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Environmental Research Jan 2023The incidence of infertility currently affects about 15% of the world's population. Male factors are estimated to be responsible for up to 40-50% of these cases. While... (Meta-Analysis)
Meta-Analysis Review
The incidence of infertility currently affects about 15% of the world's population. Male factors are estimated to be responsible for up to 40-50% of these cases. While the cause of these reproductive disorders is still unclear, the exposure to a family of ubiquitous compounds in our daily life, named endocrine disrupting chemicals (EDCs) could be involved. This paper was aimed at performing a systematic review and meta-analysis of population studies exploring whether human male exposure to EDCs affects male fertility. Clinical and observational studies assessing the exposure to EDCs along with sperm quality, the most common reproductive disorders, sperm DNA damage, sperm oxidative stress, fertilization rate, implantation rate, clinical pregnancy rate, live birth rate, and miscarriage rate were included. The quality assessment tool from the NHLBI-NIH was used to assure that studies met standardized quality criteria. Sensitivity analysis and heterogeneity among studies was assessed. Overall, the 32 selected articles, including 7825 individuals in the systematic review, explored 12 families of EDCs. The results revealed a high heterogeneity among studies in relation to the association between exposure to EDCs and the endpoints analyzed. Meta-analyses were performed with data from 7 articles including 479 individuals, 4 articles assessing the association between BPA in urine and sperm quality, and 3 articles evaluating PCB153 in serum and sperm quality. In the meta-analysis, we identified an unpredicted significant positive association between PCB153 exposure and sperm concentration. However, it would not be clinically relevant. No positive or inverse associations were found neither for BPA, nor for PCB153 and the rest of sperm parameters analyzed. The high disparity between studies made difficult to draw conclusions on the potential harmful effects of EDCs on male fertility. Consequently, to delineate the potential relationship that EDCs can have on male fertility, an important condition stressing the health system, further investigations are required.
Topics: Pregnancy; Female; Humans; Male; Endocrine Disruptors; Semen; Spermatozoa; Fertility
PubMed: 36436552
DOI: 10.1016/j.envres.2022.114942 -
International Journal of Molecular... Jun 2022Alport syndrome (AS) is the second most common cause of inherited chronic kidney disease. This disorder is caused by genetic variants on , and genes. These genes... (Review)
Review
Alport syndrome (AS) is the second most common cause of inherited chronic kidney disease. This disorder is caused by genetic variants on , and genes. These genes encode the proteins that constitute collagen type IV of the glomerular basement membrane (GBM). The heterodimer COL4A3A4A5 constitutes the majority of the GBM, and it is essential for the normal function of the glomerular filtration barrier (GFB). Alterations in any of collagen type IV constituents cause disruption of the GMB structure, allowing leakage of red blood cells and albumin into the urine, and compromise the architecture of the GFB, inducing inflammation and fibrosis, thus resulting in kidney damage and loss of renal function. The advances in DNA sequencing technologies, such as next-generation sequencing, allow an accurate diagnose of AS. Due to the important risk of the development of progressive kidney disease in AS patients, which can be delayed or possibly prevented by timely initiation of therapy, an early diagnosis of this condition is mandatory. Conventional biomarkers such as albuminuria and serum creatinine increase relatively late in AS. A panel of biomarkers that might detect early renal damage, monitor therapy, and reflect the prognosis would have special interest in clinical practice. The aim of this systematic review is to summarize the biomarkers of renal damage in AS as described in the literature. We found that urinary Podocin and Vascular Endothelial Growth Factor A are important markers of podocyte injury. Urinary Epidermal Growth Factor has been related to tubular damage, interstitial fibrosis and rapid progression of the disease. Inflammatory markers such as Transforming Growth Factor Beta 1, High Motility Group Box 1 and Urinary Monocyte Chemoattractant Protein- 1 are also increased in AS and indicate a higher risk of kidney disease progression. Studies suggest that miRNA-21 is elevated when renal damage occurs. Novel techniques, such as proteomics and microRNAs, are promising.
