Heat shock protein (HSP) 90 is expressed in most living organisms, and several client proteins of HSP90 are necessary for cancer cell survival and growth. Previously, we found that HSP90 was cleaved ...by histone deacetylase (HDAC) inhibitors and proteasome inhibitors, and the cleavage of HSP90 contributes to their cytotoxicity in K562 leukemia cells. In this study, we first established mouse xenograft models with K562 cells expressing the wild-type or cleavage-resistant mutant HSP90β and found that the suppression of tumor growth by the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) was interrupted by the mutation inhibiting the HSP90 cleavage in vivo. Next, we investigated the possible function of thioredoxin interacting protein (TXNIP) in the HSP90 cleavage induced by SAHA. TXNIP is a negative regulator for thioredoxin, an antioxidant protein. SAHA transcriptionally induced the expression of TXNIP in K562 cells. HSP90 cleavage was induced by SAHA also in the thymocytes of normal mice and suppressed by an anti-oxidant and pan-caspase inhibitor. When the thymocytes from the TXNIP knockout mice and their wild-type littermate control mice were treated with SAHA, the HSP90 cleavage was detected in the thymocytes of the littermate controls but suppressed in those of the TXNIP knockout mice suggesting the requirement of TXNIP for HSP90 cleavage. We additionally found that HSP90 cleavage was induced by actinomycin D, β-mercaptoethanol, and p38 MAPK inhibitor PD169316 suggesting its prevalence. Taken together, we suggest that HSP90 cleavage occurs also in vivo and contributes to the anti-cancer activity of various drugs in a TXNIP-dependent manner.
Given the rise of apoptosis-resistant tumors, there exist a growing interest in developing new drugs capable of inducing different types of cell death to reduce colorectal cancer-related death rates. ...As apoptosis and necroptosis do not share cellular machinery, necroptosis induction may have a great therapeutic potential on those apoptosis-resistant cancers, despite the inflammatory effects associated with it. We have synthesized an alkynyl gold(I) complex Au(CC-2-NC5H4)(PTA) whose anticancer effect was tested on the colorectal adenocarcinoma Caco-2 cell line. With regard to its mechanism of action, this gold complex enters the mitochondria and disrupts its normal function, leading to an increase in ROS production, which triggers necroptosis. Necroptosis induction has been found dependent of TNF-α (Tumor necrosisfactor α) and TNFR1(Tumor necrosisfactor receptor 1) binding, RIP1(Receptor-Interacting Protein 1) activation and NF-κB (Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells) signaling. Moreover, the antitumor potential of Au(CC-2-NC5H4)(PTA) has also been confirmed on the 3D cancer model spheroid. Overall, the obtained data show firstly that gold complexes might have the ability of inducing necroptosis, and secondarily that our compound Au(CC-2-NC5H4)(PTA) is an interesting alternative to current chemotherapy drugs in cases of apoptosis resistance.
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•Gold(I) complex Au(CC-2-NC5H4)(PTA) induces necroptosis on Caco-2 cells.•The complex enters the mitochondria, alters its function and produces ROS increase.•Necroptosis depends on ROS increase, TNF-α, RIP-1 activation and NF-κB signaling.•Au(CC-2-NC5H4)(PTA) induces cell death on 2D and 3D colorectal carcinoma model•This is the first evidence of gold compound able to overcome apoptosis resistance.
Ochratoxin A (OTA), is a natural contaminant of the food chain worldwide involved in the development of different type of cancers in animals and humans. Several studies suggested that oxidative ...damage might contribute to increase the cytotoxicity and carcinogenicity capabilities of OTA. The aim of this study was to evaluate the possible protective effect of δ‐tocotrienol (Delta), a natural form of vitamin E, against OTA‐induced nephrotoxicity. Male Sprague–Dawley rats were treated with OTA and/or Delta by gavage for 14 days. Our results shown that OTA treatment induced the increase of reactive oxigen species production correlated to a strong reduction of Glomerular Filtration Rate (GFR) and absoluted fluid reabsorption (Jv) with conseguent significant increase in blood pressure. Consistent, we noted in the kidney of rats treated with OTA, an increase in malondialdheyde and dihydroethidium production and a reduction of the activity of the catalase, superoxide dismutase, and glutathione peroxidase. Conversly, in the rat group subjected to the concomitant treatment OTA plus Delta, we observed the restored effect, compared the OTA treatment group, on blood pressure, GFR, Jv, and all activities of renal antioxidant enzymes. Finally, as far as concern the tissue damage induced by OTA and measured evaluating fibronectin protein levels, we observed that in OTA plus Delta group this effect is not restored. Our findings releval that a mechanism underlying the renal toxicity induced by OTA is the oxidative stress and provide a new rationale to use a Delta in order to protect, at least in part, against OTA‐induced nephrotoxicity.
Our findings releval that a mechanism underlying the renal toxicity induced by OTA is the oxidative stress and provide a new rationale to use a Delta in order to protect, at least in part, against OTA‐induced nephrotoxicity.
OXIDATIVE STRESS AND PERIODONTAL DISEASE. REVIEW Alexandra Martu; Sorina Solomon; Silvia Martu ...
