Production Of Reactive Oxidative Stress Research Articles

Euphorbiasteroid Induces Apoptosis as Well as Autophagy through Modulating SHP-1/STAT3 Pathway in Hepatocellular Carcinoma Cells.

Euphorbiasteroid (EPBS) has gained attention for its activity against human lung cancer and sarcoma; however, its impact on hepatocellular carcinoma has not yet been elucidated. Here, we investigated the cytotoxic effect of EPBS on human hepatocellular carcinoma (HCC) cells. We found that EPBS induced both apoptosis and autophagy in HCC cells. Additionally, we observed that EPBS treatment suppressed the constitutive as well as the inducible activation of a signal transducer and activator of transcription 3 (STAT3) protein expression. Moreover, EPBS promoted the expression of SHP-1 protein and the production of reactive oxidative stress (ROS). Furthermore, the knockdown of SHP-1 by siRNA transfection reversed the effects of EPBS, which have inductive effects related to apoptosis and autophagy. Therefore, EPBS can potentially function as an anti-cancer agent by inducing apoptosis and autophagy when targeting the SHP-1/STAT3 pathway.

Phthalate acid esters contribute to the cytotoxicity of mask leachate: Cell-based assay for toxicity assessment

After the COVID-19 outbreak, masks have become an essential part of people lives. Although several studies have been conducted to determine the release of hazardous substances from masks, how their co-presence poses a potential exposure risk to human health remains unexplored. In this study, we quantitatively compared the leaching of substances from six different common types of masks, including phthalate acid esters (PAEs), metals, and microplastics (MPs), and comprehensively evaluated the potential cytotoxicity of different leachates. MPs smaller than 3 µm were quantified by Py-GC-MS, and reusable masks showed greater releasing potentials up to 1504 µg/g. We also detected the prevalence of PAEs in masks, with the highest release reaching 42 μg/g, with dibutyl phthalate (DBP), diisobutyl phthalate (DiBP) and bis (2-ethylhexyl) phthalate (DEHP) being the predominant types. Moreover, the antimicrobial cloth masks released 173.0 µg of Cu or 4.5 µg of Ag, representing 2.7% and 0.04% of the original masks, respectively. Our cell-based assay results demonstrated for the first time that mask leachate induced nuclear condensation with DNA damage, and simultaneously triggered high levels of glutathione and reactive oxidative stress production, which exacerbated mitochondrial fragmentation, eventually leading to cell death. Combined with substance identification and correlation analysis, PAEs were found to be the contributors to cytotoxicity. Masks containing Cu or Ag led to acidification of lysosomes and alkalinization of cells. These results strongly suggested that the levels of PAEs in the production of regulatory masks should be strictly controlled.

Effect of dexmedetomidine administration on malondialdehyde levels in lower extremity surgery using tourniquets

Introduction: The use of a tourniquet in lower extremity surgery can help surgeons optimize the surgical field. However, tourniquet inflation may create ischemic conditions in the extremity, and tourniquet deflation may pose a risk of ischemic reperfusion injury (IRI). Ischemic conditions can increase the production of reactive oxidative stress (ROS), which, if it occurs simultaneously with IRI, will produce malondialdehyde (MDA), a toxic metabolite. The prolonged use of tourniquets can cause damage to the local skin tissue at the tourniquet inflation and poses a risk of IRI to other organs. This study aims to observe the effect of dexmedetomidine administration on malondialdehyde levels in lower extremity surgery using tourniquets. Methods: This study is an observational study with a prospective cohort design to measure malondialdehyde levels in lower extremity surgery using tourniquets. When the data were normally distributed, a statistical test was performed using an independent sample t-test to compare the demographic data of the two groups. To compare the results of the observation after the induction, 15 and 120 minutes after the release of the tourniquets, a repeated measures ANOVA was performed when the data were normally distributed. Then, to examine the correlation between variables, Spearman's correlation test was applied when the data were not normally distributed. Results: In this study, almost all the subjects in the isoflurane and dex-iso groups had no significantly different characteristics, and also showed no effect of tourniquet pressure on malondialdehyde levels. Conclusion: Based on statistical analysis and discussion of the effect of dexmedetomidine administration on malondialdehyde levels in lower extremity surgery using tourniquets, it can be concluded that there was no statistically significant effect of dexmedetomidine administration on malondialdehyde levels in lower extremity surgery using tourniquets.

