ABSTRACT
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.
Subject(s)
Cell Differentiation , Cell-Derived Microparticles , Disease Models, Animal , Fibroblasts , Macrophages , Penile Induration , Smad7 Protein , Transforming Growth Factor beta1 , Animals , Penile Induration/metabolism , Penile Induration/drug therapy , Cell Differentiation/drug effects , Fibroblasts/metabolism , Fibroblasts/drug effects , Rats , Male , Smad7 Protein/metabolism , Smad7 Protein/genetics , Mice , Cell-Derived Microparticles/metabolism , RAW 264.7 Cells , Transforming Growth Factor beta1/metabolism , Macrophages/metabolism , Macrophages/drug effects , Rats, Sprague-Dawley , Mesenchymal Stem Cells/metabolism , Mesenchymal Stem Cells/cytologyABSTRACT
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.
ABSTRACT
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.
Subject(s)
Carcinoma, Transitional Cell , Penile Neoplasms , Urinary Bladder Neoplasms , Aged , Humans , Male , Carcinoma, Transitional Cell/surgery , Penile Neoplasms/diagnosis , Penis/pathology , Prognosis , Urinary Bladder Neoplasms/surgery , Urinary Bladder Neoplasms/pathology , Neoplasm MetastasisABSTRACT
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 tumours 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 patients prognosis remained poor (AU)
Subject(s)
Humans , Male , Aged , Neoplasms, Second Primary/diagnostic imaging , Penile Neoplasms/diagnostic imaging , Penile Neoplasms/secondary , Urinary Bladder Neoplasms/pathologyABSTRACT
BACKGROUND: Chronic Heart Failure (CHF) still affects millions of people worldwide despite great advances in therapeutic approaches in the cardiovascular field. Cardiac rehabilitation (CR) is known to improve disease-related symptoms, quality of life and clinical outcomes, yet implementation is suboptimal, a frequently low engagement in rehabilitation programs has been found globally. OBJECTIVE: To quantify diverse CR-engaged processes and elucidate associated factors of the various levels of CR engagement in CHF patients. METHODS: Discharged patients admitted from cardiology departments between May 2022 to July 2022 were enrolled by mobile phone text messaging, CHF patients from same department between August 2022 to December 2022 were enrolled by face-to-face. Individuals who met the inclusion criteria filled the questionnaires, including the generalized anxiety disorders scale, patient health questionnaire, cardiac rehabilitation inventory, patient activation measure, Tampa scale for kinesiophobia heart, social frailty, Patient Health Engagement Scale (PHE-s®). We obtained sociodemographic characteristics and clinical data from medical records. Chi-square tests and multivariable logistic regression analyses were performed to examine the factors associated with CR engagement phases. RESULTS: A total of 684 patients were included in the study. 52.49% patients were in the Adhesion phase. At the multivariate level, compared with the blackout phase process anxiety, monthly income (RMB yuan) equal to or more than 5,000 were the most important factor impacting CHF patients CR engagement. Compared with the Blackout phase, regular exercise or not, severe depression, previous cardiac-related hospitalizations 1 or 2 times, Age influenced patient CR engagement in the Arousal phase. Besides, compared with the Blackout phase, outcome anxiety and activation level were independent factors in the Eudaimonic Project phase. CONCLUSION: This study characterized CR engagement, and explored demographic, medical, and psychological factors-with the most important being process anxiety, monthly income, patient activation, severe depression, and previous cardiac-related hospitalizations. The associated factors of CR engagement were not identical among different phases. Our findings suggested that factors could potentially be targeted in clinical practice to identify low CR engagement patients, and strategies implemented to strengthen or overcome these associations to address low CR engagement in CHF patients.
Subject(s)
Cardiac Rehabilitation , Heart Failure , Humans , Cross-Sectional Studies , Quality of Life , Heart Failure/diagnosis , Heart Failure/therapy , Heart , SyncopeABSTRACT
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.
Subject(s)
Prostatic Neoplasms , Male , Humans , RNA-Seq , Prostatic Neoplasms/pathology , Gene Expression Profiling , Mutation , Base Sequence , Gene Expression Regulation, Neoplastic , SOXB2 Transcription Factors/genetics , SOXB2 Transcription Factors/metabolismABSTRACT
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.
ABSTRACT
In this paper, a three-electrode electrochemical detection system was designed. Platinum electrode was used as the counter electrode, saturated KCl electrode as reference electrode, and copper film material as working electrode, respectively. Cyclic voltammetry (CV) and chronoamperometry (i-t) methods were used for d-psicose scanning. CV results indicated that d-psicose presented the oxidation-reduction reacting procedure on the surface of copper film electrode. Testing parameters optimization was conducted using CV scanning in different scanning rates. d-psicose quantitative determination model was developed by i-t scanning results. The sensitivity was9419.1A×cm-2·mol/L, the detection limit was1.04311×10-8mol/L. The proposed method has some advantages including high sensitivity, low detection line, and fast response speed. Negative control testing results by using glucose, sucrose, and NaCl solutions demonstrated that the proposed method had good selectivity.
Subject(s)
Copper , Platinum , Sodium Chloride , Electrochemical Techniques , Electrodes , Glucose , SucroseABSTRACT
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.
