Bahia Djerdjouri

Catecholamine-induced cardiac mitochondrial dysfunction and mPTP opening: protective effect of curcumin

The present study was designed to characterize the mitochondrial dysfunction induced by catecholamines and to investigate whether curcumin, a natural antioxidant, induces cardioprotective effects against catecholamine-induced cardiotoxicity by preserving mitochondrial function. Because mitochondria play a central role in ischemia and oxidative stress, we hypothesized that mitochondrial dysfunction is involved in catecholamine toxicity and in the potential protective effects of curcumin. Male Wistar rats received subcutaneous injection of 150 mg·kg(-1)·day(-1) isoprenaline (ISO) for two consecutive days with or without pretreatment with 60 mg·kg(-1)·day(-1) curcumin. Twenty four hours after, cardiac tissues were examined for apoptosis and oxidative stress. Expression of proteins involved in mitochondrial biogenesis and function were measured by real-time RT-PCR. Isolated mitochondria and permeabilized cardiac fibers were used for swelling and mitochondrial function experiments, respectively. Mitochondrial morphology and permeability transition pore (mPTP) opening were assessed by fluorescence in isolated cardiomyocytes. ISO treatment induced cell damage, oxidative stress, and apoptosis that were prevented by curcumin. Moreover, mitochondria seem to play an important role in these effects as respiration and mitochondrial swelling were increased following ISO treatment, these effects being again prevented by curcumin. Importantly, curcumin completely prevented the ISO-induced increase in mPTP calcium susceptibility in isolated cardiomyocytes without affecting mitochondrial biogenesis and mitochondrial network dynamic. The results unravel the importance of mitochondrial dysfunction in isoprenaline-induced cardiotoxicity as well as a new cardioprotective effect of curcumin through prevention of mitochondrial damage and mPTP opening.

Aminoguanidine and curcumin attenuated tumor necrosis factor (TNF)-α-induced oxidative stress, colitis and hepatotoxicity in mice

The up regulation of gut mucosal cytokines such as tumor necrosis factor (TNF)-α and oxidative stress have been related to inflammatory bowel diseases (IBD) such as ulcerative colitis (UC) and Crohns disease (CD). This study investigated an immune-mediated model of colitis. TNF-α injected intraperitonally to mice induced a dose-dependent recruitment of neutrophils into abdominal mesentery. The leukocytes influx induced by TNF-α (10 μg kg(-1) body weight) increased by 3 fold liver and colon damage scores. TNF-α-colitis was characterized by hemorrhagic edemas and crypt abscesses massively infiltrated by inflammatory cells, namely neutrophils. Moreover, TNF-α-toxicity resulted in liver steatosis and foci of necrosis infiltrated by Kupffer cells and neutrophils in parenchyma and around the centrilobular veins. The involvement of oxidative stress was evaluated using aminoguanidine (AG) as selective inhibitor of inducible NO synthase (iNOS) and curcumin (Cur), the polyphenolic antioxidant of turmeric (Curcuma longa L.). TNF-α-toxicity led to significant increase in myeloperoxidase (MPO, an index of neutrophils infiltration), nitrites (stable nitric oxide metabolites) and malondialdehyde (MDA, a marker of lipid peroxides) levels and cell apoptosis in liver and colon. AG and Cur treatments significantly attenuated the hallmarks of oxidative stress, neutrophils influx and ROS-related cellular and histological damages, in TNF-α-treated mice. Taken together, our results provide insights into the role of phagocytes-derived oxidants in TNF-α-colitis in mice. Cur and AG, by inhibiting neutrophils priming and iNOsynthase could be effective against oxidative bowel damages induced in IBD by imbalanced gut immune response.

