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Pharmacology & Therapeutics Apr 2019Atherosclerosis, the principal cause of cardiovascular death worldwide, is a pathological disease characterized by fibro-proliferation, chronic inflammation, lipid...
Atherosclerosis, the principal cause of cardiovascular death worldwide, is a pathological disease characterized by fibro-proliferation, chronic inflammation, lipid accumulation, and immune disorder in the vessel wall. As the atheromatous plaques develop into advanced stage, the vulnerable plaques are prone to rupture, which causes acute cardiovascular events, including ischemic stroke and myocardial infarction. Emerging evidence has suggested that atherosclerosis is also an epigenetic disease with the interplay of multiple epigenetic mechanisms. The epigenetic basis of atherosclerosis has transformed our knowledge of epigenetics from an important biological phenomenon to a burgeoning field in cardiovascular research. Here, we provide a systematic and up-to-date overview of the current knowledge of three distinct but interrelated epigenetic processes (including DNA methylation, histone methylation/acetylation, and non-coding RNAs), in atherosclerotic plaque development and instability. Mechanistic and conceptual advances in understanding the biological roles of various epigenetic modifiers in regulating gene expression and functions of endothelial cells (vascular homeostasis, leukocyte adhesion, endothelial-mesenchymal transition, angiogenesis, and mechanotransduction), smooth muscle cells (proliferation, migration, inflammation, hypertrophy, and phenotypic switch), and macrophages (differentiation, inflammation, foam cell formation, and polarization) are discussed. The inherently dynamic nature and reversibility of epigenetic regulation, enables the possibility of epigenetic therapy by targeting epigenetic "writers", "readers", and "erasers". Several Food Drug Administration-approved small-molecule epigenetic drugs show promise in pre-clinical studies for the treatment of atherosclerosis. Finally, we discuss potential therapeutic implications and challenges for future research involving cardiovascular epigenetics, with an aim to provide a translational perspective for identifying novel biomarkers of atherosclerosis, and transforming precision cardiovascular research and disease therapy in modern era of epigenetics.
Topics: Animals; Atherosclerosis; Epigenesis, Genetic; Humans; Immunity; RNA, Untranslated; Risk Factors
PubMed: 30439455
DOI: 10.1016/j.pharmthera.2018.11.003 -
Journal of Advanced Research Dec 2023Crush syndrome (CS) is a kind of traumatic and ischemic injury that seriously threatens life after prolonged compression. It is characterized by systemic inflammatory... (Review)
Review
BACKGROUND
Crush syndrome (CS) is a kind of traumatic and ischemic injury that seriously threatens life after prolonged compression. It is characterized by systemic inflammatory reaction, myoglobinuria, hyperkalemia and acute kidney injury (AKI). Especially AKI, it is the leading cause of death from CS. There are various cell death forms in AKI, among which ferroptosis is a typical form of cell death. However, the role of ferroptosis has not been fully revealed in CS-AKI.
AIM OF REVIEW
This review aimed to summarize the evidence of ferroptosis in CS-AKI and its related molecular mechanism, discuss the therapeutic significance of ferroptosis in CS-AKI, and open up new ideas for the treatment of CS-AKI.
KEY SCIENTIFIC CONCEPTS OF REVIEW
One of the main pathological manifestations of CS-AKI is renal tubular epithelial cell dysfunction and cell death, which has been attributed to massive deposition of myoglobin. Large amounts of myoglobin released from damaged muscle deposited in the renal tubules, impeding the normal renal tubules function and directly damaging the tubules with oxidative stress and elevated iron levels. Lipid peroxidation damage and iron overload are the distinguishing features of ferroptosis. Moreover, high levels of pro-inflammatory cytokines and damage-associated molecule pattern molecules (HMGB1, double-strand DNA, and macrophage extracellular trap) in renal tissue have been shown to promote ferroptosis. However, how ferroptosis occurs in CS-AKI and whether it can be a therapeutic target remains unclear. In our current work, we systematically reviewed the occurrence and underlying mechanism of ferroptosis in CS-AKI.
