Assessment of acute, subacute genetic toxicities and immunomodulatory activity of palm (Trachycarpus fortunei) buds.

ETHNOPHARMACOLOGY RELEVANCE: Palm buds are a natural green resource of the forest, which are not only rich in nutrients but contain a large number of phenolic acids and flavonoids, among other components. It has a variety of biological activities such as antioxidant and uterine smooth muscle stimulation. AIM OF THE STUDY: To evaluate the safety of palm buds for use as a nutraceutical product and food by evaluating the toxicity, subacute toxicity and genotoxicity of the young palm buds. Also studied for its immune-enhancing activity. MATERIALS AND METHODS: Acute toxicity tests were performed in mice using the maximum tolerance method, and the manifestations of toxicity and deaths were recorded after administration of 10,000 mg/mL for 14 consecutive d (days) of observations. To assess subacute toxicity, mice were treated with palm buds (750, 1500, or 3000 mg/mL) daily for 28 days. The teratogenicity of palm buds was assessed by the Ames test, the mouse bone marrow cell micronucleus test, and the mouse spermatozoa malformation test. In addition, we evaluated the immune-enhancing ability of palm buds by the mouse carbon profile test, delayed-type metamorphosis reaction, and serum hemolysin assay. RESULTS: In the acute toxicity study, the Median Lethal Dose (LD50) was greater than 10,000 mg/kg bw in both male and female rats. There were also no deaths or serious toxicities in the subacute study. The no-observed-adverse-effect level (NOAEL) was 3000 mg/kg bw. However, the mice's food intake decreased after one week. The medium and high dose groups had a reducing effect on body weight in mice of both sexes. In addition, the changes in organ coefficients of the liver, kidney and stomach in male mice were significantly higher in the high-dose group (3.23 ± 0.35, 0.75 ± 0.05, 0.57 ± 0.05 g) than in the control group (2.94 ± 0.18, 0.58 ± 0.05, 0.50 ± 0.02 g). Hematological analyses showed that all the indices of the rats in each palm sprout dose group were within the normal range. The results of blood biochemical indicators showed that there was a significant reduction in TP in the blood of male mice in the high-dose group (44.6 ± 7.8 g/L) compared to the control group (58.3 ± 15.1 g/L). In histopathological analysis, none of the significant histopathological changes were observed. The results of the immunological experiment in mice showed that the liver coefficient and thymus coefficient of the high-dose group (8400 mg/kg) were significantly lower than the control group. There was no remarkable difference in auricle swelling between each dose palm bud group (1400, 2800, or 8400 mg/kg) and the control group. The anti-volume number of the high-dose group was significantly increased. CONCLUSION: Palm buds have non-toxic effects in vivo and have little effect on non-specific and cellular immunity in the test mice within the dose range of this experiment. The immunoenhancement in mice is mainly achieved through humoral immunity. In conclusion, our results suggest that palm buds are safe for use as healthcare products and food.

Assessment of immunomodulatory effects of five commonly used parabens on human THP-1 derived macrophages: Implications for ecological and human health impacts.

Parabens are widely used as broad-spectrum anti-microbials and preservatives in food, cosmetics, pharmaceuticals, and personal care products. Studies suggest that the utilization of parabens has substantially increased over the past years, particularly during the global pandemic of coronavirus disease 2019 (COVID-19). Although parabens are generally recognized as safe by the U.S. FDA, some concerns have been raised regarding the potential health effects of parabens associated with immunotoxicity. Herein, we comprehensively investigated several key characteristics of immunotoxicants of five commonly used parabens (methyl-, ethyl-, propyl-, butyl-, and benzyl parabens) in human THP-1 derived macrophages, which are effector cells serving as a first line of host defense against pathogens and tumor immunosurveillance. The results indicate parabens, at concentrations found in humans and biota, significantly dampened macrophage chemotaxis and secretion of major pro-inflammatory cytokines (TNF-α and IL-6) and anti-inflammatory cytokine (IL-10), corroborating the mRNA expression profile. Furthermore, some parabens were found to markedly alter macrophage adhesion and cell surface expression of costimulatory molecules, CD80+ and CD86+, and significantly increase macrophage phagocytosis. Collectively, these findings heighten awareness of potential immunotoxicity posed by paraben exposure at biologically relevant concentrations, providing implications for human health and ecological risks associated with immune dysfunctions.