Platycodin D stimulates AMPK activity to inhibit the neurodegeneration caused by reactive oxygen species-induced inflammation and apoptosis.

Alzheimer's disease (AD) was considered to be a neurodegenerative disease that caused cognitive impairment. Reactive Oxidative stress (ROS) was considered to be one of a major cause of the onset and progression of AD. Platycodin D (PD), a representative saponin from Platycodon grandiflorum, has conspicuous antioxidant activity. However, whether PD could protect nerve cell against oxidative injury remains unknown. This study investigated the regulatory effects of PD on neurodegeneration caused by ROS. To determine whether PD could play its own antioxidant role in neuronal protection. First, PD(2.5, 5mg/kg) ameliorated the memory impairment induced by AlCl3 (100mg/kg) combined with D-galactose (D-Gal) (200mg/kg) in mice, using the radial arm maze (RAM) test, and neuronal apoptosis in the hippocampus was evaluated by hematoxylin and eosin staining (HE). Next, the effects of PD (0.5, 1, and 2μM) on okadaic-acid (OA) (40nM) -induced apoptosis and inflammation of HT22cells were investigated. Mitochondrial ROS production was measured by fluorescence staining. The potential signaling pathways were identified through Gene Ontology enrichment analysis. The role of PD in regulating AMP-activated protein kinase (AMPK) was assessed using siRNA silencing of genes and an ROS inhibitor. In vivo, PD improved memory in mice, and recovered the morphological changes of brain tissue and nissl bodies. In vitro experiment, PD increased cell viability (p<0.01; p<0.05;p<0.001), decreased apoptosis (p<0.01), reduced excessive ROS and MDA, rised SOD and CAT content(p<0.01; p<0.05). Morover, it can block the inflammatory response caused by ROS. Be important, PD strengthen antioxidant ability by elevating AMPK activation both in vivo and in vitro. Furthermore, molecular docking suggested a good likelihood of PD-AMPK binding. AMPK activity is vital for the neuroprotective effect of PD, suggesting that PD may be a potential pharmaceutical agent to treat ROS-induced neurodegeneration.

Abstract 14966: Mechanisms of Protection From Radiation-Induced Endothelial Injury by Statins

Introduction: The incidental use of statins during radiation therapy has been associated with a decreased risk of long-term atherosclerotic cardiovascular (CV) disease. However, the mechanisms by which statins protect the vasculature from irradiation injury remain poorly understood. Hypothesis: Establish the mechanisms by which lipophilic and hydrophilic statins preserve endothelial function after irradiation. Methods: Cultured human coronary and umbilical vein endothelial cells irradiated with 4 Gy and mice on day 1 and 10 after head and neck irradiation with 12 Gy were assessed for endothelial dysfunction, nitric oxide and reactive oxidative stress production and various mitochondrial phenotypes. Results: Pretreatment of mice with pravastatin or atorvastatin prevented the loss of endothelium-dependent relaxation on day 1 and 10 after head and neck irradiation. Both statins inhibit the loss of nitric oxide, and the increase in cytosolic reactive oxidative stress in endothelial cells. However, only pravastatin blocked mitochondrial superoxide production, mitochondrial DNA damage and loss of electron complex activity. In contrast to atorvastatin, pravastatin also significantly reduced the expression of inflammatory markers TNF-α, NFκB p65 and p50 after irradiation. Conclusions: Our findings provide mechanistic underpinnings for the vasoprotective effects of statins after irradiation. While lipo- and hydrophilic statins shield from endothelial dysfunction after irradiation, pravastatin also prevents mitochondrial injury and decreases an inflammatory response by actions in mitochondria. A correlation with clinical studies is necessary to determine whether hydrophilic statins, such as pravastatin reduce the risk of CV disease after irradiation in humans to a greater extent than lipophilic statins.

Adiponectin Ameliorates Hyperglycemia-Induced Retinal Endothelial Dysfunction, Highlighting Pathways, Regulators, and Networks.

