Evodiamine impairs HIF1A histone lactylation to inhibit Sema3A-mediated angiogenesis and PD-L1 by inducing ferroptosis in prostate cancer.

Prostate cancer (PCa) is among the most commonly diagnosed solid cancers in male adults. However, most anti-angiogenic therapies and immunotherapies fail to achieve durable remission in advanced PCa. Integrative analysis indicated that Sema3A was negatively correlated with the pathological malignancy and was involved in angiogenesis, cell adhesion, and immune infiltrates in PCa. Sema3A significantly inhibited vascular endothelial growth factor (VEGFA)-induced colony formation, cell proliferation, and PD-L1 expression in PCa cells. Network pharmacological analysis demonstrated that evodiamine, a natural alkaloid compound derived from Evodiae fructus fruits, might regulate Sema3A, lipid metabolism, and monocarboxylic acid transport signaling of PCa. Evodiamine evidently inhibited PCa cell viability in a time-dose-dependent manner. Furthermore, evodiamine impaired angiogenesis by increasing Sema3A expression, and induced ferroptosis by reducing glutathione peroxidase 4 (GPX4) expression, which could be reversed by the ferroptosis blocker ferrostatin-1. Lactate treatment increased hypoxia-inducible factor (HIF)-1α and PD-L1 expressions while restricting Sema3A expression in PCa cells, which could be reversed by silencing monocarboxylate transporter 4 (MCT4) expression. Moreover, evodiamine markedly blocked lactate-induced angiogenesis by restricting histone lactylation and expression of HIF1A in PCa cells, further enhancing Sema3A transcription while inhibiting that of PD-L1. In vivo, evodiamine remarkably inhibited PCa xenograft growth in nude mice, repressing expressions of HIF1α, H3K18la, GPX4, PD-L1, and proliferation, while hindering angiogenesis by increasing Sema3A expression. Therefore, Sema3A represents an essential antineoplastic biomarker, while evodiamine may act as a metabolic-epigenetic modulator, as well as a promising agent in either PCa anti-angiogenic therapy or immunotherapy.

ASCL1-mediated ferroptosis resistance enhances the progress of castration-resistant prostate cancer to neurosecretory prostate cancer.

Neuroendocrine prostate cancer (NEPC) is a multi-resistant variant of prostate cancer (PCa) that frequently emerges in castration-resistant prostate cancer (CRPC). NEPC is usually associated with tumor aggression, hormone therapy resistance, and poor clinical outcome. However, the mechanisms underlying the trans-differentiation from CRPC to NEPC have not been elucidated. Achaete-scute complex-like 1 (ASCL1) plays a role in neuronal commitment and differentiation and olfactory and autonomic neuron generation. This study revealed that ASCL1 was regulated by the SRY-box transcription factor 2 (SOX2) and highly expressed in NEPC cells, which was closely related to poor prognosis. Moreover, ASCL1 overexpression significantly enhanced CRPC progression to NEPC by resisting ferroptosis. Mechanically, ferroptosis resistance was mediated by CAMP-responsive element binding protein 1 (CREB1) phosphorylation, promoted by substantially upregulated ASCL1 in NEPC cells. In addition, upregulated SOX2 induced PCa cell differentiation into neuroendocrine tumors by mediating their lineage changes. In conclusion, inhibiting the ferroptosis resistance mediated by ASCL1 could provide a new NEPC therapeutic target and increase patient survival.

Lingual Mucosal Graft Ureteroplasty for Long Proximal Ureteral Stricture: 6 Years of Experience with 41 Cases.

