-
Advances in Therapy Dec 2019Leber's hereditary optic neuropathy (LHON) is a relatively common, rapidly progressing inherited optic neuropathy wherein LHON-affected eyes undergo optic nerve atrophy...
Leber's hereditary optic neuropathy (LHON) is a relatively common, rapidly progressing inherited optic neuropathy wherein LHON-affected eyes undergo optic nerve atrophy due to retinal ganglion cell (RGC) loss. It is a maternally inherited (or sporadic) mitochondrial disorder caused primarily by mutations in genes that encode components of respiratory complex (RC)1 in mitochondria. Mitochondrial deficiency of RC1 compromises ATP production and oxidative stress management in RGCs. The most common LHON-causing mutations are 11778G>A, 3460G>A, and 14484T>C point mutations in MT-ND4, MT-ND1, and MT-ND6. The unusually high mitochondrial load of RGCs makes them particularly sensitive to these mutations. Patients with LHON may be prescribed ubiquinone (a component of RC3) or idebenone, a ubiquinone analogue with enhanced bioavailability to act downstream of RC1. The challenge of accessing the inner mitochondrial membrane with gene therapy for LHON, and other mitochondrial diseases, may be overcome by incorporation of a specific mitochondrion-targeting sequence (MTS) that enables allotropic expression of a nucleus-transcribed ND4 transgene. Because LHON penetrance is incomplete among carriers of the aforementioned mutations, identification of environmental factors, such as heavy smoking, that interact with genetics in the phenotypic expression of LHON may be helpful toward preventing or delaying disease development. LHON has become a model for mitochondrial and neurogenerative diseases owing to it having a clearly identified genetic cause and its early onset and rapid progression characteristics. Hence, LHON studies and genetic treatment advances may inform research of other diseases.
Topics: DNA, Mitochondrial; Electron Transport Complex I; Genetic Therapy; Humans; Mutation; Optic Atrophy, Hereditary, Leber; Phenotype; Point Mutation
PubMed: 31605306
DOI: 10.1007/s12325-019-01113-2 -
International Journal of Molecular... Sep 2023Cocaine abuse is a serious public health problem as this drug exerts a plethora of functional and histopathological changes that potentially lead to death. Cocaine... (Review)
Review
Cocaine abuse is a serious public health problem as this drug exerts a plethora of functional and histopathological changes that potentially lead to death. Cocaine causes complex multiorgan toxicity, including in the heart where the blockade of the sodium channels causes increased catecholamine levels and alteration in calcium homeostasis, thus inducing an increased oxygen demand. Moreover, there is evidence to suggest that mitochondria alterations play a crucial role in the development of cocaine cardiotoxicity. We performed a systematic review according to the Preferred Reporting Items for Systemic Reviews and Meta-Analysis (PRISMA) scheme to evaluate the mitochondrial mechanisms determining cocaine cardiotoxicity. Among the initial 106 articles from the Pubmed database and the 17 articles identified through citation searching, 14 final relevant studies were extensively reviewed. Thirteen articles included animal models and reported the alteration of specific mitochondria-dependent mechanisms such as reduced energy production, imbalance of membrane potential, increased oxidative stress, and promotion of apoptosis. However, only one study evaluated human cocaine overdose samples and observed the role of cocaine in oxidative stress and the induction of apoptosis though mitochondria. Understanding the complex processes mediated by mitochondria through forensic analysis and experimental models is crucial for identifying potential therapeutic targets to mitigate or reverse cocaine cardiotoxicity in humans.
Topics: Animals; Humans; Cardiotoxicity; Cocaine; Cocaine-Related Disorders; Heart; Mitochondria; Oxidative Stress
PubMed: 37833964
DOI: 10.3390/ijms241914517 -
Anti-cancer Agents in Medicinal... 2018This systematic review aims to elucidate the role of melatonin (N-acetyl-5-metoxy-tryptamine) (MLT) in the prevention and treatment of cancer. MLT is a pineal gland...
