Effect modification of diabetic status on the association between exposure to particulate matter and cardiac arrhythmias in a general population: A systematic review and meta-analysis.

Particulate matter (PM) has various health effects, including cardiovascular diseases. Exposure to PM and a diagnosis of diabetes mellitus (DM) have been associated with an increased risk of cardiac arrhythmias. However, no comprehensive synthesis has been conducted to examine the modifying effect of DM on the association between PM and arrhythmia events. Thus, the objectives of this review were to investigate whether the association of PM is linked to cardiac arrhythmias and whether DM status modifies its effect in the general population. The search was conducted on PubMed/MEDLINE and Embase until January 18, 2023. We included cohort and case-crossover studies reporting the effect of PM exposure on cardiac arrhythmias and examining the role of diabetes as an effect modifier. We used the DerSimonian and Laird random-effects model to calculate the pooled estimates. A total of 217 studies were found and subsequently screened. Nine studies met the inclusion criteria, and five of them were included in the meta-analysis. The participants numbered 4,431,452, with 2,556 having DM. Exposure to PM of any size showed a significant effect on arrhythmias in the overall population (OR 1.10, 95% CI 1.04-1.16). However, the effect modification of DM was not significant (OR 1.18 (95% CI 1.01-1.38) for DM; OR 1.08 (95% CI 1.02-1.14) for non-DM; p-value of subgroup difference = 0.304). Exposure to higher PM concentrations significantly increases cardiac arrhythmias requiring hospital or emergency visits. Although the impact on diabetic individuals is not significant, diabetic patients should still be considered at risk. Further studies with larger sample sizes and low bias are needed.

Effects of glyphosate-based herbicides and glyphosate exposure on sex hormones and the reproductive system: From epidemiological evidence to mechanistic insights.

Glyphosate-based herbicides (GBHs) containing glyphosate as the active component are extensively used worldwide. Concerns have arisen about their potential risk to human, as glyphosate has been detected in human body fluids. Current controversies surround the endocrine-disrupting properties and transgenerational inheritance of diseases and germline epimutations resulting from exposure to GBHs and glyphosate. This review discusses evidence from in vitro, in vivo, and clinical studies on their impact on sex hormone regulation and reproductive system. Evidence suggests that they act as endocrine-disrupting chemicals, which altering sex hormone levels. Mechanistically, they interfere with hormone signaling pathways by disrupting proteins involved in hormone transport and metabolism. Pathological changes have been observed in male and female reproductive systems, potentially leading to reproductive toxicity. Prenatal exposure may lead to transgenerational inheritance of pathologies and sperm epimutations. However, due to the complexity of glyphosate formulations containing adjuvants identifying higher risk components in environmental exposure becomes challenging.

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.

Functional roles of orexin in obstructive sleep apnea: From clinical observation to mechanistic insights.

Obstructive sleep apnea is the most common sleep-related breathing disorder. Repetitive episodes of the obstructive respiratory events lead to arousal, sleep fragmentation, and excessive daytime sleepiness. Orexin, also known as hypocretin, is one of the most important neurotransmitters responsible for sleep and arousal regulation. Deficiency of orexin has been shown to be involved in the pathogenesis of narcolepsy, which shares cardinal symptoms of sleep apnea and excessive daytime sleep with obstructive sleep apnea. However, the relationship between orexin and obstructive sleep apnea is not well defined. In this review, we summarize the current evidence, from in vitro, in vivo, and clinical data, regarding the association between orexin and obstructive sleep apnea. The effects of orexin on sleep apnea, as well as how the consequences of obstructive sleep apnea affect the orexin system function are also discussed. Additionally, the contrary findings are also included and discussed.

Repurposing metformin as a potential treatment for inflammatory bowel disease: Evidence from cell to the clinic.