BACKGROUND: Management of a long proximal ureteral stricture is challenging. Lingual mucosal graft ureteroplasty (LMGU) is a novel minimally invasive technique for ureteral reconstruction that avoids the morbidity of bowel interposition or autotransplantation. OBJECTIVE: To evaluate the long-term effectiveness of LMGU for managing long, complex proximal ureteral strictures in a multi-institutional cohort of patients. DESIGN, SETTING, AND PARTICIPANTS: This retrospective study involved data for 41 patients treated with LMGU at three centers between June 2015 and January 2021. SURGICAL PROCEDURE: LMGU was performed using either an onlay ureteroplasty in which the diseased ureter was incised ventrally and repaired with a lingual mucosal graft (LMG) to widen the ureteral lumen, or an augmented anastomotic technique in which the obliterated segment of the ureter was excised and reanastomosed primarily on dorsal side, and an LMG was placed on the ventral side. MEASUREMENTS: Pre-, intra-, and postoperative variables and outcomes were assessed. A descriptive statistical analysis was performed. RESULTS AND LIMITATIONS: Of 41patients, 40 were operated with laparoscopic procedures and one with a robot. Twenty-four (59%) patients underwent an onlay ureteroplasty, and 17 (41%) underwent an augmented anastomotic ureteroplasty. The reconstructed ureter was wrapped with omentum in 90% of cases. The median (range) stricture length was 4.8 cm (2.0-8.0), operative time was 166 min (98-306), and estimated blood loss was 65 ml (15-220). No open conversions and intraoperative complications occurred. At a median follow-up of 35 mo (range 13-80), the overall success rate was 97.6% (40/41). CONCLUSIONS: LMGU is a safe, feasible, and effective long-term technique for managing long, complex proximal ureteral strictures. PATIENT SUMMARY: We reported a novel technique for long proximal complex ureteral strictures using an onlay lingual mucosal graft (LMG). Our 6-yr outcomes demonstrate that onlay LMG ureteroplasty is a safe, feasible, and effective long-term procedure for ureteral reconstruction.

Laparoscopic onlay lingual mucosal graft ureteroplasty combined with ureterovesical reimplantation for one-stage reconstruction of complex ureteral strictures: a case report.

The treatment of ureteral stricture is a challenging task, especially when multiple strictures are present. Here, we report on a 63-year-old male patient diagnosed with hydronephrosis with left ureteral strictures who was admitted to our hospital. During treatment, a left percutaneous nephrostomy tube was inserted for hydronephrosis. Antegrade and retrograde pyelography were performed simultaneously. The results suggested there were 3 segment ureteral strictures in the left ureter: 2 located in the distal ureter and 1 in the proximal ureter. The treatment choices for multiple ureteral strictures are kidney autotransplantation or an ileal ureteral replacement (IUR), which are both morbid procedures and are technically challenging. With the excellent results of lingual mucosal graft (LMG) in ureteroplasty, this patient underwent a one-stage left ureter reconstruction with combined laparoscopic LMG ureteroplasty and ureterovesical reimplantation. However, disease of the oral mucosa and a reduced bladder volume caused by radio cystitis or chemical cystitis, may limit the use of this technique. Regular postoperative antegrade pyelography and the Whitaker test showed the unimpeded drainage of the left ureter. Based on the satisfactory outcome of this patient, combined laparoscopic LMG ureteroplasty and ureterovesical reimplantation for unilateral multiple ureteral strictures is a viable option that has fewer complications.

Should surgical drainage after lateral transperitoneal laparoscopic adrenalectomy be routine?-A retrospective comparative study.

BACKGROUND: Whether to use surgical drains after abdominal surgery or not has received much attention since a hundred years ago. Nowadays, lateral transperitoneal laparoscopic adrenalectomy (LTLA) is a widely used technique to treat adrenal tumors worldwide. However, the placement of drains after LTLA remains controversial. METHODS: Data of 150 patients, who underwent LTLA between October 2014 and September 2020 by the same lead surgeon, were collected, including demographic, pathology, preoperative, operative variables and postoperative complications. The patients were divided into two groups, with and without drainage. The postoperative recovery of the two groups was compared. RESULTS: Among 150 patients (65 men and 85 women, median age 48 years, median BMI 23.53), 89 patients had no drainage and 61 patients had drainage after surgery. Variables of the two groups were analyzed. Placement of drains correlated with long operative time (P<0.01). Patients with drain had longer hospital stays (P<0.001) and a higher incidence of postoperative complications (P=0.022). Other factors, including tumor size (P=0.61), tumor location (P=0.387), ASA score (P=0.687), pathology (P=0.55), VAS pain score (P=0.41), intraoperative blood loss (P=0.11), were not found to be significantly associated with drain placement. There was no conversion to open surgery in both groups. Moreover, no mortality was observed in either group. CONCLUSIONS: This study revealed that it is feasible and safe not to leave a drain in selective and uncomplicated patients and that surgical drainage should not be routine after LTLA.

