ACAT1 as a Therapeutic Target and its Genetic Relationship with Alzheimer's Disease

2019 ◽  
Vol 16 (8) ◽  
pp. 699-709
Author(s):  
Jessica Sarahi Alavez-Rubio ◽  
Teresa Juarez-Cedillo
Keyword(s):  
Genetic Relationship ◽  
Therapeutic Target ◽  
Drug Targets ◽  
Animal Studies ◽  
Cholesterol Acyltransferase ◽  
Cholesterol Homeostasis ◽  
Beneficial Effects ◽  
New Therapeutic Approaches ◽  
Area Of Interest ◽  
Information Gap

Background: Alzheimer´s disease (AD) is a chronic and progressive disease which impacts caregivers, families and societies physically, psychologically and economically. Currently available drugs can only improve cognitive symptoms, have no impact on progression and are not curative, so identifying and studying new drug targets is important. There are evidences which indicate disturbances in cholesterol homeostasis can be related with AD pathology, especially the compartmentation of intracellular cholesterol and cytoplasmic cholesterol esters formed by acyl-CoA: cholesterol acyltransferase 1 (ACAT1) can be implicated in the regulation of amyloid-beta (Aβ) peptide, involved in AD. Blocking ACAT1 activity, beneficial effects are obtained, so it has been suggested that ACAT1 can be a potential new therapeutic target. The present review discusses the role of cholesterol homeostasis in AD pathology, especially with ACAT inhibitors, and how they have been raised as a therapeutic approach. In addition, the genetic relationship of ACAT and AD is discussed. Conclusion: Although there are several lines of evidence from cell-based and animal studies that suggest that ACAT inhibition is an effective way of reducing cerebral Aβ, there is still an information gap in terms of mechanisms and concerns to cover before passing to the next level. Additionally, an area of interest that may be useful in understanding AD to subsequently propose new therapeutic approaches is pharmacogenetics; however, there is still a lot of missing information in this area.

scholarly journals Plasma Gelsolin: Indicator of Inflammation and Its Potential as a Diagnostic Tool and Therapeutic Target

2018 ◽  
Vol 19 (9) ◽  
pp. 2516 ◽  
Author(s):  
Ewelina Piktel ◽  
Ilya Levental ◽  
Bonita Durnaś ◽  
Paul Janmey ◽  
Robert Bucki
Keyword(s):  
Therapeutic Target ◽  
Animal Studies ◽  
Recent Progress ◽  
Mechanisms Of Action ◽  
Current Data ◽  
Clinical Use ◽  
Plasma Gelsolin ◽  
Beneficial Effects ◽  
Potential Biomarker ◽  
Efficacy Of Treatment

Gelsolin, an actin-depolymerizing protein expressed both in extracellular fluids and in the cytoplasm of a majority of human cells, has been recently implicated in a variety of both physiological and pathological processes. Its extracellular isoform, called plasma gelsolin (pGSN), is present in blood, cerebrospinal fluid, milk, urine, and other extracellular fluids. This isoform has been recognized as a potential biomarker of inflammatory-associated medical conditions, allowing for the prediction of illness severity, recovery, efficacy of treatment, and clinical outcome. A compelling number of animal studies also demonstrate a broad spectrum of beneficial effects mediated by gelsolin, suggesting therapeutic utility for extracellular recombinant gelsolin. In the review, we summarize the current data related to the potential of pGSN as an inflammatory predictor and therapeutic target, discuss gelsolin-mediated mechanisms of action, and highlight recent progress in the clinical use of pGSN.

HBOT Application at Cases of Gingival Inflammation

2019 ◽  
Author(s):  
Ilma Robo
Keyword(s):  
Root Resorption ◽  
Periodontal Diseases ◽  
Therapeutic Effects ◽  
Clinical Effects ◽  
Gingival Inflammation ◽  
Beneficial Effects ◽  
New Therapeutic Approaches ◽  
Short Period ◽  
Mechanical Therapy ◽  
The Impact

