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Advanced Science (Weinheim,... Jul 2024Conventional androgen deprivation therapy (ADT) targets the androgen receptor (AR) inhibiting prostate cancer (PCa) progression; however, it can eventually lead to...
Genetically Engineered Membrane-Coated Nanoparticles for Enhanced Prostate-Specific Membrane Antigen Targeting and Ferroptosis Treatment of Castration-Resistant Prostate Cancer.
Conventional androgen deprivation therapy (ADT) targets the androgen receptor (AR) inhibiting prostate cancer (PCa) progression; however, it can eventually lead to recurrence as castration-resistant PCa (CRPC), which has high mortality rates and lacks effective treatment modalities. The study confirms the presence of high glutathione peroxidase 4 (GPX4) expression, a key regulator of ferroptosis (i.e., iron-dependent program cell death) in CRPC cells. Therefore, inducing ferroptosis in CRPC cells might be an effective therapeutic modality for CRPC. However, nonspecific uptake of ferroptosis inducers can result in undesirable cytotoxicity in major organs. Thus, to precisely induce ferroptosis in CRPC cells, a genetic engineering strategy is proposed to embed a prostate-specific membrane antigen (PSMA)-targeting antibody fragment (gy1) in the macrophage membrane, which is then coated onto mesoporous polydopamine (MPDA) nanoparticles to produce a biomimetic nanoplatform. The results indicate that the membrane-coated nanoparticles (MNPs) exhibit high specificity and affinity toward CRPC cells. On further encapsulation with the ferroptosis inducers RSL3 and iron ions, MPDA/Fe/RSL3@M-gy1 demonstrates superior synergistic effects in highly targeted ferroptosis therapy eliciting significant therapeutic efficacy against CRPC tumor growth and bone metastasis without increased cytotoxicity. In conclusion, a new therapeutic strategy is reported for the PSMA-specific, CRPC-targeting platform for ferroptosis induction with increased efficacy and safety.
PubMed: 38946578
DOI: 10.1002/advs.202401095 -
Gynecological Endocrinology : the... Dec 2024To determine whether ultrasonic manifestations of Hashimoto's thyroiditis (HT) related to embryo qualities or pregnancy outcomes in women with thyroid autoimmunity (TAI)...
OBJECTIVE
To determine whether ultrasonic manifestations of Hashimoto's thyroiditis (HT) related to embryo qualities or pregnancy outcomes in women with thyroid autoimmunity (TAI) undergoing fertilization/intracytoplasmic sperm injection.
METHODS
Our study was a retrospective cohort study. A total of 589 euthyroid women enrolled from January 2017 to December 2019. 214 TAI women and 375 control women were allocated in each group according to serum levels of thyroid peroxidase antibodies (TPOAb) and/or anti-thyroglobulin antibodies (TgAb). Basal serum hormone levels and thyroid ultrasound were assessed, embryo qualities, pregnancy outcomes were collected from medical records. Diagnosis of thyroid ultrasound was used for subanalysis. Logistic regression was used to evaluate outcomes of embryo development and pregnancy.
RESULTS
Implantation rate was significantly lower in euthyroid women with TAI compared with control group (TAI group: 65.5% vs. Control group: 73.0%, adjusted OR (95% CI): 0.65 (0.44, 0.97), = 0.04). We further stratified TAI group into two groups: one group with HT features under ultrasound and another group with normal thyroid ultrasound. After regression analysis, TAI women with HT morphological changes had a lower chance of implantation compared with control group (TAI group with HT: 64.1% vs. Control group: 73.0%, adjusted OR (95% CI): 0.63 (0.41, 0.99), = 0.04), while there was no significant difference on implantation rate between TAI women with normal thyroid ultrasound and control group. Other outcomes, such as embryo qualities and pregnancy rate, were comparable between TAI and control groups.
CONCLUSIONS
A higher risk of implantation failure was seen among euthyroid women with TAI, especially women with HT morphological changes under ultrasound. The underlying mechanisms of implantation failure among euthyroid HT patients need further research.
Topics: Humans; Female; Adult; Pregnancy; Sperm Injections, Intracytoplasmic; Retrospective Studies; Embryo Implantation; Thyroid Gland; Ultrasonography; Fertilization in Vitro; Hashimoto Disease; Pregnancy Rate; Autoantibodies; Pregnancy Outcome; Autoimmunity
PubMed: 38946301
DOI: 10.1080/09513590.2024.2368832 -
Journal of the Chinese Medical... Jul 2024Hirsutella sinensis (HS) is a mycelium isolated from the fruiting body of the medicinal mushroom Cordyceps sinensis. This study explored whether HS treatment affects...
