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Molecular Neurobiology Apr 2016Mitochondrial dysfunction has been reported to be involved in the pathophysiology of autism spectrum disorder (ASD). Studies investigating the possible association... (Meta-Analysis)
Meta-Analysis Review
Mitochondrial dysfunction has been reported to be involved in the pathophysiology of autism spectrum disorder (ASD). Studies investigating the possible association between ASD and polymorphism in SLC25A12, which encodes the mitochondrial aspartate/glutamate carrier, have yielded inconsistent results. We conducted a systematic review and meta-analysis of such studies to elucidate if and which SLC25A12 single nucleotide polymorphisms (SNPs) are associated with ASD. We searched PubMed, Ovid, Web of Science, and ERIC databases through September 20th, 2014. Odds ratios (ORs) were aggregated using random effect models. Sensitivity analyses were conducted based on study design (family-based or case-control). Fifteen out of 79 non-duplicate records were retained for qualitative synthesis. We pooled 10 datasets from 9 studies with 2001 families, 735 individuals with ASD and 632 typically developing (TD) individuals for the meta-analysis of rs2292813, as well as 11 datasets from 10 studies with 2016 families, 852 individuals with ASD and 1058 TD individuals for the meta-analysis of rs2056202. We found a statistically significant association between ASD and variant in rs2292813 (OR = 1.190, 95% CI 1.052-1.346, P = 0.006) as well as in rs2056202 (OR = 1.206, 95% CI 1.035-1.405, P = 0.016). Sensitivity analyses including only studies with family-based design demonstrated significant association between ASD and polymorphism in rs2292813 (OR = 1.216, 95% CI 1.075-1.376, P = 0.002) and rs2056202 (OR = 1.267, 95% CI 1.041-1.542, P = 0.018). In contrast, sensitivity analyses including case-control design studies only failed to find a significant association. Further research on the role of SLC25A12 and ASD may pave the way for potential innovative therapeutic interventions.
Topics: Autism Spectrum Disorder; Case-Control Studies; Datasets as Topic; Family Health; Genotype; Humans; Mitochondria; Mitochondrial Membrane Transport Proteins; Polymorphism, Single Nucleotide
PubMed: 25663199
DOI: 10.1007/s12035-015-9116-3 -
Biomedicine & Pharmacotherapy =... Sep 2023Neurodegenerative diseases (NDDs) encompass a range of conditions that involve progressive deterioration and dysfunction of the nervous system. Some of the common NDDs... (Review)
Review
Neurodegenerative diseases (NDDs) encompass a range of conditions that involve progressive deterioration and dysfunction of the nervous system. Some of the common NDDs include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Although significant progress has been made in understanding the pathological mechanisms of NDDs in recent years, the development of targeted and effective drugs for their treatment remains challenging. Kaempferol is a flavonoid whose derivatives include kaempferol-O-rhamnoside, 3-O-β-rutinoside/6-hydroxykaempferol 3,6-di-O-β-d-glucoside, and kaempferide. Emerging studies have suggested that kaempferol and its derivatives possess neuroprotective properties and may have potential therapeutic benefits in NDDs. Here, we aimed to provide a theoretical basis for the use of kaempferol and its derivatives in the clinical treatment of NDDs. We systematically reviewed the literature in the PubMed, Web of Science, and Science Direct databases until June 2022 using the search terms "kaempferol," "kaempferol derivatives," "NDDs," "pharmacokinetics," and "biosynthesis" according to the reporting items for systematic review (PRISMA) standard. Based on combined results of in vivo and in vitro studies, we summarize the basic mechanisms and targets of kaempferol and its derivatives in the management of AD, PD, HD, and ALS. Kaempferol and its derivatives exert a neuroprotective role mainly by preventing the deposition of amyloid fibrils (such as Aβ, tau, and α-synuclein), inhibiting microglia activation, reducing the release of inflammatory factors, restoring the mitochondrial membrane to prevent oxidative stress, protecting the blood-brain barrier, and inhibiting specific enzyme activities (such as cholinesterase). Kaempferol and its derivatives are promising natural neuroprotective agents. By determining their pharmacological mechanism, kaempferol and its derivatives may be new candidate drugs for the treatment of NDDs.
