Browsing by Subject "Carbon Monoxide"

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    Carbon Monoxide and Exercise Prevents Diet-Induced Obesity and Metabolic Dysregulation Without Affecting Bone.
    (Obesity (Silver Spring, Md.), 2020-05) Gasier, Heath G; Yu, Tianzheng; Swift, Joshua M; Metzger, Corrine E; McNerny, Erin M; Swallow, Elizabeth A; Piantadosi, Claude A; Allen, Matthew R

    Objective

    Carbon monoxide (CO) may counteract obesity and metabolic dysfunction in rodents consuming high-fat diets, but the skeletal effects are not understood. This study investigated whether low-dose inhaled CO (250 ppm) with or without moderate intensity aerobic exercise (3 h/wk) would limit diet-induced obesity and metabolic dysregulation and preserve bone health.

    Methods

    Obesity-resistant (OR) rats served as controls, and obesity-prone (OP) rats were randomized to sedentary, sedentary plus CO, exercise, or CO plus exercise. For 10 weeks, OP rats consumed a high-fat, high-sucrose diet, whereas OR rats consumed a low-fat control diet. Measurements included indicators of obesity and metabolism, bone turnover markers, femoral geometry and microarchitecture, bone mechanical properties, and tibial morphometry.

    Results

    A high-fat, high-sucrose diet led to obesity, hyperinsulinemia, and hyperleptinemia, without impacting bone. CO alone led only to a modest reduction in weight gain. Exercise attenuated weight gain and improved the metabolic profile; however, bone fragility increased. Combined CO and exercise led to body mass reduction and a metabolic state similar to control OR rats and prevented the exercise-induced increase in bone fragility.

