Biomedical subjects

S Parthasarathy

Publications and source records attributed to S Parthasarathy.

At least 73 records · Page 4Linked to original sources

PubMed1998

Evidence for oxidatively modified lipid-protein complexes in endometrium and endometriosis.

OBJECTIVE: To evaluate for the presence of oxidatively modified lipid-protein complexes in endometriosis and endometrium of women with endometriosis and controls. DESIGN: Controlled clinical study. SETTING: Academic tertiary care center. PATIENT(S): Women undergoing surgery for pelvic pain, infertility, endometriosis, or tubal ligation controls. INTERVENTION(S): Biopsy of endometrium and endometriosis. MAIN OUTCOME MEASURE(S): Staining with antibodies to oxidatively modified lipid proteins (HNE-7, MDA2), macrophages (HAM-56), and muscle cell actin (HHF-35). RESULT(S): Both endometrium and endometriosis tissues contain stromal cells that immunostain with HAM-56 and show immunostaining (both intracellular and extracellular) with HNE-7 and MDA2. Some endometriotic implants show patchy staining with HHF-35. Endometrium was devoid of staining with HHF-35. Control staining with nonimmune sera in both tissues was also devoid of staining. CONCLUSION(S): These data strongly implicate the occurrence of oxidative stress in endometriosis tissue. These data also suggest that oxidative modification is a normal physiological process in endometrium.

Adult↗

PubMed1998

Macrophage scavenger receptor(s) and oxidatively modified proteins in endometriosis.

OBJECTIVE: To determine whether cultured human peritoneal macrophages have functional scavenger receptor(s) and whether activation of macrophages in endometriosis may involve an increase in scavenger receptor activity. DESIGN: A controlled clinical study comparing peritoneal fluid (PF) macrophages of women with endometriosis and controls without endometriosis. SETTING: Women undergoing laparoscopic evaluation and treatment in a tertiary medical center. PATIENT(S): Twenty-one women undergoing evaluation for pelvic pain or infertility and 10 women undergoing elective laparoscopic tubal ligation. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Evidence for functional macrophage scavenger receptor and evidence of ligands for the scavenger receptor in PF. RESULT(S): Peritoneal macrophages of women with endometriosis degrade significantly more endothelial cell-low density lipoprotein (EC-LDL) and copper-oxidized LDL (Cu-LDL) than native LDL. Macrophages of women with endometriosis also incorporate more labeled oleic acid into cholesteryl ester in the presence of oxidized LDL (Ox-LDL) than in the presence of native LDL. Western blot analysis demonstrates the presence of adducts between lipid peroxidation products and proteins in PF of patients with and without endometriosis. The PF of women with endometriosis competes with labeled Ox-LDL for uptake by mouse peritoneal macrophages in a dose-dependent manner. CONCLUSION(S): We demonstrate for the first time that human macrophages have functional scavenger receptor(s) and that activation of macrophages in endometriosis involves an increase in scavenger receptor activity. Two lines of evidence indicate the presence of ligands for the scavenger receptor in PF.

Adult↗

PubMed1998

Rod models of DNA: sequence-dependent anisotropic elastic modelling of local bending phenomena.

Local bending phenomena can be predicted by elastic models that incorporate sequence-dependent anisotropic-bendability (SDAB). SDAB models consider DNA to be an initially straight, segmented, elastic rod, in which the flexibility of each segment is greater towards the major groove than it is in other directions. While local bending can be predicted by static-geometry models as well, SDAB models, in addition, qualitatively explain such phenomena as the affinity of protein binding and kinking. A set of prediction tools is available at http:/(/)www.icgeb.trieste.it/dna.

Animals↗

PubMed1998

Oxidation and the spermatozoa.

The unusually high content of phospholipid-bound polyunsaturated fatty acids (PUFA) in the sperm plasma membrane drew attention to their potential physiological significance. Docosahexaenoic acid (22:6) is quantitatively the most important fatty acid. The high PUFA content of sperm membranes makes them vulnerable to peroxidative changes, since PUFA containing two or more double bonds are readily attacked by oxygen radicals. The effects of oxidation on sperm function have been suggested as detrimental as well as beneficial. Generation of reactive oxygen species (ROS) and peroxidation of sperm membrane can bring negative effects on motility, midpiece abnormalities, and sperm-oocyte fusion. ROS trigger sperm hyperactivation, and may support the capacitation of spermatozoa and fertilization. Spermatozoa are protected by various antioxidants and antioxidant enzymes in the seminal plasma or in spermatozoa itself. When the gametes are cultured in vitro, they become more susceptible to oxidative damage. Addition of antioxidants in the media brought beneficial effects in preventing loss of motility and inhibiting lipid peroxidation. Treating patients with antioxidants has shown to have a positive effect on improving fertilization in limited data. The mechanism of antioxidant effects on spermatozoa needs to be further studied.