Melatonin administration to wild-type mice and nontreated NLRP3 mutant mice share similar inhibition of the inflammatory response during sepsis

The NLRP3 inflammasome is involved in the innate immune response during inflammation. Moreover, melatonin blunts the NF‐κB/NLRP3 connection during sepsis. Thus, we compared the roles of the NLRP3 inflammasome and/or melatonin treatment in the septic response of wild‐type and NLRP3−/− mice. Mouse myocardial tissue was used for this purpose. The nuclear turnover of NF‐κB was enhanced during sepsis, with an increase in TNFα, iNOS, and pro‐IL‐1β. The lack of inflammasome in NLRP3−/− mice significantly reduced that response and blunted IL‐1β maturation due to the lack of caspase‐1. Clock and Bmal1 did not change in both mouse strains, enhancing Chrono expression in mutants. RORα, which positively regulates Bmal1, was enhanced at a similar extend in both mouse strains, whereas the expression of the Bmal1 repressor, Rev–Erbα, increased in WT but was depressed in NLRP3−/− mice. Nampt, transcriptionally controlled by Bmal1, increased in WT mice together with Sirt1, whereas they remained unchanged in NLRP3−/− mice. Melatonin treatment reduced the septic response in a comparable manner as did the lack of NLRP3, but unlike the latter, it normalized the clock genes turnover through the induction of RORα and repression of Rev–Erbα and Per2, leading to enhanced Nampt and Sirt1. The lack of NLRP3 inflammasome converts sepsis to a moderate inflammatory disease and identifies NLRP3 as a main target for the treatment of sepsis. The efficacy of melatonin in counteracting the NLRP3 inflammasome activation further confirms the indoleamine as a useful therapeutic drug against this serious condition.

Hyperhomocysteinemia Is a Risk Factor for Alzheimer's Disease in an Algerian Population

BACKGROUND AND AIMSnThere is growing evidence that increased blood concentration of total homocysteine (tHcy) may be a risk factor for Alzheimers disease (AD). The present study was conducted to evaluate the association of serum tHcy and other biochemical risk factors with AD.nnnMETHODSnThis is a case-control study including 41 individuals diagnosed with AD and 46 nondemented controls. Serum levels of all studied biochemical parameters were performed.nnnRESULTSnUnivariate logistic regression showed a significant increase of tHcy (p = 0.008), urea (p = 0.036) and a significant decrease of vitamin B12 (p = 0.012) in AD group vs. controls. Using multivariate logistic regression, tHcy (p = 0.007, OR = 1.376) appeared as an independent risk factor predictor of AD. There was a significant positive correlation between tHcy and creatinine (p <0.0001). A negative correlation was found between tHcy and vitamin B12 (p <0.0001).nnnCONCLUSIONSnOur findings support that hyperhomocysteinemia is a risk factor for AD in an Algerian population and is also associated with vitamin B12 deficiency.

Oxidative Status and Plasma Lipid Profile in β-Thalassemia Patients

Abstract β-Thalassemia (β-thal) is a genetic disorder, representing a major health problem in Algeria. It is associated with altered lipid levels and a state of oxidative stress that can lead to cardiac complications and premature death. We examined the plasma lipid profile and redox status of 46 patients with β-thal major (β-TM) and β-thal intermedia (β-TI) compared to 36 healthy subjects. Plasma lipids including total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were investigated. Oxidative status was evaluated by measuring malondialdehyde (MDA), reduced glutathione (GSH) and catalase (CAT) activity. The potential relationships between these parameters and the hemoglobin (Hb) blood concentrations, serum ferritin, duration and frequency of transfusion, splenectomy as well as age, were examined. Our data indicated that the study patients were under increased state of oxidative stress associated with hypertriglyceridemia, and hypocholesterolemia. The CAT activity was negatively correlated with Hb concentration and LDL-C/TG ratio and positively with years of transfusion. The elevated TC/HDL-C ratio particularly in β-TM patients who were younger, correlated positively with ferritinemia and triglyceride levels and suggested an increased coronary risk. This heightened risk state should lead to the inclusion of this index (TC/HDL-C) in clinical management, particularly in splenectomized patients.