This systematic review aims to elucidate the role of melatonin (N-acetyl-5-metoxy-tryptamine) (MLT) in the prevention and treatment of cancer. MLT is a pineal gland secretory product, an evolutionarily highly conserved molecule; it is also an antioxidant and an impressive protector of mitochondrial bioenergetic activity. MLT is characterized by an ample range of activities, modulating the physiology and molecular biology of the cell. Its physiological functions relate principally to the interaction of G Protein-Coupled MT1 and MT2 trans-membrane receptors (GPCRs), a family of guanidine triphosphate binding proteins. MLT has been demonstrated to suppress the growth of various tumours both, in vivo and in vitro. In this review, we analyze in depth, the antioxidant activity of melatonin, aiming to illustrate the cancer treatment potential of the molecule, by limiting or reversing the changes occurring during cancer development and growth.
Topics: Animals; Antineoplastic Agents; Antioxidants; Humans; Melatonin; Neoplasms; Oxidative Stress; Receptors, Melatonin
PubMed: 29173185
DOI: 10.2174/1871520617666171121120223 -
Frontiers in Neuroscience 2022There is a dose-response relationship between tooth loss and cognitive impairment, while tooth loss can be an independent risk factor for Alzheimer's disease (AD) and...
Tooth Loss-Associated Mechanisms That Negatively Affect Cognitive Function: A Systematic Review of Animal Experiments Based on Occlusal Support Loss and Cognitive Impairment.
BACKGROUND
There is a dose-response relationship between tooth loss and cognitive impairment, while tooth loss can be an independent risk factor for Alzheimer's disease (AD) and vascular dementia (VaD). Tooth loss can also accelerate nerve damage and neurodegeneration. However, the associated mechanisms remain poorly understood.
OBJECTIVE
To conduct a systematic review of animal experiments on cognitive decline caused by the loss of occlusal support performed over the past 10 years and summarize the possible underlying mechanisms.
METHODS
"Tooth Loss," "Edentulous," "Tooth Extraction and Memory Loss," "Cognition Impairment," and "Dementia" were used as keywords to search PubMed, Embase, SCI, ScienceDirect, and OpenGrey. A total of 1,317 related articles from 2010 to 2021 were retrieved, 26 of which were included in the review after screening according to predetermined inclusion and exclusion criteria. Comprehensiveness was evaluated using ARRIVE guidelines and the risk of bias was assessed using SYCLE'S risk of bias tool.
RESULTS
The putative mechanisms underlying the cognitive impairment resulting from the loss of occlusal support are as follows: (1) The mechanical pathway, whereby tooth loss leads to masticatory motor system functional disorders. Masticatory organ activity and cerebral blood flow decrease. With reduced afferent stimulation of peripheral receptors (such as in the periodontal membrane) the strength of the connections between neural pathways is decreased, and the corresponding brain regions degenerate; (2) the aggravation pathway, in which tooth loss aggravates existing neurodegenerative changes. Tooth loss can accelerates nerve damage through apoptosis and mitochondrial autophagy, increases amyloid deposition in the brain; and (3) the long-term inflammatory stress pathway, which involves metabolic disorders, microbial-gut-brain axis, the activation of microglia and astrocytes, and inflammatory cascade effect in central nervous system.
CONCLUSION
The loss of occlusal support may lead to cognitive dysfunction through the reduction of chewing-related stimuli, aggravation of nerve damage, and long-term inflammatory stress.
PubMed: 35221901
DOI: 10.3389/fnins.2022.811335 -
International Journal of Geriatric... May 2020Lewy body dementia (LBD) causes more morbidity, disability, and earlier mortality than Alzheimer disease. Molecular mechanisms underlying neurodegeneration in LBD are...
