ABSTRACT
Renal ischemia-reperfusion injury (IRI) is one of the most important causes of acute kidney injury (AKI). Interleukin (IL)-37 has been suggested as a novel anti-inflammatory factor for the treatment of IRI, but its application is still limited by its low stability and delivery efficiency. In this study, we reported a novel engineered method to efficiently and easily prepare neutrophil membrane-derived vesicles (N-MVs), which could be utilized as a promising vehicle to deliver IL-37 and avoid the potential side effects of neutrophil-derived natural extracellular vesicles. N-MVs could enhance the stability of IL-37 and targetedly deliver IL-37 to damaged endothelial cells of IRI kidneys via P-selectin glycoprotein ligand-1 (PSGL-1). In vitro and in vivo evidence revealed that N-MVs encapsulated with IL-37 (N-MV@IL-37) could inhibit endothelial cell apoptosis, promote endothelial cell proliferation and angiogenesis, and decrease inflammatory factor production and leukocyte infiltration, thereby ameliorating renal IRI. Our study establishes a promising delivery vehicle for the treatment of renal IRI and other endothelial damage-related diseases.
Subject(s)
Endothelial Cells , Interleukin-1 , Kidney , Neutrophils , Reperfusion Injury , Animals , Reperfusion Injury/drug therapy , Interleukin-1/administration & dosage , Male , Humans , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Kidney/metabolism , Neutrophils/drug effects , Neutrophils/metabolism , Mice, Inbred C57BL , Apoptosis/drug effects , Human Umbilical Vein Endothelial Cells , Membrane Glycoproteins/administration & dosage , Cell Proliferation/drug effects , Acute Kidney Injury , Mice , Nanoparticles/administration & dosage , Nanoparticles/chemistryABSTRACT
Thraustochytrids are marine microorganisms known for their fast growth and ability to store lipids, making them useful for producing polyunsaturated fatty acids (PUFAs), biodiesel, squalene, and carotenoids. However, the high cost of production, mainly due to expensive fermentation components, limits their wider use. A significant challenge in this context is the need to balance production costs with the value of the end products. This review focuses on integrating the efficient utilization of waste with Thraustochytrids fermentation, including the economic substitution of carbon sources, nitrogen sources, and fermentation water. This approach aligns with the 3Rs principles (reduction, recycling, and reuse). Furthermore, it emphasizes the role of Thraustochytrids in converting waste into lipid chemicals and promoting sustainable circular production models. The aim of this review is to emphasize the value of Thraustochytrids in converting waste into treasure, providing precise cost reduction strategies for future commercial production.
Subject(s)
Conservation of Natural Resources , Fermentation , Stramenopiles , Waste Products , Biofuels , Biotechnology/economics , Biotechnology/methods , Carbon/metabolism , Fatty Acids, Unsaturated/metabolism , Lipids/biosynthesis , Lipids/chemistry , Stramenopiles/metabolismABSTRACT
Schizochytrium sp. hasreceived much attention for itsability to synthesize and accumulate high-level docosahexaenoic acid (DHA), which can reach nearly 40 % of total fatty acids. In this study, the titer of DHA in Schizochytrium sp. was successfully improved by enhancing DHA storage through overexpressing the diacylglycerol acyltransferase (ScDGAT2C) gene, as well as optimizing the supply of precursors and cofactors required for DHA synthesis by response surface methodology. Notably, malic acid, citric acid, and biotin showed synergistic and time-dependent effects on DHA accumulation. The maximum lipid and DHA titers of the engineered Schizochytrium sp. strain reached 84.28 ± 1.02 g/L and 42.23 ± 0.69 g/L, respectively, with the optimal concentration combination (1.62 g/L malic acid + 0.37 g/L citric acid + 8.28 mg/L biotin) were added 48 h after inoculation. This study provides an effective strategy for improving lipid and DHA production in Schizochytrium sp.
