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Chemotherapy exhibits numerous side effects in anti-tumour therapy. The clinical experiments indicated that deuterium-depleted water (DDW) monotherapy or in combination with chemotherapy was beneficial in inhibiting cancer development. To further understand the potential mechanism of DDW in cancer therapy, we performed a systematic review. The data from experiments published over the past 15 years were included. PubMed, Cochrane and Web of Science (January 2008 to November 2023) were systemically searched. Fifteen studies qualified for review, including fourteen in vivo and in vitro trials and one interventional trial. The results showed that DDW alone or in combination with chemotherapy effectively inhibited cancer progression in most experiments. The combination treatment enhances the therapeutic effect on cancer compared with chemotherapeutic monotherapy. The inhibitory role of DDW in tumours is through regulating the reactive oxygen species (ROS)-related genes in Kelch-like ECH-associated protein 1 (Keap 1) and Nuclear erythroid 2-related factor 2 (Nrf2) signalling pathways, further controlling ROS production. An abnormal amount of ROS can inhibit the tumour progression. More extensive randomized controlled trials should be conducted to evaluate the accurate effect of DDW in Keap1-Nrf2 signalling pathways. [ABSTRACT FROM AUTHOR]

Background: Particulate matter (PM) is a major air pollutant that affects human health worldwide. PM can pass through the skin barrier, thus causing skin diseases such as heat rash, allergic reaction, infection, or inflammation. However, only a few studies have been conducted on the cytotoxic effects of PM exposure on large-scale animals. Therefore, herein, we investigated whether and how PM affects rhesus macaque skin fibroblasts. Methods: Rhesus macaque skin fibroblasts were treated with various concentrations of PM10 (1, 5, 10, 50, and 100 μg/mL) and incubated for 24, 48, and 72 h. Then, cell viability assay, TUNEL assay, and qRT-PCR were performed on the treated cells. Further, the reactive oxygen species, glutathione, and cathepsin B levels were determined. The MTT assay revealed that PM10 (>50 μg/mL) proportionately reduced the cell proliferation rate. Results: PM10 treatment increased TUNEL-positive cell numbers, following the pro-apoptosis-associated genes (CASP3 and BAX) and tumor suppressor gene TP53 were significantly upregulated. PM10 treatment induced reactive oxidative stress. Cathepsin B intensity was increased, whereas GSH intensity was decreased. The mRNA expression levels of antioxidant enzyme-related genes (CAT, GPX1 and GPX3) were significantly upregulated. Furthermore, PM10 reduced the mitochondrial membrane potential. The mRNA expression of mitochondrial complex genes, such as NDUFA1, NDUFA2, NDUFAC2, NDUFS4, and ATP5H were also significantly upregulated. In conclusion, these results showed that PM10 triggers apoptosis and mitochondrial damage, thus inducing ROS accumulation. These findings provide potential information on the cytotoxic effects of PM10 treatment and help to understand the mechanism of air pollution-induced skin diseases. [ABSTRACT FROM AUTHOR]

The combined toxicological effects of airborne particulate matter (PM), such as PM2.5, and Asian sand dust (ASD), with surrounding chemicals, particularly quinones, on human airway epithelial cells remain underexplored. In this study, we established an in vitro combination exposure model using 1,2-naphthoquinones (NQ) and 9,10-phenanthroquinones (PQ) along with heated PM (h-PM2.5 and h-ASD) to investigate their potential synergistic effects. The impacts of quinones and heated PM on tetrazolium dye (WST-1) reduction, cell death, and cytokine and reactive oxygen species (ROS) production were examined. Results revealed that exposure to 9,10-PQ with h-PM2.5 and/or h-ASD dose-dependently increased WST-1 reduction at 1 μM compared to the corresponding control while markedly decreasing it at 10 μM. Higher early apoptotic, late apoptotic, or necrotic cell numbers were detected in 9,10-PQ + h-PM2.5 exposure than in 9,10-PQ + h-ASD or 9,10-PQ + h-PM2.5 + h-ASD. Additionally, 1,2-NQ + h-PM2.5 exposure also resulted in an increase in cell death compared to 1,2-NQ + h-ASD and 1,2-NQ + h-PM2.5 + h-ASD. Quinones with or without h-PM2.5, h-ASD, or h-PM2.5 + h-ASD significantly increased ROS production, especially with h-PM2.5. Our findings suggest that quinones, at relatively low concentrations, induce cell death synergistically in the presence of h-PM2.5 rather than h-ASD and h-PM2.5 + h-ASD, partially through the induction of apoptosis with increased ROS generation. [ABSTRACT FROM AUTHOR]

Aims: Acetaminophen (APAP) overdose is the most common cause of acute liver failure in the United States. Liver glutathione (GSH) depletion and sustained P-JNK (c-Jun-N-terminal kinase) activation are key modulators in the mechanism leading to hepatic necrosis. GSH depletion is directly related to the consumption of GSH by APAP metabolites N-acetyl-p-benzoquinone imine (NAPQI). We previously noticed that the glutamate–cysteine ligase catalytic subunit (GCLC), the rate-limiting enzyme in GSH synthesis, rapidly decreased at the same time P-JNK increased. Our aims were to determine if JNK was directly responsible for decreased GCLC causing impaired recovery of GSH and if this was an important factor in determining APAP hepatotoxicity. Results: Immunoprecipitation of JNK after APAP identified binding to GCLC. Expression of a site-directed mutated canonical JNK docking site in GCLC was resistant to degradation and led to rapid restoration of GSH and inhibited sustained JNK activation. The JNK-resistant GCLC markedly protected against necrosis and alanine aminotransferase (ALT) elevation. The proteolytic loss of GCLC was abrogated by inhibition of the proteasome, ubiquitination, or calpain. Innovation: Using mutated-GCLC resistant to JNK-induced degradation, the results allowed us to identify impaired GSH recovery as an important contributor to early progression of APAP toxicity after the metabolism of APAP and initial GSH depletion had occurred. Conclusion: Activated JNK interacts directly with GCLC and leads to proteolytic degradation of GCLC. Degradation of GCLC impairs GSH recovery after APAP allowing the continued activation of JNK. Conversely, rapid recovery of GSH inhibits the sustained activation of the mitogen-activated protein (MAP) kinase cascade and dampens APAP toxicity by suppressing the continued activation of JNK. Antioxid. Redox Signal. 38, 1071–1081. [ABSTRACT FROM AUTHOR]

Simple Summary: Excellent quality of early embryonic development contributes to a successful pregnancy. At present, most in vitro cultured embryos can only develop to the blastocyst stage at most, because an in vitro culture (IVC) system cannot replace the physiological environment in vivo. During IVC, excessive accumulated reactive oxygen species in embryos cannot be easily metabolized, which will cause oxidative stress and suppress embryo development. In this study, we found that anti-oxidation capacity of early embryo was improved by adding 6-gingerol to IVC. Moreover, 6-gingerol can also improve blastocyst rate, cell proliferation, mitochondrial function, inhibit cell apoptosis, autophagy, and regulate functional genes expression in blastocyst. These results are helpful to optimize the early embryo culture system, and thus provide a theoretical basis for improving the early embryo quality and the efficiency of subsequent pregnancy. 6-Gingerol, the main active ingredient in ginger, exhibits a variety of biological activities, such as antioxidant, anti-inflammatory, and anticancer activities, and can affect cell development. However, the effects of 6-gingerol on mammalian reproductive processes, especially early embryonic development, are unclear. This study explored whether 6-gingerol can be used to improve the quality of in vitro-cultured porcine embryos. The results showed that 5 μM 6-gingerol significantly increased the blastocyst formation rates of porcine early embryos. 6-Gingerol attenuated intracellular reactive oxygen species accumulation and autophagy, increased intracellular glutathione levels, and increased mitochondrial activity. In addition, 6-gingerol upregulated NANOG, SRY-box transcription factor 2, cytochrome c oxidase subunit II, mechanistic target of rapamycin kinase, and RPTOR independent companion of MTOR complex 2 while downregulating Caspase 3, baculoviral IAP repeat containing 5, autophagy related 12, and Beclin 1. Most importantly, 6-gingerol significantly increased the levels of p-extracellular regulated protein kinase 1/2 while reducing the levels of p-c-Jun N-terminal kinase 1/2/3 and p-p38. These results indicate that 6-gingerol can promote the development of porcine early embryos in vitro. [ABSTRACT FROM AUTHOR]

