NAD metabolism in aging and cancer

NAD+ and its derivatives NADH, NADP+, and NADPH are essential cofactors in redox reactions and electron transport pathways. NAD serves also as substrate for an extensive series of regulatory enzymes including cyclic ADP-ribose hydrolases, mono(ADP-ribosyl)transferases, poly(ADP-ribose) polymerases, and sirtuin deacetylases which are O-acetyl-ADP-ribosyltransferases. As a result of the numerous and diverse enzymes that utilize NAD as well as depend on its synthesis and concentration, significant interest has developed in its role in a variety of physiologic and pathologic processes, and therapeutic initiatives have focused both on augmenting its levels as well as inhibiting some of its pathways. In this article, we examine the biosynthesis of NAD, metabolic processes in which it is involved, and its role in aging, cancer, and other age-associated comorbidities including neurodegenerative, cardiovascular, and metabolic disorders. Therapeutic interventions to augment and/or inhibit these processes are also discussed. Impact statement NAD is a central metabolite connecting energy balance and organismal growth with genomic integrity and function. It is involved in the development of malignancy and has a regulatory role in the aging process. These processes are mediated by a diverse series of enzymes whose common focus is either NAD’s biosynthesis or its utilization as a redox cofactor or enzyme substrate. These enzymes include dehydrogenases, cyclic ADP-ribose hydrolases, mono(ADP-ribosyl)transferases, poly(ADP-ribose) polymerases, and sirtuin deacetylases. This article describes the manifold pathways that comprise NAD metabolism and promotes an increased awareness of how perturbations in these systems may be important in disease prevention and/or progression.

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Gut Microbiota and Metabolic Disorders: Advances in Therapeutic Interventions

Critical Reviews in Immunology ◽

10.1615/critrevimmunol.2019030614 ◽

2019 ◽

Vol 39 (4) ◽

pp. 223-237 ◽

Cited By ~ 1

Author(s):

Muhammad Sajid Hamid Akash ◽

Fareeha Fiayyaz ◽

Kanwal Rehman ◽

Shakila Sabir ◽

Muhammad Hidayat Rasool

Keyword(s):

Gut Microbiota ◽

Metabolic Disorders ◽

Therapeutic Interventions

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Effects of Maternal Obesity and Gestational Diabetes Mellitus on the Placenta: Current Knowledge and Targets for Therapeutic Interventions

Current Vascular Pharmacology ◽

10.2174/1570161118666200616144512 ◽

2020 ◽

Vol 19 (2) ◽

pp. 176-192

Author(s):

Samantha Bedell ◽

Janine Hutson ◽

Barbra de Vrijer ◽

Genevieve Eastabrook

Keyword(s):

Diabetes Mellitus ◽

Gestational Diabetes ◽

Gestational Diabetes Mellitus ◽

Maternal Obesity ◽

Environmental Changes ◽

Current Knowledge ◽

Therapeutic Interventions ◽

Placental Development ◽

Exchange Site ◽

And Function

: Obesity and gestational diabetes mellitus (GDM) are becoming more common among pregnant women worldwide and are individually associated with a number of placenta-mediated obstetric complications, including preeclampsia, macrosomia, intrauterine growth restriction and stillbirth. The placenta serves several functions throughout pregnancy and is the main exchange site for the transfer of nutrients and gas from mother to fetus. In pregnancies complicated by maternal obesity or GDM, the placenta is exposed to environmental changes, such as increased inflammation and oxidative stress, dyslipidemia, and altered hormone levels. These changes can affect placental development and function and lead to abnormal fetal growth and development as well as metabolic and cardiovascular abnormalities in the offspring. This review aims to summarize current knowledge on the effects of obesity and GDM on placental development and function. Understanding these processes is key in developing therapeutic interventions with the goal of mitigating these effects and preventing future cardiovascular and metabolic pathology in subsequent generations.

