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Inhibitory effects of 4,5-didehydrogeranylgeranoic acid (dGGA) on the development of tumors were investigated in spontaneous hepatoma mice, C3H/HeNCrj. Experiment 1: Male mice at 8 weeks of age were raised on a basal diet, and then provided with a diet containing 0.02% dGGA from 32 to 91 weeks of age. Experiment 2: dGGA was administered to the animals only once at different time points, from 2 months to 17 months after birth, respectively. Experiment 3: dGGA was administered twice to the mice at different time points: at 5 months and 11 months, and at 8 months and 11 months, respectively. When the inhibitory effects on tumor development were evaluated with the incidences of tumors, average numbers, and weight of tumors per mouse, there was a marked relationship between the time of single or dual dosing and the inhibitory effects of dGGA. The greatest inhibitory effects were observed in Experiment 3 in the group of animals given dGGA at the ages of 8 and 11 months, which were far superior to the results with a large dose of the compounds for a long time. These results might indicate that dGGA administered at the right time in the right amount effectively prevents the development of cancer.

Inhibitory effects of 4,5-didehydrogeranylgeranoic acid (dGGA) on the development of tumors were investigated in spontaneous hepatoma mice, C3H/HeNCrj. Experiment 1: Male mice at 8 weeks of age were raised on a basal diet, and then provided with a diet containing 0.02% dGGA from 32 to 91 weeks of age. Experiment 2: dGGA was administered to the animals only once at different time points, from 2 months to 17 months after birth, respectively. Experiment 3: dGGA was administered twice to the mice at different time points: at 5 months and 11 months, and at 8 months and 11 months, respectively. When the inhibitory effects on tumor development were evaluated with the incidences of tumors, average numbers, and weight of tumors per mouse, there was a marked relationship between the time of single or dual dosing and the inhibitory effects of dGGA. The greatest inhibitory effects were observed in Experiment 3 in the group of animals given dGGA at the ages of 8 and 11 months, which were far superior to the results with a large dose of the compounds for a long time. These results might indicate that dGGA administered at the right time in the right amount effectively prevents the development of cancer. [ABSTRACT FROM AUTHOR]

IntroductionIn humans, adversity in childhood exerts enduring effects on brain and increases the vulnerability to psychiatric diseases. It also leads to a higher risk of eating disorders and obesity. Maternal separation (MS) in mice has been used as a proxy of stress during infancy. We hypothesized that MS in mice affects motivation to obtain palatable food in adulthood and changes gene expression in reward system.MethodsMale and female pups from C57Bl/6J and C3H/HeN mice strains were subjected to a daily MS protocol from postnatal day (PND) 2 to PND14. At adulthood, their motivation for palatable food reward was assessed in operant cages.ResultsCompared to control mice, male and female C3H/HeN mice exposed to MS increased their instrumental response for palatable food, especially when the effort required to obtain the reward was high. Importantly, this effect is shown in animals fed ad libitum. Transcriptional analysis revealed 375 genes differentially expressed in the nucleus accumbens of male MS C3H/HeN mice compared to the control group, some of these being associated with the regulation of the reward system (e.g., Gnas, Pnoc). Interestingly, C57Bl/6J mice exposed to MS did not show alterations in their motivation to obtain a palatable reward, nor significant changes in gene expression in the nucleus accumbens.ConclusionMS produces long-lasting changes in motivation for palatable food in C3H/HeN mice, but has no impact in C57Bl/6J mice. These behavioral alterations are accompanied by drastic changes in gene expression in the nucleus accumbens, a key structure in the regulation of motivational processes.

