The relationship between the degree of malnutrition and changes in selected parameters of the immune response in critically ill patients.

Patients treated in intensive care units (ICUs) are at high risk of malnutrition and the resulting homeostasis, metabolic, histological and immunological disorders, especially leading to organ failure and increased susceptibility to infection. In 163 patients with malnutrition [mild in 33 (19.6%), moderate in 69 (42.9%), severe in 61 (37.4%)] treated in the ICU, changes in the concentration of selected proteins [interleukin (IL)-1Ra, tumor necrosis factor α (TNF-α), soluble tumour necrosis factor receptor-1 (sTNFR1), IL-6, IL-10, sTLR4, MyD88, A20, HSP70, HMGB1] were examined. In the whole group of malnourished patients, median values of sTNFR1, TNF-α, IL-6, TLR4, IL-1Ra were significantly increased, while the levels of MyD88 and A20 proteins were significantly reduced (in comparison to the well-nourished healthy group). Only the sTNFR1 protein showed a significant difference between mild, moderate and severe malnutrition, and increased concentrations as the severity of malnutrition increased (the correlation study found that as the degree of malnutrition increased, the sTNFR1 concentrations increased; p = 0.0000, R = 0.5442). It was observed that death was significantly more frequent in the group of patients who on the first day of hospitalization in the ICU scored 5 or more points on the NRS 2002 scale (p = 0.0004). In the patients who died significantly higher concentrations of sTNFR1, IL-6, IL-10, HSP70 were observed in comparison to the patients who survived. The present results are encouraging and indicate the desirability of undertaking multicentre clinical trials including monitoring of sTNFR1 in assessing the severity of malnutrition and immune disorders in the first hours after admission to the ICU, because it can be assumed that without early diagnosis of innate immunity disorders any attempts at their modulation may be ineffective.

The soluble tumor necrosis factor receptor 1 as a potential early diagnostic and prognostic markers in intensive care unit patients with severe infections.

INTRODUCTION: Substantial causes of high mortality (30-50%) of people with severe infections treated in intensive care units (ICUs) are still inadequately known in terms of mechanisms and insufficient diagnostic tools for immune responses in sepsis. MATERIAL AND METHODS: The aim of this study was to establish a practical value of determining the concentration of chosen proteins (by ELISA) in peripheral blood as potential in early diagnostics of severe infections, paying special attention to their prognostic values. RESULTS: In 163 patients treated in ICUs, changes were assessed in the concentration of chosen proteins relating to the TLR4 receptor signalling pathway, including its effectors of pro- and anti-inflammatory cytokines (IL-1Ra, TNF-α, sTNFR1, IL-6, IL-10, sTLR4, MyD88, TNFAIP3/A20, HSP70, and HMGB1). In the analysis of changes in the process of immune response in severely ill patients with and without infections, a significantly higher concentration of sTNFR1 was observed in patients with infections than those who deceased. In the ROC curves tests, it was noted that an assessment of the concentration of sTNFR1 proteins (AUC = 0.686 and cut-off point = 24.841 pg/ml) was a particularly efficient tool, with prognostic significance in patients with infections. CONCLUSIONS: In other patients treated in an ICU, the efficiency of determining IL-6 (AUC = 0.736) was confirmed and at the same time, the effectiveness of this cytokine in predicting death in cases with infections was excluded. The results of the present study are encouraging, suggesting the benefits of undertaking multi-center clinical trials, which consider monitoring sTNFR1 in different groups of patients with infections treated in intensive care units.

Angiogenesis modulation by exogenous antioxidants.

