Comparative effects of the herbal constituent parthenolide (Feverfew) on lipopolysaccharide-induced inflammatory gene expression in murine spleen and liver

BACKGROUND: Parthenolide, a major sesquiterpene lactone present in extracts of the herb Feverfew, has been investigated for its inhibitory effects on mediators of inflammation, including the proinflammatory cytokines. Although parthenolide's anti-inflammatory effects have been investigated in vitro, little in vivo data are available. Moreover, the molecular mechanisms for these inhibitory effects are not fully understood. The objective of this study was to test the hypothesis that parthenolide suppresses lipopolysaccharide (LPS)-induced serum (interleukin) IL-6, tumor necrosis factor (TNF)-α, IL-1β and cyclooxygenase (COX)-2 expression in mice as indicated by reduced splenic and liver mRNA levels. METHODS: Mice were co-treated i.p. with LPS (1 mg/kg bw) and parthenolide (5 mg/kg bw) and blood, spleen and liver collected. Serum was analyzed for IL-6, TNF-α and IL-1β by ELISA. Total RNA was extracted from spleen and liver, and real-time RT-PCR was used to determine relative mRNA expression of IL-1β, IL-6, TNF-α and COX-2. RESULTS: LPS induced increases in serum IL-6 and TNF-α concentrations with only IL-6 being suppressed in parthenolide-treated mice. Induction of IL-6 mRNA was reduced, TNF-α and COX-2 mRNAs unchanged, and IL-1β mRNA increased in spleens of parthenolide plus LPS co-treated animals compared to LPS-only. No significant differences were observed in inflammatory gene expression between these two groups in liver samples. Overall, mRNA expression of each proinflammatory gene was much higher in spleen when compared to liver. CONCLUSION: In summary, only one gene, IL-6, was modestly suppressed by parthenolide co-exposure which contrasts with many in vitro studies suggesting anti-inflammatory effects of this compound. Also, LPS evoked greater effects in spleen than liver on expression of proinflammatory genes. Further study of the effects of parthenolide and other herbal constituents on inflammatory gene expression using model animal systems as described here are critical to evaluating efficacy of such supplements as well as elucidating their mechanisms of action

Impact of environmental factors on growth and satratoxin G production by strains of Stachybotrys chartarum

The black mould Stachybotrys chartarum and its mycotoxins have been linked to damp building-associated illnesses. The objective of this study was to determine the effects of water availability (water activity, aw) and temperature on growth and production of satratoxin G (SG) by a macrocyclic trichothecene-producing strain (IBT 7711) and non-producing strain (IBT 1495) of S. chartarum. Growth studies were carried out on potato dextrose agar modified with glycerol to 0.995-0.92 aw at 10-37 °C. Growth extension was measured and the cultures were extracted after 10 days and a competitive enzyme-linked immunosorbent assay (ELISA) method used to quantify the SG content. Growth was optimal at 25 to 30 °C at 0.995 aw, but this was modified to 0.98 aw at 30 °C for both strains (1.4- 1.6 mm/day, respectively). The ELISA method revealed that, in contrast to growth, SG production was maximal at 20 °C with highest production at 0.98 aw (approximately 250 μg/g mycelia). When water was freely available (0.995 aw), SG was maximally produced at 15 °C and decreased as temperature was increased. Interestingly, the strain classified as a non-toxigenic produced very low amounts of SG (<1.6 μg/g mycelia) that were maximal at 25 °C and 0.98 aw. Contour maps for growth and SG production were developed from these data sets. These data have shown, for the first time, that growth and SG production profiles are very different in relation to key environmental conditions in the indoor environment. This will be very useful in practically determining the risk from exposure to S. chartarum and its toxins in the built env

Satratoxin G from the Black Mold Stachybotrys chartarum Evokes Olfactory Sensory Neuron Loss and Inflammation in the Murine Nose and Brain

