RESUMO
Prolonged and persistent hypermetabolism and excessive inflammatory response after severe trauma is detrimental and associated with poor outcome. The predisposing pathology or signals mediating this complex response are essentially unknown. As the liver is the central organ mediating the systemic metabolic responses and considering that adult hepatic stem cells are on top of the hierarchy of cell differentiation and may pass epigenetic information to their progeny, we asked whether liver progenitor cells are activated, signal hypermetabolism upon post-traumatic cellular stress responses, and pass this to differentiated progeny. We generated Sox9CreERT2 : ROSA26 EYFP mice to lineage-trace the periportal ductal progenitor cells (PDPCs) and verify the fate of these cells post-burn. We observed increased proliferation of PDPCs and their progeny peaking around two weeks post-burn, concomitant with the hepatomegaly and the cellular stress responses. We then sorted out PDPCs, PDPC-derived hepatocytes and mature hepatocytes, compared their transcriptome and showed that PDPCs and their progeny present a significant up-regulation in signalling pathways associated with inflammation and metabolic activation, contributing to persistent hypermetabolic and hyper-inflammatory state. Furthermore, concomitant down-regulation of LXR signalling in PDPCs and their progeny implicates the therapeutic potential of early and short-term administration of LXR agonists in ameliorating such persistent hypermetabolism.
Assuntos
Fígado/irrigação sanguínea , Fígado/patologia , Sistema Porta/patologia , Células-Tronco/patologia , Ferimentos e Lesões/metabolismo , Animais , Queimaduras/complicações , Queimaduras/genética , Queimaduras/patologia , Proliferação de Células , Regulação para Baixo , Hepatomegalia/etiologia , Hepatomegalia/patologia , Temperatura Alta , Inflamação/complicações , Inflamação/genética , Inflamação/patologia , Receptores X do Fígado/metabolismo , Camundongos Transgênicos , Receptores do Ácido Retinoico/metabolismo , Transdução de Sinais , Estresse Fisiológico , Transcriptoma/genética , Ferimentos e Lesões/complicações , Ferimentos e Lesões/genéticaRESUMO
Competitive interactions can have striking and enduring effects on behavior, but the mechanisms underlying this experience-induced plasticity are unclear, particularly in females. Naked mole-rat (NMR) colonies are characterized by the strictest social and reproductive hierarchy among mammals, and represent an ideal system for studies of social competition. In large matriarchal colonies, breeding is monopolized by one female and 1-3 males, with other colony members being socially subordinate and reproductively suppressed. To date, competition for breeding status has been examined in-colony, with female, but not male, aggression observed following the death/removal of established queens. To determine whether this sex difference extends to colony-founding contexts, and clarify neural and endocrine mechanisms underlying behavioral change in females competing for status, we examined neurogenesis and steroid hormone concentrations in colony-housed subordinates, and NMRs given the opportunity to transition status via pair-housing. To this end, Ki-67 and doublecortin immunoreactivity were compared in the hippocampal dentate gyrus (DG) and basolateral amygdala (BLA) of colony-housed subordinates, and subordinates housed with a same-sex (SS) or opposite-sex (OS) conspecific. Results suggest that OS pairing in eusocial mammals promotes cooperation and enhances hippocampal plasticity, while SS pairing is stressful, resulting in enhanced HPA activation and muted hippocampal neurogenesis relative to OS pairs. Data further indicate that competition for status is confined to females, with female-female housing exerting contrasting effects on hippocampal and amygdalar neurogenesis. These findings advance understanding of social stress effects on neuroplasticity and behavior, and highlight the importance of including female-dominated species in research on aggression and intrasexual competition.
Assuntos
Hormônios/sangue , Abrigo para Animais , Ratos-Toupeira/fisiologia , Neurogênese/fisiologia , Caracteres Sexuais , Comportamento Social , Animais , Proteína Duplacortina , Feminino , Habitação , Masculino , Ratos-Toupeira/sangue , Plasticidade Neuronal/fisiologia , Reprodução/fisiologia , Meio SocialRESUMO
Anti-Black racism has contributed to significant disparities in health status for Black individuals in Canada. Dermatology is one area where these health disparities are evident. Lack of appropriate medical education regarding dermatologic conditions in persons of color has been associated with worse health outcomes. This project improved representation in a preclerkship dermatology medical school curriculum, through a constructivist approach, by adding images and discussion points of skin diseases in persons of color to existing teaching sessions. Student evaluations demonstrated strong agreement with improved exposure to images of dark skin and improved comfort in identifying skin conditions in persons of color. This intervention represents an effective approach to updating representation in the dermatology curriculum.
