Small-Molecules as Chemiluminescent Probes to Detect Lipase Activity.

The set-up of highly sensitive detection tools to evaluate lipase activity remains a central goal in different fields. In this context, we proposed new chemiluminescent 1,2-dioxetane luminophores, sharing an octanoyl triggerable group, to monitor lipase activity. We herein report the synthesis and both the evaluation of their luminescence emission profile and their enzyme-substrate specificity, generated by three different commercial lipases (Candida cylindracea, Pseudomonas fluorescens, and Mucor miehei) and one esterase (porcine liver esterase, PLE, as a literature control). Remarkably, the present study confirmed the applicability of these 1,2-dioxetane luminophores as (i) highly efficient, broad-range, chemiluminescent probes for the detection and the enzymatic activity evaluation of lipases and as (ii) promising candidates for the future development of both flash- and glow-type luminescence assays.

Inhibition of Ceramide Synthesis Reduces α-Synuclein Proteinopathy in a Cellular Model of Parkinson's Disease.

Parkinson's disease (PD) is a proteinopathy associated with the aggregation of α-synuclein and the formation of lipid-protein cellular inclusions, named Lewy bodies (LBs). LB formation results in impaired neurotransmitter release and uptake, which involve membrane traffic and require lipid synthesis and metabolism. Lipids, particularly ceramides, are accumulated in postmortem PD brains and altered in the plasma of PD patients. Autophagy is impaired in PD, reducing the ability of neurons to clear protein aggregates, thus worsening stress conditions and inducing neuronal death. The inhibition of ceramide synthesis by myriocin (Myr) in SH-SY5Y neuronal cells treated with preformed α-synuclein fibrils reduced intracellular aggregates, favoring their sequestration into lysosomes. This was associated with TFEB activation, increased expression of TFEB and LAMP2, and the cytosolic accumulation of LC3II, indicating that Myr promotes autophagy. Myr significantly reduces the fibril-related production of inflammatory mediators and lipid peroxidation and activates NRF2, which is downregulated in PD. Finally, Myr enhances the expression of genes that control neurotransmitter transport (SNARE complex, VMAT2, and DAT), whose progressive deficiency occurs in PD neurodegeneration. The present study suggests that counteracting the accumulation of inflammatory lipids could represent a possible therapeutic strategy for PD.

Clarifying the Use of Benzylidene Protecting Group for D-(+)-Ribono-1,4-Lactone, an Essential Building Block in the Synthesis of C-Nucleosides.

In the last two years, nucleosides analogues, a class of well-established bioactive compounds, have been the subject of renewed interest from the scientific community thanks to their antiviral activity. The COVID-19 global pandemic, indeed, spread light on the antiviral drug Remdesivir, an adenine C-nucleoside analogue. This new attention of the medical community on Remdesivir prompts the medicinal chemists to investigate once again C-nucleosides. One of the essential building blocks to synthetize these compounds is the D-(+)-ribono-1,4-lactone, but some mechanistic aspects linked to the use of different carbohydrate protecting groups remain unclear. Here, we present our investigations on the use of benzylidene as a ribonolactone protecting group useful in the synthesis of C-purine nucleosides analogues. A detailed 1D and 2D NMR structural study of the obtained compounds under different reaction conditions is presented. In addition, a molecular modeling study at the B3LYP/6-31G* level of theory with the SM8 solvation model for CHCl3 and DMSO to support the obtained results is used. This study allows for clarifying mechanistic aspects as the side reactions and structural rearrangements liked to the use of the benzylidene protecting group.

Inhibition of Sphingolipid Synthesis as a Phenotype-Modifying Therapy in Cystic Fibrosis.

