Oxidative stress and inflammatory responses are closely implicated in the progression of renal interstitial fibrosis, thereby leading to chronic kidney disease. Cryptotanshinone (CTS) is a natural ...compound involved in antioxidant and anti‐inflammatory activities. We evaluated the effects of CTS on inflammation and oxidative stress in obstructed kidneys. Mice received gastric gavage of CTS from 7 days before unilateral ureteral obstruction operation to 1 week after surgery. Administration of CTS at 50 and 100 mg/kg/day significantly decreased collagen production, as shown by Masson staining. Immunohistochemistry staining and RT‐PCR confirmed that CTS reduced extracellular matrix proteins, such as fibronectin and collagen‐1, in the obstructed kidneys in a dose‐dependent manner. Furthermore, immunohistochemistry staining indicated that CTS inhibited infiltration of the macrophage (CD68‐positive) and lymphocyte (CD3‐positive) cells, which were associated with the suppression of the nuclear factor‐κB signalling activation. CTS increased superoxide dismutase, catalase and glutathione while decreased malondialdehyde production. More importantly, CTS activated Nrf‐2 and HO‐1 in the obstructed kidneys for 7 days. CTS could protect renal interstitial fibrosis by ameliorating inflammation and oxidative stress, which might be through the regulation of NF‐κB and Nrf‐2/HO‐1 signalling pathways.
Background
A growing number of studies indicate that circular RNAs (circRNAs) play critical roles in human diseases, and show great potential as biomarkers and therapeutic targets. This study aimed ...to investigate the expression and function of circANKS1B in prostate cancer (PC).
Methods
The expression of circANKS1B and miR‐152‐3p was analyzed by real‐time quantitative reverse‐transcription polymerase chain reaction (qRT‐PCR). Cell migration and invasion were measured using a transwell assay. The interaction between circANKS1B and miR‐152‐3p was confirmed by a dual‐luciferase reporter gene assay. Rescue experiments were conducted to determine whether circANKS1B regulated the invasion of PC cells via the circANKS1B‐miR‐152‐3p‐TGF‐α pathway.
Results
The expression of circANKS1B was markedly upregulated in both PC cells and tissues. Moreover, high circANKS1B expression was associated with poor prognosis in PC patients. Dual‐luciferase reporter assay indicated that circANKS1B directly bound to miR‐152‐3p. Furthermore, circANKS1B negatively regulated miR‐152‐3p expression. Knockdown of circANKS1B markedly suppressed cell migration and invasion and TGF‐α expression in PC cells, whereas the effects of circANKS1B silencing were reversed by miR‐152‐3p deficiency. In addition, the impact of miR‐152‐3p silencing on invasion of circANKS1B‐deficient PC cells was also abrogated by TGF‐α deficiency. Overall, circANKS1B acts as a sponge for miR‐152‐3p to promote PC progression by upregulating TGF‐α expression.
Conclusion
Our findings reveal that circANKS1B may be a potential prognostic biomarker and therapeutic target for PC.
Background
Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a prevalent disease of the urogenital system. Alcohol has been reported to be closely related to CP/CPPS. Thus, we intended to ...verify the role of alcohol in CP/CPPS and determine the underlying mechanism.
Methods
We induced experimental autoimmune prostatitis (EAP) mouse model by intradermally injecting a mixture of prostate antigens (PAgs) and complete Freund's adjuvant on days 0 and 28. Mice were treated with alcohol (control‐alcohol and EAP‐alcohol groups) or vehicle (control‐vehicle, and EAP‐vehicle groups) from day 32 to 42. Forty‐two days after PAg injection, the pathological appearance of the prostate tissues was evaluated, and histological analyses of the prostate were performed. Chronic pelvic pain was assessed by applying von Frey filaments to the lower abdomen. Proinflammatory cytokines were detected by enzyme‐linked immunosorbent assay tests. Then, we explored the effects of the NLRP3 inhibitor MCC950 on chronic pelvic pain and prostatic inflammation in this model.