    Conclusions

    CO and aerobic exercise training prevent obesity and metabolic sequelae of nutrient excess while stabilizing bone physiology.
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    Characterization of Clostridium ljungdahlii OTA1: a non-autotrophic hyper ethanol-producing strain.
    (Applied microbiology and biotechnology, 2017-02) Whitham, Jason M; Schulte, Mark J; Bobay, Benjamin G; Bruno-Barcena, Jose M; Chinn, Mari S; Flickinger, Michael C; Pawlak, Joel J; Grunden, Amy M
    A Clostridium ljungdahlii lab-isolated spontaneous-mutant strain, OTA1, has been shown to produce twice as much ethanol as the C. ljungdahlii ATCC 55383 strain when cultured in a mixotrophic medium containing fructose and syngas. Whole-genome sequencing identified four unique single nucleotide polymorphisms (SNPs) in the C. ljungdahlii OTA1 genome. Among these, two SNPs were found in the gene coding for AcsA and HemL, enzymes involved in acetyl-CoA formation from CO/CO2. Homology models of the respective mutated enzymes revealed alterations in the size and hydrogen bonding of the amino acids in their active sites. Failed attempts to grow OTA1 autotrophically suggested that one or both of these mutated genes prevented acetyl-CoA synthesis from CO/CO2, demonstrating that its activity was required for autotrophic growth by C. ljungdahlii. An inoperable Wood-Ljungdahl pathway resulted in higher CO2 and ethanol yields and lower biomass and acetate yields compared to WT for multiple growth conditions including heterotrophic and mixotrophic conditions. The two other SNPs identified in the C. ljungdahlii OTA1 genome were in genes coding for transcriptional regulators (CLJU_c09320 and CLJU_c18110) and were found to be responsible for deregulated expression of co-localized arginine catabolism and 2-deoxy-D-ribose catabolism genes. Growth medium supplementation experiments suggested that increased arginine metabolism and 2-deoxy-D-ribose were likely to have minor effects on biomass and fermentation product yields. In addition, in silico flux balance analysis simulating mixotrophic and heterotrophic conditions showed no change in flux to ethanol when flux through HemL was changed whereas limited flux through AcsA increased the ethanol flux for both simulations. In characterizing the effects of the SNPs identified in the C. ljungdahlii OTA1 genome, a non-autotrophic hyper ethanol-producing strain of C. ljungdahlii was identified that has utility for further physiology and strain performance studies and as a biocatalyst for industrial applications.
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    Heme Oxygenase-1/Carbon Monoxide System and Embryonic Stem Cell Differentiation and Maturation into Cardiomyocytes.
    (Antioxid Redox Signal, 2016-03-01) Suliman, Hagir B; Zobi, Fabio; Piantadosi, Claude A
    AIMS: The differentiation of embryonic stem (ES) cells into energetically efficient cardiomyocytes contributes to functional cardiac repair and is envisioned to ameliorate progressive degenerative cardiac diseases. Advanced cell maturation strategies are therefore needed to create abundant mature cardiomyocytes. In this study, we tested whether the redox-sensitive heme oxygenase-1/carbon monoxide (HO-1/CO) system, operating through mitochondrial biogenesis, acts as a mechanism for ES cell differentiation and cardiomyocyte maturation. RESULTS: Manipulation of HO-1/CO to enhance mitochondrial biogenesis demonstrates a direct pathway to ES cell differentiation and maturation into beating cardiomyocytes that express adult structural markers. Targeted HO-1/CO interventions up- and downregulate specific cardiogenic transcription factors, transcription factor Gata4, homeobox protein Nkx-2.5, heart- and neural crest derivatives-expressed protein 1, and MEF2C. HO-1/CO overexpression increases cardiac gene expression for myosin regulatory light chain 2, atrial isoform, MLC2v, ANP, MHC-β, and sarcomere α-actinin and the major mitochondrial fusion regulators, mitofusin 2 and MICOS complex subunit Mic60. This promotes structural mitochondrial network expansion and maturation, thereby supporting energy provision for beating embryoid bodies. These effects are prevented by silencing HO-1 and by mitochondrial reactive oxygen species scavenging, while disruption of mitochondrial biogenesis and mitochondrial DNA depletion by loss of mitochondrial transcription factor A compromise infrastructure. This leads to failure of cardiomyocyte differentiation and maturation and contractile dysfunction. INNOVATION: The capacity to augment cardiomyogenesis via a defined mitochondrial pathway has unique therapeutic potential for targeting ES cell maturation in cardiac disease. CONCLUSION: Our findings establish the HO-1/CO system and redox regulation of mitochondrial biogenesis as essential factors in ES cell differentiation as well as in the subsequent maturation of these cells into functional cardiac cells.
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    Long-term dynamics of death rates of emphysema, asthma, and pneumonia and improving air quality.
    (Int J Chron Obstruct Pulmon Dis, 2014) Kravchenko, J; Akushevich, I; Abernathy, AP; Holman, S; Ross, WG; Lyerly, HK