Abstract Zinc nanostructures (ZnONSs) have attracted much attention due to their morphological, physicochemical, and electrical properties, which were entailed for various biomedical applications such as cancer and diabetes treatment, anti-inflammatory activity, drug delivery. ZnONS play an important role in inducing cellular apoptosis, triggering excess reactive oxygen species (ROS) production, and releasing zinc ions due to their inherent nature and specific shape. Therefore, several new synthetic organometallic method has been developed to prepare ZnO crystalline nanostructures with controlled size and shape. Zinc oxide nanostructures’ crystal size and shape can be controlled by simply changing the physical synthesis condition such as microwave irradiation time, reaction temperature, and TEA concentration at reflux. Physicochemical properties which are determined by the shape and size of ZnO nanostructures, directly affect their biological applications. These nanostructures can decompose the cell membrane and accumulate in the cytoplasm, which leads to apoptosis or cell death. In this study, we reviewed the various synthesis methods which affect the nano shapes of zinc particles, and physicochemical properties of zinc nanostructures that determined the shape of zinc nanomaterials. Also, we mentioned some macromolecules that controlled their physicochemical properties in a green and biological approaches. In addition, we present the recent progress of ZnONSs in the biomedical fields, which will help centralize biomedical fields and assist their future research development.

AimTo investigate the hypothesis that treatment with dimethyl fumarate (DMF) may ameliorate liver ischemia/reperfusion injury (I/RI).MethodsRats were divided into 3 groups: sham, control (CTL), and DMF. DMF (25 mg/kg, twice/d) was orally administered for 2 d before the procedure. The CTL and DMF rats were subjected to ischemia for 1 h and reperfusion for 2 h. The serum alanine aminotransferase (ALT) and malondialdehyde (MDA) levels, adenosine triphosphate (ATP), NO × metabolites, anti-oxidant enzyme expression level, anti-inflammatory effect, and anti-apoptotic effect were determined.ResultsHistological tissue damage was significantly reduced in the DMF group (Suzuki scores: sham: 0 ± 0; CTL: 9.3 ± 0.5; DMF: 2.5 ± 1.2; sham vs CTL, P < 0.0001; CTL vs DMF, P < 0.0001). This effect was associated with significantly lower serum ALT (DMF 5026 ± 2305 U/L vs CTL 10592 ± 1152 U/L, P = 0.04) and MDA (DMF 18.2 ± 1.4 μmol/L vs CTL 26.0 ± 1.0 μmol/L, P = 0.0009). DMF effectively improved the ATP content (DMF 20.3 ± 0.4 nmol/mg vs CTL 18.3 ± 0.6 nmol/mg, P = 0.02), myeloperoxidase activity (DMF 7.8 ± 0.4 mU/mL vs CTL 6.0 ± 0.5 mU/mL, P = 0.01) and level of endothelial nitric oxide synthase expression (DMF 0.38 ± 0.05-fold vs 0.17 ± 0.06-fold, P = 0.02). The higher expression levels of anti-oxidant enzymes (catalase and glutamate-cysteine ligase modifier subunit and lower levels of key inflammatory mediators (nuclear factor-kappa B and cyclooxygenase-2 were confirmed in the DMF group.ConclusionDMF improved the liver function and the anti-oxidant and inflammation status following I/RI. Treatment with DMF could be a promising strategy in patients with liver I/RI.

The polycyclic aromatic hydrocarbon quinone derivative 9,10-phenanthrenequinone (9,10-PQ) is one of the most abundant and toxic components found in diesel exhaust particles (DEPs). These DEPs are created during diesel fuel combustion and are considered the main source of urban air pollution. As 9,10-PQ can produce excessive reactive oxygen species (ROS) through redox cycling, it has been shown to exert potent cytotoxic effects against various cell types. However, the mechanisms underlying this cytotoxicity remain unclear. In this study, we showed that 9,10-PQ exerts cytotoxicity by impairing mitotic progression and spindle assembly in HeLa cells. Exposure to 9,10-PQ impaired spindle assembly and chromosome alignment, resulting in delayed mitotic entry and progression in HeLa cells. Furthermore, 9,10-PQ exposure decreased the CEP192 and p-Aurora A levels at the spindle poles. Notably, these mitotic defects induced by 9,10-PQ were not rescued by scavenging ROS, implying the ROS-independent activity of 9,10-PQ. Therefore, our results provide the first evidence that 9,10-PQ exerts its cytotoxicity through specific inhibition of mitotic progression and spindle assembly, independent of ROS. [ABSTRACT FROM AUTHOR]

Abstract Background Acquired resistance to therapeutic drugs has become an important issue in treating ovarian cancer. Studies have shown that the prevalent chemotherapy resistance (cisplatin, paclitaxel etc.) for ovarian cancer occurs partly because of decreased production of reactive oxygen species within the mitochondria of ovarian cancer cells. Main Body Nuclear erythroid-related factor-2 (Nrf2) mainly controls the regulation of transcription of genes through the Keap1-Nrf2-ARE signaling pathway and protects cells by fighting oxidative stress and defending against harmful substances. This protective effect is reflected in the promotion of tumor cell growth and their resistance to chemotherapy drugs. Therefore, inhibition of the Nrf2 pathway may reverse drug resistance. In this review, we describe the functions of Nrf2 in drug resistance based on Nrf2-associated signaling pathways determined in previous studies. Conclusions Further studies on the relevant mechanisms of Nrf2 may help improve the outcomes of ovarian cancer therapy.

The global application of engineered nanomaterials and nanoparticles (ENPs) in commercial products, industry, and medical fields has raised some concerns about their safety. These nanoparticles may gain access into rivers and marine environments through industrial or household wastewater discharge and thereby affect the ecosystem. In this study, we investigated the effects of silver nanoparticles (AgNPs) and zinc oxide nanoparticles (ZnONPs) on zebrafish embryos in aquatic environments. We aimed to characterize the AgNP and ZnONP aggregates in natural waters, such as lakes, reservoirs, and rivers, and to determine whether they are toxic to developing zebrafish embryos. Different toxic effects and mechanisms were investigated by measuring the survival rate, hatching rate, body length, reactive oxidative stress (ROS) level, apoptosis, and autophagy. Spiking AgNPs or ZnONPs into natural water samples led to significant acute toxicity to zebrafish embryos, whereas the level of acute toxicity was relatively low when compared to Milli-Q (MQ) water, indicating the interaction and transformation of AgNPs or ZnONPs with complex components in a water environment that led to reduced toxicity. ZnONPs, but not AgNPs, triggered a significant delay of embryo hatching. Zebrafish embryos exposed to filtered natural water spiked with AgNPs or ZnONPs exhibited increased ROS levels, apoptosis, and lysosomal activity, an indicator of autophagy. Since autophagy is considered as an early indicator of ENP interactions with cells and has been recognized as an important mechanism of ENP-induced toxicity, developing a transgenic zebrafish system to detect ENP-induced autophagy may be an ideal strategy for predicting possible ecotoxicity that can be applied in the future for the risk assessment of ENPs. [ABSTRACT FROM AUTHOR]

