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Pediatric Nephrology (Berlin, Germany) Jun 2023Valproic acid is prescribed for epilepsy and as prophylaxis for bipolar disorder and migraine headaches. It has also been implicated as a cause of a kidney tubular... (Review)
Review
BACKGROUND
Valproic acid is prescribed for epilepsy and as prophylaxis for bipolar disorder and migraine headaches. It has also been implicated as a cause of a kidney tubular injury.
METHODS
We undertook a review of the literature to characterize the biochemical and histopathological features of the overt kidney tubular injury and to evaluate the possible existence of a pauci-symptomatic injury. The pre-registered review (CRD42022360357) was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology. Searches were conducted in Excerpta Medica, the National Library of Medicine, and Web of Science. The gray literature was also considered.
RESULTS
For the final analysis, we retained 36 articles: 28 case reports documented 48 individuals with epilepsy on valproic acid for 7 months or more and presenting with features consistent with an overt kidney tubular injury. The following disturbances were noted: hypophosphatemia (N = 46), normoglycemic glycosuria (N = 46), total proteinuria (N = 45), metabolic acidosis (N = 36), hypouricemia (N = 27), tubular proteinuria (N = 27), hypokalemia (N = 23), and hypocalcemia (N = 8). A biopsy, obtained in six cases, disclosed altered proximal tubular cells with giant and dysmorphic mitochondria. Eight case series addressed the existence of a pauci- or even asymptomatic kidney injury. In the reported 285 subjects on valproic acid for 7 months or more, an isolated tubular proteinuria, mostly N-acetyl-β-glucosaminidase, was often noted.
CONCLUSIONS
Valproic acid may induce an overt kidney tubular injury, which is associated with a proximal tubular mitochondrial toxicity. Treatment for 7 months or more is often associated with a pauci- or oligosymptomatic kidney tubular injury. A higher resolution version of the Graphical abstract is available as Supplementary information.
Topics: Humans; Valproic Acid; Kidney Tubules, Proximal; Kidney; Proteinuria; Epilepsy
PubMed: 36645492
DOI: 10.1007/s00467-022-05869-8 -
BioMed Research International 2022Arsenic is a known environmental carcinogenic agent. However, under certain circumstances, it may exert anticancer effects. In this systematic review, we aim to provide... (Review)
Review
Arsenic is a known environmental carcinogenic agent. However, under certain circumstances, it may exert anticancer effects. In this systematic review, we aim to provide information on recent developments in studies on arsenic antitumor effects in breast cancer. Research included in the review refers to experimental data from studies. The data was collected using search terms "breast cancer," "arsenic," and "anticancer" (25.05.2021). Only studies in English and published in the last 10 years were included. The search identified 123 studies from the EBSCOhost, PubMed, and Scopus databases. In the selection process, thirty full-texts were evaluated as eligible for the review. The literature of the last decade provides a lot of information on mechanisms behind anticancer effects of arsenic on breast cancer. Similar to arsenic-induced carcinogenesis, these mechanisms include the activation of the redox system and the increased production of free radicals. Targets of arsenic action are systems of cell membranes, mitochondria, pathways of intracellular transmission, and the genetic apparatus of the cell. Beneficial effects of arsenic use are possible due to significant metabolic differences between cancer and healthy cells. Further efforts are needed in order to establish modes and doses of treatment with arsenic that would provide anticancer activity with minimal toxicity.
