Anti-endotoxic Effect Research Articles

Syringic acid ameliorates testicular oxidative stress via the conservation of endogenous antioxidant markers and inhibition of the activated Nrf2-Keap1-NQO1-HO1 signaling in methyl cellosolve-administered rats

IntroductionSyringic acid (SYRAC) isolated from Ban Lan Gen or Isatis root, a famous Chinese traditional medicine is known to possess antiendotoxic effect. Methyl cellosolve (MCE) on the other hand, is an important constituent of car brake fluids, pesticides, inks, paints, and liquid soaps, rendering humans inevitable to its exposure. MethodsThis study therefore investigated the effect of SYRAC treatments on MCE-induced testicular oxidative stress in rats. Six (6) groups of five (5) rats each were involved in this study that lasted for 30 days. The first group was the control that contained rats served food and water throughout, the second group were administered 100 mg/kg body weight of MCE everyday for 30 days, the third, fourth, and fifth group were treated same way as rats in second group but were treated with 25, 50, and 75 mg/kg body weight of SYRAC respectively for 30 days, while rats in the sixth group were administered 75 mg/kg body weight of SYRAC only. ResultsAt the end of administrations, RTW, testicular GSH level, and activities of GPx, GST, CAT, and SOD were significantly decreased, while MDA, total mRNA expressions of HO-1, NQO1, Keap1, and Nrf2 were significantly increased by MCE compared with control. Compared with MCE only, treatments with SYRAC significantly increased the testicular levels of NO and GSH, as well as activities of GPx, GST, SOD, and CAT, while MDA, mRNA expressions of Keap1, NQO1, Nrf2, and HO-1 were significantly decreased. ConclusionConclusively, MCE-induced testicular oxidative stress was recorded. SYRAC demonstrated a gonadoprotective effect by maintaining the normal levels of the endogenous antioxidants and inhibiting MECE-induced Nrf2 activation and ARE-dependent genes in rats.

Antimicrobial peptides in the pathogenesis of infectious complications in obstetrics and gynecology

Antimicrobial peptides (AMP) are cationic peptides of innate immune system with antiviral, antibacterial and antiprotozoal activity. AMP act as immunomodulators, promote bacterial opsonization, inhibit proteases activity, have anti-endotoxic and angiogenic effect. The review describes main types of AMPs, features of their expression in female reproductive tract depending from menstrual cycle and during pregnancy. Data about the role of AMPs in defending from sexually transmitted infections (HIV, genital herpes, HPV, gonorrhea), in pathogenesis of extrauterine pregnancy and preterm birth are described. Possibility of practical application of AMPs as alternative to antibiotics and as contraceptives is estimated.

An antimicrobial helix A-derived peptide of heparin cofactor II blocks endotoxin responses in vivo

Host defense peptides are key components of the innate immune system, providing multi-facetted responses to invading pathogens. Here, we describe that the peptide GKS26 (GKSRIQRLNILNAKFAFNLYRVLKDQ), corresponding to the A domain of heparin cofactor II (HCII), ameliorates experimental septic shock. The peptide displays antimicrobial effects through direct membrane disruption, also at physiological salt concentration and in the presence of plasma and serum. Biophysical investigations of model lipid membranes showed the antimicrobial action of GKS26 to be mirrored by peptide incorporation into, and disordering of, bacterial lipid membranes. GKS26 furthermore binds extensively to bacterial lipopolysaccharide (LPS), as well as its endotoxic lipid A moiety, and displays potent anti-inflammatory effects, both in vitro and in vivo. Thus, for mice challenged with ip injection of LPS, GKS26 suppresses pro-inflammatory cytokines, reduces vascular leakage and infiltration in lung tissue, and normalizes coagulation. Together, these findings suggest that GKS26 may be of interest for further investigations as therapeutic against severe infections and septic shock.