    BACKGROUND: The respiratory tract is a major target of exposure to air pollutants, and respiratory diseases are associated with both short- and long-term exposures. We hypothesized that improved air quality in North Carolina was associated with reduced rates of death from respiratory diseases in local populations. MATERIALS AND METHODS: We analyzed the trends of emphysema, asthma, and pneumonia mortality and changes of the levels of ozone, sulfur dioxide (SO2), nitrogen dioxide (NO2), carbon monoxide (CO), and particulate matters (PM2.5 and PM10) using monthly data measurements from air-monitoring stations in North Carolina in 1993-2010. The log-linear model was used to evaluate associations between air-pollutant levels and age-adjusted death rates (per 100,000 of population) calculated for 5-year age-groups and for standard 2000 North Carolina population. The studied associations were adjusted by age group-specific smoking prevalence and seasonal fluctuations of disease-specific respiratory deaths. RESULTS: Decline in emphysema deaths was associated with decreasing levels of SO2 and CO in the air, decline in asthma deaths-with lower SO2, CO, and PM10 levels, and decline in pneumonia deaths-with lower levels of SO2. Sensitivity analyses were performed to study potential effects of the change from International Classification of Diseases (ICD)-9 to ICD-10 codes, the effects of air pollutants on mortality during summer and winter, the impact of approach when only the underlying causes of deaths were used, and when mortality and air-quality data were analyzed on the county level. In each case, the results of sensitivity analyses demonstrated stability. The importance of analysis of pneumonia as an underlying cause of death was also highlighted. CONCLUSION: Significant associations were observed between decreasing death rates of emphysema, asthma, and pneumonia and decreases in levels of ambient air pollutants in North Carolina.
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    Mindfulness training for smokers via web-based video instruction with phone support: a prospective observational study.
    (BMC complementary and alternative medicine, 2015-03-29) Davis, James M; Manley, Alison R; Goldberg, Simon B; Stankevitz, Kristin A; Smith, Stevens S
    BACKGROUND:Many smokers are unable to access effective behavioral smoking cessation therapies due to location, financial limitations, schedule, transportation issues or other reasons. We report results from a prospective observational study in which a promising novel behavioral intervention, Mindfulness Training for Smokers was provided via web-based video instruction with telephone-based counseling support. METHODS:Data were collected on 26 low socioeconomic status smokers. Participants were asked to watch eight video-based classes describing mindfulness skills and how to use these skills to overcome various core challenges in tobacco dependence. Participants received eight weekly phone calls from a smoking cessation coach who provided general support and answered questions about the videos. On the quit day, participants received two weeks of nicotine patches. RESULTS:Participants were a mean of 40.5 years of age, smoked 16.31 cigarettes per day for 21.88 years, with a mean of 6.81 prior failed quit attempts. Participants completed a mean of 5.55 of 8 online video classes with a mean of 23.33 minutes per login, completed a mean of 3.19 of 8 phone coach calls, and reported a mean meditation practice time of 12.17 minutes per day. Smoking abstinence was defined as self-reported abstinence on a smoking calendar with biochemical confirmation via carbon monoxide breath-test under 7 parts per million. Intent-to-treat analysis demonstrated 7-day point prevalence smoking abstinence at 4 and 6-months post-quit of 23.1% and 15.4% respectively. Participants showed a significant pre- to post-intervention increase in mindfulness as measured by the Five-Factor Mindfulness Questionnaire, and a significant pre- to post-intervention decrease in the Anxiety Sub-scale of the Depression Anxiety and Stress Scale. CONCLUSIONS:Results suggest that Mindfulness Training for Smokers can be provided via web-based video instruction with phone support and yield reasonable participant engagement on intervention practices and that intervention efficacy and mechanism of effect deserve further study. TRIAL REGISTRATION:ClinicalTrials.gov: NCT02164656 , Registration Date June 13, 2014.
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    Mitochondrial Quality Control as a Therapeutic Target.
    (Pharmacol Rev, 2016-01) Suliman, Hagir B; Piantadosi, Claude A
    In addition to oxidative phosphorylation (OXPHOS), mitochondria perform other functions such as heme biosynthesis and oxygen sensing and mediate calcium homeostasis, cell growth, and cell death. They participate in cell communication and regulation of inflammation and are important considerations in aging, drug toxicity, and pathogenesis. The cell's capacity to maintain its mitochondria involves intramitochondrial processes, such as heme and protein turnover, and those involving entire organelles, such as fusion, fission, selective mitochondrial macroautophagy (mitophagy), and mitochondrial biogenesis. The integration of these processes exemplifies mitochondrial quality control (QC), which is also important in cellular disorders ranging from primary mitochondrial genetic diseases to those that involve mitochondria secondarily, such as neurodegenerative, cardiovascular, inflammatory, and metabolic syndromes. Consequently, mitochondrial biology represents a potentially useful, but relatively unexploited area of therapeutic innovation. In patients with genetic OXPHOS disorders, the largest group of inborn errors of metabolism, effective therapies, apart from symptomatic and nutritional measures, are largely lacking. Moreover, the genetic and biochemical heterogeneity of these states is remarkably similar to those of certain acquired diseases characterized by metabolic and oxidative stress and displaying wide variability. This biologic variability reflects cell-specific and repair processes that complicate rational pharmacological approaches to both primary and secondary mitochondrial disorders. However, emerging concepts of mitochondrial turnover and dynamics along with new mitochondrial disease models are providing opportunities to develop and evaluate mitochondrial QC-based therapies. The goals of such therapies extend beyond amelioration of energy insufficiency and tissue loss and entail cell repair, cell replacement, and the prevention of fibrosis. This review summarizes current concepts of mitochondria as disease elements and outlines novel strategies to address mitochondrial dysfunction through the stimulation of mitochondrial biogenesis and quality control.
