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European Journal of Endocrinology Aug 2023Postpartum depression (PPD) has a major impact on maternal and offspring well-being, with multiple possible risk factors: Studies on the association of thyroid... (Meta-Analysis)
Meta-Analysis
Association of gestational thyroid function and thyroid peroxidase antibody positivity with postpartum depression: a prospective cohort study and systematic literature review with meta-analysis.
IMPORTANCE
Postpartum depression (PPD) has a major impact on maternal and offspring well-being, with multiple possible risk factors: Studies on the association of thyroid peroxidase antibody (TPOAb) positivity and thyroid function with PPD provide heterogeneous results.
OBJECTIVE
To study the association of thyroid function and TPOAb positivity with PPD.
DESIGN
We assessed the association of TPOAb and thyroid function with PPD in a population-based prospective cohort study and performed a systematic literature review and meta-analysis.
METHODS
We measured thyroid stimulating hormone (TSH), free thyroxine (FT4), and TPOAb between 9- and 17-week gestation. Postpartum depression was assessed with Edinburgh Postpartum Depression Scale at 2-month postpartum and Brief Symptom Inventory at 2-, 6-, and 36-month postpartum. Additionally, we performed a systematic literature review and meta-analysis assessing this association.
RESULTS
In the present study, there was no association of thyroid function with PPD (TSH: odds ratio [OR] 0.83, 95% CI 0.58-1.19, P = .32; FT4: OR 0.99, 95% CI 0.95-1.05, P = .86) or TPOAb positivity with PPD (OR 0.79, 95% CI 0.47-1.33, P = .37). An impaired thyroidal response to human chorionic gonadotropin (hCG), a surrogate marker for TPOAb positivity, was associated with a lower risk of PPD (P for interaction TSH = 0.04; FT4 = 0.06). Our systematic review and meta-analysis included 3 articles that were combined with the present study. There was no statistically significant association of TPOAb positivity with PPD (OR 1.93, 95% CI 0.91-4.10, P = .08), but the results were heterogeneous (I2 = 79%).
CONCLUSIONS AND RELEVANCE
There was no significant association of TPOAb positivity, TSH, or FT4 with PPD. Our systematic review and meta-analysis revealed high heterogeneity of the current literature. Although TPOAb-positive women should be monitored for postpartum thyroiditis, our findings do not support routinely screening for PPD.
Topics: Female; Humans; Thyroid Gland; Iodide Peroxidase; Prospective Studies; Depression, Postpartum; Autoantibodies; Thyrotropin; Thyroxine
PubMed: 37486224
DOI: 10.1093/ejendo/lvad092 -
Journal of Cellular and Molecular... Jul 2023Trauma represents one of the leading causes of death worldwide. Traumatic injuries elicit a dynamic inflammatory response with systemic release of inflammatory...
Trauma represents one of the leading causes of death worldwide. Traumatic injuries elicit a dynamic inflammatory response with systemic release of inflammatory cytokines. Disbalance of this response can lead to systemic inflammatory response syndrome or compensatory anti-inflammatory response syndrome. As neutrophils play a major role in innate immune defence and are crucial in the injury-induced immunological response, we aimed to investigate systemic neutrophil-derived immunomodulators in trauma patients. Therefore, serum levels of neutrophil elastase (NE), myeloperoxidase (MPO) and citrullinated histone H3 (CitH3) were quantified in patients with injury severity scores above 15. Additionally, leukocyte, platelet, fibrinogen and CRP levels were assessed. Lastly, we analysed the association of neutrophil-derived factors with clinical severity scoring systems. Although the release of MPO, NE and CitH3 was not predictive of mortality, we found a remarkable increase in MPO and NE in trauma patients as compared with healthy controls. We also found significantly increased levels of MPO and NE on Days 1 and 5 after initial trauma in critically injured patients. Taken together, our data suggest a role for neutrophil activation in trauma. Targeting exacerbated neutrophil activation might represent a new therapeutic option for critically injured patients.
Topics: Humans; Neutrophils; Histones; Cytokines; Neutrophil Activation; Multiple Trauma; Peroxidase
PubMed: 37328954
DOI: 10.1111/jcmm.17786 -
Frontiers in Endocrinology 2023Studies suggest that thyroid peroxidase antibody (TPOAb) positivity exposure during pregnancy may contribute to changes in placental morphology and pathophysiology....
