Activation of SIRT1/Nrf2/HO-1 and Beclin-1/AMPK/mTOR autophagy pathways by eprosartan ameliorates testicular dysfunction induced by testicular torsion in rats.

Testicular torsion carries the ominous prospect of inducing acute scrotal distress and the perilous consequence of testicular atrophy, necessitating immediate surgical intervention to reinstate vital testicular perfusion, notwithstanding the paradoxical detrimental impact of reperfusion. Although no drugs have secured approval for this urgent circumstance, antioxidants emerge as promising candidates. This study aspires to illustrate the influence of eprosartan, an AT1R antagonist, on testicular torsion in rats. Wistar albino rats were meticulously separated into five groups, (n = 6): sham group, eprosartan group, testicular torsion-detorsion (T/D) group, and two groups of T/D treated with two oral doses of eprosartan (30 or 60 mg/kg). Serum testosterone, sperm analysis and histopathological examination were done to evaluate spermatogenesis. Oxidative stress markers were assessed. Bax, BCL-2, SIRT1, Nrf2, HO-1 besides cleaved caspase-3 testicular contents were estimated using ELISA or qRT-PCR. As autophagy markers, SQSTM-1/p62, Beclin-1, mTOR and AMPK were investigated. Our findings highlight that eprosartan effectively improved serum testosterone levels, testicular weight, and sperm count/motility/viability, while mitigating histological irregularities and sperm abnormalities induced by T/D. This recovery in testicular function was underpinned by the activation of the cytoprotective SIRT1/Nrf2/HO-1 axis, which curtailed testicular oxidative stress, indicated by lowering the MDA content and increasing GSH content. In terms of apoptosis, eprosartan effectively countered apoptotic processes by decreasing cleaved caspase-3 content, suppressing Bax and stimulating Bcl-2 gene expression. Simultaneously, it reactivated impaired autophagy by increasing Beclin-1 expression, decreasing the expression of SQSTM-1/p62 and modulate the phosphorylation of AMPK and mTOR proteins. Eprosartan hold promise for managing testicular dysfunction arising from testicular torsion exerting antioxidant, pro-autophagic and anti-apoptotic effect via the activation of SIRT1/Nrf2/HO-1 as well as Beclin-1/AMPK/mTOR pathways.

Vincamine alleviates intrahepatic cholestasis in rats through modulation of NF-kB/PDGF/klf6/PPARγ and PI3K/Akt pathways.

The defect in the hepatobiliary transport system results in an impairment of bile flow, leading to accumulation of toxic compounds with subsequent liver disorders. Vincamine, a plant indole alkaloid that is utilized as a dietary supplement, has been known for its promising pharmacological activities. For the first time, the present study was planned to estimate, at the molecular level, the potentiality of vincamine against alfa-naphthyl isothiocyanate (ANIT)-induced hepatic cholestasis. Liver function tests were analyzed. Hepatic activity of SOD and levels of GSH and MDA were assessed. Hepatic contents of bax, bcl2, NF-kB, PPARγ, catalase, heme-oxygenase-1, NTCP, and BSEP were evaluated using ELISA. mRNA levels of NF-kB, IL-1ß, IL-6, TNFα, PDGF, klf6, PPARγ, and P53 were examined using qRT-PCR. PI3K, Akt and cleaved caspase-3 proteins were assessed using western blotting. Histopathological analyses were performed using hematoxylin & eosin staining. ANIT-induced hepatic cholestasis elevated liver function tests, including AST, ALT, GGT, ALP, and total bilirubin. ANIT reduced the protein expression of NTCP and BSEP hepatic transporters. It induced the expression of the inflammatory genes, TNFα, IL-6, IL-1ß, and PDGF, and the expression of NF-kB at the genetic and protein level and suppressed the anti-inflammatory genes, klf6 and PPARγ. Also, antioxidant markers were reduced during ANIT induction such as GSH, SOD, catalase, heme-oxygenase-1 and PI3K/Akt pathway, while MDA levels were elevated. Furthermore, the expression of P53 gene, bax and cleaved caspase 3 proteins were activated, while bcl2 was inhibited. Also, the histopathological analysis showed degeneration of hepatocytes and inflammatory cellular infiltrates. However, vincamine treatment modulated all these markers. It improved liver function tests. It inhibited the expression of NF-kB, TNFα, IL-6, IL-1ß and PDGF and activated the expression of klf6 and PPARγ. Furthermore, vincamine reduced MDA levels and induced GSH, SOD, catalase, heme-oxygenase-1 and PI3K/Akt pathway. Additionally, it inhibited expression of P53 gene, bax and cleaved caspase 3 proteins. More interestingly, vincamine showed better outcomes on the hepatic histopathological analysis and improved the alterations induced by ANIT. Vincamine alleviated hepatic dysfunction during ANIT-induced intrahepatic cholestasis through its anti-inflammatory and antioxidant efficacies by the modulation of NF-kB/PDGF/klf6/PPARγ and PI3K/Akt pathways.

