Oxidative Stress-mediated Damage Research Articles

Folic acid mitigates the developmental and neurotoxic effects of bisphenol A in zebrafish by inhibiting the oxidative stress/JNK signaling pathway

Bisphenol A (BPA) is a widespread environmental endocrine disruptor (EED) that can cause various environmental and health issues by inducing oxidative stress. The c-Jun N-terminal kinase (JNK) signaling pathway plays a crucial role in oxidative stress-mediated cellular damage. Although folic acid (FA) has demonstrated antioxidant properties, its potential protective effects against BPA-induced developmental and neurotoxicity, as well as the mechanisms involved in the JNK signaling pathway, are still not completely understood. Zebrafish embryos were exposed to different concentrations of BPA ranging from 20 to 40 µM, with or without treatment of 50 µM FA, starting at 6 hours post-fertilization (hpf). Various parameters such as hatchability, survival rate, body length, and heart rate were measured and analyzed. Transcriptome sequencing was conducted to study the changes in gene expression. Oxidative stress markers, including reactive oxygen species (ROS), lipid peroxidation (LPO), hydrogen peroxide (H2O2), and catalase (CAT) activity, were assessed. The expression of proteins related to the mitogen-activated protein kinase (MAPK)/JNK pathway was analyzed using western blot. Neurodevelopmental and apoptotic outcomes were evaluated through behavioral tests, immunofluorescence and RT-qPCR examinations. The study found that exposure to BPA led to a decrease in hatchability, survival, body length, heart rate, total antioxidant capacity and promoted apoptosis in zebrafish larvae. However, supplementation with FA was able to alleviate these negative effects. BPA exposure increased levels of ROS, LPO, and H2O2, while decreasing CAT activity in zebrafish larvae. Treatment with FA effectively reduced BPA-induced oxidative stress and restored antioxidant defense systems. Moreover, KEGG pathway enrichment analysis revealed that the MAPK signaling pathway was the most enriched signaling pathway. Further studies revealed that BPA activated the JNK signaling pathway, while FA suppressed this activation. Additionally, FA significantly improved BPA-induced neurobehavioral deficits and protected against neurocytological alterations. Our findings demonstrate that FA effectively protects against BPA-induced developmental and neurotoxic effects in zebrafish by suppressing oxidative stress and inhibiting the JNK signaling pathway. This study provides new strategies and insights for preventing BPA-induced developmental and neurotoxicity in aquatic organisms.

Protective Effects of L-Cysteine Against Cisplatin-Induced Oxidative Stress-Mediated Reproductive Damage

Cisplatin (CIS) is a widely used chemotherapeutic agent, but its side effects, such as oxidative stress, inflammation, and apoptosis, often lead to male reproductive damage. Oxidative stress, primarily caused by the excessive generation of reactive oxygen species (ROS), plays a critical role in disrupting testicular homeostasis, resulting in spermatogenic impairment and tissue injury. L-cysteine (CYS), a semi-essential amino acid with potent antioxidant and anti-inflammatory properties, may offer protection against CIS-induced oxidative damage. This study aimed to assess the protective potential of CYS against CIS-induced male reproductive toxicity using in vivo and in vitro models. In vitro, treatment of TM3 (Leydig) and TM4 (Sertoli) cells with CIS led to increased ROS levels, reduced cell viability, and elevated apoptosis and inflammation, all of which were significantly ameliorated by subsequent CYS exposure. In vivo, CIS-treated male rats displayed heightened oxidative stress, impaired spermatogenesis, and histopathological damage in reproductive organs. However, CYS administration for 21 days significantly reduced oxidative stress, improved sperm viability, and protected testicular tissues from damage. These findings suggest that CYS has a protective effect against CIS-induced oxidative stress and male reproductive damage, making it a promising therapeutic agent for mitigating CIS-induced reproductive toxicity.

Mechanistic Insights Into Redox Damage of the Podocyte in Hypertension.

