Jussara Candido | UFF - Universidade Federal Fluminense (original) (raw)

Papers by Jussara Candido

Research paper thumbnail of Persistent mdx diaphragm alterations are accompanied by increased expression and activity of calcium and muscle-specific proteins

Histology and histopathology, 2021

The mdx mouse model of Duchenne Muscular Dystrophy (DMD) presents sarcolemma instability and deve... more The mdx mouse model of Duchenne Muscular Dystrophy (DMD) presents sarcolemma instability and develops a mild multi-stage dystrophinopathy characterized by intense myonecrosis with inflammatory infiltrate at 4-weeks; muscular regeneration at 12-weeks and persistent fibrosis onwards. Mdx diaphragm muscle has a more severe phenotype with structural and functional deterioration that closely resembles the diaphragm impairment responsible for DMD human patients' morbidity. Herein, we compared calcium deposits, activity of calcium-related proteases, and expression of muscle-specific proteins in mdx diaphragm at 4-weeks and 12-weeks. We found increased calcium deposits mainly at 12-weeks, concomitant with high activity of calpains and matrix metaloprotease-9, but decreased expression of Myhc4 (Myhc IIb) and Atpa2a1 (SERCA1), and high expression of the myogenic regulatory factors Myod1 and Myog. Our results suggest that increased calcium deposits and persistent activity of calcium depend...

Research paper thumbnail of The omentum harbors unique conditions in the peritoneal cavity to promote healing and regeneration for diaphragm muscle repair in mdx mice

Cell and Tissue Research, 2020

Although the primary cause of Duchenne muscular dystrophy (DMD) is a genetic mutation, the inflam... more Although the primary cause of Duchenne muscular dystrophy (DMD) is a genetic mutation, the inflammatory response contributes directly to severity and exacerbation of the diaphragm muscle pathology. The omentum is a lymphoid organ with unique structural and immune functions serving as a sanctuary of hematopoietic and mesenchymal progenitors that coordinate immune responses in the peritoneal cavity. Upon activation, these progenitors expand and the organ produces large amounts of growth factors orchestrating tissue regeneration. The omentum of mdx mouse, a DMD murine model, is rich in milky spots and produces growth factors that promote diaphragm muscle regeneration. The present review summarizes the current knowledge of the omentum as an important immunologic structure and highlights its contribution to resolution of dystrophic muscle injury by providing an adequate environment for muscle regeneration, thus being a potential site for therapeutic interventions in DMD.

Research paper thumbnail of The omentum harbors unique conditions in the peritoneal cavity to promote healing and regeneration for diaphragm muscle repair in mdx mice

Cell and Tissue Research, 2020

Although the primary cause of Duchenne muscular dystrophy (DMD) is a genetic mutation, the inflam... more Although the primary cause of Duchenne muscular dystrophy (DMD) is a genetic mutation, the inflammatory response contributes directly to severity and exacerbation of the diaphragm muscle pathology. The omentum is a lymphoid organ with unique structural and immune functions serving as a sanctuary of hematopoietic and mesenchymal progenitors that coordinate immune responses in the peritoneal cavity. Upon activation, these progenitors expand and the organ produces large amounts of growth factors orchestrating tissue regeneration. The omentum of mdx mouse, a DMD murine model, is rich in milky spots and produces growth factors that promote diaphragm muscle regeneration. The present review summarizes the current knowledge of the omentum as an important immunologic structure and highlights its contribution to resolution of dystrophic muscle injury by providing an adequate environment for muscle regeneration, thus being a potential site for therapeutic interventions in DMD.

Research paper thumbnail of Omentum acts as a regulatory organ controlling skeletal muscle repair of mdx mice diaphragm

Cell and Tissue Research, 2019

Hibiscus sabdariffa (Linn) (family Malvaceae), is an annual dicotyledonous herbaceous shrub plant... more Hibiscus sabdariffa (Linn) (family Malvaceae), is an annual dicotyledonous herbaceous shrub plant popularly known as 'Gongura' in Hindi or 'Pulicha keerai' in Tamil, which is an indigenous edible medicinal plant used in Ayurvedic Medicine in India, China and Thailand. We have investigated the influence of Hibiscus sabdariffa leaf extract (HSEt) on the levels of circulatory ammonia, urea, lipid peroxidation products such as TBARS (thiobarbituric acid and reactive substances), HP (hydroperoxides) and liver marker enzymes such as AST (aspartate transaminase), ALT (alanine transaminase) and ALP (alkaline phosphatase), for its hepatoprotective effect in ammonium chloride induced hyperammonemia. Ammonium chloride treated rats showed a significant increase in the levels of circulatory ammonia, urea, AST, ALT, ALP, TBARS and HP. These changes were significantly decreased in rats treated with HSEt and ammonium chloride. Our results indicate that HSEt offers hepatoprotection by influencing the levels of lipid peroxidation products and liver markers in experimental hyperammonemia and this could be due to its free radical scavenging property and the presence of natural antioxidants. The exact mechanism has to be still investigated and the isolation of active constituents is required.

