The hepatotoxicity of Polygonum multiflorum: The emerging role of the immune-mediated liver injury.

Herbal and dietary supplements (HDS)-induced liver injury has been a great concern all over the world. Polygonum multiflorum Thunb., a well-known Chinese herbal medicine, is recently drawn increasing attention because of its hepatotoxicity. According to the clinical and experimental studies, P. multiflorum-induced liver injury (PM-DILI) is considered to be immune-mediated idiosyncratic liver injury, but the role of immune response and the underlying mechanisms are not completely elucidated. Previous studies focused on the direct toxicity of PM-DILI by using animal models with intrinsic drug-induced liver injury (DILI). However, most epidemiological and clinical evidence demonstrate that PM-DILI is immune-mediated idiosyncratic liver injury. The aim of this review is to assess current epidemiological, clinical and experimental evidence about the possible role of innate and adaptive immunity in the idiosyncratic hepatotoxicity of P. multiflorum. The potential effects of factors associated with immune tolerance, including immune checkpoint molecules and regulatory immune cells on the individual's susceptibility to PM-DILI are also discussed. We conclude by giving our hypothesis of possible immune mechanisms of PM-DILI and providing suggestions for future studies on valuable biomarkers identification and proper immune models establishment.

Effects Of Exercise Training On Immune Function And Implications For Nutrition Support.

No Abstract Available.

The impact of biological therapy on regulatory T cells in rheumatoid arthritis.

Regulatory T cells (Treg) are functionally defective in patients with RA. Restoring their function may not only control inflammation but also restore tolerance in these patients. Biologic therapies have been tremendously successful in treating RA. Here we review numerous reports suggesting that these immunomodulatory therapies have an impact on Treg and that this may contribute to their beneficial effects. Better understanding of their mode of action may not only lead to improvements in therapies and sustained remission but also enable the development of biomarkers of response, which would be the first steps towards personalized medicine.

Solid organ transplant recipients: clinical considerations in the application of exercise.

Over 100 000 solid organ transplants are performed worldwide each year and this has a significant impact on physical function and quality of life. However, the capacity for exercise in solid-organ recipients is reduced. Regular physical activity improves most of the indices of fitness in these patients but, with few exceptions, they do not reach the values seen in healthy controls. The reason for the 40-60% reduction in maximal exercise capacity is not clear; the disease process, need for life long immunosuppression and sedentary lifestyle all contribute. The interaction between exercise and immunosuppressing medication merits research as does the specifics of the exercise prescription for these patients. This paper reviews important features of this rapidly expanding group of patients and suggests clinical considerations in the application of exercise in this population.

Artesunate exerts an anti-immunosuppressive effect on cervical cancer by inhibiting PGE2 production and Foxp3 expression.

Artesunate (ART), derived from a common traditional Chinese medicine, has beeen used an antimalarial for several years. In this study, the effect and mechanism of ART on anti-human cervical cancer cells was examined. The level of prostaglandin E2 (PGE2 ) and the population of CD4+CD25+Foxp3 regulatory T cells (Treg) in peripheral blood were detected by flow cytometry. In vivo antitumor activity was investigated in mice with cervical cancer by the subcutaneous injection of various concentrations of ART. The concentrations of PGE2 in the supernatants of CaSki cells were measured using an ELISA kit. Cyclooxygenase-2 (COX-2) and Foxp3 expression were determined using quantitative polymerase chain reaction (qPCR) and western blot analysis. The effect of ART on the viability of CaSki and Hela cells was evaluated with a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. It was identified that the level of PGE2 and the population of CD4+CD25+Foxp3 Treg cells in the peripheral blood were significantly higher in cervical cancer patients and mice with cervical cancer. ART was capable of inhibiting orthotopic tumor growth, which correlated with a decrease in the level of PGE2 and the percentage of Treg cells in mice with cervical cancer. Furthermore, ART decreased COX-2 expression and the production of PGE2 in CaSki and Hela cells. Notably, the supernatants of CaSki cells treated with ART lowered the expression of Foxp3 in Jurkat T cells, which was capable of being reversed by exogenous PGE2 . Our data revealed that ART may elicit an anti-tumor effect against cervical cancer by inhibition of PGE2 production in CaSki and Hela cells, which resulted in the decrease of Foxp3 expression in T cells. Therefore, ART may be an effective drug for immunotherapy of cervical cancer.

