High mobility group box protein 1 sensitizes mononuclear cells to further contact with lipopolysaccharide.

Fever is an adaptive host-defense response to infection and nowadays is rightly considered to be an expression of a healthy body and a well-functioning immune system. The condition is that it must be tightly regulated. Therefore, in individual cases, fever may be detrimental and should be treated. Specific excessive febrile reaction to pathogens which occurs after aseptic injuries is one among such cases. We previously found that among necrotic products, high mobility group box protein 1 (HMGB1) released from the site of aseptic injury affects immune effectors (cells) to mediate higher fever in response to further contact with bacterial lipopolysaccharide (LPS). Here we observed that intraperitoneal (i.p.) pre-injection of recombinant HMGB1 (5 µg/rat i.p.) provoked an increase in plasma levels of prostaglandin E2 (PGE2) in rats and augmented release of interleukin (IL)-1ß and IL-6 after LPS administration at a dose of 50 µg/kg i.p. compared to rats pre-injected with saline or heat-denatured HMGB1. Furthermore, peripheral blood mononuclear cells (PBMCs) isolated from rats injected with HMGB1 were more sensitized to produce enhanced levels of IL-1ß and PGE2 when stimulated with LPS in vitro (1 µg/ml/106 cells for 4 h) compared to control animals injected with saline or heat-denatured HMGB1. We also noted a significant increase in activation of nuclear factor κB (NF-κB) in cells isolated from rats injected with HMGB1. Altogether, the obtained results suggest that HMGB1 participates in priming of immune cells to further contact with pathogens.

Invasive Assessment of the Myocardial Microcirculation during Beating Heart Coronary Artery Bypass Grafting.

Coronary artery bypass grafting may be associated with several cardiac complications, including ischemia, acute myocardial infarction, arrhythmias, or hemodynamic instability. Accumulating evidence suggests that well-developed coronary collateral circulation may protect against adverse effects, including myocardial ischemia. Assessment of myocardial microvascular perfusion is, therefore, of great clinical interest in beating heart surgery. In this paper, myocardial microvascular perfusion is continuously assessed on the beating heart using laser Doppler flowmetry in consecutive patients who underwent coronary artery bypass grafting procedures. No significant (p = 0.110) differences were found between the averaged perfusion signal (n = 42) at the baseline, during artery occlusion, or after reperfusion (732.4 ± 148.0 vs. 711.4 ± 144.1 vs. 737.0 ± 141.2, respectively). In contrast, significantly different (p < 0.001) mean perfusion signals (n = 12) were found (805.4 ± 200.1 vs. 577.2 ± 212.8 vs. 649.3 ± 220.8) in a subset of patients who presented with hemodynamic instability and myocardial ischemia. Additionally, a strong positive correlation between the plasma levels of high-sensitivity troponin I and perfusion decrease level after artery occlusion was found (r = 0.854, p < 0.001). This study argues that myocardial microvascular perfusion remains constant during coronary artery bypass grafting on the beating heart in advanced coronary artery disease. This phenomenon is most likely due to an extensive coronary collateral circulation.

Coriolus versicolor-derived protein-bound polysaccharides trigger the caspase-independent cell death pathway in amelanotic but not melanotic melanoma cells.

We have investigated the potential cell death mechanism promoted by Coriolus versicolor fungus-derived protein-bound polysaccharides (PBPs) in melanoma cells. Knowing that melanogenesis has the potential to affect the tumor behavior and melanoma therapy outcome, the cytotoxic effects of PBPs were evaluated in human SKMel-188 melanoma cell line, whose phenotype, amelanotic versus pigmented, depends on the concentration of melanin precursors in the culture medium. Our results showed that inhibitory effect of PBPs (100 and 200 µg/ml) towards melanoma cells is inversely associated with the pigmentation level. This cytotoxicity induced in nonpigmented melanoma cells by PBPs was caspase-independent; however, it was accompanied by an increased intracellular reactive oxygen species (ROS) generation. The ROS production was controlled by c-Jun N-terminal kinase (JNK) because SP600125, a JNK inhibitor, significantly reduced ROS generation and protected cells against PBPs-induced death. We also found that PBPs-induced lactate dehydrogenase release in amelanotic melanoma cells was abolished by co-treatment with receptor-interacting serine/threonine-protein kinase 1 inhibitor, implying engagement of this kinase in PBPs-induced death pathway. The results suggest that PBPs induce an alternative programmed cell death, regulated by receptor-interacting protein-1 and ROS and that this process is modified by melanin content in melanoma cells. These findings are remarkable when considering the use of commercially available Coriolus versicolor by patients who suffer from melanoma cancer.

