The Role of Vitamin D in Sleep Disorders of Children and Adolescents: A Systematic Review

This review investigates the association between vitamin D and sleep disorders. Vitamin D is an essential nutrient known to play an important role in the growth and bone health of the human body, but it also appears to play a role in sleep. The goal of our review is to examine the association between vitamin D and sleep disorders in children and adolescents. We summarize the evidence about the role and the mechanism of action of vitamin D in children and adolescents with sleep disorders such as insomnia, obstructive sleep apnea (OSA), restless legs syndrome (RLS), and other sleep disorders. Systematic electronic database searches were conducted using Pubmed and Cochrane Library. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was followed. The studies that met the established inclusion criteria were analyzed and compared. Results suggest a strict relationship between vitamin D deficiency in children and sleep disorders. There is evidence that vitamin D is implicated in the different neurochemical mechanisms involved in sleep regulation and mainly in the serotonergic and dopaminergic pathways. This might be responsible for the association of vitamin D deficiency and restless sleep, sleep hyperhidrosis, OSA, and RLS.     

Crosstalk between Schizophrenia and Metabolic Syndrome: The Role of Oxytocinergic Dysfunction

The high prevalence of metabolic syndrome in persons with schizophrenia has spurred investigational efforts to study the mechanism beneath its pathophysiology. Early psychosis dysfunction is present across multiple organ systems. On this account, schizophrenia may be a multisystem disorder in which one organ system is predominantly affected and where other organ systems are also concurrently involved. Growing evidence of the overlapping neurobiological profiles of metabolic risk factors and psychiatric symptoms, such as an association with cognitive dysfunction, altered autonomic nervous system regulation, desynchrony in the resting-state default mode network, and shared genetic liability, suggest that metabolic syndrome and schizophrenia are connected via common pathways that are central to schizophrenia pathogenesis, which may be underpinned by oxytocin system dysfunction. Oxytocin, a hormone that involves in the mechanisms of food intake and metabolic homeostasis, may partly explain this piece of the puzzle in the mechanism underlying this association. Given its prosocial and anorexigenic properties, oxytocin has been administered intranasally to investigate its therapeutic potential in schizophrenia and obesity. Although the pathophysiology and mechanisms of oxytocinergic dysfunction in metabolic syndrome and schizophrenia are both complex and it is still too early to draw a conclusion upon, oxytocinergic dysfunction may yield a new mechanistic insight into schizophrenia pathogenesis and treatment.     

Preserved Sleep for the Same Level of Respiratory Disturbance in Children with Prader-Willi Syndrome

Debate remains as to how to balance the use of recombinant human growth hormone (rhGH) as an important treatment in Prader-Willi syndrome (PWS) with its potential role in obstructive sleep apnea. This single-center, retrospective study assessed differences in overnight polysomnography results between children with and without PWS and changes in respiratory parameters before and after the initiation of rhGH treatment in those with PWS. Compared with age-, sex-, and body-mass-index-matched controls (n = 87), children with PWS (n = 29) had longer total sleep time (434 ± 72 vs. 365 ± 116 min; p < 0.01), higher sleep efficiency (86 ± 7 vs. 78 ± 15%; p < 0.05), and lower arousal events (8.1 ± 4.5 vs. 13.0 ± 8.9 events/h; p < 0.05). Mean oxygen saturation was lower in PWS children (94.3 ± 6.0 vs. 96.0 ± 2.0%; p < 0.05), with no other differences in respiratory parameters between groups. Eleven children with PWS (38%) met the criteria for further analyses of the impact of rhGH; polysomnography parameters did not change with treatment. Compared with other children undergoing polysomnography, children with PWS had more favorable markers of sleep continuity and lower oxygen saturation for the same level of respiratory disturbance. rhGH administration was not associated with changes in respiratory parameters in PWS.     