Diabetic retinopathy is a neurovascular complication of diabetes and the main cause of vision loss in adults. Glial cells have a key role in maintenance of central nervous system homeostasis. In the retina, the predominant element is the Müller cell, a specialized cell with radial morphology that spans all retinal layers and influences the function of the entire retinal circuitry. Müller cells provide metabolic support, regulation of extracellular composition, synaptic activity control, structural organization of the blood–retina barrier, antioxidant activity, and trophic support, among other roles. Therefore, impairments of Müller actions lead to retinal malfunctions. Accordingly, increasing evidence indicates that Müller cells are affected in diabetic retinopathy and may contribute to the severity of the disease. Here, we will survey recently described alterations in Müller cell functions and cellular events that contribute to diabetic retinopathy, especially related to oxidative stress and inflammation. This review sheds light on Müller cells as potential therapeutic targets of this disease. [ABSTRACT FROM AUTHOR]

Objectives: Diabetes is an independent risk factor for dementia. Mitochondrial dysfunction is a critical player in diabetes and diabetic complications. The present study aimed to investigate the role of mitochondrial dynamic changes in diabetes-associated cognitive impairment. Methods: Cognitive functions were examined by novel object recognition and T-maze tests. Mice hippocampi were collected for electron microscopy and immunofluorescence examination. Neuron cell line HT22 and primary hippocampal neurons were challenged with high glucose in vitro. Mitotracker-Red CM-H2X ROS was used to detect mitochondrial-derived free radicals. Results: Diabetic mice exhibited memory loss and spatial disorientation. Electron microscopy revealed that diabetic mice had larger synaptic gaps, attenuated postsynaptic density and fewer dendritic spines in the hippocampus. More round-shape mitochondria were observed in hippocampal neurons in diabetic mice than those in control mice. In cultured neurons, high glucose induced a high phosphorylated level of dynamin-related protein 1 (DRP1) and increased oxidative stress, resulting in cell apoptosis. Inhibition of mitochondrial fission by Mdivi-1 and metformin significantly decreased oxidative stress and prevented cell apoptosis in cultured cells. Treatment of Mdivi-1 and metformin restored cognitive function in diabetic mice. Conclusion: Metformin restores cognitive function by inhibiting mitochondrial fission, reducing mitochondrial-derived oxidative stress, and mitigating neuron loss in hippocampi of diabetic mice. The protective effects of metformin shed light on the therapeutic strategy of cognitive impairment. [ABSTRACT FROM AUTHOR]

Objectives: Diabetes is an independent risk factor for dementia. Mitochondrial dysfunction is a critical player in diabetes and diabetic complications. The present study aimed to investigate the role of mitochondrial dynamic changes in diabetes-associated cognitive impairment.Methods: Cognitive functions were examined by novel object recognition and T-maze tests. Mice hippocampi were collected for electron microscopy and immunofluorescence examination. Neuron cell line HT22 and primary hippocampal neurons were challenged with high glucose in vitro. Mitotracker-Red CM-H2X ROS was used to detect mitochondrial-derived free radicals.Results: Diabetic mice exhibited memory loss and spatial disorientation. Electron microscopy revealed that diabetic mice had larger synaptic gaps, attenuated postsynaptic density and fewer dendritic spines in the hippocampus. More round-shape mitochondria were observed in hippocampal neurons in diabetic mice than those in control mice. In cultured neurons, high glucose induced a high phosphorylated level of dynamin-related protein 1 (DRP1) and increased oxidative stress, resulting in cell apoptosis. Inhibition of mitochondrial fission by Mdivi-1 and metformin significantly decreased oxidative stress and prevented cell apoptosis in cultured cells. Treatment of Mdivi-1 and metformin restored cognitive function in diabetic mice.Conclusion: Metformin restores cognitive function by inhibiting mitochondrial fission, reducing mitochondrial-derived oxidative stress, and mitigating neuron loss in hippocampi of diabetic mice. The protective effects of metformin shed light on the therapeutic strategy of cognitive impairment.

Ochratoxin A (OTA), one of the major food contaminating mycotoxins, has been reported to cause renal fibrosis through pyroptosis, but the detailed mechanism of its nephrotoxicity remains to be further investigated. Autophagy can be seen in the physiological and pathological processes of the body, and whether its role is positive or negative has not been fully elucidated. The aim of this paper was to explore the role of autophagic-inflammasomal pathway on pyroptosis caused by low levels of OTA in vitro. The results showed that OTA dose-dependently decreased cell viability in PK-15 cells and the half-maximal inhibitory concentration (IC50) was 5.9 µM. OTA could significantly increase pro-inflammatory cytokines (TNF-α, IL-1β, IL-18, IL-6) expression, induced pyroptosis and NLRP3 inflammasome formation at 1.0–4.0 µM for 48 h according to the results of qPCR, Western blotting, Immunofluorescence staining and morphologic observation. But MCC950 (an inhibitor of NLRP3) treatment or caspase-1 (sicaspase-1) knockdown could restore these changes. Additionally, we further found that reactive oxygen species (ROS) contributed to OTA-induced NLRP3 inflammasome and pyroptosis in PK-15 cells as indicated by Western blotting and immunofluorescence. Besides, we indicated that OTA induced autophagy via AKT/mTOR signaling pathway. And 3-MA (an inhibitor of autophagy) treatment or ATG5 (siATG5) knockdown enhanced ROS levels and NLRP3 inflammasome formation exposed to OTA. Taken together, our results elaborated that ROS/NLRP3-inlflammasome-mediated pyroptosis could be involved in the low levels of OTA-induced nephrotoxicity, which was negatively regulated by autophagy.

The polycyclic aromatic hydrocarbon quinone derivative 9,10-phenanthrenequinone (9,10-PQ) is one of the most abundant and toxic components found in diesel exhaust particles (DEPs). These DEPs are created during diesel fuel combustion and are considered the main source of urban air pollution. As 9,10-PQ can produce excessive reactive oxygen species (ROS) through redox cycling, it has been shown to exert potent cytotoxic effects against various cell types. However, the mechanisms underlying this cytotoxicity remain unclear. In this study, we showed that 9,10-PQ exerts cytotoxicity by impairing mitotic progression and spindle assembly in HeLa cells. Exposure to 9,10-PQ impaired spindle assembly and chromosome alignment, resulting in delayed mitotic entry and progression in HeLa cells. Furthermore, 9,10-PQ exposure decreased the CEP192 and p-Aurora A levels at the spindle poles. Notably, these mitotic defects induced by 9,10-PQ were not rescued by scavenging ROS, implying the ROS-independent activity of 9,10-PQ. Therefore, our results provide the first evidence that 9,10-PQ exerts its cytotoxicity through specific inhibition of mitotic progression and spindle assembly, independent of ROS.

Diabetic retinopathy is a neurovascular complication of diabetes and the main cause of vision loss in adults. Glial cells have a key role in maintenance of central nervous system homeostasis. In the retina, the predominant element is the Müller cell, a specialized cell with radial morphology that spans all retinal layers and influences the function of the entire retinal circuitry. Müller cells provide metabolic support, regulation of extracellular composition, synaptic activity control, structural organization of the blood–retina barrier, antioxidant activity, and trophic support, among other roles. Therefore, impairments of Müller actions lead to retinal malfunctions. Accordingly, increasing evidence indicates that Müller cells are affected in diabetic retinopathy and may contribute to the severity of the disease. Here, we will survey recently described alterations in Müller cell functions and cellular events that contribute to diabetic retinopathy, especially related to oxidative stress and inflammation. This review sheds light on Müller cells as potential therapeutic targets of this disease.