High mobility group box 1 protein released in the course of aseptic necrosis of tissues sensitizes rats to pyrogenic effects of lipopolysaccharide.

It is still an open question as to whether or not aseptic injuries affect the generation of fever due to exogenous pyrogens including bacterial products. Therefore, in the present paper we have investigated the course of endotoxin fever in rats induced with lipopolysaccharide (LPS; given intraperitoneally in a dose of 50 µg/kg) 48 h after subcutaneous administration of turpentine oil (TRP; 0.1 mL per rat) that causes aseptic necrosis of tissues. We found that febrile response was significantly augmented in the animals pre-treated with turpentine compared to control rats (pre-treated with saline), and that observed excessive elevation of body temperature (Tb) was accompanied by enhanced release of fever mediators: interleukin-6 (IL-6) and prostaglandin E2 (PGE2) into plasma. Moreover, we found that sensitization to pyrogenic effects of lipopolysaccharide was associated with the increase in plasma level of high mobility group box 1 protein (HMGB1), one of the best-known damage-associated molecular patterns (DAMP), which was recently discovered as inflammatory mediator. Since the injection of anti-HMGB1 antibodies weakened observed hyperpyrexia in the animals pre-treated with turpentine, we conclude that HMGB1 is a plasma-derived factor released in the course of aseptic injury that enhances pyrogenic effects of LPS.

Extract from Coriolus versicolor fungus partially prevents endotoxin tolerance development by maintaining febrile response and increasing IL-6 generation.

Endotoxin tolerance is defined as a reduced endotoxin-induced fever following repeated injections of lipopolysaccharide (LPS). Clinical examples of endotoxin tolerance include sepsis or cystic fibrosis. This state is characterized by inhibition of pro-inflammatory cytokines production and decrease in nuclear factor-kappa B (NF-κB) activation. Extract from Coriolus versicolor (CV) fungus is classified as a biological response modifier, which exhibits various biological activities, including immunopotentiating properties. The aim of study was to examine the effect of CV extract injection on body core temperature of Wistar rats during LPS-induced endotoxin tolerance. Body temperature was measured using biotelemetry. CV extract was injected intraperitoneally (100 mg kg-1) 2 h prior to the first LPS peritoneal administration (50 µg/kg). Endotoxin tolerance was induced by three consecutive daily injections of LPS at the same dose. We also investigated the influence of CV extract pre-injection on the properties of peripheral blood mononuclear cells (PBMCs) isolated from LPS-treated rats in response to LPS stimulation ex vivo. PBMCs were isolated 2 h after the first LPS injection. After 24 h pre-incubation, the cells were stimulated with LPS (1 µg ml-1) for 4 h. Our results revealed that CV extract partially prevents endotoxin tolerance through maintaining febrile response in rats following consecutive exposure to LPS. This state was accompanied by the ability of PBMCs isolated from rats injected with CV extract and LPS to release larger amounts of interleukin 6 and greater NF-κB activation in response to LPS stimulation ex vivo compared with the cells derived from rats injected only with LPS. Data also showed that CV extract augmented mitogenic effect of LPS on PBMCs and caused increase in reactive oxygen species generation. We concluded that CV extract, by a modifying effect on body temperature during endotoxin tolerance, can be consider as the immunostimulating agent, which prevents the non-specific refractoriness described in patients with sepsis or ischemia.

Supportive Social Interactions in Infertility Treatment Decrease Cortisol Levels: Experimental Study Report.

