INS-1 Cells Undergoing Caspase-Dependent Apoptosis Enhance the Regenerative Capacity of Neighboring Cells

Our results suggest that apoptosing INS-1 cells shed microparticles that may stimulate PSP/reg induction in neighboring cells, a mechanism that may facilitate the recovery of β-cell mass in HNF1A-MODY

Efficacy of nonsurgical interventions for anterior knee pain: Systematic review and meta-analysis of randomized trials

Anterior knee pain is a chronic condition that presents frequently to sports medicine clinics, and can have a long-term impact on participation in physical activity. Conceivably, effective early management may prevent chronicity and facilitate physical activity. Although a variety of nonsurgical interventions have been advocated, previous systematic reviews have consistently been unable to reach conclusions to support their use. Considering a decade has lapsed since publication of the most recent data in these reviews, it is timely to provide an updated synthesis of the literature to assist sports medicine practitioners in making informed, evidence-based decisions. A systematic review and meta-analysis was conducted to evaluate the evidence for nonsurgical interventions for anterior knee pain

LRH-1 agonism favours an immune-islet dialogue which protects against diabetes mellitus

Type 1 diabetes mellitus (T1DM) is due to the selective destruction of islet beta cells by immune cells. Current therapies focused on repressing the immune attack or stimulating beta cell regeneration still have limited clinical efficacy. Therefore, it is timely to identify innovative targets to dampen the immune process, while promoting beta cell survival and function. Liver receptor homologue-1 (LRH-1) is a nuclear receptor that represses inflammation in digestive organs, and protects pancreatic islets against apoptosis. Here, we show that BL001, a small LRH-1 agonist, impedes hyperglycemia progression and the immune-dependent inflammation of pancreas in murine models of T1DM, and beta cell apoptosis in islets of type 2 diabetic patients, while increasing beta cell mass and insulin secretion. Thus, we suggest that LRH-1 agonism favors a dialogue between immune and islet cells, which could be druggable to protect against diabetes mellitus.the Juvenile Diabetes Research Foundation (17-2013-372 to B.R.G.), the Consejeria de Salud, Fundacion Publica Andaluza Progreso y Salud, Junta de Andalucia (PI-0727-2010 to B.R.G. and P10CTS6505 to B.S.), Consejeria de Economia, Innovacion y Ciencia (P10.CTS.6359 to B.R.G.), the Ministerio de Economia y Competidividad cofunded by Fondos FEDER (PI10/00871, PI13/00593, and BFU2017-83588-P to B.R.G.; PI14/01015, RD12/0019/0028, and RD16/0011/0034 to B.S.; PI16/00259 to A. H.) and Deutsche Forschungsgemeinschaft (GRK-1789 ´CEMMA´ and DFG SCHI-505/ 6-1 to R.S.). Special thanks to the families of the DiabetesCero Foundation that graciously supported this work (to B.R.G.). A.M.M. is a recipient of a Miguel Servet grant (CP14/ 00105) from the Instituto de Salud Carlos III co-funded by Fondos FEDER whereas E.F. M. is a recipient of a Juan de la Cierva Fellowship. I.G.H.G. is supported by a fellowship from Amarna Therapeutics. In some instances, human islets were procured through the European Consortium for Islet Transplantation funded by Juvenile Diabetes Research Foundation (3-RSC-2016-162-I-X)

Bone morphogenetic protein 3 controls insulin gene expression and is down-regulated in INS-1 cells inducibly expressing a hepatocyte nuclear factor 1A-maturity-onset diabetes of the young mutation

Inactivating mutations in the transcription factor hepatocyte nuclear factor (HNF) 1A cause HNF1A-maturity-onset diabetes of the young (HNF1A-MODY), the most common monogenic form of diabetes. To examine HNF1A-MODY-induced defects in gene expression, we performed a microarray analysis of the transcriptome of rat INS-1 cells inducibly expressing the common hot spot HNF1A frameshift mutation, Pro291fsinsC-HNF1A. Real-time quantitative PCR (qPCR), Western blotting, immunohistochemistry, reporter assays, and chromatin immunoprecipitation (ChIP) were used to validate alterations in gene expression and to explore biological activities of target genes. Twenty-four hours after induction of the mutant HNF1A protein, we identified a prominent down-regulation of the bone morphogenetic protein 3 gene (Bmp-3) mRNA expression. Reporter assays, qPCR, and Western blot analysis validated these results. In contrast, inducible expression of wild-type HNF1A led to a time-dependent increase in Bmp-3 mRNA and protein levels. Moreover, reduced protein levels of BMP-3 and insulin were detected in islets of transgenic HNF1A-MODY mice. Interestingly, treatment of naïve INS-1 cells or murine organotypic islet cultures with recombinant human BMP-3 potently increased their insulin levels and restored the decrease in SMAD2 phosphorylation and insulin gene expression induced by the HNF1A frameshift mutation. Our study suggests a critical link between HNF1A-MODY-induced alterations in Bmp-3 expression and insulin gene levels in INS-1 cells and indicates that the reduced expression of growth factors involved in tissue differentiation may play an important role in the pathophysiology of HNF1A-MODY

Effect of maternal exposure to low levels of corticosterone during lactation on the susceptibility to the TNBS-induced colitis in rat adult male and female offspring

