Abstract P608: Obesity Induced Hypertension Exacerbated Through Upregulation Of Renal Naci Cotransporter, Reversed By Increasing Pgc-1α-ho-1 Gene Expression To Restore Mitochondrial Function

Introduction: Hypertension caused by chronic obesity as a result of high calorie food intake or in leptin receptor deficient db/db mice may be linked to mitochondrial dysfunction. Previously we and others have shown that an epoxyeicosatrienoic acid agonist (EET-A), reduced adiposity and ROS resulting in normalization of BP by unknown mechanisms. We hypothesize that EET-A will attenuate BP by restoring mitochondrial function through increasing the PGC-1α-HO-1 axis and increasing urinary sodium excretion by downregulating NCC channels. Methods: Db/db mice at 16-wks of age were divided into 3 treatment groups and for an additional 16-wks received: A) control, B) EET-A 1.5mg/100g BW i.p. 2x/week and C) EET-A and lentiviral (Ln)- PGC-1α shRNA (to suppress PGC-1α protein). Oxygen consumption (VO 2 ), visceral fat and blood glucose were determined. Additionally, renal tissues were harvested to measure the type 2 Na-K-Cl cotransporters (NKCC2), epithelial Na channels- (ENaC), NaCl cotransporters (NCC), PGC-1α, HO-1, insulin receptors, and mitochondrial biogenesis markers. Results: At the conclusion of 32 weeks: Group A, developed hypertension and presented with decreased urinary Na excretion, decreased VO 2 , decreased downstream PGC-1α signaling, and mitochondrial dysfunction. There were increased levels of NCCs but not of NKCC2s or ENaCs. Renal PGC-1α, HO-1, pAMPK, and mitochondrial fusion protein Mfn 1/2, and Opa1 were decreased, p<0.05. Group B, exhibited restoration of renal levels of PGC-1α, HO-1, pAMPK, and mitochondrial biogenesis proteins Mfn 1/2 and Opa1. NCC expression was reduced and was associated with an increase in urinary Na excretion; (p<0.05). The beneficial effect of EET-A observed in group B was suppressed in group C using Ln- PGC-1α shRNA which suppressed PGC-1α expression in renal tissue > 50% and was accompanied by the onset of even more severe suppression of urinary Na excretion than in Group A. Conclusion: Treatment of obese mice with EET-agonists leads to the recruitment of PGC-1α-HO-1 which enhances mitochondrial function and induces the downregulation of NCC channels and increased sodium excretion. EET may serve as a powerful therapeutic agent for the treatment of obesity induced hypertension.

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DNA Methylation of PGC-1α Is Associated With Elevated mtDNA Copy Number and Altered Urinary Metabolites in Autism Spectrum Disorder

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.696428 ◽

2021 ◽

Vol 9 ◽

Author(s):

Sophia Bam ◽

Erin Buchanan ◽

Caitlyn Mahony ◽

Colleen O’Ryan

Keyword(s):

