DOV LICHTENBERG, Ph.D.

Emeritus Professor of Pharmacology
Previous Dean, Sackler Faculty of Medicine

Department of Physiology and Pharmacology
TEL AVIV UNIVERSITY
Ramat Aviv, Tel Aviv 69978, Israel
Office:   972-3-6407305
Fax:       972-3-640 9113
Residence: 972-3-6044283
E-mail:physidov@post.tau.ac.il

Curriculum Vita

Born in Jerusalem (1942), graduated from high school (A) in Tel Aviv (1960)

Married, a father of four children and a grandfather to 12 grandchildren

Military service: 1963-1966 Staff officer (Israel Defense Forces)

Education: BSc (1963), MSc (1967) and PhD (1972) Hebrew University

1972-1974 post-Doctoral Studies California Institute of Technology

Experience: 1968-1972 Hebrew University (Pharmacology) Assistant and Instructor.

1974-1981 Hebrew University (Pharmacology) Lecturer

1979-1981 University of Virginia (Biochemistry) Visiting Scientist

1981-2011 Tel Aviv University, Professor of Pharmacology

2011- Present Tel Aviv University, Emeritus Professor

Academic administration

1985-1990 Founder and Head, Unit of interdepartmental core facility

1989-1993 Head of department, Department of Physiology and Pharmacology

1995-1998 Founder and Head, Faculty Graduate School

1998-2002 vice Dean

2002-2006 Dean

Research Interests

The solubility of lipids in aqueous media is extremely low.

Biological fluids, however, contain high lipid concentrations

due to solubilization by surfactants (e.g. bile salts in the biliary system) or emulsification by other surface active compound (e.g. phospholipids and apolipoproteins in the blood).

In general, our research in the past 20 years involves studies of the physical-chemistry of lipid solubilization, emulsification and metabolism in health and disease.The two major issues of our current research are:

1. Oxidative modification of lipids in membranes and in plasma lipoproteins, dependence of the oxidation resistance of lipids on various factors, including physiological and pathological conditions, including lipid dislipodemiaand antioxidants and basic aspects of the mechanics involved in lipid oxidation, using both lipoproteins and liposomalmodel systems.

2. Solubilizationof lipids, phospholipids and membranes by detergents. These processes are of significance with respect to solubilizationand reconstitution of biological membranceas well as in the naturally-occurring solubilization of dietary lipids (including cholesterol). Our studies address mechanistic, thermodynamic and structural aspects of these processes

Additional projects include studies of :

1. Biliary factors which affect the precipitation of cholesterol from cholesterol-phospholipid-bile salt mixed systems (bile models) and their relevance to the pathogenesis of cholesterol gallstones.

2. Metabolism of lipid emulsions used for intravenous nutrition and their effect on bilecomposition (in collaboration with M. Rubin).

3. The use of self-assembled amphiphiles (in mixed micelles, emulsion particles and liposomes) for application of lipid-soluble drugs.

Most of our experimental work is based on the use of spectroscopic techniques (static and dynamic light scattering, spectrophotometry and spectrofluorimetry and NMR spectroscopy) electron microscopy, calorimetry, chemical and specoscopic monitoring of lipid hydrolysis.

Publications (a partial list of recent critical reviews)

Dov Lichtenberg, Hasna Ahyayauch, Alicia Alonso, and Felix M. Goni, 2013. Detergent solubilization of lipid bilayers: a balance of driving forces. Trends in Biochemical Sciences, 2013, 38, 85-93.

Dov Lichtenberg, Hasna Ahyayauch, and Felix M. Goni, 2013.The Mechanism of Detergent Solubilization of Lipid Bilayers. Biophysical Journal 105 289–299.

Pinchuk, I., Lichtenberg, D., 2013. Analysis of the kinetics of lipid peroxidation in terms of characteristic time-points. Chem. Phys. Lipids, In Press.

Dov Lichtenberg, Ilya Pinchuk, 2013. Atherogenesis, the oxidative LDL modification hypothesis revisited, Advances Bioscience & Biotechnology, 4, 48-61.

Finkler M, Lichtenberg D, Pinchuk I, 2013 The relationship between oxidative stress and exercise. J Basic Clin Physiol. Pharmacol 17:1-11

Pinchuk, I., Shoval, H., Dotan, Y., and Lichtenberg, D., 2012. Evaluation of antioxidants: Scope, limitations and relevance of assays. Chemistry and Physics of lipids

Contributions

CV Hebrew

Academic Administration (Hebrew)

Contributions to the field of oxidative stress and antioxidants

The major goal of our research in the last two decades has been to gain understanding of the mechanisms of lipid peroxidation, the damage attributed to peroxidation and the role of oxidative stress and antioxidants in health and disease. My activity in this field began in 1993. At that time, the major activity in my research group addressed the self- assembly of mixtures of different amphiphiles, in an attempt to gain understanding of the solubilization and reconstitution of biomembranes. In the summer of 1993, during a short sabbatical I spent in Graz, I met the Late Professor Herman Esterbauer, who was one of the major contributors to our understanding of the mechanisms of free radical-induced peroxidation of lipids. One of Professor Esterbauer’s contributions to the field was the spectroscopic monitoring of LDL peroxidation. The typical time dependence of this reaction is that peroxidation is preceded by a ‘lag phase’, which can be used to evaluate the resistance of the lipids to oxidation.

