bluuebunny/crossref_metadata_2025_split huggingface dataset:
Avocado Oil Improves Renal Vasorelaxation in Hypertensive Rats; Probable Role of Decreased Mitochondrial ROS Generation and Enhanced Antioxidant Capacity
Authors: de la Paz Jose Lucio Hernandez , Marquez‐Ramirez Cristian , Aguilar‐Toral Roxana , Moeno‐Jimenez Mario , Raya‐‐Farias Andres , Salgado‐Garciglia Rafael , Godinez‐Hernandez Daniel , Saavedra‐Molina Alfredo , Cortes‐Rojo Christian 
Published: November 2023

Kidney disease is a major complication of hypertension. Both mitochondrial dysfunction and increased ROS generation are involved in the exacerbated vasoconstriction observed in rodent models of hypertension in response to the increased activity of angiotensin II. Thus, the prevention of mitochondrial dysfunction along with decreased ROS generation or increased activity of antioxidant systems may improve the response to vasorelaxant and/or vasoconstrictor agents, leading to attenuation of hypertensive kidney damage. An increasing body of evidence indicates that avocado oil (AO) intake improves the mitochondrial function and its redox state in kidney, liver and brain of diabetic rats, which has been attributed to the wide array of lipophilic antioxidants contained in AO. We have observed that avocado oil consumption protects from kidney mitochondrial dysfunction elicited by L‐NAME‐induced hypertension. However, it is unknown whether this might lead to attenuation of oxidative stress because decreased ROS generation and improvement of kidney vasodilator responses. Thus, we aimed to test the effect of AO intake in rats treated with L‐NAME on ROS generation, GSH/GSSG ratio (i.e a marker of oxidative stress) in kidney mitochondria and vasodilator responses to a cholinergic agonist in isolated perfused kidney. ROS generation stimulated by complex I substrates increased twice in L‐NAME treated rats while the addition of antimycin A, a complex III inhibitor, exacerbated this effect, suggesting a role for complex III in ROS overproduction. Despite this, L‐NAME did not modified the GSH/GSSG ratio. L‐NAME rats also exhibited a decline in kidney vasorelaxation induced by carbachol. AO supplementation by 90 days (1mL/250g body weight) inhibited ROS generation by below of the values observed in control rats, increased twice the GSH/GSSG ratio and normalized the vasorelaxation stimulated by carbachol. These results suggest that AO improves renal vasorelaxation in association with a decrease in mitochondrial ROS generation and enhancement of antioxidant capacity.Support or Funding InformationSupported by Programa de Investigación 2016 de la Coordinación de la Investigación Científica de la UMSNH (CIC‐UMSNH) (CCR).
Effects of uric acid and melatonin exposure on mitochondrial complex‐I respiration, triglyceride accumulation and aconitase activity in skeletal muscle cells
Authors: Maarman Gerald Jerome , Andrew Brittany Morgan , Blackhurst Dee , Ojuka Edward 
Published: November 2023

BackgroundHyperuricemia is associated with gout, hepatic steatosis and type 2 diabetes. It induces oxidative stress, lipogenesis and mitochondrial dysfunction in the liver. However, the skeletal muscle is the greatest surface area exposed to hyperuricemia and yet no studies have investigated its effects on skeletal muscle.AimsTo establish whether hyperuricemia modulates mitochondrial function, oxidative stress and triglyceride accumulation in myotubes and whether antioxidant treatment with melatonin can counteract these effects.MethodsDifferentiated C2C12 myotubes were exposed to uric acid (750μM, 72 hrs.) or uric acid + melatonin (10nM melatonin, 72 hrs). Mitochondrial function was assessed (high‐resolution respirometry), spectrophotometry was used to assess oxidative damage to aconitase and triglyceride content. All values were compared to respective control groups (without uric acid and without melatonin).ResultsUric acid (1) reduced OXPHOS (60%) in the presence of pyruvate, glutamate and malate, (2) reduced aconitase activity by 37% and (3) increased triglyceride accumulation (52%) in C2C12 myotubes. Melatonin treatment restored OXPHOS (40%) and reduced triglyceride content (47%).ConclusionHyperuricemia dysregulates complex‐1 mediated mitochondrial respiration, induces damage to aconitase and triglyceride accumulation. Melatonin restored complex‐1 mediated mitochondrial function and normalized triglyceride accumulation. Melatonin could therefore be considered a therapy against hyperuricemia.Support or Funding InformationNational Research Foundation (South Africa) and the University of Cape Town.
Insulin‐dependent glucose uptake is regulated by mitochondrial Ca2+ handling in skeletal muscle fibers
Authors: Contreras‐Ferrat Ariel Eduardo , Díaz‐Vegas Alexis , Campos Cristian , Utreras Yildy , Valladares Denisse , Rosales Giovanni , Llanos Paola , Arias Manuel , Jaimovich Enrique 
Published: November 2023