PURPOSE: The aim of the research project was to analyze the importance of supportive social interactions in the process of infertility treatment. The acceptance rates of ART (Assisted Reproductive Technology) in Poland are lower than in western European countries and the social stigma of infertility exists. The research project draws attention to the issue of disclosure of fertility problems and the ability to seek support in Polish couples. METHODS: An experimental study was conducted with 51 heterosexual couples who qualified for IVF. The participants were randomly divided into an experimental and control group. The first stage of the research procedure, with all the couples, was to extract a saliva (cortisol) sample as a biomarker for stress. In the second stage the control group viewed an informational (non-emotional) video about human embryology. The experimental group took part in a supportive social interaction process. In the supportive social interaction process, a maximum of five couples, were led through a broad general understanding of their IVF experience by an experienced group psychologist. The third stage of the research involved the second extraction of a saliva (cortisol) sample form all participants. In addition, demographic and medical history related to fertility was collected. RESULTS: The statistical analysis indicates a significant decrease in the level of stress experienced after the supportive social interaction. The reported differences between the experimental group and the control group indicated a larger decrease of cortisol level for women and men. CONCLUSION: In the current study, the hypothesis that taking part in supportive social interaction significantly lowers stress levels (measured via cortisol) of infertile couples (men and women) was supported. Further the project indicates that a supportive social interaction has a beneficial effect on infertile couple's health and well-being. The results of the study clearly point to the benefits of couples involved in infertility treatment to express and share their experience, and in doing so, provides measurable physiological and psychological benefits.

Evaluation of the influence of in vivo exposure to extremely low-frequency magnetic fields on the plasma levels of pro-inflammatory cytokines in rats.

PURPOSE: Epidemiological data suggest that there is a link between exposure to extremely low-frequency magnetic fields (ELF-MFs), immune response, and the occurrence of neurodegenerative diseases. The exact nature of this phenomenon remains speculative and requires detailed laboratory investigation. In the present study, we evaluate changes in plasma concentration of pro-inflammatory and regulatory cytokines as well as alternations of the hematological parameters in rats exposed to an ELF-MF. MATERIALS AND METHODS: Male Wistar rats were repeatedly exposed for either 1 h/day for 7 days, or continuously for 24 h, to a sinusoidal ELF-MF (50 Hz, 7 mT). Control groups were sham exposed for either 1 h/day for 7 days, or continuously for 24 h, respectively. The levels of cytokines: interleukin (IL)-1ß, IL-2, IL-6, and IL-10 in plasma obtained from blood samples were determined using enzyme-linked immunosorbent assay (ELISA). The changes in blood parameters were determined using an automatic hematology analyzer in whole blood samples immediately after collection. RESULTS: We found that a single continuous (lasting 24 h) exposure provoked a significant increase of the plasma IL-1ß, IL-6, and IL-2 levels, and caused an elevation in blood parameters, such as white blood cells, lymphocytes, hemoglobin, and hematocrit levels. In contrast, however, repetitive exposure of rats to an ELF-MF for 1 h/day for 7 days did not lead to any changes in plasma levels of cytokines and hematological counts. CONCLUSIONS: Based on these data we conclude that exposure duration (dose-response) plays a significant role in the immune response, specifically at the cellular level. While single 24 h-lasting exposure provoked changes that indicate an immune alarm stimulation, under the conditions which are typical for therapeutic use of ELF-MFs (repeated short daily exposure) the immune potentially harmful response has not been observed.

The weakening effect of soluble epoxide hydrolase inhibitor AUDA on febrile response to lipopolysaccharide and turpentine in rat

