Lipoic Acid Supplementation Research Articles

Mitochondria as a primary determinant of angiogenic modality in pulmonary arterial hypertension.

Impaired pulmonary angiogenesis plays a pivotal role in the progression of pulmonary arterial hypertension (PAH) and patient mortality, yet the molecular mechanisms driving this process remain enigmatic. Our study uncovered a striking connection between mitochondrial dysfunction (MD), caused by a humanized mutation in the NFU1 gene, and severely disrupted pulmonary angiogenesis in adult lungs. Restoring the bioavailability of the NFU1 downstream target, lipoic acid (LA), alleviated MD and angiogenic deficiency and rescued the progressive PAH phenotype in the NFU1G206C model. Notably, significant NFU1 expression and signaling insufficiencies were also identified in idiopathic PAH (iPAH) patients' lungs, emphasizing this study's relevance beyond NFU1 mutation cases. The remarkable improvement in mitochondrial function of PAH patient-derived pulmonary artery endothelial cells (PAECs) following LA supplementation introduces LA as a potential therapeutic approach. In conclusion, this study unveils a novel role for MD in dysregulated pulmonary angiogenesis and PAH manifestation, emphasizing the need to correct MD in PAH patients with unrecognized NFU1/LA deficiency.

Lipoic acid supplementation in a preclinical model of preeclampsia mitigates maternal signs and fetal growth restriction through improved placental function

Lipoic acid supplementation in a preclinical model of preeclampsia mitigates maternal signs and fetal growth restriction through improved placental function

Effects of Lipoic Acid and High-Intensity Interval Training (HIIT) on Pancreatic VEGFR-3 Levels in Diabetic Rat Model

Objective: The purpose of this experimental research is to investigate the effects of High-Intensity Interval Training (HIIT) and Lipoic Acid (ALA) supplementation on VEGFR-3 of pancreatic in diabetic Wistar rats model. Materials and Methods: 20 male Wistar rats weighing 159 ± 3 gr and aged3 weeks, were randomly assigned into 4 groups:1) diabetes/sham, 2)diabetes/ ALA, 3)diabetes/exercise/sham, and 4) diabetes /exercise/ ALA. Diabetes was induced with streptozotocin (65 mg/kg dose) and Nicotinamide (120 mg/kg dose). After two weeks of familiarization with interval training, the rats started their main training, included 10 repetitions of 4 minutes of running on the treadmill with an intensity of 85-90% VO2max and 2 minutes of active rest between repetitions (5-10 m/min) for 5 sessions per week for 6 weeks. ALA supplement was taken at a dose of 20 mg/kg/day for 6 weeks. One-way ANOVA test used and Tukey's post hoc test at for analysis (P≤ 0.05). Results: HIIT has a significant effect on blood glucose (P= 0.004) and insulin (P= 0.001) and VEGFR3 (P= 0.001) of pancreatic tissue of diabetic rats. Conclusion: Lymphatic vessels play an important role in the pancreas and treat diabetes.The results of this research showed that HIIT and ALA increased lymphangiogenesis in the diabetic rat model.

Effects of Alpha Lipoic Acid Supplementation on Slow Skeletal Muscle Mass and Contractile Functions in Type 2 Diabetic Male Sprague Dawley Rats

Objective: To see the Effects of Alpha-Lipoic Acid (ALA) supplementation on slow skeletal muscle mass andcontractile functions in type 2 diabetic male Sprague Dawley rats.Study Design: Quasi-experimental study.Place and Duration of Study: The study was carried out at the Physiology Research Lab, Army MedicalCollege, Rawalpindi, Pakistan from June 2019 to April 2021 in collaboration with the National Institute of Health(NIH) Islamabad, Pakistan.Methods: Sixty adult SD rats were divided into three equal groups. Rats were fed on a standard diet as per NIHprotocols. After 2 weeks type 2 Diabetes mellitus (T2DM) was induced in groups 2 and 3 by injecting low dose35mg of streptozotocin (STZ) in the abdomen intraperitoneally. T2DM was successfully developed andconfirmed by measuring glucose levels through a glucometer. Group 3 was injected with Alpha Lipoic acid30mg/kg/day at the lower abdomen for the next two weeks. After 04 weeks, soleus muscles were dissected.The animal data acquisition unit (iWorx) was used for assessing the contractile functions of soleus.Results: Alpha Lipoic acid group showed improvement in muscle mass, muscle tension strength, and recoveryfrom fatigue after applying fatigue protocol as compared to group 2.Conclusion: Alpha Lipoic acid supplementation improves contractile force and delays fatigue in the soleusmuscles of diabetic rats. How to cite this: Khan BU, Yousef I, Arshad S, Ikram F, Ali A, Ullah I. Effects of Alpha Lipoic Acid Supplementation on Slow Skeletal Muscle Mass and Contractile Functions in Type 2 Diabetic Male Sprague Dawley Rats. Life and Science. 2024; 5(2): 216-221. doi: http://doi.org/10.37185/LnS.1.1.408

