ABSTRACT
Bladder cancer (BC) represents a prevalent and formidable malignancy necessitating innovative diagnostic and therapeutic strategies. Circular RNAs (circRNAs) have emerged as crucial regulators in cancer biology. In this study, we comprehensively evaluated ferroptosis levels in BC cells utilizing techniques encompassing lipid peroxidation assessment, transmission electron microscopy, and malondialdehyde (MDA) measurement. Additionally, we probed into the mechanistic intricacies by which circRNAs govern BC, employing RNA pull-down, RNA immunoprecipitation (RIP), and immunoprecipitation (IP) assays. Our investigation unveiled circSIRT5, which displayed significant downregulation in BC. Notably, circSIRT5 emerged as a promising prognostic marker, with diminished expression correlating with unfavorable clinical outcomes. Functionally, circSIRT5 was identified as an inhibitor of BC progression both in vitro and in vivo. Mechanistically, circSIRT5 exerted its tumor-suppressive activities through the formation of a ternary complex involving circSIRT5, SYVN1, and PHGDH. This complex enhanced the ubiquitination and subsequent degradation of PHGDH, ultimately promoting ferroptosis in BC cells. This ferroptotic process contributed significantly to the inhibition of tumor growth and metastasis in BC. In addition, FUS was found to accelerate the biogenesis of circSIRT5 in BC. These findings provide valuable insights into the pivotal role of circSIRT5 in BC pathogenesis, underscoring its potential as a diagnostic biomarker and therapeutic target for this malignancy.
ABSTRACT
Liquid biopsy provides a convenient and safer procedure for the diagnosis and genomic profiling of tumors that are inaccessible to biopsy by analyzing exfoliated tumor cells (ETCs) or tumor-derived cell-free DNA (cfDNA). However, its primary challenge lies in its limited accuracy in comparison to tissue-based approaches. We report a parallel single-ETC genomic sequencing (Past-Seq) method for the accurate diagnosis and genomic profiling of hard-to-biopsy tumors such as cholangiocarcinoma (CCA) and upper tract urothelial carcinoma (UTUC). For CCA, a prospective cohort of patients with suspicious biliary strictures (n = 36) was studied. Parallel single-cell whole genome sequencing and whole exome sequencing were performed on bile ETCs for CCA diagnosis and resolving mutational profiles, respectively, along with bile cfDNA sequenced for comparison. Concordant single-cell copy number alteration (CNA) profiles in multiple ETCs provided compelling evidence for generating a malignant diagnosis. Past-Seq yielded bile-based accurate CCA diagnosis (96% sensitivity, 100% specificity, and positive predictive value), surpassing pathological evaluation (56% sensitivity) and bile cfDNA CNA analysis (13% sensitivity), and generated the best performance in the retrieval tissue mutations. To further explore the applicability of Past-Seq, 10 suspicious UTUC patients were investigated with urine specimens, and Past-Seq exhibited 90% sensitivity in diagnosing UTUC, demonstrating its broad applicability across various liquid biopsies and cancer types.
ABSTRACT
Non-invasive screening for bladder cancer is crucial for treatment and postoperative follow-up. This study combines digital microfluidics (DMF) technology with fluorescence lifetime imaging microscopy (FLIM) for urine analysis and introduces a novel non-invasive bladder cancer screening technique. Initially, the DMF was utilized to perform preliminary screening and enrichment of urine exfoliated cells from 54 participants, followed by cell staining and FLIM analysis to assess the viscosity of the intracellular microenvironment. Subsequently, a deep learning residual convolutional neural network was employed to automatically classify FLIM images, achieving a three-class prediction of high-risk (malignant), low-risk (benign), and minimal risk (normal) categories. The results demonstrated a high consistency with pathological diagnosis, with an accuracy of 91% and a precision of 93%. Notably, the method is sensitive for both high-grade and low-grade bladder cancer cases. This highly accurate non-invasive screening method presents a promising approach for bladder cancer screening with significant clinical application potential.