Geranylgeranoic acid (GGA) has been developed as a preventive agent against second primary hepatoma. Recently, GGA was reported to induce cell death in human hepatoma cells via TLR4-mediated pyroptosis. We have reported that GGA is enzymatically biosynthesized from mevalonic acid in human hepatoma-derived cells and that endogenous GGA is found in most organs of rats. In addition, we found that upregulation of endogenous GGA levels by zaragozic acid A (ZAA) induced cell death in human hepatoma-derived cells. Therefore, we investigated the age-related changes in hepatic GGA and the possibility of suppressing hepatocarcinogenesis by GGA supplementation using male C3H/HeN mice that spontaneously develop hepatoma. We measured endogenous GGA and mRNA of monoamine oxidase (BMAOB), a key enzyme of GGA biosynthesis, in the liver of male C3H/HeN mice aged 6–93 weeks. We also tried suppressing spontaneous hepatocarcinogenesis by a single administration of GGA to C3H/HeN mice. Hepatic GGA content and Maob mRNA expression level age-dependently decreased in male C3H/HeN mice; some of which produced spontaneous hepatoma in 2 years. A single oral administration of GGA at 11 months of age significantly prevented hepatoma in terms of the number and weight of tumors per mouse at 24 months. Oral supplementation with GGA or geranylgeraniol significantly increased endogenous hepatic GGA contents dose-dependently; and ZAA dramatically upregulated hepatic GGA. In this study; we found an age-dependent decrease in hepatic endogenous GGA in male C3H/HeN mice and efficient prevention of spontaneous hepatoma by a single administration of GGA at 11 months of age.

Rocky Mountain spotted fever (RMSF) is a life-threatening tick-borne disease caused by Rickettsia rickettsii, which is widely distributed throughout the Americas. Over 4000 cases of RMSF are recorded annually in the United States, while only around 100 cases are reported in Brazil. Conversely, while case fatality rates in the United States oscillate around 5%, in Brazil they can surpass 70%, suggesting that differences in tick vectoring capacity, population sensitivity, and/or variability in virulence of the rickettsial strains may exist. In this study, we compared the susceptibility of C3H/HeN mice to two highly virulent strains of R. rickettsii, one from the United States (Sheila Smith) and the other from Brazil (Taiaçu). Animals inoculated with the Taiaçu strain succumbed to infection earlier and exhibited severe histological lesions in both liver and spleen sooner than mice infected with the Sheila Smith strain. These differences in survival and signs of the disease are not related to a greater proliferation of the Taiaçu strain, as there were no significant differences in the rickettsial load in mice tissues inoculated with either strain. The present study is the first step to experimentally assess differences in fatality rates of RMSF in two different regions of the American continent.

To elucidate the genetic events that occur during the development of OSCC, the present study established a model of oral malignancy using a mouse oral squamous cell carcinoma (OSCC) Sq‑1979 cell line. Sq‑1979 cells were implanted into syngeneic C3H mice. Subsequently, 233 cells and metastatic sub‑clones (L cells) from primary OSCC, as well as the metastasized lymph node tissues of Sq‑1979‑implanted mice were established. Compared with parental Sq‑1979 and 233 cells, the majority of L cells exhibited a higher proliferation rate and transplantability, and conferred a lower survival rate on the implanted mice. To investigate the genetic background of L cells, preferentially expressed genes in L cells were identified by cDNA microarray and reverse transcription‑polymerase chain reaction analyses. The expression of FYN‑binding protein (Fyb), solute carrier family 16 member 13 (Slc16a13), keratin 7, transmembrane portion 173 and Slc44a3 mRNAs was significantly elevated in L cells compared with that in Sq1979 and 233 cells. The mRNA expression was also evaluated in human OSCC and leukoplakia (LP) tissues. Among the 5 aforementioned mRNAs, the expression of FYB and SLC16A13 was significantly higher in OSCC than in LP tissues. Furthermore, the expression of SLC16A13 mRNA was significantly elevated in highly invasive OSCCs, which were classified as grades 3 and 4 by the Yamamoto‑Kohama (YK) classification of invasion, compared with those in lower grades (YK‑1 and ‑2). The model proposed in the present study could thus describe essential marker genes for the diagnosis of oral malignancies. [ABSTRACT FROM AUTHOR]

