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  1. Article ; Online: Diabetes-related perturbations in the integrity of physiologic barriers.

    Mooradian, Arshag D

    Journal of diabetes and its complications

    2023  Volume 37, Issue 8, Page(s) 108552

    Abstract: One of the hallmarks of health is the integrity of barriers at the cellular and tissue levels. The two cardinal functions of barriers include preventing access of deleterious elements of the environment (barrier function) while facilitating the transport ...

    Abstract One of the hallmarks of health is the integrity of barriers at the cellular and tissue levels. The two cardinal functions of barriers include preventing access of deleterious elements of the environment (barrier function) while facilitating the transport of essential ions, signaling molecules and nutrients needed to maintain the internal milieu (transport function). There are several cellular and subcellular barriers and some of these barriers can be interrelated. The principal physiologic barriers include blood-retinal barrier, blood-brain barrier, blood-testis barrier, renal glomerular/tubular barrier, intestinal barrier, pulmonary blood-alveolar barrier, blood-placental barrier and skin barrier. Tissue specific barriers are the result of the vasculature, cellular composition of the tissue and extracellular matrix within the tissue. Uncontrolled diabetes and acute hyperglycemia may disrupt the integrity of physiologic barriers, primarily through altering the vascular integrity of the tissues and may well contribute to the clinically recognized complications of diabetes. Although diabetes is a systemic disease, some of the organs display clinically significant deterioration in function while others undergo subclinical changes. The pathophysiology of the disruption of these barriers is not entirely clear but it may be related to diabetes-related cellular stress. Understanding the mechanisms of diabetes related dysfunction of various physiologic barriers might help identifying novel therapeutic targets for reducing clinically significant complications of diabetes.
    MeSH term(s) Female ; Pregnancy ; Male ; Humans ; Placenta ; Blood-Brain Barrier ; Blood-Retinal Barrier ; Hyperglycemia/complications ; Diabetes Complications ; Diabetes Mellitus
    Language English
    Publishing date 2023-06-20
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 1105840-7
    ISSN 1873-460X ; 1056-8727
    ISSN (online) 1873-460X
    ISSN 1056-8727
    DOI 10.1016/j.jdiacomp.2023.108552
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  2. Article ; Online: Cardioprotective antihyperglycemic drugs ameliorate endoplasmic reticulum stress.

    Mooradian, Arshag D / Haas, Michael J

    American journal of physiology. Cell physiology

    2023  Volume 326, Issue 1, Page(s) C89–C94

    Abstract: Cellular stress, notably oxidative, inflammatory, and endoplasmic reticulum (ER) stress, is implicated in the pathogenesis of cardiovascular disease. Modifiable risk factors for cardiovascular disease such as diabetes, hypercholesterolemia, saturated fat ...

    Abstract Cellular stress, notably oxidative, inflammatory, and endoplasmic reticulum (ER) stress, is implicated in the pathogenesis of cardiovascular disease. Modifiable risk factors for cardiovascular disease such as diabetes, hypercholesterolemia, saturated fat consumption, hypertension, and cigarette smoking cause ER stress whereas currently known cardioprotective drugs with diverse pharmacodynamics share a common pleiotropic effect of reducing ER stress. Selective targeting of oxidative stress with known antioxidative vitamins has been ineffective in reducing cardiovascular risk. This "antioxidant paradox" is partially attributed to the unexpected aggravation of ER stress by the antioxidative agents used. In contrast, some of the contemporary antihyperglycemic drugs inhibit both oxidative stress and ER stress in human coronary artery endothelial cells. Unlike sulfonylureas, meglitinides, α glucosidase inhibitors, and thiazolidinediones, metformin, glucagon-like peptide 1 receptor agonists, and sodium-glucose cotransporter 2 inhibitors are the only antihyperglycemic drugs that reduce ER stress caused by pharmacological agents (tunicamycin) or hyperglycemic conditions. Clinical trials with selective ER stress modifiers are needed to test the suitability of ER stress as a therapeutic target for cardiovascular disease.
    MeSH term(s) Humans ; Hypoglycemic Agents/pharmacology ; Hypoglycemic Agents/therapeutic use ; Cardiovascular Diseases/drug therapy ; Endothelial Cells ; Endoplasmic Reticulum Stress ; Antioxidants/pharmacology
    Chemical Substances Hypoglycemic Agents ; Antioxidants
    Language English
    Publishing date 2023-11-27
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 392098-7
    ISSN 1522-1563 ; 0363-6143
    ISSN (online) 1522-1563
    ISSN 0363-6143
    DOI 10.1152/ajpcell.00470.2023
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  3. Article ; Online: Endoplasmic reticulum stress: A common pharmacologic target of cardioprotective drugs.

