Cisplatin-induced peripheral neuropathy is associated with neuronal senescence-like response

Altres ajuts: Departament de Salut, programa CERCA SLT008/18/00028Cisplatin-induced peripheral neuropathy (CIPN) is a frequent serious dose-dependent adverse event that can determine dosage limitations for cancer treatment. CIPN severity correlates with the amount of platinum detected in sensory neurons of the dorsal root ganglia (DRG). However, the exact pathophysiology of CIPN is poorly understood, so the chance of developing neuroprotective treatment is reduced. The aim of this study was to determine the exact mechanisms involved in CIPN development. Methods: By single-cell RNA-sequencing (scRNAseq), we have studied the transcriptomic profile of DRG sensory neurons from a well-characterized neurophysiological mouse model of CIPN. Results :Gene Ontology analysis of the scRNAseq data indicated that cisplatin treatment induces the upregulation of biological pathways related to DNA damage response (DDR) in the DRG neuronal population. Moreover, DRG neurons also upregulated the Cdkn1a gene, confirmed later by the measurement of its protein product p21. While apoptosis activation pathways were not observed in DRG sensory neurons of cisplatin-treated mice, these neurons did express several senescence hallmarks, including senescence-associated β-galactosidase, phospho-H2AX, and nuclear factor kappa B (Nfkb)-p65 proteins. Conclusions:In this study, we determined that after cisplatin-induced DNA damage, p21 appears as the most relevant downstream factor of the DDR in DRG sensory neurons in vivo, which survive in a nonfunctional senescence-like state

The role of molecular genetics in diagnosing familial hematuria(s)

Familial microscopic hematuria (MH) of glomerular origin represents a heterogeneous group of monogenic conditions involving several genes, some of which remain unknown. Recent advances have increased our understanding and our ability to use molecular genetics for diagnosing such patients, enabling us to study their clinical characteristics over time. Three collagen IV genes, COL4A3, COL4A4, and COL4A5 explain the autosomal and X-linked forms of Alport syndrome (AS), and a subset of thin basement membrane nephropathy (TBMN). A number of X-linked AS patients follow a milder course reminiscent of that of patients with heterozygous COL4A3/COL4A4 mutations and TBMN, while at the same time a significant subset of patients with TBMN and familial MH progress to chronic kidney disease (CKD) or end-stage kidney disease (ESKD). A mutation in CFHR5, a member of the complement factor H family of genes that regulate complement activation, was recently shown to cause isolated C3 glomerulopathy, presenting with MH in childhood and demonstrating a significant risk for CKD/ESKD after 40 years old. Through these results molecular genetics emerges as a powerful tool for a definite diagnosis when all the above conditions enter the differential diagnosis, while in many at-risk related family members, a molecular diagnosis may obviate the need for another renal biopsy

A transient inflammatory response contributes to oxaliplatin neurotoxicity in mice

Abstract Objectives Peripheral neuropathy is a relevant dose‐limiting adverse event that can affect up to 90% of oncologic patients with colorectal cancer receiving oxaliplatin treatment. The severity of neurotoxicity often leads to dose reduction or even premature cessation of chemotherapy. Unfortunately, the limited knowledge about the molecular mechanisms related to oxaliplatin neurotoxicity leads to a lack of effective treatments to prevent the development of this clinical condition. In this context, the present work aimed to determine the exact molecular mechanisms involved in the development of oxaliplatin neurotoxicity in a murine model to try to find new therapeutical targets. Methods By single‐cell RNA sequencing (scRNA‐seq), we studied the transcriptomic profile of sensory neurons and satellite glial cells (SGC) of the Dorsal Root Ganglia (DRG) from a well‐characterized mouse model of oxaliplatin neurotoxicity. Results Analysis of scRNA‐seq data pointed to modulation of inflammatory processes in response to oxaliplatin treatment. In this line, we observed increased levels of NF‐kB p65 protein, pro‐inflammatory cytokines, and immune cell infiltration in DRGs and peripheral nerves of oxaliplatin‐treated mice, which was accompanied by mechanical allodynia and decrease in sensory nerve amplitudes. Interpretation Our data show that, in addition to the well‐described DNA damage, oxaliplatin neurotoxicity is related to an exacerbated pro‐inflammatory response in DRG and peripheral nerves, and open new insights in the development of anti‐inflammatory strategies as a treatment for preventing peripheral neuropathy induced by oxaliplatin

Lercanidipine in patients with chronic renal failure: the ZAFRA Study

Aim. To evaluate the safe use of a new calcium channel blocker, lercanidipine, in patients with chronic renal failure (CRF); the protective effect of calcium channel blocker on renal function in CRF patients previously treated with ACE inhibitors or angiotensin receptor blockers (ARB). Material and methods. The study included 203 CRF patients (creatinine >1,4 mg/dL for men, >1,2 mg/dL for women; or creatinine clearance <70 mL/min). All patients were receiving ACE inhibitors (63,4 %) or angiotensin II antagonist (36,6 %) therapy, but they had higher blood pressure than recommended for CRF (130/85 mmHg). No patients received diuretics. Patients were clinically evaluated 1, 3, and 6 months after starting treatment with lercanidipine. Urine and blood samples were taken during the examination. When needed, a third drug was added to the treatment, excluding diuretics. Creatinine clearance was measured using 24 h urine collection. Results. 175 patients completed the study protocol (age 63,9±11,9 years, 52,9 % males and 47,1 % females). Blood pressure (BP) significantly decreased from 162±17/93±8.3 mm Hg to 132±12/78±6 mm Hg. 89,2 % of patients showed a significant BP reduction, and 58,1 % achieved optimal BP control (<130/85 mmHg). Seven patients (3,4 %) showed adverse effects. No single case of oedema was detected, and the prevalence of adverse effects related to vasodilatation was extremely low (3 patients, 1,48 %). Plasmatic creatinine did not change (1,9±0,5 baseline vs.1,9±0,6 mg/dL), but creatinine clearance increased at the end visit (41,8±16,0 baseline vs. 45,8±18,0 mL/min, p=0,019). Plasmatic cholesterol also decreased from 221±46 to 211±35 mg/dL (p=0,001). Conclusion: Lercanidipine showed a high antihypertensive effect in CRF patients. It had a good tolerability profile and showed an interesting effect on plasmatic lipids. An improvement in renal function, assessed by creatinine clearance, was detected