Challenges and gaps in immunosafety evaluation of therapeutics: An IQ DruSafe survey.

Immunotoxicology/immunosafety science is rapidly evolving, with novel modalities and immuno-oncology among the primary drivers of new tools and technologies. The Immunosafety Working Group of IQ/DruSafe sought to better understand some of the key challenges in immunosafety evaluation, gaps in the science, and current limitations in methods and data interpretation. A survey was developed to provide a baseline understanding of the needs and challenges faced in immunosafety assessments, the tools currently being applied across the industry, and the impact of feedback received from regulatory agencies. This survey also focused on current practices and challenges in conducting the T-cell-dependent antibody response (TDAR) and the cytokine release assay (CRA). Respondents indicated that ICH S8 guidance was insufficient for the current needs of the industry portfolio of immunomodulators and novel modalities and should be updated. Other challenges/gaps identified included translation of nonclinical immunosafety assessments to the clinic, and lack of relevant nonclinical species and models in some cases. Key areas of emerging science that will add future value to immunotoxicity assessments include development of additional in vitro and microphysiological system models, as well as application of humanized mouse models. Efforts are ongoing in individual companies and consortia to address some of these gaps and emerging science.

Model-informed approach for risk management of bleeding toxicities for bintrafusp alfa, a bifunctional fusion protein targeting TGF-ß and PD-L1.

PURPOSE: Bintrafusp alfa (BA) is a bifunctional fusion protein composed of the extracellular domain of the transforming growth factor-ß (TGF-ß) receptor II fused to a human immunoglobulin G1 antibody blocking programmed death ligand 1 (PD-L1). The recommended phase 2 dose (RP2D) was selected based on phase 1 efficacy, safety, and pharmacokinetic (PK)-pharmacodynamic data, assuming continuous inhibition of PD-L1 and TGF-ß is required. Here, we describe a model-informed dose modification approach for risk management of BA-associated bleeding adverse events (AEs). METHODS: The PK and AE data from studies NCT02517398, NCT02699515, NCT03840915, and NCT04246489 (n = 936) were used. Logistic regression analyses were conducted to evaluate potential relationships between bleeding AEs and BA time-averaged concentration (Cavg), derived using a population PK model. The percentage of patients with trough concentrations associated with PD-L1 or TGF-ß inhibition across various dosing regimens was derived. RESULTS: The probability of bleeding AEs increased with increasing Cavg; 50% dose reduction was chosen based on the integration of modeling and clinical considerations. The resulting AE management guidance to investigators regarding temporary or permanent treatment discontinuation was further refined with recommendations on restarting at RP2D or at 50% dose, depending on the grade and type of bleeding (tumoral versus nontumoral) and investigator assessment of risk of additional bleeding. CONCLUSION: A pragmatic model-informed approach for management of bleeding AEs was implemented in ongoing clinical trials of BA. This approach is expected to improve benefit-risk profile; however, its effectiveness will need to be evaluated based on safety data generated after implementation.

The pathogenic role of IFN-α in thyroiditis mouse models.