Effects of alpha lipoic acid supplementation on post-thaw quality of drone semen

This study aimed to determine the effect of alpha-lipoic acid (ALA) on post-thaw quality of bee semen. In the study, semen from sexually mature drone were collected. A series of experiments were carried out in which the retrieved semen was diluted with diluents containing different ALA concentrations or without ALA supplement (control). Cryopreserved sperm were thawed, and evaluated for motility (phase-contrast microscope), plasma and acrosomal membrane integrity, mitochondrial membrane potential, and DNA fregmantation. The results obtained showed that the highest motility after thawing was observed in the groups containing ALA 0.25 mmol (P < 0.05). Likewise, plasma membrane integrity was found to be better preserved in the ALA 0.25 mmol-added group than in other groups. Acrosomal integrity were also higher in the ALA-containing groups than in the control group (P < 0.05). The results of this study show that ALA supplementation especially at 0.25 mmol improved post-thawed sperm motility, plasma membrane functionality, and mitochondrial membrane potantial quality of honeybee semen.

The Effects of Alpha Lipoic Acid on Oxidative Stress, Lipid Profile, and Blood Glucose Levels in Type 2 Diabetic Male Sprague Dawley Rats

Objective: To determine the effect of Alpha Lipoic Acid (ALA) on blood glucose, lipid profile, and oxidative stress in streptozotocin-induced type II diabetic male Sprague Dawley rats.Study Design: Laboratory-based experimental study.Place and Duration of the Study: The study was carried out at the Physiology Research Lab, Army Medical College, Rawalpindi, Pakistan, from 20th January 2021 to 24th June 2021.Methods: Thirty Sprague Dawley (SD) rats were divided into three equal groups. Group I was given a normal standard rat diet. In Groups II and III after feeding a diet rich in fat and calories for 2 weeks, after feeding a diet rich in fat and calories for 2 weeks, a single low dose of streptozotocin was injected for Type 2 Diabetes Mellitus (T2DM) induction. Alpha Lipoic Acid 30 mg/kg body weight/day was administered intraperitoneally in Group III for 01 weeks after the development of T2DM.Results: The blood glucose, lipid profile, and serum Malondialdehyde levels were deranged in the diabetic group. After Alpha Lipoic Acid supplementation, the blood glucose levels, Serum MDA, and levels of triglycerides, cholesterol, and Low Density Lipoproteins decreased, whereas High Density Lipoproteins level were significantly raised (p &lt;0.001) in group III as compared to the diabetic group II. Conclusion: Treatment with Alpha Lipoic Acid reduces oxidative stress and improve reduces oxidative stress and improves glycemic and lipid profiles in T2DM rats.&#x0D; How to cite this: khan BU, Arshad S, Ikram F, Yousef I, Naizi I, Ismaeel M. The Effects of Alpha Lipoic Acid on Oxidative Stress, Lipid Profile and Blood Glucose Levels in Type 2 Diabetic Male Sprague Dawley Rats. Life and Science. 2024; 5(1): 89-94. doi: http://doi.org/10.37185/LnS.1.1.405

Ameliorating the Cardiovascular Disorders after Ovariectomy By Alpha Lipoic Acid Supplementation

Ameliorating the Cardiovascular Disorders after Ovariectomy By Alpha Lipoic Acid Supplementation

Effect of Alpha Lipoic Acid (ALA) Supplementation in Goat Oocyte In Vitro Maturation Media on Superoxide Dismutase (SOD) and 8-Hydroxy-2'-Deoxyguanosine (8-OHdG) Levels

