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JAMA Psychiatry Sep 2022Nucleic acid damage from oxidative stress (NA-OXS) may be a molecular mechanism driving the severely increased morbidity and mortality from somatic causes in adults with... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Nucleic acid damage from oxidative stress (NA-OXS) may be a molecular mechanism driving the severely increased morbidity and mortality from somatic causes in adults with psychiatric disorders.
OBJECTIVE
To systematically retrieve and analyze data on NA-OXS across the psychiatric disorder diagnostic spectrum.
DATA SOURCES
The PubMed, Embase, and PsycINFO databases were searched from inception to November 16, 2021. A hand search of reference lists of relevant articles was also performed.
STUDY SELECTION
Key study inclusion criteria in this meta-analysis were as follows: adult human study population, measurement of any marker of DNA or RNA damage from oxidative stress, and either a (1) cross-sectional design comparing patients with psychiatric disorders (any diagnosis) with a control group or (2) prospective intervention. Two authors screened the studies, and 2 senior authors read the relevant articles in full and assessed them for eligibility.
DATA EXTRACTION AND SYNTHESIS
The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed. Two authors performed data extraction independently, and a senior coauthor was consulted in cases of disagreement. Data were synthesized with random-effects and multilevel meta-analyses.
MAIN OUTCOMES AND MEASURES
The predefined hypothesis was that individuals with psychiatric disorders have increased NA-OXS levels. The main outcome was the standardized mean differences (SMDs) among patients and controls in nucleic acid oxidation markers compared across diagnostic groups. Analyses were divided into combinations of biological matrices and nucleic acids.
RESULTS
Eighty-two studies fulfilled the inclusion criteria, comprising 205 patient vs control group comparisons and a total of 10 151 patient and 10 532 control observations. Overall, the data showed that patients with psychiatric disorders had higher NA-OXS levels vs controls across matrices and molecules. Pooled effect sizes ranged from moderate for urinary DNA markers (SMD = 0.44 [95% CI, 0.20-0.68]; P < .001) to very large for blood cell DNA markers (SMD = 1.12 [95% CI, 0.69-1.55; P < .001). Higher NA-OXS levels were observed among patients with dementias followed by psychotic and bipolar disorders. Sensitivity analyses excluding low-quality studies did not materially alter the results. Intervention studies were few and too heterogenous for meaningful meta-analysis.
CONCLUSIONS AND RELEVANCE
The results of this meta-analysis suggest that there is an association with increased NA-OXS levels in individuals across the psychiatric disorder diagnostic spectrum. NA-OXS may play a role in the somatic morbidity and mortality observed among individuals with psychiatric disorders.
Topics: Adult; Cross-Sectional Studies; Genetic Markers; Humans; Mental Disorders; Nucleic Acids; Oxidative Stress; Prospective Studies
PubMed: 35921094
DOI: 10.1001/jamapsychiatry.2022.2066 -
Biomedicines Jan 2024Acute myeloid leukemia (AML) is a diverse group of leukemias characterized by the uncontrolled proliferation of clonal neoplastic hematopoietic precursor cells with... (Review)
Review
Acute myeloid leukemia (AML) is a diverse group of leukemias characterized by the uncontrolled proliferation of clonal neoplastic hematopoietic precursor cells with chromosomal rearrangements and multiple gene mutations and the impairment of normal hematopoiesis. Current efforts to improve AML outcomes have focused on developing targeted therapies that may allow for improved antileukemic effects while reducing toxicity significantly. Gemtuzumab ozogamicin (GO) is one of the most thoroughly studied molecularly targeted therapies in adults. GO is a monoclonal antibody against CD33 IgG4 linked to the cytotoxic drug calicheamicin DMH. The use of GO as a chemotherapeutic agent is not generalized for all patients who suffer from AML, particularly for those whose health prevents them from using intensive conventional chemotherapy, in which case it can be used on its own, and those who have suffered a first relapse, where its combination with other chemotherapeutic agents is possible. This systematic review aimed to comprehensively evaluate GO, focusing on its molecular structure, mode of action, pharmacokinetics, recommended dosage, resistance mechanisms, and associated toxicities to provide valuable information on the potential benefits and risks associated with its clinical use. A systematic review of eight scientific articles from 2018 to 2023 was conducted using PRISMA analysis. The results