Publications by authors named "Isabel Baeza"

37 Publications

Interleukin 4 deficiency limits the development of a lupus-like disease in mice triggered by phospholipids in a non-bilayer arrangement.

Scand J Immunol 2021 Mar 25;93(3):e13002. Epub 2020 Dec 25.

Laboratorio de Biomembranas, Departamento de Bioquímica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Ciudad de México, México.

Non-bilayer phospholipids arrangements (NPAs) are transient molecular associations different from lipid bilayers. When they become stable, they can trigger a disease in mice resembling human lupus, which is mainly characterized by the production of anti-NPA IgG antibodies. NPAs are stabilized on liposomes or cell bilayers by the drugs procainamide or chlorpromazine, which produce drug-induced lupus in humans. Here, we evaluated the participation of the T 2 response, through its hallmark cytokine IL-4, on the development of the lupus-like disease in mice. Wild-type or IL-4 knockout BALB/c mice received liposomes bearing drug-induced NPAs, the drugs alone, or an anti-NPA monoclonal antibody (H308) to induce the lupus-like disease (the last two procedures stabilize NPAs on mice cells). IL-4 KO mice showed minor disease manifestations, compared to wild-type mice, with decreased production of anti-NPA IgG antibodies, no anti-cardiolipin, anti-histones and anticoagulant antibodies, and no kidney or skin lesions. In these mice, H308 was the only inducer of anti-NPA IgG antibodies. These findings indicate that IL-4 has a central role in the development of the murine lupus-like disease induced by NPA stabilization.
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http://dx.doi.org/10.1111/sji.13002DOI Listing
March 2021

Lupresan, a new drug that prevents or reverts the formation of nonbilayer phospholipid arrangements that trigger a murine lupus resembling human lupus.

Biochem Biophys Res Commun 2019 01 21;509(1):275-280. Epub 2018 Dec 21.

Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Ciudad de México, 11340, Mexico. Electronic address:

Non-bilayer phospholipid arrangements (NPA) are lipid associations different from the bilayer, formed by the interactions of conic anionic lipids and divalent cations that produce an inverted micelle which is inserted between the lipid layers, so the polar heads of the outer lipids spread and expose new antigens. Since these structures are transient, they are not immunogenic, but if they are stabilized by drugs, such as chlorpromazine, they become immunogenic and induce anti-NPA antibodies that trigger a lupus-like disease in mice. Chloroquine is a drug used for the treatment of lupus; chloroquine has a quinoline ring and two positive charges that interact with conic anionic lipids and prevent or revert the formation of NPA. However, the polyamine spermidine is more effective, since it has three positive charges and interacts with more lipids, but polyamines cannot be used as drugs, because they are highly toxic. Here we report the design and synthesis of Lupresan, an analogous of chloroquine with its quinoline ring but with three positive charges. Lupresan is more effective in preventing or reverting the formation of NPA than chloroquine or spermidine, and as a consequence, it decreased auto-antibody titers and healed the malar rash in mice with lupus to a greater extent than chloroquine. A drug as Lupresan could be used for the treatment of human lupus.
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http://dx.doi.org/10.1016/j.bbrc.2018.12.119DOI Listing
January 2019

Dysregulation of miR-155-5p and miR-200-3p and the Anti-Non-Bilayer Phospholipid Arrangement Antibodies Favor the Development of Lupus in Three Novel Murine Lupus Models.

J Immunol Res 2017 4;2017:8751642. Epub 2017 Dec 4.

Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, 11340 Ciudad de Mexico, Mexico.

Systemic lupus erythematosus (SLE) is characterized by deregulated activation of T and B cells, autoantibody production, and consequent formation of immune complexes. Liposomes with nonbilayer phospholipid arrangements (NPA), induced by chlorpromazine, procainamide, or manganese, provoke a disease resembling human lupus when administered to mice. These mice produce anti-NPA IgM and IgG antibodies and exhibit an increased number of TLR-expressing spleen cells and a modified gene expression associated with -dependent TLR4 signaling (including and ) and complement activation. Additionally, they showed a diminished gene expression related to apoptosis and NK cell activation. We hypothesized that such gene expression may be affected by miRNAs and so miRNA expression was studied. Twelve deregulated miRNAs were found. Six of them were common to the three lupus-like models. Their validation by qRT-PCR and TaqMan probes, including miR-342-3p, revealed that miR-155-5p and miR-200a-3p expression was statistically significant. Currently described functions for these miRNAs in autoimmune diseases such as SLE reveal their participation in inflammation, interferon production, germinal center responses, and antibody maturation. Taking into account these findings, we propose miR-155-5p and miR-200a-3p, together with the anti-NPA antibodies, as key players in the murine lupus-like models and possible biomarkers of the human SLE.
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http://dx.doi.org/10.1155/2017/8751642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5733947PMC
August 2018

Silver-pig skin nanocomposites and mesenchymal stem cells: suitable antibiofilm cellular dressings for wound healing.

J Nanobiotechnology 2018 Jan 10;16(1). Epub 2018 Jan 10.

Laboratorio de Biotecnología, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, Calz. México Xochimilco No 289 Col. Arenal de Guadalupe, C.P.14389, Mexico City, Mexico.

Background: Treatment of severe or chronic skin wounds is an important challenge facing medicine and a significant health care burden. Proper wound healing is often affected by bacterial infection; where biofilm formation is one of the main risks and particularly problematic because it confers protection to microorganisms against antibiotics. One avenue to prevent bacterial colonization of wounds is the use of silver nanoparticles (AgNPs); which have proved to be effective against non-multidrug-resistant and multidrug-resistant bacteria. In addition, the use of mesenchymal stem cells (MSC) is an excellent option to improve wound healing due to their capability for differentiation and release of relevant growth factors. Finally, radiosterilized pig skin (RPS) is a biomatrix successfully used as wound dressing to avoid massive water loss, which represents an excellent carrier to deliver MSC into wound beds. Together, AgNPs, RPS and MSC represent a potential dressing to control massive water loss, prevent bacterial infection and enhance skin regeneration; three essential processes for appropriate wound healing with minimum scaring.