Podocytes are specialized cells within the glomerular filtration barrier, which are crucial for maintaining glomerular structural integrity and convective ultrafiltration. Podocytes exhibit a unique arborized morphology with foot processes interfacing by slit diaphragms, ladder-like, multimolecular sieves, which provide size and charge selectivity for ultrafiltration and transmembrane signaling. Podocyte dysfunction, resulting from oxidative stress, dysregulated prosurvival signaling, or structural damage, can drive the development of proteinuria and glomerulosclerosis in hypertensive nephropathy. Functionally, podocyte injury leads to actin cytoskeleton rearrangement, foot process effacement, dysregulated slit diaphragm protein expression, and impaired ultrafiltration. Notably, the renin-angiotensin system plays a pivotal role in podocyte function, with beneficial AT2R (angiotensin receptor 2)-mediated nitric oxide (NO) signaling to counteract AT1R (angiotensin receptor 1)-driven calcium (Ca2+) influx and oxidative stress. Disruption of this balance contributes significantly to podocyte dysfunction and drives albuminuria, a marker of kidney damage and overall disease progression. Oxidative stress can also lead to sustained ion channel-mediated Ca2+ influx and precipitate cytoskeletal disorganization. The complex interplay between GPCR signaling, ion channel activation, and redox injury pathways underscores the need for additional research aimed at identifying targeted therapies to protect podocytes and preserve glomerular function. Earlier detection of albuminuria and podocyte injury through routine noninvasive diagnostics will also be critical in populations at the highest risk for the development of hypertensive kidney disease. In this review, we highlight the established mechanisms of oxidative stress-mediated podocyte damage in proteinuric kidney diseases, with an emphasis on a hypertensive renal injury. We will also consider emerging therapies that have the potential to selectively protect podocytes from redox-related injury.

Acute astrocyte injury in translational imaging mouse model of oxidative stress-mediated cerebrovascular damage

Acute astrocyte injury in translational imaging mouse model of oxidative stress-mediated cerebrovascular damage

Molecular and Cellular Effects of Microplastics and Nanoplastics: Focus on Inflammation and Senescence.

Microplastics and nanoplastics (MNPs) are ubiquitous environmental contaminants. Their prevalence, persistence, and increasing industrial production have led to questions about their long-term impact on human and animal health. This narrative review describes the effects of MNPs on oxidative stress, inflammation, and aging. Exposure to MNPs leads to increased production of reactive oxygen species (ROS) across multiple experimental models, including cell lines, organoids, and animal systems. ROS can cause damage to cellular macromolecules such as DNA, proteins, and lipids. Direct interaction between MNPs and immune cells or an indirect result of oxidative stress-mediated cellular damage may lead to increased production of pro-inflammatory cytokines throughout different MNP-exposure conditions. This inflammatory response is a common feature in the pathogenesis of neurodegenerative, cardiovascular, and other age-related diseases. MNPs also act as cell senescence inducers by promoting mitochondrial dysfunction, impairing autophagy, and activating DNA damage responses, exacerbating cellular aging altogether. Increased senescence of reproductive cells and transfer of MNPs/induced damages from parents to offspring in animals further corroborates the transgenerational health risks of the tiny particles. This review aims to provoke a deeper investigation into the notorious effects these pervasive particles may have on human well-being and longevity.

8-OxodG: A Potential Biomarker for Chronic Oxidative Stress Induced by High-LET Radiation.