It is well known that important events occurring in early infancy induce long-lasting changes that result to be key pathogenic factors in the development of some intestinal diseases, in which inflammatory and stress stimuli play a primary role. A non invasive postnatal rat model, the “CORT-nursed”, in which the drinking water of mother during lactation is supplemented with corticosterone, at the moderate dose of 0.2 mg/ml, comparable to that increased by mild stressful environmental events, has been shown to improve the ability of adult progeny to meet the demands of the environment (improved cognitive capabilities, reduced fearfulness in anxiogenic situations, reduced stress response, etc). Aim of this work was to study the susceptibility to TNBS-induced colitis in CORT-nursed (CR) adult males and females in comparison with their controls i.e., H2O-nursed (HR) rats. In order to do this, overnight fasted HR and CR rats, under anaesthesia, were intra-colonically infused with saline or TNBS (30 mg/kg in 0.3 mL of 50% ethanol) into the distal colon. In female rats, TNBS was infused in the luteal phase of the cycle. Four days after TNBS instillation, animals were sacrificed and, in each experimental group, were evaluated: 1) intestinal length, 2) body weight and food intake variation, 3) colonic histological damage, 4) colonic myeloperoxidase (MPO) activity, 5) plasma level of corticosterone. HR and CR healthy males showed similar values of intestinal length (22.50 ± 0.33 vs 22.05 ± 0.29 cm), body weight increase (10% vs 11% of initial weight), food intake increase (10% vs 11% of initial food), histological damage (score= 0), colonic MPO activity (145.46 ± 23.16 vs 196.33 ± 28.92 U/g protein), and plasma corticosterone (1.54 ± 0.12 vs 1.23 ± 0.21 g/100ml). In both HR and CR male rats, in comparison with healthy animals, the induction of colitis caused a significant decrease of the intestinal length (18.38 ± 0.34 vs 18.25 ± 0.31 cm), body weight (4% vs 0.1% weight lost) and food intake (11% vs 17% of consumed food), and a significant increase of histological damage (6.66 ± 0.38 vs 6.14 ± 0.52), colonic MPO activity (969.13 ± 172.41 vs 592.08 ± 69.32 U/g protein) and corticosterone levels (4.47 ± 1.21 vs 3.15 ± 1.14g/100ml). Interestingly, in CR colitic rats the reduction in body weight and food intake together with the increase in MPO activity were significantly lower than those observed in colitic HR rats. No differences in intestinal length, macroscopic score and plasmatic corticosterone levels in HR and CR colitic rats, were found. In HR and CR healthy females, all parameters studied did not result to be different. However, their colonic MPO activity (266.56± 47.21 in HR and 271.29± 43.9 U/g protein in CR) and plasmatic corticosterone levels (7.77 ± 1.96 in HR and 8.97 ± 1.98 g/100ml in CR) were significantly higher than those observed in healthy male rats. In both HR and CR female rats, in comparison with healthy animals, the induction of colitis caused a significant decrease of the intestinal length (9.8% vs 9.6%), body weight (1% vs 3% weight lost) and food intake (7% vs 10% of consumed food), but a significant increase of histological damage (5.6 times higher both in HR and CR) and colonic MPO activity (3.9 times higher both in HR and CR). No difference in corticosterone levels was seen. Differentially from what found in male, in CR females all parameters analyzed after colitis induction did not differ from those observed in HR female rats. The data presented in this study highlight how a moderate corticosterone increase in lactating mothers, by changing some events occurring early in life, can exert a permanent programmed gender-specific susceptibility to TNBS colitis in adult progeny. In particular, male rats result to be more resistant to the TNBS-induced colonic damages in comparison with female rats

The relative timing of VMO and VL in the aetiology of anterior knee pain: a systematic review and meta-analysis

Background: Anterior knee pain (AKP) is a common musculoskeletal complaint. It has been suggested that one factor that may contribute to the presence of AKP is a delay in the recruitment of the vastus medialis oblique muscle (VMO) relative to the vastus lateralis muscle (VL). There is however little consensus within the literature regarding the existence or nature of any such delay in the recruitment of the VMO within the AKP population. The purpose of this systematic review and meta-analysis was to examine the relative timing of onset of the VMO and VL in those with AKP in comparison to the asymptomatic population.  Methods: The bibliographic databases AMED, British Nursing Index, CINAHL, EMBASE, Ovid Medline, PEDro, Pubmed and the Cochrane Library were searched for studies comparing the timing of EMG onset of the VMO and VL in those with AKP versus the asymptomatic population. Studies fulfilling the inclusion criteria were independently assessed. Heterogeneity across the studies was measured. A meta-analysis of results was completed for those studies where adequate data was supplied. Where comparable methodologies had been used, results were pooled and analysed.  Results: Fourteen studies met the inclusion criteria; one prospective and thirteen observational case control. Eleven compared VMO and VL EMG onset times during voluntary active tasks while four investigated reflex response times. All used convenience sampling and did not state blinding of the assessor. Study methodologies/testing and assessment procedures varied and there was considerable heterogeneity within individual samples. Whilst a trend was identified towards a delay in onset of VMO relative to the VL in the AKP population during both voluntary active tasks and reflex activity, a substantial degree of heterogeneity across the pooled studies was identified (I2 = 69.9–93.4%, p < 0.01).  Conclusion: Findings are subject to substantial and unexplained heterogeneity. A trend was demonstrated towards a delayed onset of VMO relative to VL in those with AKP in comparison to those without. However not all AKP patients demonstrate a VMO-VL dysfunction, and this is compounded by normal physiological variability in the healthy population. The clinical and therapeutic significance is therefore difficult to assess