BACKGROUND
Hirsutella sinensis (HS) is a mycelium isolated from the fruiting body of the medicinal mushroom Cordyceps sinensis. This study explored whether HS treatment affects reproductive dysfunction in a high-fat diet (HFD)-induced mouse model and regulates various mechanisms, focusing on oxidative stress, apoptosis, inflammation, and autophagy.
METHODS
Twenty-four C57BL/6J (B6) mice were randomly divided into a standard chow diet (NCD)- or HFD-fed group for 24 weeks. During the final 8 weeks, half of the HFD-fed mice were orally administered HS (HFD+HS). Biochemical markers, including glucose, insulin, triglycerides, and total cholesterol, were assessed, and hormones, including testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH), were analyzed. Liver and testicular histology, as well as sperm quality markers such as sperm motility, sperm count, and percentage of sperm with normal morphology, were observed. The activities of the testicular antioxidants superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx) and the products of lipid peroxidation, such as MDA, were measured. The protein expression levels of apoptosis-, autophagy- and inflammation-related markers were measured.
RESULTS
The HFD-fed mice had abnormal sex hormone levels, poor sperm quality, and a destroyed testicular structure, with increased oxidative stress and apoptosis in the testis. HS supplementation in HFD-fed mice attenuated testicular apoptosis by suppressing the Bax/Bcl-xl ratio and cleaved caspase 3 protein expression. The HS-treated mice exhibited improved reproductive function, possibly due to reduced oxidative stress and apoptosis, suggesting that HS has a protective effect against HFD-induced testicular damage.
CONCLUSION
Male mice supplemented with HS exhibited attenuated poor semen quality and reduced testosterone levels brought about by high-fat diet-induced obesity by reducing oxidative stress.
PubMed: 38946025
DOI: 10.1097/JCMA.0000000000001128 -
Journal of Oleo Science 2024In this study, we evaluated the cancer cell killing activity of koji mold-derived extracts using several solvents. The koji mold lipid extract (KML) exhibited potent...
Koji Mold-derived Lipids Disrupt the Intracellular Redox State by Decreasing the GPx4 and Intracellular Glutathione Levels, Promoting Membrane Lipid Peroxidation, and Inducing Ferroptosis in HL-60 Cells.
In this study, we evaluated the cancer cell killing activity of koji mold-derived extracts using several solvents. The koji mold lipid extract (KML) exhibited potent cytotoxicity against a human leukemia cell line. Fractionation of the KML via silica gel chromatography revealed the presence of active components in fraction (Fr.) 6. Cytotoxic effects of Fr. 6 were inhibited by the ferroptosis inhibitors, ferrostatin-1 and SRS11-92, and the iron chelator, deferoxamine. Interestingly, ferroptosis inhibitors failed to prevent the KML-induced cell death. Fr. 6 decreased the expression of glutathione peroxidase 4 (GPx4) and increased the level of peroxidized plasma membrane lipids. Furthermore, Fr. 6 decreased the intracellular glutathione levels. Overall, our results suggest that Fr. 6 included in KML induces ferroptosis in HL-60 cells.