Oxidative stress-mediated biomolecular damage is a characteristic feature of ionizing radiation (IR) injury, leading to genomic instability and chronic health implications. Specifically, a dose- and linear energy transfer (LET)-dependent persistent increase in oxidative DNA damage has been reported in many tissues and biofluids months after IR exposure. Contrary to low-LET photon radiation, high-LET IR exposure is known to cause significantly higher accumulations of DNA damage, even at sublethal doses, compared to low-LET IR. High-LET IR is prevalent in the deep space environment (i.e., beyond Earth's magnetosphere), and its exposure could potentially impair astronauts' health. Therefore, the development of biomarkers to assess and monitor the levels of oxidative DNA damage can aid in the early detection of health risks and would also allow timely intervention. Among the recognized biomarkers of oxidative DNA damage, 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-OxodG) has emerged as a promising candidate, indicative of chronic oxidative stress. It has been reported to exhibit differing levels following equivalent doses of low- and high-LET IR. This review discusses 8-OxodG as a potential biomarker of high-LET radiation-induced chronic stress, with special emphasis on its potential sources, formation, repair mechanisms, and detection methods. Furthermore, this review addresses the pathobiological implications of high-LET IR exposure and its association with 8-OxodG. Understanding the association between high-LET IR exposure-induced chronic oxidative stress, systemic levels of 8-OxodG, and their potential health risks can provide a framework for developing a comprehensive health monitoring biomarker system to safeguard the well-being of astronauts during space missions and optimize long-term health outcomes.

Evaluation of Respiratory Toxicity Potential of Acrylamide in Zebrafish: Oxidative Stress Parameters, mRNAs Expression, and Histomorphological Changes in Gills

Anthropogenic contamination of surface water by chemicals is a worldwide concern, which affects human health and aquatic organisms including fish. Acrylamide (ACR), a Neo-Formed Contaminants (NFC) leads to serious toxic effects on the respiratory system of marine inhabitants. The mechanisms underlying ACR-induced oxidative stress and altered mRNA expressions in zebrafish are unclear. The present investigation aimed to evaluate the effects of ACR exposure for 28 days on the activity or level of antioxidant response elements (ARE), mRNA expressions of antioxidant genes and histomorphological changes in the gills of adult zebrafish. The 270 adult zebrafish were randomly allocated into 03 experimental groups viz. control group, T1 group (ACR: 8.5 mg/L) and T2 group (ACR: 17 mg/L). After 28 days of ACR exposure, Superoxide Dismutase (SOD) activity was significantly (p<0.01) decreased in the gills of zebrafish of the T2 group; and no change in Catalase (CAT) activity was observed in both the treatment groups. The levels of reduced Glutathione (GSH) were significantly (p<0.001) decreased and Malondialdehyde (MDA) were significantly (p<0.001) increased in a concentration-dependent manner. The sod and nuclear factor erythroid 2-related factor 2 (nrf2) mRNA expressions were significantly (p<0.001) downregulated in the gills of zebrafish of both treatment groups. Noticeable histomorphological alterations were recorded in the gills of zebrafish of the T2 group. Alterations in ARE activity, mRNA expressions of antioxidant genes and histopathological findings suggest ACR exposure has been shown to produce oxidative stress-mediated damage in the gills of adult zebrafish.

Seabuckthorn pulp extract alleviates UV-B-induced skin photo-damage by significantly reducing oxidative stress-mediated endoplasmic reticulum stress and DNA Damage in human primary skin fibroblasts and Balb/c mice skin.

Skin homeostasis is predominantly compromised by exposure to UV-B irradiation, leading to several physiopathological processes at cellular and tissue levels that deteriorate skin function and integrity. The current study investigated the photo-protective role of seabuckthorn fruit pulp (SBT) extract against UV-B-induced damage in primary human skin fibroblasts (HDFs) and Balb/C mice skin. We subjected HDFs and Balb/C mice to UV-B irradiation and measured multiple cellular damage indicators. We found that UV-B-irradiated HDFs treated with SBT had a considerably greater survival rate than cells exposed to UV-B radiation alone. The UV-B irradiation-induced ROS generation led to the degradation of the extracellular matrix, inflammation, DNA damage, endoplasmic reticulum (ER) stress, and apoptosis. SBT treatment significantly reduced these manifestations. Topical application of SBT alleviated UV-B-induced epidermal thickening, leukocyte infiltration, and degradation of extracellular matrix in Balb/c mice skin. Based on our results, we conclude that SBT has the potential to be developed as a therapeutic/cosmetic remedy for the prevention of skin photo-damage.

Association of catechol-o-methyltransferase gene polymorphism with preeclampsia and biomarkers of oxidative stress: Study protocol for a prospective case-control study in Pakistan.