Results: We synthesized stable 10 nm-diameter spherical AgNPs that showed 21- and 16-fold increase in bacteria growth inhibition (in comparison to antibiotics) against clinical strains Staphylococcus aureus and Stenotrophomonas maltophilia, respectively. RPS samples were impregnated with different AgNPs suspensions to develop RPS-AgNPs nanocomposites with different AgNPs concentrations. Nanocomposites showed inhibition zones, in Kirby-Bauer assay, against both clinical bacteria tested. Nanocomposites also displayed antibiofilm properties against S. aureus and S. maltophilia from RPS samples impregnated with 250 and 1000 ppm AgNPs suspensions, respectively. MSC were isolated from adipose tissue and seeded on nanocomposites; cells survived on nanocomposites impregnated with up to 250 ppm AgNPs suspensions, showing 35% reduction in cell viability, in comparison to cells on RPS. Cells on nanocomposites proliferated with culture days, although the number of MSC on nanocomposites at 24 h of culture was lower than that on RPS.

Conclusions: AgNPs with better bactericide activity than antibiotics were synthesized. RPS-AgNPs nanocomposites impregnated with 125 and 250 ppm AgNPs suspensions decreased bacterial growth, decreased biofilm formation and were permissive for survival and proliferation of MSC; constituting promising multi-functional dressings for successful treatment of skin wounds.
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http://dx.doi.org/10.1186/s12951-017-0331-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5761131PMC
January 2018

Corrigendum: Anti-Lipid IgG Antibodies Are Produced Germinal Centers in a Murine Model Resembling Human Lupus.

Front Immunol 2017 12;8:440. Epub 2017 Apr 12.

Department of Cell Biology, Center for Research and Advanced Studies, CINVESTAV-IPN, Instituto Politécnico Nacional (IPN) , Mexico City , Mexico.

[This corrects the article on p. 396 in vol. 7, PMID: 27746783.].
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http://dx.doi.org/10.3389/fimmu.2017.00440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5388691PMC
April 2017

Anti-Lipid IgG Antibodies Are Produced Germinal Centers in a Murine Model Resembling Human Lupus.

Front Immunol 2016 29;7:396. Epub 2016 Sep 29.

Department of Cell Biology, Center for Research and Advanced Studies, CINVESTAV-IPN, National Polytechnic Institute , Mexico City , Mexico.

Anti-lipid IgG antibodies are produced in some mycobacterial infections and in certain autoimmune diseases [such as anti-phospholipid syndrome, systemic lupus erythematosus (SLE)]. However, few studies have addressed the B cell responses underlying the production of these immunoglobulins. Anti-lipid IgG antibodies are consistently found in a murine model resembling human lupus induced by chlorpromazine-stabilized non-bilayer phospholipid arrangements (NPA). NPA are transitory lipid associations found in the membranes of most cells; when NPA are stabilized they can become immunogenic and induce specific IgG antibodies, which appear to be involved in the development of the mouse model of lupus. Of note, anti-NPA antibodies are also detected in patients with SLE and leprosy. We used this model of lupus to investigate the cellular mechanisms that lead to the production of anti-lipid, class-switched IgG antibodies. In this murine lupus model, we found plasma cells (Gr1, CD19, CD138) producing NPA-specific IgGs in the draining lymph nodes, the spleen, and the bone marrow. We also found a significant number of germinal center B cells (IgD, CD19, PNA) specific for NPA in the draining lymph nodes and the spleen, and we identified the presence of NPA in these germinal centers. By contrast, very few NPA-specific, extrafollicular reaction B cells (B220, Blimp1) were found. Moreover, when assessing the anti-NPA IgG antibodies produced during the experimental protocol, we found that the affinity of these antibodies progressively increased over time. Altogether, our data indicate that, in this murine model resembling human lupus, B cells produce anti-NPA IgG antibodies mainly via germinal centers.
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http://dx.doi.org/10.3389/fimmu.2016.00396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5040728PMC
September 2016

Nonbilayer Phospholipid Arrangements Are Toll-Like Receptor-2/6 and TLR-4 Agonists and Trigger Inflammation in a Mouse Model Resembling Human Lupus.

J Immunol Res 2015 19;2015:369462. Epub 2015 Oct 19.

Biochemistry Department, National School of Biological Sciences, National Polytechnic Institute (IPN), 11340 Mexico City, DF, Mexico.

Systemic lupus erythematosus is characterized by dysregulated activation of T and B cells and autoantibodies to nuclear antigens and, in some cases, lipid antigens. Liposomes with nonbilayer phospholipid arrangements induce a disease resembling human lupus in mice, including IgM and IgG antibodies against nonbilayer phospholipid arrangements. As the effect of these liposomes on the innate immune response is unknown and innate immune system activation is necessary for efficient antibody formation, we evaluated the effect of these liposomes on Toll-like receptor (TLR) signaling, cytokine production, proinflammatory gene expression, and T, NKT, dendritic, and B cells. Liposomes induce TLR-4- and, to a lesser extent, TLR-2/TLR-6-dependent signaling in TLR-expressing human embryonic kidney (HEK) cells and bone marrow-derived macrophages. Mice with the lupus-like disease had increased serum concentrations of proinflammatory cytokines, C3a and C5a; they also had more TLR-4-expressing splenocytes, a higher expression of genes associated with TRIF-dependent TLR-4-signaling and complement activation, and a lower expression of apoptosis-related genes, compared to healthy mice. The percentage of NKT and the percentage and activation of dendritic and B2 cells were also increased. Thus, TLR-4 and TLR-2/TLR-6 activation by nonbilayer phospholipid arrangements triggers an inflammatory response that could contribute to autoantibody production and the generation of a lupus-like disease in mice.
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http://dx.doi.org/10.1155/2015/369462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4629040PMC
September 2016

Hypocholesterolemic and choleretic effects of three dimethoxycinnamic acids in relation to 2,4,5-trimethoxycinnamic acid in rats fed with a high-cholesterol/cholate diet.

Pharmacol Rep 2015 Jun 29;67(3):553-9. Epub 2014 Dec 29.

Biochemistry Department, National School of Biological Sciences, National Polytechnic Institute, Mexico City, Mexico. Electronic address:

Background: 2,4,5-Trimethoxycinnamic acid (2,4,5-TMC) is the major and non-toxic metabolite of α-asarone, which retains hypocholesterolemic and choleretic activities. We compared the activities of 2,4,5-TMC with those of 2,4-dimethoxycinnamic acid (2,4-DMC), 3,4-DMC and 3,5-DMC, to understand the role of the methoxyls on carbons 2, 4 and 5 on the pharmacologic properties of these compounds.

