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Abstract : Lathosterol and other Noncholesterol Sterols in Treatment of Hereditary Hypercholesterolemias: 20-Year Experience among School Children and Adolescents
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Abstract: Aims: This paper presents our 20-year experience with diagnosing heterozygous familial hypercholesterolemia (HFH) and monitoring its diet and drug treatment in 94 children (6-18 years) by means of noncholesterol sterols (NCS), namely lathosterol (Lat) and desmosterol (Des) as cholesterol synthesis precursors, and campesterol (Cam) and sitosterol (Sit) as cholesterol absorption precursors. Patients and Methods:Four groups were included in the study: (1) 64 children with genetically confirmed HFH; (2) 30 children with clinical and laboratory symptoms of HFH where the relevant genetic mutations have not been found; (3) 77 children with alimentary hyperlipidemia (AH), and (4) 84 healthy children as a control group. The followed-up markers were routine lipid profile comprising total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triacylglycerides (TAG), complemented by apolipoprotein A1 (ApoA), apolipoprotein B (ApoB), lipoprotein(a) (Lp(a)), low-density lipoprotein receptor (LDL-R), apolipoprotein E (ApoE) polymorphism, and plasma NCS (Lat, Des, Cam and Sit), the latter being established by means of GC/MS. The medical treatment of HFH patients consisted of simvastatin and ezetimibe. Correlations between TC lowering and decrease in Lat and other NCS values during combination treatment were examined in various types of hypercholesterolemia. Results: HFH patients, whether genetically confirmed or not, exhibit a significant decrease in Lat (and in milder concentrations also Des) which correlates directly to the TC lowering during the combination therapy (r = 0.912 for Lat; r = 0.798 for Des; p<0.001). Cam and Sit do not correlate with the TC lowering at all (r = -0.378 for Cam; r = -0.208 for Sit). By contrast, high TC levels in AH patients are not accompanied by significantly elevated Lat levels, and, therefore, caloric restriction cannot result in significant Lat or Des decrease (p<0.001). Lat and Des levels are also high following drug treatment interruption during long vacations or when the drug treatment is neglected. Compensatory elevation of Cam and Sit occurs in 50% of treated children patients after the desirable TC level below 4.8 mmol/l has been achieved and maintained. In our experience, the combination of statin and ezetimibe is the most efficacious therapy to lower TC together with Lat and Des in children with HFH. Conclusions: Inclusion precursors for cholesterol synthesis and absorption in laboratory testing improve differential diagnosis of HFH, and makes monitoring and/or treatment of pediatric patients more precise and convenient. Keywords: Noncholesterol sterols, lathosterol, desmosterol, campesterol, sitosterol, phytosterols, heterozygous familial hypercholesterolemia, alimentary hyperlipidemia, monitoring diet and drug treatment, simvastatins, ezetimibe. |
Abstract : Safety and Efficacy of Methanol Fraction of Moringa oleifera as Antihypertensive in L-NAME Induced Hypertensive Rabbits: Bedside to Bench, Implications for Bench Back to Bedside
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Abstract: Context: Hypertension, a global menace requires innovative research into the use of Moringa oleifera being promoted and traditionally used as alternative therapy. Objective: To innovatively evaluate the mechanistic effect, safety and efficacy of the methanol fraction of M. oleifera (MMO) leaves on L-NAME induced hypertensive rabbits. Methods: Rabbits were divided into six groups: Control, L-NAME alone, L-NAME with 100, 200 or 400 mg/kg of MMO and enalapril. Inclusion and exclusion criteria were similar baseline parameters and Day 3 systolic blood pressure (SBP) less than baseline SBP respectively. The primary outcome was a 10% reduction of SBP on Day 21. Enalapril group was excluded from analysis. Safety was assessed with liver and renal functions, hydrogen peroxide and nitric oxide concentrations to elucidate mechanistic effect. Results: Moringa 100 mg/kg, 200 mg/kg and 400 mg/kg reduced SBP by 4.75, 18.00 and 15.25 mmHg (F=22.123, p=0.000). SBP control was achieved with MMO 200mg/kg, 14% reduction and 400mg/kg, 12% reduction. Nitric oxide concentration, 0.06, 0.094 and 0.114mmol (F= 30.255, p= 0.000) dose-dependently increased and was most predictive of SBP control (r2=0.802, p=0.000). Nitric oxide production was inversely related to heart/body weight ratio which was dose-dependently reduced. MMO reduced hydrogen peroxide and ALT level but no significant effect on urea, HDL, and TG. Conclusion: MMO reduced SBP and dose-dependently increased nitric oxide concentration in L-NAME induced hypertensive rabbits. The effect may be mediated via activation of nitric oxide pathway. MMO demonstrated a potent anti-oxidant activity and safety. Effect on ventricular hypertrophy needs further evaluation. Keywords: Moringa, hypertension, nitric-oxide, anti-oxidant, intention-to-treat, per protocol. |
Abstract : Non-Muscle Myosin IIA (Myh9) is in the Nucleus of S-Phase Entering NT2-D1 Cells
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Abstract: Non-muscle myosin IIA is a cytoplasmic protein that works in concert with F-actin to produce cell movement. The heavy chain of this protein is codified by the MYH9 gene. The presence of motor proteins as myosin or mono and F-actin and their role in transcription has recently been observed. Prep1–the transcription factor of HOXB genes– constitutes a dimer with Pbx1, which induces HOXB gene expression. Prep1 has been found purifying with β-actin and Myh9. HOXB transcription initiates when cells enter in S-phase, during which DNA duplication and transcription occur at the same time. Here, we have shown that Myh9 co-localizes with Prep1 in the nucleus and in the periphery of the nucleolus in S-phase NT2-D1 cells. Furthermore, we have shown that Myh9 purifies with Pbx1 from nuclear extracts of S-phase entering NT2-D1 cells –and not from cytoplasmic extracts. Taking into account these results, we conclude that Myh9 is in the nucleus of the S-phase entering NT2-D1 cells and might have a role in HOXB transcription. Keywords: Myosin9, Hox genes, NT2-D1 cells, S-phase. |
Abstract : Platelets Mitochondrial Function Depends on Coenzyme Q10 Concentration in Human Young, Not in Elderly Subjects
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Abstract: Ageing is characterized by a progressive decline in the physiological functions of various organs. Mitochondrial alterations occurring in senescence. Antioxidants, including coenzyme Q10 concentration, fall with ageing and contribute to enhanced oxidative stress age-related diseases. The impairment of platelet mitochondrial function occurs in a broad spectrum of diseases. The aim of this study was to evaluate mitochondrial function in platelets in elderly and young human controls and correlate it with a concentration of coenzyme Q10. Platelets mitochondrial function was determined by the use of High-Resolution Respirometry method. We did not find significantly decreased platelet mitochondrial function in elderly subjects. Dependence of platelets mitochondrial respiratory chain function and ATP production at Complex I on a concentration of coenzyme Q10 in platelets and whole blood in young not in elderly human volunteers was documented. This dependence was not found for Complex II in any group. Platelet mitochondrial coenzyme Q10 concentration was insufficient for improving platelet mitochondrial function in elderly human subjects. Recommending supplementation with coenzyme Q10 in elderly and aged humans is waranted. High-Resolution Respirometry method offers a perspective to diagnose mitochondrial energy metabolism which might be useful for further studies in patients with mitochondrial disorders. Our results could contribute to the explanation of platelets mitochondrial function in elderly and aged human subjects. Keywords: Platelets, mitochondria, High-Resolution Respirometry, coenzyme Q10, age.
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