Research paper thumbnail of Pattern of cardiotoxin-induced muscle remodeling in distinct TLR-4 deficient mouse strains

Histochemistry and cell biology, Jan 14, 2017

Tissue damage triggers innate immune response mediated by Toll-like receptor 4 (TLR) that recogni... more Tissue damage triggers innate immune response mediated by Toll-like receptor 4 (TLR) that recognizes endogenous host danger molecules associated with cell death and tissue inflammation, although the precise role of TLR-4 signaling in muscle tissue repair is still uncertain. Previously, we observed that TLR-4 exerted a protective effect preventing excessive muscular damage induced by Bothrops jararacussu crude venom. This study aimed to evaluate the involvement of TLR-4 at early stages of muscular tissue remodeling in distinct mouse strains after injection of purified snake venom. Muscular injury was induced by injection of 25 µl (0.05 mg/ml) of cardiotoxin (CTX) from Naja mossambica in the gastrocnemius muscle of C3H/HeN (wild-type); C3H/HeJ mice that express a non-functional TLR-4 receptor, C57BL/6 and Tlr4 (-/-) (B6 background) mice. Comparing to control, Tlr4 (-/-) mice presented at early stages (3 DPI) of muscle injury mild inflammation with low MMP-9 activity, scarce macrophage...

Research paper thumbnail of Leishmania amazonensis infection induces behavioral alterations and modulates cytokine and neurotrophin production in the murine cerebral cortex

Journal of Neuroimmunology, 2016

Neurological symptoms have been associated with Leishmania infection, however little is known abo... more Neurological symptoms have been associated with Leishmania infection, however little is known about how the nervous system is affected in leishmaniasis. This work aimed to analyze parasitic load, production of cytokines/ neurotrophins in the prefrontal cortex and behavioral changes in BALB/c mice infected with Leishmania amazonensis. At 2 and 4 months post-infection, infected mice showed a decrease in IFN-γ, IL-1, IL-6, IL-4, IL-10 cytokines and BDNF and NGF neurotrophins in prefrontal cortex associated with increased anxiety behavior. Parasite DNA was found in brain of all animals at 4 months post-infection, when the levels of IBA-1 (activated macrophage/microglia marker) and TNF-α was increased in the prefrontal cortex. However TNF-α returned to normal levels at 6 months post-infection suggesting a neuroprotective mechanism.

Research paper thumbnail of Leite PEC et al may 2014

Research paper thumbnail of SELECTIVE ACTIVATION OF alpha 7 NICOTINIC ACETYLCHOLINE RECEPTOR SUBUNIT (nAChR alpha 7) REDUCES INFLAMMATION AND IMPROVES MUSCLE REGENERATION OF mdx DYSTROPHIC

Research paper thumbnail of Selective activation of α7 nicotinic acetylcholine receptor (nAChRα7) inhibits muscular degeneration in mdx dystrophic mice

Brain Research, 2014

Amount evidence indicates that α7 nicotinic acetylcholine receptor (nAChRα7) activation reduces p... more Amount evidence indicates that α7 nicotinic acetylcholine receptor (nAChRα7) activation reduces production of inflammatory mediators. This work aimed to verify the influence of endogenous nAChRα7 activation on the regulation of full-blown muscular inflammation in mdx mouse with Duchenne muscular dystrophy. We used mdx mice with 3 weeks-old at the height myonecrosis, and C57 nAChRα7 þ/þ wild-type and nAChRα7 À / À knockout mice with muscular injury induced with 60 mL 0.5% bupivacaine (bp) in the gastrocnemius muscle. Pharmacological treatment included selective nAChRα7 agonist PNU282987 (0.3 mg/kg and 1.0 mg/kg) and the antagonist methyllycaconitine (MLA at 1.0 mg/kg) injected intraperitoneally for 7 days. Selective nAChRα7 activation of mdx mice with PNU282987 reduced circulating levels of lactate dehydrogenase (LDH, a marker of cell death by necrosis) and the area of perivascular inflammatory infiltrate, and production of inflammatory mediators TNFα and metalloprotease MMP-9 activity. Conversely, PNU282987 treatment increased MMP-2 activity, an indication of muscular tissue remodeling associated with regeneration, in both mdx mice and WTα7 mice with bp-induced muscular lesion. Treatment with PNU282987 had no effect on α7KO, and MLA abolished the nAChRα7 agonist-induced anti-inflammatory effect in both mdx and WT. In conclusion, nAChRα7 activation inhibits muscular inflammation and activates tissue remodeling by

Research paper thumbnail of Pattern of metalloprotease activity and myofiber regeneration in skeletal muscles ofmdx mice

Muscle & Nerve, 2008

Matrix metalloproteases (MMPs) are key regulatory molecules in the formation, remodeling, and deg... more Matrix metalloproteases (MMPs) are key regulatory molecules in the formation, remodeling, and degradation of extracellular matrix components in both physiological and pathological processes. Skeletal muscles of mdx dystrophic mice show distinct patterns of inflammation and regeneration, suggesting that factors within the microenvironment influence the adaptive responses of muscles with predominantly slow-twitch or fast-twitch fibers. This study aimed to verify the pattern of MMP activity in gastrocnemius, soleus, and diaphragm muscles and correlate it with the regenerative capability at distinct stages of the mdx myopathy. Marked inflammation and myonecrosis was associated with increased MMP-9 activity and TNF-alpha (tumor necrosis factor-alpha) production, whereas muscle regeneration, evidenced by NCAM (neural cell adhesion molecule) expression and MMP-2 activity, varied at different stages of the disease. Soleus muscles showed a high percentage of NCAM-positive myofibers in the early stages (2 weeks) of the disease, but they appeared in the gastrocnemius muscles at 12 weeks and in the diaphragm at 24 weeks. Increased MMP-2 activity in the diaphragm throughout all stages of the disease suggests important tissue remodeling, which is probably associated with persistent inflammation. The results indicate that the microenvironment of distinct skeletal muscle may influence a particular kinetic pattern of MMP activity, which ultimately favors persistent inflammation and myofiber regeneration at different stages of the myopathy in mdx mice.