A still growing body of evidence suggests the importance of epoxyeicosatrienoic acids (EETs) in the regulation of inflammatory response; therefore, drugs that stabilize their levels by targeting the soluble epoxide hydrolase (sEH), an enzyme responsible for their metabolism, are currently under investigation. The effect of sEH inhibitors on molecular components of fever mechanism, i.e., on synthesis of pro-inflammatory cytokines or prostaglandins, has been repeatedly proven; however, the hypothesis that sEH inhibitors affect febrile response has never been tested. The aim of this study was to examine if sEH inhibition affects core body temperature (Tb) as well as Tb changes during febrile response to infectious (lipopolysaccharide; LPS) or non-infectious (turpentine; TRP) stimuli. Male Wistar rats were implanted intra-abdominally with miniature biotelemeters to monitor Tb. A potent sEH inhibitor 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA) was suspended in olive oil and administrated into animals in the intraperitoneal (i.p.) dose of 15 mg/kg, which, as we showed, has no significant influence on normal Tb. We have found that AUDA injected 3 h after LPS (50 μg/kg i.p.) significantly weakened febrile rise of Tb. Moreover, injection of sEH inhibitor 7 h after turpentine (administrated subcutaneously in a dose of 100 μL/rat) markedly reduced the peak period of aseptic fever. Obtained results provide first experimental evidence that sEH inhibitors possess anti-pyretic properties. Therefore, medicines targeting sEH enzymatic activity should be considered as a complement to the arsenal of topical medications used to treat fever especially in clinical situations when non-steroidal anti-inflammatory drugs are ineffective

Allergens and food additives, including potentially harmful ones, present in food products that are preferred by children and adolescents.

INTRODUCTION: The proper development of a child is linked with proper nutrition, including nutritional habits which are formed from childhood. THE AIM OF THE STUDY: The aim of the study was to establish a list of the most popular food products among children and to develop a register of potentially dangerous substances on a Facebook website. MATERIALS AND METHODS: A website was created on Facebook. The participants provided lists of favorite dishes or products. RESULTS: The study involved 264 participants. An inverse correlation was observed with reference to the age of the subjects and the occurrence of sugar syrup in their diet (R=-0.20; p<0.001), glucose-fructose (R= -0.18; p< 0.004), and glucose (R=-0.13; p< 0.039) syrups. The most common potential food allergens are: gluten (R=0.28; p<0.001), eggs (R=0.28; p<0.001), and wheat (R=0.25; p<0.001). The main substances added to food that are present in a child's diet that increase proportionally with reference to the child's age are: salicylates (R=0.37; p<0.001), iron and ammonium sulfates (R=0.21; p<0.001). CONCLUSION: The choices of favorite products are related to age and sex. Products containing gluten, the consumption of which increases with age, carry a risk of undiagnosed celiac disease and non-celiac gluten sensitivity in people with a genetic predisposition. Facebook has fulfilled its role as an effective tool for gathering information about the food preferences of children and adolescents.

The weakening effect of soluble epoxide hydrolase inhibitor AUDA on febrile response to lipopolysaccharide and turpentine in rat.

A still growing body of evidence suggests the importance of epoxyeicosatrienoic acids (EETs) in the regulation of inflammatory response; therefore, drugs that stabilize their levels by targeting the soluble epoxide hydrolase (sEH), an enzyme responsible for their metabolism, are currently under investigation. The effect of sEH inhibitors on molecular components of fever mechanism, i.e., on synthesis of pro-inflammatory cytokines or prostaglandins, has been repeatedly proven; however, the hypothesis that sEH inhibitors affect febrile response has never been tested. The aim of this study was to examine if sEH inhibition affects core body temperature (Tb) as well as Tb changes during febrile response to infectious (lipopolysaccharide; LPS) or non-infectious (turpentine; TRP) stimuli. Male Wistar rats were implanted intra-abdominally with miniature biotelemeters to monitor Tb. A potent sEH inhibitor 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA) was suspended in olive oil and administrated into animals in the intraperitoneal (i.p.) dose of 15 mg/kg, which, as we showed, has no significant influence on normal Tb. We have found that AUDA injected 3 h after LPS (50 µg/kg i.p.) significantly weakened febrile rise of Tb. Moreover, injection of sEH inhibitor 7 h after turpentine (administrated subcutaneously in a dose of 100 µL/rat) markedly reduced the peak period of aseptic fever. Obtained results provide first experimental evidence that sEH inhibitors possess anti-pyretic properties. Therefore, medicines targeting sEH enzymatic activity should be considered as a complement to the arsenal of topical medications used to treat fever especially in clinical situations when non-steroidal anti-inflammatory drugs are ineffective.