OBJECTIVES
Lewy body dementia (LBD) causes more morbidity, disability, and earlier mortality than Alzheimer disease. Molecular mechanisms underlying neurodegeneration in LBD are poorly understood. We aimed to do a systematic review of all genetic association studies that investigated people with LBD for improving our understanding of LBD molecular genetics and for facilitating discovery of novel biomarkers and therapeutic targets for LBD.
METHODS
We systematically reviewed five online databases (PROSPERO protocol: CRD42018087114) and completed the quality assessment using the quality of genetic association studies tool.
RESULTS
Eight thousand five hundred twenty-one articles were screened, and 75 articles were eligible to be included. Genetic associations of LBD with APOE, GBA, and SNCA variants have been replicated by two or more good quality studies. Our meta-analyses confirmed that APOE-ε4 is significantly associated with dementia with Lewy bodies (pooled odds ratio [POR] = 2.70; 95% CI, 2.37-3.07; P < .001) and Parkinson's disease dementia (POR = 1.60; 95% CI, 1.21-2.11; P = .001). Other reported genetic associations that need further replication include variants in A2M, BCHE-K, BCL7C, CHRFAM7A, CNTN1, ESR1, GABRB3, MAPT, mitochondrial DNA (mtDNA) haplogroup H, NOS2A, PSEN1, SCARB2, TFAM, TREM2, and UCHL1.
CONCLUSIONS
The reported genetic associations and their potential interactions indicate the importance of α-synuclein, amyloid, and tau pathology, autophagy lysosomal pathway, ubiquitin proteasome system, oxidative stress, and mitochondrial dysfunction in LBD. There is a need for larger genome-wide association study (GWAS) for identifying more LBD-associated genes. Future hypothesis-driven studies should aim to replicate reported genetic associations of LBD and to explore their functional implications.
Topics: Aged, 80 and over; Alzheimer Disease; Biomarkers; Female; Genome-Wide Association Study; Humans; Lewy Bodies; Lewy Body Disease; Lysosomal Membrane Proteins; Male; Membrane Glycoproteins; Receptors, Immunologic; Receptors, Scavenger; alpha-Synuclein
PubMed: 31898332
DOI: 10.1002/gps.5260 -
Nutrients Jun 2020Exercise overproduces oxygen reactive species (ROS) and eventually exceeds the body's antioxidant capacity to neutralize them. The ROS produce damaging effects on the...
Exercise overproduces oxygen reactive species (ROS) and eventually exceeds the body's antioxidant capacity to neutralize them. The ROS produce damaging effects on the cell membrane and contribute to skeletal muscle damage. Selenium (Se), a natural mineral trace element, is an essential component of selenoproteins that plays an important role in antioxidant defense. The activity of the enzyme glutathione peroxidase (GPx), a highly-efficient antioxidant enzyme, is closely dependent on the presence of Se. These properties of Se may be potentially applicable to improve athletic performance and training recovery. We systematically searched for published studies to evaluate the effectiveness of Se supplementation on antioxidant defense system, muscle performance, hormone response, and athletic performance among physically active individuals. We used the Preferred Reporting Elements for Systematic Reviews and Meta-Analysis (PRISMA) guidelines and searched in SCOPUS, Web of Science (WOS), and PubMed databases to identify published studies until March 2020. The systematic review incorporated original studies with randomized controlled crossover or parallel design in which intake of Se administered once a day was compared with the same placebo conditions. No exclusions were applied for the type of physical exercise performed, the sex, nor the age of the participants. Among 150 articles identified in the search, 6 met the criteria and were included in the systematic review. The methodological quality of the studies was evaluated using the McMaster Critical Review Form. Oral Se supplementation with 180 µg/day or 240 µg/day (selenomethionine) and 200 µg/day (Sodium Selenite), significantly decreased lipid hydroperoxide levels and increased GPx in plasma, erythrocyte, and muscle. No significant effects were observed on athletic performance, testosterone hormone levels, creatine kinase activity, and exercise training-induced adaptations on oxidative enzyme activities or on muscle fiber type myosin heavy chain expression. In addition, Se supplementation showed to have a dampening effect on the mitochondria changes in chronic and acute exercise. In summary, the use of Se supplementation has no benefits on aerobic or anaerobic athletic performance but it may prevent Se deficiencies among athletes with high-intensity and high-volume training. Optimal Se plasma levels may be important to minimize chronic exercise-induced oxidative effects and modulate the exercise effect on mitochondrial changes.