Topics: Humans; Acute Kidney Injury; Cell Death; Crush Syndrome; Ferroptosis; Myoglobin
PubMed: 36702249
DOI: 10.1016/j.jare.2023.01.016 -
African Journal of Disability 2019Many patients with Down syndrome (PWDS) have poor cardiometabolic risk profiles, aerobic capacities and weak hypotonic muscles, primarily because of physical inactivity... (Review)
Review
BACKGROUND
Many patients with Down syndrome (PWDS) have poor cardiometabolic risk profiles, aerobic capacities and weak hypotonic muscles, primarily because of physical inactivity and poor diet.
OBJECTIVES
This study discusses the benefits of exercise therapy on body composition, aerobic capacity, muscle strength, proprioception and cardiometabolic profiles of PWDS.
METHODS
A literature review using the Crossref metadatabase, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), focusing on the period 2007-2018, was undertaken. Each record was judged adopting the modified Downs and Black Appraisal Scale. The literature investigation identified 15 701 records. Records were excluded if they were published before 2007, pertained to the impact of exercise on intellectual disabilities beyond Down syndrome or the impact of medical, pharmaceutical, nutrition and psychological interventions among PWDS and were published in languages besides English. Nineteen articles were synthesised into this commentary.
RESULTS
PWDS have a heightened cardiometabolic risk profile and high oxidative stress associated with elevated insulin resistance, poor insulin sensitivity, atherosclerosis and hypertension. PWDS have low aerobic capacity (VO), peak heart rates, muscle strength, agility and balance. Regular physical activity is beneficial to improve their VO and muscle strength. Moreover, regular physical activity reduces lipid peroxidation and arterial cell wall damage, the pathogenesis of atheroma is limited.
CONCLUSION
Exercise therapy compliance seems to have a positive impact on the cardiometabolic risk profile, muscle strength and aerobic work capacity of PWDS. Nonetheless, additional vigorous experimental investigations are necessary to better understand the effect of exercise therapy on the aerobic, strength, proprioception and cardiometabolic risk profile of PWDS.
PubMed: 31745461
DOI: 10.4102/ajod.v8i0.576 -
The Cochrane Database of Systematic... Sep 2019Neuromuscular diseases (NMDs) are a heterogeneous group of diseases affecting the anterior horn cell of spinal cord, neuromuscular junction, peripheral nerves and...
BACKGROUND
Neuromuscular diseases (NMDs) are a heterogeneous group of diseases affecting the anterior horn cell of spinal cord, neuromuscular junction, peripheral nerves and muscles. NMDs cause physical disability usually due to progressive loss of strength in limb muscles, and some NMDs also cause respiratory muscle weakness. Respiratory muscle training (RMT) might be expected to improve respiratory muscle weakness; however, the effects of RMT are still uncertain. This systematic review will synthesize the available trial evidence on the effectiveness and safety of RMT in people with NMD, to inform clinical practice.
OBJECTIVES
To assess the effects of respiratory muscle training (RMT) for neuromuscular disease (NMD) in adults and children, in comparison to sham training, no training, standard treatment, breathing exercises, or other intensities or types of RMT.
SEARCH METHODS
On 19 November 2018, we searched the Cochrane Neuromuscular Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase. On 23 December 2018, we searched the US National Institutes for Health Clinical Trials Registry (ClinicalTrials.gov), the World Health Organization International Clinical Trials Registry Platform, and reference lists of the included studies.
SELECTION CRITERIA
We included randomized controlled trials (RCTs) and quasi-RCTs, including cross-over trials, of RMT in adults and children with a diagnosis of NMD of any degree of severity, who were living in the community, and who did not need mechanical ventilation. We compared trials of RMT (inspiratory muscle training (IMT) or expiratory muscle training (EMT), or both), with sham training, no training, standard treatment, different intensities of RMT, different types of RMT, or breathing exercises.
DATA COLLECTION AND ANALYSIS
We followed standard Cochrane methodological procedures.