BACKGROUND/AIMS: Cystic Fibrosis (CF) is an inherited disease associated with a variety of mutations affecting the CFTR gene. A deletion of phenylalanine 508 (F508) affects more than 70% of patients and results in unfolded proteins accumulation, originating a proteinopathy responsible for inflammation, impaired trafficking, altered metabolism, cholesterol and lipids accumulation, impaired autophagy at the cellular level. Lung inflammation has been extensively related to the accumulation of the lipotoxin ceramide. We recently proved that inhibition of ceramide synthesis by Myriocin reduces inflammation and ameliorates the defence response against pathogens infection, which is downregulated in CF. Here, we aim at demonstrating the mechanisms of Myriocin therapeutic effects in Cystic Fibrosis broncho-epithelial cells. METHODS: The effect of Myriocin treatment, on F508-CFTR bronchial epithelial cell line IB3-1 cells, was studied by evaluating the expression of key proteins and genes involved in autophagy and lipid metabolism, by western blotting and real time PCR. Moreover, the amount of glycerol-phospholipids, triglycerides, and cholesterols, sphingomyelins and ceramides were measured in treated and untreated cells by LC-MS. Finally, Sptlc1 was transiently silenced and the effect on ceramide content, autophagy and transcriptional activities was evaluated as above mentioned. RESULTS: We demonstrate that Myriocin tightly regulates metabolic function and cell resilience to stress. Myriocin moves a transcriptional program that activates TFEB, major lipid metabolism and autophagy regulator, and FOXOs, central lipid metabolism and anti-inflammatory/anti-oxidant regulators. The activity of these transcriptional factors is associated with the induction of PPARs nuclear receptors activity, whose targets are genes involved in lipid transport compartmentalization and oxidation. Transient silencing of SPTCL1 recapitulates the effects induced by Myriocin. CONCLUSION: Cystic Fibrosis bronchial epithelia accumulate lipids, exacerbating inflammation. Myriocin administration: i) activates the transcriptions of genes involved in enhancing autophagy-mediated stress clearance; ii) reduces the content of several lipid species and, at the same time, iii) enhances mitochondrial lipid oxidation. Silencing the expression of Sptlc1 reproduces Myriocin induced autophagy and transcriptional activities, demonstrating that the inhibition of sphingolipid synthesis drives a transcriptional program aimed at addressing cell metabolism towards lipid oxidation and at exploiting autophagy mediated clearance of stress. We speculate that regulating sphingolipid de novo synthesis can relieve from chronic inflammation, improving energy supply and anti-oxidant responses, indicating an innovative therapeutic strategy for CF.

Interaction between polyphenols intake and PON1 gene variants on markers of cardiovascular disease: a nutrigenetic observational study.

BACKGROUND: Paraoxonase 1 (PON1) gene polymorphisms and polyphenols intake have been reported independently associated to lipid profile and susceptibility to atherosclerosis and cardiovascular disease. However, the interaction between these factors remains to be investigated. We performed an observational nutrigenetic study to examine whether the interaction between polyphenols and anthocyanins intake and PON1 genetic variants can modulate biomarkers of cardiovascular health in an Italian healthy population. METHODS: We recruited 443 healthy volunteers who participated in the EC funded ATHENA project (AnThocyanin and polyphenols bioactive for Health Enhancement through Nutritional Advancement). Data collection included detailed demographic, clinical, dietary, lifestyle, biochemical and genetic data. Polyphenols and anthocyanins intake was measured by 24 h dietary recall repeated three times a year in order to get seasonal variations. We tested the interaction between 18 independent tagging SNPs in PON1 gene and polyphenols intake on HDL, LDL, cholesterol, triglycerides and atherogenic index of plasma. RESULTS: Without considering the genetic background, we could not observe significant differences in the lipid profile between high and low polyphenols and anthocyanins intake. Using a nutrigenetic approach, we identified protective genotypes in four independent polymorphisms that, at Bonferroni level (p ≤ 0.0028), present a significant association with increased HDL level under high polyphenols and anthocyanins intake, compared to risk genotypes (rs854549, Beta = 4.7 per C allele; rs854552, Beta = 5.6 per C allele; rs854571, Beta = 3.92 per T allele; rs854572, Beta = 3.94 per C allele). CONCLUSIONS: We highlight the protective role of genetic variants in PON1 towards cardiovascular risk under high polyphenols and anthocyanins consumption. PON1 variants could represent novel biomarkers to stratify individuals who might benefit from targeted dietary recommendation for health promotion and strategies of preventive medicine.

Relevance of Mediterranean diet and glucose metabolism for nephrolithiasis in obese subjects.