Preeclampsia is one of the three leading causes of worldwide maternal mortality. Oxidative stress-mediated endothelial damage is expected to be an ultimate common mechanism in the pathophysiology of preeclampsia. The role of bioamines is also well-established in the induction of preeclampsia. This project is aimed to understand the factors which may affect the induction, progression, and aggravation of preeclampsia and oxidative stress during pregnancy. This study will explore the methylation pattern of the Catechol-O-methyltransferase gene to determine its role in the pathogenesis of preeclampsia, association of Val158Met polymorphism with a wide range of oxidative stress biomarkers, major antioxidants vitamins, and blood pressure regulating amines in preeclamptic Pakistani women. In this prospective case-control study, 85 preeclamptic and 85 normotensive pregnant women will be recruited in their third trimesters. DNA will be extracted from peripheral blood and Val158Met polymorphism in the Catechol-O-methyltransferase gene will be examined on PCR amplified product digested with Hin1II (NlaIII) restriction enzyme, further validated by Sanger sequencing. Methylation-sensitive PCR will also be performed. Oxidative stress biomarkers, antioxidant vitamins, bioamines, and catechol-O-methyltransferase levels will be measured by ELISA. The data will be used to correlate maternal and fetal outcomes in both groups. This study will help to identify and understand the multifactorial path and cause-effect relationship of gene polymorphism, oxidative stress biomarkers, major antioxidants vitamins, and blood pressure regulating amines in the pathogenesis and aggravation of preeclampsia in the Pakistani population. The outcome of this project will be particularly helpful in reducing the incidence of preeclampsia and further improving its management.

Lemon Peel Water Extract: A Novel Material for Retinal Health, Protecting Retinal Pigment Epithelial Cells against Dynamin-Related Protein 1-Mediated Mitochondrial Fission by Blocking ROS-Stimulated Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Pathway.

Previous studies showed that NaIO3 can induce oxidative stress-mediated retinal pigment epithelium (RPE) damage to simulate age-related macular degeneration (AMD). Lemon peel is rich in antioxidants and components that can penetrate the blood-retinal barrier, but their role in retinal oxidative damage remains unexplored. Here, we explore the protection of lemon peel ultrasonic-assisted water extract (LUWE), containing large amounts of flavonoids and polyphenols, against NaIO3-induced retinal degeneration. We initially demonstrated that LUWE, orally administered, prevented retinal distortion and thinning on the inner and outer nuclei layers, downregulating cleaved caspase-3 protein expression in RPE cells in NaIO3-induced mice. The effect of LUWE was achieved through the suppression of apoptosis and the associated proteins, such as cleaved PARP and cleaved caspase-3, as suggested by NaIO3-induced ARPE-19 cell models. This is because LUWE reduced reactive oxygen species-mediated mitochondrial fission via regulating p-Drp-1 and Fis1 expression. We further confirmed that LUWE suppresses the expression of p-MEK-1/2 and p-ERK-1/2 in NaIO3-induced ARPE-19 cells, thereby providing the protection described above, which was confirmed using PD98059 and U0126. These results indicated that LUWE prevents mitochondrial oxidative stress-mediated RPE damage via the MEK/ERK pathway. Elucidation of the molecular mechanism may provide a new protective strategy against retinal degeneration.

Do the same chlorinated organophosphorus flame retardants that cause cytotoxicity and DNA damage share the same pathway?

