Journal of ISSN: 2581-7310 Inno Volume 1: 2 Health Science and Development J Health Sci Dev 2018

Linoleic Acid: The Code of Life?

Joseph Eldor1* 1Joseph Eldor, Theoretical Medicine Institute, Jerusalem, Israel

Abstract Article Information Intralipid® 20% is made up of 20% Soybean Oil, 1.2% Egg Yolk Article Type: : Research Phospholipids, 2.25% Glycerine, and Water for Injection. The major Article Number: JHSD114 component fatty acids are linoleic acid (44-62%), oleic acid (19-30%), Received Date: 30 August, 2018 palmitic acid (7-14%), a-linolenic acid (4-11%) and stearic acid (1.4- Accepted Date: 26 September, 2018 5.5%). It means that the various effects of Intralipid are based 63% to Published Date: 10 September, 2018 92% on linoleic acid and oleic acid. *Corresponding author: Joseph Eldor, Theoretical Are these 2 fatty acids the Code of Life? Medicine Institute, Jerusalem, Israel, Tel: +972-2-5835528; Email: csen_international(at)csen.com Linoleic acid has effects on the mitochondria. Linoleic acid has effects on Cancer. Linoleic acid has effects on Aging. Citation: Eldor J (2018) Linoleic Acid: The Code of Life?. Keywords Linoleic acid, Oleic acid, Intralipid, Mitochondria, Cancer, J Health Sci Dev Vol: 1, Issu: 2 (18-32). Aging.

The Basis of Intralipid Copyright: © 2018 Eldor J. This is an open-access article Intralipid® 20% (A 20% I.V. Fat Emulsion) Pharmacy Bulk Package distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, is a sterile, non-pyrogenic fat emulsion intended as a source of calories distribution, and reproduction in any medium, provided the and essential fatty acids for use in a pharmacy ad- mixture program. It original author and source are credited. is made up of 20% Soybean Oil, 1.2% Egg Yolk Phospholipids, 2.25% Glycerine, and Water for Injection. In addition, sodium hydroxide has been added to adjust the pH so that the final product pH is 8. pH range is 6 to 8.9. of neutral triglycerides of predominantly unsaturated fatty acids. The majorThe component soybean oil fatty is a acidsrefined are natural linoleic product acid (44-62%), consisting oleic of a acid mixture (19- 30%), palmitic acid (7-14%), a-linolenic acid (411%) and stearic acid (1.4-5.5%). It means that the various effects of Intralipid are based 63% to 92% on linoleic acid and oleic acid. Are these 2 fatty acids the Code of Life? Linoleic acid belongs to one of the two families of essential fatty acids, which means that the human body cannot synthesize it from other food components.

Linoleic Acid (C18H32O2) A carboxylic acid, is a polyunsaturated omega-6 fatty acid, an

It18-carbon typically chain occurs with in naturetwo double as a bondstriglyceride in cisconfiguration. ester; free fatty A shorthand acids are typicallynotation lowlike in“18:2 foods. (n-6)” or “18:2 cis-9, 12” may be used in literature. Linoleic acid belongs to one of the two families of essential fatty acids, which means that the human body cannot synthesize it from other food components. The word “linoleic” derived from the Greek word linon (flax). Oleic means “of, relating to, or derived from oil of olive” or www.innovationinfo.org apoptosis by enhancing cellular oxidant status and inducing double bond produces oleic acid. mitochondrial dysfunction [2]. “of or relating to oleic acid” because saturating the omega-6 Colorectal cancer is common in developed countries. Oleic acid (C18H34O2) Polyunsaturated fatty acids (PUFAs) have been reported to Oleic acid is a fatty acid that occurs naturally in various possess tumoricidal action, but the exact mechanism of their animal and vegetable fats and oils. It is an odourless, colourless action is not clear. oil, though commercial samples may be yellowish. In In the present study, we studied the effect of various n-6 and n-3 fatty acids on the survival of the colon cancer cells chemical terms, oleic acid is classified as a monounsaturated LoVo and RKO and evaluated the possible involvement of a cis-9. It has the formula CH3(CH2)7CH=CH(CH2)7COOH. The omega-9 fatty acid, abbreviated with a lipid number of 18:1 mitochondrial pathway in their ability to induce apoptosis which is mostly composed of oleic acid. [3]. term “oleic” means related to, or derived from, olive oil Linoleic Acid and Cancer eicosapentaenoic acid and docosahexaenoic acid (ALA, EPA Conjugated Linoleic Acid (CLA) is fatty acid found andIt DHA was respectively) observed and n-6 that linoleic n-3 acid, α-linolenic gamma linolenic acid, endogenously in food sources that prevents new tumor acid and arachidonic acid (LA, GLA and AA respectively) development and reduces the growth of existing tumors in induced apoptosis of the colon cancer cells LoVo and RKO at laboratory animals. CLA exerts its anti-carcinogenic effect by reducing VEGF and bFGF serum levels and by blocking The semi-differentiated colon cancer cell line RKO was more sensitiveconcentrations to the above cytotoxic 120 μMaction (p< of 0.01 PUFAs compared compared to control). to the to tumor growth and survival. Although the ability of CLA undifferentiated colon cancer cell line LoVo. PUFA treated toflk-1 inhibit receptors, angiogenesis thereby in inhibiting the peripheral vascular nervous growth system critical is cells showed an increased number of lipid droplets in their well characterized, it remains unknown whether CLA also cytoplasm. PUFA-induced apoptosis of LoVo and RKO cells affects vascular morphology in the central nervous system. is mediated through a mitochondria-mediated pathway as Therefore, in the present study, exercising and sedentary evidenced by loss of mitochondrial membrane potential, animals received either standard rat chow or a specially generation of ROS, accumulation of intracellular Ca(2+), formulated diet consisting of 0.5% CLA for 24 days. The activation of caspase-9 and caspase-3, decreased ATP level brains were then examined to determine the extent of and increase in the Bax/Bcl2 expression ratio. vascular growth in the cerebellum, a region known to exhibit robust exercise-induced angiogenesis. Our results indicate PUFAs induced apoptosis of colon cancer cells through a mitochondrial dependent pathway [3]. Activity and expression of fatty acid synthase (FAS), a critical enzyme anti-angiogenicthat CLA administration effect of CLAsignificantly in the brain, reduces and suggestsangiogenesis that in the de novo biosynthesis of fatty acids in mammals, is CLAin the be cerebellum. explored as This a therapeutic study is the treatment first to demonstrate for cancer andthe exquisitely sensitive to nutritional regulation of lipogenesis tumors in the brain [1]. in liver or adipose tissue. Surprisingly, a number of studies have demonstrated hyperactivity and overexpression of Some polyunsaturated fatty acids (PUFAs), if not all, FAS (oncogenic antigen-519) in a biologically aggressive have been shown to have tumoricidal action, but their exact subset of human breast carcinomas, suggesting that mechanism(s) of action is not clear. In the present study, we FAS-dependent neoplastic lipogenesis is unresponsive observed that n-6 PUFA linoleic acid (LA) inhibited tumor to nutritional regulation. We have assessed the role of omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) on the enzymatic activity and protein expression of tumor- Analysiscell growth of cell at highmitochondrial concentrations membrane (above potential, 300 μM); reactive while associated FAS in SK-Br3 human breast cancer cells, an oxygenlow concentrations species (ROS) (100200 formation, μM) promoted malondialdehyde proliferation (MDA) [2]. experimental paradigm of FAS over expressing tumor cells accumulation and superoxide dismutase (SOD) activity suggested that anti-cancer action of LA is due to enhanced the cytosolic proteins [4]. Of the omega-3 PUFAs tested, ROS generation and decreased cell antioxidant capacity alpha-linolenicin which FAS enzyme acid (ALA) constitutes dramatically up to reduced 28%, by FAS weight, activity of that resulted in mitochondrial damage. Of the three cell in a dose-dependent manner (up to 61%). omega-3 PUFA lines tested, semi-differentiated colorectal cancer cells RKO docosahexaenoic acid (DHA) demonstrated less marked but were most sensitive to the cytotoxic action of LA, followed by undifferentiated colorectal cancer cell line (LOVO) while whereas eicosapentaenoic acid (EPA) was not effective. Of the the normal human umbilical vein endothelial cells (HUVEC) omega-6still significant fatty acids inhibitory tested, effects gamma-linolenic on FAS activity acid (up (GLA) to 37%), was were the most resistant (the degree of sensitivity to LA is the most effective dose-dependent inhibitor of FAS activity, with a greater than 75% FAS activity reduction. Remarkably, primed by mitochondrial apoptotic pathway. Preincubation omega-6 PUFAs linoleic acid (LA) and arachidonic acid as follows: RKO>LOVO>HUVEC). LA induced cell death was (ARA), suppressors of both hepatic and adipocytic FAS- of differentiated and semi-differentiated cells to the subsequentof cancer cells exposure with 100 to μM LA. LA The for relative 24 hr enhanced resistance sensitivity of LOVO on the activity of tumor associated FAS in SK-Br3 breast cells to the cytotoxic action of LA is due to a reduction in cancerdependent cells. lipogenesis, Western blotting had no significantstudies showed inhibitory that effectsdown- the activation of caspase-3. Thus, LA induced cancer cell regulation of FAS protein expression tightly correlated with