RESUMO
BACKGROUND: Profound skeletal muscle wasting and weakness is common after severe burn and persists for years after injury contributing to morbidity and mortality of burn patients. Currently, no ideal treatment exists to inhibit muscle catabolism. Metformin is an anti-diabetic agent that manages hyperglycemia but has also been shown to have a beneficial effect on stem cells after injury. We hypothesize that metformin administration will increase protein synthesis in the skeletal muscle by increasing the proliferation of muscle progenitor cells, thus mitigating muscle atrophy post-burn injury. METHODS: To determine whether metformin can attenuate muscle catabolism following burn injury, we utilized a 30% total burn surface area (TBSA) full-thickness scald burn in mice and compared burn injuries with and without metformin treatment. We examined the gastrocnemius muscle at 7 and 14 days post-burn injury. RESULTS: At 7 days, burn injury significantly reduced myofiber cross-sectional area (CSA) compared to sham, p < 0.05. Metformin treatment significantly attenuated muscle catabolism and preserved muscle CSA at the sham size. To investigate metformin's effect on satellite cells (muscle progenitors), we examined changes in Pax7, a transcription factor regulating the proliferation of muscle progenitors. Burned animals treated with metformin had a significant increase in Pax7 protein level and the number of Pax7-positive cells at 7 days post-burn, p < 0.05. Moreover, through BrdU proliferation assay, we show that metformin treatment increased the proliferation of satellite cells at 7 days post-burn injury, p < 0.05. CONCLUSION: In summary, metformin's various metabolic effects and its modulation of stem cells make it an attractive alternative to mitigate burn-induced muscle wasting while also managing hyperglycemia.
Assuntos
Queimaduras/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Metformina/farmacologia , Metformina/farmacocinética , Músculo Esquelético/citologia , Músculo Esquelético/efeitos dos fármacos , Atrofia Muscular/tratamento farmacológico , Fator de Transcrição PAX7/metabolismo , Células-Tronco/efeitos dos fármacos , Animais , Queimaduras/metabolismo , Queimaduras/patologia , Hipoglicemiantes/farmacologia , Masculino , Camundongos , Atrofia Muscular/patologia , Células-Tronco/citologiaRESUMO
In recent decades, there have been tremendous improvements in burn care that have allowed patients to survive severe burn injuries that were once fatal. However, a major limitation of burn care currently is the development of hypertrophic scars in approximately 70% of patients. This significantly decreases the quality of life for patients due to the physical and psychosocial symptoms associated with scarring. Current approaches to manage scarring include surgical techniques and non-surgical methods such as laser therapy, steroid injections, and compression therapy. These treatments are limited in their effectiveness and regularly fail to manage symptoms. As a result, the development of novel treatments that aim to improve outcomes and quality of life is imperative. Drug delivery that targets the molecular cascades of wound healing to attenuate or prevent hypertrophic scarring is a promising approach that has therapeutic potential. In this review, we discuss current treatments for scar management after burn injury, and how drug delivery targeting molecular signaling can lead to new therapeutic strategies.
Assuntos
Queimaduras/complicações , Queimaduras/tratamento farmacológico , Cicatriz Hipertrófica/tratamento farmacológico , Cicatriz Hipertrófica/etiologia , Sistemas de Liberação de Medicamentos , Transdução de Sinais/efeitos dos fármacos , HumanosRESUMO
BACKGROUND: Severe burn results in a systemic response that leads to significant muscle wasting. It is believed that this rapid loss in muscle mass occurs due to increased protein degradation combined with reduced protein synthesis. Alterations in the microenvironment of muscle progenitor cells may partially account for this pathology. The aim of this study was to ascertain the response of muscle progenitor cells following thermal injury in mice and to enlighten the cellular cascades that contribute to the muscle wasting. METHODS: C57BL/6 mice received a 20% total body surface area (TBSA) thermal injury. Gastrocnemius muscle was harvested at days 2, 7, and 14 following injury for protein and histological analysis. RESULTS: We observed a decrease in myofiber cross-sectional area at 2 days post-burn. This muscle atrophy was compensated for by an increase in myofiber cross-sectional area at 7 and 14 days post-burn. Myeloperoxidase (MPO)-positive cells (neutrophils) increased significantly at 2 days. Moreover, through Western blot analysis of two key mediators of the proteolytic pathway, we show there is an increase in Murf1 and NF-κB 2 days post-burn. MPO-positive cells were also positive for NF-κB, suggesting that neutrophils attain NF-κB activity in the muscle. Unlike inflammatory and proteolytic pathways, the number of Pax7-positive muscle progenitor cells decreased significantly 2 days post-burn. This was followed by a recovery in the number of Pax7-positive cells at 7 and 14 days, suggesting proliferation of muscle progenitors that accompanied regrowth. CONCLUSION: Our data show a biphasic response in the muscles of mice exposed to burn injury, with phenotypic characteristics of muscle atrophy at 2 days while compensation was observed later with a change in Pax7-positive muscle progenitor cells. Targeting muscle progenitors may be of therapeutic benefit in muscle wasting observed after burn injury.