AIM: Patients with chronic hepatitis C are frequently treated with interferon (IFN)-α. Autoimmune thyroid disease occurs in 20% ~ 40% of IFN-α-treated patients. In this study, the effects of IFN-α administration on triggering and regulating autoimmune thyroiditis in various animal models were evaluated. MAIN METHODS: Exogenous IFN-α was given to naive CBA mice, and both thyroglobulin (TG) immunization-induced (CBA) and spontaneous autoimmune thyroiditis (NOD·H-2 h4) models. Thyroid function, and anti-thyroglobulin antibody (ATA) and B-cell-activating factor (BAFF) levels were measured. Alterations in transcriptome profiles were analyzed. KEY FINDINGS: In the TG-induced thyroiditis model, IFN-α administration reduced plasma free thyroxine levels but did not alter ATA titers, BAFF levels, or the severity of histological changes. Interestingly, even without changes in thyroid functions, four of eight mice in the IFN-α alone group exhibited thyroiditis compared to the control group. Immunologically, mice in the IFN-α group exhibited profound CD3+ cell infiltration in the thyroid and higher plasma BAFF levels compared to the control group. Meanwhile, pathological and serological alterations after IFN-α administration were not observed in the NOD·H-2 h4 model. An RNA sequencing analysis revealed that immunoregulatory signatures were not excited by IFN-α treatment in naive CBA mice. Meanwhile, innate and adaptive immunity, inflammatory cytokine, chemokine, and cell-killing signaling pathways were all stimulated by IFN-α administration after TG immunization of CBA mice. SIGNIFICANCE: We confirmed the remarkable effects of IFN-α in both initiating thyroid immunity and modulating thyroid function and immunoregulatory signatures in established autoimmune thyroiditis. We suggest that IFN-α should be administered with caution in clinical settings.

Lenalidomide and dexamethasone in relapsed/refractory immunoglobulin light chain (AL) amyloidosis: results from a large cohort of patients with long follow-up.

Lenalidomide and dexamethasone (RD) is a standard treatment in relapsed/refractory immunoglobulin light chain (AL) amyloidosis (RRAL). We retrospectively investigated toxicity, efficacy and prognostic markers in 260 patients with RRAL. Patients received a median of two prior treatment lines (68% had been bortezomib-refractory; 33% had received high-dose melphalan). The median treatment duration was four cycles. The 3-month haematological response rate was 31% [very good haematological response (VGHR) in 18%]. The median follow-up was 56·5 months and the median overall survival (OS) and haematological event-free survival (haemEFS) were 32 and 9 months. The 2-year dialysis rate was 15%. VGHR resulted in better OS (62 vs. 26 months, P < 0·001). Cardiac progression predicted worse survival (22 vs. 40 months, P = 0·027), although N-terminal prohormone of brain natriuretic peptide (NT-proBNP) increase was frequently observed. Multivariable analysis identified these prognostic factors: NT-proBNP for OS [hazard ratio (HR) 1·71; P < 0·001]; gain 1q21 for haemEFS (HR 1·68, P = 0·014), with a trend for OS (HR 1·47, P = 0·084); difference between involved and uninvolved free light chains (dFLC) and light chain isotype for OS (HR 2·22, P < 0·001; HR 1·62, P = 0·016) and haemEFS (HR 1·88, P < 0·001; HR 1·59, P = 0·008). Estimated glomerular filtration rate (HR 0·71, P = 0·004) and 24-h proteinuria (HR 1·10, P = 0·004) were prognostic for renal survival. In conclusion, clonal and organ biomarkers at baseline identify patients with favourable outcome, while VGHR and cardiac progression define prognosis during RD treatment.

Panchvalkala, a traditional Ayurvedic formulation, exhibits antineoplastic and immunomodulatory activity in cervical cancer cells and C57BL/6 mouse papilloma model.

