Effect of Non-psychotropic Plant-derived Cannabinoids on Bladder Contractility: Focus on Cannabigerol.

There are anecdotal reports that some Cannabis preparations may be useful for bladder dysfunctions. Here, we investigated the effect of a number of non-psychotropic phytocannabinoids, namely cannabidiol (CBD), cannabigerol (CBG), cannabidivarin (CBDV), Δ9-tetrahydrocannabivarin (THCV) and cannabichromene (CBC) on mouse bladder contractility in vitro. CBG, THCV, CBD and CBDV, but not CBC, at concentration ranging from 10−8M to 10−4M, decreased (with similar potency), the contractions induced by acetylcholine without significantly modifying the contractions induced by electrical stimulation. The rank order of efficacy was CBG=THCV>CBD>CBDV. In depth studies on CBG showed that the effect of this phytocannabinoid on acetylcholine-induced contractions was not affected by CB1or CB2receptor antagonists. Additionally, CBG also reduced acetylcholine-induced contractions in the human bladder

Ethical Issues in the Use of Suboptimal Kidneys for Transplants: an Italian Point of View

The shortage of organs leads to the need for utilizing suboptimal kidneys for transplantation. The distinction between optimal, marginal, and suboptimal kidneys leads surgeons to face not only technical problems but also ethical and legal issues related to clinical advantages offered by the transplant of a nonstandard kidney and the acquisition of consent. Between 1999 and 2015, we performed 658 transplants, 49 (7.5%) using suboptimal kidneys. All patients were alive and with vital graft throughout follow-up. We did not encounter any major surgical complications. From a technical point of view, our experience and literature review confirm that transplant of suboptimal kidney leads to good clinical results but exposes patients to a increased risks of surgical complications. Therefore, these interventions must take place in hospitals fully prepared for this type of surgery and performed by experienced transplant surgeons with proper matching between organ and recipient. Considering the insufficient resources available, from an ethical and legal point of view, doctors play an essential role in optimizing the use of these kidneys by avoiding wastage of organs, ensuring that transplants are done in suitable patients, and that patients are fully informed and aware of the risks and benefits associated with the specific suboptimal kidney being transplanted. We believe that, in highly specialized centers, the number of suboptimal kidney transplants should be increased, as their use has shown good clinical results and carries fewer ethical issues compared with marginal kidneys. Further, suboptimal kidneys may also be proposed for use in young patients with end-stage renal disease

Effect of Non-psychotropic Plant-derived Cannabinoids on Bladder Contractility: Focus on Cannabigerol

There are anecdotal reports that some Cannabis preparations may be useful for bladder dysfunctions. Here, we investigated the effect of a number of non- psychotropic phytocannabinoids, namely cannabidiol (CBD), cannabigerol (CBG), cannabidivarin (CBDV), Δ9-tetrahydrocannabivarin (THCV) and cannabichromene (CBC) on mouse bladder contractility in vitro. CBG, THCV, CBD and CBDV, but not CBC, at concentration ranging from 10(-8) M to 10(-4) M, decreased (with similar potency), the contractions induced by acetylcholine without significantly modifying the contractions induced by electrical stimulation. The rank order of efficacy was CBG=THCV>CBD>CBDV. In depth studies on CBG showed that the effect of this phytocannabinoid on acetylcholine-induced contractions was not affected by CB1 or CB2 receptor antagonists. Additionally, CBG also reduced acetylcholine-induced contractions in the human bladder

Effect of Non-psychotropic Plant-derived Cannabinoids on Bladder Contractility: Focus on Cannabigerol

There are anecdotal reports that some Cannabis preparations may be useful for bladder dysfunctions. Here, we investigated the effect of a number of non- psychotropic phytocannabinoids, namely cannabidiol (CBD), cannabigerol (CBG), cannabidivarin (CBDV), Δ9-tetrahydrocannabivarin (THCV) and cannabichromene (CBC) on mouse bladder contractility in vitro. CBG, THCV, CBD and CBDV, but not CBC, at concentration ranging from 10(-8) M to 10(-4) M, decreased (with similar potency), the contractions induced by acetylcholine without significantly modifying the contractions induced by electrical stimulation. The rank order of efficacy was CBG=THCV>CBD>CBDV. In depth studies on CBG showed that the effect of this phytocannabinoid on acetylcholine-induced contractions was not affected by CB1 or CB2 receptor antagonists. Additionally, CBG also reduced acetylcholine-induced contractions in the human bladder

Therapeutic targeting of P2X4 receptor and mitochondrial metabolism in clear cell renal carcinoma models.

BackgroundClear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cancer. Large-scale metabolomic data have associated metabolic alterations with the pathogenesis and progression of renal carcinoma and have correlated mitochondrial activity with poor survival in a subset of patients. The aim of this study was to determine whether targeting mitochondria-lysosome interaction could be a novel therapeutic approach using patient-derived organoids as avatar for drug response.MethodsRNAseq data analysis and immunohistochemistry were used to show overexpression of Purinergic receptor 4 (P2XR4) in clear cell carcinomas. Seahorse experiments, immunofluorescence and fluorescence cell sorting were used to demonstrate that P2XR4 regulates mitochondrial activity and the balance of radical oxygen species. Pharmacological inhibitors and genetic silencing promoted lysosomal damage, calcium overload in mitochondria and cell death via both necrosis and apoptosis. Finally, we established patient-derived organoids and murine xenograft models to investigate the antitumor effect of P2XR4 inhibition using imaging drug screening, viability assay and immunohistochemistry.ResultsOur data suggest that oxo-phosphorylation is the main source of tumor-derived ATP in a subset of ccRCC cells expressing P2XR4, which exerts a critical impact on tumor energy metabolism and mitochondrial activity. Prolonged mitochondrial failure induced by pharmacological inhibition or P2XR4 silencing was associated with increased oxygen radical species, changes in mitochondrial permeability (i.e., opening of the transition pore complex, dissipation of membrane potential, and calcium overload). Interestingly, higher mitochondrial activity in patient derived organoids was associated with greater sensitivity to P2XR4 inhibition and tumor reduction in a xenograft model.ConclusionOverall, our results suggest that the perturbed balance between lysosomal integrity and mitochondrial activity induced by P2XR4 inhibition may represent a new therapeutic strategy for a subset of patients with renal carcinoma and that individualized organoids may be help to predict drug efficacy