Introduction: This study explains about the effect of Alpha Lipoic Acid (ALA) supplementation in goat oocyte In Vitro maturation media on Superoxide Dismutase (SOD) levels and 8-Hydroxy-2'-Deoxyguanosine (8-OHdG) levels with the aim of determining the status of balanced intracellular redox status and good oocyte quality. Objective: This laboratory experimental study contained three treatment groups: no ALA (P0), 25 μmol/L ALA supplementation (P1), and 50 μmol/L ALA supplementation (P2). SOD and 8-OHdG levels were measured using the ELISA method. SOD levels in group P0 were 1.41±0.40 pg/mL, group P1 were 2.04±0.50 pg/mL, and group P2 were 3.65±1.20 pg/mL. Data on 8-OHdG levels in the P0 group was 51.17±27.58 pg/mL, the P1 group was 11.21±5.98 pg/mL, and the P2 group was 12.66±6.01 pg/mL. Results: The P1 group could not significantly increase the SOD level of the P0 group (p&gt;0.05), while the P2 group could significantly increase the SOD level of the P0 group (p&lt;0.05). Data on 8-OHdG levels in the P1 and P2 groups decreased significantly when compared to the P0 group (p&lt;0.05). Conclusion: ALA supplementation at a dose of 50 µmol/L in goat oocyte In Vitro maturation media can increase SOD levels and reduce 8-OHdG levels.

The effects of alpha lipoic acid (ALA) supplementation on blood pressure in adults: a GRADE-assessed systematic review and dose-response meta-analysis of randomized controlled trials.

There have been various clinical studies on the effect of Alpha lipoic acid (ALA) supplementation on blood pressure (BP), but the findings from these are contradictory. Therefore, we performed a systematic review and dose-response meta-analysis to summarize the relation of ALA supplementation and systolic blood pressure (SBP) and diastolic blood pressure (DBP) in adults. A comprehensive search was conducted in Medline (PubMed), Embase, Scopus, and ProQuest up to July 2023. Randomized controlled trials (RCTs) evaluating the effect of ALA on SBP and DBP were included. The pooled weighted mean difference (WMD) of included trials was estimated using a random-effects model. The dose-dependent effect was also assessed. A total of 11 RCTs with the participation of 674 patients were included. The result of the meta-analysis indicated that using ALA supplementation significantly reduced the SBP (WMD = -5.46 mmHg; 95% CI: -9.27, -1.65; p < 0.001) and DBP (WMD = -3.36 mmHg, 95% CI: -4.99, -1.74; p < 0.001). The ALA administrations significantly reduced SBP and DBP at the dosages of <800 mg/day, when administered for ≤12 weeks. The present meta-analysis revealed that ALA supplementation could exert favorable effects on SBP and DBP. Further well-designed studies with larger samples are needed to ascertain the long-term effects of ALA on BP. https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=447658, identifier PROSPERO: CRD42023447658.

Recessive MECR pathogenic variants cause an LHON-like optic neuropathy

BackgroundLeber’s hereditary optic neuropathy (LHON) is a mitochondrial disorder characterised by complex I defect leading to sudden degeneration of retinal ganglion cells. Although typically associated with pathogenic variants in mitochondrial...

Effect of Alpha Lipoic Acid Supplementation on Oxidative Stress and Lipid Parameters in Women Diagnosed with Low-Grade Squamous Intraepithelial Lesions (LSILs): A Double-Blind, Randomized, Placebo-Controlled Trial.

Limited scientific evidence shows that alpha lipoic acid (ALA) can induce regression rates of low-grade squamous intraepithelial lesions (LSILs), but the mechanisms of these effects have not been elucidated. To gain a broader insight into its therapeutic potential and mechanisms of action, the effects of 3 months of supplementation with 600 mg of ALA on antioxidant and lipid status parameters in 100 patients with LSILs were investigated in a randomized, placebo-controlled study. The obtained results are discussed in terms of patients' initial metabolic status and diet quality (particularly nutritional intake of antioxidants). The obtained results showed that oxidative status biomarkers were not significantly affected by ALA supplementation. However, serum superoxide dismutase (SOD) activity was positively affected in the subgroup of patients with higher dietary antioxidant intake. Surprisingly, ALA supplementation resulted in a small but statistically significant increase in serum low density lipoprotein (LDL), and the observed effect was significantly affected by the initial lipid status of the participants. Larger studies are necessary to gain additional insights on the clinical significance of ALA as an antioxidant and hypolipemic agent and to optimize its potential application in LSIL treatment.