    Mooradian, Arshag D / Haas, Michael J

    European journal of pharmacology

    2022  Volume 931, Page(s) 175221

    Abstract: Despite the advances made in cardiovascular disease prevention, there is still substantial residual risk of adverse cardiovascular events. Contemporary evidence suggests that additional reduction in cardiovascular disease risk can be achieved through ... ...

    Abstract Despite the advances made in cardiovascular disease prevention, there is still substantial residual risk of adverse cardiovascular events. Contemporary evidence suggests that additional reduction in cardiovascular disease risk can be achieved through amelioration of cellular stresses, notably inflammatory stress and endoplasmic reticulum (ER) stress. Only two clinical trials with anti-inflammatory agents have supported the role of inflammatory stress in cardiovascular risk. However, there are no clinical trials with selective ER stress modifiers to test the hypothesis that reducing ER stress can reduce cardiovascular disease. Nevertheless, the ER stress hypothesis is supported by recent pharmacologic studies revealing that currently available cardioprotective drugs share a common property of reducing ER stress. These drug classes include angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, mineralocorticoid receptor blockers, β-adrenergic receptor blockers, statins, and select antiglycemic agents namely, metformin, glucagon like peptide 1 receptor agonists and sodium glucose cotransporter 2 inhibitors. Although these drugs ameliorate common risk factors for cardiovascular disease, such as hypertension, hypercholesterolemia and hyperglycemia, their cardioprotective effects may be partially independent of their principal effects on cardiovascular risk factors. Clinical trials with selective ER stress modifiers are needed to test the hypothesis that reducing ER stress can reduce cardiovascular disease.
    MeSH term(s) Humans ; Adrenergic beta-Antagonists/pharmacology ; Angiotensin Receptor Antagonists/pharmacology ; Cardiovascular Diseases/drug therapy ; Cardiovascular Diseases/prevention & control ; Endoplasmic Reticulum Stress ; Sodium-Glucose Transporter 2 Inhibitors/pharmacology
    Chemical Substances Adrenergic beta-Antagonists ; Angiotensin Receptor Antagonists ; Sodium-Glucose Transporter 2 Inhibitors
    Language English
    Publishing date 2022-08-23
    Publishing country Netherlands
    Document type Journal Article ; Review
    ZDB-ID 80121-5
    ISSN 1879-0712 ; 0014-2999
    ISSN (online) 1879-0712
    ISSN 0014-2999
    DOI 10.1016/j.ejphar.2022.175221
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  4. Article ; Online: Potential Therapeutic Agents That Target ATP Binding Cassette A1 (ABCA1) Gene Expression.

    Haas, Michael J / Mooradian, Arshag D

    Drugs

    2022  Volume 82, Issue 10, Page(s) 1055–1075

    Abstract: The cholesterol efflux protein ATP binding cassette protein A1 (ABCA) and apolipoprotein A1 (apo A1) are key constituents in the process of reverse-cholesterol transport (RCT), whereby excess cholesterol in the periphery is transported to the liver where ...