The treatment of periodontal diseases, mainly of their origin, with the most common clinical manifestation in form of gingival inflammation, is manifold and powerful, including: mechanical therapy, antibiotic, antiseptic and various approaches to treatment, which are recommended to be used within a short period of time. New therapeutic approaches have been proven as alternative treatment to conventional therapy, or in combination with conventional therapies, to reduce the number of periodontopathic pathogens in gingival sulcus. HBOT has a detrimental effect on periodontal microorganisms, as well as beneficial effects on the healing of periodontal tissue, increasing oxygen pressure in gingival pockets. Our study is aimed at reviewing the current published literature on hyperbaric oxygen therapy and focuses on role of HBOT as a therapeutic measure for the individual with periodontal disease in general and for the impact on the recovery of gingival inflammation. HBOT and periodontal treatment together, reduce up to 99% of the gram-negative anaerobic load of subgingival flora. HBOT, significantly reduces subgingival anaerobic flora. Clinical effects in 2-year follow-up of treated patients are sensitive. Reduction of gingival hemorrhage indexes, depth of peritoneum, plaque index, occurs in cases of combination of HBOT and detraction. Reduced load persists up to 2 months after therapy. The significant increase in connective tissue removal starts at the end of 2nd week, to achieve the maximum in week 3-6 of application. HBOT used for re-implantation, stimulates the healing of periodontal membrane, pulp, prevents root resorption, healing of periodontal lining tissues. HBOT, significantly reduces the hemorrhage index with 1.2 value difference, 0.7mm probe depth, reduces gingival fluid by 2. HGH exposure is increased by gingival blood flow, with a difference of 2 in measured value. The therapeutic effects of HBOT in the value of the evaluation index can be saved up to 1-year post treatment.

scholarly journals Regulation of Eosinophilia in Asthma—New Therapeutic Approaches for Asthma Treatment

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 817
Author(s):  
Ruth P. Cusack ◽  
Christiane E. Whetstone ◽  
Yanqing Xie ◽  
Maral Ranjbar ◽  
Gail M. Gauvreau
Keyword(s):  
Drug Targets ◽  
Airflow Obstruction ◽  
Chronic Inflammatory Disease ◽  
Therapeutic Approaches ◽  
Eosinophilic Asthma ◽  
Airway Eosinophilia ◽  
Gm Csf ◽  
New Therapeutic Approaches ◽  
Cellular Apoptosis ◽  
Reversible Airflow Obstruction

Asthma is a complex and chronic inflammatory disease of the airways, characterized by variable and recurring symptoms, reversible airflow obstruction, bronchospasm, and airway eosinophilia. As the pathophysiology of asthma is becoming clearer, the identification of new valuable drug targets is emerging. IL-5 is one of these such targets because it is the major cytokine supporting eosinophilia and is responsible for terminal differentiation of human eosinophils, regulating eosinophil proliferation, differentiation, maturation, migration, and prevention of cellular apoptosis. Blockade of the IL-5 pathway has been shown to be efficacious for the treatment of eosinophilic asthma. However, several other inflammatory pathways have been shown to support eosinophilia, including IL-13, the alarmin cytokines TSLP and IL-33, and the IL-3/5/GM-CSF axis. These and other alternate pathways leading to airway eosinophilia will be described, and the efficacy of therapeutics that have been developed to block these pathways will be evaluated.

scholarly journals The Effects of Medicinal Plants and Bioactive Natural Compounds on Homocysteine

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3081
Author(s):  
Mohammad Amin Atazadegan ◽  
Mohammad Bagherniya ◽  
Gholamreza Askari ◽  
Aida Tasbandi ◽  
Amirhossein Sahebkar
Keyword(s):  
Clinical Trials ◽  
Medicinal Plants ◽  
Vascular Endothelium ◽  
Animal Studies ◽  
Natural Compounds ◽  
Herbal Products ◽  
Mortality And Morbidity ◽  
Beneficial Effects ◽  
Serum Homocysteine ◽  
Prevention And Treatment

Background: Among non-communicable diseases, cardiovascular diseases (CVDs) are the leading cause of mortality and morbidity in global communities. By 2030, CVD-related deaths are projected to reach a global rise of 25 million. Obesity, smoking, alcohol, hyperlipidemia, hypertension, and hyperhomocysteinemia are several known risk factors for CVDs. Elevated homocysteine is tightly related to CVDs through multiple mechanisms, including inflammation of the vascular endothelium. The strategies for appropriate management of CVDs are constantly evolving; medicinal plants have received remarkable attention in recent researches, since these natural products have promising effects on the prevention and treatment of various chronic diseases. The effects of nutraceuticals and herbal products on CVD/dyslipidemia have been previously studied. However, to our knowledge, the association between herbal bioactive compounds and homocysteine has not been reviewed in details. Thus, the main objective of this study is to review the efficacy of bioactive natural compounds on homocysteine levels according to clinical trials and animal studies. Results: Based on animal studies, black and green tea, cinnamon, resveratrol, curcumin, garlic extract, ginger, and soy significantly reduced the homocysteine levels. According to the clinical trials, curcumin and resveratrol showed favorable effects on serum homocysteine. In conclusion, this review highlighted the beneficial effects of medicinal plants as natural, inexpensive, and accessible agents on homocysteine levels based on animal studies. Nevertheless, the results of the clinical trials were not uniform, suggesting that more well-designed trials are warranted.

scholarly journals Beneficial Effects of Acetyl-DL-Leucine (ADLL) in a Mouse Model of Sandhoff Disease