Introduction: In humans, adversity in childhood exerts enduring effects on brain and increases the vulnerability to psychiatric diseases. It also leads to a higher risk of eating disorders and obesity. Maternal separation (MS) in mice has been used as a proxy of stress during infancy. We hypothesized that MS in mice affects motivation to obtain palatable food in adulthood and changes gene expression in reward system., Methods: Male and female pups from C57Bl/6J and C3H/HeN mice strains were subjected to a daily MS protocol from postnatal day (PND) 2 to PND14. At adulthood, their motivation for palatable food reward was assessed in operant cages., Results: Compared to control mice, male and female C3H/HeN mice exposed to MS increased their instrumental response for palatable food, especially when the effort required to obtain the reward was high. Importantly, this effect is shown in animals fed ad libitum . Transcriptional analysis revealed 375 genes differentially expressed in the nucleus accumbens of male MS C3H/HeN mice compared to the control group, some of these being associated with the regulation of the reward system (e.g., Gnas , Pnoc ). Interestingly, C57Bl/6J mice exposed to MS did not show alterations in their motivation to obtain a palatable reward, nor significant changes in gene expression in the nucleus accumbens., Conclusion: MS produces long-lasting changes in motivation for palatable food in C3H/HeN mice, but has no impact in C57Bl/6J mice. These behavioral alterations are accompanied by drastic changes in gene expression in the nucleus accumbens, a key structure in the regulation of motivational processes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Benoit, Henry, Fneich, Mathou, Xia, Foury, Jouin, Junien, Capuron, Jouneau, Moisan, Delpierre, Gabory and Darnaudéry.)

Introduction: Clonorchis sinensis is one of the most important foodborne pathogens in humans, and can cause biliary diseases such as gallstones, cholecystitis, cholangitis, and cholangiocarcinoma. Toll-like receptors (TLRs) as sensors are crucial to initiating both innate and adaptive immune defenses against pathogens. However, little is known about the hepatic expression of TLRs of hosts induced by C. sinensis infection. Methodology: In the present study, the expression and distribution of TLR2 and TLR4 were investigated in a mouse model of clonorchiasis on days 28, 56, 84, and 112 post-infection (PI) using real-time quantitative reverse transcription polymerase chain reaction (PCR) and immunohistochemically staining, respectively. The levels of cytokines that are mediated by TLR2 and TLR4 were also evaluated using a cytometric bead array. Results: Results showed that the transcripts of TLR2 and TLR4 were upregulated on day 28 PI in C. sinensis-infected mice compared with non-infected ones (p < 0.01). In addition, their proteins were strongly immunohistochemically positive in the cytoplasm and membrane of endothelial cells, fibroblasts, and biliary epithelium cells of C. sinensis-infected mice. The levels of interleukin (IL)-4, IL-10, tumor necrosis factor alpha (TNF-a) and interferon gamma (IFN-?) were increased with activation of TLR2 and TLR4. Conclusions: The expression of TLR2 and TLR4 is upregulated against C. sinensis infection, which suggests that TLR2 and TLR4 might be involved in immune responses during C. sinensis infection. [ABSTRACT FROM AUTHOR]

Objective: Three modeling methods were used to establish a mouse primary liver cancer model, and compared them to find a more optimal modeling method. Methods: Forty 15-day-old C3H/HeN male mice were randomly divided into groups I-IV, 10 mice in each group. Group Ⅰ were not treated; Group Ⅱ were intraperitoneally injected with 25 mg/kg diethylnitrosamine (DEN) once; Group Ⅲ were intraperitoneally injected with 100 mg/kg DEN once; Group Ⅳ were intraperitoneally injected with 25 mg/kg DEN once and followed by another intraperitoneal injection of 100 mg/kg DEN at 42 days of age. The mortality of mice in each group was analyzed. At the 18th week of modeling, blood was collected from eyeballs after anesthesia, and liver was taken from abdominal cavity after neck was broken. The appearance of liver, the number of cancer nodules and the incidence of liver tumor were observed. The histopathological changes of liver were observed by HE staining. The serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were detected. Results: At the 18th week of modeling, compared with the group I, serum levels of ALT and AST in groups II-IV were increased significantly ( P ＜0.05); The number of cancer nodules and the incidence of tumors in the surviving mice of groups III and IV were also increased significantly ( P ＜0.05). At the 18th week of modeling, no mice died in both groups I and II, and the incidence of liver cancer was 0%; The incidence of liver cancer in surviving mice in both groups III and IV was 100%, but the mortality rate of mice in group III was as high as 50%, and that in group IV was only 20%. Conclusion: C3H/HeN male mice can successfully establish a mouse liver cancer model by intraperitoneal injection of 25 mg/kg of DEN once at the age of 15 days and another intraperitoneal injection of 100 mg/kg of DEN once at the age of 42 days with short cycle and low mortality, which is an ideal method to establish a primary liver cancer model.