BACKGROUND: Nephrolithiasis is more frequent and severe in obese patients from different western nations. This may be supported by higher calcium, urate, oxalate excretion in obese stone formers. Except these parameters, clinical characteristics of obese stone formers were not extensively explored. AIMS: In the present paper we studied the relationship between obesity and its metabolic correlates and nephrolithiasis. MATERIALS AND METHODS: We studied 478 Caucasian subjects having BMI ≥ 25 kg/m². The presence of nephrolithiasis, hypertension, diabetes mellitus and metabolic syndrome were noted. They underwent measurements of anthropometry (BMI and waist circumference, body composition), serum variables (fasting glucose, serum lipids and serum enzymes) and Mediterranean diet (MedDiet) nutritional questionnaire. RESULTS: 45 (9.4%) participants were stone formers. Subjects with high serum concentrations of triglycerides (≥ 150 mg/dl), fasting glucose (> 100 mg/dl) and AST (>30 U/I in F or >40 U/I in M) were more frequent among stone formers than non-stone formers.Multinomial logistic regression confirmed that kidney stone production was associated with high fasting glucose (OR = 2.6, 95% CI 1.2-5.2, P = 0.011), AST (OR = 4.3, 95% CI 1.1-16.7, P = 0.033) and triglycerides (OR = 2.7, 95% CI 1.3-5.7, P = 0.01). MedDiet score was not different in stone formers and non-stone formers. However, stone formers had a lower consumption frequency of olive oil and nuts, and higher consumption frequency of wine compared with non-stone formers. CONCLUSIONS: Overweight and obese stone formers may have a defect in glucose metabolism and a potential liver damage. Some foods typical of Mediterranean diet may protect against nephrolithiasis.

Idiopathic calcium nephrolithiasis: a review of pathogenic mechanisms in the light of genetic studies.

BACKGROUND: Calcium nephrolithiasis is a multifactorial disease with a polygenic milieu. Association studies identified genetic polymorphisms potentially implicated in the pathogenesis of calcium nephrolithiasis. The present article reviews the mechanisms of calcium stone formation and the potential contribution of gene polymorphisms to lithogenic mechanisms. SUMMARY: Endoscopy observations suggested that precipitation of calcium-oxalate on the Randall's plaque at the papilla surface may cause idiopathic calcium-oxalate stones. The Randall's plaque is a hydroxyapatite deposit in the interstitium of the kidney medulla, which resembles a soft tissue calcification. Conversely, calcium-phosphate stones may develop from crystalline deposits located at the tip of the Bellini duct. Polymorphisms of eleven genes have been associated with stones in genome-wide association studies and replicated candidate-gene association studies: VDR, SLC34A1, SLC34A4, CLDN14, and CaSR genes coding for proteins regulating tubular phosphate and calcium reabsorption; CaSR, MGP, OPN, PLAU, and UMOD genes coding for proteins preventing calcium salt precipitation; AQP1 gene coding for a water channel in the proximal tubule. The renal activity of the last gene, DGKH, is unknown. Polymorphisms in these genes may predispose to calcium-oxalate and -phosphate stones by increasing the risk of calcium-phosphate precipitation in the tubular fluid. Key Messages: Genetic findings suggest that tubular fluid supersaturation with respect to calcium and phosphate predisposes to calcium-oxalate stones by triggering cellular mechanisms that lead to the Randall's plaque formation.

Nutrition in calcium nephrolithiasis.

Idiopathic calcium nephrolithiasis is a multifactorial disease with a complex pathogenesis due to genetic and environmental factors. The importance of social and health effects of nephrolithiasis is further highlighted by the strong tendency to relapse of the disease. Long-term prospective studies show a peak of disease recurrence within 2-3 years since onset, 40-50% of patients have a recurrence after 5 years and more than 50-60% after 10 years. International nutritional studies demonstrated that nutritional habits are relevant in therapy and prevention approaches of nephrolithiasis. Water, right intake of calcium, low intake of sodium, high levels of urinary citrate are certainly important for the primary and secondary prevention of nephrolithiasis.

Modulation of gut microbiota: The effects of a fruits and vegetables supplement.