Autism Spectrum Disorder ◽

Dna Methylation ◽

Mitochondrial Dysfunction ◽

Mitochondrial Biogenesis ◽

Mitochondrial Function ◽

Copy Number ◽

Autism Spectrum ◽

Differential Methylation ◽

Mtdna Copy Number ◽

Key Genes

Autism spectrum disorder (ASD) is a complex disorder that is underpinned by numerous dysregulated biological pathways, including pathways that affect mitochondrial function. Epigenetic mechanisms contribute to this dysregulation and DNA methylation is an important factor in the etiology of ASD. We measured DNA methylation of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α), as well as five genes involved in regulating mitochondrial homeostasis to examine mitochondrial dysfunction in an ASD cohort of South African children. Using targeted Next Generation bisulfite sequencing, we found differential methylation (p < 0.05) at six key genes converging on mitochondrial biogenesis, fission and fusion in ASD, namely PGC-1α, STOML2, MFN2, FIS1, OPA1, and GABPA. PGC-1α, the transcriptional regulator of biogenesis, was significantly hypermethylated at eight CpG sites in the gene promoter, one of which contained a putative binding site for CAMP response binding element 1 (CREB1) (p = 1 × 10–6). Mitochondrial DNA (mtDNA) copy number, a marker of mitochondrial function, was elevated (p = 0.002) in ASD compared to controls and correlated significantly with DNA methylation at the PGC-1α promoter and there was a positive correlation between methylation at PGC-1α CpG#1 and mtDNA copy number (Spearman’s r = 0.2, n = 49, p = 0.04) in ASD. Furthermore, DNA methylation at PGC-1α CpG#1 and mtDNA copy number correlated significantly (p < 0.05) with levels of urinary organic acids associated with mitochondrial dysfunction, oxidative stress, and neuroendocrinology. Our data show differential methylation in ASD at six key genes converging on PGC-1α-dependent regulation of mitochondrial biogenesis and function. We demonstrate that methylation at the PGC-1α promoter is associated with elevated mtDNA copy number and metabolomic evidence of mitochondrial dysfunction in ASD. This highlights an unexplored role for DNA methylation in regulating specific pathways involved in mitochondrial biogenesis, fission and fusion contributing to mitochondrial dysfunction in ASD.

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Effects of (−)-epicatechin on mitochondria

Nutrition Reviews ◽

10.1093/nutrit/nuaa094 ◽

2020 ◽

Vol 79 (1) ◽

pp. 25-41

Author(s):

Frédéric N Daussin ◽

Elsa Heyman ◽

Yan Burelle

Keyword(s):

Mitochondrial Dysfunction ◽

Mitochondrial Biogenesis ◽

Mitochondrial Function ◽

Genetic Disorders ◽

Natural Compounds ◽

Human Diseases ◽

Therapeutic Applications ◽

Effective Strategies

Abstract Mitochondrial dysfunction is observed in a broad range of human diseases, including rare genetic disorders and complex acquired pathologies. For this reason, there is increasing interest in identifying safe and effective strategies to mitigate mitochondrial impairments. Natural compounds are widely used for multiple indications, and their broad healing properties suggest that several may improve mitochondrial function. This review focuses on (−)-epicatechin, a monomeric flavanol, and its effects on mitochondria. The review summarizes the available data on the effects of acute and chronic (−)-epicatechin supplementation on mitochondrial function, outlines the potential mechanisms involved in mitochondrial biogenesis induced by (−)-epicatechin supplementation and discusses some future therapeutic applications.

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Study of labetalol vs. methyldopa in treatment of pregnancy induced hypertension

International Journal of Reproduction Contraception Obstetrics and Gynecology ◽

10.18203/2320-1770.ijrcog20192434 ◽

2019 ◽

Vol 8 (6) ◽

pp. 2378

Author(s):

Bhakti G. Gurjar ◽

Samidha S. Malewar

Keyword(s):

Blood Pressure ◽

Treated Group ◽

Medical Problem ◽

Adverse Outcomes ◽

Medical College ◽

Increased Risk ◽

Induced Hypertension ◽

Single Centre Study ◽

Group A ◽

Group B

Background: Hypertension is a common medical problem encountered during pregnancy and is associated with increased risk of adverse outcomes. Objective of this study was to compare efficacy and safety of Labetalol and Methyldopa in controlling blood pressure in patients with PIH and pre-eclampsia.Methods: A comparative, prospective observational, single centre study conducted from November 2015 to November 2017 in women with PIH at Indira Gandhi Government Medical College, Nagpur. Group A included 100 patients treated with Labetalol while Group B included 100 patients who were given Methyldopa. Response in lowering of BP was assessed over a period of 7 days.Results: Labetalol treated group of patients showed significant fall from 143.50±7.30mmHg/101.30±3.93 (sytolic/diastolic) on 1st day to 126.10±5.49 mmHg/87.40±5.62 mmHg (sytolic/diastolic) on day 7, while systolic/diastolic BP in methyldopa group on 1st day was 145.20±7.17 mmHg/101.60±4.20 mmHg which was reduced to 129.20±4.86 mmHg/90.50±3.30 mmHg on day 7. Author found that MAP in Labetalol group reduced from 115.226±4.17 mmHg to 100.17±4.43 mmHg on day 7 while in Methyldopa group had MAP on admission 115.99±4.38 mmHg and on day 7 it reduced to 103.27±2.99mmHg which is highly significant.Conclusions: Labetalol controls systolic and diastolic blood pressure more rapidly and effectively than Methyldopa. Safety profile and adverse effects of Labetalol and Methyldopa are similar to each other.