[Role of vitamin D in the pathogenesis of chronic kidney disease]. / Ruolo della vitamina D nei pazienti con malattia renale cronica.

Chronic kidney disease (CKD) is a relevant health problem due to its worldwide increasing prevalence and the morbidity and mortality linked to its complications. Since the early stages of CKD, although patients are completely asymptomatic, important mineral homeostasis disorders occur. These disorders, involving serum levels of calcium, phosphorus, parathyroid hormone, and vitamin D, have a striking impact on patient prognosis as they affect the cardiovascular system. The new term of Chronic Kidney Disease-Mineral Bone Disease (CKD-MBD) was introduced to label bone disease during CKD as a systemic disorder tightly linked to cardiovascular calcifications and disabilities. Vitamin D deficiency has a main role in the pathogenesis of CKD-MBD, throughout the pleiotropic actions of this hormone. Vitamin D receptors (VDRs) are ubiquitous and their activation has shown protective effects against secondary hyperparathyroidism development and anti-hypertensive, anti-inflammatory, anti-fibrotic, immunomodulating, anti-proliferative, anti-diabetic and anti-proteinuric properties. These mechanisms explain, at least in part, vitamin D status influence in avoiding and delaying cardiovascular disease and CKD progression. These findings strongly support the importance of an early diagnosis of mineral homeostasis disorders in CKD and the need for correction of vitamin D deficiency to prevent related disabilities and major events.

SMAD regulatory networks construct a balanced immune system.

A balanced immune response requires combating infectious assaults while striving to maintain quiescence towards the self. One of the central players in this process is the pleiotropic cytokine transforming growth factor-ß (TGF-ß), whose deficiency results in spontaneous systemic autoimmunity in mice. The dominant function of TGF-ß is to regulate the peripheral immune homeostasis, particularly in the microbe-rich and antigen-rich environment of the gut. To maintain intestinal integrity, the epithelial cells, myeloid cells and lymphocytes that inhabit the gut secrete TGF-ß, which acts in both paracrine and autocrine fashions to activate its signal transducers, the SMAD transcription factors. The SMAD pathway regulates the production of IgA by B cells, maintains the protective mucosal barrier and promotes the balanced differentiation of CD4(+) T cells into inflammatory T helper type 17 cells and suppressive FOXP3(+) T regulatory cells. While encounters with pathogenic microbes activate SMAD proteins to evoke a protective inflammatory immune response, SMAD activation and synergism with immunoregulatory factors such as the vitamin A metabolite retinoic acid enforce immunosuppression toward commensal microbes and innocuous food antigens. Such complementary context-dependent functions of TGF-ß are achieved by the co-operation of SMAD proteins with distinct dominant transcription activators and accessory chromatin modifiers. This review highlights recent advances in unravelling the molecular basis for the multi-faceted functions of TGF-ß in the gut that are dictacted by fluid orchestrations of SMADs and their myriad partners.

Rapid expansion of T cells: Effects of culture and cryopreservation and importance of short-term cell recovery.