Results
Histological analyses showed diffuse inflammation in the stromal tissues that were characterized by severe infiltration of neutrophils and mononuclear cells in mice in the EAP‐alcohol group compared with EAP‐vehicle group. Chronic pain tests showed that the response frequency was significantly increased using a von Frey filament at forces of 0.4, 1.0, and 4.0 g in EAP‐alcohol group compared with EAP‐vehicle (P < .05). The levels of proinflammatory cytokines, including interferon (IFN)‐γ, tumor necrosis factor (TNF)‐α, IL‐17, and IL‐1β were all significantly elevated in EAP‐alcohol group compared with the EAP‐vehicle group (P < .05). However, between the control‐alcohol and control‐vehicle groups, chronic pain tests, histological assays, and cytokine determinations showed no differences. Furthermore, our results demonstrated that MCC950 could decrease the expression level of NLRP3 inflammasome–related proteins including NLRP3, ASC, and caspase‐1. The chronic pain tests, histological assays, and cytokine determinations showed that MCC950 could attenuate the chronic pain and prostatic inflammation through the inhibition of the NLRP3 inflammasome.
Conclusions
This study indicated that alcohol could aggravate the severity of prostatic inflammation in EAP model though activating the NLRP3 inflammasome. Furthermore, the role of MCC950 in inhibiting NLRP3 inflammasome and decreasing IL‐1β secretion to alleviate EAP severity may show that it is a promising therapeutic agent for CP/CPPS.
Background
Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common male genitourinary system disease. As a neuroendocrine hormone, melatonin possesses a variety of biological ...functions, among which its anti‐inflammatory effects have recently drawn substantial attention. The purpose of the current research was to study the effect of melatonin on CP/CPPS and the underlying mechanisms using a mouse model of experimental autoimmune prostatitis (EAP).
Methods
The EAP mouse model was successfully established by subcutaneously injecting a mixture of prostate antigen and complete Freund's adjuvant. On Day 42, hematoxylin‐eosin staining was used to evaluate the histological appearance of prostate tissues. Chronic pelvic pain development was assessed by suprapubic allodynia. The levels of inflammation‐related cytokines, such as interferon‐γ, interleukin (IL)‐17, and IL‐1β, were detected by enzyme‐linked immunosorbent assay. Then, we explored the anti‐inflammatory effects of melatonin on CP/CPPS by Western blotting and immunohistochemical staining, by measuring the expression of silent information regulator 1 (Sirt1) and NLRP3 inflammasome‐related proteins in EAP mice.
Results
The EAP model mice exhibited severe diffuse leukocyte infiltration and significantly increased pelvic pain compared to the control mice. In the melatonin treatment group, the histological appearance of the prostate tissues, pelvic pain development, and the levels of proinflammatory cytokines were significantly alleviated compared to the EAP + dimethyl sulfoxide group. Furthermore, we found that the protective effects of melatonin were achieved through activation of the Sirt1 pathway and downregulation of the NLRP3 inflammasome.
Conclusions
The results indicated that melatonin could attenuate prostate inflammation and pelvic pain by inhibiting the NLRP3 inflammasomes signaling pathway through the activation of Sirt1 in mice with EAP, and these efforts should provide a promising therapeutic strategy for CP/CPPS.
Background
Depressive symptoms are found in approximately 78% of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) patients, but the pathological mechanisms remain unknown. Increasing ...evidence suggests that abnormal gut microbiota may play an important role in depression. Thus, we aimed to investigate whether gut microbiota contributes to CP/CPPS‐associated depression by using a mouse model of experimental autoimmune prostatitis (EAP).
Methods
Male nonobese diabetic mice were immunized twice by subcutaneous injection of prostate antigen and adjuvant. Behavioral tests consisted of an open field test, sucrose preference test, forced swimming tests, and tail suspension test was used to confirm the depression‐like symptoms that were induced by EAP. Then, fecal samples were collected, and 16S ribosomal RNA gene sequencing was performed to detect differences in gut microbiota composition between control and EAP group. Additionally, fecal bacteria from the control and EAP mice were transplanted into antibiotics‐induced pseudo‐germ‐free mice to investigate the effects on host behaviors and the composition of gut bacteria.