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Gestational Diabetes Mellitus and Infant Adiposity at Birth: A Systematic Review and Meta-Analysis of Therapeutic Interventions

Journal of Clinical Medicine ◽

10.3390/jcm10040835 ◽

2021 ◽

Vol 10 (4) ◽

pp. 835

Author(s):

Manoja P. Herath ◽

Jeffrey M. Beckett ◽

Andrew P. Hills ◽

Nuala M. Byrne ◽

Kiran D. K. Ahuja

Keyword(s):

Diabetes Mellitus ◽

Adipose Tissue ◽

Gestational Diabetes ◽

Gestational Diabetes Mellitus ◽

Fat Mass ◽

Metabolic Disorders ◽

Later Life ◽

Therapeutic Interventions ◽

Increased Risk ◽

The Impact

Exposure to untreated gestational diabetes mellitus (GDM) in utero increases the risk of obesity and type 2 diabetes in adulthood, and increased adiposity in GDM-exposed infants is suggested as a plausible mediator of this increased risk of later-life metabolic disorders. Evidence is equivocal regarding the impact of good glycaemic control in GDM mothers on infant adiposity at birth. We systematically reviewed studies reporting fat mass (FM), percent fat mass (%FM) and skinfold thicknesses (SFT) at birth in infants of mothers with GDM controlled with therapeutic interventions (IGDMtr). While treating GDM lowered FM in newborns compared to no treatment, there was no difference in FM and SFT according to the type of treatment (insulin, metformin, glyburide). IGDMtr had higher overall adiposity (mean difference, 95% confidence interval) measured with FM (68.46 g, 29.91 to 107.01) and %FM (1.98%, 0.54 to 3.42) but similar subcutaneous adiposity measured with SFT, compared to infants exposed to normal glucose tolerance (INGT). This suggests that IGDMtr may be characterised by excess fat accrual in internal adipose tissue. Given that intra-abdominal adiposity is a major risk factor for metabolic disorders, future studies should distinguish adipose tissue distribution of IGDMtr and INGT.

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Endothelium as a Source and Target of H2S to Improve Its Trophism and Function

Antioxidants ◽

10.3390/antiox10030486 ◽

2021 ◽

Vol 10 (3) ◽

pp. 486

Author(s):

Valerio Ciccone ◽

Shirley Genah ◽

Lucia Morbidelli

Keyword(s):

Endothelial Dysfunction ◽

Vessel Wall ◽

Redox Reactions ◽

Single Layer ◽

Fine Tuning ◽

Therapeutic Approaches ◽

Impaired Wound Healing ◽

Blood Fluidity ◽

And Function ◽

And Control

The vascular endothelium consists of a single layer of squamous endothelial cells (ECs) lining the inner surface of blood vessels. Nowadays, it is no longer considered as a simple barrier between the blood and vessel wall, but a central hub to control blood flow homeostasis and fulfill tissue metabolic demands by furnishing oxygen and nutrients. The endothelium regulates the proper functioning of vessels and microcirculation, in terms of tone control, blood fluidity, and fine tuning of inflammatory and redox reactions within the vessel wall and in surrounding tissues. This multiplicity of effects is due to the ability of ECs to produce, process, and release key modulators. Among these, gasotransmitters such as nitric oxide (NO) and hydrogen sulfide (H2S) are very active molecules constitutively produced by endotheliocytes for the maintenance and control of vascular physiological functions, while their impairment is responsible for endothelial dysfunction and cardiovascular disorders such as hypertension, atherosclerosis, and impaired wound healing and vascularization due to diabetes, infections, and ischemia. Upregulation of H2S producing enzymes and administration of H2S donors can be considered as innovative therapeutic approaches to improve EC biology and function, to revert endothelial dysfunction or to prevent cardiovascular disease progression. This review will focus on the beneficial autocrine/paracrine properties of H2S on ECs and the state of the art on H2S potentiating drugs and tools.