Subject(s)
Fatty Acids , Malates , Stramenopiles , Fermentation , Docosahexaenoic Acids , Biotin , Stramenopiles/genetics , Citric AcidABSTRACT
Insufficient vascularization is still a challenge that impedes bladder tissue engineering and results in unsatisfied smooth muscle regeneration. Since bladder regeneration is a complex articulated process, the aim of this study is to investigate whether combining multiple pathways by exploiting a combination of biomaterials, cells, and bioactive factors, contributes to the improvements of smooth muscle regeneration and vascularization in tissue-engineered bladder. Autologous endothelial progenitor cells (EPCs) and bladder smooth muscle cells (BSMCs) are cultured and incorporated into our previously prepared porcine bladder acellular matrix (BAM) for bladder augmentation in rabbits. Simultaneously, exogenous vascular endothelial growth factor (VEGF) and platelet-derived growth factor BB (PDGF-BB) mixed with Matrigel were injected around the implanted cells-BAM complex. In the results, compared with control rabbits received bladder augmentation with porcine BAM seeded with BSMCs, the experimental animals showed significantly improved smooth muscle regeneration and vascularization, along with more excellent functional recovery of tissue-engineered bladder, due to the additional combination of autologous EPCs and bioactive factors, including VEGF and PDGF-BB. Furthermore, cell tracking suggested that the seeded EPCs could be directly involved in neovascularization. Therefore, it may be an effective method to combine multiple pathways for tissue-engineering urinary bladder.
Subject(s)
Endothelial Progenitor Cells , Urinary Bladder , Swine , Rabbits , Animals , Urinary Bladder/blood supply , Urinary Bladder/metabolism , Endothelial Progenitor Cells/metabolism , Vascular Endothelial Growth Factor A/pharmacology , Vascular Endothelial Growth Factor A/metabolism , Becaplermin/pharmacology , Becaplermin/metabolism , Tissue Engineering/methods , RegenerationABSTRACT
Schizochytrium sp., a microalga with high lipid content, holds the potential for co-producing docosahexaenoic acid (DHA) and carotenoids. In this study, the ability of Schizochytrium sp. to naturally produce carotenoids was systematically explored. Further, by enhancing the precursor supply of geranylgeranyl diphosphate, regulating carbon source through sugar limitation fermentation and employing a combination of response surface methodology and artificial neural networks to precisely optimize nitrogen sources, a new record of 43-fold increase in ß-carotene titer was achieved in the 5L bioreactor (653.2 mg/L). Meanwhile, a high DHA content was maintained (13.4 g/L). Furthermore, the use of corn stover hydrolysate has effectively lowered the production costs of carotenoid and DHA while sustaining elevated production levels (with total carotenoid titer and DHA titer reached 502.0 mg/L and 13.2 g/L, respectively). This study offers an efficient and cost-effective method for the co-production of carotenoid and DHA in Schizochytrium sp..
Subject(s)
Docosahexaenoic Acids , Stramenopiles , Fermentation , Carotenoids , Bioreactors , Genetic EngineeringABSTRACT
Previous clinical studies have found that the efficacy of processed Qixue Shuangbu Prescription has been significantly improved in the treatment of chronic heart failure. However, the absorbed constituents and synergistic mechanisms of processed Qixue Shuangbu Prescription to enhance the therapeutic effect of chronic heart failure remain unclear. In this study, we propose an integrated strategy combining plasma metabolomics, network pharmacology, and molecular docking to study the absorbed constituents and synergistic mechanisms of processed Qixue Shuangbu Prescription. A total of 34 prototype constituents and 24 metabolites were identified in rat plasma after administration of crude and processed Qixue Shuangbu Prescription. As a result, six potential absorbed constituents and six potential targets for the treatment of chronic heart failure were identified. In addition, the result of molecular docking indicated that the key constituents exhibited good affinity to hub targets. This study showed that the multiomics approach could effectively clarify absorbed constituents and synergistic mechanisms of traditional Chinese medicine processing from a new perspective.