In our meeting, we considered collaborating on the mutual dependencies of the physical properties of self-assembled lipids and their peroxidation induced either by transition metal ions or by free radical generators. What I learned from that meeting was that there is need for new methods that will enable evaluation of the susceptibility of lipids to peroxidation, hence the ‘oxidative stress’ and the antioxidative capacity of the (growing number) of antioxidants. In our discussion of the available methods of evaluating the 'lag phase', Professor Esterbauer stressed the problematic need to fractionate lipoproteins (particularly irreproducibilities caused by the long process of fractionation). Therefore, I decided to try to develop a method that can be used to evaluate the OS on the basis of ex-vivo measurements of peroxidation of lipids in unfractionated serum or plasma.

Given the likelihood of irreproducibilities of measurements conducted at one pre-defined time point (Pinchuk et al. 2012), my research group developed an optimized spectroscopic method capable of monitoring the kinetics of lipid peroxidation in unfractionated serum, as described below (Schnitzer et al. 1998b; Schnitzer et al. 1995a) . Armed with this method of evaluation of the susceptibility of lipids to oxidation, we studied several mechanistic and clinical aspects of OS and antioxidants in health and disease as follows.

(i) We used existing data and meta-analysis to define ‘oxidative stress’ in terms of criteria that are relevant to lipid peroxidation (Dotan et al. 2004), and to investigate the association between these criteria and oxidative stress-related diseases (Dotan, et al. 2012). Assuming that patients under high OS are likely to benefit from antioxidant supplementation, it was reasonable to expect that establishing a protocol to assay a universal criterion of OS can be used to decide who is likely to benefit from supplementation of antioxidants (Dotan et al. 2009a; Dotan et al. 2009b; Lichtenberg, 2011). Unfortunately, we learned that OS cannot be defined by a universal criterion, probably because there are different ‘types’ (or classes) of OS, each of which can be estimated on the basis of different methods (see below "Analysis of Clinical Data").

(ii) We used our optimized assay to assess the susceptibility of lipids to oxidation in individuals under different pathophysiological conditions.

(iii) We studied the effects of membrane composition on the susceptibility of oxidizable lipids and on the effect of antioxidants on lipid peroxidation in relatively simple model membranes (liposomes). This document is a short description of the results of these studies.

Development of novel methods

In Graz, I collaborated with Hermetter and Hofer in a successful attempt to develop a kinetic assay of the oxidation of fluorescent probes designed to monitor glycerol and sphingophospholipds in lipoproteins (Hofer et al, 1996).

My first activity in Tel Aviv in this field aimed at developing a method capable of monitoring lipid peroxidation in unfractionated serum. Two factors interfered with continuous monitoring of peroxidation products during peroxidation: First, copper binding to albumin inhibits peroxidation of lipids in unfractionated serum and plasma. To overcome this difficulty, a very high concentration of copper is required. Our way of overcoming this problem was to use a high concentration of citrate, which forms redox-inactive copper chelates, yet does not prevent peroxidation (Schnitzer et.al, 1998 and 1995).

In addition, albumin absorbs light with a maximum at a wavelength of 234nm, which is also the wavelength at which the absorption of hydroperoxides is maximal. Our solution to this problem is to monitor the production of hydroperoxides at 245nm (Schnitzer et al, 1997). At this wavelength, the absorption of hydroperoxide is about 70 % of its value at 234nm, whereas albumin absorbs only 15% of its maximal absorption. Thus, we give up about a third of the maximal sensitivity of the test but gain very much on the signal/noise ratio. Based on these solutions, we have developed an optimized assay of the susceptibility of lipids in diluted serum in citrate-containing medium (Schnitzer et al, 1998).

In another study, we monitored the peroxidation of lipoproteins at 4 different wavelengths and used the results to evaluate the time-dependencies of the different reaction products (Pinchuk and Lichtenberg, 1996). In a subsequent review, devoted to the mechanism of antioxidative effects, we have shown that the effect of antioxidants on the kinetics of peroxidation can be used to determine the mechanism responsible for the antioxidative effect (Pinchuk and Lichtenberg, 2002).

We also developed an assay of the capacity of antioxidants under biologically-relevant conditions (Pinchuk et al, 2011 and 2012, Pinchuk and Lichtenberg, 2015). Specifically, most tests used to evaluate antioxidants are conducted in solution, whereas the peroxidation of PUFA in vivo occurs at interfaces. We conduct a series of peroxidation experiments in serum without the assayed antioxidants and in the presence of different concentrations of the assayed antioxidant. Based on each such series of experiments, we rank antioxidants in terms of their concentration needed to double the lag preceding peroxidation (Pinchuk et al, 2011).

