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      Protective Effects of Liposomal Curcumin on Oxidative Stress/Antioxidant Imbalance, Metalloproteinases 2 and -9, Histological Changes and Renal Function in Experimental Nephrotoxicity Induced by Gentamicin

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          Abstract

          Background: Our study aimed to assess the efficiency of Curcumin nanoformulation (LCC) on experimental nephrotoxicity induced by Gentamicin in rats. Methods: Six groups of seven rats were used: C—(control group) received saline solution i.p. (i.p. = intraperitoneal), G—gentamicin (G, 80 mg/kg body weight (b.w.)), GCC1 and GCC2—with G and CC solution (single dose of 10 mg/kg b.w.-CC1, or 20 mg/kg b.w.-CC2), GLCC1 (10 mg/kg b.w.) and GLCC2 (20 mg/kg b.w.) with G and LCC administration. Oxidative stress parameters (NOx = nitric oxide, MDA = malondialdehyde, TOS = total oxidative stress), antioxidant parameters (CAT = catalase, TAC = total antioxidant capacity), matrix metalloproteinases (MMP-2 and MMP-9), and renal function parameters (creatinine, blood urea nitrogen, and urea) were measured. Kidneys histopathologic examination was made for each group. Results: Pretreatment with CC and LCC in both doses had significantly alleviating effects on assessed parameters (NOx, MDA, TOS, CAT, TAC, MMP-2, and -9) as compared with the untreated group ( p < 0.006). Histopathological aspect and renal function were significantly improved in CC and LCC groups. Liposomal formulation (LCC) showed higher efficiency on all examined parameters compared to CC ( p < 0.006). Conclusions: Our results demonstrated improving renal function and kidney cytoarchitecture, oxidative stress/antioxidant/balance, and MMPs plasma concentrations with better dose-related efficacity of LCC than CC.

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          Byproducts of normal mitochondrial metabolism and homeostasis include the buildup of potentially damaging levels of reactive oxygen species (ROS), Ca(2+), etc., which must be normalized. Evidence suggests that brief mitochondrial permeability transition pore (mPTP) openings play an important physiological role maintaining healthy mitochondria homeostasis. Adaptive and maladaptive responses to redox stress may involve mitochondrial channels such as mPTP and inner membrane anion channel (IMAC). Their activation causes intra- and intermitochondrial redox-environment changes leading to ROS release. This regenerative cycle of mitochondrial ROS formation and release was named ROS-induced ROS release (RIRR). Brief, reversible mPTP opening-associated ROS release apparently constitutes an adaptive housekeeping function by the timely release from mitochondria of accumulated potentially toxic levels of ROS (and Ca(2+)). At higher ROS levels, longer mPTP openings may release a ROS burst leading to destruction of mitochondria, and if propagated from mitochondrion to mitochondrion, of the cell itself. The destructive function of RIRR may serve a physiological role by removal of unwanted cells or damaged mitochondria, or cause the pathological elimination of vital and essential mitochondria and cells. The adaptive release of sufficient ROS into the vicinity of mitochondria may also activate local pools of redox-sensitive enzymes involved in protective signaling pathways that limit ischemic damage to mitochondria and cells in that area. Maladaptive mPTP- or IMAC-related RIRR may also be playing a role in aging. Because the mechanism of mitochondrial RIRR highlights the central role of mitochondria-formed ROS, we discuss all of the known ROS-producing sites (shown in vitro) and their relevance to the mitochondrial ROS production in vivo. Copyright © 2014 the American Physiological Society.
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            At high concentrations, free radicals and radical-derived, nonradical reactive species are hazardous for living organisms and damage all major cellular constituents. At moderate concentrations, however, nitric oxide (NO), superoxide anion, and related reactive oxygen species (ROS) play an important role as regulatory mediators in signaling processes. Many of the ROS-mediated responses actually protect the cells against oxidative stress and reestablish "redox homeostasis." Higher organisms, however, have evolved the use of NO and ROS also as signaling molecules for other physiological functions. These include regulation of vascular tone, monitoring of oxygen tension in the control of ventilation and erythropoietin production, and signal transduction from membrane receptors in various physiological processes. NO and ROS are typically generated in these cases by tightly regulated enzymes such as NO synthase (NOS) and NAD(P)H oxidase isoforms, respectively. In a given signaling protein, oxidative attack induces either a loss of function, a gain of function, or a switch to a different function. Excessive amounts of ROS may arise either from excessive stimulation of NAD(P)H oxidases or from less well-regulated sources such as the mitochondrial electron-transport chain. In mitochondria, ROS are generated as undesirable side products of the oxidative energy metabolism. An excessive and/or sustained increase in ROS production has been implicated in the pathogenesis of cancer, diabetes mellitus, atherosclerosis, neurodegenerative diseases, rheumatoid arthritis, ischemia/reperfusion injury, obstructive sleep apnea, and other diseases. In addition, free radicals have been implicated in the mechanism of senescence. That the process of aging may result, at least in part, from radical-mediated oxidative damage was proposed more than 40 years ago by Harman (J Gerontol 11: 298-300, 1956). There is growing evidence that aging involves, in addition, progressive changes in free radical-mediated regulatory processes that result in altered gene expression.
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              How antibiotics kill bacteria: from targets to networks.

