TAp73 depletion accelerates aging through metabolic dysregulation

Aging is associated with impaired scavenging of reactive oxygen species (ROS). Here, we show that TAp73, a p53 family member, protects against aging by regulating mitochondrial activity and preventing ROS accumulation. TAp73-null mice show more pronounced aging with increased oxidative damage and senescence. TAp73 deletion reduces cellular ATP levels, oxygen consumption, and mitochondrial complex IV activity, with increased ROS production and oxidative stress sensitivity. We show that the mitochondrial complex IV subunit cytochrome C oxidase subunit 4 (Cox4i1) is a direct TAp73 target and that Cox4i1 knockdown phenocopies the cellular senescence of TAp73-null cells. Results indicate that TAp73 affects mitochondrial respiration and ROS homeostasis, thus regulating aging.     

A natural antioxidant,tannic acid mitigates iron‐overload induced hepatotoxicity in Swiss albino mice through ROS regulation

Tannic acid (TA), a water soluble natural polyphenol with 8 gallic acids groups, is abundantly present in various medicinal plants. Previously TA has been investigated for its antimicrobial and antifungal properties. Being a large polyphenol, TA chelates more than 1 metal. Hence TA has been explored for potent antioxidant activities against reactive oxygen species (ROS), reactive nitrogen species (RNS) and as iron chelator in vitro thereby mitigating iron‐overload induced hepatotoxicity in vivo. Iron dextran was injected intraperitoneally in Swiss albino mice to induce iron‐overload triggered hepatotoxicity, followed by oral administration of TA for remediation. After treatment, liver, spleen, and blood samples were processed from sacrificed animals. The liver iron, serum ferritin, serum markers, ROS, liver antioxidant status, and liver damage parameters were assessed, followed by histopathology and protein expression studies. Our results show that TA is a prominent ROS and RNS scavenger as well as iron chelator in vitro. It also reversed the ROS levels in vivo and restricted the liver damage parameters as compared to the standard drug, desirox. Moreover, this natural polyphenol exclusively ameliorates the histopathological and fibrotic changes in liver sections reducing the iron‐overload, along with chelation of liver iron and normalization of serum ferritin. The protective role of TA against iron‐overload induced apoptosis in liver was further supported by changed levels of caspase 3, PARP as well as Bax/BCl‐2 ratio. Thus, TA can be envisaged as a better orally administrable iron chelator to reduce iron‐overload induced hepatotoxicity through ROS regulation.     

Cell Death by Polyvinylpyrrolidine-Coated Silver Nanoparticles is Mediated by ROS-Dependent Signaling

Silver nanoparticles (AgNPs) are widely used nanoparticles and they are mainly used in antibacterial and personal care products. In this study, we evaluated the effect of AgNPs on cell death induction in the murine dendritic cell line DC2.4. DC2.4 cells exposed to AgNPs showed a marked decrease in cell viability and an induction of lactate dehydrogenase (LDH) leakage in a time- and dose-dependent manner. In addition, AgNPs promoted reactive oxygen species (ROS)-dependent apoptosis and AgNP-induced ROS triggered a decrease in mitochondrial membrane potential. The activation of the intracellular signal transduction pathway was also observed in cells cultured with AgNPs. Taken together, our data demonstrate that AgNPs are able to induce a cytotoxic effect in DCs through ROS generation. This study provides important information about the safety of AgNPs that may help in guiding the development of nanotechnology applications.     

ROS清除剂在细菌抗生素耐受中的作用研究进展

活性氧簇(ROS)是生物在有氧环境中进行能量代谢时产生的一类分子的总称，ROS不仅在动物、植物以及细菌的生理过程中发挥着重要的作用，也在研究抗生素杀菌和细菌耐药性的产生上有着重要的功能，添加ROS清除剂有助于我们更好的研究ROS在细菌对抗菌剂耐受中的作用。本文主要通过对常见的ROS清除剂过氧化氢酶、硫脲、联吡啶、DMSO、褪黑素和其他较为常见的清除剂等化合物在抗生素杀菌过程中的作用机制、ROS清除剂添加对细菌耐受性的影响及其他生理作用进行综述，旨在对这些常见的ROS清除剂的不同功能和缺点进行一个更广泛和深入的了解，以便我们在选用相关ROS清除剂时对其作用机理有较为清楚的了解从而选取合适的ROS清除剂。     

Bromuconazole-induced hepatotoxicity is accompanied by upregulation of PXR/CYP3A1 and downregulation of CAR/CYP2B1 gene expression

Despite widespread use of bromuconazole as a pesticide for food crops and fruits, limited studies have been done to evaluate its toxic effects. Here, we evaluated the hepatotoxic effect of bromuconazole using classical toxicological (biochemical analysis and histopathological examination) and gene-based molecular methods. Male rats were treated either orally or topically with bromuconazole at doses equal to no observed adverse effect level (NOAEL) and 1/10 LD50 for 90?d. Bromuconazole increased activities of liver enzymes (ALT, AST, ALP, and ACP), and levels of bilirubin. It also induced hepatic oxidative stress as evidenced by significant decrease in the activities of superoxide dismutase (SOD), and significant increase in levels of malondialdehyde (MDA) in liver. In addition, bromuconazole caused an increase in liver weights and necrobiotic changes (vacuolation and hepatocellular hypertrophy). It also strongly induced the expression of PXR and its downstream target CYP3A1 gene as well as the activity of CYP3A1. However, it inhibited the expression of CAR and its downstream target CYP2B1 gene without significant changing in CYP2B1 activity. Overall, the oral route showed higher hepatotoxic effect and molecular changes than the dermal route and all changes were dose dependent. This is the first investigation to report that bromuconazole-induced liver oxidative damage is accompanied by upregulation of PXR/CYP3A1 and downregulation of CAR/CYP2B1.     

