Trimetazidine Reduces Endogenous Free Fatty Acid Oxidation

INTRODUCTION: The metabolic modulator trimetazidine (TMZ) has been suggested to induce a metabolic shift from myocardial fatty acid oxidation (FAO) to glucose utilization, but this mechanism remains unproven in humans. The oxidation of plasma derived FA is commonly measured in humans, whereas the contribution of FA from triglycerides stored in the myocardium has been poorly characterized. AIMS: To verify the hypothesis that TMZ induces a metabolic shift, we combined positron emission tomography (PET) and magnetic resonance spectroscopy ((1)H-MRS) to measure myocardial FAO from plasma and intracellular lipids, and myocardial glucose metabolism. Nine obese subjects were studied before and after 1 month of TMZ treatment. Myocardial glucose and FA metabolism were assessed by PET with (18)F-fluorodeoxyglucose and (11)C-palmitate. (1)H-MRS was used to measure myocardial lipids, the latter being integrated into the PET data analysis to quantify myocardial triglyceride turnover. RESULTS: Myocardial FAO derived from intracellular lipids was at least equal to that of plasma FAs (P = NS). BMI and cardiac work were positively associated with the oxidation of plasma derived FA (P ≤ 0.01). TMZ halved total and triglyceride-derived myocardial FAO (32.7 ± 8.0 to 19.6 ± 4.0 μmol/min and 23.7 ± 7.5 to 10.3 ± 2.7 μmol/min, respectively; P ≤ 0.05). These changes were accompanied by increased cardiac efficiency since unchanged LV work (1.6 ± 0.2 to 1.6 ± 0.1 Watt/g × 10(2), NS) was associated with decreased work energy from the intramyocardial triglyceride oxidation (1.6 ± 0.5 to 0.4 ± 0.1 Watt/g × 10(2), P = 0.036). CONCLUSIONS: In obese subjects, we demonstrate that myocardial intracellular triglyceride oxidation significantly provides FA-derived energy for mechanical work. TMZ reduced the oxidation of triglyceride-derived myocardial FAs improving myocardial efficiency

Congenital solitary kidney in autosomal dominant polycystic kidney disease: Where do known genes end and the unknown begin?

Key Clinical Message We present the case of a 41‐year‐old man patient diagnosed with solitary left kidney with few cysts. He has a family history of unilateral renal agenesis (URA) but no for autosomal dominant polycystic kidney disease (ADPKD). Genetic testing revealed PKD1 gene intron 11 heterozygous nucleotide variant c.2854‐23G>T, but no gene mutation implicated in URA. Just eight cases of ADPKD with one kidney have been recorded globally. PC1 and PC2 disruption, causing primary cilia malformation or absence resulting in relevant in the first embryonic development alteration. Cillia's crucial significance in many diseases will require more research

A Rare Case of Concurrent 2q34q36 Duplication and 2q37 Deletion in a Neonate with Syndromic Features

Large-scale genomic structural variations can have significant clinical implications, depending on the specific altered genomic region. Briefly, 2q37 microdeletion syndrome is a prevalent subtelomeric deletion disorder characterized by variable-sized deletions. Affected patients exhibit a wide range of clinical manifestations, including short stature, facial dysmorphism, and features of autism spectrum disorder, among others. Conversely, isolated duplications of proximal chromosome 2q are rare and lack a distinct phenotype. In this report, we provide an extensive molecular analysis of a 15-day-old newborn referred for syndromic features. Our analysis reveals an 8.5 Mb microdeletion at 2q37.1, which extends to the telomere, in conjunction with an 8.6 Mb interstitial microduplication at 2q34q36.1. Our findings underscore the prominence of 2q37 terminal deletions as commonly reported genomic anomalies. We compare our patient’s phenotype with previously reported cases in the literature to contribute to a more refined classification of 2q37 microdeletion syndrome and assess the potential impact of 2q34q36.1 microduplication. We also investigate multiple hypotheses to clarify the genetic mechanisms responsible for the observed genomic rearrangement