The consumption of an optimal amount of fruits and vegetables is known to improve physical fitness and physiological body functions. Healthy eating habits, including intake of fruits and vegetables, can modify gut microbiota. This study aimed to demonstrate the effectiveness of a formulated fruit and vegetable supplement (FVS) in modulating the antioxidant capacity and the gut microbiota composition. We enrolled 30 healthy volunteer subjects, matched for age, gender, BMI, and smoking habits, and randomized them into the FVS and the placebo (PLA) groups. Among the serum vitamins, the folic acid level was significantly higher (p = 0.001) in the FVS group than in the PLA group, whereas the vitamin B2 level was significantly higher in the PLA group than in the FVS group (p = 0.028). The antioxidant capacity, measured by using the oxygen radical absorbance capacity (ORAC) method, was also slightly higher in the FVS group than in the PLA group but did not reach statistical significance. The dietary intake, assessed by 24-h recalls, did not show any significant changes after the supplementation in both the groups. The gut microbiome composition, measured by 16S rDNA sequencing, showed no difference in both alpha and beta diversities, whereas the LEfse analysis revealed a microbial shift after the treatment, with a decreased abundance of the genus Ruminococcus from the Lachnospiraceae family (p = 0.009), and the unclassified genus from the family Erysipelotrichaceae (UC36, p = 0.003) in the FVS group compared with the PLA group (confirmed by SIAMCAT analysis, AUC = 74.1%). With a minor effect, the genus Faecalibacterium and unclassified genus and family from the order Lactobacillales (UC31) were also increased in the FVS group compared with the PLA group (p = 0.0474, p = 0.0352, respectively). SCFA measurement by gas chromatography-mass spectrometry showed an increased level of 2-methylbutyrate in the FVS group compared with the PLA group (p = 0.0385). Finally, the Spearman correlation analysis showed that in the FVS group, the genus Faecalibacterium positively correlated with 2-methyl butyrate (p = 0.040). In the PLA group, none of the significant bacteria correlated with either SCFA or serum biomarkers. The network analysis confirmed the positive correlation between genus Faecalibacterium and 2-methyl butyrate. We can conclude that the FVS in healthy individuals modified the gut microbiota composition and metabolites, and it can potentially contribute to reduce the pro-inflammatory response along with the antioxidant capacity.

Curcumin Supplementation (Meriva®) Modulates Inflammation, Lipid Peroxidation and Gut Microbiota Composition in Chronic Kidney Disease.

Chronic kidney disease (CKD) subjects suffer from high risk of cardiovascular mortality, and any intervention preventing the progression of CKD may have an enormous impact on public health. In the last decade, there has been growing awareness that the gut microbiota (GM) can play a pivotal role in controlling the pathogenesis of systemic inflammatory state and CKD progression. To ameliorate the quality of life in CKD subjects, the use of dietary supplements has increased over time. Among those, curcumin has demonstrated significant in vitro anti-inflammatory properties. In this pilot study, 24 CKD patients and 20 healthy volunteers were recruited. CKD patients followed nutritional counselling and were supplemented with curcumin (Meriva®) for six months. Different parameters were evaluated at baseline and after 3-6 months: uremic toxins, metagenomic of GM, and nutritional, inflammatory, and oxidative status. Curcumin significantly reduced plasma pro-inflammatory mediators (CCL-2, IFN-γ, and IL-4) and lipid peroxidation. Regarding GM, after 6 months of curcumin supplementation, Escherichia-Shigella was significantly lower, while Lachnoclostridium was significant higher. Notably, at family level, Lactobacillaceae spp. were found significantly higher in the last 3 months of supplementation. No adverse events were observed in the supplemented group, confirming the good safety profile of curcumin phytosome after long-term administration.

[Hyperparathyroidism as a cardiovascular risk factor in chronic kidney disease: an update from a biological-cellular perspective]. / L'iperparatiroidismo come fattore di rischio cardiovascolare nell'insufficienza renale: un update dal punto di vista biologico-cellulare.

Cardiovascular complications are the main cause of death in patients with chronic kidney disease (CKD). Among these complications, calcific arteriosclerosis and myocardial hypertrophy are the main predictors of cardiovascular morbidity and mortality. Epidemiological studies have shown their association with hyperparathyroidism, which has therefore been included among the non-traditional cardiovascular risk factors. Studies in laboratory animals have shown that PTH administration may induce calcific arteriosclerosis and myocardial hypertrophy. The former develops independently of hyperphosphatemia, but its mechanisms remain unknown. The latter is characterized by increased thickness of the myocardial fibers and especially the fibrous interstitium; its development is influenced by protein kinase C activation and the subsequent increase in cytosolic calcium as well as activation of intracellular signaling pathways inducing protein synthesis and proliferation. Different from these findings, in other studies PTH infusion was able to produce vasodilatation and to favor myocardial cell contraction and regeneration. These effects depend on protein kinase A activation. PTH may produce different and sometimes contradictory functional effects in the arteries and myocardium that are probably related to different experimental or clinical conditions. In patients with CKD and hyperparathyroidism, PTH may be considered a uremic toxin exerting its effects mainly by increasing cellular calcium. Thus, hyperparathyroidism is confirmed to be a target for the conservative therapy of CKD.