Research paper thumbnail of Changes in the microenvironment of lymphoid tissues of MDX dystrophic mice accompanies development of myonecrosis

Journal of Neuroimmunology, 1998

Similarly to the human ~isease Duchenne muscular dystrophy(DMD),mdx mice lack dystrophin and deve... more Similarly to the human ~isease Duchenne muscular dystrophy(DMD),mdx mice lack dystrophin and develop an X-linked recessive inflammatory myopathy. During onset of disease and height of myoneerosls, a period characterized by conspicuous inflammatory reaction nearby altered myofibres expression intense MHC class II molecules, it was noticeable marked changes in the microenvironment of lymphoid tissues. Thymus, spleen and draining lymph nodes (poptitesL axillar, brachial) showed reduced cellularity and characteristic atrophy accompanied by increased deposition Of extracellu[ar matrix components (ECM) fibronectin, laminin and type IV collagen. During the height of myonecresia, Mac-1 positive cells producing large amounts of TNF alpha and VLA-6 positive cells represented the predominant mononuclear population in the lesioned muscle Furthermore, intense ECM and VLA-6 immunolabelling was also observed in interfollicular areas and high endothelial venules of draining lymph nodes. Fellowtng clinical amelioration of dystrophy, mdx mice showed increased cellularity but only mild changes in the cytoarehitecture of lymphoid tissue. The results indicate that during distinct pheses of mdx muscular dystrophy, altered expression of ECM components and locally produced cytokines alter the integrity of lymphoid microenvironment, influence adhesion and mrgration of mononuclear cells into the lesioned tissue and towards local draining lymphoid tissue for subsequent activation of the immune system. Financial support: CNPq, PADCT, PRONEX, FINEP.

Research paper thumbnail of Gender dimorphism influences extracellular matrix expression and regeneration of muscular tissue in mdx dystrophic mice

Histochemistry and Cell Biology, 2000

Mdx mouse, the animal model of Duchenne muscular dystrophy, lacks dystrophin and develops an X-li... more Mdx mouse, the animal model of Duchenne muscular dystrophy, lacks dystrophin and develops an X-linked recessive inflammatory myopathy characterized by degeneration of skeletal muscle fibers and connective tissue replacement. The present work aimed to assess whether gender dimorphism in mdx mice would influence skeletal muscle pathology at ages corresponding to main histological changes in the microenvironment of muscular tissue: myonecrosis, regeneration, and fibrosis. At the height of myonecrosis (6 weeks postnatal), skeletal muscles of male mdx mice showed increased sarcolemmal permeability, numerous inflammatory foci, and marked deposition of the extracellular matrix components (ECM) type I collagen and laminin. In contrast, age-matched mdx females showed mild ECM deposition, discrete myonecrosis, but increased numbers of regenerating fibers expressing the satellite cell marker NCAM. In contrast ovariectomized mdx females showed decreased numbers of regenerating fibers. Older (24 and 48 weeks postnatal) mdx females showed extensive fibrosis with increased sarcolemmal permeability and marked deposition of ECM components than corresponding males. These results suggest a role for female hormones in the control of myonecrosis probably by promoting regeneration of muscular tissue and mitigating inflammation especially at ages under the critical influence of sex hormones.

Research paper thumbnail of Expression of Extracellular Matrix Ligands and Receptors in the Muscular Tissue and Draining Lymph Nodes of mdx Dystrophic Mice

Clinical Immunology, 1999

The mdx mouse, an animal model of Duchenne muscular dystrophy, develops an X-linked recessive inf... more The mdx mouse, an animal model of Duchenne muscular dystrophy, develops an X-linked recessive inflammatory myopathy. During onset of disease and height of myonecrosis, mdx mice also display important changes in the microenvironment of lymphoid tissues. Draining lymph nodes showed reduced cellularity and atrophy accompanied by intense immunolabeling for fibronectin, laminin, and type-IV collagen. Following clinical amelioration of dystrophy, mdx mice showed enhanced cellularity and a consistent increase in the absolute numbers of CD4 ؉ and CD8 ؉ cells expressing ␣4 high and ␣5 high extracellular matrix receptors. Furthermore, infiltrating cells in the proximity of myonecrosis expressed ␣4, ␣5, and ␣6 integrin chains during both height of myonecrosis and muscular tissue regeneration. Such results indicate that during distinct phases of muscular dystrophy, altered expression of extracellular matrix ligands and receptors may be influencing myonecrosis by promoting adhesion and migration of mononuclear cells into the altered skeletal muscle and toward local draining lymphoid tissue.

Research paper thumbnail of Persistent activation of omentum influences the pattern of muscular lesion in the mdx diaphragm

Cell and Tissue Research, 2012

The mdx (X chromosome-linked muscular dystrophy) mouse develops a multi-staged disorder character... more The mdx (X chromosome-linked muscular dystrophy) mouse develops a multi-staged disorder characterized by muscle degeneration and reactive fibrosis. Skeletal muscles of mdx mice are not equally susceptible to degeneration. The aim of this study was to verify whether the intense remodeling of the mdx diaphragm could be attributed to influences from the peritoneal microenvironment and omentum, a lymphohematopoietic tissue rich in progenitor cells and trophic factors. At ages corresponding to increased muscular regeneration (12 weeks) and activation of fibrosis (24 weeks), the mdx omentum exhibited (1) morphological and functional characteristics of activation with enlarged milk-spots, an accumulation of CD4(+), CD8(+) and CD19(+)B220(+) B lymphocytes; (2) the formation of clusters positive for proliferating cell nuclear antigen, mainly in B220(+)-rich areas organized in a follicular structure with a germinative center without any challenge by external antigen inducers; (3) clusters with cells positive for fibroblast growth factor-2, numerous Sca-1(+)CD3(-)CD19(-)Mac-1(-) progenitor cells and increased CD4(+), CD8(+) and CD3(+)NK1.1(+) cells in the peritoneal cavity. Omentectomy reduced areas with F4/80(+) inflammatory infiltrate the activity of matrix metalloproteases 9 and 2, collagen deposition and areas with regenerating myofibers in the diaphragm. Thus, persistent activation of the omentum influences the pattern of inflammation and regeneration of the mdx diaphragm partly via the activation of progenitor cells and the production of growth factors that influence the physiopathology of the muscular tissue remodeling.