Methods: The methoxycinnamic acids were administered to high-cholesterol/cholate-fed rats. We measured bile flow, and quantified bile acids, phospholipids and cholesterol in bile, and cholesterol and cholesterol-lipoproteins in serum. The inhibition of HMG-CoA reductase by the methoxycinnamic acids was evaluated in vitro.

Results: The four methoxycinnamic acids decreased serum cholesterol, without affecting the concentration of HDL-cholesterol. 2,4,5-TMC produced the highest decrease in LDL-cholesterol, 73.5%, which exceeds the range of statins (20-40%), and produced the highest inhibition of the activity of HMG-CoA reductase. 3,4-DMC produced the highest increase in bile flow, bile acids and phospholipids concentrations, and reduction in bile cholesterol, which led to a decrease in the biliary cholesterol saturation index.

Conclusions: 2,4,5-TMC (which has three methoxyls) had the highest hypocholesterolemic activity, while 3,4-DMC, which lacks the methoxyl in carbon 2 but conserves the two other methoxyls in an adjacent position, had the highest choleretic activity and a probable cholelitholytic activity. In methoxycinnamic acids with two methoxyls in non-adjacent positions (2,4-DMC and 3,5-DMC), the hypocholesterolemic and choleretic activities were not as evident. 2,4,5-TMC and 3,4-DMC, which did not cause liver damage during the treatment period, should be further explored as a hypocholesterolemic and choleretic compounds in humans.
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http://dx.doi.org/10.1016/j.pharep.2014.12.009DOI Listing
June 2015

Trypanocidal effect of the benzyl ester of N-propyl oxamate: a bi-potential prodrug for the treatment of experimental Chagas disease.

BMC Pharmacol Toxicol 2015 Apr 22;16:10. Epub 2015 Apr 22.

Biochemistry Department, National School of Biological Sciences, National Polytechnic Institute, 11340, Mexico City, Mexico.

Background: Chagas disease, which is caused by Trypanosoma cruzi, is a major health problem in Latin America, and there are currently no drugs for the effective treatment of this disease. The energy metabolism of T. cruzi is an attractive target for drug design, and we previously reported that inhibitors of α-hydroxy acid dehydrogenase (HADH)-isozyme II exhibit trypanocidal activity. N-Propyl oxamate (NPOx) is an inhibitor of HADH-isozyme II, and its non-polar ethyl ester (Et-NPOx) is cytotoxic to T. cruzi. A new derivative of NPOx has been developed in this study with higher trypanocidal activity, which could be used for the treatment of Chagas disease.

Methods: The benzyl ester of NPOx (B-NPOx) was synthesized and its activity evaluated towards epimastigotes and bloodstream trypomastigotes (in vitro), as well as mice infected with T. cruzi (in vivo). The activity of B-NPOx was also compared with those of Et-NPOx, benznidazole (Bz) and nifurtimox (Nx). NINOA, Miguz, Compostela, Nayarit and INC-5 T. cruzi strains were used in this study.

Results: Polar NPOx did not penetrate the parasites and exhibited no trypanocidal activity. In contrast, the hydrophobic ester B-NPOx exhibited trypanocidal activity in vitro and in vivo. B-NPOx exhibited higher trypanocidal activity than Et-NPOx, Bz and Nx towards all five of the T. cruzi strains. The increased activity of B-NPOx was attributed to its hydrolysis inside the parasites to give NPOx and benzyl alcohol, which is an antimicrobial compound with trypanocidal effects. B-NPOx was also effective against two strains of T. cruzi that are resistant to Bz and Nx.

Conclusion: B-NPOx exhibited higher in vitro (2- to 14.8-fold) and in vivo (2.2- to 4.5-fold) trypanocidal activity towards T. cruzi than Et-NPOx. B-NPOx also exhibited higher in vitro (2- to 24-fold) and in vivo (1.9- to 15-fold) trypanocidal activity than Bz and Nx. B-NPOx is more lipophilic than Et-NPOx, allowing for better penetration into T. cruzi parasites, where the enzymatic cleavage of B-NPOx would give NPOx and benzyl alcohol, which are potent trypanocidal agents. Taken together with its low toxicity, these results suggest that B-NPOx could be used as a potent prodrug for the treatment of Chagas disease.
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http://dx.doi.org/10.1186/s40360-015-0010-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4409700PMC
April 2015

Therapeutic efficacy of liposomes containing 4-(5-pentadecyl-1,3,4-oxadiazol-2-yl)pyridine in a murine model of progressive pulmonary tuberculosis.

Pulm Pharmacol Ther 2015 Jun 2;32:7-14. Epub 2015 Apr 2.

Sección de Patología Experimental, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ), Col. Vasco de Quiroga No. 15, Delegación Tlalpan, 14080 México, D.F., Mexico. Electronic address:

Background And Objectives: Tuberculosis (TB) is one of the deadliest infectious diseases and comprises a global public health concern because co-infection with Human immunodeficiency virus (HIV) and, in particular, the continuous isolation of new Multidrug-resistant strains (MDR), rendering the discovery of novel anti-TB agents a strategic priority. One of the most effective first-line mycobactericidal drugs is Isoniazid (INH). Previously, we reported in vitro anti-mycobacterial activity against sensitive and MDR Mycobacterium tuberculosis strains of a new oxadiazole obtained from the hybridization of INH and palmitic acid. The present study evaluated the therapeutic potential of liposomes including Phosphatidylcholine (PC) and L-α Phosphatidic acid (PA) or PC and Cholesterol (Chol) containing 4-(5-pentadecyl-1,3,4-oxadiazol-2-yl)pyridine in BALB/c male mice infected by intratracheal (i.t.) route with drug-sensitive or MDR M. tuberculosis.

Methods: The lipophilic 4-(5-pentadecyl-1,3,4-oxadiazol-2-yl)pyridine was obtained to mix INH and palmitoyl chloride. The in vivo anti-TB effect of this oxadiazole derivative contained in two different liposomes was tested in BALB/c mice infected with a sensitive strain of M. tuberculosis, initiating treatment 2 months post-infection, by i.t. route, of 50 μg of oxadiazole derivative for 1 month. In a second stage, mice were infected with an MDR (resistant to first-line drugs) and treated with 150 μg of an oxadiazole derivative carried by PC + Chol liposomes for 2 months. The effect of the oxadiazole derivative in vivo was determined by the quantification of lung bacilli loads and histopathology.