Subject(s)
Drugs, Chinese Herbal , Heart Failure , Rats , Animals , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/therapeutic use , Molecular Docking Simulation , Medicine, Chinese Traditional/methods , Metabolomics/methods , Computational Biology , Heart Failure/drug therapyABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Qixue Shuangbu Prescription (QSP) is a classical traditional Chinese medicine prescription, which has widely used for the treatment of chronic heart failure (CHF). Preliminary clinical studies have shown that the efficacy of processed QSP (P-QSP) in treating CHF is greater than crude QSP (C-QSP). However, the pharmacokinetic characteristics of its major bioactive components under pathological conditions are unclear. AIM OF STUDY: This study aims to compare pharmacokinetics of seven bioactive components after oral administration of C-QSP and P-QSP in CHF model rats. MATERIALS AND METHODS: Ginsenoside Rb1, ginsenoside Re, ginsenoside Rg1, ferulic acid, astragaloside IV, calycosin-7-O-ß-D-glucoside, and paeoniflorin in QSP were used as the target components. CHF model in rats was induced by the intraperitoneal injection of doxorubicin. A microdialysis combined with UPLC-MS/MS method was first established to compare the pharmacokinetics of seven major bioactive components in CHF model rats after oral administration of C-QSP and P-QSP. RESULTS: This method was successfully applied to the pharmacokinetic investigation of seven major components of C-QSP and P-QSP following oral administration in CHF model rats. Compared with the C-QSP group, the Cmax, AUC0-t and AUC0-∞ of ginsenoside Rb1, ginsenoside Re, ginsenoside Rg1, ferulic acid, astragaloside IV and paeoniflorin significantly increased (P < 0.05) in the P-QSP group, which suggested that the absorptivity and bioavailability were increased. Lower T1/2, MRT0-t of ginsenoside Rb1, gerulic acid and higher T1/2, MRT0-t of ginsenoside Rb1, astragaloside IV, paeoniflorin in the P-QSP group, which indicated that eliminated more quickly or slowly, respectively. CONCLUSIONS: The pharmacokinetic parameters of bioactive components were significantly changed for better bioavailability and absorption, longer lasting time elimination, which were beneficial for enhancing therapeutic efficacy in the P-QSP group. This study will provide a new perspective to explain the pharmacokinetic-pharmacodynamic correlation of P-QSP on the treatment of CHF.
Subject(s)
Drugs, Chinese Herbal , Heart Failure , Rats , Animals , Rats, Sprague-Dawley , Tandem Mass Spectrometry/methods , Chromatography, High Pressure Liquid/methods , Chromatography, Liquid , Microdialysis , Prescriptions , Heart Failure/drug therapy , Administration, OralABSTRACT
The present study was performed to assess the protective effect of fluoxetine (FLX) on renal ischemia-reperfusion injury (IRI) via the regulation of miR-450b-5p/Nrf2 axis in male rats. In vivo, these male rats were randomly divided into different treatment groups. The rats were administered with FLX (20 mg/kg, intraperitoneally) once daily for 3 days before operation. The pathomorphological changes of renal tissues were assessed by histological examination and Masson staining. In vitro, HK-2 cells were used to detect the activity by CCK-8 assay in Hypoxia/Reoxygenation (H/R) group and Hypoxia/Reoxygenation+Fluoxetine (H/R+FLX) group. In addition, the oxidative stress biomarkers were evaluated. Subsequently, Nrf2, NF-κB, and Nrf2-dependent antioxidant enzymes, were detected by Western blot assay. In vivo, the pathological changes and serological renal function were significantly relieved in the rats with the pre-treatment of FLX, compared to IRI group. After FLX stimulation, the expression levels of oxidative stress indices significantly decreased, while tissue antioxidant indices significantly increased, compared to IRI group. The differently expressed miRNAs on renal IRI in male rats were screened out by miRNA microarray, especially showing that miR-450b-5p was selected as the target miRNA. Following miR-450b-5p agomir injection, the pathological changes and oxidative stress biomarkers significantly aggravated, whether in IRI group or IRI+FLX group. Bioinformatics analysis and double-luciferase reporter assay demonstrated that miR-450b-5p directly targeted Nrf2. The expression level of NF-κB significantly increased, while the expression levels of Nrf2 and Nrf2-dependent antioxidant enzymes significantly decreased after miR-450b-5p agomir injection. Furthermore, the expression levels of Nrf2 and it-dependent antioxidant enzymes were apparently increased in ischemic kidney after the transfection of miR-450b-5p mimic+recombination protein Nrf2, as well as the decreased expression levels of intracellular ROS and iNOS. In vitro, FLX significantly increased HK-2 cell viability, and relieved H/R HK-2 cell oxidative injury via down-regulating ROS and iNOS. In addition, H/R-induced oxidative damage was recovered with miR-450b-5p mimic and recombination protein Nrf2. Consequently, FLX played an important protective role in renal IRI-induced oxidative damage by promoting antioxidation via targeting miR-450b-5p/Nrf2 axis.
