Increasing evidence in both experimental and clinical studies suggests that oxidative stress plays a major role in the pathogenesis of both types of diabetes mellitus. Free radicals are formed disproportionately in diabetes by glucose oxidation, nonenzymatic glycation of proteins, and the subsequent oxidative degradation of glycated proteins. Abnormally high levels of free radicals and the simultaneous decline of antioxidant defense mechanisms can lead to damage of cellular organelles and enzymes, increased lipid peroxidation, and development of insulin resistance. These consequences of oxidative stress can promote the development of complications of diabetes mellitus. Changes in oxidative stress biomarkers, including superoxide dismutase, catalase, glutathione reductase, glutathione peroxidase, glutathione levels, vitamins, lipid peroxidation, nitrite concentration, nonenzymatic glycosylated proteins, and hyperglycemia in diabetes, and their consequences, are discussed in this review. In vivo studies of the effects of various conventional and alternative drugs on these biomarkers are surveyed. There is a need to continue to explore the relationship between free radicals, diabetes, and its complications, and to elucidate the mechanisms by which increased oxidative stress accelerates the development of diabetic complications, in an effort to expand treatment options.

Diabetes, oxidative stress, and antioxidants: a review

Blood-brain barrier tight junction permeability and ischemic stroke.

Immunomodulatory and therapeutic properties of the Nigella sativa L. seed

The metalloproteinases degrade extracellular matrix (ECM) components and activate growth factors, thereby contributing to physiological events (tissue remodeling in pregnancy, wound healing, angiogenesis) and pathological conditions (cancer, arthritis, periodontitis). The intent of this review is to bring together various studies on transcriptional and post-transcriptional control of metalloproteinase expression. Certainly, much information is known as to the cis-elements and corresponding trans-activators regulating expression of these genes. We discuss the fact that a number of the metalloproteinase promoters share common structural features and, therefore, not surprisingly are co-regulated in their expression to some extent. More recently, much effort has been devoted to understanding the role of chromatin in regulating gene expression. While this area has been understudied with respect to matrix metalloproteinase (MMP) regulation, the literature indicates a convincing role for both histone modifications and chromatin-remodeling motors in controlling expression of multiple metalloproteinases. In addition to transcriptional control, mRNA stability and protein translation also contribute to the metalloproteinase product amount. We discuss such studies and how various biological cues, including TGF-β, regulate the levels of certain collagenases either solely through mRNA stabilization or by jointly targeting transcriptional and post-transcriptional mechanisms. We also discuss the current deficits in our knowledge, concerning tissue-specific expression and why despite elevated amounts/activity of trans-activators targeting MMP promoters in tumor cells, nevertheless, MMP expression is largely restricted to the stromal compartment. Finally, we argue for potential technologies to regulate MMP expression of utility in pathological conditions where these enzymes are aberrantly expressed. J. Cell. Physiol. 211: 19–26, 2007. © 2006 Wiley-Liss, Inc.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1002/jcp.20948

Regulation of matrix metalloproteinase gene expression.

https://www.kidney-international.org/article/S0085-2538(15)54676-0/pdf

New insights into the mechanism of aminoglycoside nephrotoxicity: an integrative point of view

The antioxidant and pro-oxidant effects of thymoquinone (TQ), a natural main constituent of the volatile oil of Nigella saliva seeds, and a synthetic structurally-related tert-butylhydroquinone (TBHQ), were examined in vitro. Both TQ and TBHQ efficiently inhibited iron-dependent microsomal lipid peroxidation in a concentration-dependent manner with median inhibitory concentration (IC50) values of 16.8 and 14.9 microM, respectively. TBHQ was stronger than TQ as a scavenger of 2,2'-diphenyl-p-picrylhydrazyl radical (DPPH) (IC50 = 5 microM, 200 times more active than TQ) and as a scavenger of hydroxyl radical (OH*) with an IC50 of 4.6 microM (approximately 10 times more active than TQ). TQ was more active than TBHQ as a superoxide anion scavenger with IC50 of 3.35 microM compared to 18.1 microM for TBHQ. Only TBHQ significantly promoted DNA damage in the bleomycin-Fe(III) system. The results suggest that both TQ and TBHQ have strong antioxidant potentials through scavenging ability of different free radicals. Moreover, the data indicate that TQ is acting mainly as a potent superoxide anion scavenger.

Thymoquinone is a potent superoxide anion scavenger

The influence of thymoquinone on doxorubicin-induced hyperlipidemic nephropathy in rats

Dysregulation of extracellular matrix turnover is an important feature of many inflammatory processes. Rat renal mesangial cells express high levels of matrix metalloproteinase 9 (MMP-9) in response to inflammatory cytokines such as interleukin-1 beta. We demonstrate that NO does strongly destabilize MMP-9 mRNA, since different luciferase reporter gene constructs containing the MMP-9 3' untranslated region (UTR) displayed significant reduced luciferase activity in response to the presence of NO. Moreover, by use of an in vitro degradation assay we found that the cytoplasmic fractions of NO-treated cells contained a higher capacity to degrade MMP-9 transcripts than those obtained from control cells. An RNA electrophoretic mobility shift assay demonstrated that three of four putative AU-rich elements present in the 3' UTR of MMP-9 were constitutively occupied by the mRNA-stabilizing factor HuR and that the RNA binding was strongly attenuated by the presence of NO. The addition of recombinant glutathione transferase-HuR prevented the rapid decay of MMP-9 mRNA, whereas the addition of a neutralizing anti-HuR antibody caused an acceleration of MMP-9 mRNA degradation. Furthermore, the expression of HuR mRNA and protein was significantly reduced by exogenously and endogenously produced NO. These inhibitory effects were mimicked by the cGMP analog 8-bromo-cGMP and reversed by LY-83583, an inhibitor of soluble guanylyl cyclase. These results demonstrate that NO acts in a cGMP-dependent mechanism to inhibit the expression level of HuR, thereby reducing the stability of MMP-9 mRNA.

Mohamed H. Abdel-Wahab

Papers

Thymoquinone is a potent superoxide anion scavenger

The influence of thymoquinone on doxorubicin-induced hyperlipidemic nephropathy in rats

Nitric oxide increases the decay of matrix metalloproteinase 9 mRNA by inhibiting the expression of mRNA-stabilizing factor HuR.

Influence of p-coumaric acid on doxorubicin-induced oxidative stress in rat's heart

Protective effects of vitamin e and probucol against gentamicin-induced nephrotoxicity in rats.