Effects of antibiotics on biochemical parameters,leukocytes and Reactive Oxygen Species (ROS) in bitches after ovariectomy

It is well known that following surgical procedures, a variety of patho-physiological alterations occurs in the host, such as changes in haemodynamic, endocrine and immune functions, as well as increase in Reactive Oxygen Species (ROS). Antibiotic administration, a common practice used in surgery, affects immune functions and ROS generation. Our study was aimed to investigate the effect of five different antibiotic regimens: amoxicillin, benzylpenicillin/dihydrostreptomycin, sulfametazine/sulfamerazine/ sulfathiazole, enrofloxacin, lincomycin/spectinomycin, administered twice (2 hours before skin incision and 6 hours after the end of the surgical suture), on biochemical parameters, leukocytes and ROS concentrations, in bitches undergoing open laparotomic ovariectomy. All treated bitches recovered from surgery without developing either systemic dysfunctions, or infections at the surgical site. Mean healing time was 7?±?3 days. An increase in white blood cell count, in differential leukocyte count and in ROS concentrations occurred 24 hours after the end of surgery, followed by a gradual decrease to basal values within the fourth day after surgery. The biochemical parameters remained quite constant throughout the study. In conclusion, our results show that the above antibiotic regimens, administered only twice, are efficient in inducing an uneventful recovery after laparotomic ovariectomy and preventing the development of infections in the bitch.     

Tephrosin-induced autophagic cell death in A549 non-small cell lung cancer cells

Anticancer effect of tephrosin (1) has been documented; however, the molecular mechanisms underlying the cytotoxicity of tephrosin in cancer cells remain unclear. In the present paper, the proliferation inhibition rate of several cancer cells was tested using the MTT assay; cell cycle, reactive oxygen species (ROS), and mitochondrial membrane potential (MMP) were determined by flow cytometry; poly(ADP-ribose) polymerase (PARP) cleavage and heat shock protein 90 (Hsp90) expression were evaluated by Western blotting; autophagy was examined by confocal microscopy and light chain 3 (LC3) conversion assay. The results showed that exposure of the cells to tephrosin induced significant proliferation inhibition in a dose-dependent manner, especially on A549 with G₂/M being arrested. Tephrosin was not found to induce cell apoptosis as PARP cleavage was not detected after 24 h treatment, but the formation of acidic vesicular organelle of autophagy character was found, and autophagy was further confirmed by the increase in the ratio of LC3-II to LC3-I. It was observed that tephrosin induced ROS generation and Hsp90 expression inhibition. These results indicate that tephrosin induces A549 cancer cell death via the autophagy pathway, and the roles of ROS generation and Hsp90 expression inhibition in this process need further study in the future.     

4-Hydroxynonenal regulates mitochondrial function in human small airway epithelial cells

Prolonged exposure to oxidative stress causes Acute Lung Injury (ALI) and significantly impairs pulmonary function. Previously we have demonstrated that mitochondrial dysfunction is a key pathological factor in hyperoxic ALI. While it is known that hyperoxia induces the production of stable, but toxic 4-hydroxynonenal (4-HNE) molecule, it is unknown how the reactive aldehyde disrupts mitochondrial function. Our previous in vivo study indicated that exposure to hyperoxia significantly increases 4-HNE-Protein adducts, as well as levels of MDA in total lung homogenates. Based on the in vivo studies, we explored the effects of 4-HNE in human small airway epithelial cells (SAECs). Human SAECs treated with 25 μM of 4-HNE showed a significant decrease in cellular viability and increased caspase-3 activity. Moreover, 4-HNE treated SAECs showed impaired mitochondrial function and energy production indicated by reduced ATP levels, mitochondrial membrane potential, and aconitase activity. This was followed by a significant decrease in mitochondrial oxygen consumption and depletion of the reserve capacity. The direct effect of 4-HNE on the mitochondrial respiratory chain was confirmed using Rotenone. Furthermore, SAECs treated with 25 μM 4-HNE showed a time-dependent depletion of total Thioredoxin (Trx) proteins and Trx activity. Taken together, our results indicate that 4-HNE induces cellular and mitochondrial dysfunction in human SAECs, leading to an impaired endogenous antioxidant response.     

ROS act as an upstream signal to mediate cadmium-induced mitophagy in mouse brain

As a well known generator of reactive oxygen species (ROS), cadmium (Cd) is found to be an effective inducer of mitophagy in mouse kidney and liver cells. Here, we aim to elucidate whether Cd can also initiate mitophagy in mouse brain and what role ROS play in this process. Our results showed that Cd caused overproduction of ROS. Meanwhile, Cd induced mitophagy, as indicated by the collapse of mitochondrial membrane potential (MMP), formation of mitophagosomes, increases of PINK1 level and LC3-II/LC3-I ratio and decrease of mitochondrial mass. Scavenging of ROS by N-acetyl-l-cysteine (NAC) or acetyl-l-carnitine (ALC) rescued MMP and mitochondrial mass, and squelched PINK1 level, mitochondrial accumulation of Parkin and LC3-II/LC3-I ratio, suggesting that ROS were associated with Cd-induced mitophagy. Cyclosporine A (CsA), an inhibitor of mitophagy, blocked Cd-induced mitophagy and PINK1/Parkin pathway but failed to suppress ROS increase, revealing that ROS are the causes rather than the results of Cd-induced mitophagy. In conclusion, this study suggested that ROS functioned on the upstream of PINK1/Parkin pathway to mediate Cd-induced mitophagy.