ABSTRACT
Protein posttranslational modification regulates several biological mechanisms, including tumor progression. In this study, we show that the mitochondrial Sirtuin 4 (SIRT4), which has ADP-ribosylation activity, plays a role in prostate cancer (PCa) progression. Firstly, SIRT4 expression was verified in PCa tissues and cell lines by quantitative real-time PCR (qRT-PCR) and western blotting. Subsequently, we established stable PC-3 and 22rv1 cells that overexpressed SIRT4 and knocked down SIRT4, respectively. The functions of SIRT4 in PCa were explored through various phenotype experiments. The mechanism underlying the functions of SIRT4 was investigated through western blotting, immunoprecipitation, immunofluorescence, and nuclear and cytoplasmic extraction assays. We revealed that SIRT4 inhibited cell progression both in vivo and in vitro. Mechanistically, on the one hand, SIRT4 promoted the ADP-ribosylation of glutamate dehydrogenase 1 to inhibit the glutamine metabolism pathways. On the other hand, SIRT4 inhibited the phosphorylation of AKT, thereby affecting p21 phosphorylation and its cellular localization for cell cycle arrest. In conclusion, our study indicates that SIRT4 is directly associated with PCa progression and could be a novel target for PCa therapy.
ABSTRACT
Background: Prolyl 4-hydroxylase subunit alpha 1 (P4HA1) provides the majority of the catalytic site of the active P4H enzyme. Emerging evidence has revealed that P4HA1 participates in the initiation and development of several malignant tumors. However, a pan-cancer analysis of P4HA1 has not been performed. Methods: In this study, we carried out an in-depth analysis of the expression patterns and prognostic value of P4HA1 using the datasets of The Cancer Genome Atlas (TCGA) and Kaplan-Meier Plotter. Genomic and epigenetic alterations of P4HA1 and the correlation of P4HA1 with DNA methylation in different cancers were also analyzed across multiple databases. In addition, the purity-adjusted partial Spearman's correlation test was utilized to evaluate the correlation between P4HA1 expression and immune cell infiltration. We also further explored the biological function and mechanism of P4HA1 in renal cell carcinoma (RCC). Results: We characterized the expression profiles and prognostic values of P4HA1 in multiple cancer types. P4HA1 expression was increased in clear cell renal cell carcinoma (RCC) compared to adjacent normal tissues, and P4HA1 positively correlated with the overall survival (OS) and disease-free survival (DFS) in papillary RCC. In addition, a positive correlation between P4HA1 expression and immune cell infiltration was observed in clear cell RCC. We also identified a strong correlation between P4HA1 expression and immune checkpoint gene expression, microsatellite instability, and tumor mutation burden in chromophobe RCC. Finally, the results of in vitro experiments verified that overexpression of P4HA1 promoted the proliferation, migration, invasion, and epithelial-mesenchymal transition of RCC cells. Conclusion: Overall, our study has suggested that P4HA1 might play a significant role in tumorigenesis in RCC and may be a prognostic biomarker and therapeutic target for several malignant tumors, including RCC.
ABSTRACT
Endothelial progenitor cells (EPCs), which are a type of stem cell, have been found to have strong angiogenic and tissue repair capabilities. Extracellular vesicles (EVs) contain many effective components, such as cellular proteins, microRNAs, messenger RNAs, and long noncoding RNAs, and can be secreted by different cell types. The functions of EVs depend mainly on their parent cells. Many researchers have conducted functional studies of EPC-derived EVs (EPC-EVs) and showed that they exhibit therapeutic effects on many diseases, such as cardiovascular disease, acute kidney injury, acute lung injury, and sepsis. In this review article, we comprehensively summarized the biogenesis and functions of EPCs and EVs and the potent role of EPC-EVs in the treatment of various diseases. Furthermore, the current problems and future prospects have been discussed, and further studies are needed to compare the therapeutic effects of EVs derived from various stem cells, which will contribute to the accelerated translation of these applications in a clinical setting.