Inflammatory bowel disease (IBD) comprises a group of intestinal disorders, including ulcerative colitis and Crohn's disease. Currently, the incidence and prevalence of IBD are increasing globally. Although both biologic agents and small molecule drugs have been available for treatment of IBD patients, approximately one third of treated patients do not respond to these treatments. Therefore, novel therapy or repurposing of drugs have been extensively studied to obtain an effective therapy for IBD patients. Among these drugs, metformin has been reported to exert beneficial effects in many organs via its anti-inflammatory effect. Additionally, evidence from cellular to clinical models of IBD demonstrated significant positive effects of metformin on inflammatory pathways, oxidative stress, gut barrier integrity, and gut microbiota. In this review, the beneficial effects of metformin on IBD are comprehensively summarized and discussed using the results of in vitro, in vivo, and clinical studies. Increased understanding of these protective effects and the underlying mechanisms may pave the way for effective use of metformin in IBD patients.

Corrigendum to "Effect of intensive weekend mindfulness-based intervention on BDNF, mitochondria function, and anxiety. A randomized, crossover clinical trial" [Compr. Psychoneuroendocrinol. (2022) 100137].

[This corrects the article DOI: 10.1016/j.cpnec.2022.100137.].

Effect of intensive weekend mindfulness-based intervention on BDNF, mitochondria function, and anxiety. A randomized, crossover clinical trial.

Background: The previous metanalysis found that Mind-body intervention (MBI) improves neuropsychologic well-being and may increase brain-derived growth factor (BDNF). BDNF is a neurotrophic factor related to neuroplasticity. Objective: To evaluate the effect of the short intensive MBI compared to control-relaxation on Site on BDNF and examine if this change is related to mitochondria function or stress-related neurohormonal activity. Methods: Randomized, controlled, two-period cross-over trial conducted in a medical center in Thailand. Healthy-meditation naive Nurse and Occupational Therapy Students, 23 assigned randomly to MBI, and 24 relaxations at the site for 8 h during the weekend. The wash-out period was three months between the two periods. All volunteers took the blood test for BDNF, mitochondrial oxidative phosphorylation (OXPHOS), Cortisol, and Heart rate variability (HRV) measurement before and Visual Analogue Scale for Anxiety (VAS-A), forward and backward digit span after each period. Results: A total of 40 participants finished the trials. The cross over trial analysis showed a significant treatment effect between MBI and Relaxation on-site for the mean VAS-A as 9.89 (95% CI 4.81 to 19.47; P = 0.001), serum BDNF as 1.24 (95% CI 0.16 to 2.32; P = 0.04), and OXPHOS complex-1 was decreased 0.41 (95% CI 0.03-0.29 p = 0.03). There were no significant differences for digit span, cortisol, and HRV. Conclusion: In healthy meditation naïve females, even a short period of MBI may increase serum BDNF and reduce anxiety more than relaxation on-site. The more reduction of OXPHOS complex-1 in the mindfulness group suggests oxidative stress may be a more sensitive indicator than stress-related neurohormonal activity.

Mechanisms and Interventions on Acute Lower Limb Ischemia/Reperfusion Injury: A Review and Insights from Cell to Clinical Investigations.

BACKGROUND: This review aims to highlight mechanistic insights on skeletal muscle ischemia/reperfusion injury (IRI), a potentially life-threatening complication after acute lower limb ischemia. Lower limb IRI produces a wide spectrum of manifestations, ranging from local skeletal muscle necrosis to multi-organ failure. There is increasing evidence from both in vitro and in vivo reports to demonstrate several promising interventions that have successfully reduced IRI in skeletal muscle ischemic models. However, clinical studies to confirm their benefits are still lacking. METHODS: We conducted a comprehensive search of English literature listed in the PubMed database (All related published articles shown in PubMed until September 2020 have been included in this review), using the following keywords: acute limb ischemia, acute arterial occlusion, compartment syndrome, ischemic reperfusion injury, revascularization, and hypoxic reoxygenation. RESULTS: A total of 58 articles pertinent to acute limb ischemia models were identified. The underlying mechanisms associated with IRI in skeletal muscle are due to excessive mitochondrial production of reactive oxygen species (ROS), cellular apoptosis and activation of inflammatory cascades. Several therapeutic interventions including both pharmacological and nonpharmacological treatments have been investigated and some showed promising results. These interventions include anti-oxidation, anti-inflammation, anti-hypertension, controlled-reperfusion, and ischemic preconditioning. Further clinical studies are needed to warrant their use in a clinical setting for lower limb IRI treatment. CONCLUSIONS: This review comprehensively summarizes the mechanisms underlying IRI in lower limb ischemia. The reports currently available regarding the potential therapeutic interventions against lower limb IRI from in vitro, in vivo and clinical studies are presented and discussed. These findings may provide mechanistic insights for devising the strategies to improve the clinical outcomes in IRI patients in the near future. Further clinical studies are needed to warrant their use in a clinical setting for lower limb IRI treatment.