The pineal hormone melatonin activates two G-protein coupled receptors (MT1 and MT2) to regulate in part biological functions. The MT1 and MT2 melatonin receptors are heterogeneously distributed in the mammalian brain including humans. In the mouse, only a few reports have assessed the expression of the MT1 melatonin receptor expression using 2-iodomelatonin binding, in situ hybridization and/or polymerase chain reaction (PCR). Here, we described a transgenic mouse in which red fluorescence protein (RFP) is expressed under the control of the endogenous MT1 promoter, by inserting RFP cDNA at the start codon of MTNR1a gene within a bacterial artificial chromosome (BAC) and expressing this construct as a transgene. The expression of RFP in the brain of this mouse was examined either directly under a fluorescent microscope or immunohistochemically using an antibody against RFP (RFP-MT1). RFP-MT1 expression was observed in many brain regions including the subcommissural organ, parts of the ependyma lining the lateral and third ventricles, the aqueduct, the hippocampus, the cerebellum, the pars tuberalis, the habenula and the habenula commissure. This RFP-MT1 transgenic model provides a unique tool for studying the distribution of the MT1 receptor in the brain of mice, its cell-specific expression and its function in vivo. [ABSTRACT FROM PUBLISHER]

Objectives: Intake of dietary fibers promotes the production of short-chain fatty acids (SCFAs), which can affect host inflammation via gut microbial fermentation. Although partially hydrolyzed guar-gum (PHGG) is a water-soluble dietary fiber with lower viscosity, its benefits in acute inflammation are yet to be determined. The aim of this study was to investigate the effect of PHGG intake on the lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-α production., Methods: Nine-wk-old male C3 H/HeN mice were used in this study, and they were randomly divided into control diet (CD) and CD + 5% PHGG (GGCD) groups. After a dietary intervention of 6 wk, LPS (1 mg/kg) was injected into the orbital vein. Plasma TNF-α concentration and SCFAs in cecum contents were then measured. Also, the effect of gut microbiota on LPS-induced TNF-α production was evaluated in PHGG-fed mice before and after antibiotic treatment., Results: PHGG intake accelerated a dramatic suppression of LPS-induced TNF-α production (P < 0.01). PHGG-induced low pH in feces (P < 0.05) indicates that the gut microbiota induced high fermentation. Indeed, SCFAs in cecum contents of GGCD mice were significantly higher than in the CD group (P < 0.05). Furthermore, PHGG intake after antibiotic treatment did not induce the suppression of TNF-α., Conclusion: These results demonstrated that inflammation was inhibited by habitual PHGG ingestion, suggesting that this phenomenon might be associated with changes in gut microbiota-induced SCFAs production., (Copyright © 2022 Elsevier Inc. All rights reserved.)

