Abstract
Background
Benign prostatic hyperplasia (BPH) is a prevalent disease affecting elderly men, with chronic inflammation being a critical factor in its development. Omentin-1, also known as intelectin-1 (ITLN-1), is an anti-inflammatory protein primarily found in the epithelial cells of the small intestine. This study aimed to investigate the potential of ITLN-1 in mitigating BPH by modulating local inflammation in the prostate gland.
Methods
Our investigation involved two in vivo experimental models. Firstly, ITLN-1 knockout mice (Itln-1−/−) were used to study the absence of ITLN-1 in BPH development. Secondly, a testosterone propionate (TP)-induced BPH mouse model was treated with an ITLN-1 overexpressing adenovirus. We assessed BPH severity using prostate weight index and histological analysis, including H&E staining, immunohistochemistry, and enzyme-linked immunosorbent assay. In vitro, the impact of ITLN-1 on BPH-1 cell proliferation and inflammatory response was evaluated using cell proliferation assays and enzyme-linked immunosorbent assay.
Results
In vivo, Itln-1−/− mice exhibited elevated prostate weight index, enlarged lumen area, and higher TNF-α levels compared to wild-type littermates. In contrast, ITLN-1 overexpression in TP-induced BPH mice resulted in reduced prostate weight index, lumen area, and TNF-α levels. In vitro studies indicated that ITLN-1 suppressed the proliferation of prostate epithelial cells and reduced TNF-α production in macrophages, suggesting a mechanism involving the inhibition of macrophage-mediated inflammation.
Conclusion
The study demonstrates that ITLN-1 plays a significant role in inhibiting the development of BPH by reducing local inflammation in the prostate gland. These findings highlight the potential of ITLN-1 as a therapeutic target in the management of BPH.
Highlights
-
1.
ITLN-1 knockout mice presented heavier prostate weights and higher inflammation levels in the prostate than their WT littermates.
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2.
In a testosterone propionate-induced BPH mouse model, adenovirus-mediated ITLN-1 overexpression led to a reduction in prostate weight and local inflammation.
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3.
ITLN-1 can inhibit prostate epithelial cell proliferation by suppressing macrophage-mediated inflammatory responses.
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4.
Targeting ITLN-1 could be an effective therapeutic approach for preventing or treating BPH in elderly men.
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Introduction
Benign prostatic hyperplasia (BPH) is a prevalent age-related condition among elderly men, characterized by prostate enlargement, leading to urinary complications and a reduced quality of life (Zeng et al. 2022). BPH affects approximately 25% of men aged 50 to 59 years, and 50% of men aged over 60 years, with the prevalence increasing with age (Wei et al. 2005). Currently, the management of BPH often involves pharmacological interventions and, in severe cases, surgical procedures (Miernik and Gratzke 2020; Zitoun et al. 2020). However, these treatments can be costly and may have undesirable side effects, including sexual dysfunction and decreased libido (Giuliano et al. 2013; Srinivasan and Wang 2020). Consequently, there exists a pressing need for novel therapeutic strategies to impede or decelerate the progression of BPH.
Recent research has highlighted the significant roles of metabolic syndrome and chronic inflammation in the development and progression of BPH (Chang et al. 2019; Park et al. 2022; Passos et al. 2021). Chronic prostatic inflammation, in particular, is a key factor in the pathogenesis of BPH (** et al. 2023; Lin et al. 2008). This correlation suggests that omentin-1 may play a role in mediating the beneficial effects of these interventions on BPH.