Co-operation of the endogenous and exogenous defense system maintains redox homeostasis and is essential for health. The endogenous defense system includes enzymatic (e.g. superoxide dismutase, catalase) and non-enzymatic, low molecular-weight scavengers (e.g. glutathione, ascorbic acid). Pathogenesis of many serious diseases (e.g. cancer, ischemic heart disease) includes oxidative stress which can disturb angiogenesis, the process of formation of new blood vessels sprouting from the existing one. Antioxidants, through reduction of oxidative stress and influence on neovascularization, may modulate progress and results of therapy in those diseases where such processes play an important role. Herein the impact of exogenous antioxidants on angiogenesis and factors modulating this process is presented. Most synthetic antioxidants whose activity has been described (namely N-acetylcysteine, pentoxifylline, synthetic analogue of curcumin, synthetic analogue of epigallocatechin-3 gallate [EGCG], tripertenoids) exert an inhibitory effect on neovascularization. A similar effect was also exhibited by several natural origin antioxidants (e.g. resveratrol, EGCG), which suggests that their application in therapy might normalize excessive angiogenesis. Some natural origin antioxidants e.g. purple coneflower and preparations consisting of natural antioxidants such as Padma 28 and Immunal forte increase a too low baseline level of angiogenesis and decreases a too high level. These preparations exert a regulatory effect on and may normalize neovascularization. They can be used in the case of diseases associated with too low or too high angiogenesis.

Disorders noticed during development of pancreatic cancer: potential opportunities for early and effective diagnostics and therapy.

Pancreatic cancer, with a total five-year survival rate below 5%, represents a disease with a high level of malignancy. Some of the pancreatic cancer bad prognosis factors are nutrition disorders. Malnutrition, neither recognized nor properly referred to by the healthcare system, leads to well-documented negative health consequences in hospitalized patients including their impaired immunity, delayed post-surgery wound healing, a high risk of infectious complications, morbidity and mortality. There are numerous factors contributing to the development of pancreatic cancer, including telomerases, inflammation, angiogenesis, epigenetics and genetics factors, miRNA, pancreatic cancer stem cells. On the basis of molecular analyses, it has been established that precursor injuries may trigger pancreatic cancer when added to genetic alterations. Perhaps, combination of few presently used methods, like signal transduction modulated by K-ras, STAT3 activation, HMGB1 releasing, presence of oxidative stress and free radicals secretion, genes for proangiogenic growth factors activation or tissue-specific miRNA genes expression - will solve the problem of inadequate diagnostics.

The effect of pentoxifylline on L-1 sarcoma tumor growth and angiogenesis in Balb/c mice.

Methyloxantines are present in many herbs and vegetal foods, among them in tea, coffee and chocolate. Previous studies revealed that theophylline and theobromine have anti-angiogenic properties. Anti-tumor properties of theobromine were also described. Pentoxifylline (3,7-dimethyl-1-(5-oxohexyl)xanthine, PTX) is a synthetic xanthine derivative. It is a phosphodiesterase inhibitor and has various anti-inflammatory abilities. Pentoxifylline is widely used in therapy of inflammatory arterial diseases such as intermittent claudication of upper and lower limbs as well as in coronary heart disease. The aim of our research was to evaluate the effect of pentoxifylline (individually and in combination with non-steroidal anti-inflammatory drug sulindac), on L-1 sarcoma angiogenic activity and tumor formation in syngeneic Balb/c mice. Pre-incubation of tumor cells for 90 min with various PTX concentrations resulted in dose-dependent decrease of their ability to induce newly-formed blood vessels after transplantation into the skin of recipient mice. Administration of PTX to mice, recipients of tumor cells, slows tumor growth and reduces its volume. Synergistic inhibitory effect of PTX and sulindac, expressed as % of tumors sixth and thirteen day after subcutaneous grafting of L-1 sarcoma into syngeneic Balb/c mice, was observed.

The modulatory influence of some Echinacea-based remedies on antibody production and cellular immunity in mice.

UNLABELLED: Echinacea purpurea-containing remedies are herbal medicines used in respiratory tract infections and several inflammatory conditions as enhancers of non-specific and modulators of specific cellular immunity. They also exert anti-inflammatory, anti-viral, and anti-microbial activity. The aim of the present study was to compare the in vivo influence of orally administered three Echinacea purpurea-based remedies (IMMUNAL drops, ECHINACEA FORTE drops, IMMUNAL FORTE tablets) on some parameters of cellular and humoral immunity in mice. RESULTS: Feeding mice for seven days with IMMUNAL drops resulted in enhanced anti-SRBC antibody production and modulatory effect on proliferative response to PHA of their splenic lymphocytes. No stimulatory effect was observed on splenocytes chemokinesis. Mice fed with ECHINACEA FORTE drops presented enhanced response to PHA of their splenocytes. However, contrary to the previous group, no enhancement of antibody production was observed. In this group, lymphocyte-induced immunological angiogenesis (LIA) and chemokinesis (spontaneous migration - SM) of spleen lymphocytes was diminished after feeding mice with both doses (LIA) or with a higher dose (SM) of remedy. Lymphocyte-induced immunological angiogenesis activity of splenocytes collected from animals fed with prophylactic and therapeutic IMMUNAL FORTE tablet doses did not differ from the controls.