Efficacy of GreenLight laser prostatectomy in urinary retention.

INTRODUCTION: The objective of our study was to evaluate the efficacy and durability of GreenLight laser prostatectomy for the management of acute urinary retention (AUR) and chronic urinary retention (CUR) and to determine outcomes compared to patients without preoperative urinary retention (UR). METHODS: We conducted a retrospective study of prospectively collected data from individuals who underwent GreenLight laser prostatectomy at our institution from May 2018 to July 2022. Patient demographics and outcome measures were recorded, including indications for the procedure, median urinary volume drained, or median postvoid residual urine volume (PVR) before catheterization or GreenLight laser prostatectomy. CUR was defined as PVR >300 mL in males able to void and initial catheter drainage >1000 mL in males unable to void in the absence of pain. All patients had postoperative followup visits at one, three, six, and 12 months. Our evaluation included the International Prostate Symptom Score (IPSS), quality-of-life (QoL) assessment, maximum urinary flow rate (Qmax), PVR, and catheter-free status. RESULTS: One hundred sixty-eight males who underwent GreenLight laser prostatectomy were included in our study. The UR group consisted of 88 patients (50 AUR and 38 CUR), and the lower urinary tract symptoms (LUTS) group was comprised of 80 individuals. There were no statistically significant differences between the AUR and CUR subgroups regarding demographics. The UR group had a significantly higher age and a significantly higher postoperative catheterization time compared to the LUTS cohort. The CUR subgroup had a significantly higher PVR at one, three, and six months compared to the AUR subgroup, although other outcome measures were similar between the two cohorts. During three- and six-month followup visits, the UR group had a significantly higher PVR than the LUTS cohort. At 12 months postoperative, the LUTS group had a higher catheter-free rate than the UR group (p=0.001). The successful first trial of void (TOV) rate for the UR and LUTS groups were 83% and 80%, respectively. At 12-month followup, the catheter-free rate for the UR and LUTS cohorts was 87.5% and 100%, respectively. CONCLUSIONS: GreenLight laser prostatectomy is an effective and durable treatment for UR, with a high catheter-free rate and comparable outcomes when performed to manage LUTS.

Evolutionary preservation of CpG dinucleotides in RAG1 may elucidate the relatively high rate of methylation-mediated mutagenesis of RAG1 transposase.

Recombination-activating gene 1 (RAG1) is a vital player in V(D)J recombination, a fundamental process in primary B cell and T cell receptor diversification of the adaptive immune system. Current vertebrate RAG evolved from RAG transposon; however, it has been modified to play a crucial role in the adaptive system instead of being irreversibly silenced by CpG methylation. By interrogating a range of publicly available datasets, the current study investigated whether RAG1 has retained a disproportionate level of its original CpG dinucleotides compared to other genes, thereby rendering it more exposed to methylation-mediated mutation. Here, we show that 57.57% of RAG1 pathogenic mutations and 51.6% of RAG1 disease-causing mutations were associated with CpG methylation, a percentage that was significantly higher than that of its RAG2 cofactor alongside the whole genome. The CpG scores and densities for all RAG ancestors suggested that RAG transposon was CpG denser. The percentage of the ancestral CpG of RAG1 and RAG2 were 6% and 4.2%, respectively, with no preference towards CG containing codons. Furthermore, CpG loci of RAG1 in sperms were significantly higher methylated than that of RAG2. In conclusion, RAG1 has been exposed to CpG mediated methylation mutagenesis more than RAG2 and the whole genome, presumably due to its late entry to the genome later with an initially higher CpG content.

Modulating Nrf-2/HO-1, apoptosis and oxidative stress signaling pathways by gabapentin ameliorates sepsis-induced acute kidney injury.

PURPOSE: Globally, sepsis, which is a major health issue resulting from severe infection-induced inflammation, is the fifth biggest cause of death. This research aimed to evaluate, for the first time, the molecular effects of gabapentin's possible nephroprotective potential on septic rats by cecal ligation and puncture (CLP). METHODS: Sepsis was produced by CLP in male Wistar rats. Evaluations of histopathology and renal function were conducted. MDA, SOD, GSH, TNF-α, IL-1ß, and IL-6 levels were measured. qRT-PCR was utilized to determine the expression of Bax, Bcl-2, and NF-kB genes. The expression of Nrf-2 and HO-1 proteins was examined by western blotting. RESULTS: CLP caused acute renal damage, elevated the blood levels of creatinine, BUN, TNF-α, IL-1ß, and IL-6, reduced the expression of Nrf-2 and HO-1 proteins and the Bcl-2 gene expression, and upregulated NF-kB and Bax genes. Nevertheless, gabapentin dramatically diminished the degree of the biochemical, molecular, and histopathological alterations generated by CLP. Gabapentin reduced the levels of proinflammatory mediators and MDA, improved renal content of GSH and SOD, raised the expression of Nrf-2 and HO-1 proteins and Bcl-2 gene, and reduced the renal expression of NF-kB and Bax genes. CONCLUSION: Gabapentin mitigated the CLP-induced sepsis-related acute kidney injury through up-regulating Nrf-2/HO-1 pathway, repressing apoptosis, and attenuating the oxidative stress status by reducing the levels of the proinflammatory mediators and enhancing the antioxidant status.