Subject(s)
Endothelial Progenitor Cells , Extracellular Vesicles , MicroRNAs , RNA, Long Noncoding , Sepsis , Endothelial Progenitor Cells/metabolism , Extracellular Vesicles/metabolism , Humans , MicroRNAs/metabolism , RNA, Long Noncoding/metabolism , Sepsis/metabolismABSTRACT
PURPOSE: To develop and validate a nomogram for preoperative predicting the pathological upgrading of prostate cancer (PCa). METHODS: The prediction model was developed in a primary cohort that consisted of 208 PCa patients. All patients included in the study possessed both biopsy pathology specimens and radical prostatectomy pathology specimens, and completed the (68 Ga-prostate-specific membrane antigen [PSMA]) positron emission tomography/computed tomography (PET/CT) detection. The R function "createDataPartition" was used in a 7:3 ratio to randomly divide the patients into training and validation cohorts. In the training cohort, the independent predictors of pathological upgrading of PCa were determined by univariate analysis, univariate regression analysis and multivariate regression analysis. Based on these independent predictors, a nomogram was developed, and its performance was evaluated by receiver operating characteristic (ROC) curve, area under the curve (AUC) and calibration curve of training cohort and validation cohort. RESULTS: The nomogram incorporated five independent predictors including prostate volume (PV), SUVmax of the 68 Ga-PSMA PET/CT examination on prostate lesions (SUVmax ), body mass index (BMI); percentage of cancer positive biopsy cores (PPC) and biopsy International Society of Urological Pathology (ISUP) grade. The nomogram showed good diagnostic accuracy for the pathological upgrading of both the training cohort and the validation cohort (AUC = 0.818 and 0.806, respectively). The calibration curves for the two cohorts both showed optimal agreement between nomogram prediction and actual observation. CONCLUSIONS: We developed and validated a nomogram to accurately predict the risk of pathological upgrading after radical PCa surgery, which can provide accurate basis for therapeutic schedule and prognostic data of PCa patients.
Subject(s)
Positron Emission Tomography Computed Tomography , Prostatic Neoplasms , Gallium Radioisotopes , Humans , Male , Nomograms , Positron Emission Tomography Computed Tomography/methods , Prostate/pathology , Prostatectomy/methods , Prostatic Neoplasms/pathologyABSTRACT
Urethral stricture (US) remains a challenging disease without effective treatment options due to the high recurrence rate. This study aims to evaluate the preventive effect of uncultured adipose derived stromal vascular fraction (SVF) on urethral fibrosis in a rat model of US. Results demonstrated that US rats displayed hyperechogenic urethral wall with a narrowed lumen compared with sham rats, while SVF rats exhibited less extensive urethral changes. By histology, US rats showed obvious submucosal fibrosis in the urethral specimens, while SVF rats exhibited mild submucosal fibrosis with less extensive tissue changes. Furthermore, US rats showed increased gene and protein expression of collagen I (2.0 ± 0.2, 2.2 ± 0.2, all were normalized against GAPDH, including the following), collagen III (2.5 ± 0.3, 1.2 ± 0.1), and TGFß1R (2.8 ± 0.3, 1.9 ± 0.2), while SVF cells administration contributed to decreased gene and protein expression of collagen I (1.6 ± 0.2, 1.6 ± 0.2), collagen III (1.8 ± 0.4, 0.9 ± 0.1), and TGFß1R (1.8 ± 0.3, 1.3 ± 0.2), in parallel with the improvement of vascularization and increased expression of VEGF (1.7 ± 0.1) and bFGF (3.1 ± 0.3). Additionally, SVF served anti-inflammatory effect through regulation of inflammatory cytokines and cells, accompanied with conversion of the macrophage phenotype. Our findings suggested that uncultured SVF presented an inhibitory effect on stricture formation at an early stage of urethral fibrosis.