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    Research report: Charcoal type used for hookah smoking influences CO production.
    (Undersea & hyperbaric medicine : journal of the Undersea and Hyperbaric Medical Society, Inc, 2015-07) Medford, Marlon A; Gasier, Heath G; Hexdall, Eric; Moffat, Andrew D; Freiberger, John J; Moon, Richard E
    A hookah smoker who was treated for severe carbon monoxide poisoning with hyperbaric oxygen reported using a different type of charcoal prior to hospital admission, i.e., quick-light charcoal. This finding led to a study aimed at determining whether CO production differs between charcoals commonly used for hookah smoking, natural and quick-light. Our hypothesis was that quick-light charcoal produces significantly more CO than natural charcoal. A medium-sized hookah, activated charcoal filter, calibrated syringe, CO gas analyzer and infrared thermometer were assembled in series. A single 9-10 g briquette of either natural or quick-light charcoal was placed atop the hookah bowl and ignited. CO output (ppm) and temperature (degrees C) were measured in three-minute intervals over 90 minutes. The mean CO levels produced by quick-light charcoal over 90 minutes was significantly higher (3728 ± 2028) compared to natural charcoal (1730 ± 501 ppm, p = 0.016). However, the temperature was significantly greater when burning natural charcoal (292 ± 87) compared to quick-light charcoal (247 ± 92 degrees C, p = 0.013). The high levels of CO produced when using quick-light charcoals may be contributing to the increase in reported hospital admissions for severe CO poisoning.
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    Skeletal muscle mitochondrial fragmentation and impaired bioenergetics from nutrient overload are prevented by carbon monoxide.
    (American journal of physiology. Cell physiology, 2020-10) Gasier, Heath G; Dohl, Jacob; Suliman, Hagir B; Piantadosi, Claude A; Yu, Tianzheng
    Nutrient excess increases skeletal muscle oxidant production and mitochondrial fragmentation that may result in impaired mitochondrial function, a hallmark of skeletal muscle insulin resistance. This led us to explore whether an endogenous gas molecule, carbon monoxide (CO), which is thought to prevent weight gain and metabolic dysfunction in mice consuming high-fat diets, alters mitochondrial morphology and respiration in C2C12 myoblasts exposed to high glucose (15.6 mM) and high fat (250 µM BSA-palmitate) (HGHF). Also, skeletal muscle mitochondrial morphology, distribution, respiration, and energy expenditure were examined in obese resistant (OR) and obese prone (OP) rats that consumed a high-fat and high-sucrose diet for 10 wk with or without intermittent low-dose inhaled CO and/or exercise training. In cells exposed to HGHF, superoxide production, mitochondrial membrane potential (ΔΨm), mitochondrial fission regulatory protein dynamin-related protein 1 (Drp1) and mitochondrial fragmentation increased, while mitochondrial respiratory capacity was reduced. CO decreased HGHF-induced superoxide production, Drp1 protein levels and mitochondrial fragmentation, maintained ΔΨm, and increased mitochondrial respiratory capacity. In comparison with lean OR rats, OP rats had smaller skeletal muscle mitochondria that contained disorganized cristae, a normal mitochondrial distribution, but reduced citrate synthase protein expression, normal respiratory responses, and a lower energy expenditure. The combination of inhaled CO and exercise produced the greatest effect on mitochondrial morphology, increasing ADP-stimulated respiration in the presence of pyruvate, and preventing a decline in resting energy expenditure. These data support a therapeutic role for CO and exercise in preserving mitochondrial morphology and respiration during metabolic overload.
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    The CO/HO system reverses inhibition of mitochondrial biogenesis and prevents murine doxorubicin cardiomyopathy.
    (J Clin Invest, 2007-12) Suliman, Hagir B; Carraway, Martha Sue; Ali, Abdelwahid S; Reynolds, Chrystal M; Welty-Wolf, Karen E; Piantadosi, Claude A
    The clinical utility of anthracycline anticancer agents, especially doxorubicin, is limited by a progressive toxic cardiomyopathy linked to mitochondrial damage and cardiomyocyte apoptosis. Here we demonstrate that the post-doxorubicin mouse heart fails to upregulate the nuclear program for mitochondrial biogenesis and its associated intrinsic antiapoptosis proteins, leading to severe mitochondrial DNA (mtDNA) depletion, sarcomere destruction, apoptosis, necrosis, and excessive wall stress and fibrosis. Furthermore, we exploited recent evidence that mitochondrial biogenesis is regulated by the CO/heme oxygenase (CO/HO) system to ameliorate doxorubicin cardiomyopathy in mice. We found that the myocardial pathology was averted by periodic CO inhalation, which restored mitochondrial biogenesis and circumvented intrinsic apoptosis through caspase-3 and apoptosis-inducing factor. Moreover, CO simultaneously reversed doxorubicin-induced loss of DNA binding by GATA-4 and restored critical sarcomeric proteins. In isolated rat cardiac cells, HO-1 enzyme overexpression prevented doxorubicin-induced mtDNA depletion and apoptosis via activation of Akt1/PKB and guanylate cyclase, while HO-1 gene silencing exacerbated doxorubicin-induced mtDNA depletion and apoptosis. Thus doxorubicin disrupts cardiac mitochondrial biogenesis, which promotes intrinsic apoptosis, while CO/HO promotes mitochondrial biogenesis and opposes apoptosis, forestalling fibrosis and cardiomyopathy. These findings imply that the therapeutic index of anthracycline cancer chemotherapeutics can be improved by the protection of cardiac mitochondrial biogenesis.