Cardiac proteostasis in obesity and cardiovascular disease.

Cardiovascular diseases (CVD) are closely linked to protein homeostasis (proteostasis) and its failure. Beside genetic mutations that impair cardiac protein quality control, obesity is a strong risk factor for heart disease. In obesity, adipose tissue becomes dysfunctional and impacts heart function and CVD progression by releasing cytokines that contribute to systemic insulin resistance and cardiovascular dysfunction. In addition, chronic inflammation and lipotoxicity compromise endoplasmic reticulum (ER) function, eliciting stress responses that overwhelm protein quality control beyond its capacity. Impairment of proteostasis-including dysfunction of the ubiquitin-proteasome system (UPS), autophagy, and the depletion of chaperones-is intricately linked to cardiomyocyte dysfunction. Interventions targeting UPS and autophagy pathways are new potential strategies for re-establishing protein homeostasis and improving heart function. Additionally, lifestyle modifications such as dietary interventions and exercise have been shown to promote cardiac proteostasis and overall metabolic health. The pursuit of future research dedicated to proteostasis and protein quality control represents a pioneering approach for enhancing cardiac health and addressing the complexities of obesity-related cardiac dysfunction.

Quercetin improves white adipose tissue redox homeostasis in ovariectomized rats.

Estrogen deficiency is a well-known hallmark of menopause and is associated with oxidative stress and metabolic dysfunction. Quercetin (Q), a flavonoid found in fruits and vegetables, has demonstrated anti-inflammatory effects in experimental models of metabolic disorders. In this study, we aimed to investigate the effects of quercetin on retroperitoneal white adipose tissue (rWAT) redox homeostasis and systemic metabolic parameters in ovariectomized (OVX) rats. Female Wistar rats at 3 months old were divided into the following experimental groups: sham-operated treated with vehicle (DMSO 10% + PBS - 1 mL/kg); OVX (vehicle treated) and OVX-Q (25 mg/kg) - via oral gavage, daily for 5 weeks. Q did not prevent weight gain but improved glucose tolerance and blood cholesterol profile, and attenuated uterine atrophy in OVX rats. Furthermore, Q had a protective effect on rWAT, once the OVX-Q group presented lower oxidative stress levels, and reduced levels of the pro-inflammatory cytokine tumor necrosis factor alpha, compared to the OVX group. Q improved antioxidant enzyme activities such as superoxide dismutase and catalase and decreased reactive oxygen species production, in OVX-Q rats. It was followed by increased levels of total thiol content and lower lipid peroxidation. Moreover, Q reduced senescent-related genes p16INK4a and p19ARF expression which were higher in the OVX group. In conclusion, quercetin supplementation improved redox homeostasis and reduced senescence-related markers, and inflammation in rWAT, which was reflected in preserved systemic metabolic health parameters in OVX rats. These findings suggest that quercetin may have therapeutic potential for the management of metabolic disorders associated with menopause-induced estrogen deficiency.

Physical exercise improves mitochondrial function in ovariectomized rats.

Estrogen deficiency causes metabolic disorders in humans and rodents, including in part due to changes in energy expenditure. We have shown previously that skeletal muscle mitochondrial function is compromised in ovariectomized (Ovx) rats. Since physical exercise is a powerful strategy to improve skeletal muscle mitochondrial content and function, we hypothesize that exercise training would counteract the deficiency-induced skeletal muscle mitochondrial dysfunction in Ovx rats. We report that exercised Ovx rats, at 60-65% of maximal exercise capacity for 8 weeks, exhibited less fat accumulation and body weight gain compared with sedentary controls. Treadmill exercise training decreased muscle lactate production, indicating a shift to mitochondrial oxidative metabolism. Furthermore, reduced soleus muscle mitochondrial oxygen consumption confirmed that estrogen deficiency is detrimental to mitochondrial function. However, exercise restored mitochondrial oxygen consumption in Ovx rats, achieving similar levels as in exercised control rats. Exercise-induced skeletal muscle peroxisome proliferator-activated receptor-γ coactivator-1α expression was similar in both groups. Therefore, the mechanisms by which exercise improves mitochondrial oxygen consumption appears to be different in Ovx-exercised and sham-exercised rats. While there was an increase in mitochondrial content in sham-exercised rats, demonstrated by a greater citrate synthase activity, no induction was observed in Ovx-exercised rats. Normalizing mitochondrial respiratory capacity by citrate synthase activity indicates a better oxidative phosphorylation efficiency in the Ovx-exercised group. In conclusion, physical exercise sustains mitochondrial function in ovarian hormone-deficient rats through a non-conventional mitochondrial content-independent manner.

Exercise Improves Redox Homeostasis and Mitochondrial Function in White Adipose Tissue.

