Publications by authors named "José Ricardo Jensen"

12 Publications

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Liver gene regulation of hemostasis-related factors is altered by experimental snake envenomation in mice.

PLoS Negl Trop Dis 2020 06 1;14(6):e0008379. Epub 2020 Jun 1.

Laboratory of Pathophysiology, Butantan Institute, São Paulo, São Paulo, Brazil.

Few studies have addressed gene expression of hemostasis-related factors during acute thrombo-hemorrhagic diseases. Bites by the lanced-headed viper Bothrops jaracaca induce rapid hemostatic disturbances in victims, leading to systemic bleedings, thrombocytopenia and consumption coagulopathy. Although circulating levels of coagulation factors recover rapidly after administration of specific antivenom therapy, it is unclear if B. jararaca venom (BjV) upregulates the mRNA synthesis of hepatic hemostasis-related factors, or if the recovery occurs under basal conditions after the neutralization of venom components by antivenom. Thus, we aimed to investigate if BjV regulates gene expression of important hemostasis-related factors synthetized by the liver. On that account, Swiss mice were injected with saline or BjV (1.6 mg/kg b.w, s.c.), and after 3, 6 and 24 h blood samples and liver fragments were collected to analyze mRNA expression by real-time qPCR. Increased gene expression of fibrinogen chains, haptoglobin and STAT3 was observed during envenomation, particularly at 3 and 6 h. At 24h, mRNA levels of F10 were raised, while those of Serpinc1, Proc and Adamts13 were diminished. Surprisingly, F3 mRNA levels were steadily decreased at 3 h. Gene expression of Thpo, F7, F5 Tfpi, Mug1 was unaltered. mRNA levels of Vwf, P4hb, F8, F2, Plg, and Serpinf2 were minimally altered, but showed important associations with Nfkb1 gene expression. In conclusion, snakebite envenomation upregulates hepatic mRNA synthesis particularly of fibrinogen chains, and acute-phase markers. This response explains the fast recovery of fibrinogen levels after antivenom administration to patients bitten by B. jararaca snakes.
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http://dx.doi.org/10.1371/journal.pntd.0008379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289449PMC
June 2020

Genetic Predisposition to Hepatocarcinogenesis in Inbred and Outbred Mouse Lines Selected for High or Low Inflammatory Response.

J Immunol Res 2019 31;2019:5298792. Epub 2019 Mar 31.

Laboratory of Immunogenetics, Instituto Butantan, São Paulo, Brazil.

AIRmax and AIRmin mouse strains phenotypically selected for high and low acute inflammatory responsiveness (AIR) are, respectively, susceptible or resistant to developing hepatocellular carcinoma (HCC) induced by the chemical carcinogens urethane and diethylnitrosamine (DEN). Early production of TNF-, IL-1, and IL-6 in the liver after DEN treatment correlated with tumor development in AIRmax mice. Transcriptome analysis of livers from untreated AIRmax and AIRmin mice showed specific gene expression profiles in each line, which might play a role in their differential susceptibility to HCC. Linkage analysis with SNP markers in F2 (AIRmax×AIRmin) intercross mice revealed two quantitative trait loci (QTL) in chromosomes 2 and 9, which are significantly associated with the number and progression of urethane-induced liver tumors. An independent linkage analysis with an intercross population from A/J and C57BL/6J inbred mice mapped regions in chromosomes 1 and 7 associated with the progression of urethane-induced liver tumors, evidencing the heterogeneity of HCC genetic control.
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http://dx.doi.org/10.1155/2019/5298792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462334PMC
August 2019

Early Peritoneal CC Chemokine Production Correlates with Divergent Inflammatory Phenotypes and Susceptibility to Experimental Arthritis in Mice.

J Immunol Res 2019 26;2019:2641098. Epub 2019 Feb 26.

Immunogenetics Laboratory, Butantan Institute, Avenida Vital Brasil, 1500, São Paulo 05503-900, Brazil.