It remains unclear whether immune response to viral infection is inhibited by severe exercise. We determined whether exhaustive exercise inhibits interferon (IFN)-β and tumor necrosis factor (TNF)-α production after injection of synthetic double-stranded (ds) RNAs, a polyriboinosinic polyribocytidylic acid (poly I:C), as viral infection model. Male C3H/HeN mice, which were divided into exhaustive-exercised and non-exercised groups, were injected with poly I:C (5 mg/kg). Although TNF-α in response to poly I:C was significantly inhibited by exhaustive exercise, IFN-β was no different in both groups. In in-vitro experiments, catecholamines inhibited poly I:C-induced TNF-α, but not IFN-β, production in macrophages. These results suggest that anti-virus cytokine IFN-β in response to poly I:C might be maintained despite severe stressful exercise. [ABSTRACT FROM AUTHOR]

Abstract: Synthetic oligodeoxynucleotides containing unmethylated CpG motifs (CpG-ODN) have been characterized as Th1-promoting immunopotentiators, an adjuvant activity desirable for vaccination against intracellular parasites like Toxoplasma gondii. In an attempt to find new antigen–adjuvant combinations that enhance the immunogenicity of antigen candidates for toxoplasma vaccines, we analyzed the extent of protection in mice immunized with ROP2 and GRA4 recombinant proteins when co-administered with CpG-ODN. Both GRA4+CpG-ODN and ROP2+CpG-ODN formulations were shown to induce a strong humoral Th1-biased response characterized by a high IgG2a to IgG1 antibody ratio. Both vaccination regimens led to increased secretion of IFN-γ and IL-10, and negligible amounts of IL-4, upon specific re-stimulation of spleen cells from these groups of mice. After a non-lethal challenge with tissue cysts of a moderately virulent strain, only the brains from mice vaccinated with ROP2 or GRA4 in combination with CpG-ODN showed a significant reduction (63% and 62%, respectively) in their parasite load compared to the controls. The rate of protection obtained with GRA4+ROP2+CpG-ODN resulted equivalent (66%) to those achieved with the single antigens plus CpG-ODN. Taken together, these results indicate that CpG-ODN is an important candidate adjuvant for use in potential multicomponent anti-T. gondii vaccines for animals and humans. [Copyright &y& Elsevier]

Stressful exercise results in temporary immune depression. However, the impact of exercise on the immune responses via toll-like receptor (TLR) 7, which recognizes the common viral genomic feature, single-stranded RNA, remains unclear. To clarify the effect of stressful exercise on immune function in response to viral infection, we measured the changes in the plasma concentration of tumor necrosis factor (TNF)-α and interferon (IFN)-α, which are induced downstream from the TLR-ligand interaction, in exhaustive-exercised mice immediately after treatment with the imidazoquinoline R-848, which can bind to and activate TLR7. Both exhaustive-exercised (EX) and non-exercised (N-EX) male C3H/HeN mice were injected with R-848 (5 mg kg(-1)), and blood samples were collected. In addition, RAW264 cells, which are mouse macrophage cells, were cultured 30 min after epinephrine (10 μM) or norepinephrine (10 μM) treatments, and were then stimulated with R-848 (10 μg ml(-1)). In addition, the effect of propranolol (10 mg kg(-1)) as blockade of β-adrenergic receptors on R-848-induced TNF-α and IFN-α production in the exercised mice was examined. Both the TNF-α and IFN-α concentrations in the plasma of EX were significantly lower than those in the plasma of N-EX after R-848 injection (P < 0.05 and P < 0.01, respectively), although the R-848 treatment increased the plasma TNF-α and IFN-α concentrations in both groups (P < 0.01, respectively). The R-848-induced TNF-α production in RAW264 cells was significantly inhibited by epinephrine and norepinephrine pre-treatment, although IFN-α was not detected. The propranolol treatment completely inhibited exercise-induced TNF-α and IFN-α suppression in response to R-848 in the mice. These data suggest that EX induces a reduction in TNF-α and IFN-α production in response to R-848, and that these phenomena might be regulated by an exercise-induced elevation of the systemic catecholamines. [ABSTRACT FROM AUTHOR]