In a recent review (Pinchuk et al ,2012) we have demonstrated the risk of producing irreproducible results if OS is evaluated on the basis of a ‘one time-point measurement’, namely the importance of kinetic studies. Accordingly, we studied possible ways to characterize the kinetics. The results of this analysis can be used to characterize the kinetics of peroxidation in terms of rate constants and concentrations on the basis of experimentally attainable factors, particularly well-defined time points (Pinchuk and Lichtenberg, 2014a). Further development of our approach includes analysis of effects of compartmentalization of “key players”, such as hydroperoxides and tocopherol, in lipoprotein particles (Pinchuk and Lichtenberg, 2014b). These studies enable quantitate analysis of issues that we (and others) previously analyzed only qualitatively (Pinchuk et al, 1998; Pinchuk and Lichtenberg, 1999), including the conditions under which oxygen availability is the limiting factor in LDL oxidation (Raveh et al, 2002) and the dose-dependent effect of copper-chelating agents on the kinetics of LDL peroxidation (Pinchuk et al, 2001). Using our optimized assay, we also investigated the effect of hyaluronic acid-linked phosphatidylethanolamine (HyPE) on the susceptibility of LDL lipids to oxidation. Interestingly, ‘sugar decoration’ of the LDL surface slow down peroxidation of the LDL (Schnitzer et al, 2000). In another investigation, we tested the effects of a potent inhibitor of LDL-associated phospholipase A on both the activity of the enzyme and the kinetics of LDL peroxidation. We found that under conditions of complete inhibition of the enzyme, the peroxidation of the LDL lipids is not affected indicating that of LDL-associated phospholipase A does not protect LDL against lipid peroxidation in vitro (Schnitzer et al, 1998).

Lipid peroxidation in lipoprotein fractions and in mixtures of lipoproteins

Much data is available on LDL oxidation, mainly because oxidized LDL is believed to be responsible for initiation of atherosclerosis. In fact, under most conditions, HDL is more susceptible to oxidation than LDL and the hydroperoxides formed in HDL upon peroxidation may migrate to LDL (Schnitzer et al, 1995) and promote LDL peroxidation (Raveh et al, 2001 and 2000). This accords with the unexpected result that the lag preceding rapid peroxidation of serum lipids, i.e. the sensitivity of serum lipids to copper-induced peroxidation ex-vivo increases with HDL concentration (Shimonov et al, 1999).

Comparison of the kinetic profiles of copper-induced oxidation of HDL and LDL at different copper concentrations revealed that under all the studied experimental conditions HDL is more susceptible to oxidation than LDL (Raveh et al, 2001). Native HDL particles contain, on an average, 0.3 molecules of tocopherol. Hence, each particle contains either one tocopherol molecule or none. At relatively low copper concentrations, the tocopherol-containing HDL particles become oxidized prior to the Tocopherol-deficient HDL particles (Raveh et al, 2001). At high copper, the latter mechanism becomes quenched and HDL oxidation occurs via a non-inhibited, auto-accelerated mechanism. Under these conditions, the lag is a decreasing function of the ratio between bound copper and HDL, in agreement with the proposal that the higher susceptibility of HDL to copper- induced oxidation under conditions of high copper concentrations is due to the higher surface density of bound copper to HDL than to LDL (Raveh et al, 2000).

Systematic kinetic studies on the oxidation in mixtures of HDL and LDL induced by different concentrations of copper, 2_-azo bis (2-amidinopropane) hydrochloride (AAPH) and Myeloperoxidase (MPO) revealed that the apparent contradiction regarding the effects of HDL on LDL peroxidation is a result of the use of different inducers of peroxidation and of their concentrations. Specifically, oxidation of LDL induced either by AAPH or MPO is inhibited by HDL under all the studied conditions, whereas copper-induced oxidation of LDL is inhibited by HDL at low copper/lipoprotein ratio but accelerated by HDL at high copper/lipoprotein ratios (Raveh et al, 2001).

The antioxidative effects of HDL are only partially due to HDL-associated enzymes, as indicated by the finding that reconstituted HDL, containing no such enzymes, inhibits peroxidation induced by low copper concentration (Raveh et al, 2000). The effects of copper concentration can be understood in terms of the ratio of bound copper to lipoprotein. Specifically, at ‘sub-saturating’ concentrations of copper, LDL oxidation is inhibited by HDL because the added HDL binds copper, thus reducing the ratio of bound copper to lipid, consequently reducing the rate of LDL peroxidation (Raveh et al, 2001). By contrast, at high ‘supra-saturating’ copper concentrations, when the addition of HDL does not reduce the copper/lipid ratio below ‘saturation’, HDL does not protect LDL against oxidation. Furthermore, under these conditions HDL accelerates LDL oxidation, probably because part of the hydroperoxides formed in the ‘more oxidizable’ HDL migrate to the ‘less oxidizable’ LDL and enhance the oxidation of the LDL lipids by bound copper (Schnitzer et al, 1995). In addition, the peroxidation induced by transition metal ions is complex due to acceleration by its products (Pinchuk, et al. 1998).