Restoration of Penile Sensation Through Neurological Bypass in Rats.

OBJECTIVE: To explore the feasibility of the penile afferent pathway by the cutaneous branch of the genitofemoral nerve to the dorsal nerve of penile transfer in rats. METHODS: A total of 54 male rats were randomly divided into model group (n = 18), resection group (n = 18), and sham group (n = 18). In the model group, the distal stump of bilateral DNP was anastomosed to the proximal stump of the bilateral CGN through end-to-end neurorrhaphy. In the resection group, bilateral DNP was severed and ligated, and no end-to-end anastomosis was performed. Only a surgical incision was made in the sham group, and no nerve injury was caused. After the operation, the feasibility of reconstructing the penile afferent pathway was explored by fluorescent-gold retrograde neural labeling. The intracavernous pressure assessment was then carried out. The morphological examination, histological staining of nerves, and ultrastructural observation were performed accordingly. RESULTS: Fluorescent-gold labeled L1 and L2 neurons in the model group were positive. The mean ICP in the model group was (12.02 ± 2.03 mmHg), which is higher than the mean value in the resection group (0 mmHg, P < .05) but lower than that in the sham group (36.95 ± 5.33 mmHg; P < .05). The morphological studies, HE, and ultrastructure observation revealed that the regeneration of DNP axons in the model group was significantly better than that in the resection group yet did not reach the level of the sham group. CONCLUSION: This experiment preliminarily proved the feasibility of restoration of the penile afferent pathway by CGN to DNP transfer in Rats.

Laparoscopic "reverse 7" ileal ureteral replacement for bilateral extensive ureteral strictures performed completely intracorporeally: the initial experience.

PURPOSE: To present our initial experience and evaluate the feasibility of the novel technique of completely intracorporeal laparoscopic "reverse 7" ileal ureteral replacement (IUR). MATERIALS AND METHODS: Between December 2018 and September 2019, two patients underwent completely intracorporeal laparoscopic "reverse 7" IUR, which were female patients with bilateral extensive ureteral strictures (BEUS) secondary to radical hysterectomy and pelvic lymph node dissection for cervical cancer and postoperative radiotherapy. Antegrade pyelography and retrograde pyelography showed BEUS preoperatively. RESULTS: The novel technique was performed successfully by the same surgeon without conversion to open surgery. The operating time of each patient was 420 min and 410 min, respectively. Meanwhile, the estimated blood loss of each patient was 120 ml and 100 ml, respectively. There were no major complications during the perioperative period. After ureteral stent was removed, antegrade pyelography postoperatively revealed excellent drainage with the resolution of hydronephrosis in both patients. After removing of ureteral stent and nephrostomy tube, no patients have a complaint about the donor site or the onset of flank pain. CONCLUSIONS: To our knowledge, we present the initial experience with completely intracorporeal laparoscopic "reverse 7" IUR. With initial follow-up outcomes, this novel minimally invasive technique appears to be feasible and efficacious in treating BEUS in carefully selected patients.

MicroRNA-20b Promotes Cardiac Hypertrophy by the Inhibition of Mitofusin 2-Mediated Inter-organelle Ca2+ Cross-Talk.