Topics: Adult; Antioxidants; Athletic Performance; Dietary Supplements; Exercise; Humans; Muscle, Skeletal; Selenium; Selenomethionine; Sodium Selenite; Testosterone
PubMed: 32560188
DOI: 10.3390/nu12061790 -
Journal of Clinical and Translational... Jan 2018Anthraquinones are a possible treatment option for oncological patients due to their anti-cancer properties. Cancer patients often exhaust a plethora of resources that...
BACKGROUND
Anthraquinones are a possible treatment option for oncological patients due to their anti-cancer properties. Cancer patients often exhaust a plethora of resources that ultimately fail to provide fully curative measures. Alternative treatments are subsequently sought in the hope of finding a therapeutic remedy. Po¬tential regimens include aloe-emodin and its related derivatives. This review therefore summarizes the effects of aloe-emodin and other aloe components in light of their anti-proliferative and anti-carcinogenic properties.
METHODS
A systematic search was performed in PubMed for aloe-emodin and cancer in humans. Sixty abstracts of studies were selected and reviewed with subsequent screening of the full text. Thirty-eight articles were summarized.
RESULTS
Aloe-emodin possesses multiple anti-proliferative and anti-carcinogenic properties in a host of human cancer cell lines, with often multiple vital pathways affected by the same molecule. The most notable effects include inhibition of cell proliferation, migration, and invasion; cycle arrest; induction of cell death; mitochondrial membrane and redox perturbations; and modulation of immune signaling. The effects of aloe-emodin are not ubiquitous across all cell lines but depend on cell type.
CONCLUSIONS
On the basis of this systematic review, the multiple consistent effects of aloe-emodin in hu¬man-derived cancer cell lines suggest that aloe-emodin is a potential anti-cancer agent that acts on cancer cells in a pleiotropic manner.
RELEVANCE FOR PATIENTS
Cancer patients often utilize alternative therapies as a result of suboptimal efficacy of conventional treatments. Aloe-emodin might become a therapeutic option for cancer patients if the basic research is confirmed in clinical trials.
PubMed: 30895270
DOI: No ID Found -
Current Molecular Medicine 2021Diabetes mellitus (DM) is a chronic disease and a threatening problem for world health. Allopathic medications are not efficient enough in controlling DM and its...
Diabetes mellitus (DM) is a chronic disease and a threatening problem for world health. Allopathic medications are not efficient enough in controlling DM and its complications. Therefore, much attention has been directed towards the traditional medicine system. Plant derived-natural compounds with medicinal properties play an essential role in DM management and treatment. Artemisia is a varied and widespread genus of the family Asteraceae, which has more than 500 species with beneficial economic and therapeutic significance. Electronic databases such as Science Direct, Scopus, Pubmed, Web of Science, medRixv, and Wiley were used to search scientific literature. In folklore medicine, Artemisia species have been widely utilized for diabetes management. Molecular investigations have revealed that the NF-κB suppression, Notch 1 inhibition, cell cycle stop at S+G2/M-phase, enhanced Bax protein concentrations, mitochondrial membrane potential attenuation, activation of p53 and caspase, Bcl-2 regulation, and ROS formation are crucial mechanisms that could be targeted via various Artemisia species. Anti-diabetic effects of single or multiple doses of alcoholic and aqueous extracts of Artemisia species are due to the presence of bioactive compounds, and they are completely efficient in lowering levels of blood glucose in experimental examinations. In spite of the available anti-diabetic drugs, therapeutic agents obtained from the mentioned plants have been used for the treatment of this disease and its complications with less adverse impacts. Taken together, multiple lines of evidence indicated that Artemisia species could be introduced as a potential therapeutic candidate in the treatment and management of diabetes.