Development of Resistance to the Atypical Retinoid, ST1926, in the Lung Carcinoma Cell Line H460 Is Associated with Reduced Formation of DNA Strand Breaks and a Defective DNA Damage Response

Atypical retinoids are potent inducers of apoptosis, but activation of the apoptotic pathway seems to be independent of retinoid receptors. Previous studies with a novel adamantyl retinoid, ST1926, have shown that apoptosis induction is associated with an early genotoxic stress. To better understand the relevance of these events, we have selected a subline of the H460 lung carcinoma cell line resistant to ST1926. Resistant cells exhibited cross-resistance to a related molecule, CD437, but not cross-resistance to agents with different mechanisms of action. In spite of a lack of defects in intracellular drug accumulation, induction of DNA strand breaks in resistant cells required exposure to a substantially higher concentration, which was consistent with the degree of resistance. At drug concentrations causing a similar antiproliferative effect (IC(80)) and a comparable extent of DNA lesions in sensitive and resistant cells, the apoptotic response was a delayed and less marked event in resistant cells, thus indicating a reduced susceptibility to apoptosis. In spite of recognition of DNA lesions in resistant cells, as supported by phosphorylation of p53 and histone H2AX, resistant cells exhibited no activation of the mitochondrial pathways of apoptosis. Following exposure to equitoxic drug concentrations, only sensitive cells exhibited a typical stress/DNA damage response, with activation of the S-phase checkpoint. The cellular resistance to ST1926 reflects alterations responsible for a reduced generation of DNA lesions and for an enhanced tolerance of the genotoxic stress, resulting in lack of activation of the intrinsic pathway of apoptosis. The defective DNA damage response, accompanied by a reduced susceptibility to apoptosis in resistant cells, provides further support to the involvement of genotoxic stress as a critical event in mediating apoptosis induction by ST1926

Human obesity is characterized by defective fat storage and enhanced muscle fatty acid oxidation, and trimetazidine gradually counteracts these abnormalities

Bucci M, Borra R, Nagren K, Maggio R, Tuunanen H, Oikonen V, Del Ry S, Viljanen T, Taittonen M, Rigazio S, Giannessi D, Parkkola R, Knuuti J, Nuutila P, Iozzo P. Human obesity is characterized by defective fat storage and enhanced muscle fatty acid oxidation, and trimetazidine gradually counteracts these abnormalities. Am J Physiol Endocrinol Metab 301: E105-E112, 2011. First published April 19, 2011; doi: 10.1152/ajpendo.00680.2010.-An impaired ability to store fatty acids (FA) in subcutaneous adipose tissue (SAT) may be implicated in the pathogenesis of obesity-related diseases via overexposure of lean tissues and production of free radicals from FA oxidation (FAO). We studied regional FA metabolism in skeletal muscle and adipose tissue in humans and investigated the long-term effects of the FAO inhibitor trimetazidine on glucose and FA metabolism. Positron emission tomography (PET) and [C-11] palmitate were used to compare FA metabolism in SAT and skeletal muscle between eight obese and eight nonobese subjects (BMI >=/<30 kg/m(2)). A subgroup of nine subjects underwent a 1-mo trimetazidine administration. PET with [C-11] palmitate and [F-18] fluorodeoxyglucose, indirect calorimetry, and MRI before and after this period were performed to characterize glucose and FA metabolism, fat masses, skeletal muscle triglyceride, and creatine contents. Obesity was characterized by a 100% elevation in FAO and a defect in the FA esterification rate constant (P <0.05) in skeletal muscle. FA esterification was reduced by similar to 70% in SAT (P <0.001) in obese vs. control subjects. The degrees of obesity and insulin resistance were both negatively associated with esterification-related parameters and positively with FAO (P <0.05). Trimetazidine increased skeletal muscle FA esterification (P <0.01) and mildly upregulated glucose phosphorylation (P = 0.066). Our data suggest that human obesity is characterized by a defect in tissue FA storage capability, which is accompanied by a (potentially compensatory) elevation in skeletal muscle FAO; trimetazidine diverted FA from oxidative to nonoxidative pathways and provoked an initial activation of glucose metabolism in skeletal muscle