Safety and clinical outcomes of GreenLight laser prostatectomy in octogenarians.

INTRODUCTION: We evaluated the impact of age on perioperative morbidity and clinical outcomes in patients undergoing GreenLight laser prostatectomy for benign prostatic hyperplasia (BPH). METHODS: We conducted a retrospective study of prospectively collected data from individuals who underwent GreenLight laser prostatectomy from May 2018 to July 2022. Patient demographics and outcome measures were recorded, including indications for the procedure and American Society of Anesthesiology (ASA) scores. All patients had postoperative followup visits at one, three, six, and 12 months. Our evaluation included the International Prostate Symptom Score (IPSS ), quality of life (QoL) assessment, maximum urinary flow rate (Qmax), postvoid residual volume (PVR), and catheter-free status. RESULTS: One-hundred-sixty-eight males who underwent GreenLight laser prostatectomy were included. The non-octogenarian group consisted of 111 patients and the octogenarian group comprised 57 individuals. Based on ASA scores, most octogenarians were deemed high-risk (ASA III: 91.2%), while over half of non-octogenarians were lower-risk (ASA II: 53.2%) (p<0.001). Intraoperative parameters, including operative time, vaporization time, lasing time, and energy did not differ significantly between groups. There was no difference in the proportion of intraoperative complications between non-octogenarians and octogenarians (0.9% vs. 3.5%). Postoperative complications were not statistically significant between the two groups (p=0.608). There was also no observed difference in the proportion of patients requiring readmission (p=0.226) or retreatment (p=1.0). CONCLUSIONS: GreenLight laser prostatectomy is a safe and effective treatment for BPH regardless of age. It provides similar surgical and functional outcomes as younger men while maintaining the QoL of octogenarians.

Curative Effect of AD-MSCs against Cisplatin-Induced Hepatotoxicity in Rats is Potentiated by Azilsartan: Targeting Oxidative Stress, MAPK, and Apoptosis Signaling Pathways.

Despite its clinical value, cisplatin (CISP) is complicated by marked hepatotoxicity via inducing oxidative stress, inflammatory, and apoptotic pathways. This study aims to explore the protective impact of azilsartan (AZIL), an antihypertensive drug, in addition to adipose tissue-derived mesenchymal stem cells (AD-MSCs) on CISP-induced hepatotoxicity. After characterization and labeling of AD-MSCs by PKH26 dye, 54 Wistar male albino rats were randomly divided into nine groups: I (CONT), II (AZIL.H), III (CISP), IV (CISP + AZIL.L), V (CISP + AZIL.H), VI (CISP + AD-MSCs), VII (CISP + AZIL.L + AD-MSCs), VIII (CISP + AZIL.H + AD-MSCs), and IX (CISP + VITA C). Serum alanine aminotransferase (ALT), alanine aminotransferase (AST), and albumin levels were determined. Assessment of reactive oxygen species, malondialdehyde, and glutathione contents, and superoxide dismutase activity and histopathological evaluations were done on hepatic tissue. Quantitative real-time PCR was utilized to estimate the expression of TNF-α and IL-6 genes. Cell homing of labeled AD-MSCs to the liver tissues was investigated. Hepatic expression of JNK1/2, ERK1/2, p38, Bax, Bcl-2, and cleaved caspase-3 proteins was investigated by western blot analysis. CISP elevated serum ALT and AST activities, reduced albumin level, and remarkably changed the hepatic architecture. It increased the expression TNF-α and IL-6 genes, raised the expression of JNK1/2, ERK1/2, p38, Bax, and cleaved caspase-3 proteins, and diminished the Bcl-2 protein. By contrast, treatment of animals with either AZIL or AD-MSCs dramatically reduced the effects of CISP injection. Moreover, treatment with combination therapy (AZIL.L or H + AD-MSCs) considerably mitigated all previously mentioned alterations superior to AZIL or AD-MSCs alone, which might be attributed to the AZIL-enhanced homing ability of AD-MSCs into the injured liver tissue. In conclusion, the present findings demonstrated that AZIL improves the hepatoprotective potential of AD-MSCs against CISP-induced hepatotoxicity by modulating oxidative stress, mitogen-activated protein kinase, and apoptotic pathways.

LCZ696 attenuates sepsis-induced liver dysfunction in rats; the role of oxidative stress, apoptosis, and JNK1/2-P38 signaling pathways.