ISSN: 2581-7310 19 www.innovationinfo.org previously observed inhibition of FAS activity, suggesting green tea polyphenol epigallocatechin-3-gallate (EGCG) and that ALA-, DHA-, and GLA-induced changes in FAS activity resulted from effects at the protein level. We investigated and kaempferol), as well as the antibiotic triclosan, have whether the FAS inhibitory effect of GLA and omega-3 other naturally occurring flavonoids (i.e., luteolin, quercetin, PUFAs correlated with a cytotoxic effect related to a per- growth by inducing apoptotic cell death. Though the exact oxidative mechanism [4]. Measurement of cell viability by modebeen identifiedof action of and these have FASN been inhibitors shown is to under limit cancerdiscussion, cell it has been revealed that depletion of end-product fatty acids, toxic intracellular accumulation of supra-physiological correlationMTT assay indicatedbetween thea significant ability of PUFAscellular to toxicity repress after FAS ALAand concentrations of the FASN substrate malonyl-CoA and/or causeand GLA cell exposures. toxicity. In Furthermore, the presence weof anti-oxidantsobserved a significant (vitamin limited membrane synthesis and/or functioning by altered E), ALA and GLA dramatically lost their ability to inhibit FAS production of phospholipids partitioning into detergent- activity. resistant membrane microdomains (lipid raft-aggregates), can explain, at least in part, the cytostatic, cytotoxic as well Interestingly, a combination of ALA and GLA was FAS as the apoptotic effects occurring upon pharmacological inhibitory in an additive manner, and this FAS repression inhibition of FASN activity in cancer cells. was only partially reversible by vitamin E. In examining the molecular mechanisms underlying resistance of breast Moreover, several cancer-associated molecular features cancer-associated FAS to normal dietary fatty acid-induced including nonfunctioning p53, overexpression of the Her- suppression, a dramatic decrease of FAS accumulation was 2/neu (erbB-2) oncogene, and hyperactivation of the PI- found after exposure of SK-Br3 cells to mitogen-activated 3’K downstream effector protein kinase B (AKT), appear to protein kinase (MAPK) extracellular signal-regulated kinase determine an exacerbated sensitivity to FASN inhibition- (MAPK ERK1/2) inhibitor U0126, phosphatidylinositol-3’- induced cancer cell death. Although few of these inhibitors kinase (PI-3’K) blocker LY294002, and/or anti-HER-2/neu antibody trastuzumab. Interestingly, a long-term exposure potential of FASN as a target for antineoplastic intervention to pharmacological inhibitors of FAS activity cerulenin are expected to be “exclusively” selective for FASN, the [(2S,3R) 2,3-epoxy-4-oxo7E,10E-dodecadienamide] or C75 knockdown of FASN. Certainly, future studies should has eventually been confirmed by RNA interference (RNAi)- FASN inhibition and cancer cell death. Although the inducedalso resulted repression in a significant of tumor reduction associated of FASFAS mayaccumulation. result, at combinationdefinitely elucidate of FASN the structural ultimate complexity biochemical and linkuntil betweenrecently These data indicate that: a) GLA- and omega-3 PUFA- the lack of X-ray crystallography data of mammalian FASN oxidative mechanisms; b) alternatively, GLA and omega-3 PUFAsleast in havepart, froma suppressive a non-specific effect cytotoxic on FAS effect expression due to per-and a valuable target for drug development, it is hoped that the improvementcreated a significant in the challengeselectivity in and the potency exploitation of forthcoming of FASN as of the FAS substrate malonyl-CoA; c) GLA- and/or omega-3 novel FASN-targeted small molecule inhibitors by taking PUFA-inducedactivity that can repression result in theof tumor accumulation associated of toxic FAS fluxes may advantage, for instance, of the recent 4.5 A resolution X-ray represent a novel mechanism of PUFA induced cytotoxicity crystallographic map of mammalian FASN, will direct the clinically useful against breast carcinomas carrying foundation of a new family of chemotherapeutic agents in overexpression of FAS enzyme; d) fundamental differences cancer history [5]. in the ability of FAS gene to respond to normal fatty acid’s Obesity with excessive levels of circulating free fatty acids regulatory actions in lipogenic tissues may account for the (FFAs) is tightly linked to the incidence of type 2 diabetes. observed extremely high levels of FAS in breast carcinoma; and e) FAS overexpression in SK-Br3 breast cancer cells dysfunction are two major pathological changes in diabetes is driven by increases in HER-2/neu signaling, acting in andInsulin both resistance are facilitated of peripheral by excessive tissues levels and pancreatic of FFAs and/or β-cell major part through a constitutive downstream art through glucose. To gain insight into the mitochondrial mediated a constitutive downstream activation of the MAPK ERK1/2 mechanisms by which long-term exposure of INS-1 cells and PI-3’K/AKT transduction cascades [4]. The expression and activity of Fatty Acid Synthase (FASN; the sole enzyme capable of the reductive de novo to excess FFAs causes β-cell dysfunction, the effects of the synthesis of long chain fatty acids from acetyl-CoA, malonyl- unsaturated FFA linoleic acid (C 18:2, n-6) on rat insulinoma CoA, and nicotinamide adenine dinucleotide phosphate INS-1 β cells was investigated. INS-1 cells were incubated -NADPH-) is extremely low in nearly all non-malignant adult (25with mM) 0, 50, glucose 250 or 500in serum-free μM linoleic RPMI-1640 acid/0.5% (w/v)medium. BSA Cell for viability,48 h under apoptosis, culture glucose-stimulatedconditions of normal insulin (11.1 secretion, mM) or high Bcl- in many cancer types, thus creating the potential for a 2, and Bax gene expression levels, mitochondrial membrane largetissues, therapeutic whereas it index.is significantly Since the up-regulated pioneering orobservation activated potential and cytochrome c release were examined. Linoleic that inhibition of FASN activity by the mycotoxin cerulenin preferentially kills cancer cells and retards the growth of induced apoptosis when administered in 11.1 and 25 mM tumors in xenografts models, numerous in vitro and in vivo glucoseacid 500 culture μM significantly medium. Compared suppressed with cell control, viability linoleic and antineoplastic intervention. Other FASN inhibitors such as glucose culture medium but not in 11.1 mM glucose culture thestudies cerulenin have confirmed derivative the C75, potential the beta-lactone of FASN as orlistat, a target thefor medium.acid 500 μMLinoleic significantly acid increasedalso dose-dependently Bax expression inreduced 25 mM

ISSN: 2581-7310 20 www.innovationinfo.org completely by over-expression of type II hexokinase (HKII). promoted cytochrome c release from mitochondria in both This evidence has been used in modern pharmacotherapy 11.1mitochondrial mM glucose membrane and 25 potential mM glucose (ΔΨm) culture and significantly medium, to discover therapeutic target against glycolysis in cancer further reducing glucose stimulated insulin secretion, cells. Bromo pyruvate (BrPA) exhibits antagonist property which is dependent on normal mitochondrial function. against HKII and can be used to inhibit glycolysis. However, With the increase in glucose levels in culture medium, INS- the clinical application of BrPA is mostly combined with inhibition effect for healthy cells particularly erythrocytes. The results of this study indicate that chronic exposure Our strategy is to encapsulate BrPA in a selected vehicle, 1 β-cell insulin secretion function was deteriorated further. without any leakage of BrPA out of vehicle in blood stream. which involved a mitochondrial-mediated signal pathway, This structure has been constructed from chitosan embedded andto linoleic increased acid-induced glucose levels β-cell enhanced dysfunction linoleic and acid apoptosis, induced into oleic acid layer and then coated by dual combination of folic acid (FA) and bovine serum albumin (BSA). With FA as Conjugated linoleic acid, a functional lipid, produced from β-cell dysfunction [6]. an easy binding for hepatocytes, they can raise the potential Lactobacillus plantarum (LPCLA), has been demonstrated selectionspecific ligand of carrier for cancer system folate [9]. receptor and BSA that can be to possess apoptotic activity. The antiproliferative and apoptotic potential of LPCLA was here evaluated in vitro Erlotinib (ETB) is a well-established therapeutic for non- using the MDAMB231 human breast cancer cell line as small cell lung cancer (NSCLC). To overcome drug resistance a model system. Proliferation of MDA MB231 cells was and severe toxicities in the clinical application, redox- inhibited with increasing concentrations of LPCLA with responsive and pH-sensitive nanoparticle drug delivery altered morphological features like cell detachment, systems were designed for the encapsulation of ETB. rounding of cells and oligo nucleosomal fragmentation of Poly(acrylic acid)-cystamine-oleic acid (PAA-ss-OA) of LPCLA by ANNEXIN V/PI double staining. Furthermore, DNA. Flow cytometry confirmed the apoptotic potential nanoparticles (PAA-ETB-NPs) were prepared using the outcome results indicated that the apoptosis was mediated was synthesized. PAA-ss-OA-modified ETB-loaded lipid by downregulation of the NFkB pathway which in turn ofemulsification ETB-loaded andlipid solvent nanoparticles evaporation (ETB-NPs) method. and The free tumor ETB of p65 nuclear translocation, release of cytochromeC from inhibition efficacy of PAA-ETB-NPs was compared with that acted through proteasome degradation of IkBα, inhibition anticancer drugs in tumor-bearing mice. Thus, conjugated linoleic acid, a natural product derived PAA-ETB-NPs had a size of 170 nm, with a zeta potential frommitochondria probiotics, and could finally therefore overexpression be a possible of Bax potential protein. chemotherapeutic agent due to its apoptotic activity against estrogen receptor negative breast cancer cells [7]. respectively.of -32 mV. The In vitro encapsulation cytotoxicity efficiency of ETB-NPs and drugwere loadinghigher thancapacity that of ETB PAA-ETB-NPs solution. The were cytotoxicity over 85% of PAA-ETB-NPs and 2.6%, was the highest. The in vivo tumor growth inhibition by (OA)HAMLET which (humankills transformed α-lactalbumin cells, made while lethal leaving to tumour fully differentiatedcells) is a complex cells largely of α-lactalbumin unaffected. (aLA) Other and protein-lipid oleic acid by ETB-NPs and ETB solution. No obvious weight loss was PAA-ETB-NP treatment was significantly higher than that complexes show similar anticancer potential. We call such observed in any of the treatment groups, indicating that all the treatments were well tolerated. while intensely investigated, remains unresolved. To PAA-ETB-NPs could enhance the stability and anti-cancer addresscomplexes this, liprotides we report [8]. on The the cellular cell killing impact mechanisms of liprotides, of ability of ETB to treat lung cancer and are a promising drug delivery system for lung cancer treatment [10]. Triple negative breast cancer (TNBC) comprises ~20% liprotides prepared by incubating aLA with OA for 1 h at of all breast cancers and is the most aggressive mammary acts20 or more 80°C slowly, (lip20 possibly and lip80, due respectively).to intermolecular The disulphide liprotides cancer subtype. Devoid of the estrogen and progesterone bondsshowed formed similar cytotoxicityduring preparation. against MCF7 Liprotides cells, though are known lip80 receptors, along with the receptor tyrosine kinase ERB2 vesicles, prompting us to focus on the effect of liprotides on targeted therapies for patients with TNBC. This, combined to increase the fluidity of a membrane and transfer OA to with(HER2) a high that definemetastatic most rate mammary and a lower cancers, 5-year there survival are no for activation of the plasma membrane repair system, and rate than for other breast cancer phenotypes, means there wethe found cell membrane. that removal Extracellular of Ca2+ from Ca2+ the influxmedium is importantenhanced the liprotides’ killing effect. Liprotide cytotoxicity was Herein, the anti-neoplastic effects of the electrophilic fatty also increased by knockdown of Annexin A6 (ANXA6), a acidis significant nitro alkene unmet derivative, need for 10-nitro-octadec-9enoic new therapeutic strategies. acid protein involved in plasma membrane repair. We conclude (nitro-oleic acid, NO2-OA), were investigated in multiple that MCF7 cells counteract liprotide-induced membrane preclinical models of TNBC. NO2-OA reduced TNBC cell permeabilization by activating their plasma membrane growth and viability in vitro, attenuated tumor necrosis repair system, which is triggered by extracellular Ca2+ and and inhibited the tumor growth of MDA-MB-231 TNBC cell Glucose consumption in many types of cancer cells, in xenograftsfactor α (TNFα)-induced in the mammary TNBC fat cellpads migration of female and nude invasion mice. involves ANXA6 [8]. particular hepatocellular carcinoma (HCC), was followed The upregulation of these aggressive tumor cell growth,