In short, the observed interrelationship between the oxidation of HDL and LDL depends on the oxidative stress, which should be (and can be) considered in future investigations regarding the oxidation of lipoprotein mixtures.

Oxidative stress, as evaluated by different methods

The term ‘oxidative stress’ (OS) appears in thousands of publications. Yet, it is an ill-defined term due to the lack of a universal criterion (Dotan et al, 2004). In many publications, a single method (one of several hundreds existing methods) was used as a criterion of ‘oxidative stress’. In attempt to define a universal criterion, we identified publications that contained in their title or abstract the term OS and at least two methods used to evaluate it. We then looked for correlations between the OS, as evaluated by different methods. The results were unambiguous: reasonable correlations were observed between the OS determined on the basis of different tests only when the tests were of chemically similar factors (Dotan et al, 2004). Specifically, we observed reasonable correlations between results of different factors that reflect lipid peroxidation, as detected by various methods. We observed reasonable correlations between factors that reflect OS determined on the basis of the levels of DNA fragmentation products but no correlation between OS, as evaluated by a methods based on lipid peroxidation and OS, as evaluated on the basis of the level of DNA fragmentation.

In practical terms, it implies that the term OS should be used carefully, namely the method used to evaluate it should be specified (e.g. OS, as determined by TBARS), to avoid apparent irreproducibilities, as described in our recent critical review (Pinchuk et al, 2012). In more basic terms, we concluded that OS cannot be defined by a universal criterion. Our hypothesis was (and still is) that these results indicate that there are different types of OS. This does not mean that the term OS is meaningless, being dependent on method used to evaluate it but that there are different ‘types’ (or Classes) of oxidative stress, each of which can be estimated on the basis of different methods (Dotan et al, 2004).

Analysis of clinical data and of experimentally observed susceptibility of serum lipids to ex-vivo peroxidation under different conditions

In view of the apparent existence of different ‘types of OS’, we analyzed the data available on the OS, as evaluated on different in the four diseases that were most often associated with oxidative stress and found that the only pathology that is associated with oxidative stress according to all the criteria is HIV (Dotan et.al. unpublished results). Unexpectedly, CVD patients are under oxidative stress only according to measurements of lipid peroxidation (Dotan et al, 2012) and the same is true for Alzheimer's disease (AD) and diabetes mellitus (DM) (Samocha-Bonet et al, 2010).

We have also used our optimized assay for evaluation of the ‘oxidative status’ under different pathophysiological conditions. We found association between different pathophysiological states and the lag preceding rapid peroxidation. A few examples are given below:

(i) Exhaustive short physical exercise had only a slight effect on the resistance of serum lipids to oxidation, demonstrating the effectiveness of the homeostatic mechanisms (Dayan et al, 2005 ; Finkler et al, 2013 and in preparation).

(ii) Active labor is associated with OS in the mother but the OS in the fetus remains similar to that of the mother, independent of the mode of delivery (Fogel et al, 2005),

(iii) Different abdominal surgery protocols, including laparoscopic protocols, do not influence the low OS attributed to anesthesia (Rubin et al, unpublished results),

(iv) Treatment of hypercholesterolemia patients with statins increases the resistance of serum lipids to oxidation (Rubinstein et al, unpublished results).

(v) Following MI, the serum lipids are very susceptible to peroxidation and the recovery to normal levels is slow (Fainaru et al, 2002). In hemodialysis patients with history of MI the lipids are very susceptible to ex vivo peroxidation unless they are treated with vitamin E (Boaz et al, 2003).

(vi) The sensitivity of serum lipids of prostate cancer patients to peroxidation increases upon progression of the disease but this increased sensitivity lags behind the clinical symptoms, indicating that the oxidative stress is more likely to be a result rather than the cause of the cancer (Yossepowitch et al , 2007).

(vii) The mean OS of obese patients, as evaluated on the basis of the susceptibility of their serum lipids to ex-vivo peroxidation, is not different from that observed for healthy people, probably due to the high content of Urate in their blood (Samocha-Bonet et al, 2003).

(viii) The OS of women after in-term premature rupture of membranes do not differ from other women (Fainaru et al, 2007).

Altogether, we found no evidence for causal relationship between the alteration of oxidative status and specific pathology. We attribute the complexity of the observed dependence of OS on pathophysiological factors to the multifactorial network of interrelated factors responsible for maintaining a homeostatic level of a redox state. More research is required to evaluate possible causal relationship between the alteration of oxidative status and specific pathologies.