Results
EAP was successfully established and exhibited depressive‐like behaviors in mice. The 16S rRNA analysis of fecal samples indicated the abnormal composition of gut microbiota in the EAP mice compared to the control mice. In the fecal microbiota transplant study, antibiotics‐treated pseudo‐germ‐free mice presented depressive states as compared to naïve mice. Fecal bacteria transplant from EAP mice, but not from control mice, into the pseudo‐germ‐free mice, significantly exaggerated host depression‐like behaviors. Moreover, fecal bacteria transplants from control and EAP mice induced distinct alterations in α‐diversity and β‐diversity indices. In all, 24 bacteria at six phylogenetic levels were remarkably changed by the fecal bacteria transplantation.
Conclusions
Abnormal gut microbiota composition after EAP induction may contribute to the development of depression in mice. A therapeutic strategy that targets gut microbiota may provide an alternative treatment for alleviating this condition.
Reprogramming of metabolism is a hallmark of tumors, which has been explored for therapeutic purposes. Prostate cancer (PCa), particularly advanced and therapy-resistant PCa, displays unique ...metabolic properties. Targeting metabolic vulnerabilities in PCa may benefit patients who have exhausted currently available treatment options and improve clinical outcomes. Among the many nutrients, glutamine has been shown to play a central role in the metabolic reprogramming of advanced PCa. In addition to amino acid metabolism, glutamine is also widely involved in the synthesis of other macromolecules and biomasses. Targeting glutamine metabolic network by maximally inhibiting glutamine utilization in tumor cells may significantly add to treatment options for many patients. This review summarizes the metabolic landscape of PCa, with a particular focus on recent studies of how glutamine metabolism alterations affect therapeutic resistance and disease progression of PCa, and suggests novel therapeutic strategies.
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.
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.
Background
Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common disease in males. Eriocalyxin B (EriB), a natural diterpenoid purified from Isodon eriocalyx var. laxiflora, was ...previously reported to have antitumor effects via multiple immune‐related pathways. In this study, we investigated the effect of EriB on CP/CPPS using a mouse model of experimental autoimmune prostatitis (EAP) and explored its potential mechanisms.
Methods
The EAP model was established in nonobese diabetic mice by intradermal injecting a mixture of prostate antigens and Complete Freund's Adjuvant on days 0 and 28. Then, EAP mice received daily intraperitoneal injections of EriB (5 or 10 mg/kg/d) for 14 days, from days 28 to 42 (EAP+EriB5 or EAP+EriB10 groups). The histopathological appearance of the prostate tissues was evaluated. Chronic pelvic pain development was assessed by cutaneous allodynia. Inflammatory cytokines were measured by enzyme‐linked immunosorbent assay tests. We then explored anti‐inflammatory potential mechanisms of EriB by studying the effects of PI3K inhibitor wortmannin (EAP+EriB10+Wort group) and NF‐κB inhibitor SC75741 (EAP+EriB10+SC group) on prostate inflammation and pelvic pain using this model.
Results
Histological analyses revealed significant prostate inflammation in EAP mice compared with control mice. Significantly increased pelvic pain was detected in EAP mice (P < .05). Compared with the EAP+Veh group, chronic pain development, histological appearance, and cytokine levels demonstrated that EriB could alleviate the severity of EAP in a dose‐dependent manner though upregulation of the PI3K/Akt/mTOR pathway and downregulation of the NF‐κB pathway. Further mechanism research demonstrated that the PI3K/AKT/mTOR pathway could be blocked by wortmannin, but was not affected by SC75741. In addition, the NF‐κB pathway could be further inhibited by SC75741 compared with the EAP+EriB10+Veh group. However, wortmannin could reactivate the NF‐κB pathway, indicating that the PI3K/AKT/mTOR pathway negatively regulates the NF‐κB pathway during EriB treatment.
Conclusions
The results of the present study suggested that EriB could alleviate the severity of prostatic inflammation and pelvic pain in an EAP mouse model. These findings may broaden the value of EriB as a promising candidate for the treatment of CP/CPPS.
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