Sexual dimorphism in cardiometabolic and cardiac mitochondrial function in obese rats following sex hormone deprivation.

OBJECTIVE: Our study aims to test the hypothesis that poorer function of cardiac mitochondria in males, under sex hormone-deprived and obese-insulin-resistant conditions, is responsible for a worse cardiometabolic function than females. METHODS: One hundred and forty-four rats were subjected to receive either 12 weeks of normal diet (ND) or a high-fat diet (HFD) consumption following the induction of sex hormone deprivation. Temporal evaluations of metabolic parameters, cardiac autonomic modulation, left ventricular (LV) contractile, and mitochondrial functions were measured after starting each feeding protocol for 4, 8, and 12 weeks. RESULTS: After HFD feeding for 8 weeks, increased plasma insulin and HOMA index were initially observed in male HFD-fed sham-operated rats (M-HFS), male HFD-fed orchiectomized rats (M-HFO), female ND-fed ovariectomized rats (F-OVX), female HFD-fed sham-operated rats (F-HFS), and female HFD-fed ovariectomized rats (F-HFO) groups. In addition, as early as week 4, male ND-fed orchiectomized rats (M-ORX) and M-HFO exhibited impaired cardiac autonomic balance, LV contractile and mitochondrial functions, whereas M-HFS and F-HFO developed these impairments at week 8 and F-OVX and F-HFS exhibited them at week 12. CONCLUSION: We concluded that sex hormone-deprived females are prone to develop metabolic impairments, whereas males are more likely to have cardiac autonomic impairment, LV contractile and mitochondrial dysfunction even in the absence of obese-insulin-resistant condition. However, under estrogen-deprived condition, these impairments were further accelerated and aggravated by obese-insulin resistance.

The effects of doxorubicin on cardiac calcium homeostasis and contractile function.

Cancer is one of the leading causes of death globally and the number of cancer deaths is rising as a result of increased longevity. Doxorubicin (DOX) is one of the most effective anti-neoplastic drugs used to treat various forms of cancer. However, its therapeutic utility is limited by its associated cardiotoxicity, specifically cardiac contractile dysfunction. Current evidence indicates that interference with cardiac intracellular calcium (Ca2+) homeostasis is one of the major causes among the molecular and cellular determinants of DOX-induced cardiotoxicity. This contributes to the development of cardiac contractile dysfunction, which remains a major concern and obstacle in clinical applications. This review comprehensively summarizes the effects of DOX on cardiac Ca2+ homeostasis and contractile function from in vitro, ex vivo, and in vivo studies. It also highlights the information essential for the potential interventions which may support the therapeutic effectiveness in clinical practice for the attenuation of cardiotoxicity in DOX-treated patients.

Acetylcholine exerts cytoprotection against hypoxia/reoxygenation-induced apoptosis, autophagy and mitochondrial impairment through both muscarinic and nicotinic receptors.

Acetylcholine (ACh) has been shown to exert cardioprotection against myocardial ischemia/reperfusion (I/R) injury. However, whether ACh exerts its cardioprotection predominantly through the activation of muscarinic or nicotinic ACh receptors is not fully understood. We investigated the effects of hypoxia/reoxygenation (H/R) in the presence or absence of ACh receptor agonists in H9c2 cells. Cells (2.5 × 105 cells/well) were incubated in the hypoxic chamber with the ischemic solution (30 min) followed by reoxygenation (120 min) with the normal media. ACh or nicotinic ACh receptor agonist (GTS21) was applied 5 min prior to hypoxia, during hypoxia or at reoxygenation onset. Cell viability, apoptosis, ER stress, mitochondrial dynamics and biogenesis were determined. H/R significantly decreased cell viability and mitochondrial biogenesis and increased apoptosis, ER stress, mitochondrial fission and autophagic flux compared with the control. ACh and GTS21 significantly increased cell viability via reducing apoptosis, autophagy, and ER stress. However, ACh and GTS21 increased mitochondrial fusion when applied before or during hypoxia. During reoxygenation onset, only ACh increased mitochondrial biogenesis. Co-treatment with atropine reversed the beneficial effects of ACh and GTS21. Our findings demonstrated that ACh exerted cytoprotection against H/R-induced apoptosis, autophagy and mitochondrial impairment through the activation of both muscarinic and nicotinic receptors.