Lipid peroxidation and antioxidants in model membranes

Given the complexity of peroxidation and its dependence on ‘antioxidants’, we studied these issues in the relatively simple liposomes, commonly used as model membranes. These studies deepened our understanding of the complex effect of Albumin (Samocha-Bonet et al, 2004), the (protective) effects of cholesterol (Schnitzer et al, 2007a and 2007b) and the (pro-oxidative) effect of inclusion of negatively charged phospholipids (PA and PS) in the lipid bilayers on copper-induced peroxidation. Since AAPH-induced peroxidation is not affected by the charge, we attribute the effect of charge to an increased binding of copper ions to the negatively charged vesicles (Gal et al, 2003 and 2007).

The effect of low molecular weight antioxidants on lipid peroxidation is complex. Under weak or moderate oxidative stress, water-soluble antioxidants accelerate copper-induced peroxidation of liposomal polyunsaturated fatty acid residues of the phospholipids, whereas under strong oxidative stress the low molecular weight antioxidant tocopherol (vitamin E) is a potent antioxidant (Bittner et al, 2002). Interestingly, externally-added Toc promoted peroxidation whereas co-sonicated Toc inhibited peroxidation (Gal et al, 2003).

Another finding of possible importance is that peroxidation of PS-containing liposomes (but not of PA-containing liposomes) is inhibited by nanomolar concentrations of tocopherol as well as by other 12 out of 37 tested phenols (Gal et al, 2007). These 12 compounds, unlike the other 25, can form semiquinonic structures. A complex of a compound of this structure with a copper-PS complex at the liposomal interface is likely to possess the observed ‘super antioxidative-activity’ but this possibility has yet to be tested.

In reviewing the existing literature about antioxidants, we found only sparse information on the combined effect of antioxidants in their mixtures. In an attempt to clarify this issue, we have investigated the mutual effects of the two most abundant naturally occurring water soluble antioxidants urate and ascorbate (vitamin C) on each other's oxidation and fund that in mixtures of these antioxidants their peroxidation is mutually inhibited (Samocha-Bonet et al, 2005 ; Samocha-Bonet et al., 2004). We also found that these two antioxidants are potent inhibitors of the oxidation of vitamin E in liposomes made of non-oxidizable lipids and of both vitamin E and oxidizable lipids in lipids containing PLPC.

Another important finding of our studies on the oxidation of liposomal lipids is that in mixtures containing excess citrate, as in our optimized assay of the peroxidation of serum lipids, albumin promotes lipid peroxidation (Samocha-Bonet et al, 2004). This means that in our assay, the oxidizing agent is neither copper-citrate nor traces of unbound copper but a redox active copper-albumin complex of a stoichiometry of 2:1 copper/albumin.

Indiscriminate (‘preventive’) supplementation of Vitamin E

Two independent meta-analyses concluded that vitamin E supplementation increases mortality. This conclusion raised much justifiable criticism, based on the limitations of meta-analysis. In an attempt to end this controversy, we have adopted the Markov-model approach, which is free of most of the limitations involved in using meta-analyses. Using the latter decision analysis approach, we discovered that indiscriminate, high dose supplementation of (the best seller) vitamin E results in a decrease of the number of quality-adjusted life years (QALY) by 0.30 (95%CI .21 to 0.39) QALY, namely that indiscriminate supplementation of vitamin E does more harm than good (Dotan et al, 2009b). Yet, we have reasons to believe that vitamin E is a “double-edge sword” and that supplementation may be beneficial to some individuals but should not be consumed indiscriminately. The challenge is to define a criterion (or criteria) capable of predicting who is likely to benefit from supplementation of vitamin E. Preliminary studies indicate that some people (unlike others) are ‘vitamin E responders’. We therefore propose initiating vitamin E supplementation and deciding on whether to continue supplementation on the basis of the result of a relatively short term supplementation (Dotan et al, 2009b; Lichtenberg, 2011).

The role of ROS in the formation and dissociation of Amyloid fibrils

Fibrilization of amyloid polypeptides is accompanied by formation of reactive free radicals (FR), which, in turn, are assumed to further promote amyloid-related pathologies. Different polyphenols, all of which are established antioxidants, cause dissociation of ‘mature’ amyloid fibrils. Using ESR, we found that polyphenol–induced dissociation of fibrils is also accompanied by formation of free radicals. Kinetic studies show that the formation of ROS lags behind dissociation of the fibrils, indicating that if a casual relationship exists between these two processes, then formation of free radicals may be considered a consequence and not a cause of dissociation (Shoval et al, 2007 and 2008). In an attempt to gain understanding of this poorly understood process, we have monitored simultaneously both the dissociation of Aβ42 fibrils and the formation of free radicals as observed upon addition of six different polyphenols to ‘mature fibrils’. These kinetic studies show that the formation of FR lags behind dissociation of the fibrils, indicating that if a casual relationship exists between these two processes, then FR formation may be considered a consequence and not a cause of dissociation. We also found that all the studied amyloid fibrils dissociation processes were accompanied by production of free radicals.