Organophosphorus flame retardants (OPFRs) have been frequently detected with relatively high concentrations in various environmental media and are considered emerging environmental pollutants. However, their biological effect and underlying mechanism is still unclear, and whether chlorinated OPFRs (Cl-OPFRs) cause adverse outcomes with the same molecular initial events or share the same key events (KEs) remains unknown. In this study, in vitro bioassays were conducted to analyze the cytotoxicity, mitochondrial impairment, DNA damage and molecular mechanisms of two Cl-OPFRs. The results showed that these two Cl-OPFRs, which have similar structures, induced severe cellular and molecular damages via different underlying mechanisms. Both tris(2-chloroethyl) phosphate (TCEP) and tris(1-chloro-2-propyl) (TCPP) induced oxidative stress-mediated mitochondrial impairment and DNA damage, as shown by the overproduction of intracellular reactive oxygen species (ROS) and mitochondrial superoxide. Furthermore, the DNA damage caused by TCPP resulted in p53/p21-mediated cell cycle arrest, as evidenced by flow cytometry and real-time PCR. At the cellular and molecular levels, TCPP increased the sub-G1 apoptotic peak and upregulated the p53/Bax apoptosis pathway, possibly resulted in apoptosis associated with its stronger cytotoxicity. Although structurally similar to TCPP, TCEP did not induce mitochondrial impairment and DNA damage by the same KEs. These results provide insight into the toxicity of Cl-OPFRs with similar structures but different mechanisms, which is of great significance for constructing adverse outcome pathways or determining intermediate KEs.

Insulin Ameliorates Neurodegeneration in an Experimental Animal Model of Brain Aging by a Decrease of GFAP Expression and Apoptosis Inhibition

Background: Aging is one of the factors that will cause gradual changes in brain tissue and its destruction. One of the protective factors against aging is insulin. Objectives: Our study investigated insulin's neuroprotective effect by preventing oxidative stress-mediated neuronal damage. Methods: A total of 48 adult male NMRI (the Naval Medical Research Institute) mice were divided into 2 groups: Control and insulin. Insulin was administered intraperitoneally (IP) for 8 weeks to the control group and for 12 weeks to the insulin group. In this study, animals were treated with insulin, and insulin's role in the aging process was evaluated. Then, brain tissue was extracted for evaluation of oxidative stress by assessment of glutathione disulfide (GSH) and reactive oxygen species (ROS) levels, the expression of the glial fibrillary acidic protein (GFAP) as a biomarker for astrogliosis, stereological study, and the real-time polymerase chain reaction (PCR) technique evaluated the level of apoptosis biomarker. Results: The results of stereological parameters show that the volumes of the brain cortex and the number of neurons improved in the insulin group by aging as compared to the control group. The results of real-time PCR showed that the expression level of apoptotic markers decreased in the insulin group compared to the control group. In the insulin group, GSH levels were higher than in the control group, and the control group produced more ROS than the insulin group. As compared with insulin, the control group expressed more GFAP protein and increased the number of glial cells by aging. Conclusions: The results showed that insulin could have neuroprotective effects against aging changes and reduce apoptosis and cell death.

Michelia compressa-Derived Santamarine Inhibits Oral Cancer Cell Proliferation via Oxidative Stress-Mediated Apoptosis and DNA Damage.

The anti-oral cancer effects of santamarine (SAMA), a Michelia compressa var. compressa-derived natural product, remain unclear. This study investigates the anticancer effects and acting mechanism of SAMA against oral cancer (OC-2 and HSC-3) in parallel with normal (Smulow-Glickman; S-G) cells. SAMA selectively inhibits oral cancer cell viability more than normal cells, reverted by the oxidative stress remover N-acetylcysteine (NAC). The evidence of oxidative stress generation, such as the induction of reactive oxygen species (ROS) and mitochondrial superoxide and the depletion of mitochondrial membrane potential and glutathione, further supports this ROS-dependent selective antiproliferation. SAMA arrests oral cancer cells at the G2/M phase. SAMA triggers apoptosis (annexin V) in oral cancer cells and activates caspases 3, 8, and 9. SAMA enhances two types of DNA damage in oral cancer cells, such as γH2AX and 8-hydroxy-2-deoxyguanosine. Moreover, all of these anticancer mechanisms of SAMA are more highly expressed in oral cancer cells than in normal cells in concentration and time course experiments. These above changes are attenuated by NAC, suggesting that SAMA exerts mechanisms of selective antiproliferation that depend on oxidative stress while maintaining minimal cytotoxicity to normal cells.

