Therapeutic molecules for osteoarthritis treatment. role of phloretin, ipriflavone and raloxifene in lipopolysaccharide induced osteoarthritic chondrocytes

Purpose: The search of novel molecules for the treatment of osteoarthritis (OA) is complex as any new therapeutic approach should encompass these requirements: inhibition of cartilage degradation, protection of bone and inhibition of inflammation. In the last years, different drugs have been proposed though most of them did not succeed in fulfil these requirements. Moreover, few of them have been encapsulated in drug delivery systems to improve their therapeutic potential to achieve a sustained or controlled release compared to the administration of equivalent doses of the free compounds. Nanoscience has arisen in the last decades as a potential field of study in drug delivery because nanomaterials may overcome the main current limitations to achieve an efficient and localized drug delivery by improving the targeted delivery and providing a sustained or controlled delivery to prolong the therapeutic effect. On the other hand, different polyphenols and aromatic organic compounds are known to possess anti-inflammatory, antioxidant and bone density-building properties..

Fenugreek proteins and their hydrolysates prevent hypercholesterolemia and enhance the HDL antioxidant properties in rats

Purpose This paper aims to investigate the in vivo hypocholesterolemic property of fenugreek proteins (FP), Purafect-fenugreek protein hydrolysate (PFPH) and Esperase-fenugreek protein hydrolysate (EFPH) on high cholesterol (HC)-fed rats. Design/methodology/approach Rats were randomized into five groups: four were fed for four weeks a hypercholesterolemic diet and the tested products were given by gavage. The fifth group was taken as control (C) receiving the same diet without cholesterol. Findings Results showed that the elevated aspartate aminotransferase activity in HC group plasma was significantly corrected by FP and EFPH administration (-33 per cent; p = 0.0003). HC liver lipids and total cholesterol (TC) contents were not markedly affected by FP and EFPH. However, liver triglycerides (TG) contents trended to decrease in FP rats vs HC (p = 0.07), while, the TG decrease was significant in groups fed the proteins hydrolysates (p = 0.02). On the other hand, serum TC and TG decreased by 53 per cent (p = 0.0003) and 20 per cent (p = 0.04), respectively, in FP treated rats compared to HC group. This decrease was associated with a high fecal cholesterol excretion (2.5-fold higher in FP vs HC; p = 0.0001). Likewise, EFPH-treated rats exhibited lower TC compared to HC rats (p = 0.004). The very low density lipoprotins was the main affected fraction in these two groups, while there were no significant difference in apolipoproteins (Apo) B, A-I and A-IV contents between the different groups, except in FP group, where Apo A-I and A-IV decreased by 26 and 17 per cent, respectively, compared to C rats (p = 0.02). The high density lipoproteins (HDL) of rats treated with proteins hydrolysates showed a better antioxidant property compared to those of HC rats, which was accompanied with an increase in paraoxonase activity when compared to HC group. Originality/value Unlike PFPH which had almost no effect, FPs and EFPH could constitute a nutraceutical ingredient in cardiovascular disease management

Prevention of diet-induced obesity by apple polyphenols in Wistar rats through regulation of adipocyte gene expression and DNA methylation patterns

This study was conducted to determine the mechanisms implicated in the beneficial effects of apple polyphenols (APs) against diet-induced obesity in Wistar rats, described in a previous study from our group. Supplementation of high-fat sucrose diet with AP prevented adiposity increase by inhibition of adipocyte hypertrophy. Rats supplemented with AP exhibited improved glucose tolerance while adipocytes isolated from these rats showed an enhanced lipolytic response to isoproterenol. AP intake led to reduced Lep, Plin, and sterol regulatory element binding transcription factor 1 (Srebf1) mRNA levels and increased aquaporin 7 (Aqp7), adipocyte enhancer binding protein 1 (Aebp1), and peroxisome proliferator-activated receptor gamma co-activator 1 alpha (Ppargc1a) mRNA levels in epididymal adipocytes. In addition, we found different methylation patterns of Aqp7, Lep, Ppargc1a, and Srebf1 promoters in adipocytes from apple-supplemented rats compared to high-fat sucrose fed rats. The administration of AP protects against body weight gain and fat deposition and improves glucose tolerance in rats. We propose that AP exerts the antiobesity effects through the regulation of genes involved in adipogenesis, lipolysis, and fatty acid oxidation, in a process that could be mediated in part by epigenetic mechanisms

Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy.

Sphingolipid imbalance is the culprit in a variety of neurological diseases, some affecting the myelin sheath. We have used whole-exome sequencing in patients with undetermined leukoencephalopathies to uncover the endoplasmic reticulum lipid desaturase DEGS1 as the causative gene in 19 patients from 13 unrelated families. Shared features among the cases include severe motor arrest, early nystagmus, dystonia, spasticity, and profound failure to thrive. MRI showed hypomyelination, thinning of the corpus callosum, and progressive thalamic and cerebellar atrophy, suggesting a critical role of DEGS1 in myelin development and maintenance. This enzyme converts dihydroceramide (DhCer) into ceramide (Cer) in the final step of the de novo biosynthesis pathway. We detected a marked increase of the substrate DhCer and DhCer/Cer ratios in patients' fibroblasts and muscle. Further, we used a knockdown approach for disease modeling in Danio rerio, followed by a preclinical test with the first-line treatment for multiple sclerosis, fingolimod (FTY720, Gilenya). The enzymatic inhibition of Cer synthase by fingolimod, 1 step prior to DEGS1 in the pathway, reduced the critical DhCer/Cer imbalance and the severe locomotor disability, increasing the number of myelinating oligodendrocytes in a zebrafish model. These proof-of-concept results pave the way to clinical translation