ABSTRACT
BACKGROUND AND OBJECTIVE: Cryoablation is a traditional antitumor therapy with good prospects for development. The efficacy of endoscopic management as a kidney-sparing surgery for high-risk upper tract urothelial carcinoma (UTUC) remains controversial. Our aim was to evaluate the impact of endoscopic cryoablation (ECA) versus radical nephroureterectomy (RNU) on survival outcomes, renal function, and complications. METHODS: We retrospectively analyzed data for 116 patients with newly diagnosed high-risk UTUC who underwent either ECA (n = 13) or RNU (n = 103) from March 25, 2019 to December 8, 2021. Propensity score matching (1:4) using the nearest neighbor method was performed before analysis. The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), intravesical recurrence-free survival (RFS), the change in renal function, and treatment-emergent adverse events (TEAEs). KEY FINDINGS AND LIMITATIONS: At median follow-up of 28.2 mo for the ECA group and 27.6 mo for the RNU group, 2-yr OS (82% vs 84%), PFS (73% vs 71%), and intravesical RFS (81% vs 83%) rates after matching did not significantly differ. A decline in renal function was observed after RNU, but not after ECA. Five (41.7%) patients in the ECA group reported six TEAEs, and 17 patients (35.4%) in the RNU group reported 20 TEAEs. CONCLUSIONS AND CLINICAL IMPLICATIONS: In comparison to RNU, ECA for UTUC resulted in noninferior oncological outcomes and superior preservation of renal function. PATIENT SUMMARY: Our study suggests that a treatment called endoscopic cryoablation for high-risk cancer in the upper urinary tract can help in preserving kidney function, with similar survival outcomes to those after more extensive surgery. This option can be considered for selected patients with a strong preference for kidney preservation.
ABSTRACT
BACKGROUND: Bladder cancer (BCa) is among the most prevalent malignant tumors affecting the urinary system. Due to its highly recurrent nature, standard treatments such as surgery often fail to significantly improve patient prognosis. Our research aims to predict prognosis and identify precise therapeutic targets for novel treatment interventions. METHODS: We collected and screened genes related to the TGF-ß signaling pathway and performed unsupervised clustering analysis on TCGA-BLCA samples based on these genes. Our analysis revealed two novel subtypes of bladder cancer with completely different biological characteristics, including immune microenvironment, drug sensitivity, and more. Using machine learning classifiers, we identified SMAD6 as a hub gene contributing to these differences and further investigated the role of SMAD6 in bladder cancer in the single-cell transcriptome data. Additionally, we analyzed the relationship between SMAD6 and immune checkpoint genes. Finally, we performed a series of in vitro assays to verify the function of SMAD6 in bladder cancer cell lines. RESULTS: We have revealed two novel subtypes of bladder cancer, among which C1 exhibits a worse prognosis, lower drug sensitivity, a more complex tumor microenvironment, and a 'colder' immune microenvironment compared to C2. We identified SMAD6 as a key gene responsible for the differences and further explored its impact on the molecular characteristics of bladder cancer. Through in vitro experiments, we found that SMAD6 promoted the prognosis of BCa patients by inhibiting the proliferation and migration of BCa cells. CONCLUSION: Our study reveals two novel subtypes of BCa and identifies SMAD6 as a highly promising therapeutic target.