Results: In comparison with control animals, drug-sensitive, strain-infected mice treated for 1 month with 50 μg of this oxadiazole derivative contained in the liposomes of PC + Chol showed a significant, 80% decrease of live bacilli in lungs, which correlated with the morphometric observation, and the group of MDR clinical isolate-infected mice treated with 150 μg of the oxadiazole derivative contained in the same type of liposome showed significantly lower lung bacillary loads than control mice, producing 90% of bacilli burden reduction after 2 months of treatment.

Conclusion: These results confirm and extend the reported highly efficient anti-mycobacterial activity of this lipophilic oxidazole derivative when it is carried by liposomes in mice suffering from late progressive pulmonary TB induced by drug-sensitive, and most prominently by, MDR strains.
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http://dx.doi.org/10.1016/j.pupt.2015.03.004DOI Listing
June 2015

Premature impairment of methylation pathway and cardiac metabolic dysfunction in fa/fa obese Zucker rats.

J Proteome Res 2013 Apr 7;12(4):1935-45. Epub 2013 Mar 7.

Department of Animal Physiology, Faculty of Biology, Complutense University of Madrid , 28040 Madrid, Spain.

Increasing evidence suggests that obesity is a chronic inflammatory disease, in which adipose tissue is involved in a network of endocrine signals to modulate energy homeostasis. These oxidative-inflammatory pathways, which are associated with cardiovascular complications, are also observed during the aging process. In this study, we investigated the interaction between aging and the development of obesity in a hyperphagic rat model. Metabolic profiles of the liver, white adipose tissue (WAT) and heart from young and adult Zucker lean (fa/+) and obese (fa/fa) rats were characterized using a (1)H NMR-based metabonomics approach. We observed premature metabolic modifications in all studied organs in obese animals, some of which were comparable to those observed in adult lean animals. In the cardiac tissue, young obese rats displayed lower lactate and scyllo-inositol levels associated with higher creatine, choline and phosphocholine levels, indicating an early modulation of energy and membrane metabolism. An early alteration of the hepatic methylation and transsulfuration pathways in both groups of obese rats indicated that these pathways were affected before diabetic onset. These findings therefore support the hypothesis that obesity parallels some metabolic perturbations observed in the aging process and provides new insights into the metabolic modifications occurring in prediabetic state.
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http://dx.doi.org/10.1021/pr400025yDOI Listing
April 2013

Salmonella Typhi OmpS1 and OmpS2 porins are potent protective immunogens with adjuvant properties.

Immunology 2013 Aug;139(4):459-71

Medical Research Unit on Immunochemistry, National Medical Centre Siglo XXI, Mexican Social Security Institute (IMSS), Specialties Hospital, Mexico City, Mexico.

Salmonella enterica serovar Typhi (S. Typhi) is the causal agent of typhoid fever, a disease that primarily affects developing countries. Various antigens from this bacterium have been reported to be targets of the immune response. Recently, the S. Typhi genome has been shown to encode two porins--OmpS1 and OmpS2--which are expressed at low levels under in vitro culture conditions. In this study, we demonstrate that immunizing mice with either OmpS1 or OmpS2 induced production of specific, long-term antibody titres and conferred protection against S. Typhi challenge; in particular, OmpS1 was more immunogenic and conferred greater protective effects than OmpS2. We also found that OmpS1 is a Toll-like receptor 4 (TLR4) agonist, whereas OmpS2 is a TLR2 and TLR4 agonist. Both porins induced the production of tumour necrosis factor and interleukin-6, and OmpS2 was also able to induce interleukin-10 production. Furthermore, OmpS1 induced the over-expression of MHC II molecules in dendritic cells and OmpS2 induced the over-expression of CD40 molecules in macrophages and dendritic cells. Co-immunization of OmpS1 or OmpS2 with ovalbumin (OVA) increased anti-OVA antibody titres, the duration and isotype diversity of the OVA-specific antibody response, and the proliferation of T lymphocytes. These porins also had adjuvant effects on the antibody response when co-immunized with either the Vi capsular antigen from S. Typhi or inactivated 2009 pandemic influenza A(H1N1) virus [A(H1N1)pdm09]. Taken together, the data indicate that OmpS1 and OmpS2, despite being expressed at low levels under in vitro culture conditions, are potent protective immunogens with intrinsic adjuvant properties.
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http://dx.doi.org/10.1111/imm.12093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3719063PMC
August 2013

Lepromatous leprosy patients produce antibodies that recognise non-bilayer lipid arrangements containing mycolic acids.

Mem Inst Oswaldo Cruz 2012 Dec;107 Suppl 1:95-103

Biochemistry Department , National School of Biological Sciences, National Polytechnic Institute, DF, Mexico.

Non-bilayer phospholipid arrangements are three-dimensional structures that form when anionic phospholipids with an intermediate structure of the tubular hexagonal phase II are present in a bilayer of lipids. Antibodies that recognise these arrangements have been described in patients with antiphospholipid syndrome and/or systemic lupus erythematosus and in those with preeclampsia; these antibodies have also been documented in an experimental murine model of lupus, in which they are associated with immunopathology. Here, we demonstrate the presence of antibodies against non-bilayer phospholipid arrangements containing mycolic acids in the sera of lepromatous leprosy (LL) patients, but not those of healthy volunteers. The presence of antibodies that recognise these non-bilayer lipid arrangements may contribute to the hypergammaglobulinaemia observed in LL patients. We also found IgM and IgG anti-cardiolipin antibodies in 77% of the patients. This positive correlation between the anti-mycolic-non-bilayer arrangements and anti-cardiolipin antibodies suggests that both types of antibodies are produced by a common mechanism, as was demonstrated in the experimental murine model of lupus, in which there was a correlation between the anti-non-bilayer phospholipid arrangements and anti-cardiolipin antibodies. Antibodies to non-bilayer lipid arrangements may represent a previously unrecognised pathogenic mechanism in LL and the detection of these antibodies may be a tool for the early diagnosis of LL patients.
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http://dx.doi.org/10.1590/s0074-02762012000900016DOI Listing
December 2012

The T1048I mutation in ATP7A gene causes an unusual Menkes disease presentation.

BMC Pediatr 2012 Sep 19;12:150. Epub 2012 Sep 19.

Department of Biochemistry, National School of Biological Sciences, National Polytechnic Institute (IPN), Mexico City, 11340, Mexico.