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Lovastatin protects mithochondrial and renal function in kidney ischemia-reperfusion in rats

Acta Cirurgica Brasileira ◽

10.1590/s0102-86502012000700008 ◽

2012 ◽

Vol 27 (7) ◽

pp. 477-481 ◽

Cited By ~ 3

Author(s):

Silvio Tucci Junior ◽

Carlos Augusto Fernandes Molina ◽

Marcelo Ferreira Cassini ◽

Daniel Mendes Leal ◽

Cássio Antonio Botene Schineider ◽

...

Keyword(s):

Renal Function ◽

Mitochondrial Function ◽

Mitochondrial Membrane ◽

Ischemia Reperfusion ◽

Protective Action ◽

Mitochondrial Fraction ◽

Renal Ischemia ◽

Atp Production ◽

Group A ◽

Group B

PURPOSE: To investigate the effect of lovastatin on renal ischemia followed by reperfusion. METHODS: Thirty one Wistar rats submitted to left renal ischemia for 60 minutes followed by contralateral nephrectomy were divided into two groups: A (n =17, control, no treatment), and B (n=14, lovastatin 15 mg/kg/day p.o. ten days before ischemia). The animals were sacrificed at the end of ischemia, after 24 hours and at seven days after reperfusion. Survival, serum urea and creatinine levels and renal mitochondrial function were evaluated. RESULTS: Mortality was 29.4% in group A and 0.7% in group B. Urea and creatinine levels were increased in both groups, but the values were significantly lower in group B. Mitochondrial function showed decoupling in 83.4% of group A, as opposed to 38.4/% of group B. CONCLUSIONS: The result shows a protective action of renal function by lovastatin administered before ischemia/reperfusion. Since most of the mitochondrial fraction presented membranes with the ability to maintain ATP production in group B, stabilization of the mitochondrial membrane should be considered as part of the protective action of lovastatin on renal function in ischemia/reperfusion.

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Mitochondrial Dysfunction in Metabolic Disease

The Indonesian Biomedical Journal ◽

10.18585/inabj.v4i3.172 ◽

2012 ◽

Vol 4 (3) ◽

pp. 119

Author(s):

Anna Meiliana ◽

Andi Wijaya

Keyword(s):

Mitochondrial Dysfunction ◽

Mitochondrial Biogenesis ◽

Mitochondrial Function ◽

Stress Responses ◽

Metabolic Diseases ◽

Respiratory Enzymes ◽

Mitochondrial Oxidative Stress ◽

Cancer Pathways ◽

Wide Range ◽

Key Factor

BACKGROUND: Mitochondrial function and behavior are central to the physiology of humans and, consequently, "mitochondrial dysfunction" has been implicated in a wide range of disease.CONTENT: Mitochondrial ROS might attack various mitochondrial constituents, causing mitochondrial DNA mutations and oxidative damage to respiratory enzymes. A defect in mitochondrial respiratory enzymes would increase mitochondrial production of ROS, causing further mitochondrial damage and dysfunction. Mitochondrial dysfunction is associated with diseases, such as neurodegenerative disorders, cardiomyopathies, metabolic syndrome, obesity, and cancer. Pathways that improve mitochondrial function, attenuate mitochondrial oxidative stress, and regulate mitochondrial biogenesis have recently emerged as potential therapeutic targets.SUMMARY: Mitochondria perform diverse yet interconnected functions, produce ATP and many biosynthetic intermediates while also contribute to cellular stress responses such as autophagy and apoptosis. Mitochondria form a dynamic, interconnected network that is intimately integrated with other cellular compartments. It is therefore not suprising that mitochondrial dysfunction has emerged as a key factor in a myriad of diseases, including neurodegenerative, cancer, and metabolic disorders. Interventions that modulate processes involved in regulation of mitochondrial turnover, with calorie restriction and induction of mitochondrial biogenesis, are of particular interest.KEYWORDS: mitochondrial biogenesis, mitochondrial dysfunction, reactive oxygen species (ROS), metabolic diseases