BACKGROUND: Successful cell therapy relies on the identification and mass expansion of functional cells for infusion. Cryopreservation of cells is an inevitable step in most cell therapies which also entails consequences for the frozen cells. MATERIAL AND METHODS: This study assessed the impact of cryopreservation and the widely used protocol for rapid expansion of T lymphocytes. The effects on cell viability, immunocompetence and the impact on apoptotic and immunosuppressive marker expression were analyzed using validated assays. RESULTS AND CONCLUSION: Cryopreservation of lymphocytes during the rapid expansion protocol did not affect cell viability. Lymphocytes that underwent mass expansion or culture in high dose IL-2 were unable to respond to PHA stimulation by intracellular ATP production immediately after thawing (ATP = 16 ± 11 ng/ml). However, their reactivity to PHA was regained within 48 hours of recovery (ATP = 356 ± 61 ng/ml). Analysis of mRNA levels revealed downregulation of TGF-ß and IL-10 at all time points. Culture in high dose IL-2 led to upregulation of p73 and BCL-2 mRNA levels while FoxP3 expression was elevated after culture in IL-2 and artificial TCR stimuli. FoxP3 levels decreased after short-term recovery without IL-2 or stimulation. Antigen specificity, as determined by IFNγ secretion, was unaffected by cryopreservation but was completely lost after addition of high dose IL-2 and artificial TCR stimuli. In conclusion, allowing short-time recovery of mass expanded and cryopreserved cells before reinfusion could enhance the outcome of adoptive cell therapy as the cells regain immune competence and specificity.

Exercise-induced immunodepression in endurance athletes and nutritional intervention with carbohydrate, protein and fat-what is possible, what is not?

Heavily exercising endurance athletes experience extreme physiologic stress, which is associated with temporary immunodepression and higher risk of infection, particularly upper respiratory tract infections (URTI). The aim of this review is to provide a critical up-to-date review of existing evidence on the immunomodulatory potential of selected macronutrients and to evaluate their efficacy. The results of 66 placebo-controlled and/or crossover trials were compared and analysed. Among macronutrients, the most effective approach to maintain immune function in athletes is to consume ≥6% carbohydrate during prolonged exercise. Because inadequate nutrition affects almost all aspects of the immune system, a well-balanced diet is also important. Evidence of beneficial effects from other macronutrients is scarce and results are often inconsistent. Using a single nutrient may not be as effective as a mixture of several nutritional supplements. Due to limited research evidence, with the exception of carbohydrate, no explicit recommendations to reduce post-exercise URTI symptoms with single macronutrients can be derived.

Probiotic cheese attenuates exercise-induced immune suppression in Wistar rats.

Intense physical activity results in a substantial volume of stress and hence a significant probability of immunosuppression in athletes, with milk proteins being, perhaps, the most recommended protein supplements. Consumption of a probiotic cheese can attenuate immune suppression induced by exhausting exercise in rats. A popular Brazilian fresh cheese (Minas Frescal cheese) containing Lactobacillus acidophilus LA14 and Bifidobacterium longum BL05 was fed for 2wk to adult Wistar rats, which then were brought to exhaustion on the treadmill. Two hours after exhaustion, the rats were killed and material was collected for the determination of serum uric acid, total and high-density lipoprotein cholesterol fraction, total protein, triacylglycerols, aspartate aminotransferase, alanine aminotransferase, creatine kinase, and blood cell (monocyte, lymphocyte, neutrophil, and leukocyte) counts. Exercise was efficient in reducing lymphocyte counts, irrespective of the type of ingested cheese, but the decrease in the group fed the probiotic cheese was 22% compared with 48% in the animals fed regular cheese. Monocyte counts were unaltered in the rats fed probiotic cheese compared with a significant decrease in the rats fed the regular cheese. Most importantly, ingestion of the probiotic cheese resulted in a >100% increase in serum high-density lipoprotein cholesterol and a 50% decrease in triacylglycerols. We conclude that probiotic Minas Frescal cheese may be a viable alternative to enhance the immune system and could be used to prevent infections, particularly those related to the physical overexertion of athletes.

The effect of electroacupuncture on T cell responses in rats with experimental autoimmune encephalitis.

Successive electroacupuncture (EA) stimulation on Zusanli ST36 acupoints of rats with experimental autoimmune encephalitis (EAE), which is an inflammatory disease mediated by autoreactive T cells, relieved disease severity, inhibited specific T cell proliferation and rebuilt the CD4+ T cell subset balance. In addition, EA-treated rats had significantly higher ACTH concentrations in vivo compared to untreated EAE rats. These results indicated that EA stimulation could relieve the severity of EAE by restoring balance to the Th1/Th2/Th17/Treg Th cell subset responses by stimulating the hypothalamus to increase ACTH secretion.

