Knockdown of iPLA2γ enhances cisplatin-induced apoptosis by increasing ROS-dependent peroxidation of mitochondrial phospholipids in bladder cancer cells.

Cisplatin (CDDP) is a platinum-based drug with anti-cancer activity and is widely used as a standard therapy for bladder cancer. It is well known that CDDP causes cell death by increasing the generation of reactive oxygen species (ROS) and lipid peroxidation, but the mechanism of its anti-cancer effects has not been fully elucidated. There are still some problems such as chemoresistance in CDDP therapy. In the present study, we found the expression of Ca2+-independent phospholipase A2γ (iPLA2γ), which has been reported to regulate cellular redox homeostasis by inhibiting lipid peroxide accumulation, in human bladder cancer tissues. Thus, we investigated the effect of iPLA2γ knockdown on CDDP-induced bladder cancer cell death. As a result, we found that iPLA2γ knockdown significantly enhanced CDDP-induced apoptosis, intracellular and mitochondrial ROS production, cytochrome c release and caspase activation in bladder cancer cells. Moreover, mitochondrial membrane potential was decreased and peroxidation of mitochondrial phospholipids was increased by iPLA2γ knockdown. It was also shown that co-treatment of bromoenol lactone, an iPLA2 inhibitor, increased CDDP-induced apoptosis. These results indicated that iPLA2γ plays an important role in protecting bladder cancer cells from CDDP-induced apoptosis, and that iPLA2γ inhibitors might represent a novel strategy in CDDP-based multi-drug therapy.

Outcome of Modified Laparoscopic Sacrocolpopexy and Its Effect on Voiding Dysfunction.

BACKGROUND: Because of its low recurrence rate and safety, laparoscopic sacrocolpopexy (LSC) is an increasingly popular treatment for pelvic organ prolapse (POP). Although LSC may improve voiding function, it can also lead to de novo stress urinary incontinence. The exact effects of LSC on voiding function, and the mechanisms responsible, remain unclear. Therefore, in this study we prospectively evaluated the impact of LSC on voiding function by performing a pre- and postoperative urodynamic study of patients with stage 3 or worse POP. METHODS: Urinary status was evaluated before and 3 months after LSC. Pre- and postoperative evaluations included medical history, clinical examination, urodynamic studies, chain cystography, and residual urine volume measurement. Urinary symptoms were assessed using the International Prostate Symptom Score (IPSS) and the Overactive Bladder Symptom Score (OABSS). RESULTS: The nonrecurrence rate at 3 months was 82.3%. All recurrences involved bladder prolapse. In addition to the absence of a significant change in OABSS, the improvement in IPSS suggests that subjective voiding symptoms improved. Although the maximum urinary flow rate did not significantly change, bladder volume at first sensation increased, urinary storage function improved, and residual urine volume decreased. There were no perioperative complications, and no patient reported postoperative difficulty in urination or urinary retention. The retrovesical angle significantly decreased. CONCLUSIONS: The modified LSC in women with POP provides good functional outcomes in terms of IPSS, post-void residual volume (PVR), and urinary storage function.

Efficacy of Laparoscopic Partial Cystectomy with a Transurethral Resectoscope in Patients with Bladder Endometriosis: See-Through Technique.

PURPOSE: Bladder endometriosis (BE) is rare. Deep invasive endometriosis is difficult to control with medications alone; such cases need surgical treatment. Good results of laparoscopic partial cystectomy with a transurethral (TU) resectoscope by the see-through technique for patients with BE are reported. MATERIALS AND METHODS: From January 2008 to February 2016, 12 cases of symptomatic BE were seen in our institution. The chief complaints of 9 cases were micturition pain during menstruation. Preoperative cystoscopy showed a bladder mass with blueberry spots. All surgeries were performed under general anesthesia. Laparoscopic surgery was performed with a fan of 4 ports in the lower abdomen. First, the uterus and bilateral ovaries were checked. Then, the TU resectoscope was inserted. When the affected bladder wall was identified, it was again observed with the laparoscopic light source off, which made it possible to observe the twilight leaking inside from the bladder. This twilight came from the light source of the TU resectoscope via the unaffected bladder wall. In contrast, the thickness of the affected wall prevented the light from inside the bladder from passing through it. We call this the "see-through technique." The tumor was then safely dissected with both laparoscopic and TU resection procedures. Finally, the bladder was sutured by laparoscopic procedures using absorbable sterile surgical suture. The urethral catheter was removed after cystography 7 days after the operation. RESULTS: The surgical margins of all cases were negative. There has been no recurrence of BE so far in any patients. There were no major adverse events perioperatively and the urinary symptoms improved in all cases. CONCLUSIONS: By laparoscopic partial cystectomy assisted with a TU resectoscope and see-through technique, the edge of BE could be easily and precisely identified. These procedures are effective and safe for BE surgical treatment.