Background: The ATP7A gene encodes the ATP7A protein, which is a trans-Golgi network copper transporter expressed in the brain and other organs. Mutations in this gene cause disorders of copper metabolism, such as Menkes disease. Here we describe the novel and unusual mutation (p.T1048I) in the ATP7A gene of a child with Menkes disease. The mutation affects a conserved DKTGT1048 phosphorylation motif that is involved in the catalytic activity of ATP7A. We also describe the clinical course and the response to copper treatment in this patient.

Case Presentation: An 11-month-old male Caucasian infant was studied because of hypotonia, ataxia and global developmental delay. The patient presented low levels of serum copper and ceruloplasmin, and was shown to be hemizygous for the p.T1048I mutation in ATP7A. The diagnosis was confirmed when the patient was 18 months old, and treatment with copper-histidinate (Cu-His) was started immediately. The patient showed some neurological improvement and he is currently 8 years old. Because the p.T1048I mutation affects its catalytic site, we expected a complete loss of functional ATP7A and a classical Menkes disease presentation. However, the clinical course of the patient was mild, and he responded to Cu-His treatment, which suggests that this mutation leads to partial conservation of the activity of ATP7A.

Conclusion: This case emphasizes the important correlation between genotype and phenotype in patients with Menkes disease. The prognosis in Menkes disease is associated with early detection, early initiation of treatment and with the preservation of some ATP7A activity, which is necessary for Cu-His treatment response. The description of this new mutation and the response of the patient to Cu-His treatment will contribute to the growing body of knowledge about treatment response in Menkes disease.
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http://dx.doi.org/10.1186/1471-2431-12-150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3489546PMC
September 2012

Molecular organization of the non-bilayer phospholipid arrangements that induce an autoimmune disease resembling human lupus in mice.

Mol Membr Biol 2012 Mar;29(2):52-67

Biochemistry Department, National School of Biological Sciences, National Polytechnic Institute (IPN), Mexico City, Mexico.

Non-bilayer phospholipid arrangements are three-dimensional structures that can form when anionic phospholipids with an intermediate form of the tubular hexagonal phase II (H(II)), such as phosphatidic acid, phosphatidylserine or cardiolipin, are present in a bilayer of lipids. The drugs chlorpromazine and procainamide, which trigger a lupus-like disease in humans, can induce the formation of non-bilayer phospholipid arrangements, and we have previously shown that liposomes with non-bilayer arrangements induced by these drugs cause an autoimmune disease resembling human lupus in mice. Here we show that liposomes with non-bilayer phospholipid arrangements induced by Mn²⁺ cause a similar disease in mice. We extensively characterize the physical properties and immunological reactivity of liposomes made of the zwitterionic lipid phosphatidylcholine and a H(II)-preferring lipid, in the absence or presence of Mn²⁺, chlorpromazine or procainamide. We use an hapten inhibition assay to define the epitope recognized by sera of mice with the disease, and by a monoclonal antibody that binds specifically to non-bilayer phospholipid arrangements, and we report that phosphorylcholine and glycerolphosphorylcholine, which form part of the polar region of phosphatidylcholine, are the only haptens that block the binding of the tested antibodies to non-bilayer arrangements. We propose a model in which the negatively charged H(II)-preferring lipids form an inverted micelle by electrostatic interactions with the positive charge of Mn²⁺, chlorpromazine or procainamide; the inverted micelle is inserted into the bilayer of phosphatidylcholine, whose polar regions are exposed and become targets for antibody production. This model may be relevant in the pathogenesis of human lupus.
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http://dx.doi.org/10.3109/09687688.2012.667577DOI Listing
March 2012

Effect of environmental enrichment on the immunoendocrine aging of male and female triple-transgenic 3xTg-AD mice for Alzheimer's disease.

J Alzheimers Dis 2011 ;25(4):727-37

Department of Physiology (Animal Physiology II), Faculty of Biology, Complutense University of Madrid, Madrid, Spain.

We have previously shown that 3xTgAD mice (triple-transgenic mice for Alzheimer's disease, harboring PS1(M146V), AβPP(Swe), tau(P301L) transgenes) suffer detrimental changes in some key lymphocyte functions, described as health and longevity markers, with males being more affected than females and showing higher mortality rates. In the present work, 3xTgAD and wild type 129/C57BL6 male and female non- and environmentally enriched mice were used. The enriched environment (EE) began in the adulthood (6 months) and lasted for 5.5 months. The animals were sacrificed at advanced stages of the disease (15 month-old), and spleen, thymus, and plasma were obtained. The results indicate that 3xTg-AD males are especially benefitted from EE exposure, as shown by the improvement in lymphocyte functional activities such as chemotaxis and natural killer cytotoxicity, as well as in plasma corticosterone levels. By contrast, wild type females seem to be highly sensitive to EE removal, as regards the proliferation capacity of lymphocytes and their intracellular glutathione content. These results support the relevance of gender differences in AD when screening for new strategies for the control of the disease, and suggest that active life, by means of EE, should be maintained until natural death in order to preserve all the positive effects that this strategy exerts on the immune system.
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http://dx.doi.org/10.3233/JAD-2011-110236DOI Listing
November 2011

Improvement of leucocyte functions in mature and old mice after 15 and 30 weeks of diet supplementation with polyphenol-rich biscuits.

Eur J Nutr 2011 Oct 8;50(7):563-73. Epub 2011 Jan 8.

Department of Physiology (Animal Physiology II), Faculty of Biological Sciences, Complutense University, c/Jose Antonio Novais no. 2, 28040, Madrid, Spain.

Purpose: To study the effect of diet supplementation with polyphenols on several functions suffering age-related changes, in peritoneal leucocytes from mature and old mice.

Methods: Five groups of female ICR mice were used. Four groups received a supplementation (20% wt/wt) of biscuits with different cereal fractions naturally rich in polyphenols (named CO49, CO50, CO52, CO53), containing different amounts of catechin, p-hydroxybenzoic acid, vanillic acid, p-coumaric acid, sinapic acid, ferulic acid, rutin and oryzanol. The control group received only standard maintenance diet. Peritoneal suspensions were obtained after 15 and 30 weeks of diet supplementation, when the age of the animals was 49 ± 2 (mature mice) and 64 ± 2 weeks (old mice), respectively. The functions analysed were: chemotaxis of macrophages and lymphocytes, phagocytosis of particles by macrophages, intracellular superoxide anion levels, lymphoproliferative response to mitogens (concanavalin A and lipopolysaccharide), interleukin-2 secretion and natural killer (NK) activity, as functions that decrease with age, and adherence of macrophages and lymphocytes and tumour necrosis factor-α secretion as functions with age-related increase.