Antioxidants↗

PubMed1998

Endometriosis: a disease of oxidative stress?

Our central hypothesis proposes that oxidatively damaged red blood cells (RBCs), apoptotic endometrial cells or undigested endometrial tissue may signal the recruitment and activation of mononuclear phagocytes. Women with endometriosis are prone to respond to this stimulus with an inadequate macrophage scavenger receptor response although the secretory response is not impaired. Activated macrophages in the peritoneal cavity generate an oxidative stress, which consists of lipid peroxides, their degradation products, and products formed from their interaction with low-density lipoprotein (LDL) apoprotein and other proteins. The lipoproteins of the peritoneal fluid (interstitial fluid) have been shown to have lower vitamin E levels and to be more readily oxidized than plasma, so peritoneal fluid may actually contribute to the disease process actively rather than as a passive carrier of mediators of inflammation and growth. As a result of such a stress, a sterile, inflammatory reaction with secretion of growth factors, cytokines, and chemokines is generated, which is deleterious especially to successful reproduction. We propose that such a pro-oxidant environment (peritoneal fluid as well as activated macrophages) promotes growth of ectopic endometrium. The data presented in this review are just the beginning of exploring the role of oxidative stress in mediating the pathophysiology of endometriosis. Only by understanding the mechanisms involved in the pathogenesis of endometriosis can we develop the basis for new diagnostic and therapeutic approaches.

Apoptosis↗

PubMed1998

Oxygen radicals, antioxidants, and lipid peroxidation.

Reactive oxygen species derived from molecular oxygen are highly reactive metabolites. These species can be generated by cellular or acellular mechanisms. They react with all biological molecules such as protein, lipid, and carbohydrates. The reaction of these species with lipids, called lipid peroxidation, is a very well-studied phenomenon. Compounds, which scavenge these molecules, are called antioxidants. The disruption of the delicate balance between pro- and antioxidants has been implicated in the pathophysiology of many chronic diseases such as, for example, atherosclerosis. This article presents an introduction to what reactive oxygen species are and their reactions with various metabolites. It deals with lipid peroxidation in detail and with methods for measuring lipid peroxidation. This article also outlines the importance of these species in the pathology of various gynecological diseases.

Antioxidants↗

PubMed1998

Exercise and cardiovascular disease: a new perspective.

The oxidation of low density lipoprotein (LDL) has been suggested as a key event in atherogenesis. Paradoxically, exercise, which imposes an oxidative stress, is an important deterrent of cardiovascular disease. In study 1 the oxidizability of LDL was enhanced in exercisers compared with sedentary controls. The lag time of isolated LDL subjected to copper-induced in vitro oxidation was significantly shortened in the exercisers compared with sedentary subjects. This increased sensitivity was not due to a decreased presence of vitamin E. Instead, these findings suggested that the LDL of exercisers may contain increased amounts of preformed lipid peroxides, which account for the increased oxidizability. In study 2, a group x sex ANOVA revealed that male exercisers had a significantly longer mean lag time than male sedentary subjects and that females had similar mean lag times regardless of exercise group. This remained the case when statistical adjustment was made for age, body mass index, blood lipid levels, LDL, and plasma alpha-tocopherol levels. Study 1 exercisers had been in training for a shorter time (< 1 year) than study 2 exercisers (> 2 years). These findings suggest that truly "chronic" exercise (aerobic intensity over several months) decreases the susceptibility of a male exerciser's LDL to undergo oxidation. Conversely, regular aerobic stress during an overall shorter time span creates a more oxidative environment in the body, thus increasing the susceptibility of LDL to undergo oxidation. The oxidative stress of aerobic exercise does not appear to adversely affect the oxidizability of LDL in women.

Adolescent↗

PubMed1998

Partitioning of lung and chest-wall mechanics before and after lung-volume-reduction surgery.