AIM: Sepsis is a serious inflammatory response to infection with an annual incidence rate of >48 million cases and 11 million fatalities worldwide. Furthermore, sepsis remains the world's fifth-greatest cause of death. For the first time, the current study aims to evaluate the possible hepatoprotective benefits of LCZ696, a combination of an angiotensin receptor blocker (valsartan) and a neprilysin inhibitor prodrug (sacubitril), on cecal ligation and puncture (CLP)-induced sepsis in rats. MAIN METHODS: CLP was employed to induce sepsis. Hepatic malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD), interleukin-6 (IL-6), IL-1ß, tumor necrosis factor-alpha (TNF-α), and caspase 3 were assessed using ELISA. Serum alanine transaminase (ALT) and aspartate transaminase (AST) were also measured. Western blot assay was used to determine the expression of JNK1/2 and P38 proteins. The histology of liver tissues was also examined. KEY FINDINGS: CLP resulted in significant elevation of AST, ALT, MDA, IL-6, IL-1ß, TNF-α, and caspase 3 levels, and up-regulation of p/t JNK1/2, and p/t P38 proteins, as compared to the sham group. However, level of GSH, and SOD activity were reduced in CLP group. LCZ696 significantly improved all the previously mentioned biochemical and histological abnormalities better than using valsartan alone. SIGNIFICANCE: LCZ696 substantially ameliorated CLP-induced liver damage, compared to valsartan, by reducing proinflammatory mediators, inhibiting the JNK1/2 and P38 signaling pathway, and attenuating apoptosis.

Top-down holmium laser enucleation of the prostate (HoLEP) versus traditional HoLEP for the treatment of benign prostatic hyperplasia (BPH): 1-year outcomes of a randomized controlled trial.

BACKGROUND: The top-down holmium laser enucleation of the prostate (HoLEP) technique recently emerged as a safe and effective modification of traditional HoLEP. In our randomized controlled trial, we compared intraoperative and postoperative outcomes of traditional and top-down HoLEP for the treatment of benign prostatic hyperplasia (BPH) in patients with a prostate size ≥80 g. METHODS: One-hundred patients with BPH and a prostate volume ≥80 cc participated in this prospective randomized controlled trial. Outcome measures were collected and compared, including IPSS, QoL, flow rate, PVR, IIEF-15, PSA, and TRUS prostate volume changes. Perioperative complications were also recorded. All patients were followed up at 1, 3, 6, and 12 months. RESULTS: There were no significant differences in preoperative baseline characteristics between the two surgical groups. The median prostate volume for the traditional and top-down HoLEP groups was 107 and 102 cc, respectively. The operative parameters and postoperative outcomes were comparable for both cohorts. The median enucleation time for traditional HoLEP was 60 min, which was not significantly longer than that of top-down HoLEP (52 min) (p = 0.07). At 3 months follow-up, there was no statistically significant difference in transient stress urinary incontinence (SUI) in the traditional HoLEP (4.1%) versus the top-down HoLEP group (2.2%), (p = 0.61). There were no significant differences in functional and sexual outcomes between the two groups at 12 months. CONCLUSIONS: The HoLEP procedure significantly improves patients' urinary functional outcomes and has comparable postoperative outcomes regardless of the technique utilized.

Assessing the Antiproliferative Potential of a Novel Combretastatin A4 Derivative via Modulating Apoptosis, MAPK/ERK and PI3K/AKT Pathways in Human Breast Cancer Cells.

BACKGROUND: Breast cancer is the most predominant tumor in women. Even though current medications for distinct breast cancer subtypes are available, the non-specificity of chemotherapeutics and chemoresistance imposes major obstacles in breast cancer treatment. Although combretastatin A-4 (CA-4) has been well-reported to have potential anticancer activity, in vivo studies of CA-4 reveal a decrease in its activity. In this respect, a series of CA-4 analogues have been designed, from which one analog [(1-(3-chloro-4-fluorophenyl)-N-(2methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-1H-1,2,4-triazole-3-carboxamide, C25H22ClFN4O5] showed drastic cytotoxicity against breast cancer cells. Therefore, this research focused on investigating the in vitro molecular mechanism underlying the cytotoxicity of the CA-4 analogue, particularly the MAPK/ERK as well as PI3K/AKT pathways as attractive therapeutic targets in breast cancer. METHODS: The cell viability of MCF-7, MDA-MB231, and MDA-MB453 was assessed after treatment with the CA-4 analogue, and apoptosis was analyzed via Annexin V-FITC/PI dual staining. MAPK/ERK and PI3K/AKT were thoroughly assessed using western blotting. Real-time PCR was used to estimate apoptosis-related markers, including the P53, Bcl-2-associated X protein (Bax), and B-cell lymphoma 2 (Bcl2) genes. RESULTS: The CA-4 analogue reduced the survival of all cancerous cells in a concentration-dependent manner and induced apoptosis through the mitochondrial pathway (39.89 ± 1.5%, 32.82 ± 0.6%, and 23.77 ± 1.1% in MCF-7, MDA-MB231, and MDA-MB453 cells), respectively. The analogue also attenuated the expression of pMEK1/2/t-MEK1/2, p-ERK1/2/t-ERK1/2, p-PI3K/t-PI3K, and p-AKT/t-AKT proteins in all three cancer cell lines in a time-dependent manner. Furthermore, the CA-4 analogue upregulated the expression of the P53 gene and dramatically increased the ratio of Bax/Bcl2 genes. CONCLUSIONS: The enhanced cytotoxicity can be attributed to substituting the hydroxyl group in CA-4 with chlorine in the meta-position of ring B, substituting the para-methoxy group in CA-4 with fluorine in the analogue, and lastly, introducing an extension to the compound's structure (ring C). Therefore, CA-4 analogue can attenuate the proliferation of human breast cancer cells by inducing apoptosis and simultaneously suppressing the MAPK/ERK and PI3K/AKT pathways.