Research paper thumbnail of Brain sweet brain: importance of sugars for the cerebral microenvironment and tumor development

Arquivos de Neuro-Psiquiatria, 2010

The extracellular matrix (ECM) in the brain tissue is a complex network of glycoproteins and prot... more The extracellular matrix (ECM) in the brain tissue is a complex network of glycoproteins and proteoglycans that fills the intercellular space serving as scaffolding to provide structural framework for the tissue and regulate the behavior of cells via specific receptors - integrins. There is enormous structural diversity among proteoglycans due to variation in the core protein, the number of glycosaminoglycans chains, the extent and position of sulfation. The lectican family of proteoglycans interacts with growth factors, hyaluronan and tenascin forming a complex structure that regulates neuronal plasticity and ion homeostasis around highly active neurons. In this review, we will discuss the latest insights into the roles of brain glycoproteins as modulators of cell adhesion, migration, neurite outgrowth and glial tumor invasion.

Research paper thumbnail of Nicotinic acetylcholine receptor activation completely blocks osteoclastogenesis by interfering with osteoclast precursor differentiation in vitro

Annals of the Rheumatic Diseases, 2011

Research paper thumbnail of Extracellular matrix components of the mouse thymic microenvironment

Cellular Immunology, 1991

We studied the effects of recombinant interferon-y (IFN-7) on some aspects of the physiology of t... more We studied the effects of recombinant interferon-y (IFN-7) on some aspects of the physiology of two murine thymic epithelial cell (TEC) lines. Besides the expected induction of MHC class II antigens, this lymphokine was able to modulate the extracellular matrix (ECM) expression by growing TEC, as well as modulate their adhesion and proliferation patterns. As regards the influence of rIFN-7 on ECM expression, we observed that when applied in very low doses, it promoted an increase in the amounts of basement membrane proteins, mainly fibronectin. In contrast, relatively high doses of this lymphokine (lOI to lo* IU/ml) induced the opposite effect. Interestingly, both the stimulatory and the blocking effects of IFN-y on ECM expression were paralleled by equivalent modulation of cell proliferation, in both mouse and rat TEC lines. It should be pointed out that all these effects could be significantly abrogated by an anti-IFN-y monoclonal antibody. Searching for a putative mechanism that could be involved in the modulation of TEC proliferation by IFNy, we observed a clear-cut positive correlation between cell adhesion and proliferation of TEC growing onto ECM-containing substrata produced following IFN-7 treatment. The bulk of the data presented herein suggests that IFN-y may play a relevant role in TEC physiology and ontogeny, not only by inducing MHC class II antigen expression but also by regulating TEC growth via the control of extracellular matrix production by these cells.

Research paper thumbnail of Intranasal Administration of Perillyl Alcohol Activates Peripheral and Bronchus-Associated Immune System In Vivo

Archivum Immunologiae et Therapiae Experimentalis, 2014

Your article is protected by copyright and all rights are held exclusively by L. Hirszfeld Instit... more Your article is protected by copyright and all rights are held exclusively by L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland. This e-offprint is for personal use only and shall not be selfarchived in electronic repositories. If you wish to self-archive your article, please use the accepted manuscript version for posting on your own website. You may further deposit the accepted manuscript version in any repository, provided it is only made publicly available 12 months after official publication or later and provided acknowledgement is given to the original source of publication and a link is inserted to the published article on Springer's website. The link must be accompanied by the following text: "The final publication is available at link.springer.com".

Research paper thumbnail of Anti‐inflammatory activity of Eugenia punicifolia extract on muscular lesion of mdx dystrophic mice

Journal of Cellular …, 2010

Eugenia punicifolia known as ''pedra-ume caá'' is a shrub largely distributed in the Amazon regio... more Eugenia punicifolia known as ''pedra-ume caá'' is a shrub largely distributed in the Amazon region popularly used in decoctions or infusions as a natural therapeutic agent, which can interfere on cholinergic nicotinic neurotransmission. This work aimed to investigate a putative antiinflammatory effect of dichloromethane fraction of E. punicifolia extract (Ep-CM) in the muscular lesion of mdx dystrophic mice, considering that activation of cholinergic mechanisms mitigates inflammation. A polymer containing the Ep-CM was implanted in mdx gastrocnemius muscle before onset of myonecrosis for local slow and gradual release of bioactive compounds and mice sacrificed 7 days or 9 weeks after surgery. Comparing to control muscle, treatment did not alter choline acetyltransferase and acetylcholinesterase enzymatic activities, but decreased metaloproteases-9 and-2 activities and levels of tumor necrosis factor a and NFkB transcription factor. In addition, treatment also reduced levels of bioactive IL-1b form and cleaved caspase-3, related to early events of cellular death and inflammatory activation and further increased myogenin expression without affecting collagen production which is associated with fibrosis. In vivo treatment of mdx dystrophic mice with Ep-CM caused significant reduction of muscular inflammation and improved skeletal muscle regeneration without inducing fibrosis.

