Donepezil ameliorates gut barrier disruption in doxorubicin-treated rats.

An impact of donepezil against doxorubicin-induced gut barrier disruption and gut dysbiosis has never been investigated. Twenty-four male Wistar rats were divided into three groups. Each group was treated with either vehicle as a control, doxorubicin, or doxorubicin-cotreated with donepezil. Heart rate variability was assessed to reflect the impact of doxorubicin and donepezil. Then, animals were euthanized, and the ileum and its contents were collected in each case to investigate the gut barrier and gut microbiota, respectively. The microbiota-derived endotoxin, trimethylamine N-oxide (TMAO), and short-chain fatty acids (SCFAs) in the serum were determined. An increase in the sympathetic tone, endotoxins, and TMAO levels with disruption of the gut barrier and a decrease in SCFAs levels were observed in doxorubicin-treated rats. Gut microbiota of doxorubicin-treated rats was significantly different from that of the control group. Donepezil treatment significantly decreased the sympathetic tone, restored the gut barrier, and reduced endotoxin and TMAO levels in doxorubicin-treated rats. Nonetheless, donepezil administration did not alter the gut microbiota profile and levels of SCFAs in doxorubicin-treated rats. Doxorubicin impaired the autonomic balance and the gut barrier, and induced gut dysbiosis, resulting in gut toxicity. Donepezil partially improved the doxorubicin-induced gut toxicity through balancing the autonomic disturbance.

Changes in blood metabolomes as potential markers for severity and prognosis in doxorubicin-induced cardiotoxicity: a study in HER2-positive and HER2-negative breast cancer patients.

BACKGROUND: We aimed to compare the changes in blood metabolomes and cardiac parameters following doxorubicin treatment in HER2-positive and HER2-negative breast cancer patients. Additionally, the potential roles of changes in blood metabolomes as severity and prognostic markers of doxorubicin-induced cardiotoxicity were determined. METHODS: HER2-positive (n = 37) and HER2-negative (n = 37) breast cancer patients were enrolled. Cardiac function assessment and blood collection were performed at baseline and 2 weeks after completion of doxorubicin treatment in all patients, as well as at three months after completion of doxorubicin treatment in HER2-negative breast cancer patients. Blood obtained at all three-time points was processed for measuring cardiac injury biomarkers. Blood obtained at baseline and 2 weeks after completion of doxorubicin treatment were also processed for measuring systemic oxidative stress and 85 metabolome levels. RESULTS: Cardiac injury and systolic dysfunction 2 weeks after completion of doxorubicin treatment were comparable between these two groups of patients. However, only HER2-negative breast cancer patients exhibited increased systemic oxidative stress and cardiac autonomic dysfunction at this time point. Moreover, 33 and 29 blood metabolomes were altered at 2 weeks after completion of doxorubicin treatment in HER2-positive and HER2-negative breast cancer patients, respectively. The changes in most of these metabolomes were correlated with the changes in cardiac parameters, both at 2 weeks and 3 months after completion of doxorubicin treatment. CONCLUSIONS: The changes in blood metabolomes following doxorubicin treatment were dependent on HER2 status, and these changes might serve as severity and prognostic markers of doxorubicin-induced cardiotoxicity. TRIAL REGISTRATION: The study was conducted under ethical approval from the Institutional Review Board of the Faculty of Medicine, Chiang Mai University (Registration number: MED-2563-07001; Date: April 28, 2020). The study also complied with the Declaration of Helsinki.

Modulating Mitochondrial Dynamics Mitigates Cognitive Impairment in Rats with Myocardial Infarction.

BACKGROUND: We have previously demonstrated that oxidative stress and brain mitochondrial dysfunction are key mediators of brain pathology during myocardial infarction (MI).

Objective: To investigate the beneficial effects of mitochondrial dynamic modulators, including mitochondrial fission inhibitor (Mdivi-1) and mitochondrial fusion promotor (M1), on cognitive function and molecular signaling in the brain of MI rats in comparison with the effect of enalapril. METHODS: Male rats were assigned to either sham or MI operation. In the MI group, rats with an ejection Fraction less than 50% were included, and then they received one of the following treatments for 5 weeks: vehicle, enalapril, Mdivi-1, or M1. Cognitive function was tested, and the brains were used for molecular study.