Topics: Humans; Neurodegenerative Diseases; Neuroprotective Agents; Amyotrophic Lateral Sclerosis; Kaempferols; Alzheimer Disease; Parkinson Disease; Huntington Disease
PubMed: 37494786
DOI: 10.1016/j.biopha.2023.115215 -
International Journal of Molecular... Dec 2023Atrial fibrillation (AF) is a cardiac arrhythmia caused by electrophysiological anomalies in the atrial tissue, tissue degradation, structural abnormalities, and... (Review)
Review
Atrial fibrillation (AF) is a cardiac arrhythmia caused by electrophysiological anomalies in the atrial tissue, tissue degradation, structural abnormalities, and comorbidities. A direct relationship exists between AF and altered mitochondrial activity resulting from membrane potential loss, contractile dysfunction, or decreased ATP levels. This review aimed to elucidate the role of mitochondrial oxidative mechanisms in AF pathophysiology, the impact of mitochondrial oxidative stress on AF initiation and perpetuation, and current therapies. This review followed the Preferred Reporting Items for Systematic Reviews and the Meta-Analysis Extension for Scoping Reviews. PubMed, Excerpta Medica Database, and Scopus were explored until June 2023 using "MESH terms". Bibliographic references to relevant papers were also included. Oxidative stress is an imbalance that causes cellular damage from excessive oxidation, resulting in conditions such as AF. An imbalance in reactive oxygen species production and elimination can cause mitochondrial damage, cellular apoptosis, and cardiovascular diseases. Oxidative stress and inflammation are intrinsically linked, and inflammatory pathways are highly correlated with the occurrence of AF. AF is an intricate cardiac condition that requires innovative therapeutic approaches. The involvement of mitochondrial oxidative stress in the pathophysiology of AF introduces novel strategies for clinical treatment.
Topics: Humans; Atrial Fibrillation; Cardiac Conduction System Disease; Heart Diseases; Mitochondrial Diseases; Oxidative Stress
PubMed: 38203704
DOI: 10.3390/ijms25010535 -
International Journal of Molecular... Nov 2022Thymoquinone (TQ), a plant-based bioactive constituent derived from the volatile oil of , has been shown to possess some anti-neoplastic activities. The present study...
Thymoquinone (TQ), a plant-based bioactive constituent derived from the volatile oil of , has been shown to possess some anti-neoplastic activities. The present study aimed to investigate the mitochondria and apoptosis observed when TQ is applied against hepatocellular carcinoma (HepG2) and cholangiocarcinoma (HuCCT1) cells, two of the most common primary tumors of the liver. All cell lines were treated with increasing concentrations of TQ for varying durations. The anti-proliferative effect of TQ was measured using the methoxyphenyl-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay and resulted in dose- and time-dependent growth inhibition in both cell lines. Cell cycle, apoptosis, and assessment of mitochondria viability by morphology assessment and evaluation of the mitochondrial membrane potential were investigated. The present study confirms that TQ caused cell cycle arrest at different phases and induced apoptosis in both cell lines. A systematic review of rodent animal models was also carried out. Overall, our data seem to represent the most robust results, suggesting that TQ possesses promising therapeutic potential as an anti-tumor agent for the treatment of hepatocellular carcinoma and cholangiocarcinoma.