Importance of lipopolysaccharide aggregate disruption for the anti-endotoxic effects of heparin cofactor II peptides

Lipid membrane and lipopolysaccharide (LPS) interactions were investigated for a series of amphiphilic and cationic peptides derived from human heparin cofactor II (HCII), using dual polarization interferometry, ellipsometry, circular dichroism (CD), cryoTEM, and z-potential measurements. Antimicrobial effects of these peptides were compared to their ability to disorder bacterial lipid membranes, while their capacity to block endotoxic effects of LPS was correlated to the binding of these peptides to LPS and its lipid A moiety, and to charge, secondary structure, and morphology of peptide/LPS complexes. While the peptide KYE28 (KYEITTIHNLFRKLTHRLFRRNFGYTLR) displayed potent antimicrobial and anti-endotoxic effects, its truncated variants KYE21 (KYEITTIHNLFRKLTHRLFRR) and NLF20 (NLFRKLTHRLFRRNFGYTLR) provide some clues on structure–activity relations, since KYE21 retains both the antimicrobial and anti-endotoxic effects of KYE28 (although both attenuated), while NLF20 retains the antimicrobial but only a fraction of the anti-endotoxic effect, hence locating the anti-endotoxic effects of KYE28 to its N-terminus. The antimicrobial effect, on the other hand, is primarily located at the C-terminus of KYE28. While displaying quite different endotoxic effects, these peptides bind to a similar extent to both LPS and lipid A, and also induce comparable LPS scavenging on model eukaryotic membranes. In contrast, fragmentation and densification of LPS aggregates, in turn dependent on the secondary structure in the peptide/LPS aggregates, correlate to the anti-endotoxic effect of these peptides, thus identifying peptide-induced packing transitions in LPS aggregates as key for anti-endotoxic functionality. This aspect therefore needs to be taken into account in the development of novel anti-endotoxic peptide therapeutics.

Lipopolysaccharide Interactions of C-Terminal Peptides from Human Thrombin

Interactions with bacterial lipopolysaccharide (LPS), both in aqueous solution and in lipid membranes, were investigated for a series of amphiphilic peptides derived from the C-terminal region of human thrombin, using ellipsometry, dual polarization interferometry, fluorescence spectroscopy, circular dichroism (CD), dynamic light scattering, and z-potential measurements. The ability of these peptides to block endotoxic effects caused by LPS, monitored through NO production in macrophages, was compared to peptide binding to LPS and its endotoxic component lipid A, and to size, charge, and secondary structure of peptide/LPS complexes. While the antiendotoxic peptide GKY25 (GKYGFYTHVFRLKKWIQKVIDQFGE) displayed significant binding to both LPS and lipid A, so did two control peptides with either selected D-amino acid substitutions or with maintained composition but scrambled sequence, both displaying strongly attenuated antiendotoxic effects. Hence, the extent of LPS or lipid A binding is not the sole discriminant for the antiendotoxic effect of these peptides. In contrast, helix formation in peptide/LPS complexes correlates to the antiendotoxic effect of these peptides and is potentially linked to this functionality. Preferential binding to LPS over lipid membrane was furthermore demonstrated for these peptides and preferential binding to the lipid A moiety within LPS inferred.

Membrane and lipopolysaccharide interactions of C-terminal peptides from S1 peptidases

The mechanisms underlying antimicrobial and anti-endotoxic effects were investigated for a series of structurally related peptides derived from the C-terminal region of S1 peptidases. For this purpose, results on bacterial killing were compared to those on peptide-induced liposome leakage, and to ellipsometry and dual polarization interferometry results on peptide binding to, and disordering of, supported lipid bilayers. Furthermore, the ability of these peptides to block endotoxic effects caused by bacterial lipopolysaccharide (LPS), monitored through NO production in macrophages, was compared to the binding of these peptides to LPS, and to secondary structure formation in the peptide/LPS complex. Bacteria killing, occurring through peptide-induced membrane lysis, was found to correlate with liposome rupture, and with the extent of peptide binding to the lipid membrane, no adsorption threshold for peptide insertion being observed. Membrane and LPS binding was found to depend on peptide net charge, illustrated by LPS binding increasing with increasing peptide charge, and peptides with net negative charge being unable to lyse membranes, kill bacteria, and block LPS-induced endotoxic effect. These effects were, however, also influenced by peptide hydrophobicity. LPS binding was furthermore demonstrated to be necessary, but not sufficient, for anti-endotoxic effect of these peptides. Circular dichroism spectroscopy showed that pronounced helix formation occurs in peptide/LPS complexes for all peptides displaying anti-endotoxic effect, hence potentially linked to this functionality. Similarly, ordered secondary structure formation was correlated to membrane binding, lysis, and antimicrobial activity of these peptides. Finally, preferential binding of these peptides to LPS over the lipid membrane was demonstrated.