Targeting mitochondria as a therapeutic anti-gastric cancer approach.

Gastric cancer is regarded as the fifth most common cancer globally but the third most common cancer death. Although systemic chemotherapy is the primary treatment for advanced gastric cancer patients, the outcome of chemotherapy is unsatisfactory. Novel therapeutic strategies and potential alternative treatments are therefore needed to overcome the impact of this disease. At a cellular level, mitochondria play an important role in cell survival and apoptosis. A growing body of studies have shown that mitochondria play a central role in the regulation of cellular function, metabolism, and cell death during carcinogenesis. Interestingly, the impact of mitochondrial dynamics, including fission/fusion and mitophagy, on carcinogenesis and cancer progression has also been reported, suggesting the potential targeting of mitochondrial dynamics for the treatment of cancer. This review not only comprehensively summarizes the homeostasis of gastric cancer cells, but the potential therapeutic interventions for the targeting of mitochondria for gastric cancer therapy are also highlighted and discussed.

Acetylcholine receptor agonists provide cardioprotection in doxorubicin-induced cardiotoxicity via modulating muscarinic M2 and α7 nicotinic receptor expression.

The balance between cardiac sympathetic and parasympathetic activities has been intricately linked to mitochondrial function, cellular oxidative status, and immunomodulation in healthy and diseased myocardium. Cardiac autonomic neuropathy, along with the associated mitochondrial and cellular dysfunction, is an important pathophysiological feature of doxorubicin-induced cardiotoxicity (DIC). We tested the hypothesis that autonomic modulation by activation of acetylcholine receptors (AChR) effectively attenuates DIC. Rats were divided into control (0.9% sodium chloride solution) and doxorubicin groups (DOX, 3 mg/kg/d, 6 doses). Rats in the DOX group were equally subdivided into 4 interventional groups and treated for 30 days: vehicle, α7 nicotinic receptor agonist (PNU: PNU-282987, 3 mg/kg/d), muscarinic receptor agonist (BET: bethanechol, 12 mg/kg/d), and combined α7nAChR and mAChR agonists group (COM). Cardiac biochemical and functional analyses were done. The results show that AChR agonists protected the heart against DIC via improving mitochondrial and cardiac function, which was accompanied by reducing mitochondrial oxidative damage, apoptosis, and inflammation. Strikingly, PNU and BET exerted cardioprotection through different molecular pathways. PNU-mediated α7nAChR activation promoted mitochondrial fusion via upregulation of Mfn1-2 and attenuated DOX-induced autophagy. Contrarily, activation of mAChR by BET attenuated mitochondrial fission and mitophagy. The in vitro experiments confirmed the cytoprotective effects of AChR activation in DOX-treated H9c2 cells without compromising the anticancer effect of DOX in cancer cells. In conclusion, α7nAChR and mAChR agonists exerted cardioprotection against DIC via rebalancing autonomic function, improving mitochondrial function, reducing oxidative stress, and decreased cardiomyocyte apoptosis and inflammation, leading to improved cardiac function.

The morphometric study of the moderator band in Thais.