Results: MI rats exhibited cardiac dysfunction with systemic oxidative stress. Cognitive impairment was found in MI rats, along with dendritic spine loss, blood-brain barrier (BBB) breakdown, brain mitochondrial dysfunction, and decreased mitochondrial and increased glycolysis metabolism, without the alteration of APP, BACE-1, Tau and p-Tau proteins. Treatment with Mdivi-1, M1, and enalapril equally improved cognitive function in MI rats. All treatments decreased dendritic spine loss, brain mitochondrial oxidative stress, and restored mitochondrial metabolism. Brain mitochondrial fusion was recovered only in the Mdivi-1-treated group.

Conclusion: Mitochondrial dynamics modulators improved cognitive function in MI rats through a reduction of systemic oxidative stress and brain mitochondrial dysfunction and the enhancement of mitochondrial metabolism. In addition, this mitochondrial fission inhibitor increased mitochondrial fusion in MI rats.

Exercise and Caloric Restriction Exert Different Benefits on Skeletal Muscle Metabolism in Aging Condition.

Exercise and caloric restriction improve skeletal muscle metabolism. However, the benefits of exercise and caloric restriction on skeletal muscle metabolism in aging have never been compared. Seven-week-old male Wistar rats (n = 24) were divided into 4 groups (n = 6 per group) to receive either normal saline solution for 28 weeks, 150 mg/kg/day of D-galactose for 28 weeks to induce premature aging, 150 mg/kg/day of D-galactose for 28 weeks plus exercise for 16 weeks (week 13-28), or 150 mg/kg/day of D-galactose for 28 weeks plus 30% caloric restriction for 16 weeks (week 13-28). The 17-month-old rats (n = 6) were also injected with normal saline solution for 28 weeks as the naturally aged controls. At the end of week 28, total walking distance and fatty acid and carbohydrate oxidation during physical activity were determined. Then, all rats were euthanized for the collection of blood and tibialis anterior muscle. The results showed that D-galactose successfully mimicked the natural aging of skeletal muscle. Exercise and caloric restriction equally improved carbohydrate oxidation during physical activity and myogenesis. However, exercise was superior to caloric restriction in terms of improving fatty acid oxidation and oxidative phosphorylation. Interestingly, caloric restriction decreased oxidative stress, whereas exercise increased oxidative stress of skeletal muscle. All of these findings indicated that the benefits of exercise and caloric restriction on skeletal muscle metabolism during aging were different, and therefore the combination of exercise and caloric restriction might provide greater efficacy in ameliorating skeletal muscle aging.

Long-term lifestyle intervention is superior to transient modification for neuroprotection in D-galactose-induced aging rats.

AIMS: To investigate whether transient dietary restriction or aerobic exercise in young adulthood exert long-lasting protection against brain aging later in life. MAIN METHODS: Seven-week-old male Wistar rats were divided into 2 groups and given either normal saline as a vehicle (n = 8) or 150 mg/kg/day of D-galactose (n = 40) for 28 weeks, the D-galactose being used to induce aging. At week 13 of the experiment, D-galactose-treated rats were further divided into 5 groups, 1) no intervention, 2) transient dietary restriction for 6 weeks (week 13-18), 3) transient exercise for 6 weeks (week 13-18), 4) long-term dietary restriction for 16 weeks (week 13-28), and 5) long-term exercise for 16 weeks (week 13-28). At the end of week 28, cognitive function was examined, followed by molecular studies in the hippocampus. KEY FINDINGS: Our results showed that either long-term dietary restriction or aerobic exercise effectively attenuated cognitive function in D-galactose-treated rats via the attenuation of oxidative stress, cellular senescence, Alzheimer's-like pathology, neuroinflammation, and improvements in mitochondria, brain metabolism, adult neurogenesis, and synaptic integrity. Although transient interventions provided benefits in some brain parameters in D-galactose-treated rats, an improvement in cognitive function was not observed. SIGNIFICANCE: Our findings suggested that transient lifestyle interventions failed to exert a long-lasting protective effect against brain aging. Hence, novel drugs mimicking the neuroprotective effect of long-term dietary restriction or exercise and the combination of the two since young age appear to be more appropriate treatments for the elderly who are unable to engage in long-term dietary restriction or exercise.