Subject(s)
Machine Learning , Smad6 Protein , Tumor Microenvironment , Urinary Bladder Neoplasms , Humans , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/pathology , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/metabolism , Prognosis , Smad6 Protein/genetics , Smad6 Protein/metabolism , Drug Resistance, Neoplasm/genetics , Cell Line, Tumor , Cell Proliferation , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Gene Expression Regulation, NeoplasticABSTRACT
BACKGROUND: Deleterious BRCA1/2 (BRCA) mutation raises the risk for BRCA mutation-related malignancies, including breast, ovarian, prostate, and pancreatic cancer. Germline variation of BRCA exhibits substantial ethnical diversity. However, there is limited research on the Chinese Han population, constraining the development of strategies for BRCA mutation screening in this large ethnic group. METHODS: We profile the BRCA mutational spectrum, including single nucleotide variation, insertion/deletion, and large genomic rearrangements in 2,080 apparently healthy Chinese Han individuals and 522 patients with BRCA mutation-related cancer, to determine the BRCA genetic background of the Chinese Han population, especially of the East Han. Incident cancer events were monitored in 1,005 participants from the healthy group, comprising 11 BRCA pathogenic/likely pathogenic (PLP) variant carriers and 994 PLP-free individuals, including 3 LGR carriers. RESULTS: Healthy Chinese Han individuals demonstrated a distinct BRCA mutational spectrum compared to cancer patients, with a 0.53% (1 in 189) prevalence of pathogenic/likely pathogenic (PLP) variant, alongside a 3 in 2,080 occurrence of LGR. BRCA1 c. 5470_5477del demonstrated high prevalence (0.44%) in the North Han Chinese and penetrance for breast cancer. None of the 3 LGR carriers developed cancer during the follow-up. We calculated a relative risk of 135.55 (95% CI 25.07 to 732.88) for the development of BRCA mutation-related cancers in the BRCA PLP variant carriers (mean age 42.91 years, median follow-up 10 months) compared to PLP-free individuals (mean age 48.47 years, median follow-up 16 months). CONCLUSION: The unique BRCA mutational profile in the Chinese Han highlights the potential for standardized population-based BRCA variant screening to enhance BRCA mutation-related cancer prevention and treatment.
Subject(s)
BRCA1 Protein , Breast Neoplasms , Male , Humans , Adult , Middle Aged , BRCA1 Protein/genetics , Germ-Line Mutation , BRCA2 Protein/genetics , Genetic Predisposition to Disease , Early Detection of Cancer , China/epidemiology , Breast Neoplasms/diagnosis , Breast Neoplasms/epidemiology , Breast Neoplasms/genetics , MutationABSTRACT
Considering the ubiquitous presence of pyridine moieties in pharmaceutical compounds, it holds immense value to develop practical and straightforward methodologies for accessing heterocyclic aromatic hydrocarbons. In recent years, N-alkoxypyridinium salts have emerged as convenient radical precursors, enabling the generation of the corresponding alkoxy radicals and pyridine through single-electron transfer. Herein, we present the first report on visible-light-mediated intermolecular alkoxypyridylation of alkenes employing N-alkoxylpyridinium salts as bifunctional reagents with an exceptionally low catalyst loading (0.5 mol %).
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Neuroblastoma is a leading cause of death in childhood cancer cases. Unlike adult malignancies, which typically develop from aged cells through accumulated damage and mutagenesis, neuroblastoma originates from neural crest cells with disrupted differentiation. This distinct feature provides novel therapeutic opportunities beyond conventional cytotoxic methods. Previously, we reported that the mitochondrial uncoupler NEN (niclosamide ethanolamine) activated mitochondria respiration to reprogram the epigenome, promoting neuronal differentiation. In the current study, we further combine NEN with retinoic acid (RA) to promote neural differentiation both in vitro and in vivo. The treatment increased the expression of RA signaling and neuron differentiation-related genes, resulting in a global shift in the transcriptome towards a more favorable prognosis. Overall, these results suggest that the combination of a mitochondrial uncoupler and the differentiation agent RA is a promising therapeutic strategy for neuroblastoma.
ABSTRACT
The AE and damage characteristics of three types of pore-structured rock under the same working conditions are studied by means of uniaxial cyclic loading and unloading tests. The results suggest that with repeated loading and unloading, AE ringing increases as a "jump", and the denser the structure, the earlier the "jump" occurs. The AE cumulative energy shows a "step" upward trend, but there is a significant difference in the "step" spacing. By comparing the energy distribution of rocks with different pore structures, it can be seen that the smaller the porosity and the smaller the pore size, the greater the energy input and storage, and the earlier the internal failure. Compared with the other two energy-based damage calculation methods, the damage calculation method defined in this paper is closer to the true internal damage level of the rock loading cycle. The NSE value of the modified damage variable calculation method was significantly improved and it was shown that the dissipated energy before pore compaction is the main energy causing damage, after pore compaction the combined effects of dissipated energy and plastic deformation energy result in rock damage.