ISSN: 2581-7310 21 www.innovationinfo.org migration and invasion phenotypes is mediated in part by the and/or additive in esophageal cancer cells has not yet been elucidated.

2 constitutive activation of pro-inflammatory nuclear factor We conducted in vitro studies and evaluated whether OA kappa B (NF-κB) signaling in TNBC. NO -OA inhibited TNFα- and ALA alone or in combination may regulate malignant potential in OE19 and OE33 esophageal cancer cell lines includinginduced NF-κB the transcriptionalmetastasis-related activity proteins in human intercellular TNBC cells adhesionand suppressed molecule-1 downstream and urokinase-typeNFκB target gene plasminogen expression, proliferation, adhesion and/or migration. OA and/or ALA did[13]. not Both change OA the and number ALA significantly of colonies down-regulatedbut decrease colony cell inhibition by NO2-OA in TNBC cells were multifaceted, as sizes when compared to control. Also, we observed that OA NOactivator. The mechanisms accounting for NF-κB signaling 2 and/or ALA positively cross-regulates the expression levels -OA a) inhibited the inhibitor of NF-κB subunit kinase of AMPK/S6 axis. Moreover, OA and ALA up-regulated tumor suppressor genes (p53, p21, and p27) and these effects are DNAβ phosphorylation binding and c) and promoted downstream RelA inhibitorpolyubiquitination of NF-κB abolished by AMPK siRNA administration. Importantly, we anddegradation, proteasomal b) alkylated degradation. the NF-κB Comparisons RelA protein withto prevent non- observed that these effects are additively regulated by OA tumorigenic human breast epithelial MCF-10A and MCF7 and ALA in combination when compared to control in OE19 cells revealed that NO -OA more selectively inhibited TNBC 2 and OE33 esophageal cancer cell lines. function. This was attributed to more facile mechanisms for maintaining redox homeostasis in normal breast epithelium, Our novel mechanistic studies provide evidence for an important role for OA and ALA in esophageal cancer, and extents of multi-drug resistance protein-1 (1) expression suggest that OA and/or ALA might Our novel mechanistic including a more favorable thiol/disulfide balance, greater studies provide evidence for an important role for OA and ALA 2-OA-glutathione conjugates. These observations reveal that electrophilic in esophageal cancer, and suggest that OA and/or ALA might andfatty greateracid nitro MRP1-mediated alkenes react with efflux more of NOalkylation sensitive be useful agents in the management or chemoprevention of targets in TNBC cells to inhibit growth and viability [11]. esophageal cancer [13]. Gastric cancer and breast cancer have a clear tendency A proper balance between saturated and unsaturated toward metastasis and invasion to the microenvironment fatty acids (FAs) is required for maintaining cell homeostasis. predominantly composed of adipocytes. Oleic acid is an The increased demand of FAs to assemble the plasma abundant monounsaturated fatty acid that releases from membranes of continuously dividing cancer cells might unbalance this ratio and critically affect tumour outgrowth. adipocytes and impinges on different energy metabolism We unveiled the role of the stearoyl-CoA desaturase SCD5 responses. The effect and underlying mechanisms of oleic in converting saturated FAs into mono-unsaturated FAs acid on highly metastatic cancer cells are not completely during melanoma progression [14]. SCD5 is down-regulated understood. We reported that AMP-activated protein in advanced melanoma and its restored expression kinase (AMPK) was obviously activated in highly aggressive in vitro carcinoma cell lines treated by oleic acid, including gastric and in vivo, through a mechanism governing the secretion carcinoma HGC-27 and breast carcinoma MDA-MB-231 cell ofsignificantly extracellular reduced matrix melanoma proteins, malignancy,such as secreted both protein lines [12]. AMPK enhanced the rates of fatty acid oxidation acidic and rich in cysteine (SPARC) and collagen IV and of their proteases, such as cathepsin B. Enforced expression growth and migration under serum deprivation. Inactivation of SCD5 or supplementation of its enzymatic product, oleic ofand AMPK ATP productionattenuated andthese thus activities significantly of oleic promoted acid. Oleic cancer acid inhibited cancer cell growth and survival in low metastatic carcinoma cells, such as gastric carcinoma SGC7901 acid, reduced the intracellular pH (pHe>pHi) and, in turn, and breast carcinoma MCF-7 cell lines. Pharmacological appearsvesicular also trafficking to depend across on SCD5 plasma induced membranes reduction as of well the C2 as activation of AMPK rescued the cell viability by maintained subunitmelanoma of the dissemination. vacuolar H(+) This ATPase, intracellular a proton pump acidification whose results indicate that highly metastatic carcinoma cells could data support a role for SCD5 and its enzymatic product, consumeATP levels oleic by acid increasing to maintain fatty malignancy acid β-oxidation. in an AMPK- These oleicinhibition acid, changes in protection the secretion against profile malignancy, of cancer cells.offering Our contribution of fatty acid oxidation to cancer cell function Furthermore, SCD5 appears to functionally connect tumor [12].dependent manner. Our findings demonstrate the important an explanation for the beneficial Mediterranean diet. the tumor microenvironment, with consequences on tumor Both oleic acid (OA) and alpha-linolenic acid (ALA) spreadcells and and the resistance surrounding to treatment stroma [14]. toward modification of have been proposed to down-regulate cell proliferation of prostate, breast, and bladder cancer cells. However, The excess of saturated free fatty acids, such as palmitic direct evidence that OA and/or ALA suppresses to the acid, that induces lipotoxicity in hepatocytes, has been development of esophageal cancer has not been studied. implicated in the development of non-alcoholic fatty liver Also, no previous studies have evaluated how OA and/or ALA disease also associated with insulin resistance. By contrast, regulates malignant potential (cell proliferation, migration, oleic acid, a monounsaturated fatty acid, attenuates the colony formation and adhesion) and intracellular signaling effects of palmitic acid. We evaluated whether palmitic pathways, and whether their effects might be synergistic acid is directly associated with both insulin resistance