MAIN RESULTS
We included 11 studies involving 250 randomized participants with NMDs: three trials (N = 88) in people with amyotrophic lateral sclerosis (ALS; motor neuron disease), six trials (N = 112) in Duchenne muscular dystrophy (DMD), one trial (N = 23) in people with Becker muscular dystrophy (BMD) or limb-girdle muscular dystrophy, and one trial (N = 27) in people with myasthenia gravis.Nine of the trials were at high risk of bias in at least one domain and many reported insufficient information for accurate assessment of the risk of bias. Populations, interventions, control interventions, and outcome measures were often different, which largely ruled out meta-analysis. All included studies assessed lung capacity, our primary outcome, but four did not provide data for analysis (1 in people with ALS and three cross-over studies in DMD). None provided long-term data (over a year) and only one trial, in ALS, provided information on adverse events. Unscheduled hospitalisations for chest infection or acute exacerbation of chronic respiratory failure were not reported and physical function and quality of life were reported in one (ALS) trial.Amyotrophic lateral sclerosis (ALS)Three trials compared RMT versus sham training in ALS. Short-term (8 weeks) effects of RMT on lung capacity in ALS showed no clear difference in the change of the per cent predicted forced vital capacity (FVC%) between EMT and sham EMT groups (mean difference (MD) 0.70, 95% confidence interval (CI) -8.48 to 9.88; N = 46; low-certainty evidence). The mean difference (MD) in FVC% after four months' treatment was 10.86% in favour of IMT (95% CI -4.25 to 25.97; 1 trial, N = 24; low-certainty evidence), which is larger than the minimal clinically important difference (MCID, as estimated in people with idiopathic pulmonary fibrosis). There was no clear difference between IMT and sham IMT groups, measured on the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALFRS; range of possible scores 0 = best to 40 = worst) (MD 0.85, 95% CI -2.16 to 3.85; 1 trial, N = 24; low-certainty evidence) or quality of life, measured on the EuroQol-5D (0 = worst to 100 = best) (MD 0.77, 95% CI -17.09 to 18.62; 1 trial, N = 24; low-certainty evidence) over the medium term (4 months). One trial report stated that the IMT protocol had no adverse effect (very low-certainty evidence).Duchenne muscular dystrophy (DMD)Two DMD trials compared RMT versus sham training in young males with DMD. In one study, the mean post-intervention (6-week) total lung capacity (TLC) favoured RMT (MD 0.45 L, 95% CI -0.24 to 1.14; 1 trial, N = 16; low-certainty evidence). In the other trial there was no clear difference in post-intervention (18 days) FVC between RMT and sham RMT (MD 0.16 L, 95% CI -0.31 to 0.63; 1 trial, N = 20; low-certainty evidence). One RCT and three cross-over trials compared a form of RMT with no training in males with DMD; the cross-over trials did not provide suitable data. Post-intervention (6-month) values showed no clear difference between the RMT and no training groups in per cent predicted vital capacity (VC%) (MD 3.50, 95% CI -14.35 to 21.35; 1 trial, N = 30; low-certainty evidence).Becker or limb-girdle muscular dystrophyOne RCT (N = 21) compared 12 weeks of IMT with breathing exercises in people with Becker or limb-girdle muscular dystrophy. The evidence was of very low certainty and conclusions could not be drawn.Myasthenia gravisIn myasthenia gravis, there may be no clear difference between RMT and breathing exercises on measures of lung capacity, in the short term (TLC MD -0.20 L, 95% CI -1.07 to 0.67; 1 trial, N = 27; low-certainty evidence). Effects of RMT on quality of life are uncertain (1 trial; N = 27).Some trials reported effects of RMT on inspiratory and/or expiratory muscle strength; this evidence was also of low or very low certainty.
AUTHORS' CONCLUSIONS
RMT may improve lung capacity and respiratory muscle strength in some NMDs. In ALS there may not be any clinically meaningful effect of RMT on physical functioning or quality of life and it is uncertain whether it causes adverse effects. Due to clinical heterogeneity between the trials and the small number of participants included in the analysis, together with the risk of bias, these results must be interpreted very cautiously.