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COMPARISON OF INTRAVENOUS LABETALOL AND ORAL NIFEDIPINE IN MANAGEMENT OF BLOOD PRESSURE IN PATIENTS WITH SEVERE PREGNANCY INDUCED HYPERTENSION

Journal of University Medical & Dental College ◽

10.37723/jumdc.v10i4.79 ◽

2019 ◽

Vol 10 (4) ◽

pp. 26-30

Author(s):

Tehseen Aslam ◽

Nuzhat Parveen ◽

Shakeela Irfan ◽

Uzma Riaz ◽

Amin Anjum

Keyword(s):

Blood Pressure ◽

Blood Pressure Control ◽

Pressure Control ◽

Pregnancy Induced Hypertension ◽

Achieve Blood Pressure Control ◽

Achieve Blood Pressure ◽

Induced Hypertension ◽

Group A ◽

Group B ◽

Mean Time

ABSTRACT:It is estimated that 6-12% of all the pregnancies are complicated by hypertension and even all improvements pre eclempsia is a signiﬁcant reason of maternal and perinatal morbidity and mortality worldwide. Nifedipine, Labetalol and hydralazine are mostly being used in acute management of hypertension in pregnancy but so far there is no evidence that anyone drug is more eﬀective. OBJECTIVE: To compare the mean time to achieve blood pressure control of oral Nifedipine with intravenous Labetalol for management of severe pregnancy induced hypertension. METHODOLOGY: This randomized control trial was done in Obstetrics and Gynaecology department of Hilal-e-Ahmer hospital, Faisalabad over a period of 6 months from 01-07-2016 to 31-12-2016. Total 100 patients (group-A and group–B having 50 in each) were included in study. In group A, females were given 40mg oral Nifedipine and in group, females were given 20ml intravenous Labetalol. Time at administration was followed in the ward for assessment of blood pressure control. Blood pressure was noted after every 10 min. The total donation time to achieve B.P was noted (as per operational deﬁnition).The collected data was analyzed by using SPSS version 17.0. Baseline blood pressure were presented in the form of mean+SD. Both groups were compared for mean time to achieve blood pressure control by applying t- test and consider signiﬁcant at p value <5%.RESULTS: Patients were ranged between 20-40 years. Mean age of the patients was calculated as 26.98+4.54 and 27.36+4.43 years in group-A and B respectively. Gestational age shows that 64%(n=32) in Group-A 74%(37%) in Group–B were between 20-30 weeks of gestation while 36%(n=18) in Group-A were between 31-40 weeks of gestation mean±SD was calculated as 28.92+4.91 and 28.94+4.72 weeks in Group-A and B respectively. Mean time to achieve B.P control in group A was 31.24+5.62 and in group B 45.5+4.63 with p value <0.05. CONCLUSION: Mean time to achieve blood pressure control was shorter with oral Nifedipine when compared to I/V Labetalol for management of female presenting with severe pregnancy induced hypertension.