ABSTRACT
As a highly heterogeneous tumor, pancreatic ductal adenocarcinoma (PDAC) exhibits non-uniform responses to therapies across subtypes. Overcoming therapeutic resistance stemming from this heterogeneity remains a significant challenge. Here, we report that Vitamin D-resistant PDAC cells hijacked Vitamin D signaling to promote tumor progression, whereas epigenetic priming with glyceryl triacetate (GTA) and 5-Aza-2'-deoxycytidine (5-Aza) overcame Vitamin D resistance and shifted the transcriptomic phenotype of PDAC toward a Vitamin D-susceptible state. Increasing overall H3K27 acetylation with GTA and reducing overall DNA methylation with 5-Aza not only elevated the Vitamin D receptor (VDR) expression but also reprogrammed the Vitamin D-responsive genes. Consequently, Vitamin D inhibited cell viability and migration in the epigenetically primed PDAC cells by activating genes involved in apoptosis as well as genes involved in negative regulation of cell proliferation and migration, while the opposite effect of Vitamin D was observed in unprimed cells. Studies in genetically engineered mouse PDAC cells further validated the effects of epigenetic priming for enhancing the anti-tumor activity of Vitamin D. Using gain- and loss-of-function experiments, we further demonstrated that VDR expression was necessary but not sufficient for activating the favorable transcriptomic phenotype in respond to Vitamin D treatment in PDAC, highlighting that both the VDR and Vitamin D-responsive genes were prerequisites for Vitamin D response. These data reveal a previously undefined mechanism in which epigenetic state orchestrates the expression of both VDR and Vitamin D-responsive genes and determines the therapeutic response to Vitamin D in PDAC.
Subject(s)
Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Animals , Mice , Vitamin D/pharmacology , Carcinoma, Pancreatic Ductal/drug therapy , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/metabolism , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/metabolism , Azacitidine/pharmacology , Epigenesis, Genetic , Gene Expression Profiling , Cell Line, Tumor , Cell Proliferation , Gene Expression Regulation, NeoplasticABSTRACT
Viscoelasticity is a crucial property of cells, which plays an important role in label-free cell characterization. This paper reports a model-fitting-free viscoelasticity calculation method, correcting the effects of frequency, surface adhesion and liquid resistance on AFM force-distance (FD) curves. As demonstrated by quantifying the viscosity and elastic modulus of PC-3 cells, this method shows high self-consistency and little dependence on experimental parameters such as loading frequency, and loading mode (Force-volume vs. PeakForce Tapping). The rapid calculating speed of less than 1ms per curve without the need for a model fitting process is another advantage. Furthermore, this method was utilized to characterize the viscoelastic properties of primary clinical prostate cells from 38 patients. The results demonstrate that the reported characterization method a comparable performance with the Gleason Score system in grading prostate cancer cells, This method achieves a high average accuracy of 97.6% in distinguishing low-risk prostate tumors (BPH and GS6) from higher-risk (GS7-GS10) prostate tumors and a high average accuracy of 93.3% in distinguishing BPH from prostate cancer.
Subject(s)
Prostatic Hyperplasia , Prostatic Neoplasms , Male , Humans , Prostate/pathology , Viscosity , Prostatic Hyperplasia/pathology , Elastic ModulusABSTRACT
Macrophages, a heterogeneous population of innate immune cells, exhibit remarkable plasticity and play pivotal roles in coordinating immune responses and maintaining tissue homeostasis within the context of metabolic diseases. The activation of inflammatory macrophages in obese adipose tissue leads to detrimental effects, inducing insulin resistance through increased inflammation, impaired thermogenesis, and adipose tissue fibrosis. Meanwhile, adipose tissue macrophages also play a beneficial role in maintaining adipose tissue homeostasis by regulating angiogenesis, facilitating the clearance of dead adipocytes, and promoting mitochondrial transfer. Exploring the heterogeneity of macrophages in obese adipose tissue is crucial for unraveling the pathogenesis of obesity and holds significant potential for targeted therapeutic interventions. Recently, the dual effects and some potential regulatory mechanisms of macrophages in adipose tissue have been elucidated using single-cell technology. In this review, we present a comprehensive overview of the intricate activation mechanisms and diverse functions of macrophages in adipose tissue during obesity, as well as explore the potential of drug delivery systems targeting macrophages, aiming to enhance the understanding of current regulatory mechanisms that may be potentially targeted for treating obesity or metabolic diseases.