Topics: Adult; Breathing Exercises; Child; Exhalation; Humans; Muscle Weakness; Neuromuscular Diseases; Quality of Life; Randomized Controlled Trials as Topic; Vital Capacity
PubMed: 31487757
DOI: 10.1002/14651858.CD011711.pub2 -
Journal of Neurology Mar 2022Current standard treatment in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) has been proved effective, but it is poorly effective in refractory... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Current standard treatment in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) has been proved effective, but it is poorly effective in refractory patients and unclear for anti-IgG4 antibody-associated CIDP. Rituximab is a B cell-depleting monoclonal antibody. It has been applied as one of the management strategies in CIDP, but its efficacy is unknown.
OBJECTIVE
To perform a systematic review and a meta-analysis of the efficacy of rituximab treatment in CIDP patients.
METHODS
Through searches in MEDLINE, PubMed, EMBASE, BIOSOS, Web of Science, and Cochrane library on March 31st, 2021, 15 studies were identified. Patients' characteristics, treatment regime and outcome measure were extracted.
RESULTS
Ninety-six patients in 15 studies were included. The pooled estimate of responsiveness was 75% (95% CI 72-78%). The standard mean difference (SMD) of Inflammatory Neuropathy Cause and Treatment (INCAT) disability score improvement was 1.7 (95% CI 1.0-2.3, p value < 0.0001) and the Medical Research Council (MRC) score for muscle power is 1.3 (95% CI - 2.6 to - 0.1, p value 0.04). All of the anti-IgG4 antibody-positive patients showed excellent responses to rituximab treatment.
CONCLUSION
Rituximab was effective in the treatment in CIDP patients, especially in anti-IgG4 antibody-positive patients. Randomized clinical trials are needed to determine the effectiveness and safety of rituximab in CIDP patients.
Topics: Humans; Immunoglobulin G; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating; Rituximab
PubMed: 34120208
DOI: 10.1007/s00415-021-10646-y -
Redox Report : Communications in Free... Dec 2018p53 is a tumor suppressor protein involved in regulating a wide array of signaling pathways. The role of p53 in the cell is determined by the type of imposed oxidative... (Review)
Review
BACKGROUND
p53 is a tumor suppressor protein involved in regulating a wide array of signaling pathways. The role of p53 in the cell is determined by the type of imposed oxidative stress, its intensity and duration. The last decade of research has unravelled a dual nature in the function of p53 in mediating the oxidative stress burden. However, this is dependent on the specific properties of the applied stress and thus requires further analysis.
METHODS
A systematic review was performed following an electronic search of Pubmed, Google Scholar, and ScienceDirect databases. Articles published in the English language between January 1, 1990 and March 1, 2017 were identified and isolated based on the analysis of p53 in skeletal muscle in both animal and cell culture models.
RESULTS
Literature was categorized according to the modality of imposed oxidative stress including exercise, diet modification, exogenous oxidizing agents, tissue manipulation, irradiation, and hypoxia. With low to moderate levels of oxidative stress, p53 is involved in activating pathways that increase time for cell repair, such as cell cycle arrest and autophagy, to enhance cell survival. However, with greater levels of stress intensity and duration, such as with irradiation, hypoxia, and oxidizing agents, the role of p53 switches to facilitate increased cellular stress levels by initiating DNA fragmentation to induce apoptosis, thereby preventing aberrant cell proliferation.
CONCLUSION
Current evidence confirms that p53 acts as a threshold regulator of cellular homeostasis. Therefore, within each modality, the intensity and duration are parameters of the oxidative stressor that must be analyzed to determine the role p53 plays in regulating signaling pathways to maintain cellular health and function in skeletal muscle.