IntroductionThe mitochondria functions rapidly to respond to high energy food supply but the role of mitochondrial Ca2+ levels in the context of insulin signaling has not been explored.Material and MethodsMice were fed with normal chow diet (NCD) or high fat diet (HFD) for 1 (St‐HFD) or 8 (Lt‐HFD) weeks, (short‐ and long‐term) respectively. Changes in calcium levels, mitochondria membrane potential and glucose uptake were evaluated in living fibers from Flexor digitorum brevis muscle using fluorescent dyes.ResultsInsulin induced an increase in cytoplasmic and mitochondrial Ca2+ in adult fibers that was significantly smaller in fibers from short‐term HFD fed mice and completely inhibited in Lt‐HFD. In fibers from NCD fed mice, insulin‐dependent mitochondrial Ca2+ uptake was blunted by both inositol‐1,4,5‐trisphosphate receptor inhibition and knockdown. The mitochondrial potential was larger in fibers from short‐term HFD fed mice v/s NCD derived fibers and the recruited of active mitochondria was increased. The glucose analogue (2‐NBDG) uptake and the redistribution of GLUT4myc‐eGFP chimera induced by insulin were decreased in the absence of mitochondrial Ca2+ uptake in conditions of type 1inositol 1,4,5‐trisphosphate receptor knockdown.DiscussionThese effects suggest a role for mitochondrial Ca2+ uptake in a retrograde regulation of insulin signaling by mitochondria.Support or Funding InformationFinanced by FONDECYT 11130267, 1151293, PIA‐ACT1111
Caveolin‐1 Regulates Mitochondrial Dynamics by Suppressing Mfn‐2 and Drp‐1 recruitment
Authors: Jiang Ying , Toth Peter , Oliveira Suellen , Liu Yiyao , Hart Peter , Rehman Jalees , Bonini Marcelo , Minshall Richard D 
Published: November 2023

Oxygen disposition by mitochondria determines whether electrons from NADH are used for energy (ATP) or H2O2 production. Both ATP and H2O2 have widely recognized (though different) roles in cell signaling. By switching the electron flow in order to produce either metabolite in different proportions mitochondria broadly affect the cellular metabolism, cell cycle and phenotypic fate decisions. The balance between H2O2 and ATP is determined in large part by the reorganization of the mitochondrial network with fission favoring H2O2 and mitochondrial fusion favoring ATP. Fusion and fission are regulated by mitofusin 2 (Mfn‐2) and dynamin‐related protein 1 (Drp‐1), respectively. Here, we report our recent findings that caveolin‐1 (Cav‐1), a protein normally associated with signaling on the plasma membrane regulates mitochondrial fission/fusion dynamics, oxygen consumption, and H2O2 production in MDA‐MB‐231 breast cancer cells expressing relatively high levels of Cav‐1. In 231 cells, Cav‐1 siRNA simultaneously increased both Mfn‐2 and Drp‐1 expression in the mitochondrial fraction. However, less fragmented mitochondria in Cav‐1 knockdown cells suggested that enhanced fusion via Mfn‐2 overcame Drp‐1 mediated fission. Furthermore, co‐IP and fluorescence resonance energy transfer (FRET) studies showed that Cav‐1 directly interacts with both Mfn‐2 and Drp‐1 in plasma membrane fractions. Also, fluorescence recovery after photobleaching (FRAP) of mitochondrial matrix targeted DS‐Red increased after Cav‐1 knockdown indicating that the mitochondrial network may be more plastic in absence of Cav‐1 due to increase in mitochondria‐associated Mfn‐2 and Drp‐1. We observed reduced Oxygen consumption and H2O2 production in cells treated with Cav‐1 siRNA. ATP biosensor showed higher ATP/ADP ratio after 2‐deoxy‐glucose (2‐DG) treatment in Cav‐1 knockdown cells demonstrating that mitochondrial ATP generation was blocked by Cav‐1. These results suggest that Cav‐1 plays an important role in the regulation of mitochondrial fission/fusion dynamics and function by binding to Mfn‐2 and Drp‐1 at the plasma membrane, thus limiting their translocation to mitochondria where they are known to regulate fission/fusion dynamics.Support or Funding InformationFinancial support provided by the National Natural Science Foundation of China (Nos.11272083, 31470906) (YJ, YL) and NIH P01 HL60678 (RM, MGB).
Combined BH3 and Metabolic Profiling as a Method to Define Therapeutic Response and Resistance in Grade IV Astrocytomas
Authors: Silva Monica Rodriguez , Gonzalez‐Arias Sergio , Chambers Jeremy W. 
Published: November 2023