The Mystery of Red Blood Cells Extracellular Vesicles in Sleep Apnea with Metabolic Dysfunction

Sleep is very important for overall health and quality of life, while sleep disorder has been associated with several human diseases, namely cardiovascular, metabolic, cognitive, and cancer-related alterations. Obstructive sleep apnea (OSA) is the most common respiratory sleep-disordered breathing, which is caused by the recurrent collapse of the upper airway during sleep. OSA has emerged as a major public health problem and increasing evidence suggests that untreated OSA can lead to the development of various diseases including neurodegenerative diseases. In addition, OSA may lead to decreased blood oxygenation and fragmentation of the sleep cycle. The formation of free radicals or reactive oxygen species (ROS) can emerge and react with nitric oxide (NO) to produce peroxynitrite, thereby diminishing the bioavailability of NO. Hypoxia, the hallmark of OSA, refers to a decline of tissue oxygen saturation and affects several types of cells, playing cell-to-cell communication a vital role in the outcome of this interplay. Red blood cells (RBCs) are considered transporters of oxygen and nutrients to the tissues, and these RBCs are important interorgan communication systems with additional functions, including participation in the control of systemic NO metabolism, redox regulation, blood rheology, and viscosity. RBCs have been shown to induce endothelial dysfunction and increase cardiac injury. The mechanistic links between changes of RBC functional properties and cardiovascular are largely unknown. Extracellular vesicles (EVs) are secreted by most cell types and released in biological fluids both under physiological and pathological conditions. EVs are involved in intercellular communication by transferring complex cargoes including proteins, lipids, and nucleic acids from donor cells to recipient cells. Advancing our knowledge about mechanisms of RBC-EVs formation and their pathophysiological relevance may help to shed light on circulating EVs and to translate their application to clinical practice. We will focus on the potential use of RBC-EVs as valuable diagnostic and prognostic biomarkers and state-specific cargoes, and possibilities as therapeutic vehicles for drug and gene delivery. The use of RBC-EVs as a precision medicine for the diagnosis and treatment of the patient with sleep disorder will improve the prognosis and the quality of life in patients with cardiovascular disease (CVD).     

The Effect of DREADD Activation of Leptin Receptor Positive Neurons in the Nucleus of the Solitary Tract on Sleep Disordered Breathing

Obstructive sleep apnea (OSA) is recurrent obstruction of the upper airway due to the loss of upper airway muscle tone during sleep. OSA is highly prevalent, especially in obesity. There is no pharmacotherapy for OSA. Previous studies have demonstrated the role of leptin, an adipose-tissue-produced hormone, as a potent respiratory stimulant. Leptin signaling via a long functional isoform of leptin receptor, LEPR^b, in the nucleus of the solitary tract (NTS), has been implicated in control of breathing. We hypothesized that leptin acts on LEPR^b positive neurons in the NTS to increase ventilation and maintain upper airway patency during sleep in obese mice. We expressed designer receptors exclusively activated by designer drugs (DREADD) selectively in the LEPR^b positive neurons of the NTS of Lepr^b-Cre-GFP mice with diet-induced obesity (DIO) and examined the effect of DREADD ligand, J60, on tongue muscle activity and breathing during sleep. J60 was a potent activator of LEPR^b positive NTS neurons, but did not stimulate breathing or upper airway muscles during NREM and REM sleep. We conclude that, in DIO mice, the stimulating effects of leptin on breathing during sleep are independent of LEPR^b signaling in the NTS.     

Epigenetic Alterations in Pediatric Sleep Apnea

Pediatric obstructive sleep apnea has significant negative effects on health and behavior in childhood including depression, failure to thrive, neurocognitive impairment, and behavioral issues. It is strongly associated with an increased risk for chronic adult disease such as obesity and diabetes, accelerated atherosclerosis, and endothelial dysfunction. Accumulating evidence suggests that adult-onset non-communicable diseases may originate from early life through a process by which an insult applied at a critical developmental window causes long-term effects on the structure or function of an organism. In recent years, there has been increased interest in the role of epigenetic mechanisms in the pathogenesis of adult disease susceptibility. Epigenetic mechanisms that influence adaptive variability include histone modifications, non-coding RNAs, and DNA methylation. This review will highlight what is currently known about the phenotypic associations of epigenetic modifications in pediatric obstructive sleep apnea and will emphasize the importance of epigenetic changes as both modulators of chronic disease and potential therapeutic targets.     