ABBREVIATIONS
Acadl: acyl-CoA dehydrogenase, long chain; Acadm: acyl-CoA dehydrogenase, C-4 to C-12 straight chain; AIF: apoptosis-inducing factor; Akt: protein kinase B (PKB); AMPK: AMP-activated protein kinase; ATF-4: activating transcription factor 4; ATM: ATM serine/threonine kinase; Bax: BCL2 associated X, apoptosis regulator; Bcl-2: B cell Leukemia/Lymphoma 2 apoptosis regulator; Bhlhe40: basic helix-loop-helix family member e40; BH3: Borane; Bim: bcl-2 interacting mediator of cell death; Bok: Bcl-2 related ovarian killer; COX-IV: cytochrome c oxidase IV; cGMP: Cyclic guanosine monophosphate; c-myc: proto-oncogene protein; Cpt1b: carnitine palmitoyltransferase 1B; Dr5: death receptor 5; eNOS: endothelial nitric oxide synthase; ERK: extracellular regulated MAP kinase; Fas: Fas Cell surface death receptor; FDXR: Ferredoxin Reductase; FOXO3a: forkhead box O3; Gadd45a: growth arrest and DNA damage-inducible 45 alpha; GLS2: glutaminase 2; GLUT 1 and 4: glucose transporter 1(endothelial) and 4 (skeletal muscle); GSH: Glutathione; Hes1: hes family bHLH transcription factor 1; Hey1: hes related family bHLH transcription factor with YRPW motif 1; HIFI-α: hypoxia-inducible factor 1, α-subunit; HK2: Hexokinase 2; HSP70: Heat Shock Protein 70; HO: Hydrogen Peroxide; Id2: inhibitor of DNA-binding 2; IGF-1-BP3: Insulin-like growth factor binding protein 3; IL-1β: Interleukin 1 beta; iNOS: inducible nitric oxide synthase; IRS-1: Insulin receptor substrate 1; JNK: c-Jun N-terminal kinases; LY-83583: 6-anilino-5,8-quinolinedione; inhibitor of soluble guanylate cyclase and of cGMP production; Mdm 2/ 4: Mouse double minute 2 homolog (mouse) Mdm4 (humans); mtDNA: mitochondrial DNA; MURF1: Muscle RING-finger protein-1; MyoD: Myogenic differentiation 1; MyoG: myogenin; Nanog: Nanog homeobox; NF-kB: Nuclear factor-κB; NO: nitric oxide; NoxA: phorbol-12-myristate-13-acetate-induced protein 1 (Pmaip1); NRF-1: nuclear respiratory factor 1; Nrf2: Nuclear factor erythroid 2-related factor 2; P21: Cdkn1a cyclin-dependent kinase inhibitor 1A (P21); P38 MAPK: mitogen-activated protein kinases; p53R2: p53 inducible ribonucleotide reductase gene; P66Shc: src homology 2 domain-containing transforming protein C1; PERP: p53 apoptosis effector related to PMP-22; PGC-1α: Peroxisome proliferator-activated receptor gamma coactivator 1-alpha; PGM: phosphoglucomutase; PI3K: Phosphatidylinositol-4,5-bisphosphate 3-kinase; PKCβ: protein kinase c beta; PTEN: phosphatase and tensin homolog; PTIO: 2-phenyl-4, 4, 5, 5,-tetramethylimidazoline-1-oxyl 3-oxide (PTIO) has been used as a nitric oxide (NO) scavenger; Puma: The p53 upregulated modulator of apoptosis; PW1: paternally expressed 3 (Peg3); RNS: Reactive nitrogen species; SIRT1: sirtuin 1; SCO2: cytochrome c oxidase assembly protein; SOD2: superoxide dismutase 2; Tfam: transcription factor A mitochondrial; TIGAR: Trp53 induced glycolysis repulatory phosphatase; TNF-a: tumor necrosis factor a; TRAF2: TNF receptor associated factor 2; TRAIL: type II transmembrane protein.
Topics: Animals; Diet; Exercise; Humans; Muscle, Skeletal; Oxidative Stress; Oxygen; Proto-Oncogene Mas; Radiation Injuries; Tumor Suppressor Protein p53
PubMed: 29298131
DOI: 10.1080/13510002.2017.1416773 -
The Cochrane Database of Systematic... Mar 2016A decreased physical fitness has been reported in patients and survivors of childhood cancer. This is influenced by the negative effects of the disease and the treatment... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
A decreased physical fitness has been reported in patients and survivors of childhood cancer. This is influenced by the negative effects of the disease and the treatment of childhood cancer. Exercise training for adult cancer patients has frequently been reported to improve physical fitness. In recent years, literature on this subject has also become available for children and young adults with cancer, both during and after treatment. This is an update of the original review that was performed in 2011.