Study Design: Patients who had suffered from acute blunt cervical spinal cord injury (SCI) and admitted our hospital within 24 hours after injury were included in the study.Objective: We compared the respiratory function and serum reactive oxidative stress (ROS) after acute cervical SCI, and tried to find out the valuable predictors of weaning in acute cervical SCI patients.Summary Of Background Data: Ventilation impairment is a major complication of acute cervical SCI. Evidence of oxygen radical formation in secondary injury from animal SCI models demonstrates an immediate post-injury increase in ROS production after SCI. We hypothesis the serum ROS is associated with the severity of patients with acute cervical SCI.Methods: 38 adult patients who had acute cervical SCI and 58 healthy volunteers were enrolled. Respiratory function at admission, at the time of extubation and at 48 hours after extubation, serum oxidative stress, Injury Severity Score (ISS) and Japanese Orthopaedic Association (JOA) score at admission were compared.Results: The most notable predictor of mechanical ventilator > 48 hours was serum thiobarbituric acid-reactive substances (TBARS) level at admission (p = 0.027), and the cut-off value of serum TBARS level was 731.7 μmol/L (sensitivity 87.5% and specificity 78.9%). For the re-ventilation ≤ 5 days, the notable predictors were respiratory function at the time of extubation (maximal inspiratory pressure (MIP), p = 0.040; maximal expiratory pressure (MEP), p = 0.020; and tidal volume (TV), p = 0.036) and serum TBARS level at admission (p = 0.013), the cut-off value of serum TBARS level at admission was 762.3 μmol/L (sensitivity 100% and specificity 90.0%).Conclusions: In this study, respiratory function (MIP, MEP and TV) at the time of extubation can be useful optimal clinical guidelines for weaning and extubation attempts in patients with acute cervical SCI. Serum TBARS level at admission can be a useful predictor for severity in acute cervical SCI patients.Level Of Evidence: 3. [ABSTRACT FROM AUTHOR]

Ying Jiang, Xiaoqin Wang, Daode Hu Department of Clinical Pharmacology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China Abstract: The high incidence of chronic obstructive pulmonary disease (COPD), one of the most prevalent diseases worldwide, has attracted growing attention. Cigarette smoking is considered a major contributory factor in the pathogenesis and progression of COPD due to the tremendous oxidative burden that it causes, which induces an oxidant/antioxidant imbalance. Excessive oxidation induced by the excessive generation of mitochondrial reactive oxygen species disturbs the antioxidant systems and plays an important role in triggering and promoting chronic inflammation of airways. Given that mitochondria is one of the main sites of reactive oxygen species production by the oxidative phosphorylation process, oxidative stress may affect mitochondrial function by changing its structure and morphology and by affecting a series of mitochondrial proteins. In particular, PTEN-induced putative kinase 1/Parkin and p62 play critical roles in mitophagy. During the process, the Akt ubiquitin E3 ligase is an important mediator associated with cigarette smoke exposure-induced pulmonary endothelial cell death and dysfunction. Thus, understanding the underlying mechanisms of the signaling pathway may provide important information regarding the therapeutic treatment of COPD by application of alternative PTEN-induced putative kinase 1 targets or ubiquitin E3 ligase. Keywords: chronic obstructive pulmonary disease, reactive oxidative stress, reactive nitrogen stress, mitochondrial fission/fusion, mitophagy

Dexmedetomidine (DEX), a highly specific and selective α2 adrenergic receptor agonist, has been demonstrated to possess potential cardioprotective effects. However, the mechanisms underlying this process remain to be fully illuminated. In the present study, a myocardial infarction (MI) animal model was generated by permanently ligating the left anterior descending coronary artery in mice. Cardiac function and collagen content were evaluated by transthoracic echocardiography and picrosirius red staining, respectively. Apoptosis was determined by the relative expression levels of Bax and Bcl-2 and the myocardial caspase-3 activity. Additionally, nicotinamide adenine dinucleotide phosphate oxidase (NOX)-derived oxidative stress was evaluated by the relative expression of Nox2 and Nox4, along with the myocardial contents of malondialdehyde (MDA) and superoxide dismutase (SOD) activity. It was demonstrated that intraperitoneal DEX treatment (20 µg/kg/day) improved the systolic function of the left ventricle, and decreased the fibrotic changes in post-myocardial infarction mice, which was paralleled by a decrease in the levels of apoptosis. Subsequent experiments indicated that the restoration of redox signaling was achieved by DEX administration, and the over-activation of NOXs, including Nox2 and Nox4, was markedly inhibited. In conclusion, this present study suggested that DEX was cardioprotective and limited the excess production of NOX-derived ROS in ischemic heart disease, implying that DEX is a promising novel drug, especially for patients who have suffered MI. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) is one of the major long-term complications of diabetes. Lysophosphatidic acid (LPA) signaling has been implicated in renal fibrosis. In our previous study, we found that the LPA receptor 1/3 (LPAR1/3) antagonist, ki16425, protected against DN in diabetic db/db mice. Here, we investigated the effects of a specific pharmacological inhibitor of LPA receptor 1 (LPA1), AM095, on DN in streptozotocin (STZ)-induced diabetic mice to exclude a possible contribution of LPAR3 inhibition. AM095 treatment significantly reduced albuminuria and the albumin to creatinine ratio and significantly decreased the glomerular volume and tuft area in the treated group compared with the STZ-vehicle group. In the kidney of STZ-induced diabetic mice, the expression of LPAR1 mRNA and protein was positively correlated with oxidative stress. AM095 treatment inhibited LPA-induced reactive oxygen species production and NADPH oxidase expression as well as LPA-induced toll like receptor 4 (TLR4) expression in mesangial cells and in the kidney of STZ-induced diabetic mice. In addition, AM095 treatment suppressed LPA-induced pro-inflammatory cytokines and fibrotic factors expression through downregulation of phosphorylated NFκBp65 and c-Jun N-terminal kinases (JNK) in vitro and in the kidney of STZ-induced diabetic mice. Pharmacological or siRNA inhibition of TLR4 and NADPH oxidase mimicked the effects of AM095 in vitro. In conclusion, AM095 is effective in preventing the pathogenesis of DN by inhibiting TLR4/NF-κB and the NADPH oxidase system, consequently inhibiting the inflammatory signaling cascade in renal tissue of diabetic mice, suggesting that LPAR1 antagonism might provide a potential therapeutic target for DN. • AM095 improves kidney function in STZ-induced diabetic mice • AM095 reduces glomerular injury in the kidney of STZ-induced diabetic mice • AM095 suppresses reactive oxygen species production by down-regulating NADPH oxidase and TLR4 protein expression • AM095 suppresses proinflammatory cytokines and fibrotic factors expression by suppressing NF-κB and JNK signaling pathways [ABSTRACT FROM AUTHOR]