Neural Epidermal Growth Factor-Like 1–Positive Membranous Nephropathy With Rheumatoid Arthritis

Neural epidermal growth factor-like 1 (NELL1) is a recently described target antigen in membranous nephropathy (MN). NELL1-associated MN accounts for 1.5-8% of MN cases1-3 and was reportedly associated with malignant diseases,2 lipoic acid supplementation,4 and consumption of traditional indigenous medicine containing mercury.5 Therefore, NELL-1 may be an important antigen in “secondary” MN. Rheumatoid arthritis (RA) is an autoimmune inflammatory disease occasionally accompanied by MN. Complications of drugs, including gold salts, D-penicillamine, and bucillamine, are common causes of MN in RA patients.

DIGESTIBILITY, RUMEN FERMENTATION, RUMEN MICROBIOTA, AND LIPID PEROXIDATION IN SHEEP SUPPLEMENTED WITH LIPOIC ACID

Lipoic acid (LA) reduces oxidative stress and stimulates the immune system. However, data on its use in ruminants is limited. The objective of this study was to determine the effects of LA supplementation on free radical production, rumen variables, and feed digestibility in sheep fed high-grain diets. Nine rumen-cannulated Suffolk sheep were randomly assigned to three treatments: control (LA0 ), no LA inclusion; supplementation of 10 (LA10) mg LA kg-1 body weight (BW); and supplementation of 20 (LA20) mg LA kg-1 BW. In situ (ISDMD) and in vitro (IVDMD) degradation of dry matter and ruminal variables were evaluated. Total bacteria (TB), cellulolytic bacteria (CB), and protozoa (P) were also determined. Thiobarbituric acid reactive substances (TBARS) were evaluated in blood samples at the beginning and end of each experimental period. The ruminal variables and IVADDM were analyzed using a PROC GLM model with a repeated 3 × 3 latin square design, while means were compared using pairwise Tukey tests. LA supplementation did not affect (p 0.05) the ruminal variables under study. LA modified (p 0.05) ISDMD at 4 h in LA10, while no differences were found in terms of IVDMD among the treatments. The LA dose of 10 mg kg-1 BW increased CB (p 0.05) and decreased TB (p 0.05). TBARS differed (p 0.01) among the treatments and evaluation periods and were higher (p 0.05) 15 d after administration. In conclusion, LA supplementation in sheep had an antioxidant effect, reducing oxidative stress 15 d after administration, with slight differences in the ruminal variables evaluated.

The Effect of Alpha Lipoic Acid (ALA) Supplementation on the in Vitro Maturation Media of Goat Oocyte on Tumor Alpha Necrosis Factor (TNF-α) Expression and Malondialdehyde (MDA) Levels

This study aimed to determine the effect of Alpha Lipoic Acid (ALA) supplementation on in vitro maturation media of goat oocytes on Tumor Necrosis Factor Alpha (TNF-α) expression and Malondialdehyde (MDA) levels. This laboratory experimental study consisted of three treatment groups: control group (G0), 25 μmol/L ALA supplementation (G1), and 50 μmol/L ALA supplementation (G2). A total of 366 goats Cumulus Oocyte Complex (COCs) were collected, then selected into 216 COCs, and matured in vitro for 22 hours in a 5% CO2 incubator, 98% humidity, 38.50C temperature. After that, TNF-α expression was identified using Immunocytochemistry staining with the addition of TNF-α antibody and calculated using the Remmele Scale Index. Measurement of MDA levels using the ELISA method. The data obtained were analyzed using Kruskal-Wallis, One Way ANOVA, and Duncan’s in the SPSS 24 software program (p&lt;0.05). The expression value of TNF-α G0 was 0.75±1.39, G1 was 5.56±3.05, and G2 was 2.00±1.80. MDA levels of G0 were 26.52 ±2.92, G1 was 46.44 ±4.87, and G2 was 30.41±5.67. TNF-α expression data and MDA levels G0 and G2 didn’t show a significant difference, while G0 and G2 compared to G1 showed a significant difference (p&lt;0.05). ALA supplementation of 25 µmol/L increased TNF-α expression or MDA levels and 50 µmol/L on in vitro maturation media of goat oocytes could reduce TNF-α expression or MDA levels than 25 µmol/L.