ETHNOPHARMACOLOGICAL RELEVANCE: Panchvalkala, an Ayurvedic traditional formulation has references in Charak Samhita and Bhavaprakasha Nighantu for the treatment of women with endometriosis-related problems, leucorrhea and vaginal ailments. The formulation comprises of equal ratios of the barks from Ficus glomerata, Ficus virens, Ficus religiosa, Ficus benghalensis, and Thespesia populnea. AIM OF THE STUDY: The present study aimed to evaluate the anticancer and immunomodulatory activity of aqueous extract of Panchvalkala (PVaq) against cervical cancer in vitro and in vivo. MATERIALS AND METHODS: The effect of PVaq on disruption of mitochondrial membrane potential in cervical cancer cell lines, SiHa and HeLa, was studied by using JC1 dye. The expression of generic caspases in the cells after treatment with PVaq was evaluated by ELISA kit. The expression of pRb, p53, E6 and E7 proteins were evaluated by western blotting. Acute oral toxicity and DRF studies were performed in Swiss albino mice by following OECD guidelines 423 and 407, respectively. Tumor retardation study was done in C57BL/6 mouse papilloma model. The mice were divided into six groups: No tumor control (NTC), Tumor control (TC), Cisplatin (Cis) (4 mg/kg b.w.), PVaq 100, 200 mg/kg b.w and combination of PVaq (200 mg/kg b.w.) and Cisplatin (4 mg/kg b.w.). The mice were orally gavaged with PVaq daily for 14 days and cisplatin was given intravenously on every 1st, 5th and 9th day. Hematological and biochemical parameters were studied by using hematology analyzer and kits, respectively. E6 and E7 gene expression in the tumor samples was determined by qPCR. Th1 and Th2 cytokine levels were determined by ELISA. RESULTS: PVaq induced mitochondrial depolarization in SiHa and HeLa, and increased the expression of generic caspases, resulting into apoptosis. PVaq upregulated the expression of tumor suppressor proteins (p53 and pRb) and reduced the expression of viral oncoproteins (E6 and E7). Acute toxicity study displayed non-toxicity of PVaq while DRF study ensured its safe dose for further efficacy studies. PVaq reduced tumor volume and weight in mouse papilloma model and induced immunomodulation in the animals. It increased serum levels of IL-2 (Th1) with a concomitant decrease in IL-10 (Th2) cytokines. The drug did not affect body weight, food consumption and organ histopathology of the animals. CONCLUSIONS: PVaq exhibited anticancer and immunomodulatory activities against cervical cancer cells and female mouse papilloma model.

Structural characterization of novel arabinoxylan and galactoarabinan from citron with potential antitumor and immunostimulatory activities.

This study aimed to extract polysaccharides from citron and analyze their structures and potential bioactivities. Two novel polysaccharides CM-1 and CM-2 were purified from citron by DEAE-Sepharose Fast Flow and Sephadex G-100 column chromatography. Monosaccharide composition, linkage and NMR data were used to infer their sugar chains composition. The anti-breast cancer cells and immunoregulatory activities of CM-1 and CM-2 were investigated. Results indicated that CM-1 (Mw = 21,520 Da), composed of arabinose, xylose, mannose and glucose in a molar ratio of 10.78:11.53:1.00:1.70, was arabinoxylan (AX) with (1 â†’ 4)-linked ß-d-Xylp skeleton monosubstituted with α-l-Araf units at O-3 position. While CM-2 (Mw = 22,303 Da), composed of arabinose, mannose, glucose and galactose in a molar ratio of 25.46:1.45:1.00:6.57, was galactoarabinan (GA) with (1 â†’ 5)-linked α-l-Araf backbone substituted by ß-d-Galp units at O-2 and/or O-3 positions. Both polysaccharides exhibited potential inhibiting cancer and immunostimulatory activities in vitro, especially CM-1. These results provide a basis for further research on citron polysaccharides.

Plant/algal polysaccharides extracted by microwave: A review on hypoglycemic, hypolipidemic, prebiotic, and immune-stimulatory effect.

Microwave-assisted extraction (MAE) is an emerging technology to obtain polysaccharides with an extensive spectrum of biological characteristics. In this study, the hypoglycemic, hypolipidemic, prebiotic, and immunomodulatory (e.g., antiinflammatory, anticoagulant, and phagocytic) effects of algal- and plant-derived polysaccharides rich in glucose, galactose, and mannose using MAE were comprehensively discussed. The in vitro and in vivo results showed that these bioactive macromolecules with the low digestibility rate could effectively alleviate the fatty acid-induced lipotoxicity, acute hemolysis, and dyslipidemia status. The optimally extracted glucomannan- and glucogalactan-containing polysaccharides revealed significant antidiabetic effects through inhibiting α-amylase and α-glucosidase, improving dynamic insulin sensitivity and secretion, and promoting pancreatic ß-cell proliferation. These bioactive macromolecules as prebiotics not only improve the digestibility in gastrointestinal tract but also reduce the survival rate of pathogens and tumor cells by activating macrophages and producing pro-inflammatory biomarkers and cytokines. They can effectively prevent gastrointestinal disorders and microbial infections without any toxicity.