showed that GO treatment activates proapoptotic pathways and induces double-strand breaks, initiating DNA repair mechanisms. Cells defective in DNA repair pathways are susceptible to GO cytotoxicity. GO has recommended doses for newly diagnosed CD33+ AML in combination or as a single agent. Depending on the treatment regimen and patient status, GO doses vary for induction, consolidation, and continuation cycles. Multidrug resistance (MDR) involving P-glycoprotein (P-gp) is associated with GO resistance. The overexpression of P-gp reduces GO cytotoxicity; inhibitors of P-gp can restore sensitivity. Mitochondrial pathway activation and survival signaling pathways are linked to GO resistance. Other resistance mechanisms include altered pharmacokinetics, reduced binding ability, and anti-apoptotic mechanisms. GO has limited extramedullary toxicity compared to other AML treatments and may cause hepatic veno-occlusive disease (HVOD). The incidence of hepatic HVOD after GO therapy is higher in patients with high tumor burden. Hematological side effects and hepatotoxicity are prominent, with thrombocytopenia and neutropenia observed. In conclusion, GO's reintroduction in 2017 followed a thorough FDA review considering its altered dose, dosing schedule, and target population. The drug's mechanism involves CD33 targeting and calicheamicin-induced DNA damage, leading to apoptosis and resistance mechanisms, including MDR and survival signaling, which impact treatment outcomes. Despite limited extramedullary toxicity, GO is associated with hematological side effects and hepatotoxicity.
PubMed: 38255313
DOI: 10.3390/biomedicines12010208 -
Journal of Personalized Medicine Feb 2021: Exposure to ionizing radiation (IR) has increased immensely over the past years, owing to diagnostic and therapeutic reasons. However, certain radiosensitive... (Review)
Review
: Exposure to ionizing radiation (IR) has increased immensely over the past years, owing to diagnostic and therapeutic reasons. However, certain radiosensitive individuals show toxic enhanced reaction to IR, and it is necessary to specifically protect them from unwanted exposure. Although predicting radiosensitivity is the way forward in the field of personalised medicine, there is limited information on the potential biomarkers. The aim of this systematic review is to identify evidence from a range of literature in order to present the status quo of our knowledge of IR-induced changes in protein expression in normal tissues, which can be correlated to radiosensitivity. : Studies were searched in NCBI Pubmed and in ISI Web of Science databases and field experts were consulted for relevant studies. Primary peer-reviewed studies in English language within the time-frame of 2011 to 2020 were considered. Human non-tumour tissues and human-derived non-tumour model systems that have been exposed to IR were considered if they reported changes in protein levels, which could be correlated to radiosensitivity. At least two reviewers screened the titles, keywords, and abstracts of the studies against the eligibility criteria at the first phase and full texts of potential studies at the second phase. Similarly, at least two reviewers manually extracted the data and accessed the risk of bias (National Toxicology Program/Office for Health Assessment and Translation-NTP/OHAT) for the included studies. Finally, the data were synthesised narratively in accordance to synthesis without meta analyses (SWiM) method. : In total, 28 studies were included in this review. Most of the records (16) demonstrated increased residual DNA damage in radiosensitive individuals compared to normo-sensitive individuals based on γH2AX and TP53BP1. Overall, 15 studies included proteins other than DNA repair foci, of which five proteins were selected, Vascular endothelial growth factor (VEGF), Caspase 3, p16 (Cyclin-dependent kinase inhibitor 2A, CDKN2A), Interleukin-6, and Interleukin-1β, that were connected to radiosensitivity in normal tissue and were reported at least in two independent studies. : A majority of studies used repair foci as a tool to predict radiosensitivity. However, its correlation to outcome parameters such as repair deficient cell lines and patients, as well as an association to moderate and severe clinical radiation reactions, still remain contradictory. When IR-induced proteins reported in at least two studies were considered, a protein network was discovered, which provides a direction for further studies to elucidate the mechanisms of radiosensitivity. Although the identification of only a few of the commonly reported proteins might raise a concern, this could be because (i) our eligibility criteria were strict and (ii) radiosensitivity is influenced by multiple factors. : PROSPERO (CRD42020220064).