Investigation on the Antiendotoxic Effect of the Combination of Polymyxin E and Ampicillin in Dogs with Endotoxic Pyometra

The aim of this study was to determine the incidence and levels of the gram negative bacterial endotoxin, and to investigate the effects of antiendotoxemic treatment along with operation. Thirty bitches with pyometra were used in this study. The bitches were randomly allocated into two groups as Group I (treated with polymyxin E-ampisillin) and Group II (treated with ampisillin). Samples for bacteriological examination were taken from vagina, vesica urinaria and uterus of all bitches. Blood samples were collected to evaluate biochemical, haematological tests and serum toxine levels before the operation and on 7 days after operation. Gelation was carried out to determine the gram negative bacterial endotoxin level with E-toxate test kit in accordance with gelation system. Gram negative bacteria were isolated 66% in Group I and 80% Group II. Escherichia coli were dominantly (63.4%) isolated from the uteri of 30 bitches with pyometra. Before the operation, serum toxin levels were found in Group I (n=10) 1.2±0.4 EU/ml and in Group II (n=12) 0.9±0.2 EU/ml. Five bitches in Group I and 3 bitches in Group II died on the third day after operation. Survival rate was a positive correlation with toxin levels (r=0.727; P<0.01) and BUN (r=0.539; P<0.01), creatinin (r=0.504, P<0.05) before operation in recovered and dead bitches. Serum toxin levels were not different between Group I (n=6; 0.14±0.02 EU/ml) and Group II (n=11; 0.19±0.01 EU/ml) 7 days after operation. Difference of toxin levels in both groups were different (P<0.05) between the preoperation period and the 7th day after operation. Before the operation and on the 7th day after the operation, in Group I difference between band neutrophil count and in Group II ALT, ALP, BUN, creatinin, RBC, WBC, Hct, band neutrophil and lenphocyte value were found significant (P<0.05). As a result, there was a positive correlation between toxin levels and BUN-creatinin values. Also, the cases that have the increased BUN and creatinin levels along with high toxin levels were trended towards to low survival rate. After operation, in cases that performed with ampicillin were acquired more effective results contrary to the hipothesis according to polymyxin E+ampicillin combination in bitches with pyometra.

The anti-endotoxic effect of o-aminobenzoic acid from Radix Isatidis

To study the anti-endotoxic effect of o-aminobenzoic acid (OABA) isolated from Banlangen(BLG). OABA was extracted and isolated from BLG and diluted into 0.5% solution. The concentration of endotoxin (ET) pretreated with OABA was quantitatively detected using Limulus test. The inhibition of ET-induced fever by OABA was measured in rabbits. The rates of lipopolysaccharides (LPS)-induced death in mice pretreated with or without OABA were then compared. The influence of OABA on the release of TNF-alpha and NO from macrophages induced by LPS was examined in mice. After pretreatment with OABA, 84.4% of ET was destroyed. The ET-induced fever in rabbits decreased significantly and the rate of LPS-induced death in mice dropped from 70% to 20%. The release of TNF-alpha and NO induced by LPS in mice was inhibited dose-dependently when the concentration of OABA was between 0.125% and 0.5%. OABA isolated from BLG has an anti-endotoxic effect.