Background and SignificanceGrade IV astrocytomas, formerly known as glioblastoma multiforme (GBM), are the most common primary brain tumors and have the highest mortality. The therapeutic standard for managing this malignancy remains a combination of surgery, chemotherapy, and radiotherapy; however, there is no cure, nor has there been any significant advancement in the clinical approach to GBM since this protocol was established in 2005. This study aims to better understand the molecular and metabolic characteristics of GBM‐derived cell lines to better define treatment groups and potentially identify new avenues for therapy. This study utilized continuous, commercially‐available GBM cell lines U87, U118, A172, and H4, and GBM cell lines from the NCI60 bank (SF268, SF295, SF539, SNB19, SNB75 and U251) and examined the concentrations of Bcl‐2 family proteins on mitochondria and metabolic activity for each of the cell lines. The measures were correlated to IC50 values for temozolomide (TMZ).ResultsWestern blot analysis of pro‐survival and pro‐apoptotic Bcl‐2 proteins revealed that U118, U87 and SNB19 expressed high levels of Bcl‐2, while A172 had increased Bcl‐xL expression. Interestingly, Bcl‐2 and Bcl‐xL were not detected in H4 cells. Incidentally, pro‐apoptotic BH3‐only protein (Bid, Bim, Puma, etc.) levels were increased in H4 and A172 when compared to the U118 and U87 cell lines. Metabolic analysis of the cell lines revealed that U118 and SF295 cells were glutaminolytic, while U87, A172, and H4 were classified as glycolytic. We assessed cellular viability in the presence of increasing doses of TMZ for each cell line. We found that U118 and SNB19 cells were the most resistant followed by U87, SF295, U251, A172, SF539, SF268, SNB75 and H4 respectively. Interestingly, MGMT levels did not influence chemo‐responsiveness in these cell lines.ConclusionWe found that Bcl‐2 protein profiling was a useful means to determine therapeutic response and resistance. This was further enhanced by metabolic stratification, wherein glycolytic cells were shown to be more sensitive TMZ than glutaminolytic cells that may possess more stable mitochondria. In the immediate future, we will increase the cellular profiling to include mitochondrial dynamics and quality control as well. Using these approaches, we will produce a method to define GBM responses and outcomes based on their mitochondrial and metabolic context.Support or Funding InformationM.R.S. was supported by NIH/NIGMS R25 GM061347. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Effects of Turnera diffusa Will. over blood glucose and oxidative stress in kidney mitochondria diabetic‐STZ rats
Authors: Esquivel‐Gutiérrez Edgar R. , Saavedra‐Molina Alfredo , Alcaraz‐Meléndez Lilia 
Published: November 2023