Topics: Biomarkers; Collagen Type IV; Fibrosis; Humans; Kidney; Nephritis, Hereditary; Vascular Endothelial Growth Factor A
PubMed: 35806283
DOI: 10.3390/ijms23137276 -
Cancer Treatment Reviews Nov 2023PARP inhibitors (PARPi) are a standard-of-care (SoC) treatment option for patients with metastatic castration-resistant prostate cancer (mCRPC). Several clinical trials... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
PARP inhibitors (PARPi) are a standard-of-care (SoC) treatment option for patients with metastatic castration-resistant prostate cancer (mCRPC). Several clinical trials have shown the potential of combining PARPi with other anticancer agents. Therefore, we conducted a systematic review and meta-analysis to comprehensively evaluate the efficacy and safety of PARPi in patients with metastatic prostate cancer.
METHODS
MEDLINE, Cochrane CENTRAL, EMBASE, CINAHL, and Web of Science were searched on March 22nd, 2023, for phase 2 or 3 clinical trials. Efficacy (progression-free survival [PFS], overall survival [OS], PSA decline >50% [PSA50], and objective response rate [ORR]) and safety outcomes were assessed in the included studies.
RESULTS
Seventeen clinical trials (PARPi monotherapy [n = 7], PARPi + androgen-receptor signaling inhibitors [ARSI] [n = 6], and PARPi + immune checkpoint inhibitors [ICI] [n = 4]) were included in the quantitative analyses. PARPi monotherapy improved radiographic PFS and OS over SoC in mCRPC patients with alterations in BRCA1 or BRCA2 genes but not in those with alterations in the ATM gene. Higher rates of PSA50 and ORR were reported in participants treated with PARPi + ARSI than in single-agent PARPi or PARPi + ICI. Although the rate of high-grade adverse events was similar across all groups, treatment discontinuation was higher in patients treated with PARPi-based combinations than PARPi monotherapy.
CONCLUSION
The efficacy of PARPi is not uniform across mCRPC patients with alterations in DNA damage repair genes, and optimal patient selection remains a clinical challenge. No unexpected safety signals for this class of agents emerged from this analysis.
Topics: Male; Humans; Poly(ADP-ribose) Polymerase Inhibitors; Prostatic Neoplasms, Castration-Resistant; Immune Checkpoint Inhibitors; Patient Selection; Progression-Free Survival
PubMed: 37716332
DOI: 10.1016/j.ctrv.2023.102623 -
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 -
Regulatory Toxicology and Pharmacology... Oct 2023Propylene dichloride (PDC) is a chlorinated substance used primarily as an intermediate in basic organic chemical manufacturing. The United States Environmental... (Review)
Review
Propylene dichloride (PDC) is a chlorinated substance used primarily as an intermediate in basic organic chemical manufacturing. The United States Environmental Protection Agency (EPA) is currently evaluating PDC as a high-priority substance under the Toxic Substances Control Act (TSCA). We conducted a systematic review of the non-cancer and cancer hazards of PDC using the EPA TSCA and Integrated Risk Information System (IRIS) frameworks. We identified 12 epidemiological, 16 toxicokinetic, 34 experimental animal, and 49 mechanistic studies. Point-of-contact respiratory effects are the most sensitive non-cancer effects after inhalation exposure, and PDC is neither a reproductive nor a developmental toxicant. PDC is not mutagenic in vivo, and while in vitro evidence is mixed, DNA strand breaks consistently occur. Nasal tumors in rats and lung tumors in mice occurred after lifetime high-level inhalation exposure. Cholangiocarcinoma (CCA) was observed in Japanese print workers exposed to high concentrations of PDC. However, co-exposures, as well as liver parasites, hepatitis, and other risk factors, may also have contributed. The cancer mode of action (MOA) analysis revealed that PDC may act through multiple biological pathways occurring sequentially and/or simultaneously, although chronic tissue damage and inflammation likely dominate. Critically, health benchmarks protective of non-cancer effects are expected to protect against cancer in humans.