In the study reported here, we partitioned the mechanics of the respiratory system into lung and chest-wall components, using the rapid occlusion technique in seven patients with severe emphysema before lung-volume-reduction surgery and 3 mo later. Patients showed improvements in 6-min walk (p < 0.01) and dyspnea (p < 0.05). The resistances of the respiratory system and chest wall were not altered by surgery. Ohmic airway resistance did not change, but the component of lung resistance (DeltaRL) due to viscoelastic behavior (stress relaxation) and time-constant inhomogeneities (pendelluft) decreased in six patients (p < 0.03). Dynamic elastance of the lung (Edyn,L) decreased after surgery (p < 0.02), whereas dynamic elastance of the chest wall did not change. The ratio of dynamic intrinsic positive end-expiratory pressure (PEEPi) to static PEEPi, which also reflects viscoelastic properties and time-constant inhomogeneities, increased after surgery (p < 0.05). The decrease in dyspnea was related to the decrease in Edyn,L (r = 0.81, p = 0.03), and tended to be related to the decrease in DeltaRL (r = 0.71, p = 0. 07). In conclusion, lung-volume-reduction surgery decreased dynamic pressure dissipations caused by stress relaxation and time-constant inhomogeneities within lung tissue, and it had no effect on the static mechanical properties of the chest wall.

Aged↗

PubMed1998

Cycling of inspiratory and expiratory muscle groups with the ventilator in airflow limitation.

Research on patient-ventilator interactions has largely focused on inspiratory events, with little attention paid to expiration. We sought to determine the importance of the timing and magnitude of expiratory muscle activity in causing patient-ventilator dyssynchrony. Our study was done with healthy subjects receiving pressure support in whom we induced airflow limitation with a Starling resistor. The timing and magnitude of expiratory muscle activity were obtained by wire electromyographic recording of the activity of the transversus abdominis muscle, and were compared with the cycling of the ventilator and inspiratory muscle activity as determined from a flow tracing and diaphragmatic electromyogram (EMG), respectively. Induction of airflow limitation produced significant phase differences in the cycling of the subjects' expiratory muscle group and that of the machine. Some inspiratory efforts failed to trigger the ventilator, owing in part to an increase in elastic recoil consequent to the commencement of expiratory efforts before the termination of mechanical inflation. A delay in relaxation of the expiratory muscles did not interfere with the success of subsequent inspiratory efforts to trigger the ventilator. We also investigated the accuracy of two approaches for distinguishing between the contributions of expiratory muscle activity and elastic recoil to intrinsic positive end-expiratory pressure (PEEPi): the expiratory increase in gastric pressure (Pga) correlated better with transversus abdominis electromyographic activity (r = 0.7 to 0.95) than did the early inspiratory decrease in Pga (r = 0.04 to 0.53). In conclusion, the continuation of mechanical inflation into neural expiration was associated with failure of the subsequent inspiratory attempt to trigger the ventilator.

Abdominal Muscles↗

PubMed1998

Lysophosphatidyl choline, a chemotactic factor for monocytes/T-lymphocytes is elevated in endometriosis.

Inflammatory processes have been hypothesized to mediate some of the clinical sequelae associated with endometriosis. The peritoneal fluid (PF) of women with endometriosis is known to contain more inflammatory cells and their associated cytokines, chemokines, and growth factors. This work provides strong evidence for oxidative stress in the PF of women with endometriosis. 1) The low density lipoprotein (LDL) isolated from the PF of subjects with endometriosis shows a small but detectable increase in electrophoretic mobility compatible with mildly oxidized LDL compared with LDL isolated from the plasma of the same subjects and PF of controls. 2) Isolated PF-LDL of endometriosis subjects is more readily oxidized in vitro than PF-LDL of controls, or LDL isolated from plasma. 3) Vitamin E content is significantly lower in endometriosis PF compared with controls, and compared with plasma of women with endometriosis and controls. No difference is seen between plasma and PF of control subjects. 4) The ratio of phosphatidylcholine/lyso phosphatidylcholine (Ptd/lyso PtdCho) in the PF of endometriosis subjects is significantly lower compared with PF of controls. Taken together, these data provide strong evidence for a pro-oxidant environment in the peritoneal cavity of women with endometriosis. Lyso PtdCho, a product derived from phospholipase A2 action on peroxidized phosphatidylcholine and a potent chemotactic factor for monocytes and T-lymphocytes, is elevated in endometriosis. We hypothesize that the increased presence of lipid peroxidation products in the PF of endometriosis subjects may, at least partly, account for the recruitment of leukocytes, the increase in macrophage activation, the secretion of monocyte--macrophage-derived cytokines, and the endometrial growth-promoting activity associated with endometriosis.

Adolescent↗

PubMed1998

Implications of lag time concept in the oxidation of LDL.

Oxidation of low density lipoprotein (LDL) has been implicated in the pathogenesis of atherosclerosis. The most common technique for measuring the oxidation of lipoproteins is the continuous measurement of the formation of conjugated diene at OD 234 nm. The concept of "lag time", derived from such measurements, has been used to test the efficacy of various antioxidants for their ability to inhibit the oxidation of LDL. This review will elaborate on some of the factors that might affect the lag time.