Chronic low-grade inflammation is a central pathogenic factor in the development of metabolic syndrome components (Nickel et al. 2016). Furthermore, recent clinical and preclinical evidence has confirmed that chronic inflammation also contributes to the development of BPH (Luo et al. In conclusion, our results indicate that targeting ITLN-1 could be an effective treatment strategy for BPH, as ITLN-1 plays a crucial role in suppressing local inflammation in the prostate gland. This research opens up new avenues for the development of anti-inflammatory strategies in the treatment of BPH. Mouse leukemic macrophage cell line RAW264.7 (Cat. No. CL-0190) was purchased from Procell Life Science & Technology. It was cultured in high-glucose Dulbecco’s Modified Eagle’s Medium (DMEM; Cat. No. 11965092, Gibco) supplemented with 10% heat-inactivated fetal bovine serum (FBS; Cat. No. SA301.02, CellMax) and 1% Penicillin–Streptomycin (P/S; Cat. No. P1400, Solarbio). Human prostate hyperplasia cell line BPH-1, kindly provided by Prof. Long Wang from The Third ** gene. The primers used for qRT-PCR were designed based on the gene sequences and were as follows: mus musculus Gapdh, forward, 5ʹ-CACCATGGAGAAGGCCGGGG-3′, reverse, 5′-GACGGACACATTGGGGGTAG-3′; Mus musculus Itln-1, forward, 5′-TTTCCTGCGCACGAAGAA-3′, reverse, 5′-TCATGTCACAGAAGGTCT-3′. Data were presented as mean ± standard deviation (SD) and statistically analyzed using GraphPad Prism 7.0 software. The sample size (n) for each statistical analysis is specified in the figure legends. Unpaired two-tailed Student’s t-test was used to compare two groups, and one-way analysis of variance (ANOVA) was applied to compare multiple groups, and two-way ANOVA was used when two independent variables, in combination, affect a dependent variable. The difference was considered statistically significant at P < 0.05, P < 0.01, and P < 0.001. NS, not significant.Conclusion
Materials and methods
Cell culture
Statistical analysis
Availability of data and materials
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Abbreviations
- BPH:
-
Benign prostatic hyperplasia
- ITLN-1:
-
Intelectin-1
- TP:
-
Testosterone propionate
- H & E:
-
Hematoxylin and Eosin
- TNF-α:
-
Tumor necrosis factor-alpha
- IL-2:
-
Interleukin-2
- IL-6:
-
Interleukin-6
- Itln-1 −/− :
-
ITLN-1 knockout
- WT:
-
Wild type
- RT-qPCR:
-
Reverse transcription quantitative PCR
- PAP:
-
Prostate-specific acid phosphatase
- ELISA:
-
Enzyme-linked immunosorbent assay
- PBS:
-
Phosphate buffered saline
- Veh:
-
Vehicle
- CM:
-
Cell culture conditioned media
- EdU:
-
5-Ethynyl-2′-deoxyuridine
- Ad-Itln-1 :
-
Adenovirus encoding intelectin-1
- Ad-GFP :
-
Adenovirus encoding GFP
- Fina:
-
Finasteride
- PFU:
-
Plaque-forming units
- PFA:
-
Polyformaldehyde
- SD:
-
Standard deviation
- ANOVA:
-
Analysis of variance
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Acknowledgements
The authors thank professor Long Wang for the gift of BPH-1 cell line.
Funding
This work was supported by the Hunan Province Natural Science Foundation of China (Grant No. 2020JJ4820 to R Xu; 2023JJ20096 to Z-X Wang), and the Fundamental Research Funds for the Central Universities of Central South University (Grant No. 2022ZZTS0239 to Y-Y Wang).
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Y.-Y.W. performed majority of the experiments, analyzed data and prepared the draft manuscript. R.X. and Z.‐X.W. conceived the project and designed the experiments. G.-Q.Z. and K.X. performed the experiments. H.-B.Z. and Y.-H.H contributed to the experimental technical consultations. R. X., Z.‐X.W., H.X. and Y.-Y.W. wrote the manuscript. All authors reviewed and revised the manuscript.
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The animal experiments in this study were approved by the Ethical Review Board at **angya Hospital Central South University, ensuring that all procedures were performed in accordance with ethical guidelines.
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All of the authors have indicated that they have no conflicts of interest with regard to the content of article. This manuscript is original and has not been previously published, nor has it been simultaneously submitted to any other journal.
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Additional file 1
: Figure S1. Efficiency of Ad-Itln-1 expression in the small intestine detected by western blot. Figure S2. Fluorescence assessment of Ad-Itln-1 transfection efficiency in the small intestine.
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Wang, YY., Zhu, GQ., **a, K. et al. Omentin-1 inhibits the development of benign prostatic hyperplasia by attenuating local inflammation. Mol Med 30, 41 (2024). https://doi.org/10.1186/s10020-024-00805-y
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DOI: https://doi.org/10.1186/s10020-024-00805-y