Fever-range hyperthermia inhibits cells immune response to protein-bound polysaccharides derived from Coriolus versicolor extract.

The aim of the study was to explore whether fever-range hyperthermia (FRH) might enhance the anticancer and immunoregulatory activities of protein-bound polysaccharides (PBP), a class of fungus derived immunomodifiers used in the cancer adjuvant therapy. Blood lymphocytes and breast cancer cells (MCF-7) were cultured at 39.5°C in humidified atmosphere containing 5% CO2 for 2h. After rested at 37°C for 6h, the cells were treated with PBP extract at 100- and 300µg/ml concentration. After indicated time, the proliferative response was analyzed and cytokine mRNA expression assessment was performed by qRT-PCR. In animal model, the FRH was induced by placing rats in the Homeothermic Controller with heating blanket. Animals were heated until Tb reached 39.5°C (±0.2°C) and were maintained at this temperature for 30min. The protein-bound polysaccharides solution was injected i.p. at a dose of 100 mg/kg 6h post FRH. Twenty four hours after treatment, the blood was collected and cytokines expression analysis were performed. The results have shown that fever-range hyperthermia has an inhibitory effect on PBP extract-induced proliferative response of blood lymphocytes, as well as IL-1ß and IL-6 mRNA expression. Moreover, the temperature of 39.5°C blocks PBP-induced cytotoxicity against MCF-7 cells, which correlates with significant reduction in TNF-α level. Combined treatment of rats (FRH+PBP) results in decrease of IL-1ß, IL-6 and TNF-α mRNA expression in peripheral blood mononuclear cells compared to cells derived from rats treated with protein-bound polysaccharides extract alone. This study demonstrates that fever-range temperature inhibits immunostimulatory as well as anticancer effects mediated by protein-bound polysaccharides.

Protein-bound polysaccharides from Coriolus versicolor attenuate LPS-induced synthesis of pro-inflammatory cytokines and stimulate PBMCs proliferation.

Protein-bound polysaccharides (PBP) isolated from Coriolus versicolor (CV) are classified as biological response modifiers capable of exhibiting various biological activities, such as anti-tumour and immunopotentiating activity. Since we have found in vivo studies that the tested PBP induced prolongation of endotoxin fever in rats, the aim of the present study was to investigate the in vitro effect of the PBP on the production of pro-inflammatory cytokines by the lipolysaccharide (LPS)-stimulated rat peripheral blood mononuclear cells (PBMCs). The results showed that the PBP affect the immunomodulating properties of the LPS-treated PBMCs by the enhancement of mitogenic activity and attenuation of the LPS-induced production of interleukin (IL)-1ß and IL-6. Moreover, the tested polysaccharides peptides themselves also exhibit immunomodulatory properties manifested in the increased cell proliferation and pro-inflammatory cytokine release from PBMCs. The effect of PBP on the both phenomena was time-dependent and occurred in the U-shaped dose response manner. These findings are significant when considering the use of commercially available PBP from CV extract by cancer patients suffering from immunodeficiency, who may experience microbial infections during therapy.

N-Acetyl-l-cysteine exacerbates generation of IL-10 in cells stimulated with endotoxin in vitro and produces antipyresis via IL-10 dependent pathway in vivo.