OBJECTIVES
To evaluate the effect of a physical exercise training intervention on the physical fitness (i.e. aerobic capacity, muscle strength, or functional performance) of children with cancer within the first five years from their diagnosis (performed either during or after cancer treatment), compared to a control group of children with cancer who did not receive an exercise intervention.To determine whether physical exercise within the first five years of diagnosis has an effect on fatigue, anxiety, depression, self efficacy, and HRQoL and to determine whether there are any adverse effects of the intervention.
SEARCH METHODS
We searched the electronic databases of Cochrane Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, and PEDro; ongoing trial registries and conference proceedings on 6 September 2011 and 11 November 2014. In addition, we performed a handsearch of reference lists.
SELECTION CRITERIA
The review included randomized controlled trials (RCTs) and clinical controlled trials (CCTs) that compared the effects of physical exercise training with no training, in people who were within the first five years of their diagnosis of childhood cancer.
DATA COLLECTION AND ANALYSIS
Two review authors independently identified studies meeting the inclusion criteria, performed the data extraction, and assessed the risk of bias using standardized forms. Study quality was rated by the Grading of Recommendation Assessment, Development and Evaluation (GRADE) criteria.
MAIN RESULTS
Apart from the five studies in the original review, this update included one additional RCT. In total, the analysis included 171 participants, all during treatment for childhood acute lymphoblastic leukaemia (ALL).The duration of the training sessions ranged from 15 to 60 minutes per session. Both the type of intervention and intervention period varied in all the included studies. However, the control group always received usual care.All studies had methodological limitations, such as small numbers of participants, unclear randomization methods, and single-blind study designs in case of one RCT and all results were of moderate to very low quality (GRADE).Cardiorespiratory fitness was evaluated by the 9-minute run-walk test, timed up-and-down stairs test, the timed up-and-go time test, and the 20-m shuttle run test. Data of the 9-minute run-walk test and the timed up-and-down stairs test could be pooled. The combined 9-minute run-walk test results showed significant differences between the intervention and the control groups, in favour of the intervention group (standardized mean difference (SMD) 0.69; 95% confidence interval (CI) 0.02 to 1.35). Pooled data from the timed up-and-down stairs test showed no significant differences in cardiorespiratory fitness (SMD -0.54; 95% CI -1.77 to 0.70). However, there was considerable heterogeneity (I(2) = 84%) between the two studies on this outcome. The other two single-study outcomes, 20-m shuttle run test and the timed up-and-go test, also showed positive results for cardiorespiratory fitness in favour of the intervention group.Only one study assessed the effect of exercise on bone mineral density (total body), showing a statistically significant positive intervention effect (SMD 1.07; 95% CI 0.48 to 1.66). The pooled data on body mass index showed no statistically significant end-score difference between the intervention and control group (SMD 0.59; 95% CI -0.23 to 1.41).Three studies assessed flexibility. Two studies assessed ankle dorsiflexion. One study assessed active ankle dorsiflexion, while the other assessed passive ankle dorsiflexion. There were no statistically significant differences between the intervention and control group with the active ankle dorsiflexion test; however, in favour of the intervention group, they were found for passive ankle dorsiflexion (SMD 0.69; 95% CI 0.12 to 1.25). The third study assessed body flexibility using the sit-and-reach distance test, but identified no statistically significant difference between the intervention and control group.Three studies assessed muscle strength (knee, ankle, back and leg, and inspiratory muscle strength). Only the back and leg strength combination score showed statistically significant differences on the muscle strength end-score between the intervention and control group (SMD 1.41; 95% CI 0.71 to 2.11).Apart from one sub-scale of the cancer scale (Worries; P value = 0.03), none of the health-related quality of life scales showed a significant difference between both study groups on the end-score. For the other outcomes of fatigue, level of daily activity, and adverse events (all assessed in one study), there were no statistically significant differences between the intervention and control group.None of the included studies evaluated activity energy expenditure, time spent on exercise, anxiety and depression, or self efficacy as an outcome.