Subject(s)
Adipose Tissue , Macrophages , Obesity , Humans , Obesity/immunology , Macrophages/immunology , Macrophages/physiology , Adipose Tissue/immunology , Inflammation/immunology , Insulin Resistance , Animals , Thermogenesis/physiology , AdipocytesABSTRACT
A new lignan, named pouzolignan P (1), together with 14 known ones (2 - 15) were isolated from the roots of Pouzolzia zeylanica (L.) Benn. Their structures were deduced based on the detailed spectroscopic analysis. All the isolates were evaluated for their inhibitory activities toward the ATP citrate lyase (ACLY). Among them, four lignans, isopouzolignan K (3), gnemontanins E (5), gnetuhainin I (6), and styraxlignolide D (15) showed excellent ACLY inhibitory effect with IC50 values of 9.06, 0.59, 2.63, and 7.62 µM, respectively. These compounds were further evaluated for their cholesterol-lowing effects on ox-LDL-induced high-cholesterol HepG2 cells. Compound 15 emerges as the most potent ACLY inhibitor, which significantly decreased the TC level in a dose-dependent manner. In addition, molecular docking simulations elucidated that 15 formed a strong hydrogen-bond interaction with Glu599 of ACLY, which was an important site responsible for the enzyme catalytic activity.
Subject(s)
ATP Citrate (pro-S)-Lyase , Lignans , ATP Citrate (pro-S)-Lyase/chemistry , Molecular Docking Simulation , Enzyme Inhibitors/pharmacology , CholesterolABSTRACT
Bladder cancer (BC) is a common malignancy in males, and currently lacks ideal therapeutic approaches. Exploring emerging therapeutic targets from the perspective of endogenous peptides to improve the prognosis of bladder cancer patients holds promise. In this study, we have identified CTSGDP-13, a novel endogenous peptide, which demonstrates potential anti-cancer effects in BC. Our findings reveal that CTSGDP-13 can promote ferroptosis in BC cells, both in vitro and in vivo, leading to the inhibition of BC progression. Furthermore, we have identified TRIM25 as a downstream regulatory target of CTSGDP-13. The expression of TRIM25 is significantly upregulated in BC, and its inhibition of ferroptosis promotes BC progression. Mechanistic studies have shown that CTSGDP-13 promotes the ubiquitination and subsequent degradation of TRIM25 by disrupting its interaction with the deubiquitinase USP7. Further investigations indicate that CTSGDP-13 promotes ferroptosis in BC by regulating the USP7/TRIM25/KEAP1 axis. The elucidation of the functional mechanisms of natural CTSGDP-13 and TRIM25 holds promise in providing valuable therapeutic targets for BC diagnosis and treatment.