Results: The supplementation, in general, increased the functions that decrease with age and decreased those that increase with age. There were differences in the effects shown by the four kinds of biscuits depending on the function studied and the number of weeks of supplementation.

Conclusion: Since the immune system has been proposed as a good marker of health and predictor of longevity, diet supplementation with cereals naturally rich in polyphenols could be an important way for health preservation with age and reaching high longevity.
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http://dx.doi.org/10.1007/s00394-010-0163-2DOI Listing
October 2011

Ovariectomy causes immunosenescence and oxi-inflamm-ageing in peritoneal leukocytes of aged female mice similar to that in aged males.

Biogerontology 2011 Jun 1;12(3):227-38. Epub 2011 Jan 1.

Department of Physiology, Faculty of Biology, Complutense University of Madrid, Spain.

Immunosenescence involves age-associated restructuring changes of innate and adaptative immune functions. We have suggested that these changes of the immune system participate in the rate of ageing through modulating oxi-inflamm-ageing. Thus, age-related changes in the immune system can be biological age markers and predictors of longevity. Gender differences in oxidation status and immune functions have been observed in rats, with males showing higher oxidation and immunosenescence than females of the same age. Oestrogens are sex hormones that actively participate in modulating the mammalian immune function and, therefore, the age-related impairment of the immune response is drastically accelerated in females during the menopausal transition. Ovariectomy in rodents constitutes a good model for mimicking human oestrogen loss and thus the menopausal situation. Recently, we have shown the deleterious effects of oestrogen loss on several functions of leukocytes from immune organs in rats and mice. In addition, ovariectomised rats show similar levels in these immune functions to those in males. The present work studied several functions as well as inflammatory and oxidative stress parameters in mouse peritoneal macrophages and lymphocytes from old sham and ovariectomised females, as well as in males of the same age. In general, the results show that females, which have a higher immune response and a lower oxidation and inflammation than males, appear similar to males in the parameters studied when they have lost oestrogens by ovariectomy. Thus, these data support the positive role of oestrogens in the immune function through the ageing process.
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http://dx.doi.org/10.1007/s10522-010-9317-0DOI Listing
June 2011

Soybean and green tea polyphenols improve immune function and redox status in very old ovariectomized mice.

Rejuvenation Res 2010 Dec 6;13(6):665-74. Epub 2010 Sep 6.

Department of Physiology, Faculty of Biology, Complutense University of Madrid, Madrid, Spain.

In previous work we have observed that ovariectomy in rodents, a good model of mimicking human ovarian hormone loss, causes premature aging of the immune system. The prooxidative and inflammatory state that underlies the aging process is the base of that premature immunosenescence. It has been found that nutritional interventions with polyphenolic antioxidants constitute a good alternative to rejuvenate age-affected immune functions. In this study, we administered a diet supplemented with polyphenols (coming from soybean isoflavones and green tea) to sham-operated and ovariectomized mature mice for 15 weeks, until they reached a very old age. We have studied the effect of this supplementation on a broad range of parameters of immune function (in macrophages and lymphocytes) and oxidative stress (enzymatic and nonenzymatic antioxidant defences, oxidant compounds, and lipid peroxidation damage) in peritoneal leukocytes. The results showed that ovariectomy accelerates the age-related impairment of immune functions in very old mice as well as the oxidative and proinflammatory imbalance, and that the administration of soybean isoflavones and green tea improve the immune and redox state in these animals. Because the immune system is a good marker of health and a predictor of longevity, we suggest that an adequate nutritional treatment with polyphenols could be a highly recommended tool to fight against the detrimental effects of the lack of female sex hormones, through an improvement of the immune cell functions and redox state.
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http://dx.doi.org/10.1089/rej.2010.1049DOI Listing
December 2010

Environmental enrichment improves age-related immune system impairment: long-term exposure since adulthood increases life span in mice.

Rejuvenation Res 2010 Aug;13(4):415-28

Department of Physiology (Animal Physiology II), Faculty of Biological Sciences, Madrid Complutense University, Madrid, Spain.

Age-related changes in immunity have been shown to highly influence morbidity and mortality. The aim of the present work was to study the effects of environmental enrichment (EE) (8-16 weeks) on several functions and oxidative stress parameters of peritoneal leukocytes, previously described as health and longevity markers, in mice at different ages, namely adult (44 +/- 4 weeks), old (69 +/- 4 weeks), and very old (92 +/- 4 weeks). Mortality rates were monitored in control and enriched animals, and effects on survival of long-term exposure to EE until natural death were determined. The results showed that exposure to EE was efficient in improving the function (i.e., macrophage chemotaxis and phagocytosis, lymphocyte chemotaxis and proliferation, natural killer cell activity, interleukin-2 and tumor necrosis factor-alpha levels) and decreasing the oxidative-inflammatory stress (i.e., lowered oxidized glutathione content, xanthine oxidase activity, expression of Toll-like receptors 2 and 4 on CD4 and CD8 cells, and increased reduced glutathione and glutathione peroxidase and catalase activities) of immune cells. These positive effects of EE were especially remarkable in animals at older ages. Importantly, long-term exposure to EE from adult age and until natural death stands out as a useful strategy to extend longevity. Thus, the present work confirms the importance of maintaining active mental and/or physical activity aiming to improve quality of life in terms of immunity, and demonstrates that this active life must be initiated at early stages of the aging process and preserved until death to improve life span.
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http://dx.doi.org/10.1089/rej.2009.0989DOI Listing
August 2010

Effects of growth hormone, melatonin, oestrogens and phytoestrogens on the oxidized glutathione (GSSG)/reduced glutathione (GSH) ratio and lipid peroxidation in aged ovariectomized rats.

Biogerontology 2010 Dec 20;11(6):687-701. Epub 2010 Jun 20.

Department of Physiology, Complutense University of Madrid, Spain.