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Cellular and Molecular Players in the Interplay between Adipose Tissue and Breast Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms22031359 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1359

Author(s):

Francesca Reggiani ◽

Paolo Falvo ◽

Francesco Bertolini

Keyword(s):

Breast Cancer ◽

Adipose Tissue ◽

Metabolic Disorders ◽

Current Knowledge ◽

Therapeutic Interventions ◽

Preclinical Research ◽

The World ◽

Adipose Cells

The incidence and severity of obesity are rising in most of the world. In addition to metabolic disorders, obesity is associated with an increase in the incidence and severity of a variety of types of cancer, including breast cancer (BC). The bidirectional interaction between BC and adipose cells has been deeply investigated, although the molecular and cellular players involved in these mechanisms are far from being fully elucidated. Here, we review the current knowledge on these interactions and describe how preclinical research might be used to clarify the effects of obesity over BC progression and morbidity, with particular attention paid to promising therapeutic interventions.

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The impact of chronic disease and disability on the elderly

South African Journal of Physiotherapy ◽

10.4102/sajp.v55i3.567 ◽

1999 ◽

Vol 55 (3) ◽

pp. 9-14

Author(s):

C. J. Eales

Keyword(s):

Health Care ◽

Chronic Disease ◽

Chronic Diseases ◽

Health Care Systems ◽

The Elderly ◽

Therapeutic Interventions ◽

Elderly Persons ◽

Care Systems ◽

And Function ◽

The Impact

Health care systems for elderly people should aim to delay the onset of illness, reducing the final period of infirmity and illness to the shortest possible time. The most effective way to achieve this is by health education and preventative medicine to maintain mobility and function. Changes in life style even in late life may result in improved health, effectively decreasing the incidence of chronic diseases associated with advancing age. This paper presents the problems experienced by elderly persons with chronic diseases and disabilities with indications for meaningful therapeutic interventions.

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Alpha-Tocopherol Metabolites (The Vitamin E Metabolome) and Their Interindividual Variability during Supplementation

Antioxidants ◽

10.3390/antiox10020173 ◽

2021 ◽

Vol 10 (2) ◽

pp. 173

Author(s):

Desirée Bartolini ◽

Rita Marinelli ◽

Danilo Giusepponi ◽

Roberta Galarini ◽

Carolina Barola ◽

...

Keyword(s):

Vitamin E ◽

Target Genes ◽

Interindividual Variability ◽

Pregnane X Receptor ◽

Alpha Tocopherol ◽

Therapeutic Interventions ◽

Intrinsic Variability ◽

Blood Leukocytes ◽

Definition Of ◽

And Function

The metabolism of α-tocopherol (α-TOH, vitamin E) shows marked interindividual variability, which may influence the response to nutritional and therapeutic interventions with this vitamin. Recently, new metabolomics protocols have fostered the possibility to explore such variability for the different metabolites of α-TOH so far identified in human blood, i.e., the “vitamin E metabolome”, some of which have been reported to promote important biological functions. Such advances prompt the definition of reference values and degree of interindividual variability for these metabolites at different levels of α-TOH intake. To this end, a one-week oral administration protocol with 800 U RRR-α-TOH/day was performed in 17 healthy volunteers, and α-TOH metabolites were measured in plasma before and at the end of the intervention utilizing a recently validated LC-MS/MS procedure; the expression of two target genes of α-TOH with possible a role in the metabolism and function of this vitamin, namely pregnane X receptor (PXR) and the isoform 4F2 of cytochrome P450 (CYP4F2) was assessed by immunoblot in peripheral blood leukocytes. The levels of enzymatic metabolites showed marked interindividual variability that characteristically increased upon supplementation. With the exception of α-CEHC (carboxy-ethyl-hydroxychroman) and the long-chain metabolites M1 and α-13′OH, such variability was found to interfere with the possibility to utilize them as sensitive indicators of α-TOH intake. On the contrary, the free radical-derived metabolite α-tocopheryl quinone significantly correlated with the post-supplementation levels of α-TOH. The supplementation stimulated PXR, but not CYP4F2, expression of leucocytes, and significant correlations were observed between the baseline levels of α-TOH and both the baseline and post-supplementation levels of PXR. These findings provide original analytical and molecular information regarding the human metabolism of α-TOH and its intrinsic variability, which is worth considering in future nutrigenomics and interventions studies.