2020 ◽  
Vol 9 (4) ◽  
pp. 1050 ◽  
Author(s):  
Ecem Kaya ◽  
David A. Smith ◽  
Claire Smith ◽  
Barry Boland ◽  
Michael Strupp ◽  
...  
Keyword(s):  
Mouse Model ◽  
Sandhoff Disease ◽  
Lysosomal Storage ◽  
Gm2 Ganglioside ◽  
Beneficial Effects ◽  
New Therapeutic Approaches ◽  
Late Endosomes ◽  
Altered Glucose ◽  
Cerebellar Ataxias ◽  
Niemann Pick

Sandhoff disease is a rare neurodegenerative lysosomal storage disease associated with the storage of GM2 ganglioside in late endosomes/lysosomes. Here, we explored the efficacy of acetyl-DL-leucine (ADLL), which has been shown to improve ataxia in observational studies in patients with Niemann–Pick Type C1 and other cerebellar ataxias. We treated a mouse model of Sandhoff disease (Hexb-/-) (0.1 g/kg/day) from 3 weeks of age with this orally available drug. ADLL produced a modest but significant increase in life span, accompanied by improved motor function and reduced glycosphingolipid (GSL) storage in the forebrain and cerebellum, in particular GA2. ADLL was also found to normalize altered glucose and glutamate metabolism, as well as increasing autophagy and the reactive oxygen species (ROS) scavenger, superoxide dismutase (SOD1). Our findings provide new insights into metabolic abnormalities in Sandhoff disease, which could be targeted with new therapeutic approaches, including ADLL.

scholarly journals Tea Polyphenols in Promotion of Human Health

Nutrients ◽  
2018 ◽  
Vol 11 (1) ◽  
pp. 39 ◽  
Author(s):  
Naghma Khan ◽  
Hasan Mukhtar
Keyword(s):  
Green Tea ◽  
Animal Studies ◽  
Neurological Diseases ◽  
Black Tea ◽  
Polyphenolic Compounds ◽  
Tea Polyphenols ◽  
Beneficial Effects ◽  
Gallocatechin Gallate ◽  
Prevention Of Cancer ◽  
Pharmacologically Active

Tea is the most widely used beverage worldwide. Japanese and Chinese people have been drinking tea for centuries and in Asia, it is the most consumed beverage besides water. It is a rich source of pharmacologically active molecules which have been implicated to provide diverse health benefits. The three major forms of tea are green, black and oolong tea based on the degree of fermentation. The composition of tea differs with the species, season, leaves, climate, and horticultural practices. Polyphenols are the major active compounds present in teas. The catechins are the major polyphenolic compounds in green tea, which include epigallocatechin-3-gallate (EGCG), epigallocatechin, epicatechin-3-gallate and epicatechin, gallocatechins and gallocatechin gallate. EGCG is the predominant and most studied catechin in green tea. There are numerous evidences from cell culture and animal studies that tea polyphenols have beneficial effects against several pathological diseases including cancer, diabetes and cardiovascular diseases. The polyphenolic compounds present in black tea include theaflavins and thearubigins. In this review article, we will summarize recent studies documenting the role of tea polyphenols in the prevention of cancer, diabetes, cardiovascular and neurological diseases.

Ontogeny of acyl-CoA: cholesterol acyltransferase in rat liver, intestine, and adipose tissue

1992 ◽  
Vol 262 (4) ◽  
pp. G599-G602
Author(s):  
M. T. Little ◽  
P. Hahn
Keyword(s):  
Adipose Tissue ◽  
Rat Liver ◽  
Animal Studies ◽  
Coenzyme A ◽  
Cholesterol Metabolism ◽  
Cholesterol Acyltransferase ◽  
Dietary Manipulation ◽  
Acat Activity ◽  
Brown Adipose ◽  
Acyl Coenzyme A

The development of acyl-coenzyme A: cholesterol acyltransferase (ACAT), was determined in the rat liver, intestine, and white (WAT) and brown adipose tissue (BAT). Animal studies have shown that dietary manipulation of cholesterol metabolism during an animal's early development can have persistent and permanent effects. Therefore it is important that the ontogeny of ACAT, one of the key enzymes in cholesterol metabolism, be clearly established. White Wistar rats were killed on day 21 of gestation, at birth, and on postnatal days 10, 14, 18, 21, 22, 25, 30, and 60. The tissues were rapidly excised, microsomes were prepared, and the activity of ACAT was measured as the rate of incorporation of [1-14C]oleoyl coenzyme A into cholesterol esters. Age-specific changes were observed in three of the four tissues investigated. Rat liver and intestine possess significant amounts of ACAT activity throughout development with marked variations in activity during this time. ACAT activity in BAT is low and variable throughout development with the exception of high activity noted in the adult animal. WAT contained little or no ACAT activity during development.