Thulium Fiber Laser vs Pulse-Modulated Holmium MOSES Laser in Flexible Ureteroscopy for the Management of Kidney Stones: A Single-Center Retrospective Analysis.

Introduction and Objective: The study's primary objective was to compare the laser efficiency and clinical outcomes of two widely used systems, the holmium MOSES laser and the thulium fiber laser (TFL), in managing kidney stones. The secondary outcomes were to evaluate the impact of stone composition on laser efficacy. Methods: We conducted a retrospective review of patients who underwent flexible ureteroscopy (f-URS) for solitary renal calculi between December 2020 and August 2022 at our institution and had a 3-month postoperative CT scan. Patient demographics and stone parameters were recorded, including stone site, size, volume, and density. Intraoperative data were collected and analyzed, including total operative time, ureteroscopy time, lasing time, technique, total energy delivered, and stone composition. All patients underwent a CT scan at 3 months follow-up. We recorded the presence of residual stones and the percentage of stone volume reduction. Ablation efficiency was calculated by dividing the energy utilized (J) by the stone volume (mm3). The ablation speed was calculated by dividing the stone volume (mm3) by the lasing time (seconds). Patients with a stone size <4 mm were deemed stone-free. Results: The MOSES and TFL groups comprised 62 and 49 patients, respectively. There were no significant differences between groups for baseline patient demographics or stone characteristics. The two modalities had comparable total energy, laser time, efficacy, and ablation speeds. No differences were detected in stone-free rates or complications between both groups. When dealing with calcium phosphate stones, we observed that the lasing time was significantly shorter with MOSES than TFL (7.95 vs 10.85 minutes, respectively [p = 0.01]). Conclusions: MOSES and TFL laser systems had comparable efficacy for lithotripsy of renal calculi during f-URS; however, calcium phosphate stones had a longer lasing time with TFL. REB Number: 100210.

Vincamine Ameliorates Epithelial-Mesenchymal Transition in Bleomycin-Induced Pulmonary Fibrosis in Rats; Targeting TGF-ß/MAPK/Snai1 Pathway.

Idiopathic pulmonary fibrosis is a progressive, irreversible lung disease that leads to respiratory failure and death. Vincamine is an indole alkaloid obtained from the leaves of Vinca minor and acts as a vasodilator. The present study aims to investigate the protective activity of vincamine against EMT in bleomycin (BLM)-induced pulmonary fibrosis via assessing the apoptotic and TGF-ß1/p38 MAPK/ERK1/2 signaling pathways. In bronchoalveolar lavage fluid, protein content, total cell count, and LDH activity were evaluated. N-cadherin, fibronectin, collagen, SOD, GPX, and MDA levels were determined in lung tissue using ELISA. Bax, p53, bcl2, TWIST, Snai1, and Slug mRNA levels were examined using qRT-PCR. Western blotting was used to assess the expression of TGF-ß1, p38 MAPK, ERK1/2, and cleaved caspase 3 proteins. H & E and Masson's trichrome staining were used to analyze histopathology. In BLM-induced pulmonary fibrosis, vincamine reduced LDH activity, total protein content, and total and differential cell count. SOD and GPX were also increased following vincamine treatment, while MDA levels were decreased. Additionally, vincamine suppressed the expression of p53, Bax, TWIST, Snail, and Slug genes as well as the expression of factors such as TGF-ß1, p/t p38 MAPK, p/t ERK1/2, and cleaved caspase 3 proteins, and, at the same time, vincamine increased bcl2 gene expression. Moreover, vincamine restored fibronectin, N-Catherine, and collagen protein elevation due to BLM-induced lung fibrosis. In addition, the histopathological examination of lung tissues revealed that vincamine attenuated the fibrotic and inflammatory conditions. In conclusion, vincamine suppressed bleomycin-induced EMT by attenuating TGF-ß1/p38 MAPK/ERK1/2/TWIST/Snai1/Slug/fibronectin/N-cadherin pathway. Moreover, it exerted anti-apoptotic activity in bleomycin-induced pulmonary fibrosis.

Holmium Laser Xpeeda Vaporization vs GreenLight XPS Vaporization of the Prostate for Benign Prostatic Obstruction: 1-Year Results from a Randomized Controlled Clinical Study.