Satratoxin G (SG) is a macrocyclic trichothecene mycotoxin produced by Stachybotrys chartarum, the “black mold” suggested to contribute etiologically to illnesses associated with water-damaged buildings. Using an intranasal instillation model in mice, we found that acute SG exposure specifically induced apoptosis of olfactory sensory neurons (OSNs) in the olfactory epithelium. Dose–response analysis revealed that the no-effect and lowest-effect levels at 24 hr postinstillation (PI) were 5 and 25 μg/kg body weight (bw) SG, respectively, with severity increasing with dose. Apoptosis of OSNs was identified using immunohistochemistry for caspase-3 expression, electron microscopy for ultrastructural cellular morphology, and real-time polymerase chain reaction for elevated expression of the proapoptotic genes Fas, FasL, p75NGFR, p53, Bax, caspase-3, and CAD. Time-course studies with a single instillation of SG (500 μg/kg bw) indicated that maximum atrophy of the olfactory epithelium occurred at 3 days PI. Exposure to lower doses (100 μg/kg bw) for 5 consecutive days resulted in similar atrophy and apoptosis, suggesting that in the short term, these effects are cumulative. SG also induced an acute, neutrophilic rhinitis as early as 24 hr PI. Elevated mRNA expression for the proinflammatory cytokines tumor necrosis factor-α, interleukin-6 (IL-6), and IL-1 and the chemokine macrophage-inflammatory protein-2 (MIP-2) were detected at 24 hr PI in both the ethmoid turbinates of the nasal airways and the adjacent olfactory bulb of the brain. Marked atrophy of the olfactory nerve and glomerular layers of the olfactory bulb was also detectable by 7 days PI along with mild neutrophilic encephalitis. These findings suggest that neurotoxicity and inflammation within the nose and brain are potential adverse health effects of exposure to satratoxins and Stachybotrys in the indoor air of water-damaged buildings

Deoxynivalenol-Induced Proinflammatory Gene Expression: Mechanisms and Pathological Sequelae

The trichothecene mycotoxin deoxynivalenol (DON) is commonly encountered in human cereal foods throughout the world as a result of infestation of grains in the field and in storage by the fungus Fusarium. Significant questions remain regarding the risks posed to humans from acute and chronic DON ingestion, and how to manage these risks without imperiling access to nutritionally important food commodities. Modulation of the innate immune system appears particularly critical to DON’s toxic effects. Specifically, DON induces activation of mitogen-activated protein kinases (MAPKs) in macrophages and monocytes, which mediate robust induction of proinflammatory gene expression—effects that can be recapitulated in intact animals. The initiating mechanisms for DON-induced ribotoxic stress response appear to involve the (1) activation of constitutive protein kinases on the damaged ribosome and (2) autophagy of the chaperone GRP78 with consequent activation of the ER stress response. Pathological sequelae resulting from chronic low dose exposure include anorexia, impaired weight gain, growth hormone dysregulation and aberrant IgA production whereas acute high dose exposure evokes gastroenteritis, emesis and a shock-like syndrome. Taken together, the capacity of DON to evoke ribotoxic stress in mononuclear phagocytes contributes significantly to its acute and chronic toxic effects in vivo. It is anticipated that these investigations will enable the identification of robust biomarkers of effect that will be applicable to epidemiological studies of the human health effects of this common mycotoxin

Deoxynivalenol and its toxicity

Deoxynivalenol (DON) is one of several mycotoxins produced by certain Fusarium species that frequently infect corn, wheat, oats, barley, rice, and other grains in the field or during storage. The exposure risk to human is directly through foods of plant origin (cereal grains) or indirectly through foods of animal origin (kidney, liver, milk, eggs). It has been detected in buckwheat, popcorn, sorgum, triticale, and other food products including flour, bread, breakfast cereals, noodles, infant foods, pancakes, malt and beer. DON affects animal and human health causing acute temporary nausea, vomiting, diarrhea, abdominal pain, headache, dizziness, and fever. This review briefly summarizes toxicities of this mycotoxin as well as effects on reproduction and their antagonistic and synergic actions

Mapping of Dynamic Transcriptome Changes Associated With Silica-Triggered Autoimmune Pathogenesis in the Lupus-Prone NZBWF1 Mouse