    Abstract The cholesterol efflux protein ATP binding cassette protein A1 (ABCA) and apolipoprotein A1 (apo A1) are key constituents in the process of reverse-cholesterol transport (RCT), whereby excess cholesterol in the periphery is transported to the liver where it can be converted primarily to bile acids for either use in digestion or excreted. Due to their essential roles in RCT, numerous studies have been conducted in cells, mice, and humans to more thoroughly understand the pathways that regulate their expression and activity with the goal of developing therapeutics that enhance RCT to reduce the risk of cardiovascular disease. Many of the drugs and natural compounds examined target several transcription factors critical for ABCA1 expression in both macrophages and the liver. Likewise, several miRNAs target not only ABCA1 but also the same transcription factors that are critical for its high expression. However, after years of research and many preclinical and clinical trials, only a few leads have proven beneficial in this regard. In this review we discuss the various transcription factors that serve as drug targets for ABCA1 and provide an update on some important leads.
    MeSH term(s) ATP Binding Cassette Transporter 1/genetics ; ATP-Binding Cassette Transporters/genetics ; ATP-Binding Cassette Transporters/metabolism ; Adenosine Triphosphate ; Animals ; Cholesterol/metabolism ; Gene Expression ; Humans ; Mice ; Transcription Factors/genetics ; Transcription Factors/metabolism
    Chemical Substances ABCA1 protein, human ; ABCA1 protein, mouse ; ATP Binding Cassette Transporter 1 ; ATP-Binding Cassette Transporters ; Transcription Factors ; Adenosine Triphosphate (8L70Q75FXE) ; Cholesterol (97C5T2UQ7J)
    Language English
    Publishing date 2022-07-21
    Publishing country New Zealand
    Document type Journal Article ; Review
    ZDB-ID 120316-2
    ISSN 1179-1950 ; 0012-6667
    ISSN (online) 1179-1950
    ISSN 0012-6667
    DOI 10.1007/s40265-022-01743-x
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    Zs.A 762: Show issues Location:
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  5. Article: In search for an alternative to sugar to reduce obesity.

    Mooradian, Arshag D

    International journal for vitamin and nutrition research. Internationale Zeitschrift fur Vitamin- und Ernahrungsforschung. Journal international de vitaminologie et de nutrition

    2019  Volume 89, Issue 3-4, Page(s) 113–117

    Abstract: ... with sugar or hollowing out the sugar crystals. Naturally occurring rare sugars such as D-allulose (D-psicose ... D-tagatose, D-sorbose and D-allose are attractive sweeteners. They do have the bulk and the mouth ... fill of table sugar with reduced caloric content (0.2 kcal/g for D-allulose). Additional ...

    Abstract Consumption of table sugar has been increasing despite the warnings of public health officials as to the potential adverse consequences of sugar consumption. The World Health Organization recommends restricting consumption of sugars to no more than 10% of daily caloric intake, with a proposal to lower this level to 5% or less for optimal health. Unfortunately substituting sugar with the currently available artificial sweeteners does not appear to have favorable clinical effects. Given the health-related concerns with the currently available sweeteners such as increased risk of obesity and type 2 diabetes there is renewed interest in identifying a safe and palatable sweetener. The sweet extracts of natural plants such as stevia and monk fruit as well as naturally occurring rare sugars have become attractive alternatives. Although most of the sweeteners are sugars, there are some proteins such as braziien and miraculin that have intense sweetness and are being developed as sweeteners. Several companies are pursuing the development of "bitterness-blockers" to remove flavor defects. Other novel approaches include coating mineral carriers with sugar or hollowing out the sugar crystals. Naturally occurring rare sugars such as D-allulose (D-psicose), D-tagatose, D-sorbose and D-allose are attractive sweeteners. They do have the bulk and the mouth fill of table sugar with reduced caloric content (0.2 kcal/g for D-allulose). Additional randomized controlled trials are necessary to define the long term safety and efficacy of these sugars.
    MeSH term(s) Diabetes Mellitus, Type 2/metabolism ; Dietary Sucrose ; Humans ; Obesity ; Sugars ; Sweetening Agents/chemistry ; Sweetening Agents/metabolism
    Chemical Substances Dietary Sucrose ; Sugars ; Sweetening Agents
    Language English
    Publishing date 2019-02-12
    Publishing country Switzerland
    Document type Journal Article ; Randomized Controlled Trial
    ZDB-ID 120692-8
    ISSN 0300-9831
    ISSN 0300-9831
    DOI 10.1024/0300-9831/a000531
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  6. Article ; Online: Age-Related Resistance to Thyroid Hormone Action.