Antioxidant properties of acteoside against biological systems: Hemoglobin and cardiomyocyte as potential models

Oxidative stress has been shown to be the main cause of protein denaturation and cell death. However, the exact mechanism of antioxidants against oxidative stress-mediated protein damage and cell cytotoxicity remains largely unknown. Therefore, in this paper, the protective effects of acteoside against H2O2-inudced hemoglobin structural changes and cardiomyocyte toxicity as models were determined by different techniques. Fluorescence quenching as well as molecular docking simulation studies showed that acteoside potentially interacted with hemoglobin in a one: one binding mode mediated mainly by the involvement of hydrophobic forces. It was also shown that H2O2 caused significant changes in the structure of hemoglobin as well as heme degradation, reversed by acteoside. Additionally, UV–visible studies exhibited that acteoside decreased the generation of methemoglobin triggered by H2O2. Cellular assays displayed that acteoside could mitigate the cardiomyocyte toxicity induced by H2O2 through regulation of LDH release, generation of reactive oxygen species (ROS) and 3,4-methylenedioxyamphetamine (MDA), mitochondrial membrane potential (MMP) collapse, as well as superoxide dismutase (SOD), catalase (CAT), caspase-9, and caspase-3 activities. In conclusion, acteoside may hold great promise for the control of protein-related disorders as well as cardiovascular diseases.

Engineered Multifunctional Zinc-Organic Framework-Based Aggregation-Induced Emission Nanozyme for Accelerating Spinal Cord Injury Recovery.

Functional recovery following a spinal cord injury (SCI) is challenging. Traditional drug therapies focus on the suppression of immune responses; however, strategies for alleviating oxidative stress are lacking. Herein, we developed the zinc-organic framework (Zn@MOF)-based aggregation-induced emission-active nanozymes for accelerating recovery following SCI. A multifunctional Zn@MOF was modified with the aggregation-induced emission-active molecule 2-(4-azidobutyl)-6-(phenyl(4-(1,2,2-triphenylvinyl)phenyl)amino)-1H-phenalene-1,3-dione via a bioorthogonal reaction, and the resulting nanozymes were denoted as Zn@MOF-TPD. These nanozymes gradually released gallic acid and zinc ions (Zn2+) at the SCI site. The released gallic acid, a scavenger of reactive oxygen species (ROS), promoted antioxidation and alleviated inflammation, re-establishing the balance between ROS production and the antioxidant defense system. The released Zn2+ ions inhibited the activity of matrix metalloproteinase 9 (MMP-9) to facilitate the regeneration of neurons via the ROS-mediated NF-κB pathway following secondary SCI. In addition, Zn@MOF-TPD protected neurons and myelin sheaths against trauma, inhibited glial scar formation, and promoted the proliferation and differentiation of neural stem cells, thereby facilitating the repair of neurons and injured spinal cord tissue and promoting functional recovery in rats with contusive SCI. Altogether, this study suggests that Zn@MOF-TPD nanozymes possess a potential for alleviating oxidative stress-mediated pathophysiological damage and promoting motor recovery following SCI.

A novel A2a adenosine receptor inhibitor effectively mitigates hepatic fibrosis in a metabolic dysfunction-associated steatohepatitis mouse model.

Hepatic fibrosis exacerbates mortality and complications in progressive metabolic dysfunction-associated steatohepatitis (MASH). The role of the adenosine 2A receptor (A2aAR) in hepatic fibrosis within the context of MASH remains uncertain. This study aims to elucidate the involvement of the A2aAR signaling pathway and the efficacy of a novel potent A2aAR antagonist in treating hepatic fibrosis in MASH-induced mice fed a chlorine-deficient, L-amino acid-defined, high fat diet (CDAHFD). A2aAR overexpression in LX-2 cells increased fibrosis markers, whereas the known A2aAR antagonist, ZM241385, decreased these markers. A novel A2aAR antagonist, RAD11, not only attenuated fibrosis progression but also exhibited greater inhibition of the A2aAR signaling pathway compared to ZM241385 in mice with MASH, activated primary hepatocytes, and LX-2 cells. RAD11 exhibited a dual antifibrotic mechanism by targeting both activated HSCs and hepatocytes. Its superior antifibrotic efficacy over ZM241385 in the MASH condition stems from its ability to suppress A2aAR-mediated signaling, inhibit HSC activation, reduce hepatic lipogenesis in hepatocytes, and mitigate lipid accumulation-induced oxidative stress-mediated liver damage. This study has shed light on the relationship between A2aAR signaling and hepatic fibrosis, presenting RAD11 as a potent therapeutic agent for managing MASH and hepatic fibrosis.