Effects of melatonin on cardiac metabolic reprogramming in doxorubicin-induced heart failure rats: A metabolomics study for potential therapeutic targets.

Using mass spectrometry-based targeted metabolomics, we aimed to determine the pattern of cardiac metabolic reprogramming and energetics in doxorubicin-induced heart failure. More importantly, we aimed to identify the potential effects of melatonin on cardiac metabolic reprogramming and energetics in doxorubicin-induced heart failure. Male Wistar rats (n = 18) were randomly divided into three groups (n = 6/group) to receive either (1) normal saline solution as a control, (2) 3 mg/kg/day of doxorubicin on Days 0, 4, 8, 15, 22, and 29, or (3) 3 mg/kg/day of doxorubicin on Days 0, 4, 8, 15, 22, and 29 plus 10 mg/kg/day of melatonin on Days 0-29. On Day 30, echocardiography was carried out and heart rate variability was analyzed for the evaluation of cardiac function. The rats were euthanized on the following day to enable the collection of ventricular cardiac tissue. Compared to the control group, the hearts of rats treated with doxorubicin alone exhibited impaired cardiac function, increased glucose and ketone body utilization, decreased fat utilization, decreased succinate oxidation, and decreased production of adenosine triphosphate. The cotreatment with melatonin could restore cardiac function, glucose and ketone body utilization, and adenosine triphosphate production in the heart. Interestingly, the cotreatment with melatonin led to an increase in cardiac fatty acid oxidation, branched-chain amino acid catabolism, and anaplerosis. All of these findings highlighted the potential efficacy of melatonin with regard to cardiac metabolic reprogramming and energetics. Our findings also suggested that melatonin could be considered as an adjunctive treatment for doxorubicin-induced heart failure in clinical practice.

Chronic D-galactose administration induces natural aging characteristics, in rat's brain and heart.

We aimed to investigate the effect of chronic D-galactose exposure on the mimicking of natural aging processes based upon the hallmarks of aging. Seven-week-old male Wistar rats (n = 12) were randomly assigned to receive either normal saline solution as a vehicle (n = 6) or 150 mg/kg/day of D-galactose subcutaneously for 28 weeks. Seventeen-month-old rats (n = 6) were also included as the chronologically aged controls. At the end of week 28 of the experiment (when the rats reach 35 weeks old and 24 months old), all rats were sacrificed for brain and heart collection. Our results showed that chronic D-galactose exposure mimicked natural aging characteristics of the brain and the heart in terms of deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, and functional impairment. All of which highlight the potential of D-galactose as a substance for inducing brain and cardiac aging in animal experiments.

Higher untrained fitness exerts a neuroprotection in Independence to caloric restriction or exercise in high-fat diet-induced obesity.

We investigated whether weight maintenance following short-term caloric restriction or exercise exerted neuroprotective effects on obesity induced by a high-fat diet. We also sought to identify whether the neuroprotective effects of higher untrained fitness persisted in the obese condition, both with and without caloric restriction or exercise. Male Wistar rats were fed with either a normal diet (ND) or a high-fat diet (HFD) for 12 weeks. At week 12, untrained fitness and blood metabolic parameters were measured. The ND-fed rats continuously received a ND for 16 additional weeks. HFD-fed rats were randomly assigned to 5 groups as of the followings: 1) an additional 16 weeks of HFD without intervention, 2) 10-week weight maintenance following 6-week short-term caloric restriction, 3) long-term caloric restriction (16 weeks), 4) 10-week weight maintenance following 6 weeks of HFD plus short-term exercise, and 5) HFD plus long-term exercise (16 weeks). Untrained fitness, blood metabolic parameters, and behavioral tests were then determined. Thereafter, the rats were euthanized for molecular studies. Our results demonstrated that long-term caloric restriction had the greatest systemic metabolic benefit among all interventions. Long-term caloric restriction and exercise equally attenuated HFD-induced cognitive impairment by improving synaptic function, blood-brain barrier integrity, mitochondrial health, and neurogenesis, and reducing oxidative stress, neuroinflammation, apoptosis, and Alzheimer's-related pathology. Weight maintenance following short-term caloric restriction showed no benefit to neurogenesis. Weight maintenance following short-term exercise exerted no benefit on synaptic function, neuronal insulin signaling and metabolism, autophagy, and neurogenesis. Interestingly, we found that higher untrained fitness level at week 12 showed positive correlations with more favorable brain profiles at week 28 in HFD-fed rats, both with and without caloric restriction or exercise. All of these findings suggested that higher untrained fitness exerts neuroprotection in HFD-induced obesity independently of caloric restriction or exercise. Therefore, targeting enhancement of untrained fitness may lead to more effective treatment of neurodegeneration in obese condition.