A Narrative Review of the Association between Obstructive Sleep Apnea and Glaucoma in Adults

Background: Obstructive sleep apnea (OSA) is a sleep disorder, primarily of the upper airway, which not only has a significant impact on quality of life but is also associated with various systemic diseases. Several ophthalmological diseases are also associated with OSA, especially glaucoma. The purpose of this review is to take a closer look at the causality and mutual influence. Methods: A systematic literature search was conducted using PubMed. A total of 19 studies with 316,178 adult participants were included. Results: Eleven of the sixteen studies concentrating on the prevalence of glaucoma in patients with OSA showed an association of both entities. One paper found a higher risk for progression of glaucoma in OSA patients. Five of the sixteen included studies failed to show a correlation between OSA and glaucoma. One study out of three surveying specific ophthalmological parameters showed an influence of OSA therapy on retinal nerve fiber layer (RNFL) thinning and vision. One study showed a rise in intraocular pressure (IOP), while two other studies showed no increase under continuous positive airway pressure (CPAP). Conclusions: Our findings suggest an association between OSA and glaucoma and, especially, between OSA and thinning of RNFL. CPAP therapy appears to be also suitable for patients with comorbid glaucoma.     

Obesity and Its Metabolic Complications: The Role of Adipokines and the Relationship between Obesity,Inflammation, Insulin Resistance,Dyslipidemia and Nonalcoholic Fatty Liver Disease

Accumulating evidence indicates that obesity is closely associated with an increased risk of metabolic diseases such as insulin resistance, type 2 diabetes, dyslipidemia and nonalcoholic fatty liver disease. Obesity results from an imbalance between food intake and energy expenditure, which leads to an excessive accumulation of adipose tissue. Adipose tissue is now recognized not only as a main site of storage of excess energy derived from food intake but also as an endocrine organ. The expansion of adipose tissue produces a number of bioactive substances, known as adipocytokines or adipokines, which trigger chronic low-grade inflammation and interact with a range of processes in many different organs. Although the precise mechanisms are still unclear, dysregulated production or secretion of these adipokines caused by excess adipose tissue and adipose tissue dysfunction can contribute to the development of obesity-related metabolic diseases. In this review, we focus on the role of several adipokines associated with obesity and the potential impact on obesity-related metabolic diseases. Multiple lines evidence provides valuable insights into the roles of adipokines in the development of obesity and its metabolic complications. Further research is still required to fully understand the mechanisms underlying the metabolic actions of a few newly identified adipokines.     

Elevated Monocytic Interleukin-8 Expression under Intermittent Hypoxia Condition and in Obstructive Sleep Apnea Patients

Obstructive sleep apnea (OSA) is a disease with great cardiovascular risk. Interleukin-8 (IL-8), an important chemokine for monocyte chemotactic migration, was studied under intermittent hypoxia condition and in OSA patients. Monocytic THP-1 cells were used to investigate the effect of intermittent hypoxia on the regulation of IL-8 by an intermittent hypoxic culture system. The secreted protein and mRNA levels were studied by means of enzyme-linked immunosorbent assay and RT/real-time PCR. The chemotactic migration of monocytes toward a conditioned medium containing IL-8 was performed by means of the transwell filter migration assay. Peripheral venous blood was collected from 31 adult OSA patients and RNA was extracted from the monocytes for the analysis of IL-8 expression. The result revealed that intermittent hypoxia enhanced the monocytic THP-1 cells to actively express IL-8 at both the secreted protein and mRNA levels, which subsequently increased the migration ability of monocytes toward IL-8. The ERK, PI3K and PKC pathways were demonstrated to contribute to the activation of IL-8 expression by intermittent hypoxia. In addition, increased monocytic IL-8 expression was found in OSA patients, with disease severity dependence and diurnal changes. This study concluded the monocytic IL-8 gene expression can be activated by intermittent hypoxia and increased in OSA patients.     

Glymphatic System Dysfunction and Sleep Disturbance May Contribute to the Pathogenesis and Progression of Parkinson’s Disease