A moderator band, also known as the septomarginal trabecula, is a group of muscle bundles located in the ventricle of almost all human hearts. The morphology of the moderator band has various forms and several studies have focused mostly on its structure. Thus, in the present study, we sought to study the morphology and morphometry of the moderator band and tried to rearrange the criteria based on the previous studies to classify the moderator band in Thais. The study investigated 67 formalin-fixed human hearts of both sexes obtained from Thai donors aged 24-101 years with mean age at death 69.92 years. The moderator band was evident in 66 of the 67 specimens (98.51%). The moderator band had the mean or median of overall length, thickness, distance to the base of the tricuspid valve, distance to the base of the pulmonary valve, distance to the apex of the right ventricle, the angle at the septal connection, and angle of the papillary, which were 18.9 ± 6.4 mm, 3.17 (2.04-4.55) mm, 33.0 ± 7.97 mm, 38.8 ± 9.62 mm, 56.4 ± 8.09 mm, 50 (30-105)°, 73.9 ± 30.1°, respectively. The mean distance originating point from the supraventricular crest to the anterior papillary muscle was 0.396 ± 0.07 of the distance from the base of the tricuspid valve to the apex of the right ventricle. Our present classification found that crest-like and thick moderator band with complex secondary branching at high origin (type IVc), and low origin (type IVd) were the most common subtypes. This study provided both anatomical and clinical information that should be useful in cardiac surgery, radiology, and cardiac electrophysiological interventions.

Cardioprotective effects of melatonin and metformin against doxorubicin-induced cardiotoxicity in rats are through preserving mitochondrial function and dynamics.

Doxorubicin (Dox) is widely used in chemotherapy regimens for several malignant conditions. Unfortunately, cumulative and irreversible cardiotoxicity of Dox is the most prominent adverse effect which limits its use. Several pharmacological interventions which exert antioxidant properties, including melatonin and metformin, have demonstrated beneficial effects against various cardiac pathological conditions. However, the exact molecular mechanisms underlying their cardioprotective effects are not completely understood. We hypothesized that treatment with either melatonin or metformin provides cardioprotection against Dox-induced cardiotoxicity through mitochondrial protection. Thirty-two male Wistar rats received 6 doses of either 0.9% normal saline solution (0.9% NSS, n = 8) or Dox (3 mg/kg, i.p., n = 24). The Dox-treated rats (n = 8/group) were co-treated with: 1) Vehicle (0.9% NSS), 2) Melatonin (10 mg/kg/day), and 3) Metformin (250 mg/kg/day) for 30 consecutive days via oral gavage. Following the treatment, left ventricular (LV) function, oxidative stress, inflammation, mitochondrial function, dynamics, biogenesis and bioenergetics, mitophagy, autophagy, and apoptosis were determined. Dox induced excessive oxidative stress, inflammation, autophagy, apoptosis, reduced mitochondrial function, dynamics balance, biogenesis, and bioenergetics leading to LV dysfunction. Treatment with either melatonin or metformin exerted equal measures of cardioprotection via reducing oxidative stress, inflammation, autophagy, apoptosis, and improved mitochondrial function, dynamics balance, biogenesis, and bioenergetics in the Dox-treated rats. Melatonin and metformin exerted both anti-cancer and cardioprotective properties, suggesting they have potential roles in concomitant therapy in cancer patients receiving Dox treatment.

Hyperbaric oxygen therapy effectively alleviates D-galactose-induced-age-related cardiac dysfunction via attenuating mitochondrial dysfunction in pre-diabetic rats.

Currently, the prevalence of obesity in aging populations is fast growing worldwide. Aging induced by D-galactose (D-gal) is proven to cause the worsening of cardiac dysfunction in pre-diabetic rats via deteriorating cardiac mitochondrial function. Hyperbaric oxygen therapy (HBOT) has been shown to attenuate D-gal-induced cognitive deterioration through decreased inflammation and apoptosis. We tested the hypothesis that HBOT alleviates D-gal induced cardiac dysfunction via improving mitochondrial function in pre-diabetic rats. Wistar rats (n=56) were fed normal diet or high-fat diet for 12 weeks. For subsequent 8 weeks, they were subcutaneously injected either vehicle (0.9% normal saline) or D-gal (150mg/kg/day). Rats were randomly subdivided into 7 groups at week 21: sham-treated (normal diet fed rats with vehicle (NDV), high-fat diet fed rats with vehicle (HFV), normal diet fed rats with D-gal (NDDg), high-fat diet fed rats with D-gal (HFDg)) and HBOT-treated (HFV, NDDg, HFDg). Sham rats received ambient pressure of oxygen while HBOT-treated ones received 100% oxygen given once daily for 60 minutes at 2 atmosphere absolute. HBOT reduced metabolic impairments, mitochondrial dysfunction and increased autophagy, resulting in an improvement of cardiac function in aged pre-diabetic rats.