ISSN: 2581-7310 22 www.innovationinfo.org and lipoapoptosis in mouse and human hepatocytes and observations demonstrate that OA, GcMAF and NO can be the impact of oleic acid in the molecular mechanisms that mediate both processes [15]. In human and mouse hepatocytes palmitic acid at a lipotoxic concentration stimulationproperly combined and tumor and volume specifically reduction delivered avoiding to advanced harmful triggered early activation of endoplasmic reticulum (ER) side-effectscancer patients [17]. with significant effects on immune system stress-related kinases, induced the apoptotic transcription factor CHOP, activated caspase 3 and increased the can no longer be doubted, but little is known about the percentage of apoptotic cells. These effects concurred mechanismsThe beneficial of action effects behind of oleic this acid phenomenon. in cancer processesThe aim with decreased IR/IRS1/Akt insulin pathway. Oleic acid of the present review is to clarify whether oleic acid has an suppressed the toxic effects of palmitic acid on ER stress effect on important mechanisms related to the carcinogenic activation, lipoapoptosis and insulin resistance. Besides, oleic acid suppressed palmitic acid-induced activation of bibliographies of selected articles were inspected for S6K1. This protection was mimicked by pharmacological furtherprocesses reference. [18]. We We searchedfocused our electronic research on databases two cellular and or genetic inhibition of S6K1 in hepatocytes. In conclusion, proliferation and cell death or apoptosis. palmitic acid as a common and novel mechanism by which transformations characterizing cancer development: itsthis inhibition is the first by study oleic highlightingacid prevents the ER activation stress, lipoapoptosis of S6K1 by Numerous studies have reported an inhibition in cell and insulin resistance in hepatocytes [15]. proliferation induced by oleic acid in different tumor cell lines. Herein, oleic acid could suppress the over-expression Telomerase is a ribonucleoprotein complex that elongates of HER2 (erbB-2), a well-characterized oncogene which telomeric DNA and appears to play an important part in the plays a key role in the etiology, invasive progression and cellular immortalization of cancers. In the screening of potent metastasis in several human cancers. In addition, oleic acid inhibitors of human telomerase, several inhibitors have could play a role in intracellular calcium signaling pathways been discovered from natural and chemical sources. Some linked to the proliferation event. Regarding cell death, oleic compounds potently inhibit the activity of human telomerase. acid has been shown to induce apoptosis in carcinoma cells. The mechanisms behind the apoptotic event induced by acid, respectively, were found to be inhibitors of human oleic acid could be related to an increase in intracellular Rubromycins and fatty acids such as β-rubromycin and oleic ROS production or caspase 3 activity. Several unsaturated fatty acids have been reported to induce apoptosis through telomerase. The IC(50) values of β-rubromycin and oleic revealed that these compounds competitively inhibited the a release of calcium from intracellular stores. However, acid were 8.60 and 8.78 μM, respectively. A kinetic study activity of telomerase with respect to the substrate of the evidence regarding such a role in oleic acid is lacking. primer and dNTP. The energy-minimized three-dimensional Oleic acid plays a role in the activation of different intracellular pathways involved in carcinoma cell 20.3structure Å in ofthese β-rubromycin compound andstructures oleic acid were was suggested calculated to and be development. Such a role could be the root of its antitumoral importantdesigned. Thefor telomeraseV-shaped curve inhibition. and molecule The three-dimensional length of 18.7- structure of the active site of telomerase (i.e., the binding site Linoleiceffects reported Acid Effects in clinical on studies the Mitochondria [18]. Cardiolipin is a signature phospholipid of major functional suggestof the primer a potential and dNTPstructure substrate) for the mightdevelopment have a “pocket”of more fatty acid composition of cardiolipin is commonly viewed potentthat could inhibitors “join” theseof human compounds. telomerase These [16]. results appear to assignificance highly regulated in mitochondria. due to its Inhigh heart levels mitochondria of linoleic acid the Oleic Acid (OA) has been shown to have anticancer properties mediated by interaction with proteins such as species. However, analysis of data from a comprehensive compilation(18:2n-6) and of the studies dominant reporting presence changes of a 4×18:2 in fattymolecular acid complexes of OA and Gc protein-derived macrophage composition of cardiolipin in heart and liver mitochondria activatingα-lactalbumin factor and (GcMAF) lactoferrins. that inhibits Therefore, per we se synthesizedcancer cell in response to dietary fat shows that, in heart the accrual proliferation and metastatic potential [17]. We hypothesised that OA-GcMAF complexes could exploit the anticancer availability at up to 20% of total dietary fatty acid and properties of both OA and GcMAF in a synergistic manner. thereafterof 18:2 into is regulated. cardiolipin In conformsliver, no dietary strongly conformer to its dietary trend We postulated that the stimulating effects of GcMAF on macrophages might lead to release of nitric oxide (NO). is apparent for 18:2 with regulated lower levels across the Patients with advanced cancer were treated at the dietary range for 18:2. When 18:2 and docosahexaenoic acid Immuno Biotech Treatment Centre with OA-GcMAF-based (22:6n-3) are present in the same diet, 22:6 is incorporated integrative immunotherapy in combination with a low- respectively.into cardiolipin Changes of heart in fatty and acid liver composition at the expense in response of 18:2 carbohydrate, highprotein diet, fermented milk products towhen dietary 22:6 isfat up are to ~20%also compared and 10% offor total the dietarytwo other fatty main acid containing naturallyproduced GcMAF, Vitamin D3, omega-3 mitochondrial phospholipids, phosphatidylcholine and fatty acids and lowdose acetylsalicylic acid. phosphatidylethanolamine, and the potential consequences Measuring the tumor by ultrasonographic techniques, we observed a decrease of tumour volume of about 25%. These [19]. of replacement of 18:2 with 22:6 in cardiolipin are discussed ISSN: 2581-7310 23 www.innovationinfo.org The oxidation and nitration of unsaturated fatty acids by oxides of nitrogen yield electrophilic derivatives that can not different between the dietary groups. Consistent with modulate protein function via post-translational protein (PE). As a result of this resistance, CL 18:2ω6 content was activity was also not different between the dietary groups. However,the lack of correlational changes in CL analysis 18:2ω6 using content, data mitochondrial obtained from COX rats modifications. The biological mechanisms accounting for fatty acid nitration and the specific structural characteristics forof products fatty acid remain nitration to be in defined. vitro and Herein, in vivo conjugated, yielding linoleic up to across the dietary groups showed a significant relationship 10acid greater (CLA) isextent identified of nitration as the primary products endogenous as compared substrate with COX(p=0.009, activity R(2)=0.21). thereby making Specifically, this lipid the molecule results suggest a potential that bis-allylic linoleic acid [5]. Multiple enzymatic and cellular factorCL 18:2ω6 related content to mitochondrialmay positively healthinfluence and mitochondrial function in mechanisms account for CLA nitration, including reactions skeletal muscle [22]. P450 epoxidation of linoleic acid has catalyzed by mitochondria, activated macrophages, and been associated with many pathological conditions that often lead to acute renal failure. However, there is only metabolites are detected in the plasma of healthy humans suggestive evidence that linoleic acid mono epoxides and/ andgastric are acidification. increased in tissuesNitroalkene undergoing derivatives episodes of CLA of andischemia their or linoleic diols directly induce mitochondrial dysfunction. reperfusion. Dietary CLA and nitrite supplementation in Using isolated rabbit renal cortical mitochondria (RCM), rodents elevates NO(2)-CLA levels in plasma, urine, and we found that linoleic acid (50 microM) and the linoleic tissues, which in turn induces heme oxygenase-1 (HO- acid monoepoxide, cis-12,13-epoxy-9octadecenoic acid 1) expression in the colonic epithelium. These results (12,13-EOA, 50 microM) increased state 4 and oligomycin- insensitive respiration and reduced state 3 and oligomycin- electrophilic products that can modulate adaptive cell sensitive respiration. Concomitant with these effects, linoleic signalingaffirm that mechanisms metabolic [20]. and inflammatory reactions yield acid and 12,13-EOA decreased mitochondrial membrane potential (DeltaPsi). In contrast, the hydrolyzed product of Airway epithelial injury is the hallmark of various 12,13-EOA, 12,13dihydroxyoctadecenoic acid (12,13-DHOA, respiratory diseases, but its mechanisms remain poorly 50 microM), had no effect on state 3, state 4, oligomycin- understood. While 13-S-hydroxyoctadecadienoic acid sensitive, and oligomycin insensitive respiration, and (13-S-HODE) is produced in high concentration during DeltaPsi. Neither linoleic acid nor its metabolites altered mitochondrial degradation in reticulocytes little is known uncoupled respiration, which suggests that these compounds about its role in asthma pathogenesis. We show that have no effect on electron transport chain in RCM. Nucleotides extracellular 13-S-HODE induces mitochondrial dysfunction such as ATP (0.5 mM) and GDP (0.5 mM) partially prevented and airway epithelial apoptosis. This is associated with the decrease in DeltaPsi but did not attenuate the increase features of severe airway obstruction, lung remodeling, in oligomycin-insensitive respiration after exposure to linoleic acid (50 microM) and 12,13-EOA (50 microM). cytokines and drastic airway neutrophilia in mouse. These results demonstrate that linoleic acid metabolism to Further,increase 13-S-HODE in epithelial induced stress features related are pro-inflammatory attenuated by inhibiting Transient Receptor Potential Cation Channel, mitochondrial dysfunction in RCM. The increase in state 4 Vanilloid-type 1 (TRPV1) both in mouse model and human respirationthe 12,13-DHOA concomitant is a detoxification with decreases pathway in state that 3 respiration prevents and DeltaPsi suggest that, in addition to uncoupling effects, to human asthma, as 13-S-HODE levels are increased in linoleic acid and 12,13-EOA may have other effects, such as humanbronchial asthmatic epithelial airways. cells. Blocking These findingsof 13-S-HODE are relevantactivity alterations of mitochondrial membranes. The inability of ATP or disruption of TRPV1 activity attenuated airway injury and GDP to fully attenuate the uncoupling effects of linoleic and asthma mimicking features in murine allergic airway acid and 12,13-EOA suggests that these effects are mediated through a nucleotide-independent mechanism [23]. Cardiac induces mitochondrial dysfunction and airway epithelial injuryinflammation. [21]. These findings indicate that 13-S-HODE clinical problem with limited treatment options available. Cardiolipin (CL) is an inner-mitochondrial membrane Weischaemia-reperfusion previously showed (IR)that injurycardio remainsprotection a against significant IR phospholipid that is important for optimal mitochondrial injury by nitro-fatty acids, such as nitro-linoleate (LNO2), known to be positively associated with cytochrome c oxidase nucleotide translocase 1 (ANT1). Thus, it was hypothesized (COX)function. activity. Specifically, However, CL and this CL linoleic association (18:2ω6) has content not been are thatinvolves conjugation covalent modificationof LNO2 to ofthe mitochondrial mito-chondriotropic adenine examined in skeletal muscle. In this study, rats were fed high triphenylphosphonium (TPP(+)) moiety would enhance fat diets with a naturally occurring gradient in linoleic acid its protective properties. TPP(+) -LNO2 was synthesized from aminopropyl-TPP(+) and LNO2 , and characterized by oil [SO], 75.1%) in an attempt to alter both mitochondrial direct infusion MS/MS. Its effects were assayed in primary CL(coconut fatty acyloil [CO], composition 5.8%; flaxseed and COX oil [FO],activity 13.2%; in rat safflower mixed cultures of cardio myocytes from adult C57BL/6 mice and hind-limb muscle. In general, mitochondrial membrane lipid in mitochondria from these cells, exposed to stimulated IR composition was fairly resistant to dietary treatments as (SIR) conditions (oxygen and metabolite deprivation for 1h only modest changes in fatty acyl composition were detected followed by normal conditions for 1h) by measuring viability in CL and other major mitochondrial phospholipids such as by LDH release and exclusion of Trypan blue. Nitro-alkylated phosphatidylcholine (PC) and phosphatidylethanolamine mitochondrial proteins were also measured by Western

ISSN: 2581-7310 24 www.innovationinfo.org blots, using antibodies to TPP(+). TPP(+) -LNO2 protected increased Bax expression in 25 mM glucose culture medium cardio myocytes from SIR injury more potently than the but not in 11.1 mM glucose culture medium. Linoleic acid also dose-dependently reduced mitochondrial membrane mitochondrial proteins, including ANT1, in a manner sensitiveparent compound to the mitochondrial LNO2. In addition, uncoupler TPP(+) carbonylcyanide- LNO2 modified c release from mitochondria in both 11.1 mM glucose and 25potential mM glucose (ΔΨm) culture and significantly medium, further promoted reducing cytochrome glucose inhibitor carboxyatractyloside. Similar protein nitro- stimulated insulin secretion, which is dependent on normal alkylationp-trifluoromethoxyphenylhydrazone was obtained in cells and in isolated (FCCP) andmitochondria, the ANT1 mitochondrial function. With the increase in glucose levels in to TPP(+) -LNO2 . Together, these results emphasize the deteriorated further. The results of this study indicate that importanceindicating the of cellANT1 membrane as a target was for not the a significantprotective barriereffects culture medium, INS-1 β-cell insulin secretion function was of LNO2, and suggest that TPP(+) -conjugated electrophilic and apoptosis, which involved a mitochondrial-mediated lipid compounds may yield novel tools for the investigation signalchronic pathway, exposure andto linoleic increased acid-induced glucose β-celllevels dysfunction enhanced of cardioprotection [24].