Parkinson’s disease (PD) is a multisystem alpha-synucleinopathic neurodegenerative disease and the most prevalent neurodegenerative disorder after Alzheimer’s disease with a high incidence rate in the elderly population. PD is highly multifactorial in etiology and has complex and wide-ranging pathogenic mechanisms. Environmental exposures and genetic predisposition are prominent risk factors. However, current evidence suggests that an intimate link may exist between the risk factor of sleep disturbance and PD pathogenesis. PD is characterized by the pathological hallmarks of alpha-synuclein aggregations and dopaminergic neuron degeneration in the substantia nigra. The loss of dopamine-producing neurons results in both motor and non-motor symptoms, most commonly, bradykinesia, tremor, rigidity, psychiatric disorders, sleep disorders and gastrointestinal problems. Factors that may exacerbate alpha-synuclein accumulation and dopamine neuron loss include neuroinflammation and glymphatic system impairment. Extracellular alpha-synuclein can induce an inflammatory response which can lead to neural cell death and inhibition of neurogenesis. The glymphatic system functions most optimally to remove extracellular brain solutes during sleep and therefore sleep disruption may be a crucial progression factor as well as a risk factor. This literature review interprets and analyses data from experimental and epidemiological studies to determine the recent advances in establishing a relationship between glymphatic system dysfunction, sleep disturbance, and PD pathogenesis and progression. This review addresses current limitations surrounding the ability to affirm a causal link between improved glymphatic clearance by increased sleep quality in PD prevention and management. Furthermore, this review proposes potential therapeutic approaches that could utilize the protective mechanism of sleep, to promote glymphatic clearance that therefore may reduce disease progression as well as symptom severity in PD patients.     

Disruption of Circadian Rhythm Genes in Obstructive Sleep Apnea Patients—Possible Mechanisms Involved and Clinical Implication

Obstructive sleep apnea (OSA) is a chronic condition characterized by recurrent pauses in breathing caused by the collapse of the upper airways, which results in intermittent hypoxia and arousals during the night. The disorder is associated with a vast number of comorbidities affecting different systems, including cardiovascular, metabolic, psychiatric, and neurological complications. Due to abnormal sleep architecture, OSA patients are at high risk of circadian clock disruption, as has been reported in several recent studies. The circadian clock affects almost all daily behavioral patterns, as well as a plethora of physiological processes, and might be one of the key factors contributing to OSA complications. An intricate interaction between the circadian clock and hypoxia may further affect these processes, which has a strong foundation on the molecular level. Recent studies revealed an interaction between hypoxia-inducible factor 1 (HIF-1), a key regulator of oxygen metabolism, and elements of circadian clocks. This relationship has a strong base in the structure of involved elements, as HIF-1 as well as PER, CLOCK, and BMAL, belong to the same Per-Arnt-Sim domain family. Therefore, this review summarizes the available knowledge on the molecular mechanism of circadian clock disruption and its influence on the development and progression of OSA comorbidities.     

Reconstitution of Monocyte Subsets and PD-L1 Expression but Not T Cell PD-1 Expression in Obstructive Sleep Apnea Patients upon PAP Therapy

Obstructive sleep apnea (OSA) is characterized by nocturnal breathing intermissions resulting in oxidative stress and eventually, a low-grade systemic inflammation. The study aimed to investigate the impact of positive airway pressure (PAP) therapy on the inflammatory milieu as measured by monocyte and T cell phenotypic alterations. Participants were assessed for their OSA severity before PAP therapy and about six months later, including patient-reported outcome and therapy usage by telemetry readout. The distributions of the CD14/CD16-characterized monocyte subsets as well as the CD4/CD8-characterized effector T cell subsets with regard to their PD-1 and PD-L1 expression were analyzed by flow cytometry from blood samples. Data of 25 patients revealed a significant reconstitution of the monocyte subset distribution and a decrease in PD-L1 expression on pan-monocytes and CD8⁺ T cells without an association to initial AHI and overweight. The PD-1 expression was still increased on T cell subsets, especially on CD4⁺ TH17/22 cells. We conclude that PAP therapy might have a rapid effect on the monocyte phenotype and overall PD-L1 expression levels. However, T cell immune alterations especially on TH17/22 cells persist longer, indicating an ongoing disturbance of the adaptive immune system.     

The Genetic Basis for the Increased Prevalence of Metabolic Syndrome among Post-Traumatic Stress Disorder Patients

Post-traumatic stress disorder (PTSD) is a highly debilitating psychiatric disorder that can be triggered by exposure to extreme trauma. Even if PTSD is primarily a psychiatric condition, it is also characterized by adverse somatic comorbidities. One illness commonly co-occurring with PTSD is Metabolic syndrome (MetS), which is defined by a set of health risk/resilience factors including obesity, elevated blood pressure, lower high-density lipoprotein cholesterol, higher low-density lipoprotein cholesterol, higher triglycerides, higher fasting blood glucose and insulin resistance. Here, phenotypic association between PTSD and components of MetS are tested on a military veteran cohort comprising chronic PTSD presentation (n = 310, 47% cases, 83% male). Consistent with previous observations, we found significant phenotypic correlation between the various components of MetS and PTSD severity scores. To examine if this observed symptom correlations stem from a shared genetic background, we conducted genetic correlation analysis using summary statistics data from large-scale genetic studies. Our results show robust positive genetic correlation between PTSD and MetS (r_g[SE] = 0.33 [0.056], p = 4.74E-09), and obesity-related components of MetS (r_g = 0.25, SE = 0.05, p = 6.4E-08). Prioritizing genomic regions with larger local genetic correlation implicate three significant loci. Overall, these findings show significant genetic overlap between PTSD and MetS, which may in part account for the markedly increased occurrence of MetS among PTSD patients.     