BackgroundThe pathophysiology of diabetic retinopathy (DR) is multifaced. A low level of circulating adiponectin (APN) in type 2 diabetes is associated with microvasculature complications, and its role in the evolution of DR is complex.AimThis study is designed to explore the potential impact of APN in the pathogenesis of DR, linking the changes in cellular and biological processes with the pathways, networks, and regulators involved in its actions.MethodsHuman microvascular retinal endothelial cells (HMRECs) were exposed to 30mM glucose (HG) and treated with globular adiponectin (30μg/mL) for 24 hours. The cells were evaluated for reactive oxidative stress (ROS) and apoptosis. RT-PCR profile arrays were utilized to evaluate the profile of genes involved in endothelial functions, angiogenesis, extracellular matrix, and adhesion molecules for hyperglycemic HMRECs treated with adiponectin. In addition, the barrier function, leukocyte migration, and angiogenesis were evaluated. The differential expressed genes (DEGs) were outlined, and bioinformatic analysis was applied.ResultsAdiponectin suppresses ROS production and apoptosis in HMRECs under HG conditions. Adiponectin improved migration and barrier functions in hyperglycemic cells. The bioinformatic analysis highlighted that the signaling pathways of integrin, HMGB1, and p38 AMPK, are mainly involved in the actions of APN on HMRECs. APN significantly affects molecular functions, including the adhesion of cells, chemotaxis, migration of WBCs, and angiogenesis. STAT3, NFKB, IKBKB, and mir-8 are the top upstream regulators, which affect the expressions of the genes of the data set, while TNF and TGFB1 are the top regulators.ConclusionAdiponectin significantly counteracts hyperglycemia at various cellular and molecular levels, reducing its impact on the pathophysiological progression towards DR in vitro using HMRECs. Adiponectin ameliorates inflammatory response, oxidative stress, and endothelial barrier dysfunction using a causal network of NFBk complex, TNF, and HMGB1 and integrin pathways.

(−)-α-Bisabolol as a protective agent against epithelial renal cytotoxicity induced by amphotericin B

IntroductionAmphotericin B (AmB), used for systemic fungal infections, has a limited clinical application because of its high nephrotoxicity. Natural antioxidant and anti-inflammatory substances have been widely studied for protection against drug-induced nephrotoxicity. α-Bisabolol (BIS) has demonstrated a nephroprotective effect on both in vitro and in vivo models. AimsThe aim of this work was to evaluate the effect of BIS against AmB-induced nephrotoxicity in vitro. Material and methodsLLC-MK2 cells were pre- and post-treated with non-toxic BIS concentrations and/or AmB IC50 (13.97 μM). Cell viability was assessed by MTT [(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)] assay. Flow cytometry analyses were used to assess cell death mechanism, production of reactive oxidative stress (ROS) and mitochondrial transmembrane potential. Kidney Injury Molecule-1 (KIM-1) levels were measured via ELISA. Key findingsThe present work showed that BIS pretreatment (125; 62.5 and 31.25 μM) increased cell viability when compared to the group treated only with AmB IC50. AmB treatment induced both necrosis (7-AAD-labeled cells) and late apoptosis (AnxV-labeled). BIS was able to prevent the occurrence of these events. These effects were associated with a decrease of ROS accumulation, improving transmembrane mitochondrial potential and protecting against tubular cell damage, highlighted by the inhibition of KIM-1 release after BIS treatment. SignificanceBIS presented a potential effect on model of renal cytotoxicity induced by AmB, bringing perspectives for the research of new nephroprotective agents.

Involvement of CYP2E1-ROS-CD36/DGAT2 axis in the pathogenesis of VPA-induced hepatic steatosis in vivo and in vitro

Valproic acid (VPA) is a widely prescribed antiepileptic drug, which may cause steatosis in the liver. Oxidative stress is associated with the progression of VPA-induced hepatic steatosis. However, the potential mechanisms are not fully understood. In this study, we demonstrated the involvement of CYP2E1-ROS-CD36/DGAT2 axis in the pathogenesis of VPA-induced hepatic steatosis in vitro and in vivo. First, VPA treatment (500 mg/kg in mice, 5 mM in LO2 cells) induced hepatic steatosis and enhanced reactive oxidative stress (ROS) level, and ROS scavenger, N-acetyl-L-cysteine (NAC, 200 mg/kg in mice, 1 mM in LO2 cells) reversed the changes. Next, we observed the enhanced expression and enzymatic activity of cytochrome P450 2E1 (CYP2E1) in VPA-treated mice and LO2 cells. Importantly, VPA-induced ROS accumulation and hepatic steatosis were attenuated when CYP2E1 was inhibited using CYP2E1 inhibitor, diallyl sulfide (DAS, 100 mg/kg in mice, 1 mM in LO2 cells) or in CYP2E1-knockdown cell line, suggesting that CYP2E1 plays a potential role in ROS production following hepatic steatosis. Furthermore, gene expression analysis showed that the mRNA levels of cluster of differentiation 36 (CD36), a fatty acid translocase protein and distinct diacylglycerol acyltransferase 2 (DGAT2) were significantly upregulated in mice and LO2 cells after VPA treatment, while the change was alleviated by NAC and DAS. Meanwhile, time course experiments demonstrated that the increase of CYP2E1 level occurred earlier than that of ROS, CD36 and DGAT2, and ROS generation preceded the onset of hepatic steatosis. Taken together, VPA treatment enhances the expression and enzymatic activity of CYP2E1, which promotes ROS production and then causes CD36 and DGAT2 overproduction and hepatic steatosis in mice and LO2 cells, which provides a novel insight into VPA-induced hepatic steatosis.