Fasting: How to Guide.

Fasting potentials are the most interesting topics in the Nutritional Era. Fasting consists of the catabolism of lipids, proteins, and carbohydrates to maintain blood glucose levels in a normal range. The action mechanisms of fasting were firstly understood in minor organisms and later in humans. Nutritional interventions of caloric restriction could attenuate age-associated epigenetic alterations and could have a protective effect against cellular alterations, promoting longevity and health span. While most fasting studies point out the weight and fat mass decreases, it is important to define specific guidelines for fasting and non-fasting days to enhance adherence, minimize the dropout rates of the interventions, and maximize body composition improvement. Although the panorama of evidence on fasting and caloric restriction is wide, there is a lack of a safe fasting protocol to guide physicians in its prescription. The main goal is to identify a how to use guide, a major posology of fasting, inserted within a huge dietetic personalized strategy leading to an optimal and healthy nutritional status.

Myriocin modulates the altered lipid metabolism and storage in cystic fibrosis.

Cystic fibrosis (CF) is a hereditary disease mostly related to ΔF508 CFTR mutation causing a proteinopathy that is characterized by multiple organ dysfunction, primarily lungs chronic inflammation, and infection. Defective autophagy and accumulation of the inflammatory lipid ceramide have been proposed as therapeutic targets. Accumulation of lipids and cholesterol was reported in the airways of CF patients, together with altered triglycerides and cholesterol levels in plasma, thus suggesting a disease-related dyslipidemia. Myriocin, an inhibitor of sphingolipids synthesis, significantly reduces inflammation and activates TFEB-induced response to stress, enhancing fatty acids oxidation and promoting autophagy. Myriocin ameliorates the response against microbial infection in CF models and patients' monocytes. Here we show that CF broncho-epithelial cells exhibit an altered distribution of intracellular lipids. We demonstrated that lipid accumulation is supported by an enhanced synthesis of fatty acids containing molecules and that Myriocin is able to reduce such accumulation. Moreover, Myriocin modulated the transcriptional profile of CF cells in order to restore autophagy, activate an anti-oxidative response, stimulate lipid metabolism and reduce lipid peroxidation. Moreover, lipid storage may be altered in CF cells, since we observed a reduced expression of lipid droplets related proteins named perilipin 3 and 5 and seipin. To note, Myriocin up-regulates the expression of genes that are involved in lipid droplets biosynthesis and maturation. We suggest that targeting sphingolipids de novo synthesis may counteract lipids accumulation by modulating CF altered transcriptional profile, thus restoring autophagy and lipid metabolism homeostasis.

Spns2 Transporter Contributes to the Accumulation of S1P in Cystic Fibrosis Human Bronchial Epithelial Cells.

The role of S1P in Cystic Fibrosis (CF) has been investigated since 2001, when it was first described that the CFTR channel regulates the inward transport of S1P. From then on, various studies have associated F508del CFTR, the most frequent mutation in CF patients, with altered S1P expression in tissue and plasma. We found that human bronchial epithelial immortalized and primary cells from CF patients express more S1P than the control cells, as evidenced by mass spectrometry analysis. S1P accumulation relies on two- to four-fold transcriptional up-regulation of SphK1 and simultaneous halving of SGPL1 in CF vs. control cells. The reduction of SGPL1 transcription protects S1P from irreversible degradation, but the excessive accumulation is partially prevented by the action of the two phosphatases that are up-regulated compared to control cells. For the first time in CF, we describe that Spns2, a non-ATP dependent transporter that normally extrudes S1P out of the cells, shows deficient transcriptional and protein expression, thus impairing S1P accrual dissipation. The in vitro data on CF human bronchial epithelia correlates with the impaired expression of Spns2 observed in CF human lung biopsies compared to healthy control.

Simple and Complex Sugars in Parkinson's Disease: a Bittersweet Taste.