    Mooradian, Arshag D

    Drugs & aging

    2019  Volume 36, Issue 11, Page(s) 1007–1014

    Abstract: The age-related resistance to thyroid hormones (THs) explains the paucity of symptoms and signs of hyperthyroidism in older adults and may partly explain the myriad of symptoms and signs of hypothyroidism in biochemically euthyroid older people. This ... ...

    Abstract The age-related resistance to thyroid hormones (THs) explains the paucity of symptoms and signs of hyperthyroidism in older adults and may partly explain the myriad of symptoms and signs of hypothyroidism in biochemically euthyroid older people. This review considers the available data on the mechanisms underlying TH resistance with aging and compares these physiologic changes with the changes observed in congenital TH resistance syndromes. Aging is associated with alterations in TH economy along with a host of changes in the responsiveness of various tissues to THs. The age-related resistance to THs can be attributed to decreased TH transport to tissues, decreased nuclear receptor occupancy, decreased activation of thyroxine to triiodothyronine, and alterations in TH responsive gene expression. Although an increase in serum TH levels is expected in syndromes of TH resistance, unchanged serum TH levels in the euthyroid elderly is the result of increased sensitivity to TH negative feedback with increased suppression of thyroid-stimulating hormone, decreased thyroidal sensitivity to thyroid-stimulating hormone, and decreased TH production and secretion. The current clinical evidence suggests that the age-related TH resistance is mostly an adaptive response of the aging organism. It is tempting to speculate that similar changes can occur prematurely in a group of younger people who present with signs and symptoms of hypothyroidism despite normal serum thyroid function tests.
    MeSH term(s) Aged ; Aged, 80 and over ; Aging/genetics ; Aging/metabolism ; Animals ; Humans ; Hyperthyroidism/genetics ; Hyperthyroidism/metabolism ; Hypothyroidism/genetics ; Hypothyroidism/metabolism ; Iodide Peroxidase/genetics ; Male ; Receptors, Thyroid Hormone/genetics ; Thyroid Hormones/blood ; Thyroid Hormones/genetics ; Thyroid Hormones/metabolism ; Thyroxine/blood ; Thyroxine/genetics ; Thyroxine/metabolism ; Triiodothyronine/blood ; Triiodothyronine/genetics ; Triiodothyronine/metabolism
    Chemical Substances Receptors, Thyroid Hormone ; Thyroid Hormones ; Triiodothyronine (06LU7C9H1V) ; Iodide Peroxidase (EC 1.11.1.8) ; Thyroxine (Q51BO43MG4)
    Language English
    Publishing date 2019-09-12
    Publishing country New Zealand
    Document type Journal Article ; Review
    ZDB-ID 1075770-3
    ISSN 1179-1969 ; 1170-229X
    ISSN (online) 1179-1969
    ISSN 1170-229X
    DOI 10.1007/s40266-019-00711-7
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  7. Article ; Online: Evidence-Based Cardiovascular Risk Management in Diabetes.

    Mooradian, Arshag D

    American journal of cardiovascular drugs : drugs, devices, and other interventions

    2019  Volume 19, Issue 5, Page(s) 439–448

    Abstract: Multipronged risk management in diabetes has contributed to the recent decline in cardiovascular mortality. Few antihyperglycemic drugs have been conclusively shown to have cardioprotective effects. These include metformin, liraglutide, semaglutide, ... ...