Proteomic Biomarkers of the Apnea Hypopnea Index and Obstructive Sleep Apnea: Insights into the Pathophysiology of Presence,Severity, and Treatment Response

Obstructive sleep apnea (OSA), a disease associated with excessive sleepiness and increased cardiovascular risk, affects an estimated 1 billion people worldwide. The present study examined proteomic biomarkers indicative of presence, severity, and treatment response in OSA. Participants (n = 1391) of the Stanford Technology Analytics and Genomics in Sleep study had blood collected and completed an overnight polysomnography for scoring the apnea–hypopnea index (AHI). A highly multiplexed aptamer-based array (SomaScan) was used to quantify 5000 proteins in all plasma samples. Two separate intervention-based cohorts with sleep apnea (n = 41) provided samples pre- and post-continuous/positive airway pressure (CPAP/PAP). Multivariate analyses identified 84 proteins (47 positively, 37 negatively) associated with AHI after correction for multiple testing. Of the top 15 features from a machine learning classifier for AHI ≥ 15 vs. AHI < 15 (Area Under the Curve (AUC) = 0.74), 8 were significant markers of both AHI and OSA from multivariate analyses. Exploration of pre- and post-intervention analysis identified 5 of the 84 proteins to be significantly decreased following CPAP/PAP treatment, with pathways involving endothelial function, blood coagulation, and inflammatory response. The present study identified PAI-1, tPA, and sE-Selectin as key biomarkers and suggests that endothelial dysfunction and increased coagulopathy are important consequences of OSA, which may explain the association with cardiovascular disease and stroke.     

Metabolic Syndrome: Updates on Pathophysiology and Management in 2021

Metabolic syndrome (MetS) forms a cluster of metabolic dysregulations including insulin resistance, atherogenic dyslipidemia, central obesity, and hypertension. The pathogenesis of MetS encompasses multiple genetic and acquired entities that fall under the umbrella of insulin resistance and chronic low-grade inflammation. If left untreated, MetS is significantly associated with an increased risk of developing diabetes and cardiovascular diseases (CVDs). Given that CVDs constitute by far the leading cause of morbidity and mortality worldwide, it has become essential to investigate the role played by MetS in this context to reduce the heavy burden of the disease. As such, and while MetS relatively constitutes a novel clinical entity, the extent of research about the disease has been exponentially growing in the past few decades. However, many aspects of this clinical entity are still not completely understood, and many questions remain unanswered to date. In this review, we provide a historical background and highlight the epidemiology of MetS. We also discuss the current and latest knowledge about the histopathology and pathophysiology of the disease. Finally, we summarize the most recent updates about the management and the prevention of this clinical syndrome.     

Chronic Inflammation as the Underlying Mechanism of the Development of Lung Diseases in Psoriasis: A Systematic Review

Psoriasis is a systemic inflammatory disease caused by dysfunctional interactions between the innate and adaptive immune responses. The systemic inflammation in psoriasis may be associated with the development of comorbidities, including lung diseases. In this review, we aimed to provide a summary of the evidence regarding the prevalence of lung diseases in patients with psoriasis and the potential underlying mechanisms. Twenty-three articles published between March 2010 and June 2021 were selected from 195 initially identified records. The findings are discussed in terms of the prevalence of asthma, chronic obstructive pulmonary disease, interstitial lung disease, obstructive sleep apnea, pulmonary hypertension, and sarcoidosis in psoriasis. A higher prevalence of lung diseases in psoriasis has been confirmed in asthma, chronic obstructive pulmonary disease, obstructive sleep apnea, and pulmonary hypertension. These conditions are important as they are previously unrecognized causes of morbidity and mortality in psoriasis. The development of lung diseases in patients with psoriasis can be explained by several mechanisms, including common risk factors, shared immune and molecular characteristics associated with chronic inflammation, as well as other mechanisms. Understanding the prevalence of lung diseases in psoriasis and their underlying mechanisms can help implement appropriate preventative and therapeutic strategies to address respiratory diseases in patients with psoriasis.     