Curcumin synergistically promotes inhibition of cancer cell growth by celecoxib

Cyclooxygenase-2 (COX-2) plays a central role in the development of colorectal cancer via its antiapoptotic effects, increased invasiveness, and promotion of angiogenesis. Several in vitro, in vivo, and clinical studies have previously indicated that the specific COX-2 inhibitor, celecoxib may prevent colorectal cancer. However, the long-term use of celecoxib is limited due to its cardiovascular toxicity. Curcumin is one of the most a potent antioxidants. It is also an effective anti-inflammatory and antitumor drug whose chemo-preventive efficacy has been attributed, at least in part, to its ability to inhibit COX-2, inhibit the activation of transcription factors-activator protein and/ or down-regulate epidermal growth factor receptor. In short, both Curcumin and celecoxib inhibit COX-2 by different mechanisms.

Dr Lev-Ari and Prof Arber therefore expected Curcumin to promote celecoxib inhibition of cancer cells. In fact, we found that Curcumin synergistically potentiates the growth-inhibitory and pro-apoptotic effects of celecoxib in both colorectal cancer cells and osteoarthritis synovial adherent cells, shifting the dose-response curve of celecoxib to the left. Both these effects probably involves inhibition of the COX-2 more than one pathway and may involve other non COX-2 pathways (Lev Ari et al, 2005 and 2006). This synergistic effect is clinically important because it can occur in the Serum of patients receiving standard, non-toxic anti-inflammatory or antineoplastic dosages of celecoxib (Lev Ari et al, 2008).

References

Assali, A., Fainaru, O., Fainaru, M., Adler, Y., Pinchuk, I., and Lichtenberg, D., 1999. Acute myocardial, infarction is associated with increased susceptibility of serum lipids to copper-induced peroxidation in-vitro. Atherosclerosis 144, 42-43.

Bittner, O., Gal, S., Pinchuk, I., Danino, D., Shinar, H., and Lichtenberg, D., 2002. Copper-induced peroxidation of liposomal palmitoyllinoleoylphosphatidylcholine (PLPC), effect of antioxidants and its dependence on the oxidative stress. Chemistry and Physics of Lipids 114, 81-98.

Boaz, M., Smetana, S., Matas, Z., Bor, A., Pinchuk, I., Fainaru, M., Green, M.S., and Lichtenberg, D., 2003. Lipid oxidation kinetics in hemodialysis patients with and without history of myocardial infarction. Israel Medical Association Journal 5, 692-696.

Dayan, A., Rotstein, A., Pinchuk, I., Vodovicz, A., Lencovski, Z., Lichtenberg, D., and Inbar, O., 2005. Effect of a short-term graded exhaustive exercise on the susceptibility of serum lipids to oxidation. International Journal of Sports Medicine 26, 732-738.

Dotan, Y., Lichtenberg, D., and Pinchuk, I., 2004. Lipid peroxidation cannot be used as a universal criterion of oxidative stress. Progress in Lipid Research 43, 200-227.

Dotan, Y., Lichtenberg, D., and Pinchuk, I., 2009. No evidence supports vitamin E indiscriminate supplementation. Biofactors 35, 469-473.

Dotan, Y., Lichtenberg, D., and Pinchuk, I., 2012. Are CVD patients under oxidative stress? in: Parthasarathy, S. (Ed.), Atherogenesis InTech, pp. 413-424.

Dotan, Y., Pinchuk, I., Lichtenberg, D., and Leshno, M., 2009. Decision Analysis Supports the Paradigm That Indiscriminate Supplementation of Vitamin E Does More Harm than Good. Arteriosclerosis Thrombosis and Vascular Biology 29, 1304-130.

Fainaru, O., Almog, B., Pinchuk, I., Kupferminc, M.J., Lichtenberg, D., and Many, A., 2002. Active labour is associated with increased oxidisibility of serum lipids ex vivo. Bjog-An International Journal of Obstetrics and Gynaecology 109, 938-941.

Fainaru, O., Almog, R., Pinchuk, I., Lichtenberg, D., Lessing, J.B., and Kupferminc, M.J., 2007. Serum lipid oxidizibility in term premature rupture of the membranes. European Journal of Obstetrics Gynecology and Reproductive Biology 131, 28-31.

Fainaru, O., Fainaru, M., Assali, A.R., Pinchuk, I., and Lichtenberg, D., 2002. Acute myocardial infarction is associated with increased susceptibility of serum lipids to copper-induced peroxidation in vitro. Clinical Cardiology 25, 63-68.

Fainaru, O., Lichtenberg, D., Pinchuk, I., Almog, B., Gamzu, R., and Kupferminc, M., 2003. Preeclampsia is associated with increased susceptibility of serum lipids to copper-induced peroxidation in vitro. Acta Obstetricia et Gynecologica Scandinavica 82, 711-715.

Finkler M, Lichtenberg D, Pinchuk I, 2013 The relationship between oxidative stress and exercise. J Basic Clin Physiol Pharmacol 17:1-11

Fogel, I., Pinchuk, I., Kupferminc, M.J., Lichtenberg, D., and Fainaru, O., 2005. Oxidative stress in the fetal circulation does not depend on mode of delivery. American Journal of Obstetrics and Gynecology 193, 241-246.