Occurrence, mitigation and in vitro cytotoxicity of nivalenol, a type B trichothecene mycotoxin - Updates from the last decade (2010-2020).

The present review aims to give an overview of the literature of the last decade (2010-2020) concerning the occurrence of the type B trichothecene mycotoxin nivalenol (NIV) and its in vitro toxicity, with the purpose of updating information regarding last researches on this mycotoxin. The most recent studies on the possible methods for preventing Fusarium spp. growth and NIV production are also discussed. Recently, various environmental factors have been shown to influence strongly NIV occurrence. However, Fusarium spp. of the NIV genotype have been found almost worldwide. With regard to NIV cytotoxicity, NIV has been reported to cause a marked decrease in cell proliferation in different mammalian cells. In particular, the recent data suggest that organs containing actively proliferating cells represent the main targets of NIV. Moreover, NIV resulted to cause immunosuppression, gastrointestinal toxicity and genotoxicity. However, sufficient evidence of carcinogenicity in humans is currently lacking, and the International Agency for Research on Cancer (IARC) classifies it as a group 3 carcinogen. Further researches and the discovery of effective treatment strategies to prevent NIV contamination and to counteract its toxicity are urgently required against this common food-borne threat to human health and livestock.

Limonene-carvacrol: A combination of monoterpenes with enhanced antileishmanial activity.

BACKGROUND: Leishmaniasis is a parasitosis with a wide incidence in developing countries. The drugs which are indicated for the treatment of this infection usually are able to promote high toxicity. PURPOSE: A combination of limonene and carvacrol, monoterpenes present in plants with antiparasitic activity may constitute an alternative for the treatment of these diseases. METHODS: In this study, the antileishmania activity against Leishmania major, cytotoxicity tests, assessment of synergism, parasite membrane damage tests as well as molecular docking and immunomodulatory activity of limonene-carvacrol (Lim-Car) combination were evaluated. RESULTS: The Lim-Car combination (5:0; 1:1; 1:4; 2:3; 3:2; 4:1 and 0:5) showed potential antileishmania activity, with mean inhibitory concentration (IC50) ranging from 5.8 to 19.0 µg.mL-1. They demonstrated mean cytotoxic concentration (CC50) ranging from 94.1 to 176.0 µg.mL-1, and did not show significant hemolytic effect. In the investigation of synergistic interaction, the 4:1 Lim-Car combination showed better fractional inhibitory concentration (FIC) index as well as better activity on amastigotes and IS. The samples caused considerable damage to the parasite membrane this monoterpene activity seems to be more related to Trypanothione Reductase (TryR) enzyme interaction, demonstrated in the molecular docking assay. In addition, the 4:1 Lim-Car combination stimulated macrophage activation, and showed at was the best association, with reduction of infection and infectivity of parasitized macrophages. CONCLUSION: The 4:1 Lim-Car combination appears to be a promising candidate as a monotherapeutic antileishmania agent.

Exopolysaccharide from Porphyridium cruentum (purpureum) is Not Toxic and Stimulates Immune Response against Vibriosis: The Assessment Using Zebrafish and White Shrimp Litopenaeus vannamei.