Factors Associated With Prolonged Mechanical Ventilation and Reventilation in Acute Cervical Spinal Cord Injury Patients.

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. 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 patients with acute cervical SCI. 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 postinjury increase in ROS production after SCI. We hypothesize that the serum ROS is associated with the severity of patients with acute cervical SCI. Thirty-eight 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 and Japanese Orthopaedic Association score at admission were compared. The most notable predictor of mechanical ventilation more than 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 reventilation ≤5 days, the notable predictors were respiratory function at the time of extubation (maximal inspiratory pressure, P = 0.040; maximal expiratory pressure, P = 0.020; and tidal volume, 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%). In this study, respiratory function (maximal inspiratory pressure, maximal expiratory pressure, and tidal volume) 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. 3.

Heat shock protein 27 influences the anti-cancer effect of curcumin in colon cancer cells through ROS production and autophagy activation

The problem of therapeutic resistance and chemotherapeutic efficacy is tricky and critical in the management of colorectal cancer (CRC). Curcumin is a promising anti-cancer agent. Heat shock protein 27 (HSP27) is correlated with CRC progression and is said to affect CRC response to different therapies. However, the role of HSP27 on the therapeutic efficacy of curcumin remains unknown. HSP27 was silenced using small hairpin RNA (shRNA) technique. The cytotoxic and apoptotic effects of curcumin were assessed by sulforhodamine B (SRB) colorimetric assay, flow cytometric cell cycle analysis, and annexin V/propidium iodide (PI) double-labeling assays. Total reactive oxygen species (ROS)/superoxide and autophagy detection were performed, and the levels of apoptosis-related proteins were examined by Western blotting. It was found that the silencing of HSP27 (HSP27-KD) resulted in increased treatment resistance to curcumin in CRC cells. In addition, cell cycle analysis showed that the curcumin treatment caused cell cycle arrest at the G2/M phase in the control group, and apoptosis was reduced in the HSP27-KD group. Curcumin treatment also resulted in a decrease in anti-apoptotic proteins, p-Akt, Akt, Bcl-2 and p-Bad, and increase in pro-apoptotic proteins Bad and c-PARP levels in the control cells but not in the HSP27-KD cells. This was also followed by low reactive oxygen/nitrogen species (ROS/RNS), superoxide and autophagy induction levels in the HSP27-KD cells as compared to the control cells. Therefore, as silencing of HSP27 increases curcumin resistance by reducing apoptosis and reactive oxidative stress production, HSP27 is a potential selective target for curcumin treatment in CRC.

Salivary melatonin and total antioxidant capacity in reproductive and postmenopausal women

Background: Periodontal inflammation causes an increased production of reactive oxidative stress leading to the production of reactive oxidative species, which causes tissue damage. Various studies have shown that Melatonin hormone is a potent antioxidant. Aim: To assess and compare the total antioxidant capacity and melatonin hormone level in saliva of healthy women, women with chronic periodontitis in reproductive and postmenopausal age groups, so as to render a comprehensive treatment in future. Materials and Methods: Total of 80 women were selected and divided into 4 groups. 20 aged 24-35 yr as group A with GI <1, 20 as group B aged 24-35 yr with GI ≥1 and CAL ≥3 mm. 20 aged 47-55 yrs as group C with GI <1 and 20 aged 47-55 yrs as group D with GI ≥1 and CAL ≥3 mm. Saliva samples were collected from all the groups and estimated for Total Antioxidant Levels and Melatonin hormone. Results were subjected to statistical analysis. Statistical analysis: The data obtained was subjected to student t test. Results: In the present study, there was significant reduction in both parameters in women with periodontitis when compared to healthy groups in both age groups with statistical significance P < 0.005 in reproductive age group. Conclusion: Salivary Melatonin could be used not only as one of the markers of the periodontal disease progression but also could be employed as an adjunct to traditional periodontal therapy in the therapeutic front owing to its protective nature.