Introduction and Objective: To compare the safety and efficacy of Holmium Laser Xpeeda Vaporization and GreenLight XPS Vaporization of the prostate in patients with prostate size ≤80 g. Methods: Ninety-two men with benign prostatic hyperplasia (BPH) and prostate size ≤80 g scheduled for laser prostatectomy were included in this prospective randomized trial. Outcome measures were collected and compared, including International Prostate Symptom Score (IPSS), quality of life (QoL), flow rate, postvoid residual urine volume (PVR), International Index of Erectile Dysfunction (IIEF)-15, prostate-specific antigen (PSA), transrectal ultrasound prostate volume, and catheterization time. Perioperative complications were also recorded. Patients were offered a trial of void (TOV) 3 hours after their procedures. All patients were followed-up at 1, 3, 6, and 12 months. Results: There were no significant differences in preoperative baseline data between the two surgical groups. Operative parameters and postoperative outcomes were comparable. Effective same-day TOV was noted in 73.1% and 72.7% of the Xpeeda and GreenLight XPS patients, respectively (p = 0.98). All patients were discharged home within 24 hours of their surgeries. The laser energy and postoperative complications were significantly lower in the Xpeeda group (p = 0.002 and p = 0.026, respectively). At 3 months, the PSA levels significantly dropped in both groups (p = 0.002 and p < 0.001). There were no significant differences in functional and sexual outcomes between the two groups at 12 months. Conclusions: Holmium Laser Xpeeda Vaporization and GreenLight XPS Vaporization are safe and effective in the treatment of BPH. Same-day discharge with early TOV is a feasible option. Clinical Trials.gov Identifier: NCT04386941.

Hepatoprotective potential of gabapentin in cecal ligation and puncture-induced sepsis; targeting oxidative stress, apoptosis, and NF-kB/MAPK signaling pathways.

AIMS: Sepsis is a severe inflammatory response to infection with an incidence rate exceeding 48 million cases and 11 million sepsis-related deaths yearly. Furthermore, sepsis remains the fifth most common cause of death worldwide. The present study aimed to examine, for the first time, the potential hepatoprotective activity of gabapentin on cecal ligation and puncture (CLP)-induced sepsis in rats at the molecular level. MAIN METHODS: CLP was used as a model of sepsis in male Wistar rats. Histological examination and liver functions were evaluated. Levels of MDA, GSH, SOD, IL-6, IL-1ß, and TNF-α were investigated using ELISA. mRNA levels of Bax, Bcl-2, and NF-kB were assessed by qRT-PCR. Western blotting investigated the expression of ERK1/2, JNK1/2, and cleaved caspase 3 proteins. KEY FINDINGS: CLP resulted in liver damage, elevated serum levels of ALT, AST, ALP, MDA, TNF-α, IL-6, and IL-1ß, increased expression of ERK1/2, JNK1/2, and cleaved caspase 3 proteins, and upregulated Bax and NF-κB genes expression while it down-regulated Bcl-2 gene expression. However, gabapentin treatment significantly reduced the severity of CLP-induced biochemical, molecular, and histopathological changes. Gabapentin attenuated the levels of the proinflammatory mediators, decreased the expression of JNK1/2, ERK1/2, and cleaved caspase 3 proteins, suppressed Bax and NF-κB genes expression and increased the expression of the Bcl-2 gene. SIGNIFICANCE: Consequently, Gabapentin reduced hepatic injury resulting from CLP-induced sepsis by reducing proinflammatory mediators, attenuating apoptosis, and inhibiting the intracellular MAPK (ERK1/2, JNK1/2)-NF-kB signaling pathway.

Azilsartan Modulates HMGB1/NF-κB/p38/ERK1/2/JNK and Apoptosis Pathways during Renal Ischemia Reperfusion Injury.

Renal ischemia/reperfusion (IR) injury is characterized by an unexpected impairment of blood flow to the kidney. Azilsartan is an angiotensin receptor blocker that is approved for the management of hypertension. The present study aimed to investigate, on molecular basics, the nephroprotective activity of azilsartan on renal IR injury in rats. Rats were assigned into four groups: (1) Sham group, (2) Azilsartan group, (3) IR group, and (4) IR/Azilsartan-treated group. Histological examination and renal function were evaluated. Levels of KIM-1, HMGB1, caspase 3, GPX, SOD, NF-κB, and p53 proteins were investigated using ELISA. mRNA levels of IL-1ß, IL6, IL10, TNF-α, NF-κB, p53, and bax were assessed by qRT-PCR. Expression of p38, JNK, and ERK1/2 proteins was investigated by Western blotting. IR injury resulted in tissue damage, elevation of creatinine, BUN, KIM-1, HMGB1, caspase 3, NF-κB, and p53 levels, decreasing GPX and SOD activities, and up-regulation of NF-κB, IL-1ß, IL6, TNF-α, p53, and bax genes. Furthermore, it up-regulated the expression of phosphorylated/total ratio of p38, ERK1/2, and JNK proteins. Interestingly, treatment of the injured rats with azilsartan significantly alleviated IR injury-induced histopathological and biochemical changes. It reduced the creatinine, BUN, KIM-1, HMGB1, caspase-3, NF-κB, and p53 levels, elevated GPX and SOD activities, down-regulated the expression of NF-κB, IL-1ß, IL6, TNF-α, p53, and bax genes, and up-regulated IL10 gene expression. Furthermore, it decreased the phosphorylated/total ratio of p38, ERK1/2, and JNK proteins. Azilsartan exhibited nephroprotective activity in IR-injured rats via its antioxidant effect, suppression of inflammation, attenuation of apoptosis, and inhibition of HMGB1/NF-κB/p38/ERK1/2/JNK signaling pathway.