The therapeutic use of polyunsaturated fatty acids linoleicAn uncoupling acid induced protein β-cell wasdysfunction recently [26]. discovered in plant (PUFA) in preserving insulin sensitivity has gained interest mitochondria and demonstrated to function similarly to in recent decades; however, the roles of linoleic acid (LA) the uncoupling protein of brown adipose tissue. In this

on a self-generating Percoll gradient in the presence of ALAand αon linolenic attenuating acid the (ALA) development remain poorly of insulin understood. resistance We 0.5%work, bovine green serum tomato albumin fruit mitochondria to deplete mitochondria were purified of (IR)investigated in obesity. the efficacyFollowing of dietsa 12-wk enriched intervention, with either LA LA and or endogenous free fatty acids. The uncoupling protein activity ALA both prevented the shift toward an IR phenotype and was induced by the addition of linoleic acid during the resting state, and in the progressively uncoupled state, as well as during phosphorylating respiration in the presence independentmaintained muscle-specific of changes in insulin skeletal sensitivity muscle mitochondrialotherwise lost of benzohydroxamic acid, an inhibitor of the alternative contentin obese andcontrol oxidative animals. capacity, The beneficial as obese effects control of ALA and wereALA oxidase and with succinate (+ rotenone) as oxidizable treated rats showed similar increases in these parameters. substrate. Linoleic acid strongly stimulated the resting However, ALA increased the propensity for mitochondrial respiration in fatty acid-depleted mitochondria but had no effect on phosphorylating respiration, suggesting no H2O2 emission and catalase content within whole muscle and reduced markers of oxidative stress (4-HNE and activity of the uncoupling protein in this respiratory state. protein carbonylation). In contrast, LA prevented changes Progressive uncoupling of state 4 respiration decreased in markers of mitochondrial content, respiratory function, the stimulation by linoleic acid. The similar respiratory rates in phosphorylating and fully uncoupled respiration H2O2 emission, and oxidative stress in obese animals, thereby resembling levels seen in lean animals. Together, the data in the presence and absence of linoleic acid suggested that a rate-limiting step on the dehydrogenase side of the have divergent impacts on skeletal muscle mitochondrial respiratory chain was responsible for the insensitivity of contentsuggest thatand LAfunction. and ALA Moreover, are efficacious we propose in preventing that LA IR hasbut phosphorylating respiration to linoleic acid. Indeed, the value in preserving insulin sensitivity in the development ADP/O ratio determined by ADP/O pulse method was of obesity, thereby challenging the classical view that n-6 decreased by linoleic acid, indicating that uncoupling PUFAs are detrimental [25]. Obesity with excessive levels protein was active during phosphorylating respiration and of circulating free fatty acids (FFAs) is tightly linked to the was able to divert energy from oxidative phosphorylation. incidence of type 2 diabetes. Insulin resistance of peripheral Moreover, the respiration rates appeared to be determined by membrane potential independently of the presence of pathological changes in diabetes and both are facilitated by linoleic acid, indicating that linoleic acid-induced stimulation excessivetissues and levels pancreatic of FFAs and/or β-cell dysfunctionglucose. To gain are insight two major into of respiration is due to a pure protonophoric activity without the mitochondrial mediated mechanisms by which long- any direct effect on the electron transport chain [27]. dysfunction, the effects of the unsaturated FFA linoleic acid conjugated linoleic acids (CLA) suggest that CLA are term exposure of INS-1 cells to excess FFAs causes β-cell maximallyThe beneficial conserved effects and raise exerted the byquestion low amountsabout their of

(C 18:2, n-6) on rat insulinoma INS-1 β cells was investigated. normalINS-1 cells (11.1 were mM) incubated or high with (25 0,mM) 50, 250glucose or 500 in serum-freeμM linoleic mitochondrial oxidizability. Cis-9,trans-11-C(18:2) (CLA1) RPMI-1640acid/0.5% (w/v) medium. BSA forCell 48 viability,h under cultureapoptosis, conditions glucose- of (palmitoleicand trans-10,cis-12C(18:2) acid; PA), as substrates (CLA2) for were total fatty compared acid (FA) to stimulated insulin secretion, Bcl-2, and Bax gene expression oxidationcis-9,cis-12-C(18:2) and for the (linoleicenzymatic acid; steps LA) required and cis-9-C(16:1)for the entry levels, mitochondrial membrane potential and cytochrome of FA into rat liver mitochondria. Oxygen consumption rate was lowest when CLA1 was used as a substrate with that suppressed cell viability and induced apoptosis when on CLA2 being intermediate between it and the respiration administeredc release were in examined. 11.1 and Linoleic25 mM acidglucose 500 culture μM significantly medium. on LA and PA. The order of the radio labelled FA oxidation

Compared with control, linoleic acid 500 μM significantly rate was PA>>LA>CLA2>CLA1. Transesterification to ISSN: 2581-7310 25 www.innovationinfo.org acylcarnitines of the octadecadienoic acids were similar, preserves CL and mitochondrial function in the failing heart while uptake across inner membranes of CLA1 and, to a and may be a useful adjuvant therapy for this condition [30]. lesser extent, of CLA2 was greater than that of LA or PA. Prior In the study reported here the effect of conjugated linoleic oxidation of CLA1 or CLA2 made re-isolated mitochondria acid (CLA) and vitamin A on the polyunsaturated fatty acid much less capable of oxidising PA or LA under carnitine- composition, chemiluminescence and per-oxidizability index dependent conditions, but without altering the carnitine- of microsomes and mitochondria isolated from rat liver was independent oxidation of octanoic acid. Therefore, the CLA analyzed. The effect of CLA on the polyunsaturated fatty studied appeared to be both poorly oxidizable and capable acid composition of native microsomes was evidenced by of interfering with the oxidation of usual FA at a step close to stains and confocal microscope imaging, the patterns of an statistically significant p<0.007 decrease of linoleic acid mitochondrialthe beginning ofdistribution, the beta-oxidative mitochondrial cycle [28]. inner Using membrane specific C18:2 n6, whereas in mitochondria it was observed a decrease potential and reactive oxygen species (ROS) levels during p<0.0001 of arachidonic acid C20:4 n6 when compared with bovine oocyte maturation were determined in the presence Avitamin groups A andwhen control compared groups. with Docosahexaenoic control. After incubationacid C22:6 or absence of physiological concentrations of linoleic acid ofn3 microsomesin mitochondria or mitochondria was reduced pin < an0.04 ascorbate in CLA and (0.4 vitamin mM)- Fe++ (2.15 microM) system (120 min at 37 degrees C) it distribution in control oocytes at 0h was mainly peripheral was observed that the total cpm/mg protein originated and(LA; changed100µM) orto α-linolenica diffused acidpattern (ALA; after 50µM). 1h of Mitochondrial culture; this was maintained up to 24h. Mitochondrial clusters were microsomes or mitochondria obtained from CLA group observed during the early hours of maturation (1-4h); the from light emission: chemiluminescence was lower in liver majority of these were arranged in perinuclear fashion. LA (received orally: 12.5 mg/daily during 10 days) than in the the mitochondria from a peripheral to a diffuse pattern and maximalvitamin Ainduced group chemiluminescence (received intraperitoneal in microsomes injection: relative daily asupplementation decreased percentages resulted of in: oocytes (1) delayed showing redistribution perinuclear of to0.195 vitamin g/ kgA and during control 10 days).groups, CLA whereas reduced in mitochondria significantly mitochondrial clusters, (2) decreased mitochondrial inner the effect was observed relative to control group. The membrane potential at 1 and 24h compared with the polyunsaturated fatty acid composition of liver microsomes control and (3) higher ROS levels, associated with a lower or mitochondria changed by CLA and vitamin A treatment. nuclear maturation rate. In contrast, ALA supplementation The polyunsaturated fatty acids mainly affected when had no effect on mitochondrial distribution and activity microsomes native and per-oxidized from control group and decreased ROS levels compared with the control; this were compared were linoleic, linolenic and arachidonic acids, was associated with an increased nuclear maturation rate. while in vitamin A group linoleic and arachidonic acid were In conclusion, LA induced alterations in mitochondrial mainly per-oxidized, whereas in CLA group only arachidonic distribution and activity as well as increasing ROS levels, acid was altered. In mitochondria obtained from the three which mediate, at least in part, the inhibitory effect on groups arachidonic acid and docosahexaenoic acid showed oocyte maturation [29]. Cardiolipin (CL) is a tetra-acyl phospholipid that provides structural and functional support were compared. As a consequence the per-oxidizability index, to several proteins in the inner mitochondrial membrane. a parametersignificant decreasebased on whenthe maximal native andrate per-oxidizedof oxidation ofgroups fatty The majority of CL in the healthy mammalian heart contains four linoleic acid acyl chains (L(4)CL). A selective loss of L(4) vitamin A and control groups. The simultaneous analysis of CL is associated with mitochondrial dysfunction and heart per-oxidizabilityacids, show significant index, changeschemiluminescence in the CLA group and fatty compare acid failure in humans and animal models. We examined whether composition demonstrated that CLA is more effective than supplementing the diet with linoleic acid would preserve vitamin A protecting microsomes or mitochondria from per- cardiac L(4)CL and attenuate mitochondrial dysfunction oxidative damage [31]. and contractile failure in rats with hypertensive heart failure. Male spontaneously hypertensive heart failure rats A novel mitochondria-targeted antioxidant (TPP-OH) was (21 months of age) were administered diets supplemented synthesized by attaching the natural hydrophilic antioxidant caffeic acid to an aliphatic lipophilic carbon chain containing a triphenylphosphonium (TPP) cation. This compound has (control)with high for linoleate 4 weeks. safflower HLSO preserved oil (HLSO) L(4)CL or lard and (10%total similar antioxidant activity to caffeic acid as demonstrated CLw/w; to 90% 28% of kilocalorie non-failing fat) levels or (vs. without 61-75% supplemental in control and fat by measurement of DPPH/ABTS radical quenching and lard groups), and attenuated 17-22% decreases in state 3 mitochondrial respiration observed in the control and than its precursor as indicated by the relative partition redox potentials, but is significantly more hydrophobic was intrinsic related to the ortho-catechol system, as the lard groups (P<0.05). Left ventricular fractional shortening methoxylationcoefficients. The of antioxidantthe phenolic activity functions, of bothnamely compounds in TPP- was significantly higher in HLSO vs. control (33 ± 2 vs. 29 OCH and dimethoxycinnamic acid, gave compounds with effect± 2%, of P lard < 0.05), supplementation. while plasma HLSO insulin also levels increased were serum lower negligible antioxidant action [3]. The incorporation of the concentrations(5.4 ± 1.1 vs. 9.1 of ± 2.3several ng/mL; eicosanoid P<0.05), withspecies no significantcompared lipophilic TPP cation to form TTP-OH and TPP-OCH allowed with control and lard diets, but had no effect on plasma the cinnamic derivatives to accumulate within mitochondria glucose or blood pressure. Moderate consumption of HLSO in a process driven by the membrane potential [3]. However,