Neuronal homeostasis depends on both simple and complex sugars (the glycoconjugates), and derangement of their metabolism is liable to impair neural function and lead to neurodegeneration. Glucose levels boost glycation phenomena, a wide series of non-enzymatic reactions that give rise to various intermediates and end-products that are potentially dangerous in neurons. Glycoconjugates, including glycoproteins, glycolipids, and glycosaminoglycans, contribute to the constitution of the unique features of neuron membranes and extracellular matrix in the nervous system. Glycosylation defects are indeed frequently associated with nervous system disturbances and neurodegeneration. Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms associated with the loss of dopaminergic neurons in the pars compacta of the substantia nigra. Neurons present intracytoplasmic inclusions of α-synuclein aggregates involved in the disease pathogenesis together with the impairment of the autophagy-lysosome function, oxidative stress, and defective traffic and turnover of membrane components. In the present review, we selected relevant recent contributions concerning the direct involvement of glycation and glycosylation in α-synuclein stability, impaired autophagy and lysosomal function in PD, focusing on potential models of PD pathogenesis provided by genetic variants of glycosphingolipid processing enzymes, especially glucocerebrosidase (GBA). Moreover, we collected data aimed at defining the glycomic profile of PD patients as a tool to help in diagnosis and patient subtyping, as well as those pointing to sugar-related compounds with potential therapeutic applications in PD.

Cystic Fibrosis Defective Response to Infection Involves Autophagy and Lipid Metabolism.

Cystic fibrosis (CF) is a hereditary disease, with 70% of patients developing a proteinopathy related to the deletion of phenylalanine 508. CF is associated with multiple organ dysfunction, chronic inflammation, and recurrent lung infections. CF is characterized by defective autophagy, lipid metabolism, and immune response. Intracellular lipid accumulation favors microbial infection, and autophagy deficiency impairs internalized pathogen clearance. Myriocin, an inhibitor of sphingolipid synthesis, significantly reduces inflammation, promotes microbial clearance in the lungs, and induces autophagy and lipid oxidation. RNA-seq was performed in Aspergillusfumigatus-infected and myriocin-treated CF patients' derived monocytes and in a CF bronchial epithelial cell line. Fungal clearance was also evaluated in CF monocytes. Myriocin enhanced CF patients' monocytes killing of A. fumigatus. CF patients' monocytes and cell line responded to infection with a profound transcriptional change; myriocin regulates genes that are involved in inflammation, autophagy, lipid storage, and metabolism, including histones and heat shock proteins whose activity is related to the response to infection. We conclude that the regulation of sphingolipid synthesis induces a metabolism drift by promoting autophagy and lipid consumption. This process is driven by a transcriptional program that corrects part of the differences between CF and control samples, therefore ameliorating the infection response and pathogen clearance in the CF cell line and in CF peripheral blood monocytes.

An Innovative Lipidomic Workflow to Investigate the Lipid Profile in a Cystic Fibrosis Cell Line.

Altered lipid metabolism has been associated to cystic fibrosis disease, which is characterized by chronic lung inflammation and various organs dysfunction. Here, we present the validation of an untargeted lipidomics approach based on high-resolution mass spectrometry aimed at identifying those lipid species that unequivocally sign CF pathophysiology. Of n.13375 mass spectra recorded on cystic fibrosis bronchial epithelial airways epithelial cells IB3, n.7787 presented the MS/MS data, and, after software and manual validation, the final number of annotated lipids was restricted to n.1159. On these lipids, univariate and multivariate statistical approaches were employed in order to select relevant lipids for cellular phenotype discrimination between cystic fibrosis and HBE healthy cells. In cystic fibrosis IB3 cells, a pervasive alteration in the lipid metabolism revealed changes in the classes of ether-linked phospholipids, cholesterol esters, and glycosylated sphingolipids. Through functions association, it was evidenced that lipids variation involves the moiety implicated in membrane composition, endoplasmic reticulum, mitochondria compartments, and chemical and biophysical lipids properties. This study provides a new perspective in understanding the pathogenesis of cystic fibrosis and strengthens the need to use a validated mass spectrometry-based lipidomics approach for the discovery of potential biomarkers and perturbed metabolism.

Glucagon-like peptide-1 receptor and sarcoglycan delta genetic variants can affect cardiovascular risk in chronic kidney disease patients under hemodialysis.