Gal, S., Lichtenberg, D., Bor, A., and Pinchuk, I., 2007. Copper-induced peroxidation of phosphatidylserine-containing liposomes is inhibited by nanomolar concentrations of specific antioxidants. Chemistry and Physics of Lipids 150, 186-203.

Gal, S., Pinchuk, I., and Lichtenberg, D., 2003. Peroxidation of liposomal palmitoyllinoleoylphosphatidylcholine (PLPC), effects of surface charge on the oxidizability and on the potency of antioxidants. Chemistry and Physics of Lipids 126, 95-110.

Hofer, G., Lichtenberg, D., Kostner, G.M., and Hermetter, A., 1996. Oxidation of fluorescent glycero- and sphingophospholipids in human plasma lipoproteins: Alkenylacyl subclasses are preferred targets. Clinical Biochemistry 29, 445-450.

Lev-Ari, S., Lichtenberg, D., and Arber, N., 2008. Compositions for treatment of cancer and inflammation. Recent Patents on Anti-Cancer Drug Discovery 3, 55-62.

Lev-Ari, S., Strier, L., Kazanov, D., Elkayam, O., Lichtenberg, D., Caspi, D., and Arber, N., 2006. Curcumin synergistically potentiates the growth-inhibitory and pro-apoptotic effects of celecoxib in osteoarthritis synovial adherent cells. Rheumatology 45, 171-177.

Lev-Ari, S., Strier, L., Kazanov, D., Madar-Shapiro, L., Dvory-Sobol, H., Pinchuk, I., Marian, B., Lichtenberg, D., and Arber, N., 2005. Celecoxib and curcumin synergistically inhibit the growth of colorectal cancer cells. Clinical Cancer Research 11, 6738-6744.

Lichtenberg D and Pinchuk I, 2013. Atherogenesis, the oxidized LDL modification hypothesis- revisited Advances in Bioscience and Biotechnology, in press.

Lichtenberg D, 2011. Who is likely to gain from high dose supplementation of vitamin E? Harefuah, 150, 37-40 (In Hebrew, an English Abstract is available).

Pinchuk, I. and Lichtenberg, D., 1996. Continuous monitoring of intermediates and final products of oxidation of low-density lipoprotein by means of UV-spectroscopy. Free Radical Research 24, 351-360.

Pinchuk, I. and Lichtenberg, D., 1999. Copper-induced LDL peroxidation: interrelated dependencies of the kinetics on the concentrations of copper, hydroperoxides and tocopherol. Febs Letters 450, 186-190.

Pinchuk, I. and Lichtenberg, D., 2002. The mechanism of action of antioxidants against lipoprotein peroxidation, evaluation based on kinetic experiments. Progress in Lipid Research 41, 279-314.

Pinchuk, I. and Lichtenberg, D., 2014a. Analysis of the kinetics of lipid peroxidation in terms of characteristic time-points. Chemistry and Physics of Lipids, 178, 63-76.

Pinchuk, I. and Lichtenberg, D., 2014b. The effect of compartmentalization on the kinetics of transition metal ion-induced LDL peroxidation. Abstract of ISOFRR annual meeting.

Pinchuk, I. and Lichtenberg, D., 2015. Prolongation of the Lag Time Preceding Peroxidation of Serum Lipids: A Measure of Antioxidant Capacity. in Advanced Protocols in Oxidative Stress III, Armstrong, D. (Ed.), Humana Press.

Pinchuk, I., Gal, S., and Lichtenberg, D., 2001. The dose-dependent effect of copper-chelating agents on the kinetics of peroxidation of low-density lipoprotein (LDL). Free Radical Research 34, 349-362.

Pinchuk, I., Schnitzer, E., and Lichtenberg, D., 1998. Kinetic analysis of copper-induced peroxidation of LDL. Biochimica et Biophysica Acta-Lipids and Lipid Metabolism 1389, 155-172.

Pinchuk, I., Shoval, H., Bor, A., Schnitzer, E., Dotan, Y., and Lichtenberg, D., 2011. Ranking antioxidants based on their effect on human serum lipids peroxidation. Chemistry and Physics of Lipids 164, 42-48.

Pinchuk, I., Shoval, H., Dotan, Y., and Lichtenberg, D., 2012. Evaluation of antioxidants: Scope, limitations and relevance of assays. Chemistry and Physics of Lipids 165, 638-647.

Raveh, O., Pinchuk, I., Fainaru, M., and Lichtenberg, D., 2001. Kinetics of lipid peroxidation in mixtures of HDL and LDL, mutual effects. Free Radical Biology and Medicine 31, 1486-1497.

Raveh, O., Pinchuk, I., Fainaru, M., and Lichtenberg, D., 2002. Oxygen availability as a possible limiting factor in LDL oxidation. Free Radical Research 36, 1109-1114.

