TNF Blockade Reduces Prostatic Hyperplasia and Inflammation while Limiting BPH Diagnosis in Patients with Autoimmune Disease
Renee E. VickmanLaTayia Aaron-BrooksRenyuan ZhangNadia A. LanmanBrittany LapinVictoria GilMax GreenbergTakeshi SasakiGregory M. CresswellMeaghan M. BromanJacqueline PetkewiczPooja TalatyBrian T. HelfandAlexander P. GlaserChi‐Hsiung WangOmar E. FrancoTimothy L. RatliffKent L. NastiukSusan E. CrawfordSimon W. Hayward
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Abstract Benign prostatic hyperplasia (BPH) is ostensibly linked to autoimmune (AI) diseases, but whether the prostate is a target of systemic inflammation associated with AI conditions is unknown. Prostatic inflammation is linked to fibrosis, hyperplasia, and reduced responses to BPH-related medical therapies. This study was conducted to determine if AI disease correlates with BPH diagnosis and whether systemic targeting of an inflammatory mediator limits prostatic inflammation and hyperplasia. Patient medical records (n=112,152) were evaluated to determine BPH prevalence among different AI diseases. Inflammatory cells from human BPH tissues were analyzed by single-cell (sc)RNA-seq and the tumor necrosis factor (TNF)α-antagonist etanercept was tested in two murine models of prostatic enlargement. BPH prevalence was significantly higher among patients with AI disease compared to unaffected individuals. However, AI patients treated with TNFα-antagonists had a significantly reduced incidence of BPH. Data from scRNA- seq identified macrophages as a dominant source of TNFα and in vitro assays confirmed that TNFα stimulates BPH-derived fibroblast proliferation. In the AI patient cohort and murine models, systemic treatment with TNFα-antagonists decreased prostatic epithelial proliferation, macrophage infiltration, and epithelial NFκB activation compared to control tissues. These studies are the first to show that patients with AI diseases have a heightened susceptibility to BPH and that the TNFα-signaling axis is important for BPH pathogenesis. Macrophage-secreted TNFα may mechanistically drive BPH via chronic activation of the signaling axis and NFκB. TNFα blockade appears to be a promising new pharmacological approach to target inflammation and suppress BPH. One sentence summary Patient data and mouse models suggest that repurposing tumor necrosis factor alpha blockade reduces inflammation-mediated prostatic hyperplasia.Keywords:
Prostatic Diseases
Pathogenesis
Objective:To investigate the effect of Qianliean on the treatment of benign prostatic hyperplasia and the related mechanism.Method:Rat model of benign prostatic hyperplasia was established by castration followed by injection of testosterone.The rats were randomly divided into 5 groups:the normal group,the model group,the Qianliean high-dose group,the Qianliean low-dose group,Longbishu group.The rats were treated accordingly and sacrificed after 30 d.The prostates were sampled and weighed,and the prostate index was calculated.Light microscopic and immunohistochemical specimens were prepared and investigated.Result:Prostatic weight,prostatic index and basic fibroblast growth factorlevelsin(bFGF) expression levels in three treatment groups were significantly lower than that of the model group,in particular for the Qianliean of high-dose group.Model group showed marked pathological changes in prostate tissue,Qianliean low-dose group showed alleviated pathological changes in prostate tissue compared with the model group,high-dose group and Longbishu group rats prostate tissue showed obvious improvement in pathological changes.Conclusion: Qianliean can decrease prostate wet weight in rat and alleviate pathological damage in prostate.The mechanism may be related to the inhibition of prostate tissue bFGF release.
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【Objective】To observe the effection of LongBiKang on expression of bax/bcl-2 in prostate tissues of the rats with benign prostatic hyperplasia.【Methods】Male SD rats were grouped in control group model group QianLieLang group LongBiKang low-dose group LongBiKang middle-dose group and LongBiKang high-dose group.Rats were removal both of didymus and injected testosterone propionate to make model of rat benign prostatic hyperplasia.And then prostate humid weigh prostate index number bax/bcl-2 and pathological organization were observed.【Results】The bax protein expresses: prostate gland organization assumes the strong masculine gender in control group,assumes the weak masculine gender in model group.Each treatment group's bax protein expression is stronger than the model group.The bcl-2 protein expresses prostate organization assumes the weak masculine gender in control group,but expresses assumes the masculine gender in the model group.Each treatment group's bcl-2 protein for weak masculine expression.under the light microhraph,the pathological organization in LongBiKang high-dose group get close to control group.【Conclusions】LongBiKang can regulate the expression of bax/bcl-2 to suppress BPH.