Topics: Artemisia; Diabetes Mellitus; Humans; Hypoglycemic Agents; Phytotherapy; Plant Extracts
PubMed: 33397259
DOI: 10.2174/1566524020999210101234317 -
Current Reviews in Clinical and... 2022PI3K/AKT/mTOR (phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin) signaling pathway is an important signal transduction pathway mediated by...
Targeting Abnormal PI3K/AKT/mTOR Signaling in Intracerebral Hemorrhage: A Systematic Review on Potential Drug Targets and Influences of Signaling Modulators on Other Neurological Disorders.
PI3K/AKT/mTOR (phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin) signaling pathway is an important signal transduction pathway mediated by enzyme-linked receptors with many biological functions in mammals. This pathway modulates the epigenetic modification of DNA and target gene histones and plays a significant role in regulating biological activity, disease progression, oncogenesis, and cancer progression. PI3K/AKT/mTOR signaling pathway involves and mediates many cellular processes such as nutrient uptake, proliferation, anabolic reactions, and cell survival. Several studies have shown that PI3K/AKT/mTOR has been a promising therapeutic approach to intracerebral hemorrhage (ICH). ICH is characterized by the progressive development of hematoma, which leads to the structural destabilization of the neurons and glial cells, leading to neuronal deformation, further contributing to mitochondrial dysfunction, membrane depolarization, oligaemia, and neurotransmitter imbalance. Partial suppression of cell metabolism and necrosis can occur, depending on the degree of mitochondrial dysfunction. Therefore in the following review, we discuss whether or not the activation of the PI3K/AKT/mTOR signaling pathway could minimize neuronal dysfunction following ICH. We further elaborate the review by discussing the updated pathophysiology of brain hemorrhage and the role of molecular targets in other neurodegenerative diseases. This review provides current approachable disease treatment in various disease states, single and dual PI3K/AKT/mTOR signaling pathway modulators.
Topics: Animals; Cerebral Hemorrhage; Mammals; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases
PubMed: 34455956
DOI: 10.2174/1574884716666210726110021 -
Frontiers in Neuroscience 2021Iron has been increasingly implicated in the pathology of neurodegenerative diseases. In the past decade, development of the new magnetic resonance imaging technique,...
Iron has been increasingly implicated in the pathology of neurodegenerative diseases. In the past decade, development of the new magnetic resonance imaging technique, quantitative susceptibility mapping (QSM), has enabled for the more comprehensive investigation of iron distribution in the brain. The aim of this systematic review was to provide a synthesis of the findings from existing QSM studies in neurodegenerative diseases. We identified 80 records by searching MEDLINE, Embase, Scopus, and PsycInfo databases. The disorders investigated in these studies included Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Wilson's disease, Huntington's disease, Friedreich's ataxia, spinocerebellar ataxia, Fabry disease, myotonic dystrophy, pantothenate-kinase-associated neurodegeneration, and mitochondrial membrane protein-associated neurodegeneration. As a general pattern, QSM revealed increased magnetic susceptibility (suggestive of increased iron content) in the brain regions associated with the pathology of each disorder, such as the amygdala and caudate nucleus in Alzheimer's disease, the substantia nigra in Parkinson's disease, motor cortex in amyotrophic lateral sclerosis, basal ganglia in Huntington's disease, and cerebellar dentate nucleus in Friedreich's ataxia. Furthermore, the increased magnetic susceptibility correlated with disease duration and severity of clinical features in some disorders. Although the number of studies is still limited in most of the neurodegenerative diseases, the existing evidence suggests that QSM can be a promising tool in the investigation of neurodegeneration.
PubMed: 33679303
DOI: 10.3389/fnins.2021.618435