[Display omitted] • Isofraxidin reduces pyroptosis in ulcerative colitis (UC) • Isofraxidin upregulates Nrf2, reduces ROS, and alleviated DSS-induced UC. • Isofraxidin may be promising for UC treatment. Ulcerative colitis (UC), a non-specific gastrointestinal disease, is commonly managed with aminosalicylic acids and immunosuppressive agents to control inflammation and relieve symptoms, despite frequent relapses. Isofraxidin is a coumarin compound extracted from traditional Chinese medicine, exhibiting anti-inflammatory and antioxidant properties; however, its alleviating effect on UC remains unclear. Therefore, we investigated the mechanism of isofraxidin in lipopolysaccharide (LPS)-induced cell inflammation in human intestinal epithelial cell (HIEC) and human colorectal adenocarcinoma cells (Caco-2), as well as in dextran sulfate sodium (DSS)-induced UC in mice. We established colitis models in HIEC and Caco-2 cells and mice with LPS and DSS, respectively. Additionally, NLRP3 knockout mice and HIEC cells transfected with NLRP3 silencing gene and ML385 illustrated the role of isofraxidin in pyroptosis and oxidative stress. Data from cells and mice analyses were subjected to one-way analysis of variance or a paired t -test. Isofraxidin significantly alleviated LPS-induced cell inflammation and reduced lactic dehydrogenase release. Isofraxidin also reversed DSS- or LPS-induced pyroptosis in vivo and in vitro , increasing the expression of pyroptosis-related proteins. Moreover, isofraxidin alleviated oxidative stress induced by DSS or LPS, reducing reactive oxidative species (ROS), upregulation nuclear factor erythroid 2–related factor 2 (Nrf2), and promoting its entry into the nucleus. Mechanistically, ML385 reversed the inhibitory effect of isofraxidin on ROS and increased pyroptosis. Isofraxidin can inhibit pyroptosis through upregulating Nrf2, promoting its entry into the nucleus, and reducing ROS, thereby alleviating DSS-induced UC. Our results suggest isofraxidin as a promising therapeutic strategy for UC treatment. [ABSTRACT FROM AUTHOR]

Oxidative stress is one of the major etiologies of ovarian dysfunction, including premature ovarian failure (POF). Previous reports have demonstrated the therapeutic effects of human placenta-derived mesenchymal stem cells (PD-MSCs) in an ovariectomized rat model (OVX). However, their therapeutic mechanism in oxidative stress has not been reported. Therefore, we investigated to profile the exosome of serum and demonstrate the therapeutic effect of PD-MSCs transplantation for the ovary function. We established an OVX model by ovariectomy and PD-MSCs transplantation was conducted by intravenous injection. Additionally, various factors in the exosome were profiled by LC-MS analysis. As a result, the transplanted PD-MSCs were engrafted into the ovary and the existence of antioxidant factors in the exosome. A decreased expression of oxidative stress markers and increased expression of antioxidant markers were shown in the transplantation (Tx) in comparison to the non-transplantation group (NTx) (* p < 0.05). The apoptosis factors were decreased, and ovary function was improved in Tx in comparison to NTx (* p < 0.05). These results suggest that transplanted PD-MSCs restore the ovarian function in an OVX model via upregulated antioxidant factors. These findings offer new insights for further understanding of stem cell therapy for reproductive systems.

Background: Rheumatoid arthritis (RA) has been associated with air pollution, possibly due to the augmentation of inflammatory effects. In this study, we aimed to determine the roles of inflammatory pathways and microRNA involved in the pathogenesis of RA fibroblast-like synoviocytes (FLS) inflammation induced by particulate matter. Methods: The inflammatory mediators, messenger RNAs, microRNAs and their interrelationships were investigated using western blotting, QPCR, ELISA and immunohistochemistry. Results: Particulate matter (PMs) induced an increase in the expression of interleukin-6 (IL-6) and cyclooxygenase-II (COX-II) in RA-FLS and microRNA-137 was found definitely to mediate the inflammatory pathways. PMs-induced generation of reactive oxygen species (ROS) in RA-FLS was attenuated by pretreatment with antioxidants. Nox-dependent ROS generation led to phosphorylation of ERK1/2, p38 and JNK, followed by downregulation of microRNA-137. In vivo studies, the joints of rats exposed to PMs revealed synovial fibroblast inflammation under pathologic examination and the expressions of IL-6 and COX-II were obviously increased. PMs exposure results in activated ROS-mediated mitogen-activated protein kinase (MAPK) signaling pathways and cause increased IL-6 and COX-II through downregulation of hsa-miRNA-137, which lead to inflammation and RA exacerbation. Conclusions: microRNA-137 plays an important role in PMs-induced RA acute exacerbation through MAPK signaling pathways and IL-6/COX-II activation. Targeting these mechanisms can potentially be used to develop new therapeutic strategies and prevention of RA inflammation in the future.

Abstract: Aim: To examine the properties of Schisandrin C as an anti‐inflammatory and antioxidant compound, and whether its characteristics promote mitochondrial biogenesis in human dental pulp cells (HDPCs). Methodology: HDPCs were extracted from fresh third molars and cultured for experiments. Reactive oxidative stress (ROS) and nitric oxide (NO) formation were analysed by a Muse cell analyser. Western blotting and gelatin zymography were used to identify the presence of antioxidants, as well as anti‐inflammatory and mitochondrial biogenesis with specific antibody. An unpaired Student's t‐test was used for statistical analysis. Results: Schisandrin C inhibited lipopolysaccharide‐stimulated inflammatory molecules; interleukin 1 beta, tumour necrosis factor alpha, intracellular adhesion molecule‐1, vascular cell adhesion molecule‐1, matrix metalloproteinase‐2 and ‐9, NO production, ROS formation, nuclear factor kappa B translocation (P < 0.05) through the mitogen‐activated protein kinase pathway. Schisandrin C increased the expression of superoxide dismutase enzymes as well as haem oxygenase‐1 and peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha through the phosphorylated‐protein kinase B (p‐Akt) and nuclear factor erythroid 2‐related factor‐2 pathways (P < 0.05). The anti‐inflammatory and antioxidant properties of Schisandrin C promoted mitochondrial biogenesis. Conclusions: Schisandrin C has the potential to reduce inflammation and oxidation and to promote mitochondrial biogenesis. Therefore, Schisandrin C may be considered for use as an anti‐inflammatory compound for oral inflammation through mitochondrial biogenesis. [ABSTRACT FROM AUTHOR]

Background: Intense exercise has the potential to increase oxidative stress and cause muscle damage. Mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB) are two major regulators of gene transcription in response to oxidative stress in the skeletal muscle. Pure capillarisin (CAP) isolated from Artemisia capillaris Thunberg is known to have antioxidant and anti-inflammatory effects.Hypothesis/purpose: We hypothesized CAP to exert antioxidant activity against exercise-induced oxidative stress and suppress acute inflammatory response. We aimed to investigate skeletal muscle recovery after intense exercise with or without CAP administration.Study Design: Eccentric exercise was conducted to induce muscle damage (C57BL6 mice, 13m/min for 60min downhill running). Mice were divided into four groups (n=6): the rested control, exercised, and exercised with CAP treatments (20mg/kg and 80mg/kg, ip injection 24h prior to exercise) groups.Method: After the intense exercise, mice were sacrificed immediately, and after 24h the gastrocnemius muscles and blood plasma were collected for further study. The DCFH-DA and TBARS assays were conducted for anti-oxidative capacity. Muscle damage markers, creatinine phosphate kinase (CPK) and lactate dehydrogenase (LDH) were investigated at plasma level. Muscle data were examined with H&E staining and microscopy. MAPK and NF-κB pathway, chemokine and cytokine productions were confirmed by western blotting and RT-PCR.Results: From DCFH-DA and TBARS assays, exercise increased the level of ROS production, but these changes were suppressed by CAP treatment. Exercise induced muscle damage by raising the levels of soluble muscle enzymes, such as CPK and LDH. However, this result was improved in CAP-treated groups at plasma level. Exercise activated MAPK (ERK 1/2 and JNK but not p38) and NF-κB (nuclear p50 and p65, and cytosolic p-IκBα) subunits at protein level but CAP attenuated these increase in a dose dependent manner. At the mRNA level, the chemokines CINC-1 and MCP-1, and cytokine IL-6 in gastrocnemius muscle were increased by exercise, whereas CAP suppressed these increase.Conclusion: Overall, our results indicate that CAP, as a single compound, can attenuate muscle damage by exerting antioxidant and anti-inflammatory effects. Thus, CAP is a potential candidate for the muscle protective agent in the future. [ABSTRACT FROM AUTHOR]