Topics: Humans; HL-60 Cells; Phospholipid Hydroperoxide Glutathione Peroxidase; Ferroptosis; Lipid Peroxidation; Glutathione; Oxidation-Reduction; Deferoxamine; Cyclohexylamines; Lipids; Phenylenediamines; Membrane Lipids; Iron Chelating Agents
PubMed: 38945927
DOI: 10.5650/jos.ess24043 -
Journal of Nutritional Science and... 2024Excessive immune response and inflammation are associated with an increased risk of various diseases. In particular, excessive myeloperoxidase (MPO) activity in... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
Excessive immune response and inflammation are associated with an increased risk of various diseases. In particular, excessive myeloperoxidase (MPO) activity in neutrophils causes inflammatory reactions and lifestyle-related diseases. Adlay has a long history of being used as a traditional Chinese medicine. Polyphenols present in adlay seeds are expected to have the effect of suppressing excessive immune and inflammatory responses. Here, we conducted a randomized, double-blind, parallel group, placebo-controlled study was conducted to evaluate the suppressing effects of adlay seeds extract on excessive immune responses. One hundred and twenty adults participated in the study and they were equally divided into an adlay tea intake group and a placebo group. MPO activity was significantly elevated in the placebo group after 8-wk ingestion, while no significant change was observed in the adlay group. Vascular endothelial functions improved in the adlay group, especially in subjects over 40 y old. These results indicate that adlay tea intake may suppress an excessive immune and inflammatory responses, and improve arterial stiffness. Since caffeic acid, p-coumaric acid, and ferulic acid detected in adlay tea are known to inhibit MPO activity, these polyphenols may be the major functional molecules. Collectively, adlay tea is considered to have a preventative effect against lifestyle-related diseases through improving vascular endothelial function by effects to maintain immune homeostasis of the contained polyphenols. This trial was registered at University Hospital Medical Information Network Clinical Trials Registry (UMIN000032263).
Topics: Humans; Double-Blind Method; Male; Female; Adult; Tea; Homeostasis; Middle Aged; Endothelium, Vascular; Polyphenols; Peroxidase; Seeds; Plant Extracts; Inflammation; Caffeic Acids; Medicine, Chinese Traditional
PubMed: 38945894
DOI: 10.3177/jnsv.70.280 -
Physiologia Plantarum 2024Maize (Zea mays L.) is an important food crop with a wide range of uses in both industry and agriculture. Drought stress during its growth cycle can greatly reduce maize...
Maize (Zea mays L.) is an important food crop with a wide range of uses in both industry and agriculture. Drought stress during its growth cycle can greatly reduce maize crop yield and quality. However, the molecular mechanisms underlying maize responses to drought stress remain unclear. In this work, a WRKY transcription factor-encoding gene, ZmWRKY30, from drought-treated maize leaves was screened out and characterized. ZmWRKY30 gene expression was induced by dehydration treatments. The ZmWRKY30 protein localized to the nucleus and displayed transactivation activity in yeast. Compared with wild-type (WT) plants, Arabidopsis lines overexpressing ZmWRKY30 exhibited a significantly enhanced drought stress tolerance, as evidenced by the improved survival rate, increased antioxidant enzyme activity by superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT), elevated proline content, and reduced lipid peroxidation recorded after drought stress treatment. In contrast, the mutator (Mu)-interrupted ZmWRKY30 homozygous mutant (zmwrky30) was more sensitive to drought stress than its null segregant (NS), characterized by the decreased survival rate, reduced antioxidant enzyme activity (SOD, POD, and CAT) and proline content, as well as increased malondialdehyde accumulation. RNA-Seq analysis further revealed that, under drought conditions, the knockout of the ZmWRKY30 gene in maize affected the expression of genes involved in reactive oxygen species (ROS), proline, and myo-inositol metabolism. Meanwhile, the zmwrky30 mutant exhibited significant downregulation of myo-inositol content in leaves under drought stress. Combined, our results suggest that ZmWRKY30 positively regulates maize responses to water scarcity. This work provides potential target genes for the breeding of drought-tolerant maize.
Topics: Zea mays; Reactive Oxygen Species; Droughts; Plant Proteins; Gene Expression Regulation, Plant; Homeostasis; Inositol; Transcription Factors; Arabidopsis; Plants, Genetically Modified; Stress, Physiological; Antioxidants; Plant Leaves; Drought Resistance
PubMed: 38945803
DOI: 10.1111/ppl.14423 -
Journal of Ethnopharmacology Jun 2024Zuogui Pill (ZGP) is a traditional herbal formula of Chinese Medicine with a long history of use in alleviating ovarian aging.
Zuogui Pills Alleviate Cyclophosphamide-induced Ovarian Aging by Reducing Oxidative Stress and Restoring the Stemness of Oogonial Stem Cells through the Nrf2/HO-1 Signaling Pathway.
ETHNOPHARMACOLOGICAL RELEVANCE
Zuogui Pill (ZGP) is a traditional herbal formula of Chinese Medicine with a long history of use in alleviating ovarian aging.
AIM OF THE STUDY
To examine the impact of ZGP on oxidative stress and the stemness of oogonial stem cells (OSCs) in cyclophosphamide (CTX)-induced ovarian aging, as well as its molecular mechanisms involving the nuclear factor erythroid 2-related factor 2 (Nrf2, NFE2L2)/heme oxygenase-1 (HO-1, Hmox1) pathway.