Exopolysaccharides, or extracellular polysaccharides (EPS, sPS), represent a valuable metabolite compound synthesized from red microalgae. It is a non-toxic natural agent and can be applied as an immunostimulant. The toxicity test of exopolysaccharides from Porphyridium has been done in vivo using zebrafish (Danio rerio) embryonic model, or the ZET (zebrafish embryotoxicity test). The administration of extracellular polysaccharides or exopolysaccharides (EPS) from microalgae Porphyridium cruentum (synonym: P. purpureum) to shrimps Litopenaeus vannamei was investigated to determine the effect of this immunostimulant on their non-specific immune response and to test if this compound can be used as a protective agent for shrimps in relation to Vibrio infection. For immune response, exopolysaccharides were given to shrimps via the immersion method on day 1 and booster on day 8. Shrimp hemocytes were taken on day 1 (EPS administration), day 7 (no treatment), day 8 (EPS booster) and day 9 (Vibrio infection) and tested for their immune response on each treatment. The result shows that the EPS is not toxic, as represented by the normal embryonic development and the mortality data. In the Pacific white shrimps, an increase in the values of all immune parameters was shown, in line with the increasing EPS concentration, except for the differential hemocyte count (DHC). In detail, an increase was noted in total hemocytes (THC) value, phagocytotic activity (PA) and respiratory burst (RB) in line with the EPS concentration increase. These results and other previous studies indicate that EPS from Porphyridium is safe, enhances immune parameters in shrimp rapidly, and has the ability to act as an immunostimulant or an immunomodulator. It is a good modulator for the non-specific immune cells of Pacific white shrimps, and it can be used as a preventive agent against vibriosis.

CAR-T and checkpoint inhibitors: toxicities and antidotes in the emergency department.

INTRODUCTION: New cancer treatments with immunotherapy have led to unique toxicities affecting cancer patients. As cancer-related visits to the emergency department increase, the emergency physician and the medical toxicologist should be aware of immunotherapy-related toxicities. In this review we discuss immune related adverse events (irAEs) from chimeric antigen receptor T (CAR-T) cell therapy and immune checkpoint inhibitors (ICI). DISCUSSION: While presentation of the irAEs may mimic common conditions, it is important to recognize them as they may be life-threatening. A thorough history and examination of the patient, including their cancer treatment history in the past year is crucial. Conditions such as cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS), which can occur after CAR-T treatment, can progress rapidly to a fatal outcome if not recognized and managed in a timely manner. ICI can affect any organ system and irAEs may present like a typical autoimmune disease of the affected organ. While most of the irAEs we discuss in this review will benefit from treatment with glucocorticoids, it is important to know the grade of the condition, as it will determine the treatment dose, route and further management considerations. CONCLUSION: Patients experiencing irAEs from ICI and CAR-T can present with subtle symptoms that can rapidly progress if not recognized early. The emergency physician and the medical toxicologist should keep in mind these toxicities and the patient's oncologic history to adequately recognize and manage these conditions.

The effect of exposure to crude oil on the immune system. Health implications for people living near oil exploration activities.

People who reside near oil exploration activities may be exposed to toxins from gas flares or oil spills. The impact of such exposures on the human immune system has not been fully investigated. In this review, research investigating the effects of crude oil on the immune system is evaluated. The aim was to obtain a greater understanding of the possible immunological impact of living near oil exploration activities. In animals, the effect of exposure to crude oil on the immune system depends on the species, dose, exposure route, and type of oil. Important observations included; hematological changes resulting in anemia and alterations in white blood cell numbers, lymph node and splenic atrophy, genotoxicity in immune cells, modulation of cytokine gene expression and increased susceptibility to infectious diseases. In humans, there are reports that exposure to crude oil can increase the risk of developing certain types of cancer and cause immunomodulation.Abbreviations: A1AT: alpha-1 antitrypsin; ACH50: hemolytic activity of the alternative pathway; AHR: aryl hydrocarbon receptor; BALF: bronchoalveolar lavage fluid; COPD: chronic obstructive pulmonary disease; CYP: cytochrome P450; DNFB: 2, 4-dinitro-1-fluorobenzene; G-CSF: granulocyte-colony stimulating factor; IFN: interferon; IL: interleukin; 8-IP: 8-isoprostane; ISG15: interferon stimulated gene; LPO: lipid peroxidation; LTB4: leukotriene B4; M-CSF: macrophage-colony stimulating factor; MMC: melanomacrophage center; MPV: mean platelet volume; NK: natural killer; OSPM: oil sail particulate matter; PAH: polycyclic aromatic hydrocarbon; PBMC: peripheral blood mononuclear cell; PCV: packed cell volume; RBC: red blood cell; ROS: reactive oxygen species; RR: relative risk; TH: T helper; TNF: tumour necrosis factor; UV: ultraviolet; VNNV: Viral Nervous Necrosis Virus; WBC: white blood cell.