Subject(s)
Oral Submucous Fibrosis , Urethral Stricture , Adipose Tissue/metabolism , Animals , Collagen/metabolism , Fibrosis , Oral Submucous Fibrosis/metabolism , Rats , Stromal Cells/metabolism , Stromal Vascular Fraction , Urethral Stricture/metabolism , Urethral Stricture/prevention & controlABSTRACT
BACKGROUND: Polo-like kinase 1 (PLK1) belongs to polo-like kinases family and affects cell cycles. However, the role of PLK1 in some malignant tumors remains unclear. METHODS: To obtain a comprehensive view of PLK1 expression patterns, public databases including The Cancer Genome Atlas, Cancer Cell Line Encyclopedia, the Genotype-Tissue Expression, and human cell landscape databases were employed. The correlation of PLK1 expression with prognosis, immune infiltrations, immune checkpoint genes, tumor mutational burden (TMB), microsatellite instability (MSI), mismatch repair (MMR), and DNA methylation was examined. Besides, we validated the results of clear cell renal cell carcinoma (ccRCC) in two cohorts, with quantitative real-time PCR, Western blot, and loss-of-function experiments. RESULTS: By mining public datasets, we discovered that PLK1 expression in tumor tissues and cancer cell lines displayed heterogeneity compared to normal controls across different cancers. Besides, high expression of PLK1 results in shorter survival time in 15 cancer types, especially in ccRCC. PLK1 expression showed strong association with immune cell infiltration and immune checkpoint genes across cancer types. Moreover, we identified a strong association between PLK1 expression and TMB, MSI MMR, and DNA methylation. PLK1 was validated to be highly expressed in ccRCC tissues and promote ccRCC cell proliferation, migration, invasion, and cell cycle. Mechanistically, PLK1 could regulate forkhead box protein M1 and target cell cycle-associated genes to participate in cell cycle control. CONCLUSION: PLK1 has important prognostic value and is associated with tumor immunity across cancer types including ccRCC.
ABSTRACT
BACKGROUND: Underactive bladder (UAB) is a common clinical problem but related research is rarely explored. As there are currently no effective therapies, the administration of adipose stromal vascular fraction (ad-SVF) provides a new potential method to treat underactive bladder. METHODS: Male Sprague-Dawley rats were induced by partial bladder outlet obstruction (PBOO) for four weeks and randomly divided into three groups: rats treated with PBS (Sham group); rats administrated with ad-SVF (ad-SVF group) and rats performed with ad-SVF spheroids (ad-SVFsp group). After four weeks, urodynamic studies were performed to evaluate bladder functions and all rats were sacrificed for further studies. RESULTS: We observed that the bladder functions and symptoms of UAB were significantly improved in the ad-SVFsp group than that in the Sham group and ad-SVF group. Meanwhile, our data showed that ad-SVF spheroids could remarkably promote angiogenesis, suppress cell apoptosis and stimulate cell proliferation in bladder tissue than that in the other two groups. Moreover, ad-SVF spheroids increased the expression levels of bFGF, HGF and VEGF-A than ad-SVF. IVIS Spectrum small-animal in vivo imaging system revealed that ad-SVF spheroids could increase the retention rate of transplanted cells in bladder tissue. CONCLUSIONS: Ad-SVF spheroids improved functions and symptoms of bladder induced by PBOO, which contributes to promote angiogenesis, suppress cell apoptosis and stimulate cell proliferation. Ad-SVF spheroids provide a potential treatment for the future patients with UAB.