Alkenes↗

PubMed1998

Regulation of endothelial nitric oxide synthase gene expression by oxidized linoleic acid.

Hypercholesterolemia is associated with impairments in endothelium-dependent vascular relaxations. Paradoxically, endothelial production of nitrogen oxides is increased in early stages of hypercholesterolemia. Prior work has shown that oxidized low density lipoprotein (LDL) has both stimulatory and inhibitory effects on endothelial nitric oxide synthase expression (eNOS) and has focused on lysophosphatidyl choline (LPC) as a component of oxidized LDL which may modulate this effect. Another biologically active component of oxidized LDL is 13-hydroperoxyoctadecadienoic acid (13-HPODE), an oxidized form of linoleic acid. The purpose of this study was to determine the effect of HPODE on the expression of eNOS in bovine aortic endothelial cells (BAECs). Twenty four hour treatment of endothelial cells with HPODE caused a dose-dependent increase in eNOS mRNA levels as assessed by Northern analysis. The time response studies show that HPODE treatment significantly increased eNOS mRNA levels at 12 and 24 h. Concomitant with the increase in eNOS mRNA levels, 20 microM HPODE treatment significantly increased eNOS protein content and enzyme activity. Nuclear run-on studies indicated that the rate of transcription of eNOS gene was significantly elevated 4 h after HPODE treatment when compared to control cultures. Also, actinomycin D studies demonstrated that the half-life of eNOS mRNA was increased from 6 h to 12 h by HPODE treatment. Thus, HPODE-induced up-regulation of eNOS expression is mediated by both transcriptional and posttranscriptional mechanisms. These observations suggest that endothelial cells may attempt to compensate for oxidative injury by increasing expression of eNOS in early stages of hypercholesterolemia.

Animals↗

PubMed1998

Generation and initial characterization of a novel polyclonal antibody directed against homocysteine thiolactone-modified low density lipoprotein.

Elevated plasma homocysteine (homocysteinemia) are presumed to be responsible for the development of coronary artery disease, however, the precise etiology is unclear. We examined the possibility that the adduct formed from the reaction between homocysteine thiolactone, a metabolic product of homocysteine, and apolipoprotein B-100 lysyl residues of low density lipoprotein (LDL) was immunogenic. New Zealand White rabbits were immunized with this adduct at 6-week intervals. Antisera collected following the 3rd immunization was assayed for antibody titers using solid phase ELISA techniques. Titers (defined as the inverse of the greatest serum dilution in which there was a significant difference (P < 0.05) between the percentage antibody bound from the antiserum and the pre-immune serum) were approximately 10(5). In competition-based ELISAs, homocysteine thiolactone-treated LDL competed for binding with the antiserum, as the 50% inhibitory concentration was approximately 10 microg/ml. Neither homocysteine, homocystine (homocysteine disulfide), nor Cu2-oxidized LDL competed for binding. LDL in which lysyl residues were derivatized by acetylation or methylation were not recognized by the antiserum. Homocysteine thiolactone-treated plasma competed for binding to the antiserum, whereas native plasma did not. All lipoprotein fractions from the homocysteine thiolactone-treated plasma competed for binding to the antiserum. We conclude that homocysteine thiolactone-modified LDL is highly immunogenic and specific for homocysteine thiolactone-modified lysines. The potential for using this antibody as a diagnostic tool for measuring plasma homocysteine concentrations and the implications for understanding diseases induced by homocysteinemia are discussed.

Antibody Specificity↗

PubMed1998

Estradiol as an antioxidant: incompatible with its physiological concentrations and function.

Estradiol has been documented to inhibit the oxidation of low density lipoprotein (LDL). We show that physiological concentrations of estradiol do not inhibit the oxidation of LDL by copper. LDL samples isolated from a) premenopausal and postmenopausal women and from b) women at different time periods during their menstrual cycle, who differ vastly in plasma estradiol levels, were also oxidized at the same rates by copper. In contrast, LDL samples isolated from c) women who were hyperstimulated during in vitro fertilization (IVF), with estradiol concentrations above 2000 pg/ml, were resistant to oxidation by copper. However, these LDL samples were also oxidized at a higher rate by peroxidases. More importantly, subjects with high estradiol levels also showed an increase in myeloperoxidase (MPO) protein in the plasma. Based on these results, we conclude that at physiologic concentrations, it is unlikely that estradiol could act as an antioxidant. In fact, the ability of estradiol to induce MPO and become a prooxidant might instead suggest that MPO-mediated oxidative clearance of LDL from plasma by liver might favorably influence the outcome of atherosclerosis.