The inflammatory and autoimmune events preceding clinical symptoms in rheumatoid arthritis (RA) and other autoimmune diseases are difficult to study in human patients. Therefore, animal models that share immunologic and clinical features with human RA, such as pristane-induced arthritis (PIA), are valuable tools for assessing the primordial events related to arthritis susceptibility. PIA-resistant HIII and susceptible LIII mice were injected i.p. with pristane, and peritoneal lavage fluid was harvested in the early (7 days) and late (35 days) preclinical phases of PIA. Chemokine and cytokine levels were measured in lavage supernatant with ELISA, peritoneal inflammatory leukocytes were immunophenotyped by flow cytometry, and gene expression was determined by qRT-PCR. Leukocyte recruitment was quantitatively and qualitatively divergent in the peritoneum of HIII and LIII mice, with an early increase of CC chemokines (CCL2/CCL3/CCL5/CCL12/CCL22) in the susceptible LIII strain. Also, cytokines such as IL-12p40, IL-23, and IL-18 were elevated in LIII mice while IL-6 was increased in HIII animals. The results show that an early peritoneal CC chemokine response is an important feature of arthritis susceptibility and defines potential biomarkers in this model.
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http://dx.doi.org/10.1155/2019/2641098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413398PMC
July 2019

miRNA Expression and Interaction with Genes Involved in Susceptibility to Pristane-Induced Arthritis.

J Immunol Res 2018 16;2018:1928405. Epub 2018 Dec 16.

Laboratório de Imunogenética, Instituto Butantan, São Paulo 05503000, Brazil.

Pristane-induced arthritis (PIA) in mice is an experimental model that resembles human rheumatoid arthritis, a chronic autoimmune disease that affects joints and is characterized by synovial inflammation and articular cartilage and bone destruction. AIRmax and AIRmin mouse lines differ in their susceptibility to PIA, and linkage analysis in this model mapped arthritis severity QTLs in chromosomes 5 and 8. miRNAs are a class of small RNA molecules that have been extensively studied in the development of arthritis. We analyzed miRNA and gene expression profiles in peritoneal cells of AIRmax and AIRmin lines, in order to evaluate the genetic architecture in this model. Susceptible AIRmax mice showed higher gene (2025 vs 1043) and miRNA (240 vs 59) modulation than resistant AIRmin mice at the onset of disease symptoms. miR-132-3p/212-3p, miR-106-5p, miR-27b-3p, and miR-25-3p were among the miRNAs with the highest expression in susceptible animals, showing a negative correlation with the expression of predicted target genes (, , and ). Our study showed that global gene and miRNA expression profiles in peritoneal cells of susceptible AIRmax and resistant AIRmin lines during pristane-induced arthritis are distinct, evidencing interesting targets for further validation.
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http://dx.doi.org/10.1155/2018/1928405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6311868PMC
April 2019

Gut dysbiosis in mice genetically selected for low antibody production.

Gut Pathog 2017 7;9:43. Epub 2017 Aug 7.

Department of Microbiology and Immunology, Institute of Biosciences of the State University of São Paulo (UNESP), Campus de Rubião Junior, Botucatu, SP 18618-961 Brazil.

Background: Dysbiosis is linked to the cause of several human diseases, many of which having an immunity related component. This work investigated whether mice genetically selected for low or high antibody production display differences in intestinal bacterial communities, and consisted in the comparison of fecal 16SV6-V8 rDNA PCR amplicons resolved by temperature gradient gel electrophoresis (TGGE) of five each of low (LIII) and high (HIII) antibody producing mice. 16SV6 rDNA amplicons of 2 mice from each line were sequenced.

Results: LIII mice were grouped in a single TGGE cluster, displayed a low α-diversity, and were distinguished by low Firmicutes/Bacteroidetes ratio.

Conclusion: The results suggest that genetically driven low antibody production in mice is associated with gut dysbiosis.
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http://dx.doi.org/10.1186/s13099-017-0193-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5547450PMC
August 2017

Distinct gene expression profiles provoked by polyacrylamide beads (Biogel) during chronic and acute inflammation in mice selected for maximal and minimal inflammatory responses.

Inflamm Res 2016 Apr 28;65(4):313-23. Epub 2016 Jan 28.

Laboratório de Imunogenética, Instituto Butantan, Avenida Vital Brasil 1500, São Paulo, SP, 05503900, Brazil.