A Case of Primary Malignant Lymphoma of the Prostate Gland Presenting as Right Lower Back Pain and Dysuria.

A 73-year-old man presented with right lower back pain and dysuria. Right hydronephrosis and a large pelvic large mass were seen on computed tomography (CT). Although his prostate-specific antigen (PSA) was 0.5 ng/mL, an irregularly enlarged, stony, hard prostate was palpable on digital rectal examination. A prostate tumor was suspected, and a transrectal prostate biopsy and right transurethral ureteral stent placement were performed. Histological and immunohistochemical studies revealed diffuse large B-cell lymphoma. Positron emission tomography-computed tomography showed abnormal uptake in the stomach, cecum, right obturator lymph nodes, para-aortic lymph nodes, and dorsal left kidney. No abnormal findings were seen on bone marrow histology. Clinical stage IVA was confirmed according to Ann Arbor criteria. The patient achieved a complete response after 8 cycles of combination chemotherapy with rituximab, pirarubicin, cyclophosphamide, vincristine, and prednisolone.

Treatment Results of Transurethral Resection of the Prostate by Non-Japanese Board-Certified Urologists for Benign Prostate Hyperplasia: Analysis by Resection Volume.

INTRODUCTION: Transurethral resection of the prostate (TURP) is the gold standard for surgical treatment of benign prostatic hyperplasia (BPH), but it has complications such as bleeding and transurethral resection syndrome. The treatment results of TURP performed by non-Japanese board-certified urologists were examined, and the results were analyzed according to the resection volume to determine how much resection volume was suitable for non-Japanese board-certified urologists. MATERIALS AND METHODS: A total of 72 cases that underwent TURP for BPH at our hospital were examined. The patients were divided into three groups by resection volume (<20 g, 20-30 g, >30 g). The operators were five non-Japanese board-certified urologists. Various clinical factors were examined among the three groups before and after TURP. RESULTS: The average operation time and resection volume were significantly different among the groups. There were more transfused cases with greater resection volume. The changes from before to after TURP in the International Prostate Symptom Score, total prostate volume, and maximum flow rate were significantly different among the three groups, but the rates of these changes were not. CONCLUSIONS: In this study, TURP performed by non-Japanese board-certified urologists was relatively safe and achieved sufficient efficacy. Cases with resection volume less than 20 g appear the most appropriate for non-Japanese board-certified urologists.

Angiotensin-I converting enzyme inhibitory activity of hydrolysates from oat (Avena sativa) proteins by in silico and in vitro analyses.

The potential for producing antihypertensive peptides from oat proteins through enzymatic hydrolysis was assessed in silico and confirmed in vitro. Thermolysin (EC 3.4.24.27) was predicted using BIOPEP database as the enzyme that would theoretically produce the most angiotensin I converting enzyme (ACE) inhibitory peptides from oat. Experimental evidence confirmed that strong ACE-inhibitory activity was produced under various hydrolysis conditions. Hydrolysates produced under high enzyme-to-substrate ratio (3%) short time (20 min) (HEST) and low enzyme-to-substrate ratio (0.1%) long time (120 min) (LELT) conditions had IC(50) values of 30 and 50 microg/mL, respectively. After simulated gastrointestinal digestion, the IC(50) of the HEST hydrolysate was 35 microg/mL whereas the IC(50) of the LELT hydrolysate was higher at 85 microg/mL. Ultrafiltration revealed that potent ACE-inhibitory peptides had molecular weights below 3 kDa. This study demonstrates the usefulness of in silico analysis to select enzymes for hydrolysis of proteins not previously examined as sources of bioactive peptides.

Structure-activity relationship studies of 5-benzylaminoimidazo[1,2-c]pyrimidine-8-carboxamide derivatives as potent, highly selective ZAP-70 kinase inhibitors.