Growth variables, feed efficacy, survival rate, and antioxidant capacity of European seabass (Dicentrarchus labrax L.) larvae treated with Coenzyme Q10 or lipoic acid

A 30-day feeding trial was performed to assess the potential of the dietary supplementation of Coenzyme Q10 (CoQ10) and lipoic acid on acclimatized European seabass larvae with a preliminary weight and length of 2.7 mg and 12.42 mm (25 dph = days post-hatching). Seven experimental groups were fed on the basal micro-diet (56 % crude protein and 13 % crude lipid) without any supplement in the control group or with the addition of CoQ10 at levels of 5, 10, and 15 mg/kg or α-lipoic acid at levels of 50, 100, and 150 mg/kg, respectively. Larvae fed on a diet enriched with CoQ10 at levels of 5 and 10 mg/kg showed the highest values for final weight, weight gain, specific growth rate (SGR), the protein efficiency ratio (PER), and the lowest value for feed conversion ratio (FCR) as well as no morphological or histological abnormalities. Also, the group fed a diet supplemented with CoQ10 at 5 mg/kg gave the highest values for final length and survival. The survival rate ranged from 54.59 % to 79.82 % and the lowest rate was in the group fed a diet enhanced with lipoic acid at 150 mg/kg. Meanwhile, the lowest records for final weight, weight gain, protein efficiency ratio, and the presence of morphological and histological abnormalities were in groups fed on the control diet and with high levels of lipoic acids (100 and 150 mg/kg). Moreover, all lipoic acid groups showed deleterious signs in the histological structure of the intestine and liver. However, significantly lower values of catalase (CAT) and glutathione peroxidase (GPx) were found in the fish group fed on the basal diet, while the peak values were in groups fed on diets fortified with CoQ10 at 5 and 10 mg/kg. In addition, larvae fed CoQ10 at levels of 5 or 10 mg/kg performed better in terms of CAT and GPx activities than that fed lipoic acid at levels of 100 or 150 mg/kg. Furthermore, the control group displayed lower levels of insulin-like growth factor 1 (IGF-1), CAT, and GPx -related gene expressions while considerable upregulations of IGF-1 and GPx were noted in larvae groups fed on diets improved with CoQ10 at levels of 5 or 10 mg/kg and lipoic acid at 50 mg/kg compared to the others. Also, upregulations in CAT were found with CoQ10 at levels of 5 or 10 mg/kg compared to their counterparts in the other groups. In conclusion, dietary CoQ10 at 5 or 10 mg/kg improves the performance and well-being of European seabass.

Effects of alpha lipoic acid supplementation on serum lipid profile in patients with metabolic syndrome: A randomized, double-blind, placebo-controlled clinical trial.

Alpha lipoic acid (ALA) is considered a strong antioxidant with anti-inflammatory properties. Moreover, a number of previous studies have shown its lipid-lowering properties. Therefore, we designed this study to investigate the effects of ALA on lipid profile in patients with metabolic syndrome (MetS), which can lead to an increased risk of cardiovascular disease (CVD) and premature mortality. A total 46 patients with MetS were randomly divided into two groups. They received either 600 mg ALA (n = 23) or 600 mg placebo (n = 23) for 12 weeks. The body weight, height, body mass index (BMI), waist circumference (WC), fasting blood sugar (FBS), hemoglobin A1C (HbA1c), and blood pressure (BP) were assessed at baseline of the study. Physical activity level and dietary intake were assessed at baseline and end of the study. Serum lipid profile including triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and total cholesterol (TC) were measured before and after 12 weeks of intervention. Baseline characteristics were similar in the ALA and placebo groups (P > 0.05). However, there were statistically significant differences in plasma levels of TG (-36.82 ± 42.48 versus 6.15 ± 25.04 mg/dl, P = 0.001) and TC (-8.91 ± 20.65 versus 10.84 ± 22.97 mg/dl, P = 0.01) after 12 weeks between the ALA group and the placebo group. Yet, there were no statistically significant differences in plasma levels of HDL-C and LDL-C after 12 weeks between the ALA group and the placebo group. The results suggest that daily supplementation of 600 mg ALA for 12 weeks may improve the lipid profile in patients with MetS.