Assessment of plasma chitotriosidase activity, CCL18/PARC concentration and NP-C suspicion index in the diagnosis of Niemann-Pick disease type C: A prospective observational study

Background: Niemann-Pick disease type C (NP-C) is a rare, autosomal recessive neurodegenerative disease caused by mutations in either the NPC1 or NPC2 genes. The diagnosis of NP-C remains challenging due to the non-specific, heterogeneous nature of signs/symptoms. This study assessed the utility of plasma chitotriosidase (ChT) and Chemokine (C-C motif) ligand 18 (CCL18)/pulmonary and activation-regulated chemokine (PARC) in conjunction with the NP-C suspicion index (NP-C SI) for guiding confirmatory laboratory testing in patients with suspected NP-C. Methods: In a prospective observational cohort study, incorporating a retrospective determination of NP-C SI scores, two different diagnostic approaches were applied in two separate groups of unrelated patients from 51 Spanish medical centers (n = 118 in both groups). From Jan 2010 to Apr 2012 (Period 1), patients with =2 clinical signs/symptoms of NP-C were considered ''suspected NP-C'' cases, and NPC1/NPC2 sequencing, plasma chitotriosidase (ChT), CCL18/PARC and sphingomyelinase levels were assessed. Based on findings in Period 1, plasma ChT and CCL18/PARC, and NP-C SI prediction scores were determined in a second group of patients between May 2012 and Apr 2014 (Period 2), and NPC1 and NPC2 were sequenced only in those with elevated ChT and/or elevated CCL18/PARC and/or NP-C SI =70. Filipin staining and 7-ketocholesterol (7-KC) measurements were performed in all patients with NP-C gene mutations, where possible. Results: In total across Periods 1 and 2, 10/236 (4%) patients had a confirmed diagnosis o NP-C based on gene sequencing (5/118 4.2%] in each Period): all of these patients had two causal NPC1 mutations. Single mutant NPC1 alleles were detected in 8/236 (3%) patients, overall. Positive filipin staining results comprised three classical and five variant biochemical phenotypes. No NPC2 mutations were detected. All patients with NPC1 mutations had high ChT activity, high CCL18/PARC concentrations and/or NP-C SI scores =70. Plasma 7-KC was higher than control cut-off values in all patients with two NPC1 mutations, and in the majority of patients with single mutations. Family studies identified three further NP-C patients. Conclusion: This approach may be very useful for laboratories that do not have mass spectrometry facilities and therefore, they cannot use other NP-C biomarkers for diagnosis

Treatment Patterns and Use of Resources in Patients With Tuberous Sclerosis Complex: Insights From the TOSCA Registry

Tuberous Sclerosis Complex (TSC) is a rare autosomal-dominant disorder caused by mutations in the TSC1 or TSC2 genes. Patients with TSC may suffer from a wide range of clinical manifestations; however, the burden of TSC and its impact on healthcare resources needed for its management remain unknown. Besides, the use of resources might vary across countries depending on the country-specific clinical practice. The aim of this paper is to describe the use of TSC-related resources and treatment patterns within the TOSCA registry. A total of 2,214 patients with TSC from 31 countries were enrolled and had a follow-up of up to 5 years. A search was conducted to identify the variables containing both medical and non-medical resource use information within TOSCA. This search was performed both at the level of the core project as well as at the level of the research projects on epilepsy, subependymal giant cell astrocytoma (SEGA), lymphangioleiomyomatosis (LAM), and renal angiomyolipoma (rAML) taking into account the timepoints of the study, age groups, and countries. Data from the quality of life (QoL) research project were analyzed by type of visit and age at enrollment. Treatments varied greatly depending on the clinical manifestation, timepoint in the study, and age groups. GAB Aergics were the most prescribed drugs for epilepsy, and mTOR inhibitors are dramatically replacing surgery in patients with SEGA, despite current recommendations proposing both treatment options. mTOR inhibitors are also becoming common treatments in rAML and LAM patients. Forty-two out of the 143 patients (29.4%) who participated in the QoL research project reported inpatient stays over the last year. Data from non-medical resource use showed the critical impact of TSC on job status and capacity. Disability allowances were more common in children than adults (51.1% vs 38.2%). Psychological counseling, social services and social worker services were needed by <15% of the patients, regardless of age. The long-term nature, together with the variability in its clinical manifestations, makes TSC a complex and resource-demanding disease. The present study shows a comprehensive picture of the resource use implications of TSC

Newly Diagnosed and Growing Subependymal Giant Cell Astrocytoma in Adults With Tuberous Sclerosis Complex: Results From the International TOSCA Study

The onset and growth of subependymal giant cell astrocytoma (SEGA) in tuberous sclerosis complex (TSC) typically occurs in childhood. There is minimal information on SEGA evolution in adults with TSC. Of 2,211 patients enrolled in TOSCA, 220 of the 803 adults (27.4%) ever had a SEGA. Of 186 patients with SEGA still ongoing in adulthood, 153 (82.3%) remained asymptomatic, and 33 (17.7%) were reported to ever have developed symptoms related to SEGA growth. SEGA growth since the previous scan was reported in 39 of the 186 adults (21%) with ongoing SEGA. All but one patient with growing SEGA had mutations in TSC2. Fourteen adults (2.4%) were newly diagnosed with SEGA during follow-up, and majority had mutations in TSC2. Our findings suggest that surveillance for new or growing SEGA is warranted also in adulthood, particularly in patients with mutations in TSC2