GSDMD-mediated pyroptosis dominantly promotes left ventricular remodeling and dysfunction in post-myocardial infarction: a comparison across modes of programmed cell death and mitochondrial involvement.

BACKGROUND: Myocardial infarction (MI) has recently accounted for more than one-third of global mortality. Multiple molecular pathological pathways, such as oxidative stress, inflammation, and mitochondrial dysfunction, have been recognized as possible mechanisms in the development of MI. Furthermore, different phases of ischemic injury following the progression of MI were also associated with multiple types of programmed cell death (PCDs), including apoptosis, necroptosis, ferroptosis, and pyroptosis. However, it remains unknown whether which types of PCDs play the most dominant role in post-myocardial infarction (post-MI). METHOD: In this study, we used a preclinical rat model of MI induced by permanent left anterior descending coronary artery (LAD) ligation (n = 6) or a sham operated rat model (n = 6). After a 5-week experiment, cardiac function and morphology, mitochondrial studies, and molecular signaling analysis of PCDs were determined. RESULTS: Herein, we demonstrated that post-MI rats had considerably impaired cardiac geometry, increased oxidative stress, myocardial injuries, and subsequently contractile dysfunction. They also exhibited worsened cardiac mitochondrial function and dynamic imbalance. More importantly, we found that post-MI mediated abundant myocardial cell death through multiple PCDs, including apoptosis, necroptosis, and pyroptosis, but not ferroptosis. CONCLUSION: In this study, we provide the first insights into the mechanism of PCDs by pyroptosis, which is leveraged as the most dominant mode of cell death after MI.

Blood metabolomes as non-invasive biomarkers and targets of metabolic interventions for doxorubicin and trastuzumab-induced cardiotoxicity.

This study aimed to identify the alterations of blood metabolome levels and their association with cardiac dysfunction and cardiac injury following treatment with doxorubicin and trastuzumab. Eight-week-old male Wistar rats were divided into four groups (n = 6 per group) to receive intraperitoneal injection with either: (1) 1 mL of normal saline solution (NSS) at days 0, 4, 8, 15, 22, and 29 (control group for doxorubicin); (2) 3 mg/kg/day of doxorubicin at days 0, 4, 8, 15, 22, and 29 (doxorubicin group); (3) 1 mL of NSS at days 0-6 (control group for trastuzumab); or (4) 4 mg/kg/day of trastuzumab at days 0-6 (trastuzumab group). Four days after the last injected dose, cardiac function was determined. The rats were then euthanized to collect venous blood and the heart for the quantification of 107 serum and 100 cardiac metabolomes using mass spectrometry-based targeted metabolomics. We observed strong relationships between 72 cardiac versus 61 serum metabolomes in doxorubicin and trastuzumab groups. Moreover, significant correlations between cardiac function and the cardiac injury biomarker versus 28 and 58 serum metabolomes were revealed in doxorubicin and trastuzumab-treated rats, respectively. Interestingly, the patterns of both serum and cardiac metabolome alterations differed between doxorubicin and trastuzumab groups. Our findings emphasize the potential role of the constituents of the blood metabolome as non-invasive biomarkers to assess severity and prognosis of heart failure induced by doxorubicin and trastuzumab. These findings may contribute to the development of metabolic-targeted therapy specific for cardioprotection during different phases of cancer treatment.