Liver injury after methylprednisolone pulse therapy in multiple sclerosis is usually due to idiosyncratic drug-induced toxicity rather than autoimmune hepatitis.

BACKGROUND: In patients with multiple sclerosis (MS), development of hepatic injury has been sporadically reported after methylprednisolone (MP) pulse therapy. Some studies suggest autoimmune hepatitis, while other studies reported direct hepatotoxicity as a cause for hepatic injury. Here, we studied the pathological mechanism of such liver injury in patients with MS. METHODS: From 2005 to 2016, eight patients with MS developed liver injury after MP pulse therapy. Their average age was 38 years (range: 28-49 years, all female). Autoimmune antibodies were measured and a liver biopsy was performed in seven patients. RESULTS: Liver injury developed within two weeks in two patients and later (30-90 days after MP) in six patients. No hepatitis-related autoantibody or hepatitis virus were found. All cases were classified as hepatocellular injury and none as cholestatic or mixed. A liver biopsy in five cases revealed centrilobular necrosis with lobular infiltrates of inflammatory cells, suggesting drug-induced acute hepatitis. The biopsy findings in another case suggested a residual stage of acute hepatitis. Only one patient showed portal expansion with periportal fibrosis, suggesting autoimmune hepatitis. All patients recovered spontaneously or with only hepatoprotective drugs, although one patient with possible autoimmune hepatitis recovered slowly. CONCLUSION: Liver injury develops usually later than two weeks after MP treatment. The prognosis is good in most cases and rarely autoimmune hepatitis may be involved.

Effects of chloromethylisothiazolinone/methylisothiazolinone (CMIT/MIT) on Th2/Th17-related immune modulation in an atopic dermatitis mouse model.

Exposure to chloromethylisothiazolinone/methylisothiazolinone (CMIT/MIT) has been associated with allergic contact dermatitis and occupational asthma. Despite this association however, no study has investigated the effects of CMIT/MIT exposure on the development of atopic dermatitis (AD). This study was conducted to investigate the influence of epicutaneous exposure to CMIT/MIT on AD in a mouse model and the underlying biological mechanisms. BALB/C mice were exposed to CMIT/MIT for 3 weeks and AD was developed using ovalbumin (OVA) epidermal sensitization. CMIT/MIT epicutaneous exposure in normal mice significantly enhanced AD-like phenotypes (e.g., transepidermal water loss, clinical score, total serum immunoglobulin E level and infiltration of inflammatory cells). In addition, CMIT/MIT exposure significantly augmented the mRNA expression level of T helper (Th) 2-related cytokines (thymic stromal lymphopoietin, interleukin (IL)-6 and IL-13), Th2 chemokine (chemokine (C-C motif) ligand 17) and the population of CD4+IL-4+ cells in the skin. Moreover, mice exposed to CMIT/MIT in the OVA challenge had greater AD-like phenotypes, higher IL-4 and IL-17A skin mRNA expression levels, and a larger population of CD4+IL-4+- and IL-17A+-producing cells in the skin-draining lymph nodes. Our current findings in a mouse model thus suggest that CMIT/MIT exposure may cause AD symptoms through the dysregulation of Th2/Th17-related immune responses.

An international validation study of the IL-2 Luc assay for evaluating the potential immunotoxic effects of chemicals on T cells and a proposal for reference data for immunotoxic chemicals.

To evaluate the immunotoxic effects of xenobiotics, we have established the Multi-ImmunoTox assay, in which three stable reporter cell lines are used to evaluate the effects of chemicals on the IL-2, IFN-γ, IL-1ß and IL-8 promoters. Here, we report the official validation study of the IL-2 luciferase assay (IL-2 Luc assay). In the Phase I study that evaluated five coded chemicals in three sets of experiments, the average within-laboratory reproducibility was 86.7%. In the Phase II study, 20 coded chemicals were evaluated at multiple laboratories. In the combined results of the Phase I and II studies, the between-laboratory reproducibility was 80.0%. These results suggested that the IL-2 Luc assay was reproducible both between and within laboratories. To determine the predictivity, we collected immunotoxicological information and constructed the reference data by classifying the chemical into immunotoxic compounds targeting T cells or others according to previously reported criteria. When compared with the reference data, the average predictivity of the Phase I and II studies was 75.0%, while that of additional 60 chemicals examined by the lead laboratory was 82.5%. Although the IL-2 Luc assay alone is not sufficient to predict immunotoxicity, it will be a useful tool when combined with other immune tests.