Topics: Animals; Carcinoma, Hepatocellular; Cell Line, Tumor; Liver Neoplasms; Benzoquinones; Apoptosis; Cholangiocarcinoma; Mitochondria; Bile Ducts, Intrahepatic; Bile Duct Neoplasms
PubMed: 36498999
DOI: 10.3390/ijms232314669 -
Journal of Advanced Research Jan 2018With the development of nanotechnology, silver nanoparticles (Ag-NPs) have become one of the most in-demand nanoparticles owing to their exponential number of uses in... (Review)
Review
With the development of nanotechnology, silver nanoparticles (Ag-NPs) have become one of the most in-demand nanoparticles owing to their exponential number of uses in various sectors. The increased use of Ag-NPs-enhanced products may result in an increased level of toxicity affecting both the environment and living organisms. Several studies have used different model cell lines to exhibit the cytotoxicity of Ag-NPs, and their underlying molecular mechanisms. This review aimed to elucidate different properties of Ag-NPs that are responsible for the induction of cellular toxicity along with the critical mechanism of action and subsequent defense mechanisms observed . Our results show that the properties of Ag-NPs largely vary based on the diversified synthesis processes. The physiochemical properties of Ag-NPs (e.g., size, shape, concentration, agglomeration, or aggregation interaction with a biological system) can cause impairment of mitochondrial function prior to their penetration and accumulation in the mitochondrial membrane. Thus, Ag-NPs exhibit properties that play a central role in their use as biocides along with their applicability in environmental cleaning. We herein report a current review of the synthesis, applicability, and toxicity of Ag-NPs in relation to their detailed characteristics.
PubMed: 30046482
DOI: 10.1016/j.jare.2017.10.008 -
Journal of Neurology, Neurosurgery, and... Aug 2013Cerebral amyloid angiopathy (CAA) is common in the ageing brain and is associated with dementia and lobar intracerebral haemorrhage. We systematically reviewed genetic... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND AND PURPOSE
Cerebral amyloid angiopathy (CAA) is common in the ageing brain and is associated with dementia and lobar intracerebral haemorrhage. We systematically reviewed genetic associations with CAA to better understand its pathogenesis.
METHODS
We comprehensively sought and critically appraised published studies of associations between any genetic polymorphism and histopathologically confirmed CAA. We assessed the effects of genotype by calculating study specific and pooled odds ratios (ORs) in meta-analyses, and assessed small study bias.
RESULTS
58 studies (6855 participants) investigated apolipoprotein E (APOE) genotype and sporadic CAA. Meta-analysis of 24 (3520 participants) of these showed an association of APOE ε4 with CAA (ε4 present vs absent, pooled OR 2.7, 95% CI 2.3 to 3.1, p<0.00001), which was dose dependent, robust to potential small study biases and occurred irrespective of dementia status. There was no significant association between APOE ε2 and CAA. Among 24 studies (4703 participants) of other genetic polymorphisms, there was preliminary evidence of an association with CAA of polymorphisms in the transforming growth factor β1 gene (two studies, 449 participants), translocase of outer mitochondrial membrane 40 gene (one study, 723 participants) and the complement component receptor 1 gene (one study, 544 participants). There were insufficient data to draw conclusions from 24 studies (∼200 participants) of APOE and hereditary CAA or familial Alzheimer's disease.
CONCLUSIONS
There is convincing evidence for a dose dependent association between APOE ε4 and sporadic CAA. Further work is needed to better understand the mechanism of this association and to further investigate other genetic associations with CAA.
Topics: Aged; Alzheimer Disease; Apolipoprotein E4; Apolipoproteins E; Cerebral Amyloid Angiopathy; Data Interpretation, Statistical; Databases, Genetic; Humans; Polymorphism, Genetic
PubMed: 23457231
DOI: 10.1136/jnnp-2012-303898 -
The Cochrane Database of Systematic... 2003Dementia is a common mental health problem affecting 5% of those over 65. Various pathological processes are linked to memory impairment in dementia, particularly those... (Review)
Review
BACKGROUND
Dementia is a common mental health problem affecting 5% of those over 65. Various pathological processes are linked to memory impairment in dementia, particularly those affecting the cholinergic neurotransmitter system. Acetyl-l-carnitine (ALC) is derived from carnitine and is described as having several properties which may be beneficial in dementia. This includes activity at cholinergic neurons, membrane stabilization and enhancing mitochondrial function. Work on the effects of ALC has been ongoing since the 1980s yet the efficacy of ALC in cognitive decline remains unclear. Early studies suggested a beneficial effect of ALC on cognition and behaviour in aging subjects. However, later, larger studies have not supported these findings. Some of the difficulties lie in the early and later studies differing widely in methodology and assessment tools used, and are therefore difficult to compare. ALC is not currently in routine clinical use.