N-Acetyl-l-cysteine (NAC) is a well-known medication, primarily used as a mucolytic agent in pulmonary disease. Recently, we have found that NAC possesses antipyretic properties. The aim of the present study was to investigate the mechanism by which NAC attenuates fever. The concentration of interleukin (IL)-10 and prostaglandin (PG) E2 were measured using ELISA kit in the supernatants aspirated after stimulation of peripheral blood mononuclear cells (PBMCs) with lipopolysaccharide (LPS, 1µg/mL) and NAC (10mM). The body temperature of the Wistar rats was measured using biotelemetry system. To inhibit endotoxic fever, NAC (200mg/kg; i.p.) was injected into the rats one hour prior to the LPS administration (50µg/kg; i.p.). The pre-treatment of LPS-stimulated PBMCs with NAC resulted in a significant decrease in PGE2 concentration in comparison to the cells treated with LPS alone (PGE2 level was 386.1±61.9pg/mL vs. 2078.9±157.9pg/mL, respectively, p<0.001). Furthermore, in these cells we observed a significant increase in IL-10 level (142.1±2.62pg/mL in NAC+LPS stimulated cells vs. 54.4±0.6pg/mL in LPS stimulated cells, p<0.001). The injection of anti-IL-10 antibody into the rats abolished antipyretic properties of NAC. Body temperature in animals treated with anti-IL-10+NAC/LPS was 38.28±0.12°C vs. 37.73±0.06°C in IgG+NAC/LPS rats (p<0.001) and 38.31±0.20°C in NaCl/LPS-treated animals (n.s.). Based on these data, we conclude that NAC acts as an antipyretic via IL-10 stimulation. This finding provides a new insight into the immunopharmacology of NAC, and we believe that in a future it will contribute to the new and/or more accurate application of NAC in medicine.

Polysaccharide peptides from Coriolus versicolor exert differential immunomodulatory effects on blood lymphocytes and breast cancer cell line MCF-7 in vitro.

The protein-bound polysaccharides (PBP), isolated from Coriolus versicolor (CV) fungus, are considered as natural compounds with potential therapeutic applications. The immunopotentiating and antitumor activity of polysaccharopeptides has been previously examined, however similar findings could not be achieved. The source of PBP, variations in extraction process as well as environmental factors seems to affect the biological properties of these active CV components. Since further analysis are needed to draw more definite conclusion, the present study aimed to investigate the immunomodulatory properties of the PBP extract, isolated from commercially available capsules of C. versicolor. Our results revealed that the effect mediated by PBP extract depends on the target cells. We reported that the polysaccharopeptides induced a significant decrease in breast cancer MCF-7 cells growth, which was TNF-α-dependent phenomenon. Interestingly, the level of two others cytokines, IL-1ß and IL-6 was not affected. On the other hand, in this study we noticed that protein-bound polysaccharides extracted from CV significantly augmented the proliferative response of blood lymphocytes in a time-dependent manner, which was associated with IL-6 and IL-1ß mRNA upregulation. Moreover we found that the cells response to PBP stimuli might be inversely related to its concentration.

Polysaccharide peptide from Coriolus versicolor induces interleukin 6-related extension of endotoxin fever in rats.

PURPOSE: Polysaccharide peptide (PSP) extracted from the Coriolus versicolor mushroom is frequently suggested as an adjunct to the chemo- or radiotherapy in cancer patients. In a previous study we showed that PSP induced a tumour necrosis factor-α (TNF-α)-dependent anapyrexia-like response in rats. Thus, PSP appears to be a factor which modifies a number of pathophysiological responses. Because of this, PSP is suggested as a potential adjuvant for cancer therapy during which cancer patients frequently contract microbial infections accompanied by fever. The aim of the present study was to investigate whether or not PSP can modulate the course of the fever in response to an antigen such as lipopolysaccharide (LPS). MATERIALS AND METHODS: Body temperature (Tb) of male Wistar rats was measured by biotelemetry. PSP was injected intraperitoneally (i.p.) at a dose of 100 mg kg(-1), 2 h before LPS administration (50 µg kg(-1), i.p.). The levels of interleukin (IL)-6 and TNF-α in the plasma of rats were estimated 3 h and 14 h post-injection of PSP using a standard sandwich ELISA kit. RESULTS: We report that i.p. pre-injection of PSP 2 h before LPS administration expanded the duration of endotoxin fever in rats. This phenomenon was accompanied by a significant elevation of the blood IL-6 level of rats both 3 h and 14 h post-injection of PSP. Pre-treatment i.p. of the rats with anti-IL-6 antibody (30 µg/rat) prevented the PSP-induced prolongation of endotoxin fever. CONCLUSIONS: Based on these data, we conclude that PSP modifies the LPS-induced fever in IL-6-related fashion.