Mild postnatal separation stress reduces repeated stress-induced immunosuppression in adult BALB/c mice.

OBJECTIVES: Different inbred mouse strains but also each animal of the same strain show an individually different stress response which is influenced by genetic and environmental factors such as early life experiences. In this study, we investigated consequences of mild postnatal stress exposure on the stress coping style of adult BALB/c mice. METHODS: We used a model of mild early life stress where neonatal mice were repeatedly separated from the dam staying with their siblings for 1-h each day during the first two postnatal weeks. The environment during maternal separation was adapted to the nest (bedding, 37 degrees C warm). RESULTS: Adult female BALB/s mice that underwent the maternal separation protocol or were not isolated from the dam in early life were exposed to combined acoustic and restraint stress in adulthood. Repeated maternal separation which was performed under ambient conditions increased the stress coping ability of mice at the age of 12 weeks when exposed to this psychological stressors. By acoustic and restraint stress-induced alterations such as high corticosterone levels, an anti-inflammatory immune conditioning with an ex vivo hyperinducibility of interleukin-10 of splenocytes and a massive loss of body weight were significantly reduced in the maternally separated group compared with conventionally bred control mice. CONCLUSIONS: Mild maternal separation in early life modifies the stress coping style of adult female BALB/c mice to a more stress-resistant phenotype which shows reduced repeated stress-induced immune suppression and weight loss and is linked to reduced release of glucocorticoids after stress exposure.

Methylenedioxymethamphetamine (Ecstasy) decreases neutrophil activity and alters leukocyte distribution in bone marrow, spleen and blood.

OBJECTIVE: Looking for possible neuroimmune relationships, we analyzed the effects of methylenedioxymethamphetamine (MDMA) administration on neuroendocrine, neutrophil activity and leukocyte distribution in mice. METHODS: Five experiments were performed. In the first, mice were treated with MDMA (10 mg/kg) 30, 60 min and 24 h prior to blood sample collection for neutrophil activity analysis. In the second experiment, the blood of naïve mice was collected and incubated with MDMA for neutrophil activity in vitro analysis. In the third and fourth experiments, mice were injected with MDMA (10 mg/kg) and 60 min later, blood and brain were collected to analyze corticosterone serum levels and hypothalamic noradrenaline (NA) levels and turnover. In the last experiment, mice were injected with MDMA 10 mg/kg and 60 min later, blood, bone marrow and spleen were collected for leukocyte distribution analysis. RESULTS: Results showed an increase in hypothalamic NA turnover and corticosterone serum levels 60 min after MDMA (10 mg/kg) administration, a decrease in peripheral blood neutrophil oxidative burst and a decrease in the percentage and intensity of neutrophil phagocytosis. It was further found that MDMA (10 mg/kg) treatment also altered leukocyte distribution in blood, bone marrow and spleen. In addition, no effects were observed for MDMA after in vitro exposure both in neutrophil oxidative burst and phagocytosis. CONCLUSION: The effects of MDMA administration (10 mg/kg) on neutrophil activity and leukocyte distribution might have been induced indirectly through noradrenergic neurons and/or hypothalamic-pituitary-adrenal axis activations.

Effects of L-arginine and L-lysine mixtures on splenic sympathetic nerve activity and tumor proliferation.