Ovariectomy constitutes a commonly used model in rats and mice for human menopause. After ovariectomy, an imbalance between oxidant production and antioxidant levels appears in favour of the former, with increased oxidative stress and consequently an acceleration of ageing. In the present work, the levels of reduced glutathione (GSH), a relevant antioxidant, and oxidized glutathione (GSSG), an oxidant compound, as well as lipid peroxidation (through malondialdehyde (MDA) levels), were studied in liver, heart, kidney and spleen homogenates of old (24 months of age) unovariectomized and ovariectomized female Wistar rats. The results showed a significant increase of the GSSG/GSH ratio, a marker of oxidative stress, and higher MDA production in all the studied organs of ovariectomized rats as compared with unovariectomized animals. These data confirm the idea that ovariectomy accelerates the ageing process. Administration of growth hormone (GH), melatonin (MEL) and oestrogens (OE), as well as soybean phytoestrogens (PE) for 10 weeks, between 22 and 24 months of age, was able to decrease oxidative stress in the investigated organs of ovariectomized old rats, therefore slowing down the ageing process in those animals.
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http://dx.doi.org/10.1007/s10522-010-9282-7DOI Listing
December 2010

Membrane fusion inducers, chloroquine and spermidine increase lipoplex-mediated gene transfection.

Biochem Biophys Res Commun 2010 May 8;396(2):549-54. Epub 2010 May 8.

Biochemistry Department, National Polytechnic Institute, Mexico City 11340, Mexico.

Gene transfection into mammalian cells can be achieved with viral and non-viral vectors. Non-viral vectors, such as cationic lipids that form lipoplexes with DNA, are safer and more stable than viral vectors, but their transfection efficiencies are lower. Here we describe that the simultaneous treatment with a membrane fusion inducer (chlorpromazine or procainamide) plus the lysosomotropic agent chloroquine increases lipoplex-mediated gene transfection in human (HEK293 and C-33 A) and rat (PC12) cell lines (up to 9.2-fold), as well as in situ in BALB/c mice spleens and livers (up to 6-fold); and that the polyamine spermidine increases lipoplex-mediated gene transfection and expression in cell cultures. The use of these four drugs provides a novel, safe and relatively inexpensive way to considerably increase lipoplex-mediated gene transfection efficiency.
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http://dx.doi.org/10.1016/j.bbrc.2010.04.143DOI Listing
May 2010

Differential expression of Toll-like receptor 2 and 4 on peritoneal leukocyte populations from long-lived and non-selected old female mice.

Biogerontology 2010 Aug 20;11(4):475-82. Epub 2010 Mar 20.

Departamento de Fisiología, Universidad Complutense, Madrid, España.

The aim of the present study was to determine Toll-like receptor (TLR)-2 and TLR-4 membrane expression on the major peritoneal leukocyte populations throughout the aging process, including subjects that had achieved exceptional longevity. ICR (CD1) female mice of different ages: adult (44 +/- 4 weeks), old (69 +/- 4), very old (92 +/- 4) and extreme long-lived (125 +/- 4), were used. Peritoneal leukocytes were collected, and percentages of CD11b, CD11c, CD3CD4, CD3CD8 and CD19 cells present in the samples were analysed, as well as the expression of TLR-2 and TLR-4 on them, by flow cytometry. The results showed increased TLR expression on CD11b+ cells from animals at very old ages and especially in the extreme long-lived. Old subjects showed lower percentage of CD11c+ cells, but no age-related changes were found in the TLR expression on these cells. TLRs on CD3CD4+ and CD3CD8+ cells from very old animals were increased as compared to the adults, whereas long-lived subjects showed preserved levels. However, TLR expression on CD19+ cells was higher in long-lived individuals with respect to subjects at all the other younger ages. These data suggest that differential age-related changes in the expression of TLR-2 and TLR-4 on leukocyte populations from long-lived and non-selected younger old mice could contribute to a different age-related immune remodelling in long-lived subjects, which could allow better preservation of their immune responses.
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http://dx.doi.org/10.1007/s10522-010-9270-yDOI Listing
August 2010

Trypanocidal activity of the ethyl esters of N-propyl and N-isopropyl oxamates on intracellular amastigotes of Trypanosoma cruzi acute infected mice.

J Enzyme Inhib Med Chem 2010 Feb;25(1):111-5

Departamento de Bioquímica, Escuela Nacional de Ciencias Biológicas-Instituto Politécnico Nacional, Mexico City, Mexico.

In this investigation we studied the trypanocidal activity of the ethyl esters of N-propyl (Et-NPOX) and N-isopropyl (Et-NIPOX) oxamates on bloodstream trypomastigotes and on the clinically relevant intracellular amastigotes of Trypanosoma cruzi acute infected mice. In the infected and treated mice, the levels of parasitemia were drastically reduced between days 15 and 20 of treatment and almost to zero between days 35 and 40. We also found that Et-NPOX completely eliminated amastigote nests in the myocardium of mice infected with INC-5 or NINOA T. cruzi strain, and in skeletal muscle the reduction in the number of amastigote nests was between 60 and 80% in both strains. Also, Et-NIPOX reduced by 60-80% the number of amastigote nests in the myocardium and skeletal muscle of mice infected with these T. cruzi strains. In contrast, nifurtimox, used for comparison, produced a reduction of amastigote nests of only 20-40% in the studied tissues in both strains.
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http://dx.doi.org/10.3109/14756360903027741DOI Listing
February 2010

Repeated restraint stress increases IgA concentration in rat small intestine.

Brain Behav Immun 2010 Jan 11;24(1):110-8. Epub 2009 Sep 11.

Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina y Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional. Plan de San Luis y Díaz Miron, México, DF CP 11340, Mexico.

The most abundant intestinal immunoglobulin and first line of specific immunological defense against environmental antigens is secretory immunoglobulin A. To better understand the effect of repeated stress on the secretion of intestinal IgA, the effects of restraint stress on IgA concentration and mRNA expression of the gene for the alpha-chain of IgA was assessed in both the duodenum and ileum of the rats. Restraint stress induced an increase in intestinal IgA, which was blocked by an adrenalectomy, suggesting a role of catecholamines and glucocorticoids. Whereas the blocking of glucocorticoid receptors by RU-486 did not affect the increased IgA concentration, it did reduce IgA alpha-chain mRNA expression in both segments, indicating a possible mediation on the part of glucocorticoids in IgA secretion by individual cells. Treatment with corticosterone significantly increased both the IgA concentration and IgA alpha-chain mRNA expression in ileum but not in duodenum, suggesting that glucocorticoids may act directly on IgA-antibody forming cells to increase IgA secretion in the former segment. A probable role by catecholamines was evidenced by the reduction in IgA concentration and IgA alpha-chain mRNA expression in both segments after a chemical sympathectomy with 6-hydroxydopamine (6-OHDA). Additionally, norepinephrine significantly reduced IgA alpha-chain mRNA levels but increased pIgR mRNA expression and IgA concentration in both intestinal segments. We propose that the increased intestinal IgA levels caused by repeated restraint stress is likely due to the effects of catecholamines on the transport of plgA across the epithelium.
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http://dx.doi.org/10.1016/j.bbi.2009.09.005DOI Listing
January 2010

Characterization of cationic liposomes having IL-2 expressed on their external surface, and their affinity to cervical cancer cells expressing the IL-2 receptor.