Topics: Humans; Female; Arsenic; Breast Neoplasms; Carcinogenesis; Carcinogens; Free Radicals
PubMed: 36619302
DOI: 10.1155/2022/8030931 -
Journal of Clinical Medicine Dec 2022Fatty acid translocase/cluster of differentiation 36 (FAT/CD36) is a multifunctional membrane protein activated by a high-fat diet, physical exercise, fatty acids (FAs),... (Review)
Review
Fatty acid translocase/cluster of differentiation 36 (FAT/CD36) is a multifunctional membrane protein activated by a high-fat diet, physical exercise, fatty acids (FAs), leptin, and insulin. The principal function of FAT/CD36 is to facilitate the transport of long-chain fatty acids through cell membranes such as myocytes, adipocytes, heart, and liver. Under high-energy expenditure, the different isoforms of FAT/CD36 in the plasma membrane and mitochondria bind to the mobilization and oxidation of FAs. Furthermore, FAT/CD36 is released in its soluble form and becomes a marker of metabolic dysfunction. Studies with healthy animals and humans show that physical exercise and a high-lipid diet increase FAT/CD36 expression and caloric expenditure. However, several aspects such as obesity, diabetes, Single Nucleotide polymorphisms (SNPs), and oxidative stress affect the normal FAs metabolism and function of FAT/CD36, inducing metabolic disease. Through a comprehensive systematic review of primary studies, this work aimed to document molecular mechanisms related to FAT/CD36 in FAs oxidation and trafficking in skeletal muscle under basal conditions, physical exercise, and diet in healthy individuals.
PubMed: 36615118
DOI: 10.3390/jcm12010318 -
Frontiers in Immunology 2022As the first barrier of host defense, innate immunity sets up the parclose to keep out external microbial or virus attacks. Depending on the type of pathogens, several...
As the first barrier of host defense, innate immunity sets up the parclose to keep out external microbial or virus attacks. Depending on the type of pathogens, several cytoplasm pattern recognition receptors exist to sense the attacks from either foreign or host origins, triggering the immune response to battle with the infections. Among them, cGAS-STING is the major pathway that mainly responds to microbial DNA, DNA virus infections, or self-DNA, which mainly comes from genome instability by-product or released DNA from the mitochondria. cGAS was initially found functional in the cytoplasm, although intriguing evidence indicates that cGAS exists in the nucleus where it is involved in the DNA damage repair process. Because the close connection between DNA damage response and immune response and cGAS recognizes DNA in length-dependent but DNA sequence-independent manners, it is urgent to clear the function balance of cGAS in the nucleus versus cytoplasm and how it is shielded from recognizing the host origin DNA. Here, we outline the current conception of immune response and the regulation mechanism of cGAS in the nucleus. Furthermore, we will shed light on the potential mechanisms that are restricted to be taken away from self-DNA recognition, especially how post-translational modification regulates cGAS functions.
Topics: Signal Transduction; Immunity, Innate; Nucleotidyltransferases; DNA; DNA Damage
PubMed: 36591232
DOI: 10.3389/fimmu.2022.1076784 -
International Journal of Molecular... Nov 2022Heart failure is defined as a clinical syndrome consisting of key symptoms and is due to a structural and/or functional alteration of the heart that results in increased... (Review)
Review
Heart failure is defined as a clinical syndrome consisting of key symptoms and is due to a structural and/or functional alteration of the heart that results in increased intracardiac pressures and/or inadequate cardiac output at rest and/or during exercise. One of the key mechanisms determining myocardial dysfunction in heart failure is oxidative stress. MicroRNAs (miRNAs, miRs) are short, endogenous, conserved, single-stranded non-coding RNAs of around 21-25 nucleotides in length that act as regulators of multiple processes. A systematic review following the PRISMA guidelines was performed on the evidence on the interplay between microRNA and oxidative stress in heart failure. A search of Pubmed, Embase, Scopus, and Scopus direct databases using the following search terms: 'heart failure' AND 'oxidative stress' AND 'microRNA' or 'heart failure' AND 'oxidative stress' AND 'miRNA' was conducted and resulted in 464 articles. Out of them, 15 full text articles were eligible for inclusion in the qualitative analysis. Multiple microRNAs are involved in the processes associated with oxidative stress leading to heart failure development including mitochondrial integrity and function, antioxidant defense, iron overload, ferroptosis, and survival pathways.
Topics: Humans; MicroRNAs; Heart Failure; Oxidative Stress; Antioxidants; Cardiomyopathies
PubMed: 36499336
DOI: 10.3390/ijms232315013 -
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 -
Frontiers in Cardiovascular Medicine 2022Cardiac mitochondrial dysfunction was found in ischemic heart disease (IHD). Hence, this study determined the effects of exercise training (ET) on cardiac mitochondrial...