scholarly journals Type 1 Diabetic Neuropathy and C-peptide

2004 ◽  
Vol 5 (1) ◽  
pp. 65-77 ◽  
Author(s):  
Anders A. F. Sima ◽  
Weixian Zhang ◽  
George Grunberger
Keyword(s):  
Clinical Trials ◽  
Animal Studies ◽  
Large Scale ◽  
Structural Changes ◽  
Diabetic Complication ◽  
Diabetic Patients ◽  
C Peptide ◽  
Beneficial Effects ◽  
Regulatory Effects

The most common microvascular diabetic complication, diabetic peripheral polyneuropathy (DPN), affects type 1 diabetic patients more often and more severely. In recent decades, it has become increasingly clear that perpetuating pathogenetic mechanisms, molecular, functional, and structural changes and ultimately the clinical expression of DPN differ between the two major types of diabetes. Impaired insulin/C-peptide action has emerged as a crucial factor to account for the disproportionate burden affecting type 1 patients. C-peptide was long believed to be biologically inactive. However, it has now been shown to have a number of insulin-like glucoseindependent effects. Preclinical studies have demonstrated dose-dependent effects onNa+,K+-ATPase activity, endothelial nitric oxide synthase (eNOS), and endoneurial blood flow. Furthermore, it has regulatory effects on neurotrophic factors and molecules pivotal to the integrity of the nodal and paranodal apparatus and modulatory effects on apoptotic phenomena affecting the diabetic nervous system. In animal studies, C-peptide improves nerve conduction abnormalities, prevents nodal degenerative changes, characteristic of type 1 DPN, promotes nerve fiber regeneration, and prevents apoptosis of central and peripheral nerve cell constituents. Limited clinical trials have confirmed the beneficial effects of C-peptide on autonomic and somatic nerve function in patients with type 1 DPN. Therefore, evidence accumulates that replacement of C-peptide in type 1 diabetes prevents and even improves DPN. Large-scale food and drug administration (FDA)-approved clinical trials are necessary to make this natural substance available to the globally increasing type 1 diabetic population.

scholarly journals Podocytes and the actin cytoskeleton as a feasible therapeutic target

2017 ◽  
Vol 118 (4) ◽  
Author(s):  
Sanja Sever ◽  
Changkyo Gu
Keyword(s):  
Animal Models ◽  
Actin Cytoskeleton ◽  
Therapeutic Target ◽  
Kidney Diseases ◽  
Glomerular Disease ◽  
Podocyte Injury ◽  
Chronic Kidney Diseases ◽  
Beneficial Effects ◽  
Actin Structure

Podocyte injury is a hallmark of the glomerular disease, which is a direct cause of chronic kidney diseases. Importantly, podocyte injury is a consequence of the dysregulation of the actin cytoskeleton. In diverse animal models of proteinuric glomerular disease, recovering the integrity of the actin structure in podocytes resulted in beneficial effects. In this review, we focus on the premise of targeting the actin cytoskeleton as a feasible therapeutics for treating chronic kidney diseases

scholarly journals The Role of Diet in the Pathogenesis of Cholesterol Gallstones

2019 ◽  
Vol 26 (19) ◽  
pp. 3620-3638 ◽  
Author(s):  
Agostino Di Ciaula ◽  
Gabriella Garruti ◽  
Gema Frühbeck ◽  
Maria De Angelis ◽  
Ornella de Bari ◽  
...  
Keyword(s):  
Vitamin C ◽  
Fast Food ◽  
Cholesterol Gallstone ◽  
Gallstone Disease ◽  
Gallstone Formation ◽  
Protective Role ◽  
Cholesterol Homeostasis ◽  
Major Health Problem ◽  
Cholesterol Gallstones ◽  
Beneficial Effects

: Cholesterol gallstone disease is a major health problem in Westernized countries and depends on a complex interplay between genetic factors, lifestyle and diet, acting on specific pathogenic mechanisms. Overweigh, obesity, dyslipidemia, insulin resistance and altered cholesterol homeostasis have been linked to increased gallstone occurrence, and several studies point to a number of specific nutrients as risk- or protective factors with respect to gallstone formation in humans. There is a rising interest in the identification of common and modifiable dietetic factors that put the patients at risk of gallstones or that are able to prevent gallstone formation and growth. In particular, dietary models characterized by increased energy intake with highly refined sugars and sweet foods, high fructose intake, low fiber contents, high fat, consumption of fast food and low vitamin C intake increase the risk of gallstone formation. On the other hand, high intake of monounsaturated fats and fiber, olive oil and fish (ω-3 fatty acids) consumption, vegetable protein intake, fruit, coffee, moderate alcohol consumption and vitamin C supplementation exert a protective role. : The effect of some confounding factors (e.g., physical activity) cannot be ruled out, but general recommendations about the multiple beneficial effects of diet on cholesterol gallstones must be kept in mind, in particular in groups at high risk of gallstone formation.

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