J Drug Target 2009 Aug;17(7):496-501

FES-Zaragoza, Universidad Nacional Autónoma de México, Mexico City, Mexico.

Anionic, cationic, and neutral liposomes were constructed to contain IL-2 in order to evaluate their affinity to a cervical cancer cell line (INBL) and to determine whether they can present IL-2 on their external surface. When these liposomes were co-cultured with INBL, the anionic liposomes were the only ones found to be cytotoxic. When neutral and cationic liposomes were constructed in the presence of IL-2, IL-2 was detected only on the surface of cationic liposomes by using a fluorescent anti-IL-2 antibody. By co-culturing INBL with IL-2-containing cationic liposomes, and by using fluorescent anti-IL-2 antibody, we found a strong IL-2 presence on the cell membranes thus suggesting a high affinity of the liposomes to the INBL cells.
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http://dx.doi.org/10.1080/10611860903012810DOI Listing
August 2009

[Social isolation during old age worsens cognitive, behavioral and immune impairment].

Rev Esp Geriatr Gerontol 2009 May-Jun;44(3):137-42. Epub 2009 May 8.

Departamento de Fisiología (Fisiología Animal II), Facultad de Biología, Universidad Complutense de Madrid, Madrid, España.

Introduction: Several studies by the World Health Organization indicate that widows and widowers show lower physical and mental health indexes than the age-matched general population. In addition, widowhood and social isolation are common in the elderly, with women being more affected than men due to their longer life span. Thus, the aim of the present study was to create an animal model of solitude in old age to study the behavioral, cognitive and immunological changes induced by social isolation at this late stage of life.

Material And Methods: Twenty female C57b/129sv mice, housed in groups of 4-5 until their old age (18 months), remained in groups (controls, n=10) or were isolated after reaching the age of 18 months and until they reached the age of 24 months (isolated, n=10). At this advanced age, the animals were submitted to a battery of tests to assess neophobia (corner test), anxiety (open-field test), and learning and memory (Morris water maze). Thereafter, the animals were sacrificed and the thymus was removed. The natural killer (NK) activity of the thymic cells against the YAC-1 murine tumor cell line was evaluated.

Results: Animals isolated during old age showed functional and cognitive decline, with increased neophobia and anxiety as well as learning and memory deficits. In addition, isolation reduced the NK activity of thymic cells.

Conclusions: We demonstrate the importance of social isolation and solitude during old age. Both social isolation and solitude exacerbate mental and immunological involution during this period, despite normal social life during previous stages of life.
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http://dx.doi.org/10.1016/j.regg.2008.12.001DOI Listing
September 2009

Effect of growth hormone treatment on lymphocyte functions in old male rats.

Neuroimmunomodulation 2008 26;15(4-6):279-84. Epub 2008 Nov 26.

Department of Animal Physiology, Faculty of Biology, Complutense University, Madrid, Spain.

Introduction: Age-related changes in the communication between the neuroendocrine and the immune system have been scarcely studied. Aging in mammals is associated with an impairment of the immune response, especially regarding lymphocyte functions. Furthermore, the endocrine system is also affected by aging, one of the most significant changes being the decrease in the secretion of several hormones such as growth hormone (GH).

Objective: The aim of the present work was to study whether GH replacement therapy in old male rats could improve several lymphocyte functions.

Methods: Spleen and axillary node lymphocytes from old (24 months of age) male Wistar rats were used in the present study to investigate the effect of GH (2 mg/kg daily during 10 weeks) on chemotaxis, lymphoproliferative response to the mitogen concanavalin A, interleukin 2 release and natural killer cell activity.

Results: We have found that the administration of GH can reduce or even reverse the age-related changes observed in these key immune function parameters. Moreover, we have observed that the recovery of such immune functions is able to reach similar values as those exhibited by young control animals of 6 months of age.

Conclusion: Considering that the immune system is a marker of health and a predictor of longevity, hormone replacement therapies with GH, by increasing the immune function and thus delaying or slowing down some aspects of the aging process, could facilitate successful aging.
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http://dx.doi.org/10.1159/000156471DOI Listing
February 2009

2,4,5-trimethoxycinnamic acid: the major metabolite of alpha-asarone, retains most of the pharmacological properties of alpha-asarone.

J Enzyme Inhib Med Chem 2009 Jun;24(3):903-9

Departamento de Bioquímica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Apartado Postal 4-129, Admon. 4, México City 06401, Mexico.

2,4,5-trimethoxycinnamic acid (TMC), the major and non toxic metabolite of alpha-asarone (2,4,5-trimethoxy-1-propenyl benzene), retains most of the pharmacological properties of alpha-asarone, since both substances, administered to hypercholesterolemic rats at 80 mg/kg body wt, decreased total serum cholesterol, lowered LDL-cholesterol levels and kept unaffected HDL-cholesterol levels. In addition, both substances increased bile flow, especially in hypercholesterolemic rats, by rising the secretion of bile salts, phospholipids and bile cholesterol. These drugs also reduced cholesterol levels of gallbladder bile, whereas phospholipids and bile salts concentrations were increased, decreasing the cholesterol saturation index (CSI). We also found that alpha-asarone was 20 times better inhibitor of HMG-CoA reductase than TMC. This effect on HMG-CoA reductase was the only property highly reduced in TMC in comparison with alpha-asarone, while the other pharmacological properties of alpha-asarone were retained by TMC. These experiments strongly suggest that TMC can be further studied as a possible hypocholesterolemic and cholelitholytic agent.
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http://dx.doi.org/10.1080/14756360802318902DOI Listing
June 2009