AUTHORS' CONCLUSIONS
The effects of physical exercise training interventions for childhood cancer participants are not yet convincing. Possible reasons are the small numbers of participants and insufficient study designs, but it can also be that this type of intervention is not as effective as in adult cancer patients. However, the first results show some positive effects on physical fitness in the intervention group compared to the control group. There were positive intervention effects for body composition, flexibility, cardiorespiratory fitness, muscle strength, and health-related quality of life (cancer-related items). These were measured by some assessment methods, but not all. However, the quality of the evidence was low and these positive effects were not found for the other assessed outcomes, such as fatigue, level of daily activity, and adverse events. There is a need for more studies with comparable aims and interventions, using a higher number of participants that also include diagnoses other than ALL.
Topics: Adolescent; Antineoplastic Agents; Body Mass Index; Bone Density; Child; Controlled Clinical Trials as Topic; Exercise; Female; Humans; Male; Muscle Strength; Muscle, Skeletal; Neoplasms; Physical Endurance; Physical Fitness; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Quality of Life; Randomized Controlled Trials as Topic; Range of Motion, Articular
PubMed: 27030386
DOI: 10.1002/14651858.CD008796.pub3 -
Molecular Metabolism May 2020Polycystic ovary syndrome (PCOS) is the most common endocrinopathy among reproductive age women. Although its cardinal manifestations include hyperandrogenism,...
BACKGROUND
Polycystic ovary syndrome (PCOS) is the most common endocrinopathy among reproductive age women. Although its cardinal manifestations include hyperandrogenism, oligo/anovulation, and/or polycystic ovarian morphology, PCOS women often display also notable metabolic comorbidities. An array of pathogenic mechanisms have been implicated in the etiology of this heterogeneous endocrine disorder; hyperandrogenism at various developmental periods is proposed as a major driver of the metabolic and reproductive perturbations associated with PCOS. However, the current understanding of the pathophysiology of PCOS-associated metabolic disease is incomplete, and therapeutic strategies used to manage this syndrome's metabolic complications remain limited.
SCOPE OF REVIEW
This study is a systematic review of the potential etiopathogenic mechanisms of metabolic dysfunction frequently associated with PCOS, with special emphasis on the metabolic impact of androgen excess on different metabolic tissues and the brain. We also briefly summarize the therapeutic approaches currently available to manage metabolic perturbations linked to PCOS, highlighting current weaknesses and future directions.
MAJOR CONCLUSIONS
Androgen excess plays a prominent role in the development of metabolic disturbances associated with PCOS, with a discernible impact on key peripheral metabolic tissues, including the adipose, liver, pancreas, and muscle, and very prominently the brain, contributing to the constellation of metabolic complications of PCOS, from obesity to insulin resistance. However, the current understanding of the pathogenic roles of hyperandrogenism in metabolic dysfunction of PCOS and the underlying mechanisms remain largely incomplete. In addition, the development of more efficient, even personalized therapeutic strategies for the metabolic management of PCOS patients persists as an unmet need that will certainly benefit from a better comprehension of the molecular basis of this heterogeneous syndrome.