Melatonin and metformin ameliorated trastuzumab-induced cardiotoxicity through the modulation of mitochondrial function and dynamics without reducing its anticancer efficacy.

Trastuzumab has an impressive level of efficacy as regards antineoplasticity, however it can cause serious cardiotoxic side effects manifested by impaired cardiac contractile function. Although several pharmacological interventions, including melatonin and metformin, have been reported to protect against various cardiovascular diseases, their potential roles in trastuzumab-induced cardiotoxicity remain elusive. We hypothesized that either melatonin or metformin co-treatment effectively attenuates trastuzumab-mediated cardiotoxicity through attenuating the impaired mitochondrial function and mitochondrial dynamics. Male Wistar rats were divided into control (normal saline, n = 8) and trastuzumab group (4 mg/kg/day for 7 days, n = 24). Rats in the trastuzumab group were subdivided into 3 interventional groups (n = 8/group), and normal saline, or melatonin (10 mg/kg/day), or metformin (250 mg/kg/day) were orally administered for 7 consecutive days. Cardiac parameters were determined, and biochemical investigations were carried out on blood and heart tissues. Trastuzumab induced left ventricular (LV) dysfunction by increasing oxidative stress, inflammation, and apoptosis. It also impaired cardiac mitochondrial function, dynamics, and autophagy. Treatment with either melatonin or metformin equally attenuated trastuzumab-induced cardiac injury, indicated by a marked reduction in inflammation, oxidative damage, cardiac mitochondrial injury, mitochondrial dynamic imbalance, autophagy dysregulation, and apoptosis, leading to improved LV function, as demonstrated by increased LV ejection fraction. Melatonin and metformin conferred equal levels of cardioprotection against trastuzumab-induced cardiotoxicity, which may provide novel and promising approaches for management of cardiotoxicity induced by trastuzumab.

Deferiprone has less benefits on gut microbiota and metabolites in high iron-diet induced iron overload thalassemic mice than in iron overload wild-type mice: A preclinical study.

AIMS: This study aimed to investigate the changes in gut microbiota in iron-overload thalassemia and the roles of an iron chelator on gut dysbiosis/inflammation, and metabolites, including short-chain fatty acids (SCFAs) and trimethylamine N-oxide (TMAO). MAIN METHODS: Adult male C57BL/6 mice both wild-type (WT: n = 15) and heterozygous ß-thalassemia (BKO: n = 15) were fed on either a normal (ND: n = 5/group) or a high­iron diet for four months (HFe: n = 10/group). HFe-treated WT and HFe-treated BKO groups were further subdivided into two subgroups and each subgroup given either vehicle (n = 5/subgroup) or deferiprone (n = 5/subgroup) during the last month. Gut microbiota profiles, gut barrier characteristics, levels of proinflammatory cytokines, and plasma SCFAs and TMAO were determined at the end of the study. KEY FINDINGS: HFe-fed WT mice showed distinct gut microbiota profiles from those of ND-fed WT mice, whereas HFe-fed BKO mice showed slightly different gut microbiota profiles from ND-fed BKO. Gut inflammation and barrier disruption were found only in HFe-fed BKO mice, however, an increase in plasma TMAO levels and decreased levels of SCFAs were observed in both WT and BKO mice with HFe-feeding. Treatment with deferiprone, gut dysbiosis and disturbance of metabolites were attenuated in HFe-fed WT mice, but not in HFe-fed BKO mice. Increased Verrucomicrobia and Ruminococcaceae were associated with the beneficial effects of deferiprone. SIGNIFICANCE: Iron-overload leads to gut dysbiosis/inflammation and disturbance of metabolites, and deferiprone alleviates those conditions more effectively in WT than in those that are thalassemic.

Promoting mitochondrial fusion in doxorubicin-induced cardiotoxicity: a novel therapeutic target for cardioprotection.