BACKGROUND
Studies suggest that thyroid peroxidase antibody (TPOAb) positivity exposure during pregnancy may contribute to changes in placental morphology and pathophysiology. However, little is known about the association of maternal TPOAb during pregnancy with placental morphology and cytokines. This study focuses on the effect of repeated measurements of maternal TPOAb during pregnancy on the placental morphology and cytokines.
METHODS
Based on Ma'anshan Birth Cohort (MABC) in China, maternal TPOAb levels were retrospectively detected in the first, second and third trimesters. Placental tissues were collected 30 minutes after childbirth, placental morphological indicators were obtained by immediate measurement and formula calculation, and cytokine mRNA expression was detected by real-time quantitative polymerase chain reaction (RT-qPCR) afterward. Generalized linear models and linear mixed models were analyzed for the relationships of maternal TPOAb in the first, second and third trimesters with placental indicators.
RESULTS
Totally 2274 maternal-fetal pairs were included in the analysis of maternal TPOAb levels and placental morphology, and 2122 pairs were included in that of maternal TPOAb levels and placental cytokines. Maternal TPOAb levels in early pregnancy were negatively associated with placental length, thickness, volume, weight and disc eccentricity, while positively correlated with placental IL-6, TNF-α, CRP, CD68, MCP-1, IL-10, HO-1, HIF-1α and GRP78. In mid-pregnancy, maternal TPOAb levels were negatively correlated with placental length, width and area. In late pregnancy, maternal TPOAb levels were negatively correlated with placental length, area, volume and weight. Repeated measures analysis showed that maternal TPOAb positivity tended to increase placental TNF-α, CD68 and MCP-1 while decreasing placental length, width and area than TPOAb negativity. Repeated measures analysis showed that maternal TPOAb levels were positively correlated with placental IL-6, TNF-α, CD68, MCP-1, IL-10, HO-1, HIF-1α and GRP78, while negatively correlated with placental length, area, volume, weight, and disc eccentricity.
CONCLUSION
There may be trimester-specific associations between maternal TPOAb levels and placental morphology and inflammatory and oxidative stress responses. The effect of maternal TPOAb levels on placental morphology is present throughout pregnancy. Early pregnancy may be the critical period for the association between maternal TPOAb levels and placental inflammatory and oxidative stress responses.
Topics: Pregnancy; Humans; Female; Placenta; Iodide Peroxidase; Interleukin-10; Tumor Necrosis Factor-alpha; Endoplasmic Reticulum Chaperone BiP; Interleukin-6; Retrospective Studies; Cytokines; Oxidative Stress
PubMed: 37810887
DOI: 10.3389/fendo.2023.1182049 -
Cell Death & Disease Mar 2024Caspase-2, one of the most evolutionarily conserved members of the caspase family, is an important regulator of the cellular response to oxidative stress. Given that...
Caspase-2, one of the most evolutionarily conserved members of the caspase family, is an important regulator of the cellular response to oxidative stress. Given that ferroptosis is suppressed by antioxidant defense pathways, such as that involving selenoenzyme glutathione peroxidase 4 (GPX4), we hypothesized that caspase-2 may play a role in regulating ferroptosis. This study provides the first demonstration of an important and unprecedented function of caspase-2 in protecting cancer cells from undergoing ferroptotic cell death. Specifically, we show that depletion of caspase-2 leads to the downregulation of stress response genes including SESN2, HMOX1, SLC7A11, and sensitizes mutant-p53 cancer cells to cell death induced by various ferroptosis-inducing compounds. Importantly, the canonical catalytic activity of caspase-2 is not required for its role and suggests that caspase-2 regulates ferroptosis via non-proteolytic interaction with other proteins. Using an unbiased BioID proteomics screen, we identified novel caspase-2 interacting proteins (including heat shock proteins and co-chaperones) that regulate cellular responses to stress. Finally, we demonstrate that caspase-2 limits chaperone-mediated autophagic degradation of GPX4 to promote the survival of mutant-p53 cancer cells. In conclusion, we document a novel role for caspase-2 as a negative regulator of ferroptosis in cells with mutant p53. Our results provide evidence for a novel function of caspase-2 in cell death regulation and open potential new avenues to exploit ferroptosis in cancer therapy.