    Abstract Multipronged risk management in diabetes has contributed to the recent decline in cardiovascular mortality. Few antihyperglycemic drugs have been conclusively shown to have cardioprotective effects. These include metformin, liraglutide, semaglutide, dulaglutide, and sodium-glucose cotransporter-2 inhibitors. Statins are the cornerstone of treatment for people with established coronary artery disease (CAD) or at risk of CAD. In patients with persistent low-density lipoprotein cholesterol (LDL-C) levels > 70 mg/dL, the addition of ezetimibe or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors is recommended. In general, angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers should be included in the treatment regimen. The goal is to have blood pressure < 140/90 mmHg, whereas a lower goal of < 130/80 mmHg is recommended in patients with CAD or proteinuria (> 1 g/day). Aspirin antiplatelet therapy should be restricted for people with established CAD or those with multiple CAD risk factors. While antiobesity medications have a modest role in managing obesity, bariatric surgery in people with body mass index (BMI) ≥ 40 or ≥ 35 with comorbidities can substantially affect quality of life and may reduce cardiovascular risks. Prescribing therapeutic agents should take into consideration a variety of factors, including the patient's preferences and the drug's affordability, side effect profile, and proven cardiovascular benefit.
    MeSH term(s) Cardiovascular Diseases/etiology ; Diabetes Mellitus, Type 2/drug therapy ; Evidence-Based Medicine/methods ; Humans ; Hypoglycemic Agents/adverse effects ; Hypoglycemic Agents/therapeutic use ; Risk Factors ; Risk Management
    Chemical Substances Hypoglycemic Agents
    Language English
    Publishing date 2019-02-21
    Publishing country New Zealand
    Document type Journal Article ; Review
    ZDB-ID 2052547-3
    ISSN 1179-187X ; 1175-3277
    ISSN (online) 1179-187X
    ISSN 1175-3277
    DOI 10.1007/s40256-019-00336-6
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  8. Article ; Online: Reduced cellular glucose transport confers natural protection against dextrose-induced superoxide generation and endoplasmic reticulum stress in domestic hen.

    Mooradian, Arshag D / Haas, Michael J

    Physiological reports

    2021  Volume 9, Issue 7, Page(s) e14816

    Abstract: Normal blood glucose levels in avian species are two to fourfold higher than that in humans and the higher blood glucose levels in birds do not cause adverse effects. Endothelial cells isolated from the aorta of the domestic hen (Gallus gallus domesticus) ...

    Abstract Normal blood glucose levels in avian species are two to fourfold higher than that in humans and the higher blood glucose levels in birds do not cause adverse effects. Endothelial cells isolated from the aorta of the domestic hen (Gallus gallus domesticus) and chicken aortic smooth muscle cells (CAOSMC) were compared to human coronary artery endothelial cells (HCAEC) and human primary aortic smooth muscle cells (HASMC). Superoxide (SO) generation was measured using a superoxide-reactive probe. ER stress was measured using the placental alkaline phosphatase assay (ES-TRAP). Glucose transport kinetics were determined using the
    MeSH term(s) Animals ; Biological Transport ; Cells, Cultured ; Chickens ; Endoplasmic Reticulum Stress ; Endothelial Cells/drug effects ; Endothelial Cells/metabolism ; Endothelium, Vascular/cytology ; Glucose/metabolism ; Humans ; Oxidants/pharmacology ; Oxidative Stress ; Superoxides/metabolism
    Chemical Substances Oxidants ; Superoxides (11062-77-4) ; Glucose (IY9XDZ35W2)
    Language English
    Publishing date 2021-04-04
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2724325-4
    ISSN 2051-817X ; 2051-817X
    ISSN (online) 2051-817X
    ISSN 2051-817X
    DOI 10.14814/phy2.14816
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  9. Article ; Online: Management of Hyperglycemia in Older Adults with Type 2 Diabetes.

    Gandhi, Gunjan Y / Mooradian, Arshag D

    Drugs & aging

    2021  Volume 39, Issue 1, Page(s) 39–58

    Abstract: The increasing incidence of type 2 diabetes in the general population as well as enhanced life expectancy has resulted in a rapid rise in the prevalence of diabetes in the older population. Diabetes causes significant morbidity and impairs quality of ... ...