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TO COMPARE THE EFFICACY OF LABETALOL AND METHYLDOPA IN TREATMENT OF PREGNANCY INDUCED HYPERTENSION

10.36106/gjra/0710001 ◽

2020 ◽

pp. 54-55

Author(s):

Ashish Yadav ◽

Rohitash Kularia ◽

Subash Chandra ◽

Anita Sharma

Keyword(s):

Antihypertensive Drugs ◽

Pregnancy Induced Hypertension ◽

Inclusion Criteria ◽

Hypertension In Pregnancy ◽

Induced Hypertension ◽

Group A ◽

The Mean ◽

Group B ◽

Labour Room ◽

New Onset

Background- The present study is undertaken with limited available facilities to find out the efficacy of two oral antihypertensive drugs namely labetalol and methyldopa in management of pregnancy induced hypertension. Methods- The study consisted of 100 patients with pregnancy induced hypertension attending outpatient department and admitted in ANW, or who directly came to labour room. These patients were randomly selected on lottery basis after they fulfilled the inclusion criteria. Total 100 patients were taken for the study and divided into 2 groups of 50 patients in each group. Results- The mean SBP before treatment in methyldopa group was161.33 ± 8.97 mmHg and 160.03 ± 8.23 mmHg in labetalol group which showed a fall to 138.61 ± 6.67 mmHg (methyldopa group) and 138.08 ± 5.37 mmHg (labetalol groups) after treatment. Fall of SBP was significant in both the groups. But inter group difference was not significant (p > 0.05). The mean DBP before treatment was 106.85 ± 4.33 mmHg in methyldopa group and 105.63 ± 5.23 mmHg in labetalol group which decreased to 89.31 ± 6.51 mmHg and 89.68 ± 5.26 mmHg respectively after treatment. Fall of DBP was significant in both the groups. But inter group difference was not significant (p > 0.05). Fall of MAP was significant in Group A and Group B. But inter group difference was not significant (p > 0.05). Conclusion-Labetalol and methyldopa are equally efficacious in controlling blood pressure in new onset hypertension in pregnancy.

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Relationship between lupus anticoagulant (LAC) and pregnancy-induced hypertension

Reproduction Fertility and Development ◽

10.1071/rd9951569 ◽

1995 ◽

Vol 7 (6) ◽

pp. 1569 ◽

Cited By ~ 2

Author(s):

T Matsumoto ◽

N Sagawa ◽

Y Ihara ◽

F Kobayashi ◽

H Itoh ◽

...

Keyword(s):

Lupus Anticoagulant ◽

Fetal Loss ◽

Systemic Autoimmune Disease ◽

Pregnancy Induced Hypertension ◽

Induced Hypertension ◽

History Of ◽

Group A ◽

Coagulation Assay ◽

Group B

Lupus anticoagulant (LAC), a serum antiphospholipid autoantibody, is believed to be one of the causes of infertility or fetal loss. The purpose of the present study was to evaluate the role of LAC in the pathogenesis of hypertension during pregnancy. In this study, 20 pregnant women with hypertension were classified into two groups: 14 patients who did not have hypertension before the pregnancy but developed it during the pregnancy (pregnancy-induced hypertension; Group A) and 6 patients who had hypertensive or renal disease before the pregnancy, and developed further hypertension during the pregnancy (pregnancy-aggravated hypertension; Group B). A LAC coagulation assay was performed, and the presence of LAC in each group was compared. All 14 patients in group A were LAC-negative. In contrast, 3 of the 6 patients in group B were LAC-positive, and had clinical autoimmune diseases. The incidence of pregnancy-induced hypertension was also examined in 15 pregnancies from 9 LAC-positive women who had a history of repeated fetal loss but no systemic autoimmune disease (Group C). None of these 15 pregnancies had hypertensive complications, even when they reached term. In the placentas of LAC-positive women, no characteristic changes other than fibrinoid degeneration and microscopic infarction were observed upon histological examination. These results suggest that LAC does not relate with the onset of hypertension during pregnancy.

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Mitochondrial Membrane Potential Predicts 4-Hour Sperm Motility

Biomedicines ◽

10.3390/biomedicines8070196 ◽

2020 ◽

Vol 8 (7) ◽

pp. 196 ◽

Cited By ~ 1

Author(s):

Angela Alamo ◽

Claudia De Luca ◽

Laura M. Mongioì ◽

Federica Barbagallo ◽

Rossella Cannarella ◽

...

