besides, greater than or equal to four ejaculations per week significantly increased the likelihood of CP/CPPS-like symptoms compared with one ejaculation per week (ORoccurrence : 3.051, 95% CI: 1.598-5.827, p = 0.001). For these patients, who were easily felt gastrointestinal discomfort caused by spicy food intake, they had a higher incidence to affect with CP/CPPS-like symptoms (ORoccurrence : 2.258, 95% CI: 1.858-2.745, p < 0.001). In addition, history of drug allergy and genitourinary infections were identified as independent susceptible factors for the occurrence of CP/CPPS-like symptoms (ORoccurrence : 1.689, 95% CI: 1.007-2.834, p = 0.047; ORoccurrence : 3.442, 95% CI: 2.202-5.382, p < 0.001, respectively), while the history of rheumatic immune diseases was found tightly associated with the development of CP/CPPS-like symptoms (ORdevelopment : 2.002, 95% CI: 1.008-4.058, p = 0.048). CONCLUSION: Infection/inflammatory/immune-related disorders, novel dietary habits, and lifestyles associated with the susceptibility of CP/CPPS-like symptoms' occurrence and development are identified. Altering these irregular conditions serves as potential strategies for the treatment of patients with CP/CPPS-like symptoms.
Asunto(s)
Dolor Crónico , Prostatitis , Estudios de Casos y Controles , China , Enfermedad Crónica , Humanos , Masculino , Dolor Pélvico/epidemiología , Dolor Pélvico/etiología , Prostatitis/complicaciones , SíndromeRESUMEN
BACKGROUND: Although minimally invasive surgery has been widely carried out at present, the postoperative pain of patients with lung cancer is still one of the difficult problems to solve in clinical practice. OBJECTIVE: This study explored whether indwelling pigtail catheters after lung cancer surgery can help to reduce postoperative pain and promote the recovery of patients as soon as possible. MATERIALS AND METHODS: From June 2018 to June 2020, patients who underwent thoracoscopic radical resection of lung cancer in our hospital were randomly divided into 2 groups: the pigtail catheter group and the control group. We compared the postoperative time of thoracic catheter removal, postoperative pain score, proportion of postoperative pleural effusion, postoperative hospitalization time, and postoperative complications of the 2 groups. RESULTS: A total of 1375 patients were enrolled, including 677 patients in the pigtail catheter group and 698 patients in the control group. Compared with the control group, the pigtail catheter group had an earlier time of thoracic catheter removal, lower postoperative pain score, lower proportion of pleural effusion diagnosed by postoperative chest radiograph, and shorter postoperative average hospital stay, but there was no significant difference in postoperative complications. CONCLUSION: The application of pigtail catheters after radical resection of lung cancer can reduce postoperative pain, accelerate the recovery of patients and shorten the postoperative hospital stay and is safe and reliable in clinical application.
Asunto(s)
Neoplasias Pulmonares , Derrame Pleural , Catéteres , Tubos Torácicos , Drenaje , Humanos , Neoplasias Pulmonares/cirugía , Dolor Postoperatorio/etiología , Complicaciones Posoperatorias , Estudios RetrospectivosRESUMEN
Loss of function of tuberous sclerosis complex 1 or 2 (TSC1 or TSC2) leads to the activation of mammalian target of rapamycin complex 1 (mTORC1). Hyperactivated mTORC1 plays a critical role in tumor growth, but the underlying mechanism is still not completely elucidated. Here, by analyzing Tsc1- or Tsc2-null mouse embryonic fibroblasts, rat Tsc2-null ELT3 cells, and human cancer cells, we present evidence for the involvement of epidermal growth factor receptor (EGFR) as a downstream target of mTORC1 in tumor growth. We show that mTORC1 leads to increased EGFR expression through upregulation of runt-related transcriptional factor 1 (RUNX1). Knockdown of EGFR impairs proliferation and tumoral growth of Tsc-deficient cells, while overexpression of EGFR promotes the proliferation of the control cells. Moreover, the mTOR signaling pathway has been shown to be positively correlated with EGFR in human cancers. In addition, we demonstrated that EGFR enhances cell growth through activation of signal transducer and activator of transcription 3 (STAT3). We conclude that activation of the RUNX1/EGFR/STAT3 signaling pathway contributes to tumorigenesis caused by hyperactivated mTORC1 and should be targeted for the treatment of mTORC1-related tumors, particularly TSC.