Research paper thumbnail of Persistent mdx diaphragm alterations are accompanied by increased expression and activity of calcium and muscle-specific proteins

Histology and histopathology, 2021

The mdx mouse model of Duchenne Muscular Dystrophy (DMD) presents sarcolemma instability and deve... more The mdx mouse model of Duchenne Muscular Dystrophy (DMD) presents sarcolemma instability and develops a mild multi-stage dystrophinopathy characterized by intense myonecrosis with inflammatory infiltrate at 4-weeks; muscular regeneration at 12-weeks and persistent fibrosis onwards. Mdx diaphragm muscle has a more severe phenotype with structural and functional deterioration that closely resembles the diaphragm impairment responsible for DMD human patients' morbidity. Herein, we compared calcium deposits, activity of calcium-related proteases, and expression of muscle-specific proteins in mdx diaphragm at 4-weeks and 12-weeks. We found increased calcium deposits mainly at 12-weeks, concomitant with high activity of calpains and matrix metaloprotease-9, but decreased expression of Myhc4 (Myhc IIb) and Atpa2a1 (SERCA1), and high expression of the myogenic regulatory factors Myod1 and Myog. Our results suggest that increased calcium deposits and persistent activity of calcium depend...

Research paper thumbnail of The omentum harbors unique conditions in the peritoneal cavity to promote healing and regeneration for diaphragm muscle repair in mdx mice

Cell and Tissue Research, 2020

Although the primary cause of Duchenne muscular dystrophy (DMD) is a genetic mutation, the inflam... more Although the primary cause of Duchenne muscular dystrophy (DMD) is a genetic mutation, the inflammatory response contributes directly to severity and exacerbation of the diaphragm muscle pathology. The omentum is a lymphoid organ with unique structural and immune functions serving as a sanctuary of hematopoietic and mesenchymal progenitors that coordinate immune responses in the peritoneal cavity. Upon activation, these progenitors expand and the organ produces large amounts of growth factors orchestrating tissue regeneration. The omentum of mdx mouse, a DMD murine model, is rich in milky spots and produces growth factors that promote diaphragm muscle regeneration. The present review summarizes the current knowledge of the omentum as an important immunologic structure and highlights its contribution to resolution of dystrophic muscle injury by providing an adequate environment for muscle regeneration, thus being a potential site for therapeutic interventions in DMD.

Research paper thumbnail of The omentum harbors unique conditions in the peritoneal cavity to promote healing and regeneration for diaphragm muscle repair in mdx mice

Cell and Tissue Research, 2020

Although the primary cause of Duchenne muscular dystrophy (DMD) is a genetic mutation, the inflam... more Although the primary cause of Duchenne muscular dystrophy (DMD) is a genetic mutation, the inflammatory response contributes directly to severity and exacerbation of the diaphragm muscle pathology. The omentum is a lymphoid organ with unique structural and immune functions serving as a sanctuary of hematopoietic and mesenchymal progenitors that coordinate immune responses in the peritoneal cavity. Upon activation, these progenitors expand and the organ produces large amounts of growth factors orchestrating tissue regeneration. The omentum of mdx mouse, a DMD murine model, is rich in milky spots and produces growth factors that promote diaphragm muscle regeneration. The present review summarizes the current knowledge of the omentum as an important immunologic structure and highlights its contribution to resolution of dystrophic muscle injury by providing an adequate environment for muscle regeneration, thus being a potential site for therapeutic interventions in DMD.

Research paper thumbnail of Omentum acts as a regulatory organ controlling skeletal muscle repair of mdx mice diaphragm

Cell and Tissue Research, 2019

Hibiscus sabdariffa (Linn) (family Malvaceae), is an annual dicotyledonous herbaceous shrub plant... more Hibiscus sabdariffa (Linn) (family Malvaceae), is an annual dicotyledonous herbaceous shrub plant popularly known as 'Gongura' in Hindi or 'Pulicha keerai' in Tamil, which is an indigenous edible medicinal plant used in Ayurvedic Medicine in India, China and Thailand. We have investigated the influence of Hibiscus sabdariffa leaf extract (HSEt) on the levels of circulatory ammonia, urea, lipid peroxidation products such as TBARS (thiobarbituric acid and reactive substances), HP (hydroperoxides) and liver marker enzymes such as AST (aspartate transaminase), ALT (alanine transaminase) and ALP (alkaline phosphatase), for its hepatoprotective effect in ammonium chloride induced hyperammonemia. Ammonium chloride treated rats showed a significant increase in the levels of circulatory ammonia, urea, AST, ALT, ALP, TBARS and HP. These changes were significantly decreased in rats treated with HSEt and ammonium chloride. Our results indicate that HSEt offers hepatoprotection by influencing the levels of lipid peroxidation products and liver markers in experimental hyperammonemia and this could be due to its free radical scavenging property and the presence of natural antioxidants. The exact mechanism has to be still investigated and the isolation of active constituents is required.