Abstract: Persistent exposure to inorganic lead (Pb) is known to adversely affect the immune system. In the present study, we assessed the effect of chronic Pb exposure on susceptibility to infection by the facultative intracellular pathogen Salmonella enterica serovar Typhimurium. Mice were exposed to 10 mM Pb-acetate in drinking water for ∼16 weeks, resulting in a significant level of Pb in the blood (106.2±8.9 μg/dl). Pb exposure rendered mice susceptible to Salmonella infection, manifested by increased bacterial burden in target organs and heightened mortality. Flow cytometric analysis of the splenic cellular composition in normal and Pb-exposed mice revealed no gross alteration in the ratios of B and T lymphocytes or myeloid cells. Similarly, the capacity of B and T cells to upregulate the expression of activation antigens in response to mitogenic or inflammatory stimuli was not hindered by Pb exposure. Analysis of the ability of ex vivo-cultured splenocytes to secrete cytokines demonstrated a marked reduction in IFN-γ and IL-12p40 production associated with Pb exposure. In contrast, secretion of IL-4 by splenocytes of Pb-treated mice was 3- to 3.6-fold higher than in normal mice. The increased capacity to produce IL-4 correlated with a shift in the in vivo anti-Salmonella antibody response from the protective IgG2a isotype to the Th2-induced IgG1 isotype. We conclude that chronic exposure to high levels of Pb results in a state of immunodeficiency which is not due to an overt cytotoxic or immunosuppressive mechanism, but rather is largely caused by a shift in immune responsiveness to Th2-type reactions. [Copyright &y& Elsevier]

We previously reported an antidepressant-like effect in C3H/HeN mice during the forced swimming test (FST) following treatment with the MT1/MT2 melatonin receptor ligand, luzindole. This study investigated the role melatonin receptors (MT1 and/or MT2) may play in the effect of luzindole in the FST using C3H/HeN mice with a genetic deletion of either MT1 (MT1KO) or MT2 (MT2KO) melatonin receptors. In the light phase (ZT 9–11), luzindole (30 mg/kg, i.p.) significantly decreased immobility during swimming in both wild type (WT) (135.6 ± 25.3 s, n = 7) and MT1KO (132.6 ± 13.3 s, n = 8) as compared with vehicle-treated mice (WT: 207.1 ± 6.0 s, n = 7; MT1KO: 209.5 ± 6.2 s, n = 8) ( P < 0.001). In the dark phase (ZT 20–22), luzindole also decreased time of immobility in both WT (89.5 ± 13.9 s, n = 8) and MT1KO (66.5 ± 6.4 s, n = 8) mice as compared with the vehicle treated (WT: 193.8 ± 3.5, n = 6; MT1KO: 176.6 ± 6.2 s, n = 8) ( P < 0.001). Genetic disruption of the MT1 gene did not alter the diurnal rhythm of serum melatonin in MT1KO mice (ZT 9–11: 1.3 ± 0.6 pg/mL, n = 7; ZT 20–22: 10.3 ± 1.1 pg/mL, n = 8) as compared with WT (ZT 9–11: 1.4 ± 0.7 pg/mL; ZT 20–22: 10.6 pg/mL). Swimming did not alter the serum melatonin diurnal rhythm in WT and MT1KO mice. Decreases in immobility of WT and MT1KO mice by luzindole treatment were not affected by gender or age (3 months versus 8 months). In contrast, luzindole did not decrease immobility during the FST in MT2KO mice. We conclude that the antidepressant-like effect of luzindole may be mediated through blockade of MT2 rather than MT1 melatonin receptors. [ABSTRACT FROM AUTHOR]