A new iridoid glycoside; 6- O- β-D-xylopyranoside-shanzhiside methyl ester ( 1) along with six known compounds; shanzhiside methyl ester ( 2), lamalbid ( 3), geniposidic acid ( 4), theveside ( 5), verbascoside ( 6) and arenarioside ( 7) were isolated from the roots of Lantana montevidensis. The structures of the compounds were determined through 1D and 2D NMR spectroscopic data analysis, HRESIMS, electronic circular dichorism and UPLC-UV/MS method. The total extract, chloroformic ( F1) and aqueous ( F2) fractions together with the isolated compounds were tested for their antimicrobial, antiprotozoal, antiplasmodial, anti-inflammatory, monoamine oxidase inhibition and cell viability activities in addition to free radical scavenging activity using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. The phenylpropanoid compounds ( 6 and 7) resulted in a potent antioxidant activity. Total methanolic extract together with the aqueous fraction ( F2) showed decrease in reactive oxidative stress with 57 and 66%, respectively, while the chloroformic fraction ( F1), together with the total methanolic extract, showed a decrease in iNOS with IC values 5 and 30 μg/mL, respectively. Compounds 1, 2, 3, 6, and 7 showed inhibition in the reactive oxidative stress with values 50, 60, 57, 63, and 52%, respectively. Both F1 and F2 fractions demonstrated measurable inhibition of MCF-7 breast cancer cell growth, with IC value 0.3 mg/mL. Compounds 2 and 7 showed mild monoamine oxidase inhibition. None of the tested compounds showed antimicrobial, antiplasmodial or antiprotozoal activity. [ABSTRACT FROM AUTHOR]

Oxidative stress is known to contribute to insulin resistance in diabetes, however the mechanism is not clear. Here we show that reactive oxygen species (ROS) could reprogram the glucose metabolism through upregulating the pentose pathway so as to induce insulin resistance in type 2 diabetes (T2DM). By using streptozotocin-high fat diet (STZ-HFD) induced T2DM in rats, we show that diabetic rats exhibited high level of oxidative stress accompanied with insulin resistance. Hypoxia inducible factor (HIF-1α) protein expression as well as its downstream target glucokinase (GK), were upregulated; The glycogen synthesis increased accordingly; However the glycolysis was inhibited as indicated by decreased phosphofructokinase-1 (PFK-1), pyruvate kinase (PK), phospho-PFK-2/PFK-2 (p-PFK-2/PFK-2) ratio, lactate dehydrogenase (LDH) and pyruvate dehydrogenase kinase (PDK); Pyruvate dehydrogenase (PDH) which promotes pyruvate to generate acetyl-CoA declined as well. While phospho-acetyl-CoA carboxylase/acetyl-CoA carboxylase (p-ACC/ACC) ratio increased, meaning that lipid beta-oxidation increased. The pentose pathway was activated as indicated by increased G6PD activity and NADPH level. Our results suggest that diabetic rats countervail ROS stress through increasing pentose pathway, and reprogram the energy metabolic pathway from glycolysis into lipid oxidation in order to compensate the ATP requirement of the body, which causes insulin resistance. [ABSTRACT FROM AUTHOR]

Aldosterone has been recognized as a risk factor for the development of chronic kidney disease (CKD). Studies have indicated that enhanced activation of epidermal growth factor receptor (EGFR) is associated with the development and progression of renal fibrosis. But if EGFR is involved in aldosterone-induced renal fibrosis is less investigated. In the present study, we examined the effect of erlotinib, an inhibitor of EGFR tyrosine kinase activity, on the progression of aldosterone-induced renal profibrotic responses in a murine model underwent uninephrectomy. Erlotinib-treated rats exhibited relieved structural lesion comparing with rats treated with aldosterone alone, as characterized by glomerular hypertrophy, mesangial cell proliferation and expansion. Also, erlotinib inhibited the expression of TGF-β, α-SMA and mesangial matrix proteins such as collagen Ⅳ and fibronectin. In cultured mesangial cells, inhibition of EGFR also abrogated aldosterone-induced expression of extracellular matrix proteins, cell proliferation and migration. We also demonstrated that aldosterone induced the phosphorylation of EGFR through generation of ROS. And the activation of EGFR resulted in the phosphorylation of ERK1/2, leading to the activation of profibrotic pathways. Taken together, we concluded that aldosterone-mediated tissue fibrosis relies on ROS induced EGFR/ERK activation, highlighting EGFR as a potential therapeutic target for modulating renal fibrosis. [ABSTRACT FROM AUTHOR]

Cytochrome P450 monooxygenases (P450), widely distributed multifunctional enzymes, that play an important role in the oxidative metabolism of endogenous compounds and xenobiotics. Studies have found that these enzymes show peroxidase-like activity and may thus be involved in protecting organisms against reactive oxygen species (ROS). In this work, Apis cerana cerana was used to investigate the molecular mechanisms of P450 family genes in resisting ROS damage. A cytochrome P450 gene was isolated, AccCYP336A1 . The open reading frame (ORF) of AccCYP336A1 is 1491 bp in length and encodes a predicted protein of 496 amino acids. The obtained amino acid sequence of AccCYP336A1 shared a high sequence identity with homologous proteins and contained the highly conserved features of this protein family. Quantitative real-time PCR (qRT-PCR) analysis showed that AccCYP336A1 was present in some fast developmental stages and had a higher expression in the epidermis than in other tissues. Additionally, the expression levels of AccCYP336A1 were up-regulated by cold (4 °C), heat (42 °C), ultraviolet (UV) radiation, H 2 O 2 and pesticide (thiamethoxam, deltamethrin, methomyl and phoxim) treatments. These results were confirmed by the western blot assays. Furthermore, the recombinant AccCYP336A1 protein acted as an antioxidant that resisted paraquat-induced oxidative stress. Taken together, these results suggest that AccCYP336A1 may play a very significant role in antioxidant defense against ROS damage. [ABSTRACT FROM AUTHOR]

Oxidative stress was studied in terms of reactive oxygen species (ROS) in superoxide dismutase deficient E. coli IM303 (I4) carrying pYGE and pUC 19 vector in a bioreactor to investigate cultural characteristics of the cells. The maximum specific growth rate was found for both cultures and the parameters were evaluated with Gompertz equation. The yield of pYGE was 1.5 times higher than that of the cells carrying pUC 19, indicating that the cell carrying pYGE can grow effectively under an oxidative stress condition. It was also found that the DO values were varied with pUC19 than pYGE and the ROS content of pUC19 was found to be higher than pYGE.