Keyword(s):

Membrane Potential ◽

Mitochondrial Membrane Potential ◽

Sperm Motility ◽

Mitochondrial Function ◽

Mitochondrial Membrane ◽

Seminal Fluid ◽

Fluid Collection ◽

Significant Decline ◽

Group A ◽

Group B

The evaluation of conventional and biofunctional sperm parameters is of fundamental importance for assessing male reproductive function. Among these, sperm motility is one of the most important parameters. Indeed, asthenozoospermia is a frequent cause of male infertility. Sperm motility depends on mitochondrial function and the measurement of mitochondrial membrane potential (MMP) better accounts for the function of this intracellular organelle. On the basis of these premises, the present study assessed whether the MMP predicts sperm motility at 4 h in patients with low or normal MMP. To accomplish this, 31 men were enrolled. Sperm analysis was conducted according to the WHO 2010 criteria. Particular attention was paid to the evaluation of MMP after liquefaction (T0) using JC-1 staining by flow cytometry. Sperm total and progressive motility were measured at T0 and after 4 h from seminal fluid collection (T4). Patients were divided into two groups based on their sperm mitochondrial function at T0. Group A (n = 18) was composed of men with normal mitochondrial function since they had a percentage of spermatozoa with low MMP (L-MMP) below the normal reference value of our laboratory (<36.5%). In contrast, group B (n = 13) was made up of men with impaired sperm mitochondrial function (L-MMP > 36.5%). Group A had a slight but not significant reduction in total and progressive sperm motility at T4 compared with the values recorded at T0. In contrast, patients in group B showed a significant decline in both total and progressive sperm motility at T4 compared with T0 (p < 0.05). The results of this study showed that worse mitochondrial function, assessed by staining with JC1, is associated with a significant decline in sperm motility over time. These findings may be of clinical relevance in programs of assisted reproduction techniques. Based on our knowledge, there is no other evidence in the literature that has shown this relationship in healthy men with low MMP of idiopathic etiology, but normozoospermics according to the WHO 2010 criteria.

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Mitochondrial dysfunction is associated with long-term cognitive impairment in an animal sepsis model

Clinical Science ◽

10.1042/cs20190351 ◽

2019 ◽

Vol 133 (18) ◽

pp. 1993-2004 ◽

Cited By ~ 8

Author(s):

Andressa Manfredini ◽

Larissa Constantino ◽

Milton Castro Pinto ◽

Monique Michels ◽

Henrique Burger ◽

...

Keyword(s):

Cognitive Impairment ◽

Mitochondrial Dysfunction ◽

Mitochondrial Biogenesis ◽

Mitochondrial Function ◽

Ex Vivo ◽

Mitochondrial Dynamics ◽

Cecal Ligation ◽

Inhibitory Avoidance ◽

Sepsis Survivors

Abstract Background: Several different mechanisms have been proposed to explain long-term cognitive impairment in sepsis survivors. The role of persisting mitochondrial dysfunction is not known. We thus sought to determine whether stimulation of mitochondrial dynamics improves mitochondrial function and long-term cognitive impairment in an experimental model of sepsis. Methods: Sepsis was induced in adult Wistar rats by cecal ligation and perforation (CLP). Animals received intracerebroventricular injections of either rosiglitazone (biogenesis activator), rilmenidine, rapamycin (autophagy activators), or n-saline (sham control) once a day on days 7–9 after the septic insult. Cognitive impairment was assessed by inhibitory avoidance and object recognition tests. Animals were killed 24 h, 3 and 10 days after sepsis with the hippocampus and prefrontal cortex removed to determine mitochondrial function. Results: Sepsis was associated with both acute (24 h) and late (10 days) brain mitochondrial dysfunction. Markers of mitochondrial biogenesis, autophagy and mitophagy were not up-regulated during these time points. Activation of biogenesis (rosiglitazone) or autophagy (rapamycin and rilmenidine) improved brain ATP levels and ex vivo oxygen consumption and the long-term cognitive impairment observed in sepsis survivors. Conclusion: Long-term impairment of brain function is temporally related to mitochondrial dysfunction. Activators of autophagy and mitochondrial biogenesis could rescue animals from cognitive impairment.

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