Heavy metal toxicity has an immunomodulatory effect on metallothionein and glutathione peroxidase gene expression in Cyprinus carpio inhabiting a wetland lake and a culture pond.

The study provides cumulative data on the status of the two water bodies. The study designed revealed physicochemical properties (temperature, dissolved oxygen, pH, total dissolved solids and conductivity) to be in the desirable range, however, amongst the heavy metals excepting for Cd all were found to be higher than the permissible limits set by WHO and USEPA. It was observed that these elements cast their impact on bioindices (hepatosomatic index, condition factor, spleenosomatic index and kidney somatic index), renal marker enzyme (creatine kinase), hepatic marker enzymes (aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase), histology of immune organs (liver, spleen, head-kidney and thymus) and level of serum immunoglobulin (IgM). Further, expression levels of Metallothionein (MT) and Glutathione peroxidase (GPX) genes in immune-related tissues (liver, spleen, head-kidney, thymus and blood) observed indicates metal pollution and abiotic stresses. These alterations are reliable indicators of the cellular and humoral immune response in Cyprinus carpio.

Bacterial Genotoxin-Induced DNA Damage and Modulation of the Host Immune Microenvironment.

: Bacterial genotoxins (BTGX) induce DNA damage, which results in senescence or apoptosis of the target cells if not properly repaired. Three BTGXs have been identified: the cytolethal distending toxin (CDT) family produced by several Gram-negative bacteria, the typhoid toxin produced by several Salmonella enterica serovars, and colibactin, a peptide-polyketide, produced mainly by the phylogenetic group B2 Escherichia coli. The cellular responses induced by BTGXs resemble those of well-characterized carcinogenic agents, and several lines of evidence indicate that bacteria carrying genotoxin genes can contribute to tumor development under specific circumstances. Given their unusual mode of action, it is still enigmatic why these effectors have been acquired by microbes and what is their role in the context of the biology of the producing bacterium, since it is unlikely that their primary purpose is to induce/promote cancer in the mammalian host. In this review, we will discuss the possibility that the DNA damage induced by BTGX modulates the host immune response, acting as immunomodulator, leading to the establishment of a suitable niche for the producing bacterium. We will further highlight open questions that remain to be solved regarding the biology of this unusual family of bacterial toxins.

Toxic Myopathies.

PURPOSE OF REVIEW: This article reviews the pathogenesis, clinical features, and management of toxic myopathy related to common medications, critical illness, and illicit substances. RECENT FINDINGS: Muscle symptoms are common among statin users and are usually reversible after discontinuation of the statin; rarely, however, statins trigger an immune-mediated necrotizing myopathy that persists and requires immunomodulatory therapy. Autoantibodies targeting 3-hydroxy-3-methylglutaryl coenzyme A reductase can distinguish the toxic and immune-mediated forms. Immune checkpoint inhibitors, increasingly used in the treatment of advanced cancer, have recently been associated with the development of inflammatory myositis. A reversible mitochondrial myopathy has long been associated with zidovudine, but recent reports elucidate the risk of myopathy with newer antivirals, such as telbivudine and raltegravir. SUMMARY: The medications most commonly associated with myopathy include statins, amiodarone, chloroquine, hydroxychloroquine, colchicine, certain antivirals, and corticosteroids, and myopathy can occur with chronic alcoholism. Certain clinical, electrodiagnostic, and histologic features can aid in early recognition. Stopping the use of the offending agent reverses symptoms in most cases, but specific and timely treatment may be required in cases related to agents that trigger immune-mediated muscle injury.