Subject(s)
Urinary Bladder Neck Obstruction , Urinary Bladder, Underactive , Animals , Male , Rats , Adipose Tissue/metabolism , Rats, Sprague-Dawley , Stromal Cells/metabolism , Stromal Vascular Fraction , Urinary Bladder/metabolism , Urinary Bladder Neck Obstruction/metabolism , Urinary Bladder Neck Obstruction/therapy , Urinary Bladder, Underactive/metabolismABSTRACT
BACKGROUND: Cabazitaxel has been applied to the treatment of castration-resistant prostate cancer (CRPC), but the molecular mechanism remained to be fully understood. METHODS: After treatment with Cabazitaxel alone or in combination with ionizing radiation (IR), CRPC cell viability, proliferation and apoptosis were determined by Cell Counting Kit-8 (CCK-8) assay, colony formation, and flow cytometry, respectively. Tumor volume was measured after the establishment of animal xenograft model. Relative expressions of proteins related to apoptosis (B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), and cleaved caspase 3) and phosphoinositide 3-kinase (PI3K)/AKT pathway were measured by Western blot, and the phosphorylated-PI3K/PI3K and p-AKT/AKT ratios were determined as well. RESULTS: Cell viability and proliferation were suppressed, and apoptosis was promoted in CRPC cells after Cabazitaxel treatment alone, accompanied with upregulated expressions of Bax and cleaved caspase 3 and downregulated Bcl-2 expression. Also, a single treatment with Cabazitaxel resulted in suppression of PI3K/AKT pathway activation, along with downregulated expressions of p-PI3K and p-AKT and a reduced ratio of p-PI3K/PI3K to p-AKT/AKT. Meanwhile, Cabazitaxel enhanced the effects of IR on suppressing survival and promoting apoptosis in CRPC cells through downregulating Bcl-2 and upregulating Bax and cleaved caspase 3. However, Cabazitaxel suppressed IR-induced PI3K/AKT pathway activation via downregulating p-PI3K and p-AKT, leading to a reduced ratio of p-PI3K/PI3K to p-AKT/AKT. Furthermore, Cabazitaxel further promoted the effects of IR on suppressing tumor growth in vivo. CONCLUSION: Cabazitaxel inhibited the proliferation and promoted the apoptosis and radiosensitivity of CRPC cells, which is related to the suppression of PI3K/AKT pathway, providing a therapeutic method for CRPC in clinical practice.
ABSTRACT
The expression of prostate-specific membrane antigen (PSMA) is strikingly upregulated during oncogenesis and prostate cancer (PCa) progression, but the functions of this antigen in PCa remain unclear. Here, we constructed PSMA-knockdown LNCaP and 22rv1 cell lines and performed metabonomic and transcriptomic analyses to determine the effects of PSMA on PCa metabolism and transcription. The metabolism of arginine and proline was detected using specific kits. The mRNA and protein expression levels of the identified differentially expressed genes were quantified by RT-qPCR and Western blotting. The proliferation of each cell line was evaluated through CCK-8, EdU and colony formation assays. The migration and invasion abilities of each cell line were detected using wound healing and transwell assays, respectively. PSMA knockdown led to metabolic disorder and abnormal transcription in PCa and resulted in inhibition of the proliferation and metastasis of PCa cells in vitro and in vivo. The depletion of PSMA also promoted the biosynthesis of arginine and proline, inhibited the expression of AR and PSA, and induced the expression of c-Fos and FosB. PSMA plays an important role in the metabolism, proliferation and metastasis of human PCa and may be a promising therapeutic target.
Subject(s)
Antigens, Surface/genetics , Arginine/metabolism , Glutamate Carboxypeptidase II/genetics , Proline/metabolism , Prostatic Neoplasms/pathology , Proto-Oncogene Proteins c-fos/genetics , Receptors, Androgen/genetics , Animals , Cell Line, Tumor , Cell Movement , Cell Proliferation , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Gene Knockdown Techniques , Humans , Male , Metabolomics , Mice , Neoplasm Transplantation , Prostatic Neoplasms/genetics , Prostatic Neoplasms/metabolismABSTRACT
This paper presents a meta-analysis regarding the detection rate (DR) of fluorine-18 (18F)-labeled prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) in the management of patients with prostate cancer (PCa). Relevant studies regarding 18F-PSMA PET/CT in the management of PCa published until June 1, 2021, were electronically searched in online databases including EMBASE, PubMed, and Web of Science. The primary outcome was the DR of 18F-PSMA PET/CT in managing PCa patients, while the secondary outcome was the DR of 18F-PSMA PET/CT according to Gleason scores and serum prostate-specific antigen (PSA) level. The pooled DR was calculated on a per-patient basis, with pooled odd ratios and 95% confidence intervals (CIs). In total, 17 observational studies evaluating 1019 patients with PCa met the inclusion criteria. The DR of 18F-PSMA PET/CT was 0.83 (95% CI: 0.78-0.88), in the random-effects model. Subsequently, the analysis of DR of 18F-PSMA PET/CT in PCa patients using Gleason score (≤7 vs ≥8), showed a significant difference in PCa patients. Based on the above results, the higher Gleason score of PCa patients, the higher DR of 18F-PSMA PET/CT. The DR of 18F-PSMA PET/CT in PCa was 0.57 for PSA <0.5 ng ml-1; 0.75 for PSA ≥0.5 ng ml-1 and <1.0 ng ml-1; 0.93 for PSA ≥1.0 ng ml-1 and <2.0 ng ml-1; and 0.95 for PSA ≥2.0 ng ml-1. Therefore, the significant diagnostic value was found in terms of the DR of 18F-PSMA PET/CT in managing PCa patients and was associated with Gleason score and serum PSA level.