All-Trans Retinoic Acid Has a Potential Therapeutic Role for Diabetic Nephropathy.

PurposeThe aim of this study was to examine the effects of all-trans retinoic acid (ATRA) on diabetic nephropathy.Materials and MethodsWe measured amounts of urinary albumin excretion (UAE) after administrating ATRA to Otsuka Long-Evans Tokushima Fatty (OLETF) rats. In order to understand the mechanism of action for ATRA, we administrated ATRA to examine its inhibitory action on the production of transforming growth factor-β1 (TGF-β1), protein kinase C (PKC), and reactive oxidative stress (ROS) in cultured rat mesangial cells (RMCs).ResultsAfter 16 weeks of treatment, UAE was lower in the ATRA-treated OLETF rats than in the non-treated OLETF rats (0.07±0.03 mg/mgCr vs. 0.17±0.15 mg/mgCr, p<0.01). After incubation of RMCs in media containing 30 or 5 mM of glucose, treatment with ATRA showed time- and dose-dependent decreases in TGF-β1 levels and ROS. Moreover, ATRA treatment showed a dose-dependent decrease in PKC expression.ConclusionATRA treatment suppressed UAE and TGF-β1 synthesis, which was mediated by significant reductions in PKC activity and ROS production. Our results suggest that ATRA has a potential therapeutic role for diabetic nephropathy.

The Bone Marrow-Derived Mesenchymal Cells Were Injured By Iron Overload through Catalyzing the Production of Reactive Oxidative Stress in Mice

Iron overload (IO) is a pathological phenomenon characterized by excessive iron depositing in tissue and caused by hereditary hemochromatosis or repeated blood transfusions in some diseases such as beta thalassemia, MDS. IO can induce organ dysfunctions, such as hepatic fibrosis, diabetes and cardiac diseases and even hematopoiesis suppression. Bone marrow-derived mesenchymal cells (BM-MCs), which located in the hematopoietic niche, functions as maintaining the stability of the hematopoietic microenvironment and supporting hematopoiesis via secreting many cellular factors and differentiating into other stromal cells. Our preliminary researches suggest that IO may induce murine hematopoietic cells injury and suppress hematopoiesis of IO patients. (Lu et al., Eur J Haematol, 2013; Chai et al., blood, 2013 abstract). Here we observed the inhibitory effects of IO onthe BM-MCs and preliminarily discussed the related mechanism.Mice were divided into four equal groups and designed as non-treated control mice group (control): mice were treated with isovolumic saline by intraperitoneal injection everyday. IO mice group (IO): mice were treated with 25mg/ml iron dextran by intraperitoneal injection every 3 days. The iron-chelation mice group (Deferasirox, DFX): IO mice were treated with 125mg/kg DFX by gavage everyday. Anti-oxidative group: IO mice were treated with 40 mM N-acetyl-cysteine (NAC, anti-oxidative regent) in drinking water. All experiments were carried at the same time for 4 weeks. Then BM-MCs were isolated from compact bone at the end of forth week according to the reference (Zhu H et al, Nature Protocol, 2010). Iron deposits in BM-MCs were observed by morphological study and labile iron pool (LIP) level of BM-MCs was detected using the calcein-AM method. The results suggest that the iron deposits and LIP level of BM-MCs in IO mice was significantly increased, which could be partly alleviated by DFX (p<0.05).Then, the biological characteristic and supporting function on normal bone marrow mononuclear cells (BMMNCs) of BM-MCs were evaluated. Firstly, the proliferation ability of BM-MCs was assessed by double time (DT) and cell counting kit-8(CCK8) assay. BM-MCs of IO mice showed a longer DT (2.07±0.14)d compared to that of control group (1.03±0.07)d, which could be partly reversed by DFX (1.52±0.07)d and NAC (1.68±0.03)d (P<0.05),respectively. The similar results were obtained by CCK8 assay,too. Secondly, the osteoblastic differentiation ability of BM-MCs was evaluated via ALP staining and Alizarin Red S staining, as well as osteogenic gene expression. IO inhibited the ALP expression and mineralized nodules formation of osteoblast. Meanwhile, we observed a significant decrease in ALP and RUNX2 mRNA expression by RT-PCR, which also can be reversed by iron-chelation and anti- oxidative therapy. However, Oil red O (ORO) staining indicated that lipid accumulation notablely increased in IO group lipoblast compared with control group, which meaned that IO increased adipogenic differentiation of BM-MCs. Thirdly, the supporting function of IO BM-MCs on normal BMMNCs is assessed by the colony-forming unit (CFU) assay. Normal control or IO BM-MCs were co-cultured with the same pool of normal BMMNCs, After 7 days, co-cultures containing normal BM-MCs formed more CFU than that of control group. These results suggest that the proliferation potential and the differentiation potential of BM-MCs were decreased in the IO environment.Further more, we also explored the possible mechanism of this phenomenon. Our results showed a marked increase in reactive oxidative species (ROS) level of IO group than that of control group, which could be reversed by NAC and DFX treatments, respectively (P<0.05). Quantitative RT-PCR analysis of genes associated with ROS were performed, the results showed that FOXO3 decreased in IO group compared with control group (p<0.01). However there was no significant difference in PI3K expression between IO group and control group. All above implied that FOXO3 may play an important role in IO catalyzed oxidative stress.In conclution, dysfunction of BM-MCs, an important component of hematopoietic microenvironment, may play a crucial role in the suppression of hematopoiesis during IO. Improving the function of BM-MCs may serve as a new strategy to enhance normal hematopoiesis in IO bone marrow . DisclosuresNo relevant conflicts of interest to declare.