Oral supplementations of L-arginine and L-lysine show tumor inhibition abilities. The splenic sympathetic nerve is involved in central modulation of cellular immunity and suppresses splenic natural killer cell activity in rats. An intravenous administration of a mixture of 10 mM L-arginine and L-lysine decreased splenic sympathetic nerve activity (splenic-SNA). We examined the effect of L-arginine and L-lysine mixtures on splenic-SNA in urethane-anesthetized rats by administration of 1 ml mixtures of 2 mM, 10 mM, and 50 mM L-arginine and L-lysine. We also studied the effect of the above mixtures on human colon cancer cell proliferation in athymic nude mice. An increase in splenic-SNA and tumor volume (2 mM), no effect (10 mM), and a decrease in both values (50 mM) were seen. Bivariate correlation analysis revealed a positive correlation between changes in splenic-SNA and tumor volume, indicating the tumor suppressing ability of weakened splenic-SNA.

The effects of chrysin, a Passiflora incarnata extract, on natural killer cell activity in male Sprague-Dawley rats undergoing abdominal surgery.

Chrysin, a passion flower extract, may be beneficial because of its potential to attenuate surgical suppression of natural killer (NK) cell activity. We divided 37 male Sprague-Dawley rats into 3 treatment groups: (1) rats undergoing abdominal surgery and administered isoflurane and a 5% solution of dimethyl sulfoxide in saline (vehicle), (2) rats undergoing abdominal surgery and administered isoflurane and chrysin solubilized in 5% dimethyl sulfoxide, and (3) rats not undergoing surgery but administered isoflurane and chrysin. Natural killer cell activity was measured before and 24 hours after the experiment. Analysis of covariance, with preoperative NK cell activity as the covariate, was used to compare differences in NK cell activity among groups. The Scheffe procedure was used to make post hoc comparisons. Analysis revealed a significant difference (P = .006) such that group 2 had significantly less NK cell suppression compared with groups 1 and 3. These findings suggest that chrysin may attenuate surgical suppression of NK cell activity, thereby minimizing metastatic spread of cancer.

Dietary microparticles and their impact on tolerance and immune responsiveness of the gastrointestinal tract.

Dietary microparticles are non-biological bacterial-sized particles of the gastrointestinal lumen that occur due to endogenous formation (calcium phosphate) or following oral exposure (exogenous microparticle). In the UK, about 40 mg (10(12)) of exogenous microparticles are ingested per person per day, through exposure to food additives, pharmaceutical/supplement excipients or toothpaste constituents. Once ingested, exogenous microparticles are unlikely to pass through the gastrointestinal tract without adsorbing to their surfaces some ions and molecules of the intestinal lumen. Both entropy and ionic attraction drive such interactions. Calcium ions are especially well adsorbed by dietary microparticles which then provide a positively charged surface for the attraction (adsorption) of other organic molecules such as lipopolysaccharides, peptidoglycans or protein antigen from the diet or commensal flora. The major (but not only) sites of microparticle entry into intestinal tissue are the M-cell rich lymphoid aggregates (termed Peyer's patches in the small bowel). Indeed, it is well established that this is an efficient transport route for non-biological microparticles although it is unclear why. We hypothesise that this pathway exists for "endogenous microparticles" of calcium phosphate, with immunological and physiological benefit, and that "exogenous dietary microparticles", such as titanium dioxide and the silicates, hijack this route. This overview focuses on what is known of these microparticles and outlines their potential role in immune tolerance of the gut (endogenous microparticles) or immune activation (exogenous microparticles) and inflammation of the gut.

Immunosuppressive effects of photodynamic therapy by topical aminolevulinic acid.