              Antibiotic drug-target interactions, and their respective direct effects, are generally well characterized. By contrast, the bacterial responses to antibiotic drug treatments that contribute to cell death are not as well understood and have proven to be complex as they involve many genetic and biochemical pathways. In this Review, we discuss the multilayered effects of drug-target interactions, including the essential cellular processes that are inhibited by bactericidal antibiotics and the associated cellular response mechanisms that contribute to killing. We also discuss new insights into these mechanisms that have been revealed through the study of biological networks, and describe how these insights, together with related developments in synthetic biology, could be exploited to create new antibacterial therapies.
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                Author and article information

                Contributors
                Role: Academic Editor
                Role: Academic Editor
                Journal
                Antioxidants (Basel)
                Antioxidants (Basel)
                antioxidants
                Antioxidants
                MDPI
                2076-3921
                22 February 2021
                February 2021
                : 10
                : 2
                : 325
                Affiliations
                [1 ]Department of Pathophysiology, Iuliu Hațieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; adriana.bulboaca@ 123456umfcluj.ro (A.E.B.); boarescu.paul@ 123456umfcluj.ro (P.-M.B.)
                [2 ]Department of Pharmaceutical Technology and Biopharmaceutics, Iuliu Hațieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; alinatuns@ 123456yahoo.com
                [3 ]Department of Medical Informatics and Biostatistics, Iuliu Hațieganu University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania
                [4 ]Department of Ophthalmology, Iuliu Hațieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; cristina.nicula@ 123456umfcluj.ro
                [5 ]Department of Orthodontics, Iuliu Hațieganu University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania; dana.festila@ 123456gmail.com
                [6 ]Department of Periodontology, Iuliu Hațieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; veve_alexandra@ 123456yahoo.com
                [7 ]Department of Pneumology, Iuliu Haţieganu University of Medicine and Pharmacy, 400371 Cluj-Napoca, Romania; andra_redro@ 123456yahoo.com
                [8 ]Department of Occupational Medicine, Iuliu Haţieganu University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania; armand.rajnoveanu@ 123456umfcluj.ro
                [9 ]Department of Physical Medicine and Rehabilitation, Iuliu Haţieganu University of Medicine and Pharmacy, 400347 Cluj-Napoca, Romania; dogarugabrielaumf@ 123456gmail.com
                [10 ]Department of Cell Biology, Histology and Embryology, University of Agricultural Sciences and Veterinary Medicine, 400375 Cluj-Napoca, Romania; vasile.rus@ 123456usamvcluj.ro
                [11 ]Department of Neurology, Iuliu Haţieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; angelo.bulboaca@ 123456yahoo.com (C.A.B.); ioana.stanescu.umfcluj@ 123456gmail.com (I.S.)
                [12 ]Faculty of Medicine, Iuliu Haţieganu University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania; bulboaca.alexandra@ 123456yahoo.com
                Author notes
                [* ]Correspondence: sbolboaca@ 123456umfcluj.ro ; Tel.: +40-374-834-506
                Author information
                https://orcid.org/0000-0001-6185-7129
                https://orcid.org/0000-0002-2342-4311
                https://orcid.org/0000-0002-3222-6448
                https://orcid.org/0000-0003-3377-593X
                https://orcid.org/0000-0002-0649-9426
                https://orcid.org/0000-0003-0226-1733
                https://orcid.org/0000-0001-8816-9676
                https://orcid.org/0000-0003-0613-9575
                Article
                antioxidants-10-00325
                10.3390/antiox10020325
                7926985
                b2acd1e8-0f62-47ab-8aa5-5d5dcd7f44f9
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 31 January 2021
                : 18 February 2021
                Categories
                Article

                gentamicin induced nephrotoxicity,curcumin,oxidative stress

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