Promotion of p53 expression and reactive oxidative stress production is involved in zerumbone-induced cisplatin sensitization of non-small cell lung cancer cells.

p53 signaling plays an important role in cell death. Zerumbone, a natural cyclic sesquiterpene, has shown cytotoxic activity against many cancers. This study was done to investigate the anticancer effects of zerumbone on non-small cell lung cancer (NSCLC) cells and explored the involvement of p53 signaling. Cell viability was assessed by 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium assay. Apoptosis was confirmed by annexin-V/propidium iodide staining and caspase activity assay. Mitochondrial membrane potential (Δφm) and reactive oxygen species (ROS) production were measured by flow cytometry. Depletion of p53 was achieved by transfection of specific small interfering RNA. Gene expression changes were determined by Western blot analysis. Zerumbone treatment caused a dose-dependent inhibition of A549 and H460 NSCLC cell viability. Zerumbone-induced mitochondrial apoptosis of NSCLC cells, evidenced loss of Δφm, release of mitochondrial cytochrome c, and activation of caspase-9 and -3. There was increased p53 and Bax expression and ROS production in zerumbone-treated cells. Downregulation of p53 or scavenging ROS interfered with the pro-apoptotic action of zerumbone. Combinational treatment with zerumbone and cisplatin significantly accelerated apoptosis and promoted p53 expression and ROS production in NSCLC cells, compared with each alone. These findings demonstrate that zerumbone induces mitochondrial apoptosis and enhances the susceptibility to cisplatin in NSCLC cells, which are, at least partially, mediated through activation of p53 signaling and promotion of ROS generation. This study may provide a rationale for the potential clinical application of zerumbone as a chemotherapeutic agent against NSCLC.

Targeting the mitochondrial electron transport chain in autism, a systematic review and synthesis of a novel therapeutic approach

Autism is a complex developmental disorder with an unknown etiology and without any curative treatment. The mitochondrial electron transfer chains play a major role in the production of ATP, and the generation and management of reactive oxidative stress (ROS). This paper is a systematic review of the role of the mitochondrial electron transport chain in autism, and a consequent hypothesis for treating autism is synthesized.An electronic search with pre-specified inclusion criteria was conducted in order to retrieve all the published articles about the mitochondrial electron transport chain in autism. The two databases of PUBMED and Google Scholar were searched.From one hundred twenty five retrieved titles, 12 (three case control study and 9 case reports) articles met inclusion criteria. All of the included studies indicated dysfunction of electron transport chain in autism.The mitochondrial electron transfer chain seems impaired in some children with autism and ROS production is additionally enhanced. It is hypothesized that interventions involving alternative electron shuttling may improve autism through lowering the production of ROS. In addition, it is expected that this alternative electron shuttling to cytochrome c might enhance the production of ATP which is impaired in the disorder.