Lysophosphatidylcholine exacerbates Leishmania major-dendritic cell infection through interleukin-10 and a burst in arginase1 and indoleamine 2,3-dioxygenase activities

Leishmania major is an obligate intracellular parasite hosted by phagocytes, including dendritic cells (DCs). Lysophosphatidylcholine (LPC) a pro-oxidant by-product of phospholipase A2 activity can modulate the maturation and function of DCs. However, little is known about its role in L. major infection. This study examined the effects of LPC and lipopolysaccharide (LPS) in BALB/c mouse-derived DC infection by L. major promastigotes, in vitro. Our results showed early divergent effects of LPS and LPC, which lasted up to 24h. In contrast to LPS, LPC worsened DC infection by reversing the immune balance IL-10 vs. TNF-α and IL-6, and inducing a sharp down regulation of CD40 and iNOsynthase activity. In addition, LPC potentiated xanthine oxidase stress, the production of kynurenine by indoleamine 2,3 dioxygenase (IDO), and arginase1 activity in the expense of iNOsynthase. Taken together, our results highlight some biochemical events bypassing the protective Th1 response. They suggest that LPC could facilitate the proliferation of this obligate intracellular parasite by neutralizing oxidative and nitrosative stresses and sustaining both IDO and arginase1 activities.

Ethanolic Extract of Bark from Salix aegyptiaca Ameliorates 1,2-dimethylhydrazine-induced Colon Carcinogenesis in Mice by Reducing Oxidative Stress

ABSTRACT We have previously shown that ethanolic extract from bark (EEB) of Salix aegyptiaca (Musk Willow) can inhibit proliferation and motility and induce apoptosis in colon cancer cells. Tandem mass spectrometry revealed EEB to be rich in catechin, catechol, and salicin. The present study investigated the chemopreventive effect of HPLC-fingerprinted EEB on 1,2-dimethylhydrazine (DMH)-induced aberrant crypt foci (ACF) formation in mice. DMH (20 mg/kg body weight) was weekly injected subcutaneously to mice for the first 2 weeks. EEB (100 and 400 mg/kg body weight) was provided orally from the 7th to 14th week, after which colon tissues were evaluated histologically and biochemically. DMH treatment induced high number of ACF; EEB significantly reduced the number and multiplicity of ACF, along with a restoration in goblet cells and mucin accumulation. EEB supplementation improved the markers of inflammation (myeloperoxidase and neutrophil infiltration) and oxidative stress. More importantly, EEB amplified apoptosis of neoplastic cells in the colon mucosa of DMH-treated mice. It also lowered levels of markers for early transformation events such as EGFR, nuclear β-catenin, and COX-2 in colon cancer cell lines HT-29 and HCT-116. The innocuity of EEB (up to 1600 mg/kg) to mice reinforces its potential as a chemopreventive agent.

Phytochemical composition of the Algerian Laurus nobilis L. leaves extracts obtained by solvent-free microwave extraction and investigation of their antioxidant activity

Abstract This paper focuses the phytochemical composition of bay leaves essential oils obtained by solvent-free microwave extraction (SFME) and by the hydrodistillation (HD) for comparison. Essential oils had similar qualitative but different quantitative composition. For HD and SFME, the main constituents on the oils differed respectively in 1,8-cineole (26.4–30.9)%, sabinene (9–9.6)%, alpha-terpinyl acetate (9.5–7.8)%, linalool (4.9–9.5)%, alpha-terpineol (3.3–7.6)%, alpha-pinene (9.2–4.6)%, methyl eugenol (5–6.2)% and eugenol (1.2–3.6)%. The HD essential oil and SFME volatile extract inhibited nitric oxide production by stimulated mice peritoneal neutrophils (IC50: 6.65 and 13.75) mg/mL and dose dependently scavenged superoxide anion (IC50: 0.048 and 0.058) mg/mL. Inversely, these volatile extracts enhanced myeloperoxidase release (EC50: 0.72 and 0.29) mg/mL. Moreover, the potentiating effect of laurel extracts on exocytosis granules could collaborate in trapping and killing of extracellular pathogens by neutrophils extracellular traps (NETs).