Crystalline silica (cSiO2) is a widely recognized environmental trigger of autoimmune disease. In the lupus-prone female NZBWF1 mouse, airway exposure to cSiO2 triggers pulmonary ectopic lymphoid neogenesis, systemic autoantibody elevation, and glomerulonephritis. Here we tested the hypothesis that upregulation of adaptive immune function genes in the lung precedes cSiO2-triggering of autoimmune disease in this model. The study include three groups of mice, as follows: (1) necropsied 1 d after a single intranasal instillation of 1 mg cSiO2 or vehicle, (2) necropsied 1 d after four weekly single instillations of 1 mg cSiO2 or vehicle, or (3) necropsied 1, 5, 9, or 13 weeks after four weekly single instillations of 1 mg cSiO2 or vehicle. NanoString nCounter analysis revealed modest transcriptional changes associated with innate and adaptive immune response as early as 1 d after a single cSiO2 instillation. These responses were greatly expanded after four weekly cSiO2 instillations. Concurrent with ectopic lymphoid neogenesis, dramatic increases in mRNAs associated with chemokine release, cytokine production, sustained interferon activity, complement activation, and adhesion molecules were observed. As disease progressed, expression of these genes persisted and was further amplified. Consistent with autoimmune pathogenesis, the time between 5 and 9 weeks post-instillation reflected an important transition period where considerable immune gene upregulation in the lung was observed. Upon termination of the chronic study (13 weeks), cSiO2-induced changes in transcriptome signatures were similarly robust in kidney as compared to the lung, but more modest in spleen. Transcriptomic signatures in lung and kidney were indicative of infiltration and/or expansion of neutrophils, macrophages, dendritic cells, B cells, and T cells that corresponded with accelerated autoimmune pathogenesis. Taken together, airway exposure to cSiO2 elicited aberrant mRNA signatures for both innate and adaptive immunity that were consistent with establishment of the lung as the central autoimmune nexus for launching systemic autoimmunity and ultimately, kidney injury

Health Related Quality of Life and Return to Work After Minor Extremity Injuries: a Longitudinal Study Comparing Upper Versus Lower Extremity Injuries

Purpose: To investigate the impact on health related quality of life (HRQL) during the first year after minor extremity injury and to determine whether there is a difference in recovery patterns and return to work between upper extremity injuries (UEI) and lower extremity injuries (LEI). Method: A total of 181 adults’ age 18 years or older randomly selected from patients admitted to an emergency department with minor injuries were studied. HRQL was measured using the Functional Status Questionnaire (FSQ) at 1–2 weeks, 3, 6, and 12-months post-injury. Pre-injury FSQ scores were measured retrospectively at admission. A quasi-least square (QLS) model was constructed to examine differences of FSQ scores at each measuring point for UEI and LEI. Results: Fractures of the knee/lower leg (25%) were the most frequently injured body area. Slips or falls (57%) and traffic-related events (22%) were the most common injury causes. The mean ISS was 4.2 (SD 0.86). Both groups had significant declines in the FSQ scores physical and social functioning at 1–2 weeks after injury. Patients with UEI made larger improvements in the first 3 months post-injury versus patients with LEI whose improvements extended over the first 6 months. None of the groups reached the pre-injury FSQ scores during the first post-injury year except in the subscale work performance where UEI exceeded the pre-injury scores. At 12 months post-injury, significant lower FSQ scores remained in the LEI group compared to the UEI group in intermediate activities of daily living (p = 0.036, d 0.4) and work performance (p = 0.004, d 0.7). The return to work at 3 months and 12 months were 76% and 88% for UEI and 58% and 77% for LEI. No significant differences were found between groups in the FSQ scale mental health and social interaction. Conclusions: LEI had the highest impact on HRQL and return to work during the first year which exceeded the consequences of UEI. These findings contribute to the information about the consequences of injury in order to give sufficient prognostic information to patients and different stakeholders. Future investigations should aim to investigate specific minor extremity injuries and identify factors that facilitate recovery and return to work