Changes in mitochondrial dynamics have been recognized as being one of the mechanisms related to cardiotoxicity following a high cumulative dose of doxorubicin (DOX). A mitochondrial division inhibitor-1 (Mdivi-1) and fusion promoter (M1) have been shown to be cardioprotective in a variety of cardiovascular settings, however, their anticardiotoxic efficacy against DOX therapy remains unclear. We therefore investigated whether treatment with Mdivi-1 and M1 protects the heart against DOX-induced cardiotoxicity via mitochondria-targeted pathways. Male Wistar rats (n=40) received DOX (3 mg/kg, six doses, n=32) or 3% dimethylsulfoxide (DMSO) in the normal saline solution (NSS) (n=8) as a control. DOX-injected rats were given one of four treatments beginning with the first DOX injection via intraperitoneal injection: 1) 3% DMSO in NSS (n=8), 2) Mdivi-1 (1.2 mg/kg per day, n=8), 3) M1 (2 mg/kg per day, n=8), and 4) Mdivi-1+M1 (n=8) for 30 days. Cardiac function, mitochondrial function, oxidative stress, myocardial injury, and protein expression associated with inflammation, autophagy, mitophagy, apoptosis, and mitochondrial dynamics were determined. DOX caused a significant deterioration in mitochondrial function and dynamic regulation, and an increase in markers of oxidative stress, inflammation, myocardial injury, apoptosis, autophagy, and mitophagy, resulting in impaired cardiac function. Cotreatment of DOX with Mdivi-1, M1, or a combination of the two mitigated these detrimental effects of DOX. These findings imply that either inhibiting fission or promoting fusion of mitochondria protects the heart from DOX-induced myocardial damage. Modulation of mitochondrial dynamics could be a novel therapeutic target in alleviating DOX-induced cytotoxic effects without compromising its anticancer efficacy.

Modulation of mitochondrial dynamics rescues cognitive function in rats with 'doxorubicin-induced chemobrain' via mitigation of mitochondrial dysfunction and neuroinflammation.

Doxorubicin (DOX), an effective, extensively used chemotherapeutic drug, can cause cognitive deterioration in cancer patients. The associated debilitating neurological sequelae are referred to as chemobrain. Our recent work demonstrated that Dox treatment resulted in an imbalance in mitochondrial dynamics, ultimately culminating in cognitive decline in rats. Therefore, in this study, we aim to explore the therapeutic efficacy of a pharmacological intervention, which modulates mitochondrial dynamics using a potent mitochondrial fission inhibitor (Mdivi-1) and mitochondrial fusion promoter (M1) against Dox-induced chemobrain. In the study, male Wistar rats were randomly assigned to receive either normal saline solution or six doses of Dox (3 mg·kg-1 ) via intraperitoneal injection. Then, the Dox-treated rats were intraperitoneally given either 1% DMSO as the vehicle, Mdivi-1 (1.2 mg·kg-1 ), M1 (2 mg·kg-1 ), or a combined treatment of Mdivi-1 and M1 for 30 consecutive days. Long-term learning and memory were evaluated using the novel object location task and novel object recognition task. Following euthanasia, the rat brains were dissected to enable further molecular investigation. We demonstrated that long-term treatment with mitochondrial dynamic modulators suppressed mitochondrial fission in the hippocampus following Dox treatment, leading to an improvement in brain homeostasis. Mitochondrial dynamic modulator treatments restored cognitive function in Dox-treated rats by attenuating neuroinflammation, decreasing oxidative stress, preserving synaptic integrity, reducing potential Alzheimer's related lesions, and mitigating both apoptosis and necroptosis following Dox administration. Together, our findings suggested that mitochondrial dynamics modulators protected against Dox-induced cognitive impairment by rebalancing mitochondrial homeostasis and attenuating both oxidative and inflammatory insults.

D-galactose-induced aging aggravates obesity-induced bone dyshomeostasis.