Research paper thumbnail of Pattern of cardiotoxin-induced muscle remodeling in distinct TLR-4 deficient mouse strains

Histochemistry and cell biology, Jan 14, 2017

Tissue damage triggers innate immune response mediated by Toll-like receptor 4 (TLR) that recogni... more Tissue damage triggers innate immune response mediated by Toll-like receptor 4 (TLR) that recognizes endogenous host danger molecules associated with cell death and tissue inflammation, although the precise role of TLR-4 signaling in muscle tissue repair is still uncertain. Previously, we observed that TLR-4 exerted a protective effect preventing excessive muscular damage induced by Bothrops jararacussu crude venom. This study aimed to evaluate the involvement of TLR-4 at early stages of muscular tissue remodeling in distinct mouse strains after injection of purified snake venom. Muscular injury was induced by injection of 25 µl (0.05 mg/ml) of cardiotoxin (CTX) from Naja mossambica in the gastrocnemius muscle of C3H/HeN (wild-type); C3H/HeJ mice that express a non-functional TLR-4 receptor, C57BL/6 and Tlr4 (-/-) (B6 background) mice. Comparing to control, Tlr4 (-/-) mice presented at early stages (3 DPI) of muscle injury mild inflammation with low MMP-9 activity, scarce macrophage...

Research paper thumbnail of Leishmania amazonensis infection induces behavioral alterations and modulates cytokine and neurotrophin production in the murine cerebral cortex

Journal of Neuroimmunology, 2016

Neurological symptoms have been associated with Leishmania infection, however little is known abo... more Neurological symptoms have been associated with Leishmania infection, however little is known about how the nervous system is affected in leishmaniasis. This work aimed to analyze parasitic load, production of cytokines/ neurotrophins in the prefrontal cortex and behavioral changes in BALB/c mice infected with Leishmania amazonensis. At 2 and 4 months post-infection, infected mice showed a decrease in IFN-γ, IL-1, IL-6, IL-4, IL-10 cytokines and BDNF and NGF neurotrophins in prefrontal cortex associated with increased anxiety behavior. Parasite DNA was found in brain of all animals at 4 months post-infection, when the levels of IBA-1 (activated macrophage/microglia marker) and TNF-α was increased in the prefrontal cortex. However TNF-α returned to normal levels at 6 months post-infection suggesting a neuroprotective mechanism.

Research paper thumbnail of Leite PEC et al may 2014

Research paper thumbnail of SELECTIVE ACTIVATION OF alpha 7 NICOTINIC ACETYLCHOLINE RECEPTOR SUBUNIT (nAChR alpha 7) REDUCES INFLAMMATION AND IMPROVES MUSCLE REGENERATION OF mdx DYSTROPHIC

Research paper thumbnail of Selective activation of α7 nicotinic acetylcholine receptor (nAChRα7) inhibits muscular degeneration in mdx dystrophic mice

Brain Research, 2014

Amount evidence indicates that α7 nicotinic acetylcholine receptor (nAChRα7) activation reduces p... more Amount evidence indicates that α7 nicotinic acetylcholine receptor (nAChRα7) activation reduces production of inflammatory mediators. This work aimed to verify the influence of endogenous nAChRα7 activation on the regulation of full-blown muscular inflammation in mdx mouse with Duchenne muscular dystrophy. We used mdx mice with 3 weeks-old at the height myonecrosis, and C57 nAChRα7 þ/þ wild-type and nAChRα7 À / À knockout mice with muscular injury induced with 60 mL 0.5% bupivacaine (bp) in the gastrocnemius muscle. Pharmacological treatment included selective nAChRα7 agonist PNU282987 (0.3 mg/kg and 1.0 mg/kg) and the antagonist methyllycaconitine (MLA at 1.0 mg/kg) injected intraperitoneally for 7 days. Selective nAChRα7 activation of mdx mice with PNU282987 reduced circulating levels of lactate dehydrogenase (LDH, a marker of cell death by necrosis) and the area of perivascular inflammatory infiltrate, and production of inflammatory mediators TNFα and metalloprotease MMP-9 activity. Conversely, PNU282987 treatment increased MMP-2 activity, an indication of muscular tissue remodeling associated with regeneration, in both mdx mice and WTα7 mice with bp-induced muscular lesion. Treatment with PNU282987 had no effect on α7KO, and MLA abolished the nAChRα7 agonist-induced anti-inflammatory effect in both mdx and WT. In conclusion, nAChRα7 activation inhibits muscular inflammation and activates tissue remodeling by

Research paper thumbnail of Pattern of metalloprotease activity and myofiber regeneration in skeletal muscles ofmdx mice

Muscle & Nerve, 2008

Matrix metalloproteases (MMPs) are key regulatory molecules in the formation, remodeling, and deg... more Matrix metalloproteases (MMPs) are key regulatory molecules in the formation, remodeling, and degradation of extracellular matrix components in both physiological and pathological processes. Skeletal muscles of mdx dystrophic mice show distinct patterns of inflammation and regeneration, suggesting that factors within the microenvironment influence the adaptive responses of muscles with predominantly slow-twitch or fast-twitch fibers. This study aimed to verify the pattern of MMP activity in gastrocnemius, soleus, and diaphragm muscles and correlate it with the regenerative capability at distinct stages of the mdx myopathy. Marked inflammation and myonecrosis was associated with increased MMP-9 activity and TNF-alpha (tumor necrosis factor-alpha) production, whereas muscle regeneration, evidenced by NCAM (neural cell adhesion molecule) expression and MMP-2 activity, varied at different stages of the disease. Soleus muscles showed a high percentage of NCAM-positive myofibers in the early stages (2 weeks) of the disease, but they appeared in the gastrocnemius muscles at 12 weeks and in the diaphragm at 24 weeks. Increased MMP-2 activity in the diaphragm throughout all stages of the disease suggests important tissue remodeling, which is probably associated with persistent inflammation. The results indicate that the microenvironment of distinct skeletal muscle may influence a particular kinetic pattern of MMP activity, which ultimately favors persistent inflammation and myofiber regeneration at different stages of the myopathy in mdx mice.