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Advances in high-density lipoprotein physiology: surprises, overturns, and promises

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00429.2015 ◽

2016 ◽

Vol 310 (1) ◽

pp. E1-E14 ◽

Cited By ~ 14

Author(s):

Caterina Constantinou ◽

Eleni A. Karavia ◽

Eva Xepapadaki ◽

Peristera-Ioanna Petropoulou ◽

Eugenia Papakosta ◽

...

Keyword(s):

Diabetes Mellitus ◽

Fatty Liver Disease ◽

Metabolic Disorders ◽

Density Lipoprotein ◽

Pulmonary Diseases ◽

Brain Disorders ◽

Nonalcoholic Fatty Liver ◽

Disease States ◽

And Function

Emerging evidence strongly supports that changes in the HDL metabolic pathway, which result in changes in HDL proteome and function, appear to have a causative impact on a number of metabolic disorders. Here, we provide a critical review of the most recent and novel findings correlating HDL properties and functionality with various pathophysiological processes and disease states, such as obesity, type 2 diabetes mellitus, nonalcoholic fatty liver disease, inflammation and sepsis, bone and obstructive pulmonary diseases, and brain disorders.

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Recent advances in understanding and managing psoriatic arthritis

F1000Research ◽

10.12688/f1000research.9592.1 ◽

2016 ◽

Vol 5 ◽

pp. 2670 ◽

Cited By ~ 15

Author(s):

Dafna D. Gladman

Keyword(s):

Psoriatic Arthritis ◽

Early Diagnosis ◽

Clinical Laboratory ◽

Joint Damage ◽

Screening Tools ◽

Therapeutic Interventions ◽

Joint Disease ◽

New Therapeutic Approaches ◽

Recent Advances ◽

And Function

This article reviews recent advances in psoriatic arthritis (PsA) over the past several years with emphasis on early diagnosis, better understanding of pathogenesis, and new therapeutic approaches. Early diagnosis is important, since people who present late do not fare as well. There are a number of clinical, laboratory, and ultrasound features that can help identify patients destined to develop PsA, and several screening tools have been developed. It is recognized that genetic and epigenetic factors, as well as T cells and cytokines, play a role in the pathogenesis of PsA, and several targets have been identified for therapeutic interventions. New therapies have been developed and tested in PsA and have been found to be highly effective for both skin and joint manifestations of the disease. The expectation is that, in the future, PsA patients will be treated early and more aggressively and that there will not be significant progression of joint damage. Moreover, with effective treatment of the skin and joint disease and management of risk factors for the comorbidities, we can expect to reduce their occurrence and further reduce the excess mortality and reduced quality of life and function in these patients.

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Targeting Mitochondria as Therapeutic Strategy for Metabolic Disorders

The Scientific World JOURNAL ◽

10.1155/2014/604685 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 25

Author(s):

Daniela Sorriento ◽

Antonietta Valeria Pascale ◽

Rosa Finelli ◽

Anna Lisa Carillo ◽

Roberto Annunziata ◽

...

Keyword(s):

Metabolic Syndrome ◽

Mitochondrial Dysfunction ◽

Small Molecules ◽

Metabolic Disorders ◽

Therapeutic Strategy ◽

Cell Metabolism ◽

Therapeutic Interventions ◽

Mtdna Mutations ◽

Pathological Conditions ◽

Mitochondria Targeting

Mitochondria are critical regulator of cell metabolism; thus, mitochondrial dysfunction is associated with many metabolic disorders. Defects in oxidative phosphorylation, ROS production, or mtDNA mutations are the main causes of mitochondrial dysfunction in many pathological conditions such as IR/diabetes, metabolic syndrome, cardiovascular diseases, and cancer. Thus, targeting mitochondria has been proposed as therapeutic approach for these conditions, leading to the development of small molecules to be tested in the clinical scenario. Here we discuss therapeutic interventions to treat mitochondrial dysfunction associated with two major metabolic disorders, metabolic syndrome, and cancer. Finally, novel mechanisms of regulation of mitochondrial function are discussed, which open new scenarios for mitochondria targeting.

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