We aimed to compare the time-course effect of D-galactose (D-gal)-induced aging, obesity, and their combined effects on bone homeostasis. Male Wistar rats were fed with either a normal diet (ND; n = 24) or a high-fat diet (HFD; n = 24) for 12 weeks. All rats were then injected with either vehicle or 150 mg/kg/day of D-gal for 4 or 8 weeks. Blood was collected to measure metabolic, aging, oxidative stress, and bone turnover parameters. Bone oxidative stress and inflammatory markers, as well as bone histomorphometry were also evaluated. Additionally, RAW 264.7 cells were incubated with either D-gal, insulin, or D-gal plus insulin to identify osteoclast differentiation capacity under the stimulation of receptor activator of nuclear factor κB ligand. At week 4, D-gal-induced aging significantly elevated serum malondialdehyde level and decreased trabecular thickness in ND- and HFD-fed rats, when compared to the control group. At week 8, D-gal-induced aging further elevated advanced glycation end products, increased bone inflammation and resorption, and significantly impaired bone microarchitecture in HFD-fed rats. The osteoclast number in vitro were increased in the D-gal, insulin, and combined groups to a similar extent. These findings suggest that aging aggravates bone dyshomeostasis in the obese condition in a time-dependent manner.

Mild Cognitive impairment Occurs in Rats During the Early Remodeling Phase of Myocardial Infarction.

Cognitive impairment is a common health problem among people with heart failure (HF). Increases in oxidative stress, brain inflammation, and microglial hyperactivity have been reported in preclinical models of myocardial infarction (MI)-induced HF. We tested the hypothesis that oxidative stress, brain inflammation, mitochondrial dysfunction, and cell death participate in cognitive impairment in the early remodeling phase of MI. Rats underwent either a sham or permanent left anterior descending coronary ligation to induce MI. 1-week post-operation, MI rats with % left ventricular ejection fraction (%LVEF) ≥50 were assigned as a HF with preserved ejection fraction (HFpEF) group and MI rats with %LVEF <50 were assigned as a HF with reduced ejection fraction (HFrEF) group. Cognitive function and biochemical markers were assessed at week 5. The mean value of %LVEF in HFpEF and HFrEF were 63.62 ± 8.33 and 42.83 ± 3.93 respectively, which were lower than in the sham group, suggesting that these rats developed MI with cardiac dysfunction. Hippocampal dependent cognitive impairment was observed in MI rats. Serum, brain, and mitochondrial oxidative stress were all increased in MI rats, along with apoptosis, resulting in dendritic spine loss. However, brain inflammation and AD proteins did not change. In conclusion, during the early remodeling phase of MI, a high level of oxidative stress appears to be a major contributor of cellular damage which is associated with mild cognitive impairment. However, the severity of MI, as evidenced by the %LVEF, was not associated with the degree of cognitive impairment.

Effectiveness of high cardiorespiratory fitness in cardiometabolic protection in prediabetic rats.

BACKGROUND: Caloric restriction and exercise are lifestyle interventions that effectively attenuate cardiometabolic impairment. However, cardioprotective effects of long-term lifestyle interventions and short-term lifestyle interventions followed by weight maintenance in prediabetes have never been compared. High cardiorespiratory fitness (CRF) has been shown to provide protection against prediabetes and cardiovascular diseases, however, the interactions between CRF, prediabetes, caloric restriction, and exercise on cardiometabolic health has never been investigated. METHODS: Seven-week-old male Wistar rats were fed with either a normal diet (ND; n = 6) or a high-fat diet (HFD; n = 30) to induce prediabetes for 12 weeks. Baseline CRF and cardiometabolic parameters were determined at this timepoint. The ND-fed rats were fed continuously with a ND for 16 more weeks. The HFD-fed rats were divided into 5 groups (n = 6/group) to receive one of the following: (1) a HFD without any intervention for 16 weeks, (2) 40% caloric restriction for 6 weeks followed by an ad libitum ND for 10 weeks, (3) 40% caloric restriction for 16 weeks, (4) a HFD plus an exercise training program for 6 weeks followed by a ND without exercise for 10 weeks, or (5) a HFD plus an exercise training program for 16 weeks. At the end of the interventions, CRF and cardiometabolic parameters were re-assessed. Then, all rats were euthanized and heart tissues were collected. RESULTS: Either short-term caloric restriction or exercise followed by weight maintenance ameliorated cardiometabolic impairment in prediabetes, as indicated by increased insulin sensitivity, improved blood lipid profile, improved mitochondrial function and oxidative phosphorylation, reduced oxidative stress and inflammation, and improved cardiac function. However, these benefits were not as effective as those of either long-term caloric restriction or exercise. Interestingly, high-level baseline CRF was correlated with favorable cardiac and metabolic profiles at follow-up in prediabetic rats, both with and without lifestyle interventions. CONCLUSIONS: Short-term lifestyle modification followed by weight maintenance improves cardiometabolic health in prediabetes. High CRF exerted protection against cardiometabolic impairment in prediabetes, both with and without lifestyle modification. These findings suggest that targeting the enhancement of CRF may contribute to the more effective treatment of prediabetes-induced cardiometabolic impairment.