Therapeutic targeting of P2X4 receptor and mitochondrial metabolism in clear cell renal carcinoma models

Abstract Background Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cancer. Large-scale metabolomic data have associated metabolic alterations with the pathogenesis and progression of renal carcinoma and have correlated mitochondrial activity with poor survival in a subset of patients. The aim of this study was to determine whether targeting mitochondria-lysosome interaction could be a novel therapeutic approach using patient-derived organoids as avatar for drug response. Methods RNAseq data analysis and immunohistochemistry were used to show overexpression of Purinergic receptor 4 (P2XR4) in clear cell carcinomas. Seahorse experiments, immunofluorescence and fluorescence cell sorting were used to demonstrate that P2XR4 regulates mitochondrial activity and the balance of radical oxygen species. Pharmacological inhibitors and genetic silencing promoted lysosomal damage, calcium overload in mitochondria and cell death via both necrosis and apoptosis. Finally, we established patient-derived organoids and murine xenograft models to investigate the antitumor effect of P2XR4 inhibition using imaging drug screening, viability assay and immunohistochemistry. Results Our data suggest that oxo-phosphorylation is the main source of tumor-derived ATP in a subset of ccRCC cells expressing P2XR4, which exerts a critical impact on tumor energy metabolism and mitochondrial activity. Prolonged mitochondrial failure induced by pharmacological inhibition or P2XR4 silencing was associated with increased oxygen radical species, changes in mitochondrial permeability (i.e., opening of the transition pore complex, dissipation of membrane potential, and calcium overload). Interestingly, higher mitochondrial activity in patient derived organoids was associated with greater sensitivity to P2XR4 inhibition and tumor reduction in a xenograft model. Conclusion Overall, our results suggest that the perturbed balance between lysosomal integrity and mitochondrial activity induced by P2XR4 inhibition may represent a new therapeutic strategy for a subset of patients with renal carcinoma and that individualized organoids may be help to predict drug efficacy

Third-Line chemotherapy for metastatic Urothelial Cancer: A retrospective observational study

The prognosis of locally advanced (T3/T4 or N1) and metastatic disease urothelial carcinoma is poor. In this retrospective study, we reviewed data about patients receiving third-line chemotherapy for metastatic disease, in view of the lack of data in this setting. We retrospectively analyzed medical records of patients with a pathologic diagnosis of urothelial carcinoma treated with systemic chemotherapy for metastatic disease at 4 participating Institutions between January, 2010, and January, 2015. Cox proportional hazards regression was used to evaluate the association of the chemotherapy agent used versus others with overall survival, adjusted for 5 externally validated prognostic factors in advanced urothelial carcinoma. Of 182 patients that received first-line chemotherapy/adjuvant chemotherapy as defined above, 116 patients (63.73%) received second-line salvage treatment. Fifty-Two patients were finally included in this analysis, whereas 9 were excluded due to missing data. Third-line chemotherapy was based on cyclophosphamide, platinum, vinflunine, taxanes, and gemcitabine in 16, 12, 11, 10, and 3 patients, respectively. Median PFS (progression-free survival) and OS (overall survival) of the population were 13 (10-17) and 31 (28-36) weeks. Single-Agent cyclophosphamide was associated with a PFS of 18 (13-22) and an OS of 38 (33-41) weeks, whereas platinum-based combinations were associated with a PFS of 5 weeks and an OS of 8 weeks. Multivariate analysis showed improved survival in patients treated with cyclophosphamide (hazard ratio (HR)1/40.42; 95% CI: 0.20-0.89; P1/40.025) and a worse survival in those treated with platinum-based regimens (HR: 4.37; 95% CI1/41.95-9.77; P <0.01). We observed a significantly longer overall survival in patients receiving single-Agent cyclophosphamide, with few grade 3 to 4 toxicities. Further studies should assess the efficacy of metronomic single-Agent cyclophosphamide in advanced lines of treatment, as it may yield a survival benefit with low costs and no detrimental effects on quality of life

Ginger (Zingiber officinale Roscoe) as a nutraceutical: Focus on the metabolic, analgesic, and antiinflammatory effects

Ginger (from the rizhome of Zingiber officinale Roscoe) has been widely used in ethnomedicine for the cure of several ailments. Main active ingredients include phenolic compounds named gingerols. In modern phytotherapy, ginger preparations are predominantly used to counteract nausea and vomiting in pregnant women. However, a number of other pharmacological actions of potential therapeutic interest, which might broaden the spectrum of its clinical use, have been reported. This focused review aims at giving a shot on the antinflammatory, analgesic, and metabolic actions of Zingiber officinale preparations, with a discussion on the clinical applications in knee osteoarthritis, dysmenorrhea, type-2 diabetes, hyperlipidemia, overweight, and obesity.info:eu-repo/semantics/publishedVersio