OBJECTIVES
The objective of this review is to establish whether Acetyl-l-carnitine is clinically effective in the treatment of people with dementia.
SEARCH STRATEGY
The trials were identified from a search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 8 January 2003 using the terms acetyl-l-carnitine, l-carnitine acetyl ester, acetylcarnitine.
SELECTION CRITERIA
All double-blind, randomized, trials involving people with dementia in which treatment with ALC was compared with a placebo group
DATA COLLECTION AND ANALYSIS
Data were extracted by a reviewer (SH) and entered into Revman 4.1 software. Where possible intention-to-treat data were used, but most of the analyses were of completers (people who completed the study).
MAIN RESULTS
There are 11 included trials, all of which had restricted the participants to people with Alzheimer's disease. All trials assessed the cognitive effects of ALC and in addition six considered severity of dementia, six considered functional ability and six considered clinical global impression. There were statistically significant treatment effects in favour of ALC at 12 and 24 weeks for the numbers showing improvement as determined by Clinical Global Impression, [OR 2.33, 95% CI 1.25 to 4.35, P<0.01] and [OR 3.91, 95% CI 1.32 to 11.54, P=0.01] but not as determined by the CIGIC at 52 weeks. There was no evidence of benefit for ALC in the areas of cognition, severity of dementia, functional ability or Clinical Global Impression as a continuous measure. Various adverse events were reported, but from the meta-analyses there were no statistically significant differences between treated and placebo groups.
REVIEWER'S CONCLUSIONS
There is evidence for benefit of ALC on clinical global impression, but there was no evidence using objective assessments in any other area of outcome. Given the large number of comparisons made, the statistically significant result may be due to chance. At present there is no evidence to recommend its routine use in clinical practice. Although the intention of the review was to access ALC for the treatment of all dementias, the included trials had confined themselves to participants with Alzheimer's disease. Individual patient data may add to the findings, as would trials including other types of dementia and other outcomes (e.g. mood and caregiver quality of life). However, the evidence does not suggest that ALC is likely to prove an important therapeutic agent. More work on the pharmacokinetics of ALC in humans is also required.
Topics: Acetylcarnitine; Aged; Alzheimer Disease; Dementia; Humans; Nootropic Agents; Randomized Controlled Trials as Topic
PubMed: 12804452
DOI: 10.1002/14651858.CD003158 -
Molecular Biology Reports Apr 2023FF adenosine triphosphate (ATP) synthase, also known as the complex V, is the central ATP-producing unit in the cells arranged in the mitochondrial and plasma membranes.... (Review)
Review
FF adenosine triphosphate (ATP) synthase, also known as the complex V, is the central ATP-producing unit in the cells arranged in the mitochondrial and plasma membranes. FF ATP synthase also regulates the central metabolic processes in the human body driven by proton motive force (Δp). Numerous studies have immensely contributed toward highlighting its regulation in improving energy homeostasis and maintaining mitochondrial integrity, which otherwise gets compromised in illnesses. Yet, its role in the implication of non-communicable diseases remains unknown. FF ATP synthase dysregulation at gene level leads to reduced activity and delocalization in the cristae and plasma membranes, which is directly associated with non-communicable diseases: cardiovascular diseases, diabetes, neurodegenerative disorders, cancer, and renal diseases. Individual subunits of the FF ATP synthase target ligand-based competitive or non-competitive inhibition. After performing a systematic literature review to understand its specific functions and its novel drug targets, the present article focuses on the central role of FF ATP synthase in primary non-communicable diseases. Next, it discusses its involvement through various pathways and the effects of multiple inhibitors, activators, and modulators specific to non-communicable diseases with a futuristic outlook.