[Immunomodulatory and antitumor properties of polysaccharide peptide (PSP)]. / Immunomodulujace i przeciwnowotworowe wlasciwosci polisacharydopeptydu (PSP)

Modern medicine successfully uses multiple immunomodulators of natural origin, that can affect biological reactions and support body's natural defense mechanisms including antitumor activities. Among them is a group of products derived from fungi, including schizophyllan, lentinan, polysaccharide Krestin (PSK), and polysaccharidepeptide (PSP). Present paper is focused on polysaccharidepeptide, which due to the negligible toxicity and numerous benefits for health, is increasingly used in China and Japan as an adjuvant in the treatment of cancer. PSP is a protein-polisaccharide complex with a molecular weight 100 kDa derived from Coriolus versicolor mushroom. The results of numerous studies and clinical trials confirm that it inhibits the growth of cancer cells in in vitro and in vivo settings as well as decreases cancer treatment-related adverse side effects such as fatigue, loss of appetite, nausea, vomiting, and pain. PSP is able to restore weakened immune response observed in patients with cancer during chemotherapy. Its anti-tumor effects seemed to be mediated through immunomodulatory regulation. PSP stimulates cells of the immune system, induces synthesis of cytokines such as interleukin-1ß (IL-1ß), IL-6 and tumor necrosis factor-α (TNF-α), eicosanoids including prostaglandin E2 (PGE2), histamine, reactive oxygen species and nitrogen mediators. There is a growing interest in understanding the mechanisms of PSP action. Because of its unique properties and safety, PSP may become a widely used therapeutic agent in the near future.

Heme oxygenase-1 induction by cobalt protoporphyrin enhances fever and inhibits pyrogenic tolerance to lipopolysaccharide.

Heme oxygenase-1 (HO-1) is an enzyme that catalyzes degradation of the heme and regulates its availability for newly synthetized hemeproteins such as cyclooxygenases, NO synthases and cytochrome P450. Moreover, HO-1 activity modulates synthesis of cytokines and prostaglandins. All of these factors are well-defined components of fever and pyrogenic tolerance mechanisms. We examine the effect of HO-1 induction and activation using cobalt protoporphyrin (CoPP) on changes in body temperature (Tb), plasma levels of interleukin-6 (IL-6), prostaglandin E2 (PGE2) and HO-1 protein in the course of these processes. Intraperitoneally (i.p.) pre-treatment of rats with CoPP (5 mg kg(-1)) significantly accelerated and enhanced the early stage of lipopolysaccharide (LPS)-induced fever and shortened a post-fever recovery to normal temperature. Pre-treatment with CoPP significantly potentiated the increase in plasma IL-6, PGE2 and HO-1 levels measured 4h after the LPS administration. Furthermore, induction of HO-1 attenuated the development of pyrogenic tolerance to repeated injections of LPS. Based on these data we conclude that heme oxygenase-1 may act as a physiological regulator of the febrile response intensity to bacterial infections.

Polysaccharide peptide induces a tumor necrosis factor-α-dependent drop of body temperature in rats.

Polysaccharide peptide (PSP) extracted from the Coriolus versicolor mushroom is frequently suggested as an adjunct to the chemo- or radiotherapy in cancer patients. It improves quality of the patients' life by decreasing pain, fatigue, loss of appetite, nausea, and vomiting. However, the effect of PSP on body temperature has not thus far been studied, although it is well known that treatment with other polysaccharide adjuvants, such as lipopolysaccharides, may induce fever. The aim of the present study, therefore, was to investigate the influence of PSP on temperature regulation in rats. We report that intraperitoneal injection of PSP provoked a dose-dependent decrease of temperature in male Wistar rats equipped with biotelemetry devices to monitor deep body temperature (Tb). The response was rapid (i.e., with latency of 15-20min), transient (lasting up to 5h post-injection), and accompanied by a significant elevation of the blood tumor necrosis factor-α (TNF-α) level. Pretreatment of the rats with anti-TNF-α antibody prevented the PSP-induced drop in Tb. Based on these data, we conclude that rats may develop an anapyrexia-like response to the injection of peptidopolysaccharide rather than fever, and the response was TNF-α-dependent.