ISSN: 2581-7310 26 www.innovationinfo.org increases of long-chain PUFAs (eg, arachidonic and cells against H2O2 and linoleic acid hydroperoxide-induced docosahexaenoic acids) in the mitochondrial phospholipid onlyoxidative TPP-OH stress. was anAs effective mitochondrial antioxidant: oxidative TPP-OH damage protected is cardio lipin correlates with cardiac mitochondrial associated with a number of clinical disorders, TPP-OH dysfunction and contractile impairment in aging and may be a useful lead that could be added to the family of related pathologies. In this study, we demonstrate a mitochondria-targeted antioxidants that can decrease reversal of this aged-related PUFA redistribution pattern mitochondrial oxidative damage [32]. in cardiac mitochondria from aged (25 months) C57Bl/6 mice by inhibition of delta-6 desaturase, the rate limiting Linoleic acid (LA) improves insulin resistance and enzyme in long-chain PUFA biosynthesis. Interestingly, prevents diabetes. To investigate whether linoleic acid delta-6 desaturase inhibition had no effect on age-related could protect against streptozotocin (STZ)-induced cell mitochondrial respiratory dysfunction, H2O2 release, or lipid death, rat RIN-m5F cells were exposed to STZ. SL and SO peroxidation but markedly attenuated cardiac dilatation, groups consisted of cells treated with STZ and then LA or hypertrophy, and contractile dysfunction in aged mice. oleic acid (OA) respectively. STZ treatment decreased the Taken together, the studies indicate that PUFA metabolism mitochondrial membrane potential in the STZ, SO, and SL groups. Cells of the SL group had more intact mitochondria. function but dissociates these processes from mitochondrial Increased mRNA expression of mitochondrial DNA (mtDNA) respiratorystrongly influences dysfunction phospholipid and oxidant remodeling production and in the cardiac aged and nuclear DNA (nDNA), as well as of the mitochondrial mouse heart [35]. biogenesis regulators peroxisome proliferator activated receptor gamma coactivator-1alpha (PGC-1alpha), and Despite their high metabolic rates, birds have a much mitochondrial transcription factor A (Tfam), were found higher maximum longevity (MLSP) than mammals of similar body size, and thus represent ideal models for identifying decreased in all three groups. These results suggest that longevity characteristics not linked to low metabolic rates. thein theeffects LA of group. LA on The cell insulinviability content after STZ was damage significantly occur This study shows that the fatty acid double bond content of through maintenance of mitochondrial structure and both canary (MLSP=24 years) and parakeet (MLSP=21 years) increased mitochondrial biogenesis [33]. Despite many hearts is intrinsically lower than in mouse (MLSP=3.5 years) studies elucidating the mechanisms of necrotic cell death, heart. This is caused by a redistribution between types of the role of fatty acids released during necrosis remains to unsaturated fatty acids, mainly due to a lower content of the be determined. The goals of this study were to determine whether linoleic acid could protect rabbit renal proximal the two birds in relation to the mammal. The lower double tubules (RPT) from necrotic cell death associated with bondmost contenthighly unsaturated leads to a lower docosahexaenoic sensitivity to lipid acid peroxidation, (22:6n-3) in mitochondrial dysfunction and oxidative injury and to and to a lower level of in vivo lipid peroxidation in the heart determine the mechanisms involved. Exposure to antimycin of parakeets and canaries than in that of mice. Similar results

A (10 microM) for 1 h or hypoxia (perfusion with 95% N2/5% have been previously found comparing liver mitochondria

CO2) for 1 or 2 h induced approximately 70% cellular lysis, of rats and pigeons and tissues of different mammalian as measured by lactate dehyrogenase release, versus 10% in species. All these results taken together suggest that a low controls. Preincubation with linoleic acid (100 microM) fully degree of fatty acid unsaturation is a general characteristic protected RPT from cellular lysis. RPT were also protected of longevous homeothermic vertebrate animals, both when from lysis if linoleic acid was added 15 min after the addition they have low metabolic rates (mammals of large body size) of antimycin A. Measurements of free intracellular Ca(2+) or high metabolic rates (the studied birds); this constitutive concentrations showed that linoleic acid did not prevent trait protects their tissues and organelles against free radical the rise in intracellular Ca(2+) associated with a 30-min mediated lipid peroxidation, and can contribute to their slow aging rate [36]. Cl(-) following a 30-min exposure to antimycin A was The cholesterol, phospholipid, and fatty acid amelioratedexposure to antimycinin the presence A. However, of linoleic the influx acid of [34]. extracellular Linoleic compositions in synaptic and non-synaptic mitochondria acid did not prevent cellular lysis after exposure to hypoxia/ from rat brains and the effect of aging were studied. Both reoxygenation (1h/1h) or t-butyl hydroperoxide (500 cholesterol and phospholipid contents were found to microM, 3h). These data suggest that linoleic acid protects RPT during the late phase of cell death associated with synaptic mitochondria. In both types of brain mitochondria, inhibition of the electron transport chain but not oxidative agingbe significantly decreases differentthe cholesterol in synaptic content compared by 27% and to non- the injury. Several other fatty acids also protected RPT from phospholipid content by approximately 12%. The difference lysis, and structure-activity relationship studies suggest that between these decreases observed in the organelles causes a free carboxyl terminus and at least one double bond are decreases in the cholesterol/phospholipid molar ratios required for this action [34]. for synaptic and non-synaptic mitochondria of 17 and Linoleic Acid Effects on the Mitochondrial Aging 19%, respectively. Also, the phospholipid composition is Process mitochondria. Among phospholipids, only the cardio lipin Aging results in a redistribution of polyunsaturated fatty significantly different in synaptic compared to non-synaptic acids (PUFAs) in myocardial phospholipids. In particular, synaptic mitochondria from the brains of aged rats. Instead, fraction showed a significant decrease (26%) in non- a selective loss of linoleic acid (18:2n6) with reciprocal the fatty acid composition was not significantly different ISSN: 2581-7310 27 www.innovationinfo.org in synaptic compared to non-synaptic mitochondria. The were correlated to maximum life span (MLSP) of birds. non-synaptic mitochondria, may be related to a decrease in Asin microsomeslight emission=chemiluminescence showed significant differences originated when from they cardio21% aging lipin, decrease which contains in linoleic a large acid amount(18:2), observed of this fatty only acid in [37]. correlation between the sensitivity to lipid peroxidation and bodyheart size organelles or maximum was not life statisticallyspan was obtained. significant, These a lackresults of Birds have a much higher maximum longevity (MLSP) indicate that the high resistance of bird hearts to the attack by than mammals of similar metabolic rate. Recent data showed free radicals is body size-independent and would be related that pigeon mitochondria produce oxygen radicals at a rate to the preservation of cardiac function [39]. In this study, much slower than rat mitochondria, in spite of showing we examined the effect of CLA isomers in preventing age- similar levels of oxygen consumption. Since oxidative damage associated muscle loss and the mechanisms underlying this from and to mitochondria seems important in relation to effect, using 12-months-old C57BL/6 mice fed 10% corn oil aging and longevity, and mitochondrial membranes are (CO) or a diet supplemented with 0.5% c9t11-CLA, t10c12- situated at the place where oxygen radicals are generated, CLA, or c9t11-CLA+t10c12-CLA (CLA-mix) for 6 months. we studied protein and lipid peroxidation and fatty acid composition of the three main membrane phospholipids of higher muscle mass, as compared to CO and c9t11-CLA liver mitochondria from rats (MLSP=4 years) and pigeons groups,Both t10c12-CLA measured and by CLA-mix dual-energy groups X-ray showed absorptiometry significantly (MLSP=35 years). It was found that pigeon mitochondria and muscle wet weight. Enhanced mitochondrial ATP show lower levels of fatty acid unsaturation than rat production, with higher membrane potential, and elevated mitochondria in the three lipid fractions, mainly due to a muscle antioxidant enzymes (catalase and glutathione peroxidase) production, accompanied by slight increase in H(2)O(2) production was noted in t10c12CLA and CLA-mix aresubstitution more resistant of highly to lipid unsaturated peroxidation. fatty Previous acids (20:4 research and groups, as compared to that of CO and c9t11CLA groups. has22:6) also by obtained linoleic acidexactly (18:2), the same and thatmajor these difference mitochondria in fatty Oxidative stress, as measured by serum malondialdehyde acid composition in human mitochondria when compared to those of rat. Thus, present information suggests that the liver mitochondrial membranes of especially long-lived species groups.and inflammation, Thus, CLA may as measured be a novel by dietary LPStreated supplement splenocyte that show both a low level of free radical production and a low willIL-6 preventand TNF-alpha, sarcopenia were by maintainingsignificantly redox less in balance CLA isomers during degree of fatty acid unsaturation as important constitutive aging [40]. In this communication, we show that the plant uncoupling mitochondrial protein (PUMP) present in potato investigation was to study the connection between body size, fattyprotective acid composition traits to slow and down sensitivity aging to [38]. lipid The peroxidation aim of this of that this induction is strongly stimulated when the potato heart mitochondria and microsomes isolated from different tuberstuber mitochondria are stored at is low induced temperature by aging (4 at degrees 28 degrees C). PUMPC and activity was detected by the degree of linoleic acid (LA)- coturnix var japonica), pigeon (Columba livia), duck induced ATP-sensitive mitochondrial uncoupling measured (Cairinasize bird moschata)species: manon and goose(Lonchura (Anser striata), anser), quail representing (Coturnix as a function of the decrease in membrane potential (delta a 372-fold range of body mass. Fatty acids of total lipids psi). The PUMP content was evaluated by immunoblot were determined using gas chromatography and lipid analysis using polyclonal antibodies raised against potato peroxidation was evaluated with a chemiluminescence assay. The fatty acids present in heart organelles of the different with the effect of LA on delta psi, the content of the 32 kDa bandPUMP increased that specifically during detected storage aand 32 kDawas band.stimulated In agreement by low allometric trends. In mitochondria, from the individual bird species analyzed showed a small number of significant temperature. These results support the proposed role of PUMP in plant thermogenesis and possibly in fruit ripening and senescence [41]. negativelyfatty acid related data, palmitoleicto body mass acid (r=-0.903). (C16:1 n7) Interestingly, increased noneallometrically of the calculated (r=0.878), fatty while acid variables, stearic acid the average (C18:0) fatty was Free radical damage is considered a determinant factor acid saturated, monounsaturated, polyunsaturated (PUFA) in the rate of aging. Unsaturated fatty acids are the tissue and the unsaturation index (UI) was established to show macromolecules that are most sensitive to oxidative damage. Therefore, the presence of low proportions of fatty acid unsaturation is expected in the tissues of long-lived animals. significant body size-related variations. In heart microsomes, Accordingly, the fatty acid compositions of the major liver the content of C18:0 was significantly smaller (r=-0.970) in mitochondrial phospholipid classes from eight mammals, (r=0.990)the birds and of greater UI (r=0.904) size. A was significant observed allometric in the larger increase birds. ranging in maximum life span potential (MLSP) from 3.5 Thein linoleic total n6 acidfatty (C18:2acids of n6)heart (r=0.986), mitochondria polyunsaturated did not show to 46 yr, show that the total number of double bonds is inversely correlated with MLSP in both phosphatidylcholine of the birds. Moreover, positive allometric relationships (PtdCho) and phosphatidylethanolamine (PtdEtn) (r=0.757, weresignificant shown differences for microsomes. when it wasThe correlatedtotal n3 fattyto body acids mass of cardio lipin (P=0.323). This is due not to a low content of unsaturatedP<0.03, and fatty r=0.862, acids P