Zeta-associated protein, 70 kDa (ZAP-70), a spleen tyrosine kinase (Syk) family kinase, is normally expressed on T cells and natural killer cells and plays a crucial role in activation of the T cell immunoresponse. Thus, selective ZAP-70 inhibitors might be useful not only for treating autoimmune diseases, but also for suppressing organ transplant rejection. In our recent study on the synthesis of Syk family kinase inhibitors, we discovered that novel imidazo[1,2-c]pyrimidine-8-carboxamide derivatives possessed potent ZAP-70 inhibitory activity with good selectivity for ZAP-70 over other kinases. In particular, compound 26 showed excellent ZAP-70 kinase inhibition and high selectivity for ZAP-70 over structurally related Syk. The discovery of a potent, highly selective ZAP-70 inhibitor would contribute a new therapeutic tool for autoimmune diseases and organ transplant medication.

Structure-activity relationship studies of imidazo[1,2-c]pyrimidine derivatives as potent and orally effective Syk family kinases inhibitors.

Spleen tyrosine kinase (Syk) and zeta-associated protein kinase of 70k Da (ZAP-70) are members of the Syk family and non-receptor-type protein tyrosine kinases, which play crucial roles in B- and T-cell activation. Therefore, a Syk family tyrosine kinases inhibitor would be a useful therapeutic agent for the treatment of various allergic disorders and autoimmune diseases. Previously, we reported that 1,2,4-triazolo[4,3-c]pyrimidine derivative 1 and 1,2,4-triazolo[1,5-c]pyrimidine derivative 2 showed strong inhibitory activities against Syk family kinases. These compounds also exhibited high-level suppression of IL-2 in cellular assays. However, their oral efficacies were poor in a mouse model of IL-2 production. To improve oral effectiveness, we investigated a new series of Syk family kinases inhibitors. We found that imidazo[1,2-c]pyrimidine derivatives potently inhibited the Syk family kinases. Among these agents, compound 9f not only showed strong inhibitory activities against Syk and ZAP-70 kinases in vitro, but its oral administration resulted in the in vivo suppression of both the passive cutaneous anaphylaxis reaction and Concanavalin A-induced IL-2 production in a mouse model.

A novel Syk family kinase inhibitor: design, synthesis, and structure-activity relationship of 1,2,4-triazolo[4,3-c]pyrimidine and 1,2,4-triazolo[1,5-c]pyrimidine derivatives.

Splenic tyrosine kinase (Syk) family kinases, which are members of the protein tyrosine kinase family, play crucial roles in immune responses, with Syk participating in B-cell activation and the zeta-associated protein 70 kDa (ZAP-70) kinase being involved in T-cell activation. Therefore, Syk family kinase inhibitors are candidate therapeutic agents for the treatment of various allergic disorders and autoimmune diseases. We designed 1,2,4-triazolo[4,3-c]pyrimidine and 1,2,4-triazolo[1,5-c]pyrimidine derivatives as Syk family kinase inhibitors, based on literature reports and structure-based drug design. These derivatives showed significant Syk inhibitory activities, with ZAP-70 inhibition. Representative compounds 10d and 11 not only exhibited strong inhibition of both Syk and ZAP-70 kinase but also suppressed IL-2 production by peripheral blood mononuclear cells and whole blood.

[The painful multiple mononeuropathy of acute onset in the left arm which was diagnosed as leprous neuropathy].

A 31-year-old man from Myanmar with leprous neuropathy was reported. The progress of the disease was subacute but the painful symptom at the time of the onset was acute. Multiple mononeuropathy was diagnosed by the biopsy findings of the left superficial radial nerve. He was admitted to our hospital with the complaint of the weakness of his left hand and fingers which were very painful and got worse in several weeks. Motor palsy was observed in his left ulnar, median, and radial nerves, and there was the hypesthesia or anesthesia in his left hand, forearm and the medial side of his left upper arm. On nerve conduction studies, the amplitudes of CMAP and SNAP severely diminished or not detected. The pattern was compatible with multiple mononeuropathy. The biopsy of the left superficial radial nerve was performed. The pathological findings were the destruction of nerve fascicles, replacement of nerve fibers with inflammatory cells, and Mycobacterium leprae was found with the specific stain. These findings confirmed the diagnosis of the leprous neuropathy. Leprous neuropathy is one of the commonest causes of infectious neuropathy in the world, especially in Southeast Asia. These days many foreign workers from that area are staying in Japan, and the chances to see the disease are increasing. We have to recognize leprous neuropathy as a candidate for the multiple mononeuropathy of acute onset with painful dysesthesia similar to vascular neuropathy.