OBJECTIVE
Cardiac mitochondrial dysfunction was found in ischemic heart disease (IHD). Hence, this study determined the effects of exercise training (ET) on cardiac mitochondrial respiration and cardiac mitochondrial quality control in IHD.
METHODS
A narrative synthesis was conducted after searching animal studies written in English in three databases (PubMed, Web of Science, and EMBASE) until December 2020. Studies that used aerobic exercise as an intervention for at least 3 weeks and had at least normal, negative (sedentary IHD), and positive (exercise-trained IHD) groups were included. The CAMARADES checklist was used to check the quality of the included studies.
RESULTS
The 10 included studies (CAMARADES score: 6-7/10) used swimming or treadmill exercise for 3-8 weeks. Seven studies showed that ET ameliorated cardiac mitochondrial respiratory function as manifested by decreased reactive oxygen species (ROS) production and increased complexes I-V activity, superoxide dismutase 2 (SOD2), respiratory control ratio (RCR), NADH dehydrogenase subunits 1 and 6 (ND1/6), Cytochrome B (CytB), and adenosine triphosphate (ATP) production. Ten studies showed that ET improved cardiac mitochondrial quality control in IHD as manifested by enhanced and/or controlled mitochondrial biogenesis, dynamics, and mitophagy. Four other studies showed that ET resulted in better cardiac mitochondrial physiological characteristics.
CONCLUSION
Exercise training could improve cardiac mitochondrial functions, including respiration, biogenesis, dynamics, and mitophagy in IHD.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/ display_record.php?RecordID=226817, identifier: CRD42021226817.
PubMed: 36304547
DOI: 10.3389/fcvm.2022.949744 -
Metabolism: Clinical and Experimental Jan 2023We performed a meta-analysis to determine the changes induced by calorie restriction (CR) and bariatric surgery on human skeletal muscle mitochondria. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
We performed a meta-analysis to determine the changes induced by calorie restriction (CR) and bariatric surgery on human skeletal muscle mitochondria.
METHODS
A systematic search of Medline and Web of Science was conducted. Controlled trials exploring CR (≥14 days) and mitochondrial function and/or content assessment were included. Moreover, studies analyzing weight loss following gastric surgery were included for comparison purposes. Human muscle data from 28 studies assessing CR (520 muscle samples) and from 10 studies assessing bariatric surgery (155 muscle samples) were analyzed in a random effect meta-analysis with three a priori chosen covariates.
MAIN RESULTS
We report a decrease (p < 0.05) (mean (95 % CI)) in maximal mitochondrial state 3 respiration in response to CR (-0.44 (-0.85, -0.03)) but not in response to surgery (-0.33 (-1.18, 0.52)). No changes in mitochondrial content were reported after CR (-0.05 (-0.12, 0.13)) or in response to surgery (0.23 (-0.05, 0.52)). Moreover, data from CR subjects showed a reduction in complex IV (CIV) activity (-0.29 (-0.56, -0.03)) but not in CIV content (-0.21 (-0.63, 0.22)). Similar results were obtained when the length of the protocol, the initial body mass index, and the estimated energy deficit were included in the model as covariates.
CONCLUSION
The observation of reduced maximal mitochondrial state 3, uncoupled respiration, and CIV activity without altering mitochondrial content suggests that, in human skeletal muscle, CR mainly modulates intrinsic mitochondrial function.