Adult↗

PubMed1997

Aqueous extracts of cigarette smoke promote the oxidation of low density lipoprotein by peroxidases.

Oxidation of low density lipoprotein (LDL) by cigarette smoke has been considered a potential mechanism by which smoking may promote atherosclerosis. We report in this study that cigarette smoke extract (CSE) inhibited copper-induced oxidation of LDL suggesting the presence of antioxidants in CSE. It is currently believed that peroxidases may oxidize LDL in vivo and during such oxidations antioxidants become pro-oxidants. Accordingly, when LDL was oxidized by peroxidase in the presence of CSE there was an increase in the oxidation of LDL. This is the first study suggesting that smoking may promote atherosclerosis by enhancing peroxidase-catalyzed lipid peroxidation.

Copper↗

PubMed1997

Analysis of temperature factor distribution in high-resolution protein structures.

The temperature factors obtained from X-ray refinement of proteins at high resolution show large variations from one structure to another. However, the B-values expressed in units of standard deviation about their mean value (B'-factor) at the C alpha atoms show remarkably characteristic frequency distribution. In all of the 110 proteins examined in this study, the frequency distribution exhibited a bimodal distribution. The peaks in the B'-factor frequency distribution occur at -1.1 and 0.4 for a bin size of 0.5. The peak at lower temperature factor corresponds largely to buried residues, whereas the peak at larger value corresponds to exposed residues. The distribution could be accurately described as a superposition of two Gaussian functions. The parameters describing the distribution are therefore characteristic of protein structures. The frequency distribution for a given amino acid over all the proteins also shows a similar bimodal distribution, although the areas under the two Gaussians differ from one amino acid to another. The area under the frequency distribution curve for any interval in B'-factor represents the propensity of the amino acid to occur in that interval. This propensity is related both to the hydrophilicity/hydrophobicity of the residue and the tendency of the residue to impose a different degree of rigidity on the polypeptide chain. The frequency distribution of stretches of high B'-factors departs appreciably from that expected for a random distribution. The correlation in the B-values of sequentially proximal residues is probably responsible for the bimodal distribution.

Amino Acids↗

PubMed1997

Interaction of Interceed oxidized regenerated cellulose with macrophages: a potential mechanism by which Interceed may prevent adhesions.

OBJECTIVE: The objective of the study was to determine whether Interceed oxidized regenerated cellulose (Johnson & Johnson Medical, Arlington, Tex.), because of its polyanionic nature, may compete for the macrophage scavenger receptor. STUDY DESIGN: RAW macrophages were incubated with Interceed oxidized regenerated cellulose and known scavenger receptor ligands. The production of interleukin-1beta by mouse peritoneal macrophages was measured in the presence of Interceed cellulose. RESULTS: When macrophages were incubated with Interceed cellulose, increasing concentrations inhibited the uptake of fluorescent acetyl low-density lipoprotein. In the presence of Interceed cellulose there was a decrease in the production of interleukin-1beta by mouse macrophages. CONCLUSION: These results suggest that the interaction of Interceed oxidized regenerated cellulose with macrophages with scavenger receptors may result in a decreased secretion of matrix components, inflammatory mediators, and cellular growth factors. Thus Interceed cellulose may function as a biologic barrier in preventing adhesions.

Animals↗

PubMed1997

Charge-based interactions of mammalian sperm with oocytes: inhibition of fertilization of mouse oocytes by ligands of macrophage scavenger receptor(s).

OBJECTIVE: To determine whether anionic ligands for the macrophage scavenger receptor inhibit the fertilization of mouse oocytes by mouse spermatozoa. DESIGN: In vitro study of sperm binding and two-cell embryo formation in the presence of scavenger receptor ligands. Sperm-oocyte interaction may be mediated by sulfated sugars. In this study, we tested other nonsulfated anionic ligands for the scavenger receptor for their ability to affect fertilization. The only common feature of these ligands is their anionic nature. SETTING: Oocytes and sperm from mice were used. MAIN OUTCOME MEASURE(S): Binding of sperm to oocytes and subsequent formation of two-cell embryos were determined. RESULT(S): Fucoidin, polyinosinic acid, oxidized low-density lipoprotein, acetyl low-density lipoprotein, and malondialdehyde-modified LDL inhibited the binding and fertilization of mouse sperm to mouse oocytes. Addition of fresh sperm to oocytes previously treated with sperm in the presence of these agents restored the binding and fertilization. CONCLUSION(S): These results show that charge-based interactions analogous to the interactions of the scavenger receptor with its ligands may play an important role in mammalian fertilization.

Animals↗