Oxidative stress and changes in liver sialoglycoconjugate metabolic parameters in rats with alloxanic diabetes mellitus

BACKGROUND: Oxidative stress may be one of the mechanisms for the development of complications in DM and many forms of CKD. However, the influence of this factor on the metabolism of sialoglycoconjugates, which actively participates in the regulatory processes of the body, is unknown.AIM: comparative study of the effect of lipoic acid on the parameters of liver sialoglycoconjugate metabolism in rats with alloxan diabetes mellitus.MATERIALS AND METHODS: Studies were conducted on white male rats weighing 180–220 grams. The animals were divided into three groups: in the animals of the first and second groups, alloxan diabetes mellitus (DM) was caused by a single subcutaneous injection of alloxan tetrahydrate (AT). Animals of the second group received lipoic acid intramuscularly; the third group consisted of intact rats. On 5, 10, 20, 30 and 40 days after the injection of AT, a comprehensive examination of the animal’s condition was performed: 1) determination of the level of glycemia; 2) assessment of the degree of development of oxidative stress by the content of TBK-active products in the liver; 3) study of the dynamics of the exchange of sialoglycoconjugates in the liver (free, oligo-and protein-bound sialic acids, sialidase activity).RESULTS: The study was conducted on 106 rats, each experimental group had 48 animals, control — 10. It was found that the administration of α-lipoic acid to rats with alloxan diabetes leads to a decrease in the level of glycemia. The introduction of lipoic acid in experimental animals did not reduce the sialidase activity and the content of all sialic acid fractions in the liver, although it reduced the degree of oxidative stress in the body.CONCLUSION: Supplementation of lipoic acid in experimental animals did not significantly decrease sialidase activity and content of the sialic acid fractions under study in the liver, although it did reduce the degree of oxidative stress development in the organism. The increased rate of sialic acid metabolism in the liver of alloxan-diabetic rats may indicate a restructuring of hepatocyte metabolism to adapt the whole organism to prolonged hyperglycemia under insulin deficiency conditions.

Combination of alpha lipoic acid and metformin supplement improve assisted reproductive technologies outcomes in polycystic ovary syndrome patients.

We aimed to investigating the effects of metformin (MET) in combination with alpha lipoic acid (ALA) on hormonal and biochemical parameters, in polycystic ovary syndrome (PCOS) women undergoing intracytoplasmic sperm injection (ICSI). This experimental pilot study with a randomized design was carried out on 40 PCOS women in two groups: (1) MET group, administered 1,500 mg/day MET, and (2) MET (1,500 mg/day)+ALA (1,800 mg/day) group. Drugs were administered from the third day of the previous cycle until the day of oocyte aspiration (six weeks of treatment in total). MET+ALA significantly increased the number of maturated oocytes and the rate of fertilization when compared to the MET group. Combination MET+ALA could increase significantly the number of oocytes retrieval and the number of good-quality embryos. Also, the malondialdehyde (MDA) level decreased significantly in the MET+ALA group and the total antioxidant capacity (TAC) level increased significantly in the MET+ALA group compared to the MET group. Also, fasting blood sugar (FBS), insulin, luteinizing hormone (LH), and LH/follicle stimulating hormone (FSH) levels were significantly lower in the MET+ALA group. The pregnancy outcomes showed no significant difference in the rates of biochemical pregnancy, clinical pregnancy, miscarriage, and live births between the control and study groups. The combination of MET+ALA treatment could moderate the complications of PCOS and subsequently improve oocyte and embryo quality.

Dysfunctional Mitochondria and Hemolysis are Linked by Impaired Maturation of Reticulocytes: Possible Role in Pulmonary Hypertension