A natural herbal remedy modulates angiogenic activity of bronchoalveolar lavage cells from sarcoidosis patients.

Sarcoidosis is a systemic inflammatory disease with abnormally high angiogenic activity of inflammatory cells. Reumaherb preparation consisting of three herbs: Echinacea purpurea, Harpagophytum procumbens, and Filipendula ulmaria, and it exerts anti-inflammatory, antioxidant, and analgesic activity and stimulates regenerative and immunological processes. The aim of this paper was to estimate the effect of Reumaherb on immunological angiogenesis induced by bronchoalveolar lavage (BAL) cells collected from six patients with sarcoidosis and grafted into Balb/c mice skin. After grafting, the animals were fed for three days with 0.6 or 1.2 mg of Reumaherb (calculated from recommended human daily dose) daily, suspended in 40 µl of water, or 40 µl of water alone (control group). A significant reduction of newly formed blood vessels was obtained in four cases for 1.2 mg and in three cases for 0.6 mg daily dose of this remedy. Thus, we hypothesise that Reumaherb promotes anti-angiogenic activity and may potentially be used in diseases associated with excessive blood vessel formation.

Feeding mice with Aloe vera gel diminishes L-1 sarcoma-induced early neovascular response and tumor growth.

Aloe vera (Aloe arborescens, aloe barbadensis) is a medicinal plant belonging to the Liliaceae family. Aloe vera gel prepared from the inner part of Aloe leaves is increasingly consumed as a beverage dietary supplement. Some data suggest its tumor growth modulatory properties. The aim of the present study was to evaluate in Balb/c mice the in vivo influence of orally administered Aloe vera drinking gel on the syngeneic L-1 sarcoma tumor growth and its vascularization: early cutaneous neovascular response, tumor-induced angiogenesis (TIA test read after 3 days), and tumor hemoglobin content measured 14 days after L-1 sarcoma cell grafting. Feeding mice for 3 days after tumor cell grafting with 150 µl daily dose of Aloe vera gel significantly diminished the number of newly-formed blood vessels in comparison to the controls. The difference between the groups of control and Aloe-fed mice (150 µl daily dose for 14 days) with respect to the 14 days' tumor volume was on the border of statistical significance. No difference was observed in tumor hemoglobin content.

Oral administration of Aloe vera gel, anti-microbial and anti-inflammatory herbal remedy, stimulates cell-mediated immunity and antibody production in a mouse model.

INTRODUCTION: Aloe vera (L.) Burm. f. (Aloe barbadensis Mill) Liliaceae, succulent plant native to northern Africa, is presently cultivated in many regions of the world. Traditionally, its inner part of parenchyma, which contains aloe gel, was used for the treatment of minor wounds, inflammatory skin disorders, thermal and radiation burns and to alleviate chronic osteoarthritis pain. It also possesses some antimicrobial activity. Now, aloe gel is also increasingly consumed as a dietary supplement. Some data suggest its immunomodulatory properties. THE AIM OF THE STUDY: The aim of the study was to evaluate the influence of orally administered aloe gel on some parameters of cellular and humoral immunity viz. mitogen-induced proliferation of splenic lymphocytes and their chemokinetic activity, and anti-sheep red blood cells (SRBC) antibody production in Balb/c mice. RESULTS: Daily treatment of mice for 14 and 21 days with 50 µl or 150 µl of aloe gel dose resulted in enhanced chemokinetic activity and stronger response of their splenic lymphocytes to mitogen PHA and enhancement of anti-SRBC antibody production.