Subject(s)
Ferroptosis , Urinary Bladder Neoplasms , Male , Humans , Kelch-Like ECH-Associated Protein 1 , Micropeptides , Ubiquitin-Specific Peptidase 7 , NF-E2-Related Factor 2 , Urinary Bladder Neoplasms/pathologyABSTRACT
Transurethral resection of bladder tumor (TURBT) is the first-line treatment option for non-muscle invasive bladder cancer (NMIBC), but residual tumor often remains after TURBT, thereby leading to cancer recurrence. Here, we introduce combined use of in vivo Raman spectroscopy and in vivo cryoablation as a new approach to detect and remove residual bladder tumor during TURBT. Bladder cancer (BCa) patients treated with TURBT at our urological department between Dec 2019 and Jan 2021 were collected. First, Raman signals were collected from 74 BCa patients to build reference spectra of normal bladder tissue and of bladder cancers of different pathological types. Then, another 53 BCa patients were randomly categorized into two groups, 26 patients accepted traditional TURBT, 27 patients accepted TURBT followed by Raman scanning and cryoablation if Raman detected existence of residual tumor. The recurrence rates of the two groups until Oct 2022 were compared. Raman was capable of discriminating normal bladder tissue and BCa with a sensitivity and specificity of 90.5% and 80.8 %; and discriminating invasive (T1, T2) and noninvasive (Ta) BCa with a sensitivity and specificity of 83.3 % and 87.3 %. During follow-up, 2 in 27 patients had cancer recurrence in Raman-Cryoablation group, while 8 in 26 patients had cancer recurrence in traditional TURBT group. Combined use of Raman and cryoablation significantly reduced cancer recurrence (p = 0.0394). Raman and cryoablation can serve as an adjuvant therapy to TURBT to improve therapeutic effects and reduce recurrence rate.
Subject(s)
Cryosurgery , Urinary Bladder Neoplasms , Humans , Neoplasm, Residual/surgery , Spectrum Analysis, Raman , Neoplasm Recurrence, Local/diagnosis , Neoplasm Recurrence, Local/pathology , Neoplasm Recurrence, Local/surgery , Urinary Bladder Neoplasms/diagnosis , Urinary Bladder Neoplasms/surgery , Urinary Bladder Neoplasms/pathologyABSTRACT
With advances in tissue typing, organ preservation techniques, and clinical surgery, organ transplantation has gained popularity as a treatment option for various end-stage diseases. Allogeneic transplantation has been widely adopted and extensively researched in clinical practice. Despite significant breakthroughs and progress in immunosuppression, this procedure is still associated with several adverse reactions and complications. Therefore, there is a continuing need to explore new immunological approaches to provide fresh insights and guidance for clinical transplantation. CD8+ T cells, traditionally known for their cytotoxic function and their ability to recognize transplanted organs as "non-self" entities, display cytotoxicity. However, recent studies have unveiled that CD8+ T cells have various subtypes and functions that extend beyond conventional cytotoxicity. These CD8+ T cell subtypes include Effector CD8+ T cells, Memory CD8+ T cells, and CD8Treg cells. This review examines the immune regulatory mechanisms of CD8+ T cells in allogeneic transplantation and discusses the potential applications of CD8+ T cells in treating tumors in transplant recipients who are receiving immunosuppressive therapy. These findings offer theoretical guidance for reducing post-transplant rejection reactions and improving adverse prognoses, offering new hope for improved clinical survival rate.
Subject(s)
CD8-Positive T-Lymphocytes , Graft Rejection , Transplantation, Homologous , Immunosuppression Therapy , Immune ToleranceABSTRACT
Loss of estrogen receptor (ER) pathway activity promotes breast cancer progression, yet how this occurs remains poorly understood. Here, we show that serine starvation, a metabolic stress often found in breast cancer, represses estrogen receptor alpha (ERα) signaling by reprogramming glucose metabolism and epigenetics. Using isotope tracing and time-resolved metabolomic analyses, we demonstrate that serine is required to maintain glucose flux through glycolysis and the TCA cycle to support acetyl-CoA generation for histone acetylation. Consequently, limiting serine depletes histone H3 lysine 27 acetylation (H3K27ac), particularly at the promoter region of ER pathway genes including the gene encoding ERα, ESR1. Mechanistically, serine starvation impairs acetyl-CoA-dependent gene expression by inhibiting the entry of glycolytic carbon into the TCA cycle and down-regulating the mitochondrial citrate exporter SLC25A1, a critical enzyme in the production of nucleocytosolic acetyl-CoA from glucose. Consistent with this model, total H3K27ac and ERα expression are suppressed by SLC25A1 inhibition and restored by acetate, an alternate source of acetyl-CoA, in serine-free conditions. We thus uncover an unexpected role for serine in sustaining ER signaling through the regulation of acetyl-CoA metabolism.