Impact of iron overload on bone remodeling in thalassemia.

INTRODUCTION: Iron overload, a state with excessive iron storage in the body, is a common complication in thalassemia patients which leads to multiple organ dysfunctions including the bone. Iron overload-induced bone disease is one of the most common and severe complications of thalassemia including osteoporosis. Currently, osteoporosis is still frequently found in thalassemia even with widely available iron chelation therapy. STUDY SELECTION: Relevant publications published before December 2019 in PubMed database were reviewed. Both pre-clinical studies and clinical trials were obtained using iron overload, thalassemia, osteoporosis, osteoblast, and osteoclast as keywords. RESULTS: Increased ROS production is a hallmark of iron overload-induced impaired bone remodeling. At the cellular level, oxidative stress affects bone remodeling by both osteoblast inhibition and osteoclast activation via many signaling pathways. In thalassemia patients, it has been shown that bone resorption was increased while bone formation was concurrently reduced. CONCLUSION: In this review, reports on the cellular mechanisms of iron overload-associated bone remodeling are comprehensively summarized and presented to provide current understanding this pathological condition. Moreover, current treatments and potential interventions for attenuating bone remodeling in iron overload are also summarized to pave ways for the future discoveries of novel agents that alleviate this condition.

The impact of genetic polymorphisms on weight regain after successful weight loss.

Obesity is associated with an increased risk of various diseases and mortality. Although nearly 50 % of adults have been reported trying to lose weight, the prevalence of obesity has increased. One factor that hinders weight loss-induced decrease in obesity prevalence is weight regain. Although behavioural, psychological and physiological factors associated with weight regain have been reviewed, the information regarding the relationship between weight regain and genetics has not been previously summarised. In this paper, we comprehensively review the association between genetic polymorphisms and weight regain in adults and children with obesity after weight loss. Based on this information, identification of genetic polymorphism in patients who undergo weight loss intervention might be used to estimate their risks of weight regain. Additionally, the genetic-based risk estimation may be used as a guide for physicians and dietitians to provide each of their patients with the most appropriate strategies for weight loss and weight maintenance.

Aging induced by D-galactose aggravates cardiac dysfunction via exacerbating mitochondrial dysfunction in obese insulin-resistant rats.

The prevalence of obesity and an aging population are increasing worldwide. Both obesity and aging are independently known to be associated with cardiac dysfunction. However, in obese insulin-resistant subjects, the effects of aging on metabolic status and cardiac and mitochondrial functions are not completely understood. We hypothesized that in the obese insulin-resistant condition, aging induced by D-galactose increases cardiac senescence markers and aggravates the impairment of metabolic parameters, cardiac and mitochondrial function, and increases oxidative stress, inflammation, apoptosis, and autophagy. Sixty-four male Wistar rats were fed with either normal diet (ND) or high-fat diet (HFD) for 12 weeks. Then, rats were divided into vehicle groups (0.9% NSS, subcutaneous injection (SC)) or D-galactose groups (150 mg/kg/day, SC). After 0.9%NSS or D-galactose treatment for 4 weeks and 8 weeks, metabolic and cardiac functions were determined. The heart was then removed to determine mitochondrial functions and enable biochemical studies. After 4 weeks of D-galactose injection, ND rats treated with D-galactose (NDD4), HFD rats treated with vehicle (HFV4), and HFD rats treated with D-galactose (HFD4) had reduced cardiac function, impaired cardiac mitochondrial function and autophagy, and increased oxidative stress, inflammation, and apoptosis. Interestingly, after 8 weeks, HFD rats treated with D-galactose (HFD8) had the worst impairment of cardiac and mitochondrial function, autophagy, and apoptosis in comparison to the other groups. Aging induced by D-galactose aggravated cardiac dysfunction in obese insulin-resistant rats through the worsening of cardiac mitochondrial function, autophagy, and increased apoptosis in a time-dependent manner.