Exercise has beneficial effects on energy balance and also improves metabolic health independently of weight loss. Adipose tissue function is a critical denominator of a healthy metabolism but the adaptation of adipocytes in response to exercise is insufficiently well understood. We have previously shown that one aerobic exercise session was associated with increased expression of antioxidant and cytoprotective genes in white adipose tissue (WAT). In the present study, we evaluate the chronic effects of physical exercise on WAT redox homeostasis and mitochondrial function. Adult male Wistar rats were separated into two groups: a control group that did not exercise and a group that performed running exercise sessions on a treadmill for 30 min, 5 days per week for 9 weeks. Reactive oxygen species (ROS) generation, antioxidant enzyme activities, mitochondrial function, markers of oxidative stress and inflammation, and proteins related to DNA damage response were analyzed. In WAT from the exercise group, we found higher mitochondrial respiration in states I, II, and III of Complex I and Complex II, followed by an increase in ATP production, and the ROS/ATP ratio when compared to tissues from control rats. Regarding redox homeostasis, NADPH oxidase activity, protein carbonylation, and lipid peroxidation levels were lower in WAT from the exercise group when compared to control tissues. Moreover, antioxidant enzymatic activity, reduced glutathione/oxidized glutathione ratio, and total nuclear factor erythroid-2, like-2 (NFE2L2/NRF2) protein levels were higher in the exercise group compared to control. Finally, we found that exercise reduced the phosphorylation levels of H2AX histone (γH2AX), a central protein that contributes to genome stability through the signaling of DNA damage. In conclusion, our results show that chronic exercise modulates redox homeostasis in WAT, improving antioxidant capacity, and mitochondrial function. This hormetic remodeling of adipocyte redox balance points to improved adipocyte health and seems to be directly associated with the beneficial effects of exercise.

Subacute and sublethal ingestion of microcystin-LR impairs lung mitochondrial function by an oligomycin-like effect.

Microcystin-LR (MC-LR) is a potent cyanotoxin that can reach several organs. However subacute exposure to sublethal doses of MC-LR has not yet well been studied. Herein, we evaluated the outcomes of subacute and sublethal MC-LR exposure on lungs. Male BALB/c mice were exposed to MC-LR by gavage (30 µg/kg) for 20 consecutive days, whereas CTRL mice received filtered water. Respiratory mechanics was not altered in MC-LR group, but histopathology disclosed increased collagen deposition, immunological cell infiltration, and higher percentage of collapsed alveoli. Mitochondrial function was extensively affected in MC-LR animals. Additionally, a direct in vitro titration of MC-LR revealed impaired mitochondrial function. In conclusion, MC-LR presented an intense deleterious effect on lung mitochondrial function and histology. Furthermore, MC-LR seems to exert an oligomycin-like effect in lung mitochondria. This study opens new perspectives for the understanding of the putative pulmonary initial mechanisms of damage resulting from oral MC-LR intoxication.

The Effects of Combined Physical Exercise on Serum Redox Biomarkers and Leukocyte DNA Damage of Obese Women.

Obesity is usually linked to oxidative stress, which can lead to damage to biomolecules. The combination of aerobic and strength exercises seems to induce health benefits in obese individuals, but little is known about the effects of combined physical exercise on redox homeostasis and DNA damage in this population. Thus, the aim of the current study was to determine the effects of 16 weeks of combined physical exercise on biomarkers of oxidative stress and DNA damage in obese women. 17 obese women underwent 16 weeks of a combined physical training program, 3 times per week. Anthropometric and biochemical parameters, serum superoxide dismutase (SOD) and glutathione peroxidase activity, plasma 8-isoprostane levels, and DNA and chromosomal damage were evaluated before and after physical training. Combined physical exercise training decreased body weight (83.2 ± 9.6 vs. 80.2 ± 9.6 kg), body mass index (33.8 ± 3.6 vs. 32.6 ± 3.7 kg·m-2), body fat (40.2 ± 2.6 vs. 39.0 ± 3.2%), and waist circumference (99.3 ± 9.4 vs. 94.1 ± 8.8 cm), while the fat-free mass was augmented (59.9 ± 2.9 vs. 60.7 ± 3.1 kg). Moreover, blood glucose reduced (113.5 ± 29.6 vs. 107.3 ± 28.9 mg/dL) along with high-density lipoprotein (54.6 ± 18.1 vs. 59.0 ± 18.8 mg/dL), TSH (2.1 ± 1.1 vs. 2.6 ± 1.2 mIU/mL), and free T4 (0.9 ± 0.1 vs. 1.12 ± 0.2 ng/dL) increase after physical exercise training. Plasma 8-isoprostane levels (17.24 ± 7.9 vs. 29.11 ± 17.44 pg/mL) and DNA damage (34.16 ± 7.1 vs. 45.96 ± 5.8% DNA in tail) were also higher after physical training. No changes were observed in chromosomal damage levels. These results suggest that 16 weeks of combined exercise training 3 times per week is effective in reducing body fat but also increases oxidative stress and DNA damage in obese women.

The Effect of Acute Aerobic Exercise on Redox Homeostasis and Mitochondrial Function of Rat White Adipose Tissue.