Topics: Humans; Caloric Restriction; Mitochondria, Muscle; Muscle, Skeletal; Bariatric Surgery; Mitochondria
PubMed: 36302454
DOI: 10.1016/j.metabol.2022.155336 -
International Journal of Molecular... Oct 2022Mitochondria dysfunction is implicated in the pathogenesis of cardiovascular diseases (CVD). Exercise training is potentially an effective non-pharmacological strategy... (Meta-Analysis)
Meta-Analysis Review
Mitochondria dysfunction is implicated in the pathogenesis of cardiovascular diseases (CVD). Exercise training is potentially an effective non-pharmacological strategy to restore mitochondrial health in CVD. However, how exercise modifies mitochondrial functionality is inconclusive. We conducted a systematic review using the PubMed; Scopus and Web of Science databases to investigate the effect of exercise training on mitochondrial function in CVD patients. Search terms included “mitochondria”, “exercise”, “aerobic capacity”, and “cardiovascular disease” in varied combination. The search yielded 821 records for abstract screening, of which 20 articles met the inclusion criteria. We summarized the effect of exercise training on mitochondrial morphology, biogenesis, dynamics, oxidative capacity, antioxidant capacity, and quality. Amongst these parameters, only oxidative capacity was suitable for a meta-analysis, which demonstrated a significant effect size of exercise in improving mitochondrial oxidative capacity in CVD patients (SMD = 4.78; CI = 2.99 to 6.57; p < 0.01), but with high heterogeneity among the studies (I2 = 75%, p = 0.003). Notably, aerobic exercise enhanced succinate-involved oxidative phosphorylation. The majority of the results suggested that exercise improves morphology and biogenesis, whereas findings on dynamic, antioxidant capacity, and quality, were inadequate or inconclusive. A further randomized controlled trial is clearly required to explain how exercise modifies the pathway of mitochondrial quantity and quality in CVD patients.
Topics: Humans; Antioxidants; Exercise; Cardiovascular Diseases; Mitochondria; Succinates
PubMed: 36293409
DOI: 10.3390/ijms232012559 -
Annals of Translational Medicine Sep 2022Though best known for its immunosuppressant effects, cyclosporine A (CsA) has also been studied as a treatment to mitigate ischemia-reperfusion injury (IRI) by its...
BACKGROUND
Though best known for its immunosuppressant effects, cyclosporine A (CsA) has also been studied as a treatment to mitigate ischemia-reperfusion injury (IRI) by its inhibition of the mitochondria permeability transition pore (mPTP). Despite numerous preclinical studies supporting its benefit in reducing infarct size following myocardial IRI, large randomized controlled clinical trials have been unable to show a beneficial effect. Exploring existing preclinical data can give us the opportunity to revisit some the assumptions that may have led to the failure of these studies to translate clinically. Herein, we present a systematic review of preclinical studies testing CsA to attenuate myocardial IRI (PROSPERO CRD42020159620).
METHODS
We conducted a systematic search of health research databases Ovid MEDLINE, Ovid EMBASE, Web of Science BIOSIS, and Scopus, as well as Cochrane and PROSPERO systematic review databases, on March 9, 2022 for non-human animal studies of myocardial IRI, using CsA as a treatment that reported clinically relevant outcomes. Bias was assessed using the Systematic Review Centre for Laboratory Animal Experimentation's risk of bias tool and a modified Collaborative Approach to Meta Analysis and Review of Animal Data from Experimental Studies checklist. Sub-group meta-analyses were conducted to identify potential factors influencing outcomes.
RESULTS
We identified 71 studies, 59 of which were studies of coronary occlusion. Overall, 75% of studies reported a clear positive effect of CsA in mitigating myocardial IRI by some clinically relevant parameter (e.g., infarct size). A meta-analysis including 43 coronary occlusion studies showed an overall reduction in infarct size with CsA treatment (16.09%; 95% CI: -18.50% to -13.67%). Subgroup meta-analyses identified species, age, timing of administration, and duration of ischemia as factors potentially affecting the efficacy of CsA in the setting of myocardial IRI.
CONCLUSIONS
Our systematic review and meta-analysis identifies questions that have yet to be answered by preclinical studies, highlighting important differences between these and clinical studies that should be addressed prior to proceeding with any further clinical studies using CsA to treat IRI in the heart or other organs. We also use the example of CsA to highlight general considerations for researchers attempting to translate animal studies into the clinical setting.
PubMed: 36267756
DOI: 10.21037/atm-22-618