Topics: Adipose Tissue; Androgens; Animals; Bariatric Surgery; Female; Humans; Hyperandrogenism; Insulin Resistance; Metabolic Syndrome; Mice; Obesity; Polycystic Ovary Syndrome
PubMed: 32244180
DOI: 10.1016/j.molmet.2020.01.001 -
Frontiers in Immunology 2022Recombinant Adeno-associated virus (rAAV) is one of the main delivery vectors for gene therapy. To assess immunogenicity, toxicity, and features of AAV gene therapy in... (Meta-Analysis)
Meta-Analysis
Recombinant Adeno-associated virus (rAAV) is one of the main delivery vectors for gene therapy. To assess immunogenicity, toxicity, and features of AAV gene therapy in clinical settings, a meta-analysis of 255 clinical trials was performed. A total of 7,289 patients are planned to be dosed. AAV2 was the most dominantly used serotype (29.8%, n=72), and 8.3% (n=20) of trials used engineered capsids. 38.7% (n=91) of trials employed neutralizing antibody assays for patient enrollment, while 15.3% (n=36) used ELISA-based total antibody assays. However, there was high variability in the eligibility criteria with cut-off tiers ranging from 1:1 to 1:1,600. To address potential immunogenicity, 46.3% (n=118) of trials applied immunosuppressants (prophylactic or reactive), while 32.7% (n=18) of CNS and 37.5% (n=24) of ocular-directed trials employed immunosuppressants, possibly due to the immune-privileged status of CNS and retina. There were a total of 11 patient deaths across 8 trials, and 18 out of 30 clinical holds were due to toxicity findings in clinical studies. 30.6% (n=78) of trials had treatment-emergent serious adverse events (TESAEs), with hepatotoxicity and thrombotic microangiopathy (systemic delivery) and neurotoxicity (CNS delivery) being the most prominent. Additionally, the durability of gene therapy may be impacted by two distinct decline mechanisms: 1) rapid decline presumably due to immune responses; or 2) gradual decline due to vector dilution. The durability varied significantly depending on disease indication, dose, serotypes, and patient individuals. Most CNS (90.0%) and muscle trials (73.3%) achieved durable transgene expression, while only 43.6% of ocular trials had sustained clinical outcomes. The rAAV production system can affect rAAV quality and thus immunogenicity and toxicity. Out of 186 trials that have disclosed production system information, 63.0% (n=126) of trials used the transient transfection of the HEK293/HEK293T system, while 18.0% (n=36) applied the baculovirus/Sf9 (rBac/Sf9) system. There were no significant differences in TESAEs and durability between AAV generated by rBac/Sf9 and HEK293/HEK293T systems. In summary, rAAV immunogenicity and toxicity poses significant challenges for clinical development of rAAV gene therapies, and it warrants collaborative efforts to standardize monitoring/measurement methods, design novel strategies to overcome immune responses, and openly share relevant information.
Topics: Humans; Dependovirus; HEK293 Cells; Genetic Vectors; Genetic Therapy; Immunosuppressive Agents
PubMed: 36389770
DOI: 10.3389/fimmu.2022.1001263 -
International Journal of Environmental... Apr 2020Creatine monohydrate is a nutritional supplement often consumed by athletes in anaerobic sports. Creatine is naturally found in most meat products; therefore,...
BACKGROUND
Creatine monohydrate is a nutritional supplement often consumed by athletes in anaerobic sports. Creatine is naturally found in most meat products; therefore, vegetarians have reduced creatine stores and may benefit from supplementation.
OBJECTIVE
to determine the effects of creatine supplementation on vegetarians.
DATA SOURCES
PubMed and SPORTDiscus. Eligibility criteria: Randomized controlled trials (parallel group, cross-over studies) or prospective studies.
PARTICIPANTS
Vegetarians.
INTERVENTION
Creatine supplementation. Study appraisal and synthesis: A total of 64 records were identified, and eleven full-text articles (covering nine studies) were included in this systematic review.
RESULTS
Creatine supplementation in vegetarians increased total creatine, creatine, and phosphocreatine concentrations in vastus lateralis and gastrocnemius muscle, plasma, and red blood cells, often to levels greater than omnivores. Creatine supplementation had no effect on brain levels of phosphocreatine. Creatine supplementation increased lean tissue mass, type II fiber area, insulin-like growth factor-1, muscular strength, muscular endurance, Wingate mean power output, and brain function (memory and intelligence) in vegetarian participants. Studies were mixed on whether creatine supplementation improved exercise performance in vegetarians to a greater extent compared to omnivores.
LIMITATIONS
Studies that were reviewed had moderate-high risk of bias.
CONCLUSIONS
Overall, it appears vegetarian athletes are likely to benefit from creatine supplementation.
Topics: Athletes; Cognition; Creatine; Diet, Vegetarian; Dietary Supplements; Humans; Memory; Physical Fitness; Prospective Studies; Vegetarians
PubMed: 32349356
DOI: 10.3390/ijerph17093041