ISSN: 2581-7310 29 www.innovationinfo.org Membrane glyceride content, however, remained relatively to modify cardiolipin in the aged heart whereas cardiolipin inmass the toadult the heart C18:2 remained residues. unaltered. Ischemia aloneThus, wasage-enhanced sufficient in the neutral lipid of both liver and kidney and in the polar oxidative damage occurs within mitochondria in the heart constant with age. Significant increase in oleic acid was seen during ischemia and reperfusion, especially during ischemia [47]. A comparative study was made on the fate of linoleic, thelipid polar of kidney. lipid of Significant the liver membrane increase in fractions. docosahexaenoic Possible arachidonic, and docosa-7,10,13,16-tetraenoic acids in alterationsacid and significant in membrane decrease physiochemical in linoleic acidproperties were seen and in various subcellular fractions of liver and testis from rats of membrane function due to these age related lipid changes different ages. It was demonstrated that testicular microsomes are discussed [50]. The effects of cold adaptation upon the can desaturate and elongate linoleic and arachidonic acids brown adipose tissue have been studied in rats, hamsters, in a manner similar to liver microsomes, and that testicular mice, and guinea pigs. Striking effects were found for total mitochondria can convert docosa-7,10,13,16-tetraenoic tissue as well as at the mitochondrial level, e.g., increases in acid to arachidonic acid. Testicular or liver microsomes protein and phospholipid contents, changes in phospholipid actively desaturate linoleic acid to gamma linolenic acid and fatty acid composition (a decrease in the percentage of palmitic and palmitoleic acids and an increase in stearic it was impossible to measure in vitro any direct conversion and linoleic acids), and a change in the mitochondrial eicosa-8,11,14-trienoic acid to arachidonic acid. However, polypeptide composition (a marked increase in a 32000 [n-6]) by either liver or testicular microsomes. Docosa- molecular weight polypeptide, except for hamsters). In 7,10,13,16-tetraenoicof adrenic acid (22:4 [n-6])acid tois docosapentaenoicincorporated preferentially acid (22:5 situations where animals exhibit a greatly enhanced capacity into the triglyceride fraction of total testis, mitochondria, for non-shivering thermogenesis (cold adaptation for rats, and microsomes, while linoleic and arachidonic acids are mice, and guinea pigs, birth for guinea pigs, and hibernation incorporated more into phospholipids. The capacity of ability for hamsters, dormice, and garden dormice), brown testicular microsomes, but not of liver microsomes, to fat mitochondria are characterized by the occurrence of synthesize polyunsaturated fatty acids declines with age. It large amounts of the 32000 molecular weight polypeptide is proposed that the synthesis of acids of the linoleic family characteristic of these mitochondria [51]. proceeds in two stages, a rapid one in which arachidonic acid is made and a second, slower, one in which C(22) and C(24) Conclusion acids are synthesized. In addition, there appears to be a cycle Linoleic acid has effects on the mitochondria. It has between microsomes and mitochondria that acts to conserve effects on Cancer and has effects on Aging. essential polyunsaturated C(20) and C(22) fatty acids by Is Linoleic acid the Code of life? means of synthesis and partial degradation, respectively. This cycle would restrict the loss of essential fatty acids and References might be of importance for the supply of arachidonic acid 1.

40.Sikorski AM, Hebert N, Swain RA (2008) Conjugated Linoleic Acid (CLA) inhibits new vessel growth in the mammalian brain. Brain Res 1213: 35- in testis under specific requirements and especially in older 2. Lu X, Yu H, Ma Q, Shen S, Das UN (2010) Linoleic acid suppresses (richanimals in the [48]. polyunsaturated We fed male Wistar linoleic rats acid) lifelong oil-based on virgindiets. colorectal cancer cell growth by inducing oxidant stress and Atolive 6 and(rich 24 in months,the monounsaturated liver mitochondria oleic acid)were oranalyzed sunflower for a mitochondrial DNA (mtDNA) deletion, reactive oxygen 3. mitochondrialZhang C, Yu H, dysfunction.Shen Y, Ni X, Lipids Shen S,Health et al. Dis(2015) 9: 106. Poly unsaturated fatty acids trigger apoptosis of colon cancer cells through a mitochondrial species, antioxidants, and ultrastructural alterations. An aging-related increase in the relative amount of the deletion 4. pathway.Menendez Arch JA, MedRopero Sci 11:S, Mehmi 108194. I, Atlas E, Colomer R, et al. (2004) was observed for both dietary groups, being higher in animals Overexpression and hyperactivity of breast cancer-associated fatty acid synthase (oncogenic antigen-519) is insensitive to normal arachidonic oil-fed animals. Aging led to higher superoxide dismutase, fatty acid-induced suppression in lipogenic tissues but it is selectively catalase,fed sunflower and glutathione oil. Oxidative peroxidase stress was activities lower inand virgin increased olive inhibited by tumoricidal alphalinolenic and gamma-linolenic fatty alpha-tocopherol and coenzyme Q. Mitochondria from aged acids: a novel mechanism by which dietary fat can alter mammary cristae and a higher circularity. Results suggest that the age- 5. tumorigenesis.Lupu R, Menendez Int J JAOncol (2006) 24: 1369-1383.Pharmacological inhibitors of Fatty Acid relatedanimals increase fed sunflower of the relative oil exhibited amount a of lower deleted number mtDNA of depends on fat unsaturation. Moreover, the studied mtDNA Synthase (FASN)--catalyzed endogenous fatty acidbiogenesis: a new 6. familyTuo Y, ofWang anti-cancer D, Li S, agents? Chen C Curr (2011) Pharm Long-term Biotechnol exposure 7: 483-493. of INS-1 rat deletion was correlated with mitochondrial oxidative stress insulinoma cells to linoleic acid and glucose in vitro affects cell viability and ultrastructural alterations [49]. The lipid contents of the microsomal and mitochondrial membrane fractions of and function through mitochondrial-mediated pathways. Endocrine 39: liver and kidney were determined in 6 and 24 month old 7. 128-138.Kadirareddy RH, Vemuri SG, Palempalli UM (2016) Probiotic Conjugated Linoleic Acid Mediated Apoptosis in Breast Cancer Cells by cholesterol/phospholipid was observed in all membrane rats. A significant age related increase in the molar ratio of DownregulationFrislev HS, Boye ofTL, NFκB. Nylandsted Asian Pac J, Otzen J Cancer D (2017) Prev 17: Liprotides 3395-3403. kill cancer was noted in the microsomal fractions of liver and kidney. Thefractions. relative A significant amount ageof relatedphosphatidylethanolamine reduction of phospholipid was 8. 9. cells by disrupting the plasma membrane. Sci Rep 7: 15129. found to decrease in all membrane fractions during aging. Glycolysis by Using a Micro/Nano-Lipid Bromopyruvic Chitosan Carrier Hanafy NA, Dini L, Citti C, Cannazza G, Leporatti S (2018) Inihibition of

ISSN: 2581-7310 30 www.innovationinfo.org

as a Promising Tool to Improve Treatment of Hepatocellular Carcinoma.