Research paper thumbnail of Changes in the microenvironment of lymphoid tissues of MDX dystrophic mice accompanies development of myonecrosis

Journal of Neuroimmunology, 1998

Similarly to the human ~isease Duchenne muscular dystrophy(DMD),mdx mice lack dystrophin and deve... more Similarly to the human ~isease Duchenne muscular dystrophy(DMD),mdx mice lack dystrophin and develop an X-linked recessive inflammatory myopathy. During onset of disease and height of myoneerosls, a period characterized by conspicuous inflammatory reaction nearby altered myofibres expression intense MHC class II molecules, it was noticeable marked changes in the microenvironment of lymphoid tissues. Thymus, spleen and draining lymph nodes (poptitesL axillar, brachial) showed reduced cellularity and characteristic atrophy accompanied by increased deposition Of extracellu[ar matrix components (ECM) fibronectin, laminin and type IV collagen. During the height of myonecresia, Mac-1 positive cells producing large amounts of TNF alpha and VLA-6 positive cells represented the predominant mononuclear population in the lesioned muscle Furthermore, intense ECM and VLA-6 immunolabelling was also observed in interfollicular areas and high endothelial venules of draining lymph nodes. Fellowtng clinical amelioration of dystrophy, mdx mice showed increased cellularity but only mild changes in the cytoarehitecture of lymphoid tissue. The results indicate that during distinct pheses of mdx muscular dystrophy, altered expression of ECM components and locally produced cytokines alter the integrity of lymphoid microenvironment, influence adhesion and mrgration of mononuclear cells into the lesioned tissue and towards local draining lymphoid tissue for subsequent activation of the immune system. Financial support: CNPq, PADCT, PRONEX, FINEP.

Research paper thumbnail of Gender dimorphism influences extracellular matrix expression and regeneration of muscular tissue in mdx dystrophic mice

Histochemistry and Cell Biology, 2000

Mdx mouse, the animal model of Duchenne muscular dystrophy, lacks dystrophin and develops an X-li... more Mdx mouse, the animal model of Duchenne muscular dystrophy, lacks dystrophin and develops an X-linked recessive inflammatory myopathy characterized by degeneration of skeletal muscle fibers and connective tissue replacement. The present work aimed to assess whether gender dimorphism in mdx mice would influence skeletal muscle pathology at ages corresponding to main histological changes in the microenvironment of muscular tissue: myonecrosis, regeneration, and fibrosis. At the height of myonecrosis (6 weeks postnatal), skeletal muscles of male mdx mice showed increased sarcolemmal permeability, numerous inflammatory foci, and marked deposition of the extracellular matrix components (ECM) type I collagen and laminin. In contrast, age-matched mdx females showed mild ECM deposition, discrete myonecrosis, but increased numbers of regenerating fibers expressing the satellite cell marker NCAM. In contrast ovariectomized mdx females showed decreased numbers of regenerating fibers. Older (24 and 48 weeks postnatal) mdx females showed extensive fibrosis with increased sarcolemmal permeability and marked deposition of ECM components than corresponding males. These results suggest a role for female hormones in the control of myonecrosis probably by promoting regeneration of muscular tissue and mitigating inflammation especially at ages under the critical influence of sex hormones.

Research paper thumbnail of Expression of Extracellular Matrix Ligands and Receptors in the Muscular Tissue and Draining Lymph Nodes of mdx Dystrophic Mice

Clinical Immunology, 1999

The mdx mouse, an animal model of Duchenne muscular dystrophy, develops an X-linked recessive inf... more The mdx mouse, an animal model of Duchenne muscular dystrophy, develops an X-linked recessive inflammatory myopathy. During onset of disease and height of myonecrosis, mdx mice also display important changes in the microenvironment of lymphoid tissues. Draining lymph nodes showed reduced cellularity and atrophy accompanied by intense immunolabeling for fibronectin, laminin, and type-IV collagen. Following clinical amelioration of dystrophy, mdx mice showed enhanced cellularity and a consistent increase in the absolute numbers of CD4 ؉ and CD8 ؉ cells expressing ␣4 high and ␣5 high extracellular matrix receptors. Furthermore, infiltrating cells in the proximity of myonecrosis expressed ␣4, ␣5, and ␣6 integrin chains during both height of myonecrosis and muscular tissue regeneration. Such results indicate that during distinct phases of muscular dystrophy, altered expression of extracellular matrix ligands and receptors may be influencing myonecrosis by promoting adhesion and migration of mononuclear cells into the altered skeletal muscle and toward local draining lymphoid tissue.

Research paper thumbnail of Persistent activation of omentum influences the pattern of muscular lesion in the mdx diaphragm

Cell and Tissue Research, 2012

The mdx (X chromosome-linked muscular dystrophy) mouse develops a multi-staged disorder character... more The mdx (X chromosome-linked muscular dystrophy) mouse develops a multi-staged disorder characterized by muscle degeneration and reactive fibrosis. Skeletal muscles of mdx mice are not equally susceptible to degeneration. The aim of this study was to verify whether the intense remodeling of the mdx diaphragm could be attributed to influences from the peritoneal microenvironment and omentum, a lymphohematopoietic tissue rich in progenitor cells and trophic factors. At ages corresponding to increased muscular regeneration (12 weeks) and activation of fibrosis (24 weeks), the mdx omentum exhibited (1) morphological and functional characteristics of activation with enlarged milk-spots, an accumulation of CD4(+), CD8(+) and CD19(+)B220(+) B lymphocytes; (2) the formation of clusters positive for proliferating cell nuclear antigen, mainly in B220(+)-rich areas organized in a follicular structure with a germinative center without any challenge by external antigen inducers; (3) clusters with cells positive for fibroblast growth factor-2, numerous Sca-1(+)CD3(-)CD19(-)Mac-1(-) progenitor cells and increased CD4(+), CD8(+) and CD3(+)NK1.1(+) cells in the peritoneal cavity. Omentectomy reduced areas with F4/80(+) inflammatory infiltrate the activity of matrix metalloproteases 9 and 2, collagen deposition and areas with regenerating myofibers in the diaphragm. Thus, persistent activation of the omentum influences the pattern of inflammation and regeneration of the mdx diaphragm partly via the activation of progenitor cells and the production of growth factors that influence the physiopathology of the muscular tissue remodeling.