Reactive Oxygen Species Damage Bovine Endometrial Epithelial Cells via the Cytochrome C-mPTP Pathway.

After parturition, bovine endometrial epithelial cells (BEECs) undergo serious inflammation and imbalance between oxidation and antioxidation, which is widely acknowledged as a primary contributor to the development of endometritis in dairy cows. Nevertheless, the mechanism of oxidative stress-mediated inflammation and damage in bovine endometrial epithelial cells remains inadequately defined, particularly the molecular pathways associated with mitochondria-dependent apoptosis. Hence, the present study was designed to explore the mechanism responsible for mitochondrial dysfunction-induced BEEC damage. In vivo, the expressions of proapoptotic protein caspase 3 and cytochrome C were increased significantly in dairy uteri with endometritis. Similarly, the levels of proapoptotic protein caspase 3, BAX, and cytochrome C were markedly increased in H2O2-treated BEECs. Our findings revealed pronounced BEEC damage in dairy cows with endometritis, accompanied by heightened expression of cyto-C and caspase-3 both in vivo and in vitro. The reduction in apoptosis-related protein of BEECs due to oxidant injury was notably mitigated following N-acetyl-L-cysteine (NAC) treatment. Furthermore, mitochondrial vacuolation was significantly alleviated, and mitochondrial membrane potential returned to normal levels after the removal of ROS. Excessive ROS may be the main cause of mitochondrial dysfunction. Mitochondrial permeability transition pore (mPTP) blockade by cyclophilin D (CypD) knockdown with CSA significantly blocked the flow of cytochrome C (cyto-C) and Ca2+ to the cytoplasm from the mitochondria. Our results indicate that elevated ROS and persistent opening of the mPTP are the main causes of oxidative damage in BEECs. Collectively our results reveal a new mechanism involving ROS-mPTP signaling in oxidative damage to BEECs, which may be a potential avenue for the clinical treatment of bovine endometritis.

Zinc oxide nanoparticles induce acute lung injury via oxidative stress-mediated mitochondrial damage and NLRP3 inflammasome activation: In vitro and in vivo studies

The widespread application of zinc oxide nanoparticles (ZnO-NPs) brings convenience to our lives while also renders threats to public health and ecological environment. The lung has been recognized as a primary target of ZnO-NPs, however, the detrimental effects and mechanism of ZnO-NPs on the respiratory system have not been thoroughly characterized so far. To investigate the effect of ZnO-NPs on acute lung injury (ALI), Sprague Dawley rats were intratracheally instilled with ZnO-NPs suspension at doses of 1, 2, and 4 mg/kg/day for 3 consecutive days. Our study revealed that ZnO-NPs induced ALI in rats characterized by increased airway resistance, excessive inflammatory response and lung histological damage. In addition, we identified several molecular biomarkers related to the potential mechanism of ZnO-NP-induced ALI, including oxidative stress, mitochondrial damage, and NLRP3 inflammasome activation. The results of in vitro experiments showed that the viability of A549 cells decreased with the increase in ZnO-NPs concentration. Meanwhile, it was also found that ZnO-NP treatment induced the production of ROS, the decrease in mitochondrial membrane potential and activation of NLRP3 inflammasome in A549 cells. Furthermore, to explore the underlying molecular mechanisms of ZnO-NP-induced ALI, N-acetyl-L-cysteine (a ROS scavenger), Cyclosporin A (an inhibitor for mitochondrial depolarization) and Glibenclamide (an inhibitor for NLRP3 inflammasome activity) were used to pre-treat A549 cells before ZnO-NPs stimulation in the in vitro experiments, respectively. The results from this study suggested that ZnO-NP-induced ROS production triggered the accumulation of damaged mitochondria and assembly of NLRP3 inflammatory complex, leading to maturation and release of IL-1β. Moreover, ZnO-NP-induced NLRP3 inflammasome activation was partly mediated by mitochondrial damage. Taken together, our study suggested that ZnO-NPs induced ALI through oxidative stress-mediated mitochondrial damage and NLRP3 inflammasome activation and provided insight into the mechanisms of ZnO-NPs-induced ALI.