Romanian Journal of Medical and Dental Education (Online),
07/2018, Letnik:
7, Številka:
1
Journal Article
Recenzirano
Odprti dostop
ROS (reactive oxygen species) have become increasingly worthy of attention because of their central role in the progression of many inflammatory conditions. They are described as oxygen free radicals ...and any other non-radical oxygen derivative involved in the production of oxygen radicals. ROS are involved in normal cellular metabolism and are continuously generated by cells in most tissues. Another category of substances called antioxidants exist in the cell that can effectively delay or completely inhibit ROS-induced oxidation. Under physiological conditions, ROS production is drastically increased largely due to the immune system cells and the phagocytosis process through the metabolic pathway. Consequently, high levels or increased activities can not be balanced by the antioxidant defense system, which leads to oxidative stress and tissue damage. ROS can directly damage the tissue by their action against DNA, proteins and oxidation of important enzymes. At the same time, they can act as signaling pathways or as mediators of inflammation. In recent years, numerous clinical and experimentional studies have demonstrated a strong association between oxidative stress and periodontitis. A better understanding of this association can lead us to a detailed knowledge of the pathogenic mechanisms of this disease, and so can guide us towards a more structured therapy.
Hepatic fibrosis is characterized by the excessive accumulation of extracellular matrix (ECM), primarily collagen, within the liver. Because reactive oxygen species (ROS) has been implicated in its ...pathogenesis, the use of antioxidants as a potential treatment has been broadly explored. Here, we investigated the hepatoprotective properties of ramalin (RM), a compound extracted from the Antarctic lichen Ramalina terebrata, against hepatic fibrosis in vitro and in vivo. RM suppressed hepatic stellate cell (HSC) activation in vitro without any significant signs of adverse effects on the cells tested, and the accumulation of ECM was dramatically reduced in the liver tissue. Oral administration of RM in rats noticeably improved the gross appearance of the liver with increased body and liver weight relative to the DMN injected rats, and all of the serum biochemical markers returned to the normal range. RM treatment have ameliorated hepatic fibrosis in rats induced by DMN by repressing α-smooth muscle actin (α-SMA) and upregulating heme oxygenase-1 (HO-1). In addition, RM significantly reduced collagen accumulation, and levels of malondialdehyde (MDA) and hydroxyproline (HP) in the liver tissue of DMN injected rats. The efficacy exerted by RM was through erythroid 2–related factor 2 (Nrf2) mediated antioxidant response proteins such as HO-1 and NAD(P)H quinone dehydrogenase 1 (NQO-1). Our results show the beneficial effect of RM against the progression of hepatic fibrosis.
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•New chemical substance, “Ramalin”, derived from Antarctic lichen, acts as a powerful antioxidant and ROS scavenger.•Ramalin significantly reduces hepatic stellet cell activation, while also reducing malondialdehyde (MDA), and hydroxyproline (HP).•Ramalin offers hepatoprotection effect by ameliorating DMN-induced oxidative stress and hepatotoxicity.
The antioxidant role of carotenoids in the living organism was proposed as a possible basis for the honesty of carotenoid-based signals. However, recent studies have questioned the relevance of ...carotenoids as powerful antioxidants in vivo. Current evidence does not seem to support the "antioxidant role" hypothesis, but it does not allow us to reject it either. This paper proposes some steps to solve this controversy, such as taking a dynamic approach to antioxidant responses, designing protocols that expose individuals to oxidative challenges, analyzing tissues other than blood, and obtaining measures of antioxidant capacity and oxidative damage simultaneously. However, it should be considered that, irrespective of their antioxidant potential, carotenoids might still give information on oxidative stress levels if they are particularly sensitive to free radicals. Finally, lumping together the immunostimulatory and antioxidant roles of carotenoids should be avoided as these functions are not necessarily associated.
Recently we showed that Ethanolamine Kinase 1 (ETNK1) mutations cause a decreased synthesis of phosphoethanolamine, and that phosphoethanolamine is able to modulate mitochondrial activity through ...competition with succinate for complex II. The decreased phosphoethanolamine concentration leads to increased mitochondria activity and reactive oxygen species production, which causes the accumulation of new mutations.
Heat shock protein (HSP) 90 is expressed in most living organisms, and several client proteins of HSP90 are necessary for cancer cell survival and growth. Previously, we found that HSP90 was cleaved ...by histone deacetylase (HDAC) inhibitors and proteasome inhibitors, and the cleavage of HSP90 contributes to their cytotoxicity in K562 leukemia cells. In this study, we first established mouse xenograft models with K562 cells expressing the wild-type or cleavage-resistant mutant HSP90β and found that the suppression of tumor growth by the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) was interrupted by the mutation inhibiting the HSP90 cleavage
. Next, we investigated the possible function of thioredoxin interacting protein (TXNIP) in the HSP90 cleavage induced by SAHA. TXNIP is a negative regulator for thioredoxin, an antioxidant protein. SAHA transcriptionally induced the expression of TXNIP in K562 cells. HSP90 cleavage was induced by SAHA also in the thymocytes of normal mice and suppressed by an anti-oxidant and pan-caspase inhibitor. When the thymocytes from the TXNIP knockout mice and their wild-type littermate control mice were treated with SAHA, the HSP90 cleavage was detected in the thymocytes of the littermate controls but suppressed in those of the TXNIP knockout mice suggesting the requirement of TXNIP for HSP90 cleavage. We additionally found that HSP90 cleavage was induced by actinomycin D, β-mercaptoethanol, and p38 MAPK inhibitor PD169316 suggesting its prevalence. Taken together, we suggest that HSP90 cleavage occurs also
and contributes to the anti-cancer activity of various drugs in a TXNIP-dependent manner.
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