IntroductionWe previously demonstrated that significantly elevated levels of circulating free heme (CFH) is associated with preclinical (Sugen/Hypoxia in rats) pulmonary hypertension (PH) and clinical pulmonary arterial hypertension (PAH). However, the pathogenic mechanisms of free heme release in PAH patients and animal models in the absence of hemolytic disease are yet to be elucidated.HypothesisThe mitochondria play a crucial role in reticulocyte maturation (precursors to red blood cells). Our hypothesis tests if mitochondrial dysfunction (MD) impaired reticulocyte maturation increases its fragility and causes rupture, elevating CFH levels that promote PAH.MethodsRecently reported genetic PH rat models carrying the NFU1G206C mutation spontaneously develop PH with severe MD. Erythropoiesis activation, reticulocyte counts, and CFH levels were monitored in this model. ChemiDoc imaging system was used to visualize FITC‐dextran extravasation in fresh transversely cut pulmonary slices 24 hours after FITC‐dextran injection (60 mg/kg. i.v.). Changes in right ventricle (RV) hemodynamics were used to determine the level of disease severity. Pulmonary artery smooth muscle cells (PASMCs) isolated from wild‐type (WT) and NFU1G206C rats were used to evaluate effects of free heme in vitro. Matrigel assay was used to evaluate the tube formation potential of endothelial cells (EC’s).ResultsThe NFU1G206C rats showed significantly higher erythropoietin levels and immature reticulocyte counts compared to WTs. Correspondingly, significantly elevated plasma free heme and extravasation of FITC‐dextran into lung parenchyma were observed, indicating pulmonary endothelial barrier dysfunction, previously demonstrated as an essential contributor to PH pathobiology. Notably, treatment of human pulmonary artery EC’s with 50µM heme completely abolished EC tube formation, indicating that CFH could trigger a cellular environment leading to PH. Additionally, exposing isolated PASMC from NFU1G206C to 50µM heme increased the proliferation rate by ~1.5 and ~2.9 folds compared to untreated NFU1G206C or WT PASMC. Chronic lipoic acid (LA) supplementation to restore mitochondrial function (1.7mM orally), normalized total/immature reticulocyte counts in NFU1G206C rats (WT/NFU1G206C/NFU1G206C+LA for total and immature reticulocyte, p&lt;0.002 and p&lt;0.001) and fully reversed the PAH phenotype. Alternatively, the RV systolic pressure of NFU1G206C rats was significantly (p&lt;0.0001) attenuated by blocking the heme transporter (HCP1) with sulfasalazine (SL, 20mg/ml/kg, i.p.).ConclusionWe show that mitochondrial dysfunction impaired reticulocyte maturation promotes hemolysis resulting in increased CFH. Elevated CFH can trigger pathogenic pathways leading to PH/PAH via EC barrier dysfunction and increased PASMC proliferation. Treatment approaches that improve mitochondrial metabolism (LA) or inhibit free heme entrance to the cell (SL) abrogate the PH phenotype, highlighting the critical role of free heme‐induced signaling in disease pathobiology.

NLRP-3 Expression in Pancreatic Tissue Following Moderate and High Intensity Interval Training with Liposomal Alpha-Lipoic Acid Supplement in Diabetic Rats

Introduction: Activation of NLRP-3 Inflammasome is considered an indicator of chronic inflammation in type 2 diabetes. Regular exercise training along with antioxidants supplements can control inflammation. The aim of the present study was to investigate the effect of training with different intensity and alpha lipoic acid supplement on pancreatic NLRP-3 expression in diabetic rats.&#x0D; Methods: In this experimental study, 35 Wistar rats were randomly divided into seven groups: control, diabetic, diabetic+ supplement (S), diabetic+ high intensity training (HIT), diabetic+ moderate intensity training (MIT), diabetic+ high intensity training + supplementation (HIT+S), diabetic+ moderate intensity training + supplementation (MIT+S). The HIT and MIT protocols were performed five days a week for six weeks. HIIT included 10 bouts of four minutes running (at 85–90% of VO2max) and MIT, 13 bouts of four minutes running (at 65–70% of VO2max). Alpha lipoic acid was administered orally at a dose of 20 mg/kg was given to rats once a day by gavage. Blood and tissue sample was taken 24 h after last exercise session. Real-time PCR method for the relative expression of NLRP-3 gene expression was used.&#x0D; Results: Expression of LRP-3 gene in pancreatic tissue was increased significantly in the diabetic group compared to control group (p=0.0001). In addition, S (P = 0.021), MIT (P = 0.009), HIT (P = 0.001), MIT+S (P = 0.003) and HIT+S (P = 0.0001), significantly reduced the NLRP-3 levels in pancreatic tissue compared to the diabetic group.&#x0D; Conclusion: Type 2 diabetes is associated with increased mRNA NLRP-3 in pancreatic tissue. MIT and HIT plus alpha lipoic acid can be considered as an effective intervention in decreasing pancreatic mRNA NLRP-3 in diabetic rats.