Topics: Caspase 2; Cell Death; Molecular Chaperones; Phospholipid Hydroperoxide Glutathione Peroxidase; Tumor Suppressor Protein p53; Ferroptosis
PubMed: 38429264
DOI: 10.1038/s41419-024-06560-6 -
Redox Biology Aug 2023The aim of this study was to examine, in biochemical detail, the functional role of the Arg152 residue in the selenoprotein Glutathione Peroxidase 4 (GPX4), whose...
The aim of this study was to examine, in biochemical detail, the functional role of the Arg152 residue in the selenoprotein Glutathione Peroxidase 4 (GPX4), whose mutation to His is involved in Sedaghatian-type Spondylometaphyseal Dysplasia (SSMD). Wild-type and mutated recombinant enzymes with selenopcysteine (Sec) at the active site, were purified and structurally characterized to investigate the impact of the R152H mutation on enzymatic function. The mutation did not affect the peroxidase reaction's catalytic mechanism, and the kinetic parameters were qualitatively similar between the wild-type enzyme and the mutant when mixed micelles and monolamellar liposomes containing phosphatidylcholine and its hydroperoxide derivatives were used as substrate. However, in monolamellar liposomes also containing cardiolipin, which binds to a cationic area near the active site of GPX4, including residue R152, the wild-type enzyme showed a non-canonical dependency of the reaction rate on the concentration of both enzyme and membrane cardiolipin. To explain this oddity, a minimal model was developed encompassing the kinetics of both the enzyme interaction with the membrane and the catalytic peroxidase reaction. Computational fitting of experimental activity recordings showed that the wild-type enzyme was surface-sensing and prone to "positive feedback" in the presence of cardiolipin, indicating a positive cooperativity. This feature was minimal, if any, in the mutant. These findings suggest that GPX4 physiology in cardiolipin containing mitochondria is unique, and emerges as a likely target of the pathological dysfunction in SSMD.
Topics: Glutathione Peroxidase; Phospholipid Hydroperoxide Glutathione Peroxidase; Cardiolipins; Liposomes; Mutation
PubMed: 37413766
DOI: 10.1016/j.redox.2023.102806 -
Biotechnology Advances 2023Dye-decolorizing Peroxidases (DyPs) are heme-containing enzymes in fungi and bacteria that catalyze the reduction of hydrogen peroxide to water with concomitant... (Review)
Review
Dye-decolorizing Peroxidases (DyPs) are heme-containing enzymes in fungi and bacteria that catalyze the reduction of hydrogen peroxide to water with concomitant oxidation of various substrates, including anthraquinone dyes, lignin-related phenolic and non-phenolic compounds, and metal ions. Investigation of DyPs has shed new light on peroxidases, one of the most extensively studied families of oxidoreductases; still, details of their microbial physiological role and catalytic mechanisms remain to be fully disclosed. They display a distinctive ferredoxin-like fold encompassing anti-parallel β-sheets and α-helices, and long conserved loops surround the heme pocket with a role in catalysis and stability. A tunnel routes HO to the heme pocket, whereas binding sites for the reducing substrates are in cavities near the heme or close to distal aromatic residues at the surface. Variations in reactions, the role of catalytic residues, and mechanisms were observed among different classes of DyP. They were hypothetically related to the presence or absence of distal HO molecules in the heme pocket. The engineering of DyPs for improved properties directed their biotechnological applications, primarily centered on treating textile effluents and degradation of other hazardous pollutants, to fields such as biosensors and valorization of lignin, the most abundant renewable aromatic polymer. In this review, we track recent research contributions that furthered our understanding of the activity, stability, and structural properties of DyPs and their biotechnological applications. Overall, the study of DyP-type peroxidases has significant implications for environmental sustainability and the development of new bio-based products and materials with improved end-of-life options via biodegradation and chemical recyclability, fostering the transition to a sustainable bio-based industry in the circular economy realm.