Subject(s)
Positron Emission Tomography Computed Tomography , Prostatic Neoplasms , Fluorine Radioisotopes , Humans , Male , Neoplasm Grading , Positron Emission Tomography Computed Tomography/methods , Prostate-Specific Antigen , Prostatic Neoplasms/diagnostic imagingABSTRACT
Renal cell carcinoma (RCC) originates from the epithelial cells of the renal tubules and has a high degree of malignancy and heterogeneity. Recent studies have found that exosomes regulate intercellular communication via transferring various bioactive molecules, such as circular RNAs (circRNAs), which are critical for cancer progression. However, the role of tumor cell-derived exosomal circRNAs in RCC remains unclear. In this study, we reported the high expression of circ-PRKCI in RCC tissues and serum exosomes. We also found that circ-PRKCI could be transferred exosomally from highly malignant RCC cells to relatively less malignant RCC cells. Tumor cell-derived exosomal circ-PRKCI promoted the proliferation, migration, and invasion of RCC cells, while inhibiting their apoptosis. Mechanistically, we found that circ-PRKCI promoted the proliferation of RCC via the miR-545-3p/CCND1 signaling pathway. Our study is the first to report the potential mechanisms of tumor cell-derived exosomal circ-PRKCI in RCC. In conclusion, this study will provide a new understanding about the molecular mechanisms of RCC progression.
ABSTRACT
It is widely accepted that inflammation is an important risk for the development of prostate cancer (PCa). The objective of this study was designed to investigate the potential molecular mechanism of NLR family, pyrin domain-containing protein 3 (NLRP3) inflammasome in the malignant progression of PCa. The expression level of NLRP3 was evaluated by quantitative real-time polymerase chain reaction (qRT-PCR) and fluorescence in situ hybridization. The effects of NLRP3 in the development of PCa by applying gain- and loss-of-function assays in LNCaP and PC3 cell lines were detected by CCK-8, TUNEL, and Transwell migration assays. The underlying mechanism of NLRP3 and caspase-1 in PCa was examined by the rescue experiments, western blotting, and qRT-PCR assays. In addition, the promoting effect of NLRP3 inflammasome was performed with an animal subcutaneous tumorigenesis experiment in vivo. The upregulation of NLRP3 was confirmed in PCa tissues and cell lines. Functionally, using CCK-8, TUNEL, and Transwell migration assays, these results showed that activation of NLRP3/caspase-1 inflammasome by LPS + ATP could enhance the ability of proliferation and migration; and decrease the apoptosis of LNCaP and PC3 cell lines. Western blotting assay showed that the activation of caspase-1 would increase after the stimulation of NLRP3 inflammasome by LPS + ATP. Moreover, the overexpression of NLRP3 promoted, while the knockdown of NLRP3 inhibited the malignant progression in PCa cell lines by positively regulating caspase-1. In addition, the rescue experiments revealed the association among NLRP3 and caspase-1, which showed that the overexpression vectors/inhibitors of caspase-1 could reverse the effect of knockdown/overexpression of NLRP3 in PCa cell lines in vitro. Finally, In in vivo experiment, the suppression of NLRP3 knockdown impaired tumor growth of PCa. Collectively, these results indicated that NLRP3 inflammasome played a vital role in promoting the malignant progression of PCa via the activation of caspase-1. Together, our findings provided insight into the mechanisms of NLRP3/caspase-1 inflammasome and revealed an alternative and potential target for the clinical diagnosis and treatment of PCa.