Quercetin potentiates the hepatoprotective effect of sildenafil and/or pentoxifylline against intrahepatic cholestasis: Role of Nrf2/ARE, TLR4/NF-κB, and NLRP3/IL-1ß signaling pathways.

AIM: Intrahepatic cholestasis is a common pathological condition of several types of liver disorders. In this study, we aimed to investigate the regulatory effects of quercetin (QU) on selected phosphodiesterase inhibitors against alpha-naphthyl isothiocyanate (ANIT)-induced acute intrahepatic cholestasis. METHODS: Cholestasis was induced in Wistar albino rats by ANIT as a single dose (60 mg/kg; P·O.). QU (50 mg/kg, daily, P·O.), sildenafil (Sild; 10 mg/kg, twice daily, P·O.), and pentoxifylline (PTX; 50 mg/kg, daily, P.O.) were evaluated either alone or in combinations for 10 days for their antioxidant, anti-inflammatory, and anti-pyroptotic effects. RESULTS: ANIT produced a prominent intrahepatic cholestasis as evidenced by a significant alteration in liver functions, histological structure, inflammatory response, and oxidative stress biomarkers. Furthermore, up-regulation of NF-κB-p65, TLR4, NLRP3, cleaved caspase-1, IKK-ß, and IL-1ß concurrently with down-regulation of Nrf-2, HO-1, and PPAR-γ expressions were observed after ANIT. QU, Sild, or PTX treatment significantly alleviated the disturbance induced by ANIT. These findings were further supported by the improvement in histopathological features. Additionally, co-administration of QU with Sild or PTX significantly improved liver defects due to ANIT as compared to the individual drugs. SIGNIFICANCE: Combined QU with Sild or PTX exhibited promising hepatoprotective effects and anti-cholestatic properties through modulation of Nrf2/ARE, TLR4/NF- κB, and NLRP3/IL-1ß signaling pathways.

Emergency holmium laser enucleation of the prostate (HoLEP): a novel approach in the management of refractory hematuria for patients with benign prostatic hyperplasia (BPH): a single-institution experience.

INTRODUCTION: Refractory hematuria secondary to prostatic disease typically resolves with conservative management; however, this condition may require hospitalization with extensive measures to control life-threatening bleeding. The aim of this study was to report our experience using holmium laser enucleation of the prostate (HoLEP) as an emergency treatment in this clinical setting. METHODS: We conducted a retrospective review of all patients that presented to the emergency department with refractory hematuria of prostatic origin from October 2017 to September 2021, for whom hospitalization and conservative management failed to control bleeding. All emergency HoLEP procedures were performed by a single surgeon. Preoperative and intraoperative parameters, as well as perioperative outcomes, were collected and analyzed. Postoperative outcomes included duration of foley catheterization, length of postoperative hospital stay, and hospital readmissions. RESULTS: A total of 40 emergency HoLEP procedures were performed. Our cohort had a median prostate volume of 110.5 cc and a median resected weight of 81 g. Twenty-seven patients (67.5%) were on anticoagulant or antiplatelet medications on admission. The urethral catheter was removed within 1 day in 95% of patients with a successful trial of void (TOV). Moreover, 92.5% of patients were discharged home within 24 h of their procedure. Two patients (5%) experienced clot retention within one-week post-discharge with a 2.5% overall readmission rate. All postoperative parameters, including International Prostate Symptom Score (IPSS), quality of life (QoL), maximum flow rate (Qmax), and post-void residual volume (PVR), showed significant improvement at 1 year follow up. CONCLUSION: Our experience demonstrates that emergency HoLEP is an effective treatment option for patients with refractory hematuria of prostatic origin. Further studies are warranted to consolidate our results.

Nephroprotective effect of AT-MSCs against cisplatin-induced EMT is improved by azilsartan via attenuating oxidative stress and TGF-ß/Smad signaling.