MicroRNA (miRNA) and mitofusin-2 (Mfn2) are important in the development of cardiac hypertrophy, but the target relationship and mechanism associated with Ca2+ handling between SR and mitochondria under hypertrophic condition is not established. Mfn2 expression, Mfn2-mediated interorganelle Ca2+ cross-talk, and target regulation by miRNA-20b (miR-20b) were evaluated using animal/cellular hypertrophic models with state-of-the-art techniques. The results demonstrated that Mfn2 was downregulated and miR-20b was upregulated upon the target binding profile under hypertrophic condition. Our data showed that miR-20b induced cardiac hypertrophy that was reversed by recombinant adeno-associated virus vector 9 (rAAV9)-anti-miR-20b or miR-20b antisense inhibitor (AMO-20b). The deleterious action of miR-20b on Mfn2 expression/function and mitochondrial ATP synthesis was observed and reversed by rAAV9-anti-miR-20b or AMO-20b. The targeted regulation of miR-20b on Mfn2 was confirmed by luciferase reporter and miRNA-masking. Importantly, the facts that mitochondrial calcium uniporter (MCU) activation by Spermine increased the cytosolic Ca2+ into mitochondria, manifested as enhanced histamine-mediated Ca2+ release from mitochondrial, suggesting that Ca2+ reuptake/buffering capability of mitochondria to cytosolic Ca2+ is injured by miR-20b-mediated Mfn2 signaling, by which leads cytosolic Ca2+ overload and cardiac hypertrophy through Ca2+ signaling pathway. In conclusion, pro-hypertonic miR-20b plays crucial roles in cardiac hypertrophy through downregulation of Mfn2 and cytosolic Ca2+ overload by weakening the buffering capability of mitochondria.

Identification of a 5-Gene Signature Predicting Progression and Prognosis of Clear Cell Renal Cell Carcinoma.

BACKGROUND Although the mortality rates of clear cell renal cell carcinoma (ccRCC) have decreased in recent years, the clinical outcome remains highly dependent on the individual patient. Therefore, identifying novel biomarkers for ccRCC patients is crucial. MATERIAL AND METHODS In this study, we obtained RNA sequencing data and clinical information from the TCGA database. Subsequently, we performed integrated bioinformatic analysis that includes differently expressed genes analysis, gene ontology and KEGG pathway analysis, protein-protein interaction analysis, and survival analysis. Moreover, univariate and multivariate Cox proportional hazards regression models were constructed. RESULTS As a result, we identified a total of 263 dysregulated genes that may participate in the metastasis of ccRCC, and established a predictive signature relying on the expression of OTX1, MATN4, PI3, ERVV-2, and NFE4, which could serve as significant progressive and prognostic biomarkers for ccRCC. CONCLUSIONS We identified differentially expressed genes that may be involved in the metastasis of ccRCC. Moreover, a predictive signature based on the expression of OTX1, MATN4, PI3, ERVV-2, and NFE4 could be an independent prognostic factor for ccRCC.

MicroRNA-143 promotes cardiac ischemia-mediated mitochondrial impairment by the inhibition of protein kinase Cepsilon.

The cardioprotection of protein kinase Cepsilon (PKCε) against myocardial infarction (MI) mediated by its anti-apoptotic property and underlying mechanism of targeted regulation by microRNA (miRNA) are not established. MI-induced injury, PKCε expression, and targeted regulation of miRNA-143 (miR-143) to PKCε have been evaluated using animal MI and cellular hypoxic models conjugated with series of state-of-art molecular techniques. The results demonstrated that PKCε significantly downregulated along with increased infarcted area and apoptotic and necrotic damage in MI model, and the targeted relationship and potential binding profile were established between miR-143 and PKCε. Both in vivo and in vitro ischemic tests showed that miR-143 induced apoptosis and necrosis, which was reversed by antagomiR-143 or AMO-143. The upregulation of miR-143 by transfection of miR-143 in vitro also induced cell loss, and this effect of miR-143 was completely reversed by co-transfection of miR-143 with AMO-143. The identically deleterious action of miR-143 on mitochondrial membrane potential and ATP synthesis was also observed in both animal MI and cellular hypoxic models, as well as miR-143 overexpressed models and converted by either antagomiR or AMO. Importantly, overexpression of miR-143 downregulated PKCε in all tested models and this downregulation was reversed in the presence of antagomiR or AMO. The direct targeted regulation of miR-143 on PKCε was confirmed by luciferase reporter and miRNA-masking tests. In conclusion, MI-mediated upregulation of miR-143 inhibits PKCε expression and consequently interference with the cardioprotection of PKCε to mitochondrial, and leads to mitochondrial membrane potential dissipation and myocardial death eventually.