PubMed: 37562533
DOI: 10.1016/j.yrtph.2023.105468 -
Current Oncology (Toronto, Ont.) Feb 2023Outcomes for patients with high-grade glioma remain poor. Temozolomide (TMZ) is the only drug approved for first-line treatment of glioblastoma multiforme, the most... (Review)
Review
Outcomes for patients with high-grade glioma remain poor. Temozolomide (TMZ) is the only drug approved for first-line treatment of glioblastoma multiforme, the most aggressive form of glioma. Chronotherapy highlights the potential benefit of timed TMZ administration. This is based on pre-clinical studies of enhanced TMZ-induced glioma cytotoxicity dependent on circadian, oscillating expression of key genes involved in apoptosis, DNA damage repair, and cell-cycle mediated cell death. The current systematic review's primary aim was to evaluate the efficacy and toxicity of TMZ chronotherapy. A systemic review of literature following PRISMA guidelines looking at clinical outcomes on TMZ chronotherapy on gliomas was performed. The search in the English language included three databases (PubMed, EMBASE, and Cochrane) and five conferences from 1946 to April 2022. Two independent reviewers undertook screening, data extraction, and risk-of-bias assessment. A descriptive analysis was conducted due to limited data. Of the 269 articles screened, two unique studies were eligible and underwent abstraction for survival and toxicity findings. Both studies-one a retrospective cohort study (n = 166) and the other a prospective randomized feasibility study (n = 35)-were conducted by the same academic group and suggested a trend for improved overall survival, but possibly increased toxicity when TMZ was administered in the morning (vs. evening). There was limited evidence suggesting possible therapeutic value from administering TMZ in the morning, which may be consistent with the pre-clinical observations of the importance of the timing of TMZ administration in vitro. Larger, pragmatic, prospective randomized controlled trials are needed to ascertain the value of TMZ chronotherapy to provide optimized and equitable care for this population.
Topics: Humans; Temozolomide; Retrospective Studies; Prospective Studies; Brain Neoplasms; Glioma; Chronotherapy; Randomized Controlled Trials as Topic
PubMed: 36826108
DOI: 10.3390/curroncol30020147 -
Frontiers in Immunology 2019Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is characterized by the production of autoantibodies specific for components of the cell nucleus...
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is characterized by the production of autoantibodies specific for components of the cell nucleus and that causes damage to body tissues and organs. The pathogenesis of SLE remains unclear, with numerous studies pointing to a combination of genetic and environmental factors. A critical stage in SLE development is cell necrosis, in which undegraded chromatin and nucleoproteins are released into the blood, resulting in circulating cell-free DNA and serum nucleoproteins that trigger anti-dsDNA autoantibody production. This systematic literature review aimed to examine whether SLE stems from a DNA degradation and elimination defect. An advanced literature search was conducted in PubMed using the following keywords: [("SLE" OR "Systemic Lupus Erythematosus" OR "Lupus")] AND [("DNA" OR "DNA Degradation")] AND [("Defect Elimination")]. More articles were obtained from the references of the identified articles and basic Google searches. Twenty-five peer-reviewed articles published within the past 10 years (2007-2018) were included for review. The findings of each study are summarized in , . The etiopathogenesis of SLE remains controversial, which limits therapeutic inventions for this disease. However, SLE is a DNA degradation and elimination disorder caused by uncleared histones and nuclear material that leak into the extracellular space and form cell-free DNA, triggering an immune response that destroys tissues and organs. Under normal conditions, apoptosis allows DNA and other nuclear material to be efficiently cleared through degradation and additional complex mechanisms such that this material does not trigger the immune system to produce nuclear autoantibodies.
Topics: Antibodies, Antinuclear; Cell-Free Nucleic Acids; DNA; Humans; Lupus Erythematosus, Systemic; Nucleoproteins
PubMed: 31440232
DOI: 10.3389/fimmu.2019.01697 -
Frontiers in Endocrinology 2023In the complex and dynamic processes of replication, transcription, and translation of DNA molecules, a large number of replication errors or damage can occur which lead... (Review)
Review
In the complex and dynamic processes of replication, transcription, and translation of DNA molecules, a large number of replication errors or damage can occur which lead to obstacles in the development process of germ cells and result in a decreased reproductive rate. DNA damage repair has attracted widespread attention due to its important role in the maintenance and regulation of germ cells. This study reports on a systematic review of the role and mechanism of DNA damage repair in germline development. First, the causes, detection methods, and repair methods of DNA damage, and the mechanism of DNA damage repair are summarized. Second, a summary of the causes of abnormal DNA damage repair in germ cells is introduced along with common examples, and the relevant effects of germ cell damage. Third, we introduce the application of drugs related to DNA damage repair in the treatment of reproductive diseases and related surgical treatment of abnormal DNA damage, and summarize various applications of DNA damage repair in germ cells. Finally, a summary and discussion is given of the current deficiencies in DNA damage repair during germ cell development and future research development. The purpose of this paper is to provide researchers engaged in relevant fields with a further systematic understanding of the relevant applications of DNA damage repair in germ cells and to gain inspiration from it to provide new research ideas for related fields.