Prospective Clinical Trial for Septic Arthritis:Cartilage Degradation and Inflammation Are Associated with Upregulation of Cartilage Metabolites

Background. Intra-articular infections can rapidly lead to osteoarthritic degradation. The aim of this clinical biomarker analysis was to investigate the influence of inflammation on cartilage destruction and metabolism. Methods. Patients with acute joint infections were enrolled in a prospective clinical trial and the cytokine composition of effusions (n=76) was analyzed. Characteristics of epidemiology and disease severity were correlated with levels of cytokines with known roles in cartilage turnover and degradation. Results. Higher synovial IL-1β concentrations were associated with clinical parameters indicating a higher disease severity (p<0.03) excluding the incidence of sepsis. Additionally, intra-articular IL-1β levels correlated with inflammatory serum parameters as leucocyte counts (LC) and C-reactive protein concentrations (p<0.05) but not with age or comorbidity. Both higher LC and synovial IL-1β levels were associated with increased intra-articular collagen type II cleavage products (C2C) indicating cartilage degradation. Joints with preinfectious lesions had higher C2C levels. Intra-articular inflammation led to increased concentrations of typical cartilage metabolites as bFGF, BMP-2, and BMP-7. Infections with Staphylococcus species induced higher IL-1β expression but less cartilage destruction than other bacteria. Conclusion. Articular infections have bacteria-specific implications on cartilage metabolism. Collagen type II cleavage products reliably mark destruction, which is associated with upregulation of typical cartilage turnover cytokines. This trial is registered with DRKS00003536, MISSinG

Consumption of the Total Western Diet Promotes Colitis and Inflammation-Associated Colorectal Cancer in Mice

Consumption of a Western type diet is a known risk factor for colorectal cancer. Our group previously developed the total Western diet (TWD) for rodents with energy and nutrient profiles that emulate a typical Western diet. In this study, we tested the hypothesis that consumption of the TWD would enhance colitis, delay recovery from gut injury and promote colon tumorigenesis. In multiple experiments using the azoxymethane + dextran sodium sulfate or ApcMin/+ mouse models of colitis-associated colorectal carcinogenesis (CAC), we determined that mice fed TWD experienced more severe and more prolonged colitis compared to their counterparts fed the standard AIN93G diet, ultimately leading to markedly enhanced colon tumorigenesis. Additionally, this increased tumor response was attributed to the micronutrient fraction of the TWD, and restoration of calcium and vitamin D to standard amounts ameliorated the tumor-promoting effects of TWD. Finally, exposure to the TWD elicited large scale, dynamic changes in mRNA signatures of colon mucosa associated with interferon (IFN) response, inflammation, innate immunity, adaptive immunity, and antigen processing pathways, among others. Taken together, these observations indicate that consumption of the TWD markedly enhanced colitis, delayed recovery from gut injury, and enhanced colon tumorigenesis likely via extensive changes in expression of immune-related genes in the colon mucosa

Mycotoxins that Affect the North American Agri-Food Sector: State of the Art and Directions for the Future

This paper summarises workshop discussions at the 5th international MYCORED meeting in Ottawa, Canada (June 2012) with over 200 participants representing academics, government and industry scientists, government officials and farming organisations (present in roughly equal proportions) from 27 countries. Workshops centred on how mycotoxins in food and feed affect value chains and trade in the region covered by the North American Free Trade Agreement. Crops are contaminated by one or more of five important mycotoxins in parts of Canada and the United States every year, and when contaminated food and feed are consumed in amounts above tolerable limits, human and animal health are at risk. Economic loss from such contamination includes reduced crop yield, grain quality, animal productivity and loss of domestic and export markets. A systematic effort by grain producers, primary, transfer, and terminal elevators, millers and food and feed processers is required to manage these contaminants along the value chain. Workshops discussed lessons learned from investments in plant genetics, fungal genomics, toxicology, analytical and sampling science, management strategies along the food and feed value chains and methods to ameliorate the effects of toxins in grain on animal production and on reducing the impact of mycotoxins on population health in developing countries. These discussions were used to develop a set of priorities and recommendations