Geranylgeranoic acid (GGA) has been developed as a preventive agent against second primary hepatoma. Recently, GGA was reported to induce cell death in human hepatoma cells via TLR4-mediated pyroptosis. We have reported that GGA is enzymatically biosynthesized from mevalonic acid in human hepatoma-derived cells and that endogenous GGA is found in most organs of rats. In addition, we found that upregulation of endogenous GGA levels by zaragozic acid A (ZAA) induced cell death in human hepatoma-derived cells. Therefore, we investigated the age-related changes in hepatic GGA and the possibility of suppressing hepatocarcinogenesis by GGA supplementation using male C3H/HeN mice that spontaneously develop hepatoma. We measured endogenous GGA and mRNA of monoamine oxidase (BMAOB), a key enzyme of GGA biosynthesis, in the liver of male C3H/HeN mice aged 6–93 weeks. We also tried suppressing spontaneous hepatocarcinogenesis by a single administration of GGA to C3H/HeN mice. Hepatic GGA content and Maob mRNA expression level age-dependently decreased in male C3H/HeN mice; some of which produced spontaneous hepatoma in 2 years. A single oral administration of GGA at 11 months of age significantly prevented hepatoma in terms of the number and weight of tumors per mouse at 24 months. Oral supplementation with GGA or geranylgeraniol significantly increased endogenous hepatic GGA contents dose-dependently; and ZAA dramatically upregulated hepatic GGA. In this study; we found an age-dependent decrease in hepatic endogenous GGA in male C3H/HeN mice and efficient prevention of spontaneous hepatoma by a single administration of GGA at 11 months of age. [ABSTRACT FROM AUTHOR]

Enteropathogenic and enterohemorrhagic Escherichia coli are important enteric pathogens that induce hemorrhagic colitis or even fatal hemolytic uremic syndrome. Emerging evidence shows that some bio-actives derived from fruits and vegetables may serve as alternatives to antibiotics for overcoming multidrug resistant E. coli infections. In this study, the Citrobacter rodentium (Cr) infection model was utilized to mimic E. coli-induced acute intestinal inflammation, and the effects of a cruciferous vegetable-derived cancer protective compound, indole-3-carbinol (I3C), on the immune responses of Cr-susceptible C3H/HeN mice were investigated. Dietary I3C significantly inhibited the loss of body weight and the increase in spleen size in Cr infected mice. In addition, I3C treatment reduced the inflammatory response to Cr infection by maintaining anti-inflammatory cytokine IL-22 mRNA levels while reducing expression of other pro-inflammatory cytokines including IL17A, IL6, IL1β, TNF-α, and IFN-γ. Moreover, the serum cytokine levels of IL17, TNF-α, IL12p70, and G-CSF also were down-regulated by I3C in Cr-infected mice. Additionally, dietary I3C specifically enhanced the Cr-specific IgG response to Cr infection. In general, dietary I3C reduced the Cr-induced pro-inflammatory response in susceptible C3H/HeN mice and alleviated the physiological changes and tissue damage induced by Cr infection but not Cr colonization. [ABSTRACT FROM AUTHOR]

Rocky Mountain spotted fever (RMSF) is a life-threatening tick-borne disease caused by Rickettsia rickettsii, which is widely distributed throughout the Americas. Over 4000 cases of RMSF are recorded annually in the United States, while only around 100 cases are reported in Brazil. Conversely, while case fatality rates in the United States oscillate around 5%, in Brazil they can surpass 70%, suggesting that differences in tick vectoring capacity, population sensitivity, and/or variability in virulence of the rickettsial strains may exist. In this study, we compared the susceptibility of C3H/HeN mice to two highly virulent strains of R. rickettsii, one from the United States (Sheila Smith) and the other from Brazil (Taiaçu). Animals inoculated with the Taiaçu strain succumbed to infection earlier and exhibited severe histological lesions in both liver and spleen sooner than mice infected with the Sheila Smith strain. These differences in survival and signs of the disease are not related to a greater proliferation of the Taiaçu strain, as there were no significant differences in the rickettsial load in mice tissues inoculated with either strain. The present study is the first step to experimentally assess differences in fatality rates of RMSF in two different regions of the American continent. [ABSTRACT FROM AUTHOR]