Abstract: Despite considerable research to develop carbon based materials for biomedical applications, the toxicity of carbon remains a major concern. In order to address this issue as well as to investigate the cell fate processes of neural cells from the perspective of neural tissue engineering applications, the in vitro cytocompatibility of polyacrylonitrile (PAN) derived continuous carbon nanofibers and PAN derived carbon thin films were investigated both quantitatively and qualitatively using in vitro biochemical assays followed by extensive flow cytometry analysis. The experimental results of Schwann cell fate, i.e. cell proliferation, cell metabolic activity and cell apoptosis on amorphous carbon substrates are discussed in reference to the time dependent evolution of intracellular oxidative stress. Apart from providing evidence that an electrospun carbon nanofibrous substrate can physically guide the cultured Schwann cells, this study suggested that continuous carbon nanofibers and amorphous carbon films are not cytotoxic in vitro and do not significantly induce apoptosis of Schwann cells, but in fact even facilitate their proliferation and growth. [Copyright &y& Elsevier]

Abstract: Trichothecin, one of fungal toxins which were encountered in food and in the environment, seriously threatens human and animal health. It has been shown that trichothecin changed the morphology of cellular mitochondria. However, the molecular mechanism remains unknown. Here we found that cell viability was attenuated by trichothecin. Features of apoptosis such as homosomal condensation and inter nucleosomal fragmentation were observed. In consistence with the elevated apoptosis rate, expression of anti-apoptotic protein Bcl-2 was diminished and expression of proapoptotic protein Bax was enhanced at mRNA levels. Furthermore, expression of caspase-9 and activity of caspase-3 were increased after the treatment of trichothecin. Accordingly, the mitochondrial membrane potential (∆Ψm) was decreased in a dose-dependent manner. And Ca2+ overload was induced by trichothecin, followed by the generation of reactive oxygen species (ROS). Collectedly, our results suggested that apoptosis induced by trichothecin is mediated by caspase-9 activation and the decrement of mitochondrial function resulted from the overloaded calcium and ROS production. [Copyright &y& Elsevier]

Abstract: Signal transducers and activators of transcription 3 (Stat3) is a transcription factor expressed in many cell types including osteoblasts, osteocytes, and osteoclasts. STAT3 mutations cause a rare human immunodeficiency disease that presents reduced bone mineral density and recurrent pathological fractures. To investigate the role of Stat3 in load-driven bone metabolism, two strains of osteoblast/osteocyte-selective Stat3 knockout (KO) mice were generated. Compared to age-matched littermate controls, this selective inactivation of Stat3 significantly lowered bone mineral density (7–12%, p<0.05) as well as ultimate force (21–34%, p<0.01). In ulna loading (2.50–2.75N with 120 cycles/day at 2Hz for 3 consecutive days), Stat3 KO mice were less responsive than littermate controls as indicated by reduction in relative mineralizing surface (rMS/BS, 47–59%, p<0.05) and relative bone formation rate (rBFR/BS, 64–75%, p<0.001). Furthermore, inactivation of Stat3 suppressed load-driven mitochondrial activity, which led to an elevated level of reactive oxygen species (ROS) in cultured primary osteoblasts. Taken together, the results support the notion that the loss-of-function mutation of Stat3 in osteoblasts and osteocytes diminishes load-driven bone formation and impairs the regulation of oxidative stress in mitochondria. [Copyright &y& Elsevier]

Abstract: Parkin plays an important role in the pathogenesis of Parkinson''s disease. We previously described that Nrdp1, a RING-finger ubiquitin E3 ligase, interacted with Parkin by the yeast two-hybrid assay and by co-immunoprecipitation. Here we further demonstrated that overexpression of Nrdp1 significantly reduced the endogenous Parkin level in an Nrdp1 dosage-dependent and proteasome-dependent manner. More importantly, Nrdp1 ubiquitinated Parkin and catalyzed the poly-ubiquitin chains on Parkin in vitro as well as in cells, indicating Parkin is an Nrdp1 substrate. In addition, we demonstrated that overexpression of Nrdp1 increased the production of reactive oxygen species (ROS), which was abrogated by co-expression of Parkin. Conversely, suppression of Nrdp1 by shRNA conferred SH-SY5Y cells a lower ROS level. Together, we provided evidence that interactions between Nrdp1 and Parkin negatively regulated Parkin level and affected ROS production, suggesting that Nrdp1 may play a role in Parkinson''s disease. [Copyright &y& Elsevier]

The objective of this study was to evaluate the cardiac toxicity induced by carboplatin, a second generation platinum-containing anti-cancer drug, and to test whether pravastatin can reduce this cardio-toxicity. In the present study, infusion of carboplatin (100 mg/kg) to mice resulted in decreased survival rates and abnormal cardiac histology, concomitant with increased cardiac apoptosis. In addition, treatment of cultured rat cardiomyocytes with carboplatin (100 μM for 48 h) caused marked apoptosis and increased caspase-3, -9, and cytochrome C, but decreased BCL-XL protein expression, and this was inhibited by reactive oxygen species (ROS) scavenger n-acetylcysteine. Furthermore, pretreatment of cardiomyocytes with pravastatin (20 μM) before carboplatin exposure significantly attenuated apoptosis and decreased caspase-3, -9, cytochrome C activity. Lastly, mice pre-treated with pravastatin before carboplatin treatment showed improved survival rate and cardiac function, with reduced cardiomyocyte apoptosis via activating Akt and restoring normal mitochondrial HAX-1 in heart tissue. In summary, our results show that carboplatin can induce cardiotoxicity in vivo and in cultured cells via a mitochondrial pathway related to ROS production, whereas pravastatin administration can reduce such oxidative stress thus prevented cardiac apoptosis. Therefore, pravastatin can be used as a cytoprotective agent prior to carboplatin chemotherapy. [ABSTRACT FROM AUTHOR]

Abstract: Octachlorostyrene (OCS) is a persistent and bioaccumulative toxicant (PBT) that is a halogenated aromatic compound. OCS belongs to the primary level I group chemicals designated by the US Environmental Protection Agency, which are the most concerning chemicals among the PBTs. It is known that OCS has never been commercially used but has been widely distributed in the environments. Although OCS has been occasionally measured in human samples as well as environmental samples such as water, soil, sediment, fishes, and marine mammals, the impact of OCS on human health is still unclear. It is assumed that the toxicities of OCS follow the other chlorinated chemicals, like hexachlorobenzene, and there is also possibility to be metabolized to generate radicals. In this study, cell toxicity and induction of reactive oxygen species (ROS) by OCS (6.25, 12.5, 25, 50μM) were studied in cultured human Chang liver cells. Exposure of cultured cells to OCS led to cell death, ROS increase, and cytosolic caspase-3 activation. ROS increase was related to the decreased level of GSH. Chromatin fragmentation and condensation were also shown in OCS-treated cells. These results suggest the toxicity in the human Chang liver cells by OCS may be induced through the apoptotic processes. [Copyright &y& Elsevier]