Testosterone propionate
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Abstract Introduction: The aim of the study was to examine the percentage volume of epithelium, acini, and interstitial collagen in the nonhyperplastic canine prostate and in cases of epithelial and epithelial cystic hyperplasia. Material and Methods: A histomorphometric study of 39 prostates was performed using computer image analysis. Results: The highest percentage volume of epithelium was found in cases of epithelial hyperplasia (47.8 %) and epithelial cystic hyperplasia was the correlate for acini (48.97 %). Epithelium decreased with dogs’ age (P < 0.01), whereas acini increased (P < 0.01). Interstitial collagen varied only insignificantly across age groups, but collagen was higher (12.1 %) in the nonhyperplastic prostates. With age cystic formation progressed in the canine prostate, the percentage volume of epithelium decreased and that of acini increased, but this same parameter in prostatic collagen did not change distinctly. The epithelium percentage volume increased in cases of epithelial hyperplasia but the cystic variant caused an increase in acinar volume. Conclusion: As dogs age, cystic formation progresses in the prostate, therefore the volume of epithelium decreases and that of acini increases. The volume of prostatic collagen did not change distinctly with age, and was higher in normal prostates than in both epithelial and epithelial cystic hyperplastic glands.
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Objective:observe the effect of Shunbi Yin,a prescription of Activating Blood Circulation and Dipelling Stasis Therapy,on the expression of bFGF in the prostate tissue of prostatic hyperplasia rats.Methods:Model rats of prostatic hyperplasia were created by testosterone hypodermally injected in rats.Observed the epithelia cell height,wet weight of prostate,expression of bFGF in prostate tissue.Results:the hyperplasia of epithelium and interstitium were decreased in model rats of Shunbi Yin group than other groups,and the average positive cell count were significantly lower in the prostate tissue of Shunbi Yin group rats(P0.01).Conclusion:Activating Blood Circulation and Dipelling Stasis Therapy can effect hyperplasic prostate through regulating the bFGF.
Blood stasis
Blood circulation
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Normal prostate glands from 6 men less than 30 years old and enucleated tissue of benign prostatic hyperplasia were analyzed by stereological methods. Studies on the relative volumetric amount of fibromuscular (stromal) and glandular areas of the gland reveal no statistically significant difference between the inner and outer parts of the normal prostate and between the inner part of the normal prostate and benign prostatic hyperplasia. However, in benign prostatic hyperplasia there is a significant increase in the volumetric amount of the fibromuscular tissue and a decrease in the glandular area compared to the outer part of the normal prostate and the whole normal prostate (sum of the inner and the outer parts). These stereological data are discussed with respect to the pathogenesis of benign prostatic hyperplasia.
Stereology
Prostatic Diseases
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Applying benign prostate hyperplasia model, the effect of prosate Kangfu capsule suppressing benign prostate hyperplasia in rats and mice was observed experimentally. The results showed that prostate Kangfu capsule could significantly suppress benign prostate hyperplasia caused by testosterone propionate in rats and mice, and could reduce the bulk of prostate, decrease the wet weight of prostate, depress the level of testosterone, raise the level of estradiol in rats and suppress hyperplasia of prostate lobule. It is indicated that prostate Kangfu capsule has preventive and treating effect on benign prostate haperplasia caused by testosterone propionate.
Testosterone propionate
Capsule
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Objective To observe prostate weight,epithelia cell height and the expression of PCNA in prostate tissues of the rats with benign prostatic hyperplasia(BPH).Methods The castrated SD male rats were subcutaneously injected with testosterone propionate for 30 days and BPH models were established.Under light microscopy,epithelia cell height was observed and by using immunohistochemistry, the expression of PCNA in prostate tissue was detected.Results The expression of PCNA,prostate weight and epithelial cell height in model group were significantly increased as compared with those in control group(all P0.01).There was no significant difference between Xianjia prescription high dose group and control group(P0.05).Conclusion Xianjia prescription can regulate the expression of PCNA to suppress BPH.
Testosterone propionate
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Sulpiride
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Etiology
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To investigate the expression and significance of caspase-1 in normal and hyperplastic prostate tissues.Twenty-eight paraffin-embedded sections, including 21 benign prostatic hyperplasia (BPH) and 7 normal prostate tissue samples, were investigated immunohistochemically for caspase-1.The rate of caspase-1 expression in the BPH tissues was 71.4% (15/21 ) while that in the normal prostate tissues was 100%. The expression level of caspase-1 in both epithelial cells and interstitial cells of the hyperplastic prostate tissues was obviously lower than that of the normal prostate tissues (P < 0.01). Within the BPH tissues, the expression level of caspase-1 in the epithelial cells was higher than in the interstitial cells, and the difference was statistically significant (P < 0.01).The expression of caspase-1 is dramatically reduced in the hyperplastic prostate tissues, which indicates that the decline of caspase-1-dependent apoptosis might be involved in the progress of benign prostatic hyperplasia.
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