Raveh, O., Pinchuk, I., Schnitzer, E., Fainaru, M., Schaffer, Z., and Lichtenberg, D., 2000. Kinetic analysis of copper-induced peroxidation of HDL, autoaccelerated and tocopherol-mediated peroxidation. Free Radical Biology and Medicine 29, 131-146.

Samocha-Bonet, D., Gal, S., Schnitzer, E., Lichtenberg, D., and Pinchuk, I., 2004. Lipid peroxidation in the presence of albumin, inhibitory and prooxidative effects. Free Radical Research 38, 1173-1181.

Samocha-Bonet, D., Heilbronn, L.K., Lichtenberg, D., and Campbell, L.V., 2010. Does skeletal muscle oxidative stress initiate insulin resistance in genetically predisposed individuals? Trends in Endocrinology and Metabolism 21, 83-88.

Samocha-Bonet, D., Lichtenberg, D., and Pinchuk, I., 2005. Kinetic studies of copper-induced oxidation of urate, ascorbate and their mixtures. Journal of Inorganic Biochemistry 99, 1963-1972.

Samocha-Bonet, D., Lichtenberg, D., Tomer, A., Deutsch, V., Mardi, T., Goldin, Y., bu-Abeid, S., Shenkerman, G., Patshornik, H., Shapira, I., and Berliner, S., 2003. Enhanced erythrocyte adhesiveness/aggregation in obesity corresponds to low-grade inflammation. Obesity Research 11, 403-407.

Schnitzer, E. and Lichtenberg, D., 1994. Reevaluation of the Structure of Low-Density Lipoproteins. Chemistry and Physics of Lipids 70, 63-74.

Schnitzer, E., Dagan, A., Krimsky, M., Lichtenberg, D., Pinchuk, I., Shinar, H., and Yedgar, S., 2000. Interaction of hyaluronic acid-linked phosphatidylethanolamine (HyPE) with LDL and its effect on the susceptibility of LDL lipids to oxidation. Chemistry and Physics of Lipids 104, 149-160.

Schnitzer, E., Fainaru, M., and Lichtenberg, D., 1995. Oxidation of Low-Density-Lipoprotein Upon Sequential Exposure to Copper Ions. Free Radical Research 23, 137-149.

Schnitzer, E., Pinchuk, I., and Lichtenberg, D., 2007. Peroxidation of liposomal lipids. European Biophysics Journal with Biophysics Letters 36, 499-515.

Schnitzer, E., Pinchuk, I., Bor, A., Fainaru, M., and Lichtenberg, D., 1997. The effect of albumin on copper-induced LDL oxidation. Biochimica et Biophysica Acta-Lipids and Lipid Metabolism 1344, 300-311.

Schnitzer, E., Pinchuk, I., Bor, A., Fainaru, M., Samuni, A.M., and Lichtenberg, D., 1998. Lipid oxidation in unfractionated serum and plasma. Chemistry and Physics of Lipids 92, 151-170.

Schnitzer, E., Pinchuk, I., Bor, A., Leikin-Frenkel, A., and Lichtenberg, D., 2007. Oxidation of liposomal cholesterol and its effect on phospholipid peroxidation. Chemistry and Physics of Lipids 146, 43-53.

Schnitzer, E., Pinchuk, I., Fainaru, M., Lichtenberg, D., and Yedgar, S., 1998. LDL-associated phospholipase A does not protect LDL against lipid peroxidation in vitro. Free Radical Biology and Medicine 24, 1294-1303.

Schnitzer, E., Pinchuk, I., Fainaru, M., Schafer, Z., and Lichtenberg, D., 1995. Copper-Induced Lipid Oxidation in Unfractionated Plasma - the Lag Preceding Oxidation as a Measured of Oxidation-Resistance. Biochemical and Biophysical Research Communications 216, 854-861.

Shimonov, M., Pinchuk, I., Bor, A., Beigel, I., Fainaru, M., Rubin, M., and Lichtenberg, D., 1999. Susceptibility of serum lipids to copper-induced peroxidation correlates with the level of high-density lipoprotein cholesterol. Lipids 34, 255-259.

Shoval, H., Lichtenberg, D., and Gazit, E., 2007. The molecular mechanisms of the anti-amyloid effects of phenols. Amyloid-Journal of Protein Folding Disorders 14, 73-87.

Shoval, H., Weiner, L., Gazit, E., Levy, M., Pinchuk, I., and Lichtenberg, D., 2008. Polyphenol-induced dissociation of various amyloid fibrils results in a methionine-independent formation of ROS. Biochimica et Biophysica Acta-Proteins and Proteomics 1784, 1570-1577.

Yossepowitch, O., Pinchuk, I., Gur, U., Neumann, A., Lichtenherg, D., and Baniel, J., 2007. Advanced but not localized prostate cancer is associated with increased oxidative stress. Journal of Urology 178, 1238-1243.