Turnera diffusa Will (damiana) is used in Mexican traditional medicine for treatment of various disorders including diabetes mellitus (DM). Not with standing, there is not a study that proves this effect on DM‐STZ for a long period. Also, there are not reports about the effects of damiana over the oxidative stress; a marker of damage in DM, in kidney mitochondria. By this reason, we set a main aim in this work for evaluate the antioxidant ability of this important medicinal plant in a worldwide pathology DM. To achieve this purpose we use STZ‐DM rats (65mg/kg body weight). We administered aqueous extract (150mg/kg body weight) from aerial parts of damiana. The blood glucose and animal weight was recorded every five days during 3 and 5 weeks of treatment. At the end of the treatments rats were sacrificed and kidney removed for mitochondria isolation by differential centrifugation. Lipid peroxidation, nitric oxide (NO) and nitrosylation profile in mitochondrial proteins were evaluated. Our results shown that T. diffusa in this investigation has no capacity to reduce the blood glucose at any time after 3 or 5 weeks of treatment, but induce to DM‐STZ animals to maintain the body weight, an important sign in DM. Our investigation also reveals the protection versus lipid peroxidation at the end of 5 weeks of treatment in control and DM groups (from 7.60 ± 0.38 to 6.48 ± 0.87 and 7.802 ± 0.70 to 3.358 ± 0.04 nmoles/mg prot, respectively), decreases the NO levels in both 3 and 5 weeks of treatment (from 0.703 ± 0.03 to 0.248 ± 0.05 and 0.754 ± 0.07 to 0.433 ± 0.02 μMole/mg prot, respectively). Nonetheless, nitrosylation of mitochondrial proteins remains unchanged compared with the control groups in all treatments. Finally, either control groups with or without treatments do not modifies the parameters measured in any case. In conclusion, aqueous extract from aerial parts of damiana has the capacity to mitigate the oxidative stress present in rat kidney mitochondria in DM‐STZ rats and the protector effects in this pathology is due to antioxidant properties more than lower the blood glucose.Support or Funding InformationEREG is Postdoctoral Fellow CONACYT.
Hypoxic Adaptation by a Unique Mechanism of Reprogramming Mitochondrial Metabolism
Authors: Tessman Robert T , Chavan Hementkumar , Du Gouqing , Sun Daxi , Schuetz John , Krishnamurthy Partha 
Published: November 2023

Hypoxia plays critical roles in the pathobiology of heart disease, cancer, stroke, and chronic lung disease, which are responsible for 60% of deaths in the United States. Evidence suggests that hypoxic survival often requires reprogramming of mitochondrial basal metabolism. However, our understanding of the fundamental mechanisms that regulate mitochondrial metabolism are still incomplete. During our studies evaluating the physiological significance of the mitochondrial transporter ABCB6, we uncovered a novel pathway in which loss of ABCB6 expression shifts the balance between mitochondrial respiration and glycolysis because ABCB6 expression decreased mitochondrial respiratory rate and increased glycolysis rate. More importantly, we found that the major transcriptional sensor of oxygen hypoxia‐inducible factor (HIF) was involved in the activation of Abcb6 expression under hypoxic conditions. Further, ABCB6 promoter contains hypoxia response (HRE) elements. These HREs are functional because the promoter is activated by the hypoxia mimetic, desferoxamine as well as directly by co‐transfected HIF1‐alpha. Moreover, in cells with a defective HIF, ABCB6 expression is not upregulated by hypoxia. Finally, ectopic overexpression of ABCB6 reveals that ABCB6 protects cells from the cytotoxicity induced by hypoxia. These studies reveal that ABCB6, a mitochondrial ABC transporter, is regulated by hypoxia and the major hypoxia transcription factor HIF1‐alpha. This upregulation by hypoxia is compatible with ABCB6 overexpression providing a survival advantage under hypoxic conditions.Support or Funding InformationP20RR021940‐7T32ES007079
Effect of aqueous leaf extract of Pennisetum purpurem in alloxan‐induced diabetic wistar rats
Authors: Omeodu Stephen Ike , Onyegeme‐Okerenta Blessing Minaopunye 
Published: November 2023

Some biochemical indices (aspartate aminotransferase [AST], alanine aminotransferase [ALT], total protein, amylase and glucose) were evaluated in alloxan‐induced diabetic wistar rats treated with aqueous leaf extract of Pennisetum purpurem. Sixteen wistar albino rats were grouped into four. Group 1 served as the control while Groups 2 – 4 were administered with 120 mg/kg body weight alloxan – a toxic glucose analogue that resulted in a hyperglycemic state. Group 2 did not receive any treatment and served as the negative control. Groups 3 and 4 were treated with 1200 and 1500 mg/kg body weight aqueous extract of P. purpurem respectively for seven days and thereafter, the rats were sacrificed and the effects of the plant extract on the liver investigated. Results showed that there was significant reduction (p<0.05) in AST, ALT and glucose levels when groups treated with 1200 and 1500 mg/kg body weight aqueous extract of P. purpurem were compared with the control group. On the other hand, there was no significant reduction in amylase and Total protein concentration (p>0.05) when the group treated with 1200 mg/kg body weight extract of P. purpurem was compared with the control group. However, there was significant reduction (p<0.05) in amylase and Total protein concentration when the group treated with 1500 mg/kg body weight aqueous extract of P. purpurem was compared with the control group. This study shows that the aqueous extract of P. purpurem caused a significant reduction in serum glucose, AST, ALT, amylase and total protein in alloxan‐induced diabetic rats.Support or Funding InformationResearch was funded by the authors.
Mapping Epitopes of Pan‐Ebolavirus Antibodies From Human Survivors
Authors: David Joshua A , Murin Charles D , Flyak Andrew , Turner Hannah L , Fusco Marnie L , Saphire Erica Ollmann , Crowe James E , Ward Andrew B 
Published: November 2023