Topics: Peroxidases; Biocatalysis; Lignin; Hydrogen Peroxide; Heme; Coloring Agents
PubMed: 37044267
DOI: 10.1016/j.biotechadv.2023.108153 -
International Journal of Molecular... Dec 2023Recent years have brought progress in understanding the role of the neutrophil, dispelling the dogma of homogeneous cells mainly involved in the prime defence against... (Review)
Review
Recent years have brought progress in understanding the role of the neutrophil, dispelling the dogma of homogeneous cells mainly involved in the prime defence against pathogens, shedding light on their pathogenic role in inflammatory diseases and on the importance of antineutrophil-cytoplasmic antibodies' pathogenic role in ANCA-associated vasculitides vasculitis (AAV). Myeloperoxidase (MPO) and proteinase 3 (PR3) expressed in neutrophil granulocytes are the most common targets for ANCAs and contribute to the formation of MPO-ANCAs and PR3-ANCAs which, released to the bloodstream, become an excellent diagnostic tool for AAV. In this study, we focus on increasing the clinical and experimental evidence that supports the pathogenic role of ANCAs in AAV. Additionally, we discuss the diagnostic utility of ANCAs for disease activity and prognosis in AAV. Understanding the central role of ANCAs in AAV is crucial for advancing our knowledge of these complex disorders and developing targeted therapeutic strategies in the era of personalized medicine.
Topics: Humans; Autoantibodies; Neutrophils; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Peroxidase; Myeloblastin
PubMed: 38139045
DOI: 10.3390/ijms242417217 -
BMC Medicine Sep 2023Multitarget tyrosine kinase inhibitors (mTKIs) such as Regorafenib and Sorafenib have already been approved for the treatment of many solid tumours. However, the...
BACKGROUND
Multitarget tyrosine kinase inhibitors (mTKIs) such as Regorafenib and Sorafenib have already been approved for the treatment of many solid tumours. However, the efficacy of mTKIs in colorectal cancer (CRC) is limited; the underlined mechanism remains largely elusive. Our study was aimed to find out the resistance mechanism of mTKIs in CRC.
METHODS
RNA sequencing was used to identify the expression of Activin A receptor-like type 1 (ACVRL1) under the treatment of mTKIs. Gain/loss-of-function experiments were performed to assess the biological function of ACVRL1 in resistance to mTKIs. The underlying mechanisms of ACVRL1-mediated mTKI resistance were investigated by using liquid chromatography-mass spectrometry assays (LC-MS), co-immunoprecipitation assays (Co-IP), chromatin immunoprecipitation assays, ubiquitination assays, dual luciferase reporter assays, etc. RESULTS: RNA sequencing identified the activation of ACVRL1 under the treatment of mTKIs in CRC cells. ACVRL1 knockdown and overexpression significantly affects the sensitivity of CRC cells to mTKIs both in vitro and vivo. Mechanistically, we found the β-catenin/TCF-1-KCNQ1OT1/miR-7-5p axis mediated the activation of ACVRL1. Furthermore, LC-MS assays indicated the interaction between ACVRL1 and glutathione peroxidase 2(GPX2) protein. IP assay defined ACVRL1 truncation (282-503aa) could be responsible for interacting with GPX2, and rescue experiments with ACVRL1 truncations confirmed the importance of this interaction in driving mTKI resistance. Co-IP assays confirmed that ACVRL1 associates with ubiquitin-specific peptidase 15(USP15) which directly deubiquinates GPX2 at the K187(K, lysine) site, leading to the accumulation of GPX2 protein. Rescue experiments performed with the lysine mutants in GPX2 CRISPR knockout cell model confirmed the importance of GPX2 K187 mutant. As a result, the increased ROS clearance and decreased cell apoptosis eventually lead to mTKI resistance in CRC.
CONCLUSIONS
Our results demonstrate that the Wnt/β-catenin/KCNQ1OT1/miR-7-5p/ACVRL1/GPX2 biological axis plays a vital role in CRC, targeting which may be an effective approach for overcoming mTKI resistance.
Topics: Humans; beta Catenin; Tyrosine Kinase Inhibitors; Lysine; MicroRNAs; Glutathione Peroxidase; Colorectal Neoplasms; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Activin Receptors, Type II; Ubiquitin-Specific Proteases
PubMed: 37743483
DOI: 10.1186/s12916-023-03066-4 -
Renal Failure Dec 2023To investigate the clinical characteristics, pathological features, and outcomes of patients with antineutrophil cytoplasmic antibody (ANCA)-positive systemic lupus...