Ochratoxin A (OTA), one of the major food contaminating mycotoxins, has been reported to cause renal fibrosis through pyroptosis, but the detailed mechanism of its nephrotoxicity remains to be further investigated. Autophagy can be seen in the physiological and pathological processes of the body, and whether its role is positive or negative has not been fully elucidated. The aim of this paper was to explore the role of autophagic-inflammasomal pathway on pyroptosis caused by low levels of OTA in vitro. The results showed that OTA dose-dependently decreased cell viability in PK-15 cells and the half-maximal inhibitory concentration (IC 50) was 5.9 µM. OTA could significantly increase pro-inflammatory cytokines (TNF-α, IL-1β, IL-18, IL-6) expression, induced pyroptosis and NLRP3 inflammasome formation at 1.0–4.0 µM for 48 h according to the results of qPCR, Western blotting, Immunofluorescence staining and morphologic observation. But MCC950 (an inhibitor of NLRP3) treatment or caspase-1 (sicaspase-1) knockdown could restore these changes. Additionally, we further found that reactive oxygen species (ROS) contributed to OTA-induced NLRP3 inflammasome and pyroptosis in PK-15 cells as indicated by Western blotting and immunofluorescence. Besides, we indicated that OTA induced autophagy via AKT/mTOR signaling pathway. And 3-MA (an inhibitor of autophagy) treatment or ATG5 (siATG5) knockdown enhanced ROS levels and NLRP3 inflammasome formation exposed to OTA. Taken together, our results elaborated that ROS/NLRP3-inlflammasome-mediated pyroptosis could be involved in the low levels of OTA-induced nephrotoxicity, which was negatively regulated by autophagy. [Display omitted] • Low levels of OTA treatment elevated expression of pro-inflammatory cytokines • OTA induced ROS/NLRP3-inflammasome-mediated pyroptosis in PK-15 cells. • Autophagy alleviated OTA-induced pyroptosis through negatively regulating the ROS/NLRP3 inflammasome pathway. [ABSTRACT FROM AUTHOR]

The increase in worldwide trade has caused the quality maintenance of commercialized agriproducts to be crucial in keeping its economic value. In recent years, methyl bromide (MB) has been used dominantly during quarantine and pre-shipment, despite it being an environmental hazard with global repercussions. Through this study, it was shown that Arabidopsis thaliana 's 2 h exposure to the MB treatment displayed no signs of phytotoxicity, whereas its 4 h exposure significantly interfered with growth. The transcriptomic analysis found the molecular modifications in A. thaliana after the MB fumigation with the up-regulation of genes specifically relative to the abiotic and oxidative stress, and the down-regulation of auxin transporter genes. Some important gene expressions were verified by RT-qPCR and their expression patterns were similar. Oxidative stresses via the reactive oxygen species (ROS) in relation to MB phytotoxicity were confirmed with the increased malondialdehyde in MB-4h-treated A. thaliana. Uneven distribution of auxins via lower expression of auxin transporter genes was also determined using UPLC-ESI-QqQ MS. Application of two ROS scavengers such as N -acetyl-cysteine and L -glutathione minimized MB phytotoxic effect in A. thaliana. Therefore, MB caused severe oxidative stress, and alternatives regarding the use of MB should be considered. [Display omitted] • MB, an ozone-depleting substance, has been used as a vital fumigant in quarantine. • MB phytotoxicity was evaluated using A. thaliana to understand a molecular mechanism. • The 4 h-MB fumigation at 40 mg/L caused severe phytotoxicity in all evaluation indicators. • Transcriptomic analysis revealed that ROS and auxin distribution are strongly related to phytotoxicity. [ABSTRACT FROM AUTHOR]

Oxidative stress is one of the major etiologies of ovarian dysfunction, including premature ovarian failure (POF). Previous reports have demonstrated the therapeutic effects of human placenta-derived mesenchymal stem cells (PD-MSCs) in an ovariectomized rat model (OVX). However, their therapeutic mechanism in oxidative stress has not been reported. Therefore, we investigated to profile the exosome of serum and demonstrate the therapeutic effect of PD-MSCs transplantation for the ovary function. We established an OVX model by ovariectomy and PD-MSCs transplantation was conducted by intravenous injection. Additionally, various factors in the exosome were profiled by LC-MS analysis. As a result, the transplanted PD-MSCs were engrafted into the ovary and the existence of antioxidant factors in the exosome. A decreased expression of oxidative stress markers and increased expression of antioxidant markers were shown in the transplantation (Tx) in comparison to the non-transplantation group (NTx) (* p < 0.05). The apoptosis factors were decreased, and ovary function was improved in Tx in comparison to NTx (* p < 0.05). These results suggest that transplanted PD-MSCs restore the ovarian function in an OVX model via upregulated antioxidant factors. These findings offer new insights for further understanding of stem cell therapy for reproductive systems. [ABSTRACT FROM AUTHOR]

Background: Rheumatoid arthritis (RA) has been associated with air pollution, possibly due to the augmentation of inflammatory effects. In this study, we aimed to determine the roles of inflammatory pathways and microRNA involved in the pathogenesis of RA fibroblast-like synoviocytes (FLS) inflammation induced by particulate matter. Methods: The inflammatory mediators, messenger RNAs, microRNAs and their interrelationships were investigated using western blotting, QPCR, ELISA and immunohistochemistry. Results: Particulate matter (PMs) induced an increase in the expression of interleukin-6 (IL-6) and cyclooxygenase-II (COX-II) in RA-FLS and microRNA-137 was found definitely to mediate the inflammatory pathways. PMs-induced generation of reactive oxygen species (ROS) in RA-FLS was attenuated by pretreatment with antioxidants. Nox-dependent ROS generation led to phosphorylation of ERK1/2, p38 and JNK, followed by downregulation of microRNA-137. In vivo studies, the joints of rats exposed to PMs revealed synovial fibroblast inflammation under pathologic examination and the expressions of IL-6 and COX-II were obviously increased. PMs exposure results in activated ROS-mediated mitogen-activated protein kinase (MAPK) signaling pathways and cause increased IL-6 and COX-II through downregulation of hsa-miRNA-137, which lead to inflammation and RA exacerbation. Conclusions: microRNA-137 plays an important role in PMs-induced RA acute exacerbation through MAPK signaling pathways and IL-6/COX-II activation. Targeting these mechanisms can potentially be used to develop new therapeutic strategies and prevention of RA inflammation in the future. [ABSTRACT FROM AUTHOR]

Background: Gomisin A is a lignan isolated from the hexane of Schisandra chinensis fruit extract with antioxidant properties. Oxidative stress mediated by high glucose is one of the major complications of diabetes mellitus.Purpose: This study investigates the role of gomisin A in osteoblast differentiation under high glucose-induced oxidative stress in MC3T3 E1 cells and determines its relationship with heme oxygenase-1 (HO-1) and mitochondrial biogenesis.Methods: MC3T3 E1 cells were treated by gomisin A following induced by high glucose levels and glucose oxidase to investigate the inhibitory effect of gomisin A against high glucose oxidative stress. Western blot analysis, alizarin red staining, alkaline phosphatase (ALP) activity, analysis of reactive oxygen species (ROS) and confocal microscopy were used to determine mitochondrial biogenesis, oxidative stress, osteoblast differentiation and mineralization. To analyze the role of HO-1, the MC3T3 E1 cells were treated with the HO-1 inhibitor zinc protoporphyrin IX (ZnPP).Results: Gomisin A enhanced the expression of HO-1, increased mitochondrial biogenesis factors (peroxisome proliferator-activated receptor gamma coactivator 1-alpha, nuclear respiratory factor-1, and mitochondrial transcription factor A), antioxidant enzymes (copper-zinc superoxide dismutases and manganese superoxide dismutase), osteoblast differentiation molecules (bone morphogenic protein-2/7, osteoprotegerin and Runt-related transcription factor-2) and mineralization by upregulation of ALP and alizarin red staining, which were decreased by ZnPP and high glucose oxidative stress. Similarly, gomisin A inhibited ROS which was increased by ZnPP and the high glucose-mediated oxidative stress.Conclusions: The findings demonstrated the antioxidative effects of gomisin A, and its role in mitochondrial biogenesis and osteoblast differentiation. It potentially regulated osteoblast differentiation under high glucose-induced oxidative stress via upregulation of HO-1 and maintenance of mitochondrial homeostasis. Thus, gomisin A may represent a potential therapeutic agent for prevention of bone fragility fractures and implant failure triggered by diabetes. [ABSTRACT FROM AUTHOR]