Subject(s)
Erectile Dysfunction , Mesenchymal Stem Cells , Penile Induration , Animals , Bone Marrow Cells/metabolism , Disease Models, Animal , Erectile Dysfunction/therapy , Fibrosis , Humans , Male , Mesenchymal Stem Cells/metabolism , Osteopontin/metabolism , Pancreatic Elastase , Penile Induration/pathology , Penile Induration/therapy , RNA, Small Interfering , Rats , Rats, Sprague-Dawley , Smad7 Protein/metabolism , Transforming Growth Factor beta1/genetics , Transforming Growth Factor beta1/metabolismABSTRACT
AIM: This study aimed to synthesize qualitative evidence on experiences of patients with atrial fibrillation (AF) during the course of diagnosis and treatment. We addressed three main questions: (a) What were the experiences of patients with AF during the course of diagnosis and treatment? (b) How did they respond to and cope with the disease? (c) What were the requirements during disease management? DESIGN: In this study, qualitative evidence synthesis was performed using the Thomas and Harden method. DATA SOURCES: Electronic databases, including PubMed, the Cochrane Library, Embase, Web of Science, Cumulative Index to Nursing and Allied Health Literature, the China Biomedical Database, the WanFang Database, Chinese National Knowledge Infrastructure and VIP, were searched. The databases were searched from inception to August 2021. REVIEW METHODS: Two researchers independently selected studies using qualitative assessment and review instruments for quality evaluation and thematic synthesis for the data analysis. RESULTS: A total of 2627 studies were identified in the initial search and 15 studies were included. Five analytical themes were generated: 'Diagnosing AF'; 'The impact of AF on the patients'; 'Self-reorientation in the therapeutic process'; 'Living with AF and QoL'; and 'External support to facilitate coping strategies.' CONCLUSIONS: Our findings point out unique experiences of patients across the trajectory of AF related to delayed diagnosis, feelings of nonsupport, disappointment of repeated treatment failure and multiple distress associated with unpredictable symptoms. Future research and clinical practice are expected to improve the quality of medical diagnosis and treatment, optimize administrative strategy and provide diverse health support for patients with AF. IMPACT: Understanding the experiences and needs of patients with AF in the entire disease process will inform future clinical practice in AF integrated management, which would be helpful in improving the professionalism and confidence of healthcare providers. In addition, our findings have implications for improving the effectiveness of AF diagnostic and treatment services. PATIENT OR PUBLIC CONTRIBUTION: This paper presents a review of previous studies and did not involve patients or the public.
Subject(s)
Atrial Fibrillation , Adaptation, Psychological , Atrial Fibrillation/diagnosis , Atrial Fibrillation/therapy , Health Personnel , Humans , Qualitative Research , Quality of LifeABSTRACT
Objective: This study aims to explore the influence of patient activation (PA) and relational aspects on the quality of life (QoL) in patients with Atrial Fibrillation (AF) for developing measures to improve PA and QoL. Methods: A cross-sectional study was undertaken in 2021 among 190 AF patients in Nanjing, China. Research instruments included a self-designed social-demographic characteristics scale, the Patient Activation Measure (PAM), the Atrial Fibrillation Effect on Quality of Life (AFEQT). The data analysis was performed using IBM SPSS 25.0. Spearman correlation analysis, multiple linear regression analysis, and Wilcoxon rank-sum tests were used to assess the association accordingly. Results: The average AFEQT score for the 190 AF patients was 69.32 ± 14.52. The distribution of activation Levels 1, 2, 3, and 4, were where 4.7, 34.2, 47.4, and 13.7%, respectively. The multiple linear regression analysis revealed that patient activation, work status, and cardiac rehabilitation of AF patients predicted AF-related QoL (ß = 0.270, -0.205, and 0.183, respectively; all P < 0.05). The influences of PA level on subdimensions of AF-related QoL were as follows: symptoms, daily activities and treatment concern. Conclusion: The level of QoL of patients with AF was moderate. Higher levels of patient activation in those with AF were associated with milder symptoms, more positive daily activities and fewer treatment concern. Based on our findings, we suggest that healthcare personnel should encourage AF patients to take active participation in cardiac rehabilitation, disease self-management and foster progression of PA level. Future research is warranted to develop tailor-made interventions aimed at the activation level.
ABSTRACT
Increasing lines of evidence identified that dexmedetomidine (DEX) exerted protective effects against sepsis-stimulated acute lung injury via anti-inflammation, anti-oxidation and anti-apoptosis. However, the mechanisms remain unclear. Herein, we investigated whether DEX afforded lung protection by regulating the process of mitochondrial dynamics through the HIF-1a/HO-1 pathway in vivo and in vitro. Using C57BL/6J mice exposed to lipopolysaccharide, it was initially observed that preemptive administration of DEX (50µg/kg) alleviated lung pathologic injury, reduced oxidative stress indices (OSI), improved mitochondrial dysfunction, upregulated the expression of HIF-1α and HO-1, accompanied by shifting the dynamic course of mitochondria into fusion. Moreover, HO-1-knockout mice or HO-1 siRNA transfected NR8383 cells were pretreated with HIF-1α stabilizer DMOG and DEX to validate the effect of HIF-1a/HO-1 pathway on DEX-mediated mitochondrial dynamics in a model of endotoxin-induced lung injury. We found that pretreatment with DEX and DMOG distinctly relieved lung injury, decreased the levels of mitochondrial ROS and mtDNA, reduced OSI, increased nuclear accumulation of HIF-1a and HO-1 protein in wild type mice but not HO-1 KO mice. Similar observations were recapitulated in NC siRNA transfected NR8383 cells after LPS stimulation but not HO-1 siRNA transfected cells. Concertedly, DEX reversed the impaired mitochondrial morphology in LPS stimulated-wild type mice or NC siRNA transfected NR8383 cells, upregulated the expression of mitochondrial fusion protein, while downregulated the expression of fission protein in HIF-1a/HO-1 dependent pathway. Altogether, our data both in vivo and in vitro certified that DEX treatment ameliorated endotoxin-induced acute lung injury by preserving the dynamic equilibrium of mitochondrial fusion/fission through the regulation of HIF-1a/HO-1 signaling pathway.