Photodynamic therapy (PDT) has been used for inflammatory skin disorders as well as superficial skin cancers such as solar keratosis and Bowen's disease. Whether PDT with topical application of aminolevulinic acid (ALA) and exposure to visible light has a similar immunosuppressive action to ultraviolet phototherapy was investigated using a murine contact hypersensitivity (CHS) model. The number of epidermal Langerhans cells (LC) was decreased with their morphological changes 1 day after PDT with the minimal level at 5 days and gradual recovery thereafter. Conversely, the number of CD11c(+) I-A(+) cells was significantly increased in the draining lymph nodes after PDT. This suggests that LC moved from PDT-treated skin, resulting in the decrement of epidermal LC and migration to lymph nodes. CHS response to DNFB applied on the PDT-treated skin with 20% ALA and 40 J/cm(2) visible light was significantly suppressed (local immunosuppression). When mice were treated with 80 J/cm(2) of PDT, CHS response to the antigen applied on untreated distant skin was also significantly suppressed (systemic immunosuppression). The locally or systemically immunosuppressed mice by PDT were attempted to sensitize again with DNFB on non-treated skin, but elicitation responses were significantly suppressed. However, these mice were able to be sensitized with another hapten, oxasolone. Thus, a hapten-specific immunological unresponsiveness (tolerance) was induced in mice by topical ALA-PDT. These findings suggest that PDT has a potential immunological contribution to clinical efficacy for inflammatory diseases identical to ultraviolet phototherapies.

Regional changes of brain serotonin and its metabolite 5-hydroxyindolacetic Acid and development of immunosuppression in submissive mice.

The production of submissive behavior in C57BL/6J mice during 10 or 20 days of social confrontations resulted in increases in serotonin (5-HT) content in the amygdala, hippocampus, nucleus caudatus, Al1, A10, A9, and hypothalamus. The level of 5-hydroxyindolacetic acid (5-HIAA) was higher in most structures after 20 daily encounters compared to animals tested for 10 days. The ratio 5-HIAA/5-HT was increased in the nucleus raphe, accumbens, A9, and hypothalamus in mice displaying submission during 10 and 20 confrontations. The experience of defeats during 10 days accompanied with 5-HT system activation in a number of brain structures (nucleus raphe, accumbens, and A9) produced immunosuppression. With increasing number of confrontations the ratio 5-HIAA/5-HT was decreased in the same structures and a tendency to the immune response elevation appeared.

Exercise, nutrition and immune function.

Strenuous bouts of prolonged exercise and heavy training are associated with depressed immune cell function. Furthermore, inadequate or inappropriate nutrition can compound the negative influence of heavy exertion on immunocompetence. Dietary deficiencies of protein and specific micronutrients have long been associated with immune dysfunction. An adequate intake of iron, zinc and vitamins A, E, B6 and B12 is particularly important for the maintenance of immune function, but excess intakes of some micronutrients can also impair immune function and have other adverse effects on health. Immune system depression has also been associated with an excess intake of fat. To maintain immune function, athletes should eat a well-balanced diet sufficient to meet their energy requirements. An athlete exercising in a carbohydrate-depleted state experiences larger increases in circulating stress hormones and a greater perturbation of several immune function indices. Conversely, consuming 30-60 g carbohydrate x h(-1) during sustained intensive exercise attenuates rises in stress hormones such as cortisol and appears to limit the degree of exercise-induced immune depression. Convincing evidence that so-called 'immune-boosting' supplements, including high doses of antioxidant vitamins, glutamine, zinc, probiotics and Echinacea, prevent exercise-induced immune impairment is currently lacking.

Food supplements modulate changes in leucocyte numbers in breeding male ground squirrels.

Immunosuppression may be an important cost of reproduction in breeding males. It can result from elevated levels of testosterone or stress hormones and may serve to lower the energetic cost of maintaining immune function at a time of high demand. This suggests that greater access to energy resources could reduce immunosuppression as a cost of reproduction, minimizing the trade-off between energetic investment in current reproductive effort and survival. I examined the impact of food availability on immune function by provisioning male Belding's ground squirrels in the field from the time they emerged from hibernation to the start of breeding. Temporal changes in immune status, measured by leucocyte counts, differed between provisioned males and un-provisioned controls. Provisioning advanced the increase in lymphocytes and neutrophils from after breeding to before. At the start of breeding, the leucocyte count was three times greater in provisioned males than in controls and was still nearly twice as great at the end of breeding. Control males increased all leucocyte numbers after breeding. This experiment demonstrates that variation in food intake can lead to individual variation in the extent of immunosuppression during breeding and therefore that reduced immune function may not be an obligatory cost of reproduction.