MATERIALS AND METHODS
Female Sprague-Dawley (SD) rats were randomly divided into seven groups: control, model (CTX), estradiol valerate (EV, 0.103 mg/kg), ZGP-L (low dose Zuogui Pill, 1.851 g/kg), ZGP-H (high dose Zuogui Pill, 3.702 g/kg), ML385 (30 mg/kg), and ML385+ZGP-L. After CTX modeling, the EV, ZGP-L, ZGP-H, and ML385+ZGP-L groups were treated by gavage for 8 weeks, while the ML385 and ML385+ZGP-L groups were administered the Nrf2 antagonist ML385 twice a week. OSCs were isolated after modeling and then treated with drug serum containing 10% ZGP or 10 μM ML385. The general conditions of the rats, including body weight, ovarian weight/body weight ratio, and estrous cycle, were observed. Ovarian ultrastructure, follicle and corpus luteum counts were assessed via hematoxylin and eosin (H&E) staining. Serum hormone levels were measured using enzyme-linked immunosorbent assay (ELISA). Nrf2/HO-1 pathway, stem cell, germ cell, and cell cycle biomarkers were analyzed by qPCR and Western blot. Cell viability was assessed by cell counting kit-8 (CCK-8) assay. Oxidative stress biomarkers were evaluated using flow cytometry and assay kits. Immunofluorescence was employed to detect and locate OSCs in the ovary, quantify the average fluorescence intensity, and identify OSCs.
RESULTS
After ZGP treatment, rats with CTX-induced ovarian aging exhibited improved general condition, increased body weight, higher total ovarian weight to body weight ratio, and a restoration of the estrous cycle similar to the control group. Serum levels of estradiol (E) and follicle stimulating hormone (FSH), two sex hormones, were also improved. Ovarian ultrastructure and follicle count at all stages showed improvement. Moreover, the viability and proliferation capacity of OSCs were enhanced following ZGP intervention. The Nrf2/HO-1 pathway was found to be down-regulated in CTX-induced aging ovarian OSCs. However, ZGP reversed this effect by activating the expression of Nrf2, HO-1, and NAD(P)H oxidoreductase 1 (NQO1), increasing the activity of antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX), and reducing the accumulation of malonaldehyde (MDA) and reactive oxygen species (ROS), thus restoring resistance to oxidative stress. Additionally, ZGP improved the cell cycle of OSCs, up-regulated the expression of Cyclin D1 and Cyclin E1, restored cell stemness, promoted proliferation, enhanced the expression of cell stemness markers octamer-binding transcription factor 4 (Oct4) and mouse VASA homolog (MVH), and down-regulated the expression of P21, thereby inhibiting apoptosis. The therapeutic effects of ZGP against oxidative stress and restoration of cell stemness were attenuated following inhibition of the Nrf2 signaling pathway using ML385.
CONCLUSIONS
ZGP protected against CTX-induced ovarian aging by restoring normal ovarian function, alleviating oxidative stress in aging OSCs, promoting OSCs proliferation, and restoring their stemness in rats, possibly through regulating the Nrf2/HO-1 pathway.
PubMed: 38945466
DOI: 10.1016/j.jep.2024.118505 -
Free Radical Biology & Medicine Jun 2024Innovative solutions for rapid protection against broad-spectrum infections are very important in dealing with complex infection environments. We utilized a functionally...
A Streptococcus pneumoniae endolysin mutant protein ΔA146Ply elicits rapid broad-spectrum mucosal protection in mice via upregulation of GPX4 through TLR4/IRG1/NRF2 to alleviate macrophage ferroptosis.
Innovative solutions for rapid protection against broad-spectrum infections are very important in dealing with complex infection environments. We utilized a functionally inactive mutated endolysin protein of Streptococcus pneumoniae (ΔA146Ply) to immunize mice against pneumonic infections by multidrug-resistant bacteria, Candida albicans and influenza virus type A. ΔA146Ply protection relied on both immunized tissue-resident and monocyte-derived alveolar macrophages and inhibited infection induced ferroptosis that upregulated expression of GPX4 (glutathione peroxidase) in alveolar macrophages. Ferroptosis resistance endowed macrophages with enhanced phagocytosis by inhibiting lipid peroxidation during infection. Moreover, we demonstrated ΔA146Ply upregulated GPX4 through the TLR4/IRG1/NRF2 pathway. ΔA146Ply also induced ferroptosis inhibition and phagocytosis improvement in human monocytes. This mode of action is a novel and potentially prophylactic and rapid broad-spectrum anti-infection mechanism. Our study provides new insights into protective interventions that act by regulating ferroptosis to improve multiple pathogen resistance via GPX4 targeting.
