The role of endogenous H2S formation in reversible remodeling of lung tissue during hibernation in the Syrian hamster

During hibernation, small mammals alternate between periods of metabolic suppression and low body temperature ('torpor') and periods of full metabolic recovery with euthermic temperatures ('arousal'). Previously, we demonstrated marked structural remodeling of the lung during torpor, which is rapidly reversed during arousal. We also found that cooling of hamster cells increased endogenous production of H2S through the enzyme cystathionine-beta-synthase (CBS). H2S suppresses the immune response and increases deposition of collagen. Therefore, we examined inflammatory markers and matrix metalloproteinase (MMP) activity in relation to CBS expression and H2S levels in lungs of euthermic and hibernating Syrian hamsters. Lung remodeling during torpor was confirmed by a strong increase in both collagenous and non-collagenous hydroxyproline content. The number of leukocytes in lung was unchanged in any phase of hibernation, while adhesion molecules VCAM-1 and ICAM-1, and the inflammatory marker NF-kappa B (P65) were modestly upregulated in torpor. Gelatinase activity was decreased in lungs from torpid animals, indicating inhibition of the Zn2+-dependent MMP-2 and MMP-9. Moreover, expression of CBS and tissue levels of H2S were increased in torpor. All changes normalized during arousal. Inhibition of gelatinase activity in torpor is likely caused by quenching of Zn2+ by the sulphide ion of H2S. In accord, inhibition of CBS normalized gelatinase activity in torpid animals. Conversely, NaHS decreased the gelatinase activity of euthermic animals, which was attenuated by excess Zn2+. Similar results were obtained on the activity of the Zn2+-dependent angiotensin converting enzyme. Our data indicate that increased production of H2S through CBS in hamster lungs during torpor contributes to remodeling by inhibition of gelatinase activity and possibly by suppression of the inflammatory response. Although administration of H2S is known to induce metabolic suppression in nonhibernating mammals ('suspended animation'), this is the first report implying endogenous H2S production in natural hibernation

Induction of a Torpor-Like State by 5 '-AMP Does Not Depend on H2S Production

Therapeutic hypothermia is used to reduce ischemia/reperfusion injury (IRI) during organ transplantation and major surgery, but does not fully prevent organ injury. Interestingly, hibernating animals undergo repetitive periods of low body temperature called 'torpor' without signs of organ injury. Recently, we identified an essential role of hydrogen sulfide (H2S) in entrance into torpor and preservation of kidney integrity during hibernation. A torpor-like state can be induced pharmacologically by injecting 5'-Adenosine monophosphate (5'-AMP). The mechanism by which 5'-AMP leads to the induction of a torpor-like state, and the role of H2S herein, remains to be unraveled. Therefore, we investigated whether induction of a torpor-like state by 5-AMP depends on H2S production.To study the role of H2S on the induction of torpor, amino-oxyacetic acid (AOAA), a non-specific inhibitor of H2S, was administered before injection with 5'-AMP to block endogenous H2S production in Syrian hamster. To assess the role of H2S on maintenance of torpor induced by 5'-AMP, additional animals were injected with AOAA during torpor.During the torpor-like state induced by 5'-AMP, the expression of H2S- synthesizing enzymes in the kidneys and plasma levels of H2S were increased. Blockade of these enzymes inhibited the rise in the plasma level of H2S, but neither precluded torpor nor induced arousal. Remarkably, blockade of endogenous H2S production was associated with increased renal injury.Induction of a torpor-like state by 5'-AMP does not depend on H2S, although production of H2S seems to attenuate renal injury. Unraveling the mechanisms by which 5'-AMP reduces the metabolism without organ injury may allow optimization of current strategies to limit (hypothermic) IRI and improve outcome following organ transplantation, major cardiac and brain surgery

Reversible remodeling of lung tissue during hibernation in the Syrian hamster

During hibernation, small rodents such as hamsters cycle through phases of strongly suppressed metabolism with low body temperature (torpor) and full restoration of metabolism and body temperature (arousal). Remarkably, the repetitive stress of cooling-rewarming and hypoxia does not cause irreversible organ damage. To identify adaptive mechanisms protecting the lungs, we assessed histological changes as well as the expression and localization of proteins involved in tissue remodeling in lungs from Syrian hamsters at different phases of hibernation using immunohistochemical staining and western blot analysis. In torpor (early and late) phase, a reversible increased expression of smooth muscle actin, collagen, angiotensin converting enzyme and transforming growth factor-beta was found, whereas expression of the epidermal growth factor receptor and caveolin-1 was low. Importantly, all these alterations were restored during arousal. This study demonstrates substantial alterations in protein expression mainly in epithelial cells of lungs from hibernating Syrian hamsters. These structural changes of the bronchial airway structure are termed airway remodeling and often occur in obstructive lung diseases such as asthma, chronic obstructive pulmonary disease (COPD) and lung fibrosis. Unraveling the molecular mechanism leading to reversal of airway remodeling by the end of torpor may identify possible therapeutic targets to reduce progression of this process in patients suffering from asthma, chronic obstructive pulmonary disease and lung fibrosis