Precancerous ACF induction affects their regional distribution forsaking oxidative stress implication in 1,2-dimethylhydrazine-induced colon carcinogenesis model

Colon cancer is thought to develop in a stepwise fashion. In this study, the relationship between aberrant crypt foci (ACF) regional distribution and oxidative stress evolution was studied in a murine model of initial colon carcinogenesis induced by dimethylhydrazine (DMH). Mice were given 2 weekly subcutaneous injections of DMH (20xa0mg/kg) and killed at the 10th, 12th or 14th week. ACF was scored for number, distribution and crypt multiplicity after methylene-blue coloration and histologically analyzed afterwards. Oxidative stress evaluation was assessed through myeloperoxidase activity (MPO), nitric oxide (NO), l-ornithine and malondialdehyde (MDA) levels as well as antioxidant CAT, SOD and GSH. DMH treatment showed a shift from small to large ACF but also from distal to proximal colon between week 10 and 14 (pxa0<xa00.05). This was further illustrated histologically with crypt disruption and mucin depletion. Oxidative stress imbalance was observed in all DMH-treated groups. All markers (MPO, MDA and NO) peaked at week 12 (pxa0<xa00.01) and decreased at week 14 (pxa0<xa00.05) while l-ornithine decreased through all protocol (pxa0<xa00.01). Antioxidants decreased in all points (pxa0<xa00.05) but only GSH increased at week 14 (pxa0<xa00.05). This work provided insight to response-patterns of oxidative stress between distal and proximal colon, showing for the first time a decreasing implication during the development process and suggesting other inflammatory, immunologic or microbiota implication as factors to be considered during chemotherapy approaches.

Caffeic acid combined with autoclaved Leishmania major boosted the protection of infected BALB/c mice by enhancing IgG2 production, IFN-γ/TGF-β and iNO synthase/arginase1 ratios, and the death of infected phagocytes

BackgroundImmunization with killed Leishmania promastigotes without adjuvant was considered as safe, but gave variable rates of protection. Taking advantage of the immuno-modulatory effect of caffeic acid (CA), a natural polyphenolic antioxidant, we investigated its potentiating effect in autoclaved Leishmania major (ALM)-induced protection of Leishmania major-infected BALB/c.MethodsFirst, BALB/c mice were sensitized for 6xa0weeks either with CA, or ALM alone or combined with caffeic acid (ALM–CA) or Freund’s adjuvant (ALM–FA), and subsequently infected with L. major promastigotes. Second, to test the curative effect, CA was given daily for 5xa0weeks to susceptible mice, starting on week 4 post-infection. Sera, footpads and lymph nodes (LNs) were collected at week 9 post-infection and submitted to biochemical or histological analyses.ResultsCompared to the respective controls, our results showed that CA directly healed footpad lesions and reduced the hallmarks of cutaneous leishmaniasis including oxidative inflammation, parasite load, and phagocytes influx and infestation. In sensitized mice, the protection enhanced gradually from ALM–FA, CA, ALM to ALM–CA in parallel to decreased seric IgGt levels. In contrast to ALM–FA, the combined effect of ALM and CA increased specific isotype IgG2, and decreased IL-17 and MCP-1, and phagocyte influx, as attested by the concomitant reduction in myeloperoxidase (MPO) and α-naphthyl acetate esterase (ANAE) activities. ALM–CA shifted IFN-γ/TGF-β and iNO synthase/arginase1 (iNOS/Arg1) balances in a Th1 immune response that control efficiently cutaneous lesions and LNs hypertrophy, and reactivate the death of infected phagocytes.ConclusionsTherefore, CA combined with ALM synergizes with L. major antigens for priming innate cells, through early polarization to optimal Th1 response that leads to IFN-γ and iNOS-dependent leishmanicidal activity of neutrophils and macrophages.Graphical Abstract