Members of the Ebolavirus genus including Zaire ebolavirus (EBOV), Sudan ebolavirus (SUDV) and Budibugyo ebolavirus (BDBV) cause viral hemorrhagic fever and have high case fatality rates. The current outbreak in Western Africa is the largest on record and has infected over 28,000 individuals, yet no currently approved vaccines or therapeutics exist. Previous reports have revealed that ZMapp™, a cocktail of three antibodies that target the glycoprotein (GP) of EBOV, can revert an active infection in nonhuman primates. A group of recently identified antibodies from human survivors of BDBV and EBOV infections were shown to neutralize their respective virus. Some of the BDBV antibodies were also shown to be cross‐reactive against SUDV and EBOV; however, the basis of cross‐reactivity remains unknown. Here we report single‐particle negative stain EM reconstructions of each antibody in complex with GP. The cross‐reactive antibodies have overlapping epitopes and bind at the top of GP in a subdomain termed the glycan cap which contains multiple N‐linked glycosylation sites. Interestingly, many BDBV‐specific and EBOV‐specific antibodies bind in very close proximity. Therefore, the glycan cap contains structural motifs that influence species cross‐reactivity and neutralization potential of targeting antibodies. Higher resolution structures of these antibodies will be valuable for understanding the details of this important site of vulnerability.Support or Funding InformationThis work was supported by NIAID Center for Excellence in Translational Research Grant U19AI109762 (to E.O.S., and A.B.W.). J.A.D. was supported by The Scripps Research Institute Summer Undergraduate Research Fellowship Program.
The Polyamine Pathway of Leishmania donovani as a Potential Therapeutic Target
Authors: Roberts Sigrid , Paradis Dustin , Perdeh Jasmine , Harrelson John , Jan Boitz , Yates Phil , Ullman Buddy 
Published: November 2023

Parasites of the genus Leishmania cause a variety of diseases, including fatal visceralizing infections, and affect an estimated 12 million people worldwide. Due to the absence of effective vaccines, therapeutic treatment has offered the only avenue of defense. Unfortunately, the current arsenal of drugs used to treat this neglected disease is far from ideal and the need for new therapeutic targets and a better understanding of host‐parasite interactions is urgent. Polyamines are ubiquitous, essential cations that are especially important for rapidly growing cells and the synthesis pathway for polyamines has been validated as a potential target in the related parasite, Trypanosoma brucei. In Leishmania, the polyamine biosynthetic pathway consists of four enzymes: arginase (ARG), ornithine decarboxylase (ODC), spermidine synthase (SPD), and S‐adenosylmethionine decarboxylase (ADOMETDC). These enzymes sequentially generate ornithine, putrescine and spermidine. We have generated a complete set of gene deletion mutants in Leishmania donovani (LdΔarg, LdΔodc, LdΔspd, and LdΔadometdc), in order to evaluate the polyamine biosynthetic enzymes as therapeutic targets. In vitro studies showed that the gene deletion mutants depend on the provision of downstream metabolites to survive. An evaluation of cell growth between the different cell lines uncovered that the only vital role of ornithine is as precursor for polyamine synthesis. However, putrescine, which has previously been postulated to be merely a substrate for spermidine formation, has additional essential functions and may even be more critical for cellular proliferation than spermidine. In vivo infectivity studies revealed that Ldodc exhibits profoundly reduced infectivity compared to wild type parasites, while Ldspd and Ldadometdc show a less pronounced, albeit significant, reductions in infectivity. In contrast, the Ldarg gene deletion has no effect on virulence. The observed discrepancies in infectivity phenotypes suggest a model in which the polyamine precursor ornithine is readily salvaged by intracellular parasites, whereas the polyamines putrescine and spermidine are severely limited. Our long‐term goal is to exploit the polyamine pathway for therapeutic development against leishmaniasis.Support or Funding InformationSchool of Pharmacy Research Incentive GrantNIH R01 AI041622