Topics: Humans; Adenosine Triphosphate; Glycogen Synthase; Noncommunicable Diseases; Mitochondria; Mitochondrial Membranes; Mitochondrial Proton-Translocating ATPases
PubMed: 36715790
DOI: 10.1007/s11033-023-08299-3 -
Cancer Management and Research 2019Thyroid cancer (TC) is an important common endocrine malignancy, and its incidence has increased in the past decades. The current TC diagnosis and classification tools... (Review)
Review
INTRODUCTION
Thyroid cancer (TC) is an important common endocrine malignancy, and its incidence has increased in the past decades. The current TC diagnosis and classification tools are fine-needle aspiration (FNA) and histological examination following thyroidectomy. The metabolite profile alterations of thyroid cells (oncometabolites) can be considered for current TC diagnosis and management protocols.
METHODS
This systematic review focuses on metabolite alterations within the plasma, FNA specimens, and tissue of malignant TC contrary to benign, goiter, or healthy TC samples. A systematic search of MEDLINE (PubMed), Scopus, Embase, and Web of Science databases was conducted, and the final 31 studies investigating metabolite biomarkers of TC were included.
RESULTS
A total of 15 targeted studies and 16 untargeted studies revealed several potential metabolite signatures of TC such as glucose, fructose, galactose, mannose, 2-keto-d-gluconic acid and rhamnose, malonic acid and inosine, cholesterol and arachidonic acid, glycosylation (immunoglobulin G [IgG] Fc-glycosylation), outer mitochondrial membrane 20 (TOMM20), monocarboxylate transporter 4 (MCT4), choline, choline derivatives, myo-/scyllo-inositol, lactate, fatty acids, several amino acids, cell membrane phospholipids, estrogen metabolites such as 16 alpha-OH E1/2-OH E1 and catechol estrogens (2-OH E1), and purine and pyrimidine metabolites, which were suggested as the TC oncometabolite.
CONCLUSION
Citrate was suggested as the first most significant biomarker and lactate as the second one. Further research is needed to confirm these biomarkers as the TC diagnostic oncometabolite.
PubMed: 30881111
DOI: 10.2147/CMAR.S188661 -
Journal of Medical Genetics Sep 2012Complex I deficiency is the most frequent mitochondrial disorder presenting in childhood, accounting for up to 30% of cases. As with many mitochondrial disorders,... (Review)
Review
Complex I deficiency is the most frequent mitochondrial disorder presenting in childhood, accounting for up to 30% of cases. As with many mitochondrial disorders, complex I deficiency is characterised by marked clinical and genetic heterogeneity, leading to considerable diagnostic challenges for the clinician, not least because of the involvement of two genomes. The most prevalent clinical presentations include Leigh syndrome, leukoencephalopathy and other early-onset neurodegenerative disorders; fatal infantile lactic acidosis; hypertrophic cardiomyopathy; and exercise intolerance. Causative genetic defects may involve the seven mitochondrial-encoded or 38 nuclear-encoded subunits of the enzyme, or any of an increasing number of assembly factors implicated in the correct biosynthesis of complex I within the inner mitochondrial membrane. In this review, we discuss recent advances in knowledge of the structure, function and assembly of complex I and how these advances, together with new high-throughput genetic screening techniques, have translated into improved genetic diagnosis for affected patients and their families. Approximately 25% of cases have mitochondrial DNA mutations, while a further ∼25% have mutations in a nuclear subunit or in one of nine known assembly factors. We also present a systematic review of all published cases of nuclear-encoded complex I deficiency, including 117 cases with nuclear subunit mutations and 55 with assembly factor mutations, and highlight clinical, radiological and biochemical clues that may expedite genetic diagnosis.
Topics: Animals; Biochemical Phenomena; Disease Models, Animal; Electron Transport Complex I; Humans; Mitochondrial Diseases; Phenotype
PubMed: 22972949
DOI: 10.1136/jmedgenet-2012-101159