Objective And Design: AIRmax and AIRmin mice differ in their local acute inflammatory reactions to polyacrylamide beads (Biogel). These lines were developed to identify genes that affect the intensity of the acute inflammatory response (AIR) and to investigate the cellular and molecular mechanisms of acute inflammation. Although these lines are well established, differences in their responses to chronic inflammatory Biogel exposure have not yet been described. We investigated whether the selective process that modified the acute inflammatory responses in these animals also affected the development of their chronic inflammatory responses.

Results: Inflammatory exudate cell infiltration was more intense in AIRmax than AIRmin mice at both 48 h and 30 days. Genes involved in signal transduction and immune/inflammatory responses were differentially expressed in the treated skin of AIRmax and AIRmin mice, and divergent expression of some acute inflammatory response genes was detected up to 30 days post-Biogel. However, distinct expression of several pro and anti-inflammatory response genes in both periods was observed.

Conclusion: These results indicate that the selective process for acute inflammation affected the development of chronic inflammatory responses to Biogel, suggesting common genetic control.
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http://dx.doi.org/10.1007/s00011-016-0918-1DOI Listing
April 2016

7,12-Dimethylbenz(a)anthracene-induced genotoxicity on bone marrow cells from mice phenotypically selected for low acute inflammatory response.

DNA Repair (Amst) 2016 Jan 2;37:43-52. Epub 2015 Dec 2.

Immunogenetics Laboratory, Butantan Institute, São Paulo, Brazil. Electronic address:

Exposure to polycyclic aromatic hydrocarbon (PAH) environmental contaminants has been associated with the development of mutations and cancer. 7,12-Dimethylbenz(a)anthracene ( DMBA), a genotoxic agent, reacts with DNA directly, inducing p53-dependent cytotoxicity resulting in cell death by apoptosis or giving rise to cancer. DMBA metabolism largely depends on activation of the aryl hydrocarbon receptor (AhR). Mice phenotypically selected for high (AIRmax) or low (AIRmin) acute inflammatory response present a complete segregation of Ahr alleles endowed with low (Ahr(d)) or high (Ahr(b1)) affinity to PAHs, respectively. To evaluate the role of AhR genetic polymorphism on the bone marrow susceptibility to DMBA, AIRmax and AIRmin mice were treated with a single intraperitoneal injection of DMBA (50mg/kg b.w.) in olive oil. Bone marrow cells (BMCs) were phenotyped by both flow cytometry and cytoslide preparations. Despite a significant decrease in total cell count in BM from AIRmin mice, there was an increase of blast cells and immature neutrophils at 1 and 50 days after DMBA treatment, probably due to a cell-cycle blockade at the G1/S transition leading to immature stage cell production. A panel of proteins related to cell cycle regulation was evaluated in immature BM cells (Lin(-)) by Western Blot, and DNA damage and repair were measured using an alkaline version of the Comet assay. In Lin(-) cells isolated from AIRmin mice, high levels were found in both p53 and p21 protein contents in contrast with the low levels of CDK4 and Ciclin D1. Evaluation of DNA repair in DMBA-treated BMCs, indicated long-lasting genotoxicity and cytotoxicity in BMC from AIRmin mice and a blockade of cell cycle progression. On the other hand, AIRmax mice have a high capacity of DNA damage repair and protection. These mechanisms can be associated with the differential susceptibility to the toxic and carcinogenic effects of DMBA observed in these mice.
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http://dx.doi.org/10.1016/j.dnarep.2015.11.006DOI Listing
January 2016

Trypanosoma cruzi infection in genetically selected mouse lines: genetic linkage with quantitative trait locus controlling antibody response.

Mediators Inflamm 2014 13;2014:952857. Epub 2014 Aug 13.

Laboratório de Imunogenética, Instituto Butantan, Avenida Vital Brasil 1500, 05503-900 São Paulo, SP, Brazil.