Morphofunctional Renal Alterations in Progeny of Mice Fed Rhodiola kirilowii Extracts or Epigallocatechin During Pregnancy and Lactation.

Treating infections in pregnant patients is potentially dangerous even when herbal medicines are used. Many herbal medicines, among them extracts from plants of Rhodiola genus, have antimicrobial, anti-inflammatory, and immunostimulatory properties owing to their polyphenol content; they may, however, affect fetal development due to their antiangiogenic properties. The aim of this study was to explain whether daily feeding pregnant and lactating mice with 20 mg/kg Rhodiola kirilowii aqueous (RKW) or 50% hydro-alcoholic (RKW-A) extracts, or 0.2 mg/kg epigallocatechin (EGC, antiangiogenic compound of Rhodiola extracts), may lead to abnormalities in morphology and function of the kidneys of adult progeny. Such abnormalities were not observed in the kidneys of 6-week-old offspring, neither in RKW nor in the control group. However, the progeny of RKW-A- or EGC-fed mothers presented morphometric abnormalities in the kidney structure, with a significantly higher number of glomeruli/mm2 and a lower diameter of glomeruli (RKW-A group) or a significantly higher glomeruli diameter (EGC), than in the control and RKW groups. Abnormalities in serum vascular endothelial growth factor, tumor necrosis factor (TNF)-alpha, urea, creatinine, and cystatin C levels were also found. We recommend caution in long-term use of RKW-A extract and EGC-rich foods during pregnancy and lactation.

Modulatory effects of feeding pregnant and lactating mice Rhodiola kirilowii extracts on the immune system of offspring.

Plants of Rhodiola genus are medicinal herbs that have a number of therapeutic properties, including anti-inflammatory and immunomodulatory activity. The present study aimed to determine whether the use Rhodiola kirilowii as an immunostimulant during pregnancy has an adverse effect on the development of the offspring immune system. Following mating, pregnant mice were placed in three groups that were fed during pregnancy and lactation with R. kirilowii aqueous extract (RKW; 20 mg/kg), R. kirilowii 50% hydro-alcoholic extract (RKW-A; 20 mg/kg) or water (control group), receiving water. Following birth, offspring were given six weeks to develop prior to evaluation of their immune system. Morphometric and morphological examination of the spleen did not reveal any abnormalities or differences between the experimental and control groups. However, both RKW and RKW-A splenic lymphocytes presented a diminished proliferative response to concanavalin A. RKW spleen lymphocytes demonstrated increased metabolic activity following phytohaemagglutinin (PHA) stimulation, which was associated with a higher percentage of cluster of differentiation 4 positive spleen cells and lower interleukin-17a (IL-17a) serum concentration. The RKW-A group exhibited a diminished proliferative response of spleen lymphocytes to PHA and lipopolysaccharide (LPS), and increased serum concentrations of IL-10 and tumor necrosis factor-α (TNF-α). The progeny of mice fed with RKW-A extract demonstrated a significantly lower level of anti-SRBC antibody following immunization compared with progeny of the control (P=0.0305) and RKW (P=0.0331) groups. In conclusion, caution is recommended in the use of RKW and RKW-A extracts as immunostimulants in pregnancy.

Innate immunity signaling pathways: links between immunonutrition and responses to sepsis.

Septic infections in patients treated in intensive care units show the highest mortality rates. Despite advances in treatment methods, there is still no therapy available to efficiently reduce the excessive inflammatory response, which can increase the risk of multiple organ failure. One of the ways to discover new, more efficient treatment methods involves regulating the mechanisms of inflammatory response to a massive infection. Toll-like receptors (TLRs) that recognize pathogen-associated molecular patterns play a significant role in innate antibacterial and inflammatory responses. The regulatory impact of immunonutrition on TLR expression in septic patients seems to be a promising research direction. This paper presents the main mechanisms for the innate immune response to lipopolysaccharide, based on the research results for both TLR-dependent and independent signaling pathways. Special emphasis was put on the research results for the TLR-dependent immune response and the anti-bacterial/anti-inflammatory response after applying immunonutrition with increased concentrations of glutamine and unsaturated fatty acids.