The TNFR1 antagonist Atrosimab reduces neuronal loss, glial activation and memory deficits in an acute mouse model of neurodegeneration

Abstract Tumor necrosis factor alpha (TNF-α) and its key role in modulating immune responses has been widely recognized as a therapeutic target for inflammatory and neurodegenerative diseases. Even though inhibition of TNF-α is beneficial for the treatment of certain inflammatory diseases, total neutralization of TNF-α largely failed in the treatment of neurodegenerative diseases. TNF-α exerts distinct functions depending on interaction with its two TNF receptors, whereby TNF receptor 1 (TNFR1) is associated with neuroinflammation and apoptosis and TNF receptor 2 (TNFR2) with neuroprotection and immune regulation. Here, we investigated the effect of administering the TNFR1-specific antagonist Atrosimab, as strategy to block TNFR1 signaling while maintaining TNFR2 signaling unaltered, in an acute mouse model for neurodegeneration. In this model, a NMDA-induced lesion that mimics various hallmarks of neurodegenerative diseases, such as memory loss and cell death, was created in the nucleus basalis magnocellularis and Atrosimab or control protein was administered centrally. We showed that Atrosimab attenuated cognitive impairments and reduced neuroinflammation and neuronal cell death. Our results demonstrate that Atrosimab is effective in ameliorating disease symptoms in an acute neurodegenerative mouse model. Altogether, our study indicates that Atrosimab may be a promising candidate for the development of a therapeutic strategy for the treatment of neurodegenerative diseases

Características das espécies que podem influenciar as dinâmicas populacionais de beija-flores na Floresta Atlântica no Sul do Brasil