阻塞性睡眠呼吸暂停综合征与心律失常的关系

目的探讨阻塞性睡眠呼吸暂停综合征(OSAS)对心血管系统的影响和治疗方法。方法选择阻塞性睡眠呼吸暂停综合征患者80例采用l2导联动态心电图记录系统,连续监测24h与80例健康对照组进行比较;40例行UPPP手术治疗后24h动态心电图与40例健康对照组进行比较。结果动态心电图检出有OSAS和无OSAS患者夜间心律失常的发生率存在显著统计学差异(P<0.05),有OSAS组患者夜间心律失常的发生率明显高于对照组;行PUUU手术治疗后夜间心律失常的发生率与40例健康对照组比较,2者间比较差异无显著性(P>0.05)。结论阻塞性睡眠呼吸暂停综合征的心律失常发生率较高,临床应予以足够重视。必要时需行手术治疗,治疗后心律失常发生率明显下降。     

A-FABP in Metabolic Diseases and the Therapeutic Implications: An Update

Adipocyte fatty acid-binding protein (A-FABP), which is also known as ap2 or FABP4, is a fatty acid chaperone that has been further defined as a fat-derived hormone. It regulates lipid homeostasis and is a key mediator of inflammation. Circulating levels of A-FABP are closely associated with metabolic syndrome and cardiometabolic diseases with imminent diagnostic and prognostic significance. Numerous animal studies have elucidated the potential underlying mechanisms involving A-FABP in these diseases. Recent studies demonstrated its physiological role in the regulation of adaptive thermogenesis and its pathological roles in ischemic stroke and liver fibrosis. Due to its implication in various diseases, A-FABP has become a promising target for the development of small molecule inhibitors and neutralizing antibodies for disease treatment. This review summarizes the clinical and animal findings of A-FABP in the pathogenesis of cardio-metabolic diseases in recent years. The underlying mechanism and its therapeutic implications are also highlighted.     

When the Locus Coeruleus Speaks Up in Sleep: Recent Insights,Emerging Perspectives

For decades, numerous seminal studies have built our understanding of the locus coeruleus (LC), the vertebrate brain’s principal noradrenergic system. Containing a numerically small but broadly efferent cell population, the LC provides brain-wide noradrenergic modulation that optimizes network function in the context of attentive and flexible interaction with the sensory environment. This review turns attention to the LC’s roles during sleep. We show that these roles go beyond down-scaled versions of the ones in wakefulness. Novel dynamic assessments of noradrenaline signaling and LC activity uncover a rich diversity of activity patterns that establish the LC as an integral portion of sleep regulation and function. The LC could be involved in beneficial functions for the sleeping brain, and even minute alterations in its functionality may prove quintessential in sleep disorders.     

Garlic Derived Diallyl Trisulfide in Experimental Metabolic Syndrome: Metabolic Effects and Cardioprotective Role

This study aimed to examine the effects of diallyl trisulfide (DATS), the most potent polysulfide derived from garlic, on metabolic syndrome and myocardial function in rats with metabolic syndrome (MetS). For that purpose, we used 36 male Wistar albino rats divided into control rats, rats with MetS and MetS rats treated with 40 mg/kg of DATS every second day for 3 weeks. In the first part, we studied the impact of DATS on MetS control and found that DATS significantly raised H₂S, decreased homocysteine and glucose levels and enhanced lipid and antioxidative, while reducing prooxidative parameters. Additionally, this polysulfide improved cardiac function. In the second part, we investigated the impact of DATS on ex vivo induced ischemia/reperfusion (I/R) heart injury and found that DATS consumption significantly improved cardiodynamic parameters and prevented oxidative and histo-architectural variation in the heart. In addition, DATS significantly increased relative gene expression of eNOS, SOD-1 and -2, Bcl-2 and decreased relative gene expression of NF-κB, IL-17A, Bax, and caspases-3 and -9. Taken together, the data show that DATS can effectively mitigate MetS and have protective effects against ex vivo induced myocardial I/R injury in MetS rat.