Research paper thumbnail of Brain sweet brain: importance of sugars for the cerebral microenvironment and tumor development

Arquivos de Neuro-Psiquiatria, 2010

The extracellular matrix (ECM) in the brain tissue is a complex network of glycoproteins and prot... more The extracellular matrix (ECM) in the brain tissue is a complex network of glycoproteins and proteoglycans that fills the intercellular space serving as scaffolding to provide structural framework for the tissue and regulate the behavior of cells via specific receptors - integrins. There is enormous structural diversity among proteoglycans due to variation in the core protein, the number of glycosaminoglycans chains, the extent and position of sulfation. The lectican family of proteoglycans interacts with growth factors, hyaluronan and tenascin forming a complex structure that regulates neuronal plasticity and ion homeostasis around highly active neurons. In this review, we will discuss the latest insights into the roles of brain glycoproteins as modulators of cell adhesion, migration, neurite outgrowth and glial tumor invasion.

Research paper thumbnail of Nicotinic acetylcholine receptor activation completely blocks osteoclastogenesis by interfering with osteoclast precursor differentiation in vitro

Annals of the Rheumatic Diseases, 2011

Research paper thumbnail of Extracellular matrix components of the mouse thymic microenvironment

Cellular Immunology, 1991

We studied the effects of recombinant interferon-y (IFN-7) on some aspects of the physiology of t... more We studied the effects of recombinant interferon-y (IFN-7) on some aspects of the physiology of two murine thymic epithelial cell (TEC) lines. Besides the expected induction of MHC class II antigens, this lymphokine was able to modulate the extracellular matrix (ECM) expression by growing TEC, as well as modulate their adhesion and proliferation patterns. As regards the influence of rIFN-7 on ECM expression, we observed that when applied in very low doses, it promoted an increase in the amounts of basement membrane proteins, mainly fibronectin. In contrast, relatively high doses of this lymphokine (lOI to lo* IU/ml) induced the opposite effect. Interestingly, both the stimulatory and the blocking effects of IFN-y on ECM expression were paralleled by equivalent modulation of cell proliferation, in both mouse and rat TEC lines. It should be pointed out that all these effects could be significantly abrogated by an anti-IFN-y monoclonal antibody. Searching for a putative mechanism that could be involved in the modulation of TEC proliferation by IFNy, we observed a clear-cut positive correlation between cell adhesion and proliferation of TEC growing onto ECM-containing substrata produced following IFN-7 treatment. The bulk of the data presented herein suggests that IFN-y may play a relevant role in TEC physiology and ontogeny, not only by inducing MHC class II antigen expression but also by regulating TEC growth via the control of extracellular matrix production by these cells.

Research paper thumbnail of Intranasal Administration of Perillyl Alcohol Activates Peripheral and Bronchus-Associated Immune System In Vivo

Archivum Immunologiae et Therapiae Experimentalis, 2014

Your article is protected by copyright and all rights are held exclusively by L. Hirszfeld Instit... more Your article is protected by copyright and all rights are held exclusively by L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland. This e-offprint is for personal use only and shall not be selfarchived in electronic repositories. If you wish to self-archive your article, please use the accepted manuscript version for posting on your own website. You may further deposit the accepted manuscript version in any repository, provided it is only made publicly available 12 months after official publication or later and provided acknowledgement is given to the original source of publication and a link is inserted to the published article on Springer's website. The link must be accompanied by the following text: "The final publication is available at link.springer.com".

Research paper thumbnail of Anti‐inflammatory activity of Eugenia punicifolia extract on muscular lesion of mdx dystrophic mice

Journal of Cellular …, 2010

Eugenia punicifolia known as ''pedra-ume caá'' is a shrub largely distributed in the Amazon regio... more Eugenia punicifolia known as ''pedra-ume caá'' is a shrub largely distributed in the Amazon region popularly used in decoctions or infusions as a natural therapeutic agent, which can interfere on cholinergic nicotinic neurotransmission. This work aimed to investigate a putative antiinflammatory effect of dichloromethane fraction of E. punicifolia extract (Ep-CM) in the muscular lesion of mdx dystrophic mice, considering that activation of cholinergic mechanisms mitigates inflammation. A polymer containing the Ep-CM was implanted in mdx gastrocnemius muscle before onset of myonecrosis for local slow and gradual release of bioactive compounds and mice sacrificed 7 days or 9 weeks after surgery. Comparing to control muscle, treatment did not alter choline acetyltransferase and acetylcholinesterase enzymatic activities, but decreased metaloproteases-9 and-2 activities and levels of tumor necrosis factor a and NFkB transcription factor. In addition, treatment also reduced levels of bioactive IL-1b form and cleaved caspase-3, related to early events of cellular death and inflammatory activation and further increased myogenin expression without affecting collagen production which is associated with fibrosis. In vivo treatment of mdx dystrophic mice with Ep-CM caused significant reduction of muscular inflammation and improved skeletal muscle regeneration without inducing fibrosis.