Trypanosoma cruzi infection was studied in mouse lines selected for maximal (AIRmax) or minimal (AIRmin) acute inflammatory reaction and for high (HIII) or low (LIII) antibody (Ab) responses to complex antigens. Resistance was associated with gender (females) and strain-the high responder lines AIRmax and HIII were resistant. The higher resistance of HIII as compared to LIII mice extended to higher infective doses and was correlated with enhanced production of IFN-γ and nitric oxide production by peritoneal and lymph node cells, in HIII males and females. We also analyzed the involvement of previously mapped Ab and T. cruzi response QTL with the survival of Selection III mice to T. cruzi infections in a segregating backcross [F1(HIII×LIII) ×LIII] population. An Ab production QTL marker mapping to mouse chromosome 1 (34.8 cM) significantly cosegregated with survival after acute T. cruzi infections, indicating that this region also harbors genes whose alleles modulate resistance to acute T. cruzi infection.
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http://dx.doi.org/10.1155/2014/952857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4146349PMC
May 2015

7,12-Dimethylbenz(a)anthracene-induced myelotoxicity differs in mice selected for high or low acute inflammatory response: relationship with aryl hydrocarbon receptor polymorphism.

Int J Toxicol 2014 Mar-Apr;33(2):130-42. Epub 2014 Feb 20.

Laboratório de Imunogenética, Instituto Butantan, Av Dr Vital Brazil, 1500, CEP 05503-900, São Paulo, SP, Brazil. Email:

Polycyclic aromatic hydrocarbons, such as 7,12-dimethylbenz(a)anthracene (DMBA), are environmental pollutants that exert multiple toxic and carcinogenic effects. Studies showed that these effects are mediated by activation of the aryl hydrocarbon receptor (AhR) and modulated by allelic variants of Ahr gene. Here, we investigated the effects of DMBA treatment in the inflammatory response and bone marrow (BM) hematopoietic function of maximal acute inflammatory response (AIRmax) and minimal acute inflammatory response (AIRmin) heterogeneous mouse lines selected for high and low acute inflammatory responsiveness, respectively. The phenotypic selection resulted in the segregation of the Ahr(d) and Ahr(b1) alleles that confer low and high receptor ligand-binding affinity, respectively, in AIRmax and AIRmin mice. We observed a reduction in BM mature granulocyte population in AIRmin mice 24 hours after DMBA treatment while both blast and immature myeloid cells were increased. Proliferation and differentiation of BM myeloid cells in response to in vitro granulocyte-macrophage colony-stimulating factor stimulus were impaired in AIRmin-treated mice. These DMBA effects on myeloid BM cells (BMCs) affected the in vivo leukocyte migration to an inflammatory site induced by polyacrylamide beads (Biogel P-100, Bio-Rad, France) injection in AIRmin mice. On the other hand, these alterations were not observed in DMBA-treated AIRmax mice. These data indicate that DMBA affects myeloid cell differentiation and inflammatory response and Ahr(b1) allele in the genetic background of AIRmin mice contributes to this effect.
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http://dx.doi.org/10.1177/1091581814522837DOI Listing
November 2014

Genetic control of renal tumorigenesis by the mouse Rtm1 locus.

BMC Genomics 2013 Oct 22;14:724. Epub 2013 Oct 22.

Laboratory of Immunogenetics, Instituto Butantan, Avenida Dr, Vital Brazil, 1500, 05503-900 São Paulo, Brazil.

Background: The genetic basis of susceptibility to renal tumorigenesis has not yet been established in mouse strains. Mouse lines derived by bidirectional phenotypic selection on the basis of their maximal (AIRmax) or minimal (AIRmin) acute inflammatory responsiveness differ widely in susceptibility to spontaneous and urethane-induced renal tumorigenesis. To map the functional loci modulating renal tumor susceptibility in these mice, we carried out a genome-wide genetic linkage study, using SNP arrays, in an (AIRmax x AIRmin)F2 intercross population treated with a single urethane dose at 1 week of age and phenotyped for renal tumors at 35 weeks of age.