The effect of Cornus mas extract on nıcotıne-ınduced oxıdatıve stress and ıntratestıcular damage ın male rats.

The role of oxidative stress in disease pathogenesis has been extensively investigated. Researchers have gathered sufficient evidence related to oxidative stress-mediated intratesticular damage. The aim of this was study to evaluate the effects of Cornus Mas (CM) extract on intratesticular changes in rats exposed to nicotine. Thirty Wistar albino rats were divided into four groups. The groups and the administrated agents for 35 days were as follows; Control group (n=6): 0.9% saline, intraperitoneally; Nicotine group (n=7): 4 mg/kg nicotine, subcutaneous; CM group (n=7): 1000 mg/kg CM extract in 0.5 ml saline, via gavage; Nicotine + CM Group (n=8): 4 mg/kg Nicotine, subcutaneous + 1000 mg/kg CM extract via gavage. One rat each from the groups Nicotine and CM died. In spermatogenetic and histopathological examination, significant positive changes were detected in nicotine + CM group regarding seminal parameters, apoptotic cells, Factor VIII and Johnsen score as compared to nicotine group. Oxidative stress markers were higher in nicotine group as compared to the control group. OSI and MDA levels were found to be reduced in nicotine + CM group than nicotine group. Nicotine induced a significant increase in TNF-α and IL-6 levels compared to the control group; however, CM effectively counteracted this increase. We have shown that nicotine increases testicular damage, causes apoptosis of testicular cells and adversely affects spermatogenesis by increasing inflammation. We concluded that CM extract exerted beneficial effects on spermatogenesis and minimized testicular parenchymal damage, apoptosis and angiogenesis. Rapidly increasing understanding of the complexity of oxidative stress in intratesticular is the key to unlocking the potential of ROS-targeting therapies.

Immunomodulatory Effect of a Polyherbal Formulation (Imusil) on Cyclophosphamide Induced Experimental Animal Model.

In the present study, we investigated the immunomodulatory effect of a polyherbal formulation referred to as Imusil (IM) on cyclophosphamide (CP) induced immunosuppression model. CP induced experimental animal model was used for evaluating the immunomodulatory effect of IM. For the study, animals were divided into four groups. Group I is served as the normal control, group II is treated only with CP, group III is treated with the standard drug, levamisole and group IV is treated with IM. The experimental duration was 30 days. At the end of the study, we had evaluated various parameters such as immune organ index, liver marker enzymes, antioxidants, haematological analysis, Th1/Th2 cytokine balance and humoral immune responses were examined using ELISA kits, T-lymphocyte subsets by flow cytometry, and histopathological analysis of the liver, spleen and thymus by H&E staining. The results obtained from the study revealed that the treatment of immunosuppressed animals with IM significantly (p<0.05) reversed the immune response in a positive manner. Treatment with IM properly shields the immune organs and triggers the cell-mediated and humoral immune responses accordingly. Thus, no significant changes were observed in the haematological parameters. Moreover, IM supplementation helps to boost up the antioxidant activity, thereby preventing oxidative stress-mediated damage, and also protects the liver from the toxicity induced by CP. The results suggest that IM has the ability to counteract the immunosuppressive effect of chemotherapeutic drugs by stimulating the immune system, along with its potent antioxidant and hepatoprotective properties.