PubMed: 38945457
DOI: 10.1016/j.freeradbiomed.2024.06.025 -
Comparative Biochemistry and... Jun 2024High ocean temperatures caused by global warming induce oxidative stress in aquatic organisms. Melatonin treatment and irradiation using red light-emitting diodes (LEDs)...
Effects of red-light irradiation and melatonin injection on the antioxidant capacity and occurrence of apoptosis in abalones (Haliotis discus hannai) subjected to thermal stress.
High ocean temperatures caused by global warming induce oxidative stress in aquatic organisms. Melatonin treatment and irradiation using red light-emitting diodes (LEDs) have been reported to reduce oxidative stress in a few aquatic organisms. However, the effects of red LED irradiation and melatonin injection on the antioxidant capacity and degree of apoptosis in abalones, which are nocturnal organisms, have not yet been reported. In this study, we compared the expression levels of antioxidant enzymes, total antioxidant capacity, and the degree of apoptosis in abalones subjected to red LED irradiation and melatonin treatment. The results revealed that at high water temperatures (25 °C), the mRNA expression levels of the superoxide dismutase (SOD) and glutathione peroxidase (GPx) genes and the antioxidant activity of SOD decreased in abalones in the red-LED-irradiated and melatonin-treated groups compared with those in abalones in the control group. Although high water temperatures induced DNA damage in the abalone samples, the degree of apoptosis was lower in the red-LED-irradiated and melatonin-treated groups than in the control group. Overall, the abalones in the melatonin-treated and red-LED-irradiated groups showed reduced oxidative stress and increased antioxidant enzyme levels under thermal stress compared with those in the control group. Therefore, red LED irradiation is a promising alternative to melatonin treatment, which is difficult to administer continuously for a long time, for protecting abalones from oxidative stress.
PubMed: 38945429
DOI: 10.1016/j.cbpa.2024.111689 -
Toxicology in Vitro : An International... Jun 2024Circular RNAs (circRNAs) regulate the tumorigenesis of non-small-cell lung cancer (NSCLC). CircPDSS1 (hsa_circ_0017998) has been newly discovered, and its role in NSCLC...
BACKGROUND
Circular RNAs (circRNAs) regulate the tumorigenesis of non-small-cell lung cancer (NSCLC). CircPDSS1 (hsa_circ_0017998) has been newly discovered, and its role in NSCLC remains elusive. We aimed to investigate the functional roles and downstream targets of circPDSS1 in NSCLC cells.
MATERIALS AND METHODS
Cellular viabilities were measured through the Cell Counting Kit-8 (CCK-8) assay, whereas cell death was assessed through flow cytometry. The lactate dehydrogenase activity, malondialdehyde levels, ferrous iron, and reactive oxygen species were measured using commercial assay kits. The interaction between circPDSSA/ microRNA-137 (miR-137) and miR-137/solute carrier family 7 member 11 (SLC7A11) was assayed through a dual luciferase activity assay. Finally, the mRNA and protein levels were measured using real-time reverse transcriptase-polymerase chain reaction and western blots, respectively.
RESULTS
CircPDSS1 expression was upregulated in NSCLC cells, compared with healthy lung cells. CircPDSS1 silencing suppressed the viability of NSCLC cells. Additionally, circPDSS1 knockdown induced ferroptosis rather than other types of cell death in NSCLC cells. Mechanically, circPDSS1 functions as a "sponge" to inversely control miR-137 expression, which directly targets SLC7A11. Moreover, circPDSS1 silencing causes the downregulation of glutathione peroxidase 4 (GPX4) and glutamate-cysteine ligase catalytic subunit (GCLC).
CONCLUSIONS
Targeting the circPDSS1/miR-137/SLC7A11/GPX4/GCLC axis may be a promising strategy to kill NSCLC cells.
PubMed: 38945378
DOI: 10.1016/j.tiv.2024.105887