    Abstract The increasing incidence of type 2 diabetes in the general population as well as enhanced life expectancy has resulted in a rapid rise in the prevalence of diabetes in the older population. Diabetes causes significant morbidity and impairs quality of life. Managing diabetes in older adults is a daunting task due to unique health and psychosocial challenges. Medical management is complicated by polypharmacy, cognitive impairment, urinary incontinence, injurious falls, and persistent pain. Health care providers now have several traditional and contemporary pharmacologic agents to manage diabetes. Avoidance of hypoglycemia is critical; however, evidence-based guidelines are lacking due to the paucity of clinical trials in older adults. For many in this population, maintaining independence is more important than adherence to published guidelines to prevent diabetes complications. The goal of diabetes care in older adults is to enhance the quality of life without subjecting these patients to intrusive and complicated interventions. Recent technological advancements such as continuous glucose monitoring systems can have crucial supplementary benefits in the geriatric population.
    MeSH term(s) Aged ; Blood Glucose ; Blood Glucose Self-Monitoring ; Diabetes Mellitus, Type 2/complications ; Diabetes Mellitus, Type 2/drug therapy ; Humans ; Hyperglycemia/complications ; Hyperglycemia/drug therapy ; Quality of Life
    Chemical Substances Blood Glucose
    Language English
    Publishing date 2021-12-18
    Publishing country New Zealand
    Document type Journal Article ; Review
    ZDB-ID 1075770-3
    ISSN 1179-1969 ; 1170-229X
    ISSN (online) 1179-1969
    ISSN 1170-229X
    DOI 10.1007/s40266-021-00910-1
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  10. Article ; Online: Clinical Considerations for Insulin Therapy in Older Adults with Type 1 Diabetes.

    Gandhi, Gunjan Y / Mooradian, Arshag D

    Drugs & aging

    2021  Volume 39, Issue 1, Page(s) 23–37

    Abstract: Type 1 diabetes represents an autoimmune condition with a strong inherited background, and its incidence is increasing worldwide. About 25% of such cases are diagnosed in adulthood, some even as late as the ninth decade of life. The number of older ... ...

    Abstract Type 1 diabetes represents an autoimmune condition with a strong inherited background, and its incidence is increasing worldwide. About 25% of such cases are diagnosed in adulthood, some even as late as the ninth decade of life. The number of older adults with type 1 diabetes is increasing due to improvements in care and decreased mortality rate. However, there is a lack of clinical trials in people older than 70 years of age with type 1 diabetes complicated with comorbidities, frailty, and dependency. The management of type 1 diabetes and the goals of therapy should be individualized based on the patient's health status and life expectancy. In healthier older adults, insulin treatment regimens (multiple daily insulin injections or insulin pump therapy) that approximate the normal physiology of insulin secretion should be used to achieve lower glycemic goals, while reducing the risk of hypoglycemia with frequent glucose monitoring (preferably using continuous glucose monitoring systems). For frail individuals with poor health, simpler insulin regimens and less stringent glycemic targets would be more appropriate. Poor cognition, vision and hearing, impaired mobility, depression, and chronic pain can interfere with complex insulin regimens. In these individuals, the principal goals of therapy are to reduce the acute effects of hyperglycemia, minimize hypoglycemia risk, and optimize quality of life. The newer insulin preparations and technological advances in insulin delivery and blood glucose monitoring have enhanced the management of type 1 diabetes in all age groups.
    MeSH term(s) Adult ; Aged ; Blood Glucose ; Blood Glucose Self-Monitoring ; Diabetes Mellitus, Type 1/drug therapy ; Humans ; Hypoglycemic Agents/therapeutic use ; Insulin/therapeutic use ; Quality of Life
    Chemical Substances Blood Glucose ; Hypoglycemic Agents ; Insulin
    Language English
    Publishing date 2021-10-19
    Publishing country New Zealand
    Document type Journal Article ; Review
    ZDB-ID 1075770-3
    ISSN 1179-1969 ; 1170-229X
    ISSN (online) 1179-1969
    ISSN 1170-229X
    DOI 10.1007/s40266-021-00900-3
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