Traditional pathogenesis studies of alphaviruses involves monitoring survival, viremia, and pathogen dissemination via serial necropsies; however, molecular imaging shifts this paradigm and provides a dynamic assessment of pathogen infection. Positron emission tomography (PET) with PET tracers targeted to study neuroinflammation (N,N-diethyl-2-[4-phenyl]-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-acetamide, [18F]DPA-714), apoptosis (caspase-3 substrate, [18F]CP-18), hypoxia (fluormisonidazole, [18F]FMISO), blood–brain barrier (BBB) integrity ([18F]albumin), and metabolism (fluorodeoxyglucose, [18F]FDG) was performed on C3H/HeN mice infected intranasally with 7000 plaque-forming units (PFU) of Venezuelan equine encephalitis virus (VEEV) TC-83. The main findings are as follows: (1) whole-brain [18F]DPA-714 and [18F]CP-18 uptake increased three-fold demonstrating, neuroinflammation and apoptosis, respectively; (2) [18F]albumin uptake increased by 25% across the brain demonstrating an altered BBB; (3) [18F]FMISO uptake increased by 50% across the whole brain indicating hypoxic regions; (4) whole-brain [18F]FDG uptake was unaffected; (5) [18F]DPA-714 uptake in (a) cortex, thalamus, striatum, hypothalamus, and hippocampus increased through day seven and decreased by day 10 post exposure, (b) olfactory bulb increased at day three, peaked day seven, and decreased day 10, and (c) brain stem and cerebellum increased through day 10. In conclusion, intranasal exposure of C3H/HeN mice to VEEV TC-83 results in both time-dependent and regional increases in brain inflammation, apoptosis, and hypoxia, as well as modest decreases in BBB integrity; however, it has no effect on brain glucose metabolism. [ABSTRACT FROM AUTHOR]

Mediterranean spotted fever develops from an infection with Rickettsia conorii, an obligate intracellular, Gram-negative, endotheliotropic, and tick-transmitted bacterial pathogen, and is an acute, febrile illness that can progress to life-threatening complications if not diagnosed and treated early with effective antibiotics. Despite significant morbidity and mortality, little is known about changes in gene expression that determine the host responses during in vivo infection. We have investigated the transcriptional landscape of host lungs as a prominently affected organ system in an established murine model of infection by RNA-sequencing. Ingenuity pathway analysis resulted in the identification of 1332 differentially expressed genes and 292 upstream regulators. Notably, genes encoding for ubiquitin D, aconitate decarboxylase, antimicrobial peptides, calgranulins, cytokines and chemokines, and guanylate binding proteins were highly up-regulated, whereas those involved in hemoglobin biosynthesis and heme homeostasis were significantly down-regulated. Amongst response regulators, nucleotide-binding oligomerization domain-containing protein 2 and killer cell lectin-like receptors were differentially expressed, and gene clustering revealed eukaryotic initiation factor-2, oxidative phosphorylation, and ubiquitination as the predominantly activated biological pathways. Collectively, this first global transcriptomic profiling has identified R. conorii-induced regulation of novel genes and pathways in the host lungs, further in-depth investigation of which will strengthen our understanding of the pathogenesis of human rickettsioses. [ABSTRACT FROM AUTHOR]

Spotted fever group (SFG) rickettsial species are obligate intracellular tick-borne pathogens that are responsible for important human diseases. Previous reports have demonstrated the feasibility of using recombinant surface cell antigen Sca5/OmpB to elicit protective immunity against homologous challenges using murine models of Mediterranean spotted fever and Rocky Mountain spotted fever. In addition, the feasibility of generating cross-protective immunity against related rickettsial species has also been established, but the molecular basis for these phenomena was not explored. Here, we demonstrate that vaccination of C3H/HeN mice with a recombinant OmpB domain derived from Rickettsia conorii induced high titer humoral immune responses that are capable of recognizing the native OmpB protein at the R. rickettsii outer membrane, but this immunization was not sufficient to induce effective protective immunity. In contrast, animals vaccinated with a corresponding OmpB domain derived from R. rickettsii protected animals from fatal outcomes. These results demonstrate that vaccination with nearly identical antigens may not be an effective strategy to induce wide-ranging protective immunity against related SFG Rickettsia species., (© FEMS 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)