Subject(s)
Estrogen Receptor alpha , Histones , Acetyl Coenzyme A , Estrogen Receptor alpha/genetics , Histones/genetics , Receptors, Estrogen , GlucoseABSTRACT
We have previously demonstrated abnormal gut microbial composition in castration-resistant prostate cancer (CRPC) patients, here we revealed the mechanism of gut microbiota-derived short-chain fatty acids (SCFAs) as a mediator linking CRPC microbiota dysbiosis and prostate cancer (PCa) progression. By using transgenic TRAMP mouse model, PCa patient samples, in vitro PCa cell transwell and macrophage recruitment assays, we examined the effects of CRPC fecal microbiota transplantation (FMT) and SCFAs on PCa progression. Our results showed that FMT with CRPC patients' fecal suspension increased SCFAs-producing gut microbiotas such as Ruminococcus, Alistipes, Phascolarctobaterium in TRAMP mice, and correspondingly raised their gut SCFAs (acetate and butyrate) levels. CRPC FMT or SCFAs supplementation significantly accelerated mice's PCa progression. In vitro, SCFAs enhanced PCa cells migration and invasion by inducing TLR3-triggered autophagy that further activated NF-κB and MAPK signalings. Meanwhile, autophagy of PCa cells released higher level of chemokine CCL20 that could reprogramme the tumor microenvironment by recruiting more macrophage infiltration and simultaneously polarizing them into M2 type, which in turn further strengthened PCa cells invasiveness. Finally in a cohort of 362 PCa patients, we demonstrated that CCL20 expression in prostate tissue was positively correlated with Gleason grade, pre-operative PSA, neural/seminal vesical invasion, and was negatively correlated with post-operative biochemical recurrence-free survival. Collectively, CRPC gut microbiota-derived SCFAs promoted PCa progression via inducing cancer cell autophagy and M2 macrophage polarization. CCL20 could become a biomarker for prediction of prognosis in PCa patients. Intervention of SCFAs-producing microbiotas may be a useful strategy in manipulation of CRPC.
Subject(s)
Autophagy , Bacteroidetes , Fatty Acids, Volatile , Gastrointestinal Microbiome , Macrophages , Prostatic Neoplasms, Castration-Resistant , Ruminococcus , Veillonellaceae , Fatty Acids, Volatile/metabolism , Disease Progression , Macrophages/pathology , Cell Polarity , Ruminococcus/metabolism , Prostatic Neoplasms, Castration-Resistant/microbiology , Prostatic Neoplasms, Castration-Resistant/pathology , Mice, Transgenic , Bacteroidetes/metabolism , Veillonellaceae/metabolism , Fecal Microbiota Transplantation , Humans , Male , Animals , MiceABSTRACT
The development of wearable multifunctional electromagnetic protective fabrics with multifunctional, low cost, and high efficiency remains a challenge. Here, inspired by the unique flower branch shape of "Thunberg's meadowsweet" in nature, a nanofibrous composite membrane with hierarchical structure was constructed. Integrating sophisticated 0D@2D@1D hierarchical structures with multiple heterointerfaces can fully unleash the multifunctional application potential of composite membrane. The targeted induction method was used to precisely regulate the formation site and morphology of the metal-organic framework precursor, and intelligently integrate multiple heterostructures to enhance dielectric polarization, which improves the impedance matching and loss mechanisms of the electromagnetic wave absorbing materials. Due to the synergistic enhancement of electrospinning-derived carbon nanofiber "stems", MOF-derived carbon nanosheet "petals" and transition metal selenide nano-particle "stamens", the CoxSey/NiSe@CNSs@CNFs (CNCC) composite membrane obtains a minimum reflection loss value (RLmin) of -68.40 dB at 2.6 mm and a maximum effective absorption bandwidth (EAB) of 8.88 GHz at a thin thickness of 2.0 mm with a filling amount of only 5 wt%. In addition, the multi-component and hierarchical heterostructure endow the fibrous membrane with excellent flexibility, water resistance, thermal management, and other multifunctional properties. This work provides unique perspectives for the precise design and rational application of multifunctional fabrics.