Avaliação da ação do citral na inflamação sistêmica induzida por lipopolissacarideo em camundongos obesos com dieta hiperlipídica
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Data
2020-02-19
Autores
Silva, Maycon Tavares Emilio
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Universidade Estadual Paulista (Unesp)
Resumo
A obesidade é considerada um problema de saúde pública, que tem crescido em diversos países pelo mundo. A ingestão de uma dieta rica em gordura leva a um progressivo aumento de tecido adiposo e desencadeia alterações na modulação do sistema imunológico, elevando a concentração de fator de necrose tumoral (TNF)-α, interleucina (IL)-6 e leptina, considerados biomarcadores inflamatórios sistêmicos. O processo inflamatório crônico associado ao quadro de obesidade aumenta a suscetibilidade a infecções, e resulta em alterações na homeostasia do hospedeiro capaz de promover respostas efetoras a fim de protegê-lo do patógeno. Uma das principais respostas desencadeadas pelo processo inflamatório é variação da temperatura corporal (Tc), devido a produção de mediadores inflamatórios periféricos e centrais, tais como interleucina (IL)-1β, IL-6, TNF-α. Visando minimizar os efeitos danosos da inflamação sistêmica, medicamentos como os anti-inflamatórios não esteroidais (AINEs) são empregados na terapêutica atual, porém o uso indiscriminado e crônico pode causar danos significativos aos usuários, como a formação de úlceras gástricas. O presente projeto avalia a ação do citral, um monoterpeno encontrado na composição de diferentes óleos essenciais de plantas medicinais. A literatura já relata a ação anti-inflamatória, antipirética e anti-hiperlipidêmica do citral. Porém, não são descritos a ação do citral na inflamação sistêmica induzida pelo lipopolissacarideo (LPS) em camundongos eutróficos e obesos. Para isso, utilizados camundongos Swiss machos, alimentados durante 12 semanas com dieta padrão (DP) e hiperlipídica (HFD) e posteriormente, avaliamos a ação do citral (25, 100 e 300 mg/kg) na inflamação sistêmica induzida pela injeção intraperitoneal (i.p.) de LPS. Após a administração de LPS, obtivemos os dados da Tc e dosagens de marcadores bioquímicos no soro, no hipotálamo e na mucosa gástrica. Nossos resultados comprovam a indução da obesidade pela HFD durante 12 semanas, com o significativo aumento do peso corporal e do tecido adiposo (epididimal, retroperitoneal e visceral) e alguns órgãos (fígado, baço e rins), quando comparado com os animais DP. O tratamento dos animais com citral promoveu ação dose dependente no perfil da Tc, tanto em animais DP quanto HFD. O índice térmico dos animais tratados com citral (300 mg/kg) foi significativamente menor nos animais obesos tratados com a HFD quando comparado aos animais DP, indicando uma efetiva ação criogênico desse monoterpeno no grupo obeso. O tratamento dos camundongos com citral causou redução na sinalização inflamatória periférica de TNF-α em animais DP e HFD, além de reduzir a concentração sérica de leptina em animais HFD após o desafio com LPS no período de 90 minutos. No sistema nervoso central (SNC), o citral atua reduzindo a concentração de IL-6 no hipotálamo de animais HFD. Também caracterizamos parâmetros bioquímicos renais (uréia e creatinina) e hepáticos (AST, ALT, fostatase alcalina e γ-GT) de animais expostos ao LPS e tratados com citral ou ibuprofeno (IBU), um AINEs clássico. Os parâmetros bioquímicos indicam que a dieta HFD reduziu os níveis de fosfatase alcalina dos animais obesos em comparação aos animais DP. O citral (100 mg/kg) também reduziu os níveis de fosfatase alcalina dos animais DP e elevou os níveis de ALT nos animais HFD em comparação com seus respectivos animais controle (tratados com Tween 80 + Salina). Na mucosa gástrica dos animais DP e HFD tratados com citral ou IBU não houve alterações dos níveis de marcadores para estresse oxidativo (malondialdeido - MDA e glutationa reduzida - GSH), assim como de inflamação local (mieloperoxidase - MPO). O citral atua de forma efetiva durante a inflamação sistêmica, com ação diferenciada em animais HFD quando comparado com DP.
Obesity is considered a public health problem, which has growing in many countries around the world. Ingestion of a rich fat diet leads to a progressive increase in adipose tissue and triggers changes in immune system modulation, increasing the concentration of systemic biomarkers