Evaluation of the anti‐endotoxic effects of polymyxin‐E (colistin) in dogs with naturally occurred endotoxic shock

Endotoxin is a potent stimulator of the inflammatory response and is believed to initiate the pathology in gram-negative sepsis. Agents are being searched for that bind and neutralize or block the effects of endotoxin. The aim was to study the anti-endotoxic effects of polymyxin-E (colistin) in endotoxaemic dogs. The study included a total of 30 endotoxaemic dogs, which were divided into two groups (control = 15; test = 15) of both sexes, different breeds and ages. Hetastarch colloid solution (Expahes,10 mL/kg, i.v.) with lactated Ringer's solution (20 mL/kg, i.v., Q12 h) was given to all dogs. While ampicillin was administered (Alfasilin, 10 mg/kg, i.m., Q12 h) as an antibacterial to the control group, colistin (12,500 IU/kg, i.m., Q12 h) + ampicillin were administered to the test group. The clinical examination (body temperature, pulse and respiration rates, capillary filling times, peripheral pulse qualities, dehydration degrees), hematological and biochemical examinations (WBC, RBC, HGB, HCT, thrombocyte, serum urea, creatinine and TNF-alpha) were performed both before the treatment, and 2, 4, 12 and 24 h after the treatment. In comparison with the control group, it was observed that test group had shorter capillary filling time at 24 h (P < 0.001). Moreover, the degree of dehydration in test group, was significantly improved at 24 h (P < 0.01). While the differences in peripheral pulse qualities significantly differed between 0 and 2 h in controls, at 2, 4, 24 h after treatment it was found to be significantly increased when compared with 0 h in the test group. Serum TNF-alpha concentrations were statistically decreased in the test group between 0 h and other times (P < 0.01). When compared with controls, serum TNF-alpha concentrations were lower at 2, 4, 12 and 24 h in test group (P < 0.05). Results of the study indicated that polymyxin-E (colistin) has an anti-endotoxic effect and is safe for the dogs with endotoxemia at the dosage used in this study.

Anti-endotoxic effects of syringic acid ofRadix Isatidis

The anti-endotoxic effect of syringic acid (SA) isolated from Radix Isatidis (Banlangen, BLG) was studied. SA was extracted and isolated from BLG and diluted into 1% solution. The content of SA-pretreated endotoxin (ET) was quantitatively determined using Limulus test. The ability of fever induction of ET pretreated with SA was measured using endotoxin-induced fever test in rabbits. The LPS-induced death in mice pretreated with and without SA was compared. Results showed that after pretreatment with SA, 83.16% of ET was destroyed, the ET-induced fever in rabbits relieved markedly and the LPS-induced death rate in mice dropped from 68% to 20%. It was concluded that SA isolated from BLG had anti-endotoxic effects.

Lethal effect of polymyxin B sulfate in experimental Proteus rettgeri infection in mice

The mouse model of intraperitoneal sepsis with Proteus rettgeri was used to evaluate the anti-endotoxic effect of polymyxin B sulfate. An unexpected reversal of the usual protective effect of polymyxin in experimental enterobacterial sepsis was observed in which the lethality of the infection was enhanced.

Protective effect of polymyxin B sulfate in experimental enterobacterial infection in mice

The mouse model of intraperitoneal enterobacterial sepsis was used to evaluate the anti-endotoxic effect of polymyxin B sulfate. Single or multiple therapeutic doses of polymyxin, administered either before or after lethal challenge with Serratia marcescens, produced statistically and clinically significant protective effects.

The Anti‐Endotoxin Activity of Taurolin in Experimental Animals

Taurolin, a broad spectrum bactericidal agent, protected experimental animals from the lethal effects of Escherichia coli and Bacteroides fragilis endotoxin. Taurolin also prevented the pyrexic response of rabbits to TAB vaccine. Results suggest that Taurolin exerts its antiendotoxic effect by direct reaction with the endotoxin molecule.

Antiendotoxic effect of water-soluble analogs of glucocorticoids

The results of this study indicate that in the rat the antiendotoxic action of hydrocortisone, methylprednisoline, or dexamethasone is not affected by the nature of the salt radical employed to render these steroids water soluble. Also, the administration of methylprednisolone succinate and dexamethasone phosphate in concert protects in a simple additive manner.