Hyperbaric oxygen therapy improves age induced bone dyshomeostasis in non-obese and obese conditions.

AIMS: To investigate the effects of hyperbaric oxygen therapy (HBOT) on metabolic disturbance, aging and bone remodeling in D-galactose-induced aging rats with and without obesity by determining the metabolic parameters, aging and oxidative stress markers, bone turnover markers, bone microarchitecture, and bone biomechanical strength. MATERIALS AND METHODS: Male Wistar rats were fed either a normal diet (ND; n = 18) or a HFD (n = 12) for 22 weeks. At week 13, vehicle (0.9% NaCl) was injected into ND-fed rats (NDV; n = 6), while 150 mg/kg/day of D-galactose was injected into 12 ND-fed rats (NDD) and 12 HFD-fed rats (HFDD) for 10 weeks. At week 21, rats were treated with either sham (NDVS, NDDS, or HFDDS; n = 6/ group) or HBOT (NDDH, or HFDDH; n = 6/group) for 14 days. Rats were then euthanized. Blood samples, femora, and tibiae were collected. KEY FINDINGS: Both NDD and HFDD groups developed aging as indicated by increased AGE level, increased inflammation and oxidative stress as shown by raised serum TNF-α and MDA levels, impaired bone remodeling as indicated by an increase in levels of CTX-1, TRACP-5b, and impaired bone structure/strength, when compared with those of the NDVS group. HFD aggravated these indicators of bone dyshomeostasis in D-galactose-treated rats. HBOT restored bone remodeling and bone structure/strength in the NDD group, however HBOT ameliorated bone dyshomeostasis in the HFDD group. SIGNIFICANCE: HBOT is a potential intervention to decrease the risk of osteoporosis and bone fracture in aging with or without obesity.

Inhibition of myeloid differentiation factor 2 attenuates cardiometabolic impairments via reducing cardiac mitochondrial dysfunction, inflammation, apoptosis and ferroptosis in prediabetic rats.

Systemic inflammation is a key mediator of left ventricular dysfunction (LV) in prediabetes via the activation of myeloid differentiation factor 2 (MD2)/toll-like receptor 4 complex. The MD2 inhibitor L6H21 effectively reduced systemic and cardiac inflammation in obese mice. However, its effects on cardiac function and regulated cell death pathways in the heart in prediabetes are still unknown. The prediabetic rats were divided into 3 subgroups to receive vehicle, L6H21 (10, 20, 40 mg/kg) or metformin (300 mg/kg) for 1, 2 and 4 weeks. Then, metabolic parameters, cardiac sympathovagal balance, LV function, cardiac mitochondrial function, oxidative stress, inflammation, apoptosis, necroptosis, and ferroptosis were determined. All prediabetic rats exhibited cardiac sympathovagal imbalance, LV dysfunction, and cardiac mitochondrial dysfunction. All doses of L6H21 treatment for 2- and 4-weeks attenuated insulin resistance. L6H21 at 40 mg/kg attenuated cardiac autonomic imbalance and LV dysfunction after 1 week of treatment. Both 10 and 20 mg/kg of L6H21 required longer treatment duration to show these benefits. Mechanistically, all doses of L6H21 reduced cardiac mitochondrial dysfunction after 1 week of treatment, resulting in alleviated oxidative stress and inflammation. L6H21 also effectively suppressed cardiac apoptosis and ferroptosis, but it did not affect necroptosis in prediabetic rats. L6H21 provided the cardioprotective efficacy in dose- and time-dependent manners in prediabetic rats via reduction in apoptosis and ferroptosis.