Orientador : Prof. Dr. James Joseph RoperTese (doutorado) - Universidade Federal do Paraná, Setor de Ciências Biológicas, Programa de Pós-Graduação em Ecologia e Conservação. Defesa: Curitiba, 18/03/2016Inclui referências : f. 08-14;24-28;56-62;112-120Área de concentração : Ecologia e conservaçãoResumo: A dinâmica populacional em beija-flores na América do Sul é praticamente desconhecida e pouco estudada, devido à dificuldade de captura e, consequentemente, ao baixo número de marcações e recapturas. No entanto, pela diversidade de espécies desta família e sua ampla distribuição, e o papel que desempenha na polinização de recursos efêmeros, entender a sua dinâmica populacional é importante para compreender também a sua ecologia e evolução. Aqui, começamos a preencher esta lacuna através da utilização de estudos de captura-marcação-recaptura para examinar a dinâmica da população e outros aspectos da ecologia de beija-flores. Examinamos a muda de algumas espécies e o dimorfismo sexual e identificação sexual molecular em um grupo de cinco espécies aparentemente monomórficas. Todas as espécies de beija-flores na área de estudo tendem a migrar, mas os detalhes da migração e as comparações foram difíceis de determinar, já que os indivíduos marcados não foram recapturados longe da nossa área. A espécie mais abundante e consistentemente comum foi o beija-flor-de-papo-branco (Leucochloris albicollis), com tamanho populacional variando aproximadamente entre 150-450 indivíduos (variação mensal), e com o pico de abundância em março, após a aparente temporada de reprodução entre novembro e dezembro. A sobrevivência para esta espécie foi estimada em 33% ao ano, o que é baixa para uma ave tropical. O padrão da muda das penas primárias de voo em nossa assembleia é semelhante ao já registrado em outras assembleias de beija-flores, no sentido proximal para o distal. Entretanto, em nossas espécies houve menos variação na sequência de troca das penas mais distais em comparação aos outros estudos. A muda das penas secundárias foi mais variável na sequência de troca, enquanto as retrices foram mais consistentes. O período de muda iniciou-se a partir de dezembro e se estendeu até meados de abril, mas determinar corretamente a duração do período foi difícil, uma vez que alguns indivíduos migraram enquanto realizavam a muda, delimitando a recaptura para determinar o período concreto. Três das cinco espécies aparentemente monomórficas - uma vez que o sexo foi identificado através de nossa nova técnica molecular para beija-flores - são sexualmente dicromáticas (Colibri serrirostris, Eupetomena macroura, L. albicollis) na reflexão de luz UV em suas penas. O tamanho e forma, no entanto, foram semelhantes em ambos os sexos para todas as espécies. Estes resultados demonstram que algumas espécies de beija-flores podem ser muito abundantes, mas que esta abundância pode variar amplamente ao longo do ano. Também, mostramos a existência de migração durante a muda, porém sem detalhamentos sobre a duração total deste período, permanecendo esta questão ainda desconhecida. As taxas de sobrevivência foram baixas para L. albicollis comparadas à outras espécies de aves tropicais, sugerindo relativamente alto sucesso reprodutivo. Por fim, mostramos dicromatismo sexual à luz UV (imperceptível aos seres humanos) em três das cinco espécies, sugerindo que pode haver também nas demais, mas que precisa ser descoberto em uma análise mais aprofundada das penas de outras regiões do corpo. Assim, com este estudo nós iniciamos um melhor entendimento das dinâmicas populacionais em beija-flores. Palavras-chave: coloração, dimorfismo sexual, dinâmicas populacionais, morfometria, muda das penas de voo, sexagem, TrochilidaeAbstract: Population dynamics in hummingbirds in South America is virtually unknown and unstudied, due to difficulty in their capture in numbers for mark and recapture studies. Yet, due to species diversity, distributions, the role they play as pollinators of ephemeral resources and their colorful displays, study of their population dynamics is important for understanding their ecology and evolution. Here, we begin to fill this lacuna by using capture-mark-recapture to examine population dynamics, and other aspects of hummingbird ecology. We examined molt in a variety of species and sexual dimorphism and molecular identification of the sexes in a group of five apparently monomorphic species. All hummingbird species in the study area tend to migrate, but details of migration and comparisons are difficult to determine because marked birds were never recaptured away from the study area. The most abundant and consistently common species, the Whitethroated Hummingbird (Leucochloris albicollis) had a population size that varied from ~150-450 individuals (monthly variation) in the study area, with the peak abundance in March, following after the apparent breeding season in November-December. Survival was estimated at 33% per year, which is low for a tropical bird. Molt is similar to that of other hummingbirds, from proximal to distal primary feathers, but in our study species varied less in the sequence of the most distal feathers as compared to other studies. Secondaries were quite variable in their sequence of molt, while retrices were more consistent. Molt took place beginning in December and continued to April, but defining the end of molt was difficult because species migrate while undergoing molt, and so recaptures to delimit the end of molt was not possible. Three of the five apparently monomorphic species, once sex was identified through our new molecular technique for hummingbirds, were sexually dichromatic (Colibri serrirostris, Eupetomena macroura, L. albicollis) in UV light reflectance in their feathers. Size and shape, however, were similar in both sexes. With these results, we find that hummingbird species can be very abundant, but abundance varies widely over the year, they migrate while molting but the details of their end points of migration remain unknown, and survival rates are low, suggesting relatively high reproductive success. We show sexual dichromatism in UV light (which humans do not perceive) in three of five species, and suggest that the others also are dichromatic, which will be discovered on further examination of the appropriate feathers. Thus, with this study we have begun to better understand hummingbird population dynamics. Keywords: coloration, molting of flight feathers, morphometry, population dynamics, sexing, sexual dimorphism, Trochilida

The influence of sex and diet on the characteristics of hibernation in Syrian hamsters

Research on deep hibernators almost exclusively uses species captured from the wild or from local breeding. An exception is Syrian hamster (Mesocricetus auratus), the only standard laboratory animal showing deep hibernation. In deep hibernators, several factors influence hibernation quality, including body mass, sex and diet. We examined hibernation quality in commercially obtained Syrian hamsters in relation to body mass, sex and a diet enriched in polyunsaturated fatty acids. Animals (M/F:30/30, 12 weeks of age) were obtained from Harlan (IN, USA) and individually housed at 21 A degrees C and L:D 14:10 until 20 weeks of age, followed by L:D 8:16 until 27 weeks. Then conditions were changed to 5 A degrees C and L:D 0:24 for 9 weeks to induce hibernation. Movement was continuously monitored with passive infrared detectors. Hamsters were randomized to control diet or a diet 3x enriched in linoleic acid from 16 weeks of age. Hamsters showed a high rate of premature death (n = 24, 40%), both in animals that did and did not initiate torpor, which was unrelated to body weight, sex and diet. Time to death (31.7 +/- 3.1 days, n = 12) or time to first torpor bout (36.6 +/- 1.6 days, n = 12) was similar in prematurely deceased hamsters. Timing of induction of hibernation and duration of torpor and arousal was unaffected by body weight, sex or diet. Thus, commercially obtained Syrian hamsters subjected to winter conditions showed poor survival, irrespective of body weight, sex and diet. These factors also did not affect hibernation parameters. Possibly, long-term commercial breeding from a confined genetic background has selected against the hibernation trait