The nephrotoxicity of cisplatin (CIS) is a significant complication that challenges its clinical applicability. The epithelial to mesenchymal transition (EMT) may be included in the pathogenesis of CIS-evoked nephrotoxicity. Therefore, the current study aimed to evaluate, for the first time, the possible protective effect of AZL and/or AT-MSCs against CIS-induced EMT in rats on molecular bases. Fifty-four healthy Wistar male albino rats were used in this study. Different biochemical markers of kidney function as well as oxidative stress parameters were investigated. Additionally, renal histopathological study was performed. The expression of EMT-related proteins and genes was evaluated by western blotting and qRT-PCR. CIS markedly increased SCr, BUN, uric acid and renal MDA levels, with concomitant decrease in serum total protein, renal GSH level and SOD activity. Furthermore, it suppressed the expression of Cdh1 gene, increased the α-SMA, Acta2, Cdh2 and Vim genes expression, down regulated the expression of E-cad protein and up-regulated the α-SMA, TGF-ß1, p-Smad2/3 and Snail proteins expression. Kidney tissues showed severe histopathological alterations and extensive collagen accumulation. Conversely, the treatment with either AZL or AT-MSCs significantly attenuated these alterations caused by CIS. Interestingly, the combined therapy of AZL and AT-MSCs has a superior ameliorative effect than AT-MSCs alone. In conclusion, this study, for the first time, revealed that AZL and/ or AT-MSCs successfully ameliorated the CIS-induced EMT via the inhibition of oxidative stress and TGF-ß/Smad signaling pathway. Intriguingly, AZL enhanced the effect of AT-MSCs making them promising agents for kidney protection against CIS-induced EMT.

Importance of Housekeeping Gene Optimization for the Analysis of mRNA Expression During Wound Healing in a Third-Degree Burn Injury Model.

Wound healing evaluation methods in a third-degree burn injury model are categorized as histological (re-epithelialization and granulation tissue formation) and molecular (quantitative polymerase chain reaction). In general, mRNA expression is normalized to those of the housekeeping gene. Although the housekeeping gene expression is generally stable, it has been reported that the stability of these genes depends on the wound healing process and treatment method. In this study, we identified the most stable housekeeping gene (TATA-binding protein) for studying gene expression in a third-degree burn injury model, in which wound healing was promoted by grafting human amnion-derived mesenchymal cells. We investigated the wound healing effect of human amnion-derived mesenchymal cells in the injury model. The formation of granulation tissue, the differentiation from fibroblasts to myofibroblasts, and functional vascular structure were promoted in the full-thickness skin excision site by treatment with these cells. The expression of angiogenic, pro-inflammatory and anti-inflammatory related mRNA was measured and normalized to that of the housekeeping gene, showing that treatment with the cells promoted the infiltration of endothelial cells and differentiation of M1 and M2 macrophages. In conclusion, wound healing in a third-degree burn injury model can be accurately analyzed using the optimized housekeeping gene.

Same-day trial of void and discharge following standard vs. MOSESTM holmium laser enucleation of the prostate: A single-center experience.

INTRODUCTION: We aimed to compare perioperative and postoperative outcomes and to assess the safety and feasibility of same-day trial of void (TOV) in patients who underwent standard holmium laser enucleation of the prostate (HoLEP) vs. MOSESTM HoLEP (MoLEP). METHODS: We conducted a retrospective review of prospectively collected data of patients that underwent HoLEP (100 W) or MoLEP (120 W) with same-day catheter removal three hours postoperatively at our institution from August 2018 to September 2021. Patient demographics, intraoperative parameters, and postoperative outcomes were analyzed. Data were compared as means with standard deviation and medians with interquartile range (IQR) or numbers and percentages. Continuous and categorical variables were assessed using the Mann-Whitney U test and Chi-squared test, respectively. Predictors of shorter enucleation time and failed same-day TOV were investigated. RESULTS: Of the 90 patients included, 28 underwent HoLEP while 62 had MoLEP. There was no significant difference between the groups in terms of the successful TOV (23 [82%] vs. 58 [93.5%], p=0.1) and readmission rate (3 [10.7%] vs. 1 [1.6%], p=0.08); however, the MoLEP group had a significantly shorter mean enucleation time (p<0.001), mean hemostasis time (p<0.001), mean morcellation time (p=0.003), and lower mean energy used (p<0.001). On the logistic regression model, MoLEP (odds ratio [OR] 0.03, 95% confidence interval [CI] 0.007-0.19, p<0.001), lower preoperative prostate-specific antigen (PSA) test (OR 1.25, 95% CI 1.01-1.55, p=0.03), and smaller prostate size (OR 1.06, 95% CI 1.02-1.09, p<0.001) were independent predictors of shorter enucleation time. History of preoperative retention was the only significant factor associated with a failed same-day TOV (p=0.04). There was no difference in intraoperative or postoperative complication rates or postoperative functional outcomes between the two technologies. CONCLUSIONS: Same-day TOV and discharge are feasible following standard HoLEP and MoLEP, with comparable outcomes; however, the use of MOSESTM technology offered better enucleation efficiency with excellent hemostatic potential. Preoperative retention was the only predictor of failed same-day TOV.