Purpose
To determine if chronic administration of Jun-amino terminal kinase (JNK)-inhibitors and LIM-kinase 2 (LIMK2)-inhibitors from the immediate post-injury period in a rat model of cavernous-nerve-crush-injury could normalize cavernous-veno-occlusive-function, and to compare it with phosphodiesterase type 5 (PDE5)-inhibitors.
Materials and Methods
A total of 75 12-week-old male Sprague–Dawley-rats were randomized into five groups: sham-surgery (S), cavernous-nerve-crush-injury (I), cavernous-nerve-crush-injury treated with 10.0 mg/kg LIMK2-inhibitor (L) or 10.0 mg/kg JNK-inhibitor and 10.0 mg/kg LIMK2-inhibitor (J+L) or 20.0 mg/kg udenafil (P) for five-weeks. Five-weeks after surgery, dynamic-infusion-cavernosometry, histological-studies, caspase-3-activity-assay, and Western-blot were investigated.
Results
Group-I had lower papaverine-response, higher maintenance-rate and higher drop-rate, compared to Group-S. Group-L, Group-J+L and Group-P showed improvement in the three dynamic-infusion-cavernosometry parameters. The papaverine-response and drop-rate in Group-J+L and Group-P recovered to sham-control level, but those in Group-L did not. Regarding apoptosis, Group-I had decreased content of α-smooth-muscle-actin, increased caspase-3 activity and increased cJun-phosphorylation. The cJun-phosphorylation improved only in Group-J+L. The α-smooth-muscle-actin content and caspase-3-activity in Group-J+L and Group-P improved, but those in Group-L were not. Regarding fibrosis, Group-I had decreased smooth muscle (SM)/collagen-ratio, increased protein-expression of fibronectin, and increased Cofilin-phosphorylation. Cofilin-phosphorylation was normalized in Group-L and Group-J+L, but not in Group-P. SM/collagen-ratio and protein-expression of fibronectin in Group-L, Group-J+L and Group-P improved.
Conclusions
Our data indicate that chronic inhibition of JNK and LIMK2 can restore cavernous-veno-occlusive-function by suppressing cavernous-apoptosis and cavernous-fibrosis, comparable to the results by PDE5-inhibitors. Chronic inhibition of JNK and LIMK2 might be a potential mechanism-specific targeted therapy for cavernous-veno-occlusive-dysfunction induced by cavernous nerve-injury.
Background
Cavernosal fibrosis, which is induced by cavernosal nerve (CN) injury and progresses with time, is the main cause of cavernosal veno‐occlusive dysfunction (CVOD) after radical prostatectomy.
Objectives
To determine whether daily oral administration of suberoylanilide hydroxamic acid (SAHA; vorinostat) for 5‐weeks from the immediate post‐injury period after CN injury would rectify CVOD by suppressing cavernosal fibrosis and normalizing HDAC pathway in a rat model of CN crush injury (CNCI) and to compare the results with those obtained using chronic administration of PDE5‐inhibitors (a positive control).
Methods
Fifty‐six 12‐week‐old rats were randomized into the four groups: sham surgery (S), CNCI (I), and CNCI treated with daily administration of 25.0 mg/kg SAHA (V) or 20.0 mg/kg udenafil (P). Group‐V and Group‐P received the respective treatment for 5‐weeks from the following day after CNCI. At 5 weeks after surgery, dynamic infusion cavernosometry (DIC), histological staining, and Western blot analysis were performed.
Results
Group‐I had a significantly decreased papaverine response, higher maintenance rate or drop rate, lower smooth muscle (SM)/collagen ratio, decreased SM content, and increased protein expression of HDAC2, HDAC3, TGF‐β1, and collagen‐1, compared with Group‐S. The three DIC parameters in Group‐V and Group‐P significantly improved compared to those in Group‐I. Except for the maintenance rate, the improvement in papaverine response and drop rate in Group‐V was not significantly different from that in Group‐P. Group‐V and Group‐P showed the rectification of SM/collagen ratio and protein expression of TGF‐β1 or collagen‐1. SM content was improved in Group‐P, but not in Group‐V. Group‐V showed the normalization of protein expression of both HDAC2 and HDAC3, whereas protein expression of only HDAC2 was partially restored in Group‐P.
Discussion
Treatment strategies targeting the HDAC pathway might be helpful to alleviate CVOD induced by CN injury.
Conclusions
According to our data, chronic administration of SAHA improves post‐injury CVOD by suppressing cavernosal fibrosis via rectifying the HDAC/TGF‐β1 pathway in nerve‐injured rats, comparable to that with PDE5 inhibitors.
We aim to investigate the significance of intravesical prostate protrusion (IPP) on the prognosis of non-muscle invasive bladder cancer (NMIBC) after the transurethral resection of bladder tumors (TURBT). For newly diagnosed NMIBC, we retrospectively analyzed the association between prognosis and IPP for at least a 5-year follow-up. A degree of IPP over 5 mm in a preoperative CT scan was classified as severe. The primary endpoint was recurrence-free survival, and the secondary endpoint was progression-free survival. The machine learning (ML) algorithm of a support vector machine was used for predictive model development. Of a total of 122 patients, ultimately, severe IPP was observed in 33 patients (27.0%). IPP correlated positively with age, BPH, recurrence, and prognosis. Severe IPP was significantly higher in the recurrence group and reduced in the recurrence-free survival group (p = 0.038, p =0.032). Severe IPP independently increased the risk of intravesical recurrence by 2.6 times. The addition of IPP to the known oncological risk factors in the prediction model using the ML algorithm improved the predictability of cancer recurrence by approximately 6%, to 0.803. IPP was analyzed as a potential independent risk factor for NMIBC recurrence and progression after TURBT. This anatomical feature of the prostate could affect the recurrence of bladder tumors.
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