PubMed: 33669522
DOI: 10.3390/jpm11020140 -
International Journal of Molecular... Aug 2023PARPi, in combination with ionizing radiation, has demonstrated the ability to enhance cellular radiosensitivity in different tumors. The rationale is that the exposure...
PARPi, in combination with ionizing radiation, has demonstrated the ability to enhance cellular radiosensitivity in different tumors. The rationale is that the exposure to radiation leads to both physical and biochemical damage to DNA, prompting cells to initiate three primary mechanisms for DNA repair. Two double-stranded DNA breaks (DSB) repair pathways: (1) non-homologous end-joining (NHEJ) and (2) homologous recombination (HR); and (3) a single-stranded DNA break (SSB) repair pathway (base excision repair, BER). In this scenario, PARPi can serve as radiosensitizers by leveraging the BER pathway. This mechanism heightens the likelihood of replication forks collapsing, consequently leading to the formation of persistent DSBs. Together, the combination of PARPi and radiotherapy is a potent oncological strategy. This combination has proven its efficacy in different tumors. However, in prostate cancer, there are only preclinical studies to support it and, recently, an ongoing clinical trial. The objective of this paper is to perform a review of the current evidence regarding the use of PARPi and radiotherapy (RT) in PCa and to give future insight on this topic.
Topics: Humans; Male; DNA Repair; Medical Oncology; Poly(ADP-ribose) Polymerase Inhibitors; Prostatic Neoplasms; Radiation Oncology
PubMed: 37629155
DOI: 10.3390/ijms241612978 -
Toxics Aug 2023Exposure to pesticides in Arab countries is a significant public health concern due to extensive agricultural activity and pesticide use. This systematic review aimed to... (Review)
Review
Exposure to pesticides in Arab countries is a significant public health concern due to extensive agricultural activity and pesticide use. This systematic review aimed to evaluate the genotoxic effects of agricultural pesticide exposure in the region, identify research gaps, and assess methodological limitations. Following the PRISMA guidelines, a comprehensive search yielded five relevant studies conducted in Egypt, Syria, and Jordan. Various genotoxicity assays were employed, revealing a higher level of DNA damage in exposed compared to non-exposed individuals. Farmers exposed to pesticides exhibited a significantly higher occurrence of chromosomal translocation (t(14;18)), micronuclei, and chromosomal aberrations. However, only two studies assessed cytotoxicity indirectly. The studies predominantly focused on male participants, with variations in sample size and pesticide types. The lack of detailed exposure data necessitates cautious interpretation. This review underscores the need for further research on the genotoxicity of occupational pesticide exposure in the Middle East. Future studies should adopt robust study designs, collect biological and environmental samples, conduct repeated sampling, analyze seasonal variations, and encompass diverse study sites associated with specific crop groups.
PubMed: 37624167
DOI: 10.3390/toxics11080663 -
JBRA Assisted Reproduction Jun 2023To elucidate through a systematic literature review the impact sperm DNA fragmentation has on embryos from assisted reproduction techniques. (Review)
Review
OBJECTIVE
To elucidate through a systematic literature review the impact sperm DNA fragmentation has on embryos from assisted reproduction techniques.
DATA SOURCE
Studies from the "PubMed", "Embase", and "BVS" databases were analyzed.
STUDIES SELECTION
The articles selected in the review included: cohort and case-control studies that addressed the proposed theme, published between January 1, 2017, and January 31, 2022, in English, Portuguese, and Spanish. As inclusion criteria: cohort and case-control articles. As exclusion criteria: articles outside the scope of the research, review articles, case reports, articles using animal models, abstracts, letters to the editor, and articles found duplicates in the databases.
DATA COLLECTION
Number of couples or cycles; age (men/women); collection type; DNA damage (%); assisted reproduction activity and techniques.
DATA SYNTHESIS
In in vitro fertilization, a reduction in fertilization rate, blastocyst rate, and embryo quality was observed. In addition to implantation and increased abortion rates in patients with high sperm DNA fragmentation. High rates of sperm DNA fragmentation in intracytoplasmic sperm injection led to reduced blastocyst production rate, embryo quality, implantation, and live birth rate, and in intrauterine insemination, a reduction in pregnancy rate.
CONCLUSION
Sperm DNA fragmentation was a potential limiting factor for assisted reproduction techniques.
Topics: Pregnancy; Humans; Male; Female; DNA Fragmentation; Semen; Fertilization in Vitro; Spermatozoa; Embryo Implantation
PubMed: 36749810
DOI: 10.5935/1518-0557.20220057 -
Nutrients Dec 2022Skin exposure to ultraviolet (UV) rays in the sun causes premature ageing and may predispose to skin cancers. UV radiation generates excessive free radical species,... (Review)
Review
Skin exposure to ultraviolet (UV) rays in the sun causes premature ageing and may predispose to skin cancers. UV radiation generates excessive free radical species, resulting in oxidative stress, which is responsible for cellular and DNA damage. There is growing evidence that phytonutrients such as flavonoids and carotenoids may impede oxidative stress and prevent photodamage. We conducted a systematic review of the literature to explore the effects of certain phytonutrients in preventing skin photodamage. We searched the electronic Medline (Ovid) and Pubmed databases for relevant studies published between 2002 and 2022. The main inclusion criteria were articles written in English, and studies reporting the effects of phytonutrient-containing plants of interest on the skin or skin cells exposed to UV radiation. We focused on tea, blueberries, lemon, carrot, tomato, and grapes, which are rich in flavonoids and/or carotenoids. Out of 434 articles retrieved, 40 were identified as potentially relevant. Based on our inclusion criteria, nine articles were included in the review. The review comprises three combined in vitro and animal studies, four human studies, one in vitro research, and one mixed in vitro and human study. All the studies reported positive effects of flavonoids and carotenoid-containing plant extract on UV-induced skin damage. This evidence-based review highlights the potential use of flavonoids and carotenoids found in plants in preventing the deleterious effects of UV radiation on the skin. These compounds may have a role in clinical and aesthetic applications for the prevention and treatment of sunburn and photoaging, and may potentially be used against UV-related skin cancers.
Topics: Animals; Humans; Ultraviolet Rays; Flavonoids; Carotenoids; Skin; Sunburn; Skin Neoplasms
PubMed: 36615749
DOI: 10.3390/nu15010092 -
JCO Precision Oncology 2021With the broad use of next-generation sequencing assays, it has become clear that mutations in DNA repair genes are more commonly found than previously reported. In...
PURPOSE
With the broad use of next-generation sequencing assays, it has become clear that mutations in DNA repair genes are more commonly found than previously reported. In advanced prostate cancer patients with 1/2 or mutations, poly (ADP-ribose) polymerase inhibition (PARPi) causes an increased overall survival advantage compared with patients without these mutations. This review explores the advantages and limitations of PARPi treatment and its use beyond 1/2-altered tumors. Furthermore, it discusses the benefits of current biomarkers and what role functional biomarkers and organoids may play in addressing the involvement of homologous recombination repair mutations in tumor development and progression.
METHODS
A systematic review was conducted in MEDLINE, National Library of Medicine, and ClinicalTrials.gov to identify studies published between January 1, 2016, and August 31, 2021. The search strategy incorporated terms for PARPi, BRCA, DNA damage, homologous recombination, organoids, patient-derived organoids, biomarker AND prostate cancer, breast cancer, ovarian cancer.
RESULTS
A total of 261 records remained after duplicate removal, 69 of which were included in the qualitative synthesis.
CONCLUSION
To improve the outcome of targeted therapy and increase sensitivity of tumor detection, patients should be repeatedly screened for DNA repair gene alterations and biomarkers. Future clinical studies should explore the use of PARPi beyond 1/2 mutations and focus on finding new synthetically lethal interactions.
Topics: DNA Damage; Humans; Male; Poly(ADP-ribose) Polymerase Inhibitors; Prostatic Neoplasms; Recombinational DNA Repair
PubMed: 34712892
DOI: 10.1200/PO.21.00152 -
Frontiers in Oncology 2022DNA replication is a process fundamental in all living organisms in which deregulation, known as replication stress, often leads to genomic instability, a hallmark of...
DNA replication is a process fundamental in all living organisms in which deregulation, known as replication stress, often leads to genomic instability, a hallmark of cancer. Most malignant tumors sustain persistent proliferation and tolerate replication stress increasing reliance to the replication stress response. So whilst replication stress induces genomic instability and tumorigenesis, the replication stress response exhibits a unique cancer-specific vulnerability that can be targeted to induce catastrophic cell proliferation. Radiation therapy, most used in cancer treatment, induces a plethora of DNA lesions that affect DNA integrity and, in-turn, DNA replication. Owing to radiation dose limitations for specific organs and tumor tissue resistance, the therapeutic window is narrow. Thus, a means to eliminate or reduce tumor radioresistance is urgently needed. Current research trends have highlighted the potential of combining replication stress regulators with radiation therapy to capitalize on the high replication stress of tumors. Here, we review the current body of evidence regarding the role of replication stress in tumor progression and discuss potential means of enhancing tumor radiosensitivity by targeting the replication stress response. We offer new insights into the possibility of combining radiation therapy with replication stress drugs for clinical use.
PubMed: 35875060
DOI: 10.3389/fonc.2022.838637 -
BMC Complementary Medicine and Therapies Aug 2021Lycium barbarum polysaccharide (LBP), the most abundant functional component of wolfberry, is considered a potent antioxidant and an anti-ageing substance. This review...
BACKGROUND
Lycium barbarum polysaccharide (LBP), the most abundant functional component of wolfberry, is considered a potent antioxidant and an anti-ageing substance. This review aims to outline the hallmarks of ageing in the pathogenesis of osteoarthritis (OA), followed by the current understanding of the senolytic effect of LBP and its potential use in the prevention and treatment of OA. This will be discussed through the lens of molecular biology and herbal medicine.
METHODS
A literature search was performed from inception to March 2020 using following keywords: "Lycium barbarum polysaccharide", "DNA damage", antioxidant, anti-apoptosis, anti-inflammation, anti-ageing, osteoarthritis, chondrocytes, fibroblasts, osteoblasts, osteoclasts, and "bone mesenchymal stem cell". The initial search yielded 2287 papers, from which 35 studies were selected for final analysis after screening for topic relevancy by the authors.
RESULTS
In literature different in vitro and in vivo ageing models are used to demonstrate LBP's ability to reduce oxidative stress, restore mitochondrial function, mitigate DNA damage, and prevent cellular senescence. All the evidence hints that LBP theoretically attenuates senescent cell accumulation and suppresses the senescence-associated secretory phenotype as observed by the reduction in pro-inflammatory cytokines, like interleukin-1beta, and matrix-degrading enzymes, such as MMP-1 and MMP-13. However, there remains a lack of evidence on the disease-modifying effect of LBP in OA, although its chondroprotective, osteoprotective and anti-inflammatory effects were reported.
CONCLUSION
Our findings strongly support further investigations into the senolytic effect of LBP in the context of age-related OA.
Topics: Aging; Anti-Inflammatory Agents; Drugs, Chinese Herbal; Humans; Osteoarthritis
PubMed: 34404395
DOI: 10.1186/s12906-021-03385-0