BACKGROUND: Chronic kidney disease (CKD) patients under hemodialysis show a higher risk of cardiovascular (CV) mortality and morbidity than the general population. This study aims to identify genetic markers that could explain the increased CV risk in hemodialysis. METHODS: A total of 245 CKD patients under hemodialysis were recruited and followed up for 5 years to record CV events. Genetic analysis was performed using single-nucleotide polymorphisms (SNPs) genotyping by Infinium Expanded Multi-Ethnic Genotyping Array (Illumina, San Diego, CA, USA) comparing patients with and without a history of CV events [161 cardiovascular diseases (CVDs) and 84 no CVDs]. The fixation index (Fst) measure was used to identify the most differentiated SNPs, and gene ontology analysis [Protein Analysis THrough Evolutionary Relationships (PANTHER) and Ingenuity Pathway Analysis (IPA)] was applied to define the biological/pathological roles of the associated SNPs. Partitioning tree analysis interrogated the genotype-phenotype relationship between discovered genetic variants and CV phenotypes. Cox regression analysis measured the effect of these SNPs on new CV events during the follow-up (FU). RESULTS: Fst analysis identified 3218 SNPs that were significantly different between CVD and no CVD. Gene ontology analysis identified two of these SNPs as involved in cardiovascular disease pathways (Ingenuity Pathway) and heart development (Panther) and belonging to 2 different genes: Glucagon-like peptide-1 receptor (GLP1R) and Sarcoglycan delta (SGCD). The phenotype-genotype analysis found a higher percentage of CVD patients carrying the GLP1R rs10305445 allele A (P = 0.03) and lower percentages of CVD patients carrying the SGCD rs145292439 allele A (P = 0.038). Moreover, SGCD rs145292439 was associated with higher levels of high-density lipoprotein (P = 0.015). Cox analysis confirmed the increased frequency of CV events during the 5-year FU in patients carrying GLP1R rs1035445 allele A but it did not show any significant association with SGCD rs145292439. CONCLUSIONS: This study identified GLP1R rs10305445 and SCGD rs145292439 as potential genetic markers that may explain the higher risk of CVD in hemodialysis patients.

Curcumin and Type 2 Diabetes Mellitus: Prevention and Treatment.

Type 2 diabetes mellitus (T2DM) is an ensemble of metabolic diseases that has reached pandemic dimensions all over the world. The multifactorial nature of the pathology makes patient management, which includes lifelong drug therapy and lifestyle modification, extremely challenging. It is well known that T2DM is a preventable disease, therefore lowering the incidence of new T2DM cases could be a key strategy to reduce the global impact of diabetes. Currently, there is growing evidence on the efficacy of the use of medicinal plants supplements for T2DM prevention and management. Among these medicinal plants, curcumin is gaining a growing interest in the scientific community. Curcumin is a bioactive molecule present in the rhizome of the Curcuma longa plant, also known as turmeric. Curcumin has different pharmacological and biological effects that have been described by both in vitro and in vivo studies, and include antioxidant, cardio-protective, anti-inflammatory, anti-microbial, nephro-protective, anti-neoplastic, hepato-protective, immunomodulatory, hypoglycaemic and anti-rheumatic effects. In animal models, curcumin extract delays diabetes development, improves ß-cell functions, prevents ß-cell death, and decreases insulin resistance. The present review focuses on pre-clinical and clinical trials on curcumin supplementation in T2DM and discusses the peculiar mechanisms by which curcumin might ameliorate diabetes management.

Sphingolipid Synthesis Inhibition by Myriocin Administration Enhances Lipid Consumption and Ameliorates Lipid Response to Myocardial Ischemia Reperfusion Injury.

Myocardial infarct requires prompt thrombolytic therapy or primary percutaneous coronary intervention to limit the extent of necrosis, but reperfusion creates additional damage. Along with reperfusion, a maladaptive remodeling phase might occur and it is often associated with inflammation, oxidative stress, as well as a reduced ability to recover metabolism homeostasis. Infarcted individuals can exhibit reduced lipid turnover and their accumulation in cardiomyocytes, which is linked to a deregulation of peroxisome proliferator activated receptors (PPARs), controlling fatty acids metabolism, energy production, and the anti-inflammatory response. We previously demonstrated that Myriocin can be effectively used as post-conditioning therapeutic to limit ischemia/reperfusion-induced inflammation, oxidative stress, and infarct size, in a murine model. In this follow-up study, we demonstrate that Myriocin has a critical regulatory role in cardiac remodeling and energy production, by up-regulating the transcriptional factor EB, PPARs nuclear receptors and genes involved in fatty acids metabolism, such as VLDL receptor, Fatp1, CD36, Fabp3, Cpts, and mitochondrial FA dehydrogenases. The overall effects are represented by an increased ß-oxidation, together with an improved electron transport chain and energy production. The potent immunomodulatory and metabolism regulatory effects of Myriocin elicit the molecule as a promising pharmacological tool for post-conditioning therapy of myocardial ischemia/reperfusion injury.