29. alterationMarei WF, of Wathes fatty acid DC, oxidation. Fouladi-Nashta J Lipid ResAA 43:(2012) 2112-2122. Differential effects 10. NanomaterialsTan S, Wang G (2017) (Basel) Redox-responsive 8: 1. and pH-sensitive nanoparticles of linoleic and alpha-linolenic fatty acids on spatial and temporal enhanced stability and anticancer ability of erlotinib to treat lung cancer mitochondrial distribution and activity in bovine oocytes. Reprod Fertil

11. inWoodcock vivo. Drug CC, Des Huang Devel Y, WoodcockTher 11: 3519-3529. SR, Salvatore SR, Singh B, et al. (2017) 30. DevMulligan 24: 679-690. CM, Sparagna GC, Le CH, De Mooy AB, Routh MA, et al. (2012) Nitro-fatty acid inhibition of triple negative breast cancer cell viability, Dietary linoleate preserves cardiolipin and attenuates mitochondrial

12. Limigration, S, Zhou T,invasion Li C, Dai and Z, tumorChe D, growth.et al. (2014) J Biol HighChem metastaticgastric M117: 814368. and 31. dysfunctionPalacios A, Piergiacomi in the failing V, Catalárat heart. A (2003) Cardiovasc Antioxidant Res 94: effect 460-468. of conjugated breast cancer cells consume oleic acid in an AMPK dependent manner. linoleic acid and vitamin A during non-enzymatic lipid peroxidation of

13. PLoSMoon One HS, 9:Batirel e97330. S, Mantzoros CS (2014) Alpha linolenic acid and oleic 32. Teixeirarat liver microsomesJ, Soares P, Benfeito and mitochondria. S, Gaspar A, Mol Garrido Cell Biochem J, et al. (2012) 250: 107-113. Rational acid additively down-regulate malignant potential and positively cross- discovery and development of a mitochondria-targeted antioxidant regulate AMPK/S6 axis in OE19 and OE33 esophageal cancer cells.

33. Jengbased JY, on Yeh cinnamic TS, Chiu acid YH, scaffold. Lee YC, Free Cheng Radic HH, Res et 46:al. (2009)600-611. Linoleic acid 14. BellenghiMetabolism M, 63: Puglisi 1447-1454. R, Pedini F, De Feo A, Felicetti F, et al. (2015) promotes mitochondrial biogenesis and maintains mitochondrial SCD5-induced oleic acid production reduces melanoma malignancy by structure for prevention of streptozotocin damage in RIN-m5F cells.

15. Pardointracellular V, González-Rodríguez retention of SPARC Á, and Muntané cathepsin. J, Kozma B. J Pathol SC, 236:Valverde 315-325. ÁM 34. BiosciMoran Biotechnol JH, Mitchell Biochem LA, Grant 73: DF 1262-1267. (2001) Linoleic acid prevents chloride (2015) Role of hepatocyte S6K1 in palmitic acid-induced endoplasmic reticulum stress, lipotoxicity, insulin resistance and in oleic acid-induced . influx and cellular lysis in rabbit renal proximal tubules exposed to 35. Mulliganmitochondrial CM, Le toxicants. CH, deMooy Toxicol AB, ApplNelson Pharmacol CB, Chicco 176: AJ (2014)153-161 Inhibition 16. protection.Mizushina Y,Food Takeuchi Chem Toxicol T, Sugawara 80: 298-309. F, Yoshida H (2012) Anticancer of delta-6 desaturase reverses cardiolipin remodeling and prevents contractile dysfunction in the aged mouse heart without altering

targeting telomerase inhibitors: β-rubromycin and oleic acid. Mini Rev 17. RuggieroMed Chem M, 12: Ward 1135-1143. E, Smith R, Branca JJ, Noakes D, et al. (2014) Oleic mitochondrial respiratory function. J Gerontol A Biol Sci Med Sci 69: 36. Pamplona799-809. R, Portero-Otín M, Riba D, Ledo F, Gredilla R, et al. (1999) Heart fatty acid unsaturation and lipid peroxidation, and aging rate, are Acid, deglycosylated vitamin D-binding protein, nitric oxide: a molecular lower in the canary and the parakeet than in the mouse. Aging (Milano) triadCarrillo made C, Cavia lethal Mdelto cancer. M, Alonso-Torre Anticancer Res SR 34:(2012) 3569-3578. Anti-tumor effect of

18. 19. oleic acid; mechanisms of action: a review. Nutr Hosp 27: 1860-1865. 37. 11:Ruggiero 449. FM, Cafagna F, Petruzzella V, Gadaleta MN, Quagliariello E (1992) Lipid composition in synaptic and nonsynaptic mitochondria Cortie CH, Else PL (2012) Dietary docosahexaenoic Acid (22:6) incorporates into cardiolipin at the expense of linoleic Acid (18:2): 20. analysisBonacci andG, Baker potential PR, implications.Salvatore SR, Int Shores J Mol SciD, Khoo13: 15447-15463. NK, et al. (2012) Pamplonafrom rat brains R, Prat and J, effect Cadenas of aging. S, Rojas J Neurochem C, Pérez-Campo 59: 487-491. R, et al. (1996) Conjugated linoleic acid is a preferential substrate for fatty acid nitration. Low fatty acid unsaturation protects against lipid peroxidation in liver 38.

21. JMabalirajan Biol Chem 287: U, Rehman 44071-44082. R, Ahmad T, Kumar S, Singh S, et al. (2013) mitochondria from long-lived species: the pigeon and human case. Mech Linoleic acid metabolite drives severe asthma by causing airway 39. AgeingGutiérrez Dev AM, 86: Reboredo 53-66. GR, Mosca SM, Catalá A (2009) High resistance

22. Fajardo VA, Mc Meekin L, Saint C, LeBlanc PJ (2015) Cardiolipin linoleic Effects of mass and maximum lifespan. Comp Biochem Physiol A Mol epithelial injury. Sci Rep 3: 1349. to lipid peroxidation of bird heart mitochondria and microsomes: acid content and mitochondrial cytochrome c oxidase activity are 40. RahmanIntegr Physiol M, Halade 154: 409-416. GV, El Jamali A, Fernandes G (2009) Conjugated linoleic acid (CLA) prevents age-associated skeletal muscle loss. 23. associatedMoran JH, in Nowakrat skeletal G, muscle.Grant ChemDF (2001) Phys Lipids Analysis 187: 50-55.of the toxic effects of linoleic acid, 12,13-cis-epoxyoctadecenoic acid, and 12,13dihydroxyoctadecenoic acid in rabbit renal cortical mitochondria. 41. NantesBiochem IL, Biophys Fagian ResMM, Commun Catisti R, 383: Arruda 513-518. P, Maia IG, et al. (1999) Low temperature and aging-promoted expression of PUMP in potato tuber

24. ToxicolNadtochiy Appl SM, Pharmacol Madukwe 172: J, Hagen 15061. F, Brookes PS (2014) Mitochondrially 42. Portero-Otínmitochondria. M, FEBS Bellmunt Lett 457: MJ, 103-106. Ruiz MC, Barja G, Pamplona R (2001) Correlation of fatty acid unsaturation of the major liver mitochondrial targeted nitro-linoleate: a new tool for the study of cardioprotection. Br phospholipid classes in mammals to their maximum life span potential. 25. JMatravadia Pharmacol 171:S, Herbst 2091-2098. EA, Jain SS, Mutch DM, Holloway GP (2014)

divergent impacts on skeletal muscle mitochondrial bioenergetics in 43. Both linoleic and α-linolenic acid prevent insulin resistance but have Lipids 36: 491-498. Lesnefsky EJ, Hoppel CL (2008) Cardiolipin as an oxidative target in 26. Tuo Y, Wang D, Li S, Chen C (2011) Long-term exposure of INS-1 rat 1027. obese Zucker rats. Am J Physiol Endocrinol Metab 307: E102-114. cardiac mitochondria in the aged rat. Biochim Biophys Acta 1777: 1020- insulinoma cells to linoleic acid and glucose in vitro affects cell viability 44. Schlame M, Hostetler KY (1997) Cardiolipin synthase from mammalian

and function through mitochondrial-mediated pathways. Endocrine 39: 45. mitochondria.Laganiere S, Yu Biochim BP (1993) Biophys Modulation Acta 1348: of membrane 207-213. phospholipid fatty 27. 128-138.Jarmuszkiewicz W, Almeida AM, Sluse-Goffart CM, Sluse FE, Vercesi AE

46. acidJumelle-Laclau composition M, by Rigoulet age and M,food Averet restriction. N, Leverve Gerontology X, Dubourg 39: 7-18. L, et al. phosphorylating,(1998) Linoleic acid-induced and progressively activity uncoupled of plant uncoupling respiration. mitochondrial J Biol Chem (1993) Relationships between age-dependent changes in the effect of protein in purified tomato fruit mitochondria during resting, almitrine on H(+)ATPase/ATPsynthase and the pattern of membrane

Demizieux L, Degrace P, Gresti J, Loreau O, Noël JP, et al. (2002) 273: 34882-34886. 47. fatty acid composition. Biochim Biophys Acta 1141: 90-94. 28. Conjugated linoleic acid isomers in mitochondria: evidence for an Lesnefsky EJ, Minkler P, Hoppel CL (2009) Enhanced modification of ISSN: 2581-7310 31 www.innovationinfo.org

50. Grinna LS (1977) Age related changes in the lipids of the microsomal cardiolipin during ischemia in the aged heart. J Mol Cell Cardiol 46: fat unsaturation. J Gerontol A Biol Sci Med Sci 61: 107-114. and the mitochondrial membranes of rat liver and kidney. Mech Ageing 1008-1015.Ayala S, Gaspar G, Brenner RR, Peluffo RO, Kunau W (1973) Fate of linoleic, arachidonic, and docosa-7,10,13,16-tetraenoic acids in rat 48. 51. Ricquier D, Mory G, Hemon P (1979) Changes induced by cold adaptation Dev 6: 197-205. in the brown adipose tissue from several species of rodents, with special 49. testicles.Quiles JL, J LipidOchoa Res JJ, 14:Ramirez-Tortosa 296-305. MC, Huertas JR, Mataix J (2006) Age-related mitochondrial DNA deletion in rat liver depends on dietary 1266. reference to the mitochondrial components. Can J Biochem 57: 1262-

Citation: Eldor J (2018) Linoleic Acid: The Code of Life? J Health Sci Dev Vol: 1, Issu: 2 (18-32).

ISSN: 2581-7310 32