To investigate the clinical characteristics, pathological features, and outcomes of patients with antineutrophil cytoplasmic antibody (ANCA)-positive systemic lupus erythematosus (SLE) in northwest China. This retrospective study included 491 patients with SLE tested for ANCA antibodies and 171 patients with ANCA-associated vasculitis (AAV) as controls. Subgroup analysis limited to those with renal involvement, and by ANCA antibody subtype (PR3 vs MPO). To compare the proteinuria remission rates between ANCA-positive and ANCA-negative lupus nephritis (LN) groups, a logistic regression model was used for propensity score matching based on age, hemoglobin, and baseline estimated glomerular filtration rate (eGFR). Compared to ANCA-negative SLE ( = 442), ANCA-positive SLE ( = 46) occur in older patients; however, these patients were younger than those with AAV ( = 167). The eGFR of patients with ANCA-positive LN ( = 25) was higher than that of patients having AAV with renal involvement ( = 56) but lower than that of patients with ANCA-negative LN ( = 163). Patients with SLE who had MPO-ANCA ( = 16) had higher levels of serum creatinine compared to those with PR3-ANCA ( = 30) (156.5 µmol/L vs. 45.5 µmol/L, = 0.005). During the follow-up period, the remission rate of proteinuria in patients with ANCA-positive LN was lower than that of patients with ANCA-negative LN (50% vs. 75%, = 0.008). Patients with ANCA-positive LN may have worse baseline renal function and lower protein remission rates compared to patients with ANCA-negative LN. ANCA titers should be regularly monitored throughout the follow-up period in patients with SLE, especially in cases of renal involvement.
Topics: Humans; Aged; Antibodies, Antineutrophil Cytoplasmic; Retrospective Studies; Lupus Erythematosus, Systemic; Lupus Nephritis; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Proteinuria; Peroxidase
PubMed: 37470370
DOI: 10.1080/0886022X.2023.2235431 -
PloS One 2023To evaluate the acute impact of a nutraceutical blend on immune surveillance. (Randomized Controlled Trial)
Randomized Controlled Trial
Rapid increase in immune surveillance and expression of NKT and γδT cell activation markers after consuming a nutraceutical supplement containing Aloe vera gel, extracts of Poria cocos and rosemary. A randomized placebo-controlled cross-over trial.
GOAL
To evaluate the acute impact of a nutraceutical blend on immune surveillance.
STUDY DESIGN
A randomized, double-blind, placebo-controlled, cross-over trial was conducted in 11 healthy subjects. Blood samples were taken immediately before and at 1, 2, and 3 hours after consuming placebo or 500 mg of UP360, which is a blend of botanicals from Aloe vera, Poria cocos, and rosemary (APR extract). Immunophenotyping and flow cytometry quantified numbers of monocytes, NK cells, NKT cells, CD8+ cytotoxic T cells, γδT cells, and total T cells, and expression of CD25 and CD69 activation markers. Plasma was tested for cytokines, chemokines, growth factors, and enzymatic activity of superoxide dismutase and catalase.
RESULTS
Compared to the placebo, consumption of APR extract triggered rapid increases in chemokine levels starting at 1 hour, including IP-10 (P<0.05) and MCP-1 (P<0.1), which peaked at 2 hours (P<0.01) and 3 hours (P<0.05), respectively. The stem cell-mobilizing growth factor G-CSF increased at 2 hours (P<0.05). Increased immune surveillance involved a transient effect for monocytes at 1 hour, followed by NKT cells, CD8+ cytotoxic T cells, and γδT cells at 2-3 hours. Increased immune cell alertness was seen at 1 hour by increased CD25 expression on monocytes (P<0.01), NKT cells (P<0.01), and T cells (P<0.05). NKT cells showed upregulation of CD69 at 2 hours (P<0.01). Increased enzymatic activity was seen at 2 hours for the antioxidant enzymes superoxide dismutase (P<0.05) and catalase (P<0.01).
CONCLUSION
Consumption of APR extract triggered acute changes to chemokine levels. In addition, immune alertness was increased via the expression of activation markers on multiple types of innate immune cells, followed by increased immune surveillance and antioxidant protection. This suggests a beneficial enhancement of natural immune surveillance, likely via a combination of gut-mediated cytokine release and vagus nerve communication, in combination with cellular protection from oxidative stress.
Topics: Humans; Antioxidants; Rosmarinus; Wolfiporia; Catalase; Cross-Over Studies; Dietary Supplements; Cytokines; Plant Extracts
PubMed: 37699014
DOI: 10.1371/journal.pone.0291254