Results: AIRmax mice did not develop renal tumors spontaneously nor in response to urethane, whereas in AIRmin mice renal tumors formed spontaneously (in 52% of animals) and after urethane induction (89%). The tumors had a papillary morphology and were positive for alpha-methylacyl-CoA racemase and negative for CD10. By analysis of 879 informative SNPs in 662 mice, we mapped a single quantitative trait locus modulating the incidence of renal tumors in the (AIRmax x AIRmin)F2 intercross population. This locus, which we named Renal tumor modifier QTL 1 (Rtm1), mapped to chromosome 17 at 23.4 Mb (LOD score = 15.8), with SNPs rs3696835 and rs3719497 flanking the LOD score peak. The A allele of rs3719497 from AIRmin mice was associated with a 2.5-fold increased odds ratio for renal tumor development. The LOD score peak included the Tuberous sclerosis 2 (Tsc2) gene which has already been implicated in kidney disease: loss of function by germline retroviral insertion is associated with spontaneous renal tumorigenesis in the Eker rat, and heterozygous-null Tsc2(+/-) mice develop renal cystadenomas.

Conclusions: We mapped Rtm1 as a single major locus modulating renal tumorigenesis in a murine intercross population. Thus, the AIR mouse lines can be considered a new genetic model for studying the role of germline and somatic molecular alterations in kidney neoplastic disease.
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http://dx.doi.org/10.1186/1471-2164-14-724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4046818PMC
October 2013

Genetic control of IL-1 beta production and inflammatory response by the mouse Irm1 locus.

J Immunol 2010 Aug 7;185(3):1616-21. Epub 2010 Jul 7.

Laboratório de Imunogenética, Instituto Butantan, São Paulo, Brazil.

Genome-wide linkage analysis using single nucleotide polymorphism arrays was carried out in pedigrees of mice differing in the extent of acute inflammatory response (AIRmax or AIRmin). The AIR phenotype was determined by quantifying the number of infiltrating cells in the 24-h exudate induced by Biogel P-100 s.c. injection and by ex vivo IL-1beta production by leukocytes stimulated with LPS and ATP. We mapped the major inflammatory response modulator 1 locus on chromosome 7, at the 1-logarithm of odds (LOD) confidence interval from 116.75 to 139.75 Mb, linked to the number of infiltrating cells (LOD = 3.61) through the production of IL-1beta (LOD = 9.35). Of several interesting candidate genes mapping to the inflammatory response modulator 1 locus, 28 of these were differentially expressed in the bone marrow of AIRmax and AIRmin mice. These findings represent a step toward the identification of the genes underlying this complex phenotype.
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http://dx.doi.org/10.4049/jimmunol.1000358DOI Listing
August 2010

Genetic determinants of acute inflammation regulate Salmonella infection and modulate Slc11a1 gene (formerly Nramp1) effects in selected mouse lines.

Microbes Infect 2006 Oct 7;8(12-13):2766-71. Epub 2006 Sep 7.

Laboratório de Imunogenética - Instituto Butantan, Av. Vital Brasil, 1500, São Paulo, SP 05503900, Brazil.

Two lines of mice selected to produce maximal (AIRmax) or minimal (AIRmin) acute inflammatory reactions (AIR) differ in their susceptibility to infection by Salmonella enterica serotype Typhimurium (S. Typhimurium). The LD(50) for AIRmax mice is 1000 times higher than that observed for AIRmin mice, and higher frequencies of Slc11a1 alleles (known to confer either resistance (R) or high susceptibility (S) to S. Typhimurium) were consistently found in AIRmax and AIRmin mouse lines, respectively. In order to evaluate the effect of the quantitative trait loci (QTL) segregated in AIRmax and AIRmin mice on Slc11a1 dependent susceptibility to S. Typhimurium, the R and S alleles were fixed in homozygosity in AIRmax and AIRmin backgrounds by genotype assisted breedings. These new lines were named AIRmax(RR), AIRmax(SS), AIRmin(RR), and AIRmin(SS). Acute inflammation of Slc11a1(RR) animals was more severe in comparison to their Slc11a1(SS) counterparts, implicating Slc11a1 (or other linked genes) in AIR regulation. The LD(50) of S. Typhimurium was 800-times higher for AIRmax(SS) than for AIRmin(SS), demonstrating that AIR QTL can act as modifiers of the Slc11a1(SS) susceptibility gene. Four microsatellite markers for S. Typhimurium susceptibility QTL described in other mouse lines showed specific allele fixation in AIRmax or AIRmin mice, suggesting that these chromosomal regions also segregate with inflammatory phenotypes.
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http://dx.doi.org/10.1016/j.micinf.2006.08.005DOI Listing
October 2006