Physical exercise is characterized by an increase in physical and metabolic demand in face of physical stress. It is reported that a single exercise session induces physiological responses through redox signaling to increase cellular function and energy support in diverse organs. However, little is known about the effect of a single bout of exercise on the redox homeostasis and cytoprotective gene expression of white adipose tissue (WAT). Thus, we aimed at evaluating the effects of acute aerobic exercise on WAT redox homeostasis, mitochondrial metabolism, and cytoprotective genic response. Male Wistar rats were submitted to a single moderate-high running session (treadmill) and were divided into five groups: control (CTRL, without exercise), and euthanized immediately (0 h), 30 min, 1 hour, or 2 hours after the end of the exercise session. NADPH oxidase activity was higher in 0 h and 30 min groups when compared to CTRL group. Extramitochondrial ROS production was higher in 0 h group in comparison to CTRL and 2 h groups. Mitochondrial respiration in phosphorylative state increased in 0 h group when compared to CTRL, 30 min, 1, and 2 h groups. On the other hand, mitochondrial ATP production was lower in 0 h in comparison to 30 min group, increasing in 1 and 2 h groups when compared to CTRL and 0 h groups. CAT activity was lower in all exercised groups when compared to CTRL. Regarding oxidative stress biomarkers, we observed a decrease in reduced thiol content in 0 h group compared to CTRL and 2 h groups, and higher levels of protein carbonylation in 0 and 30 min groups in comparison to the other groups. The levels returned to basal condition in 2 h group. Furthermore, aerobic exercise increased NRF2, GPX2, HMOX1, SOD1, and CAT mRNA levels. Taken together, our results suggest that one session of aerobic exercise can induce a transient prooxidative state in WAT, followed by an increase in antioxidant and cytoprotective gene expression.

Redox Signaling in Widespread Health Benefits of Exercise.

Significance: Exercise-induced reactive oxygen species (ROS) production activates multiple intracellular signaling pathways through genomic and nongenomic mechanisms that are responsible for the beneficial effects of exercise in muscle. Beyond the positive effect of exercise on skeletal muscle cells, other tissues such as white and brown adipose, liver, central nervous system, endothelial, heart, and endocrine organ tissues are also responsive to exercise. Recent Advances: Crosstalk between different cells is essential to achieve homeostasis and to promote the benefits of exercise through paracrine or endocrine signaling. This crosstalk can be mediated by different effectors that include the secretion of metabolites of muscle contraction, myokines, and exosomes. During the past 20 years, it has been demonstrated that contracting muscle cells produce and secrete different classes of myokines, which functionally link muscle with nearly all other cell types. Critical Issues: The redox signaling behind this exercise-induced crosstalk is now being decoded. Many of these widespread beneficial effects of exercise require not only a complex ROS-dependent intramuscular signaling cascade but simultaneously, an integrated network with many remote tissues. Future Directions: Strong evidence suggests that the powerful beneficial effect of regular physical activity for preventing (or treating) a large range of disorders might also rely on ROS-mediated signaling. Within a contracting muscle, ROS signaling may control exosomes and myokines secretion. In remote tissues, exercise generates regular and synchronized ROS waves, creating a transient pro-oxidative environment in many cells. These new concepts integrate exercise, ROS-mediated signaling, and the widespread health benefits of exercise.

Extinction of Vibrio cholerae in acidic substrata: contaminated fish marinated with lime juice (ceviche)

Millions of Vibrio cholerae O1 El Tor were rapidly eliminated when added to commercial ceviche prepared by marination of mahi-mahi fish in lime juice. Likewise, large masses of viable vibrios present in laboratory contaminated fish, were readily eliminated after immersion in lime juice, during the preparation of ceviche. The killing effect was evident within 5 min of exposure of vibrios to lime juice, with reductions of more than 99.9 per cent of the initial bacterial mass. After 2h of marination of fish with lime juice (the minimum recommended), no vibrios were detected in the lowest working dilutions (1:10, 1:100). The Vibrio mass eliminated by lime juice was 2 to 6 logarithms greater than the maximum infectious dose, and 4 to 8 logs greater than the minimum infectious dose to induce cholera El Tor. Also, the killing time was shorter than the elapsing time between preparing and serving food in homes or restaurants. The traditional marination of fish with lime juice or its addition to seafood and meals immediately before consumption, should be protected and promoted to prevent infection with cholera vibrios. In the face of an epidemic of cholera, consumption of ceviche prepared with lime juice would be one of the safest ways to avoid infection with V. cholerae

Extinction of Vibrio cholerae in acidic substrata: contaminated cabbage and lettuce treated with lime juice

Lime juice killed millions of Vibrio cholerae O1, El Tor, Inaba, present on cabbage and lettuce contaminated in the laboratory. The lethal effect was evident within 5 min of exposure to lime juice. No vibrios could be recovered at dilution 1:10 using alkaline peptone water (APW) and thiosulfate-citrate-bile salts-saccharose agar (TCBS). More than 99.9 per cent of the initial inoculum was effectively destroyed. The number of vibrios killed by lime juice was 2 to 6 logarithms greater than the maximum infecting dose, and 4 to 8 logs greater than the minimum infecting dose for cholera El Tor. The time interval needed for killing was smaller than the usual waiting time for serving food in homes and restaurants. The addition of lime juice to non-acidic foods, beverages and water, is strongly recommended to prevent infection with cholera vibrios and other acid-sensitive microorganisms. This measure is particularly important for rural and slum populations in the tropics and subtropics