Topics: DNA Repair; DNA Damage; Reproduction; Germ Cells; Cell Differentiation
PubMed: 37529603
DOI: 10.3389/fendo.2023.1234280 -
Frontiers in Aging 2021The effects of short-term hyperoxia on age-related diseases and aging biomarkers have been reported in animal and human experiments using different protocols; however,... (Review)
Review
The effects of short-term hyperoxia on age-related diseases and aging biomarkers have been reported in animal and human experiments using different protocols; however, the findings of the studies remain conflicting. In this systematic review, we summarized the existing reports in the effects of short-term hyperoxia on age-related diseases, hypoxia-inducible factor 1α (HIF-1α), and other oxygen-sensitive transcription factors relevant to aging, telomere length, cellular senescence, and its side effects. This review was done as described in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. A systematic search was done in PubMed, Google Scholar, and Cochrane Library and from the references of selected articles to identify relevant studies until May 2021. Of the total 1,699 identified studies, 17 were included in this review. Most of the studies have shown significant effects of short-term hyperoxia on age-related diseases and aging biomarkers. The findings of the studies suggest the potential benefits of short-term hyperoxia in several clinical applications such as for patients undergoing stressful operations, restoration of cognitive function, and the treatment of severe traumatic brain injury. Short-term hyperoxia has significant effects in upregulation or downregulation of transcription factors relevant to aging such as HIF-1α, nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-kB), and nuclear factor (erythroid-derived 2)-like 2 (NRF2) among others. Short-term hyperoxia also has significant effects to increase antioxidant enzymes, and increase telomere length and clearance of senescent cells. Some of the studies have also reported adverse consequences including mitochondrial DNA damage and nuclear cataract formation depending on the dose and duration of oxygen exposure. In conclusion, short-term hyperoxia could be a feasible treatment option to treat age-related disease and to slow aging because of its ability to increase antioxidant enzymes, significantly increase telomere length and clearance of senescent cells, and improve cognitive function, among others. The reported side effects of hyperoxia vary depending on the dose and duration of exposure. Therefore, it seems that additional studies for better understanding the beneficial effects of short-term hyperoxia and for minimizing side effects are necessary for optimal clinical application.
PubMed: 35822043
DOI: 10.3389/fragi.2021.783144 -
Iranian Journal of Public Health Jan 2024Cell aging is associated with changes in telomeres due to DNA damage arising from chronic inflammation in obese patients. The aim of the systematic review and... (Review)
Review
BACKGROUND
Cell aging is associated with changes in telomeres due to DNA damage arising from chronic inflammation in obese patients. The aim of the systematic review and meta-analysis was to find the relationship between obesity and aging or senescence.
METHODS
The systematic review was conducted through PRISMA guideline, beginning with literature search within 2012-2022 in several databases (PubMed, EBSCOHost, Science Direct, Scopus, and Cochrane) followed by screening process using predetermined PICO criteria. Original studies on the topic of obesity and senescence (aging), from preclinical studies to clinical research (cohort or cross-sectional studies) that were published within the last ten years. All studies were appraised using SYRCLE risk of bias tool for preclinical studies and Newcastle-Ottawa Scale (NOS) for cross-sectional and cohort studies. The data extraction on the studies' characteristic and outcome on aging or senescence were followed by quantitative analysis using MetaXL process on prevalence ratio and hazard ratio of obesity to comorbidities and mortality.
RESULTS
Fifteen studies were enrolled. Obesity and white adipose tissue cause increased levels of pro-inflammatory and pro-senescence cytokine and macrophage whilst the aging process lowers metabolism with increased insulin resistance and linked to increased risk of obesity. Obesity occurs in 22% (95% CI 18%-26%) of elderly population with higher prevalence rate in the women population. Obesity is associated with significant increased risk of multimorbidity by 56% (OR = 1.58 [95% CI 1.48-1.96]).
CONCLUSION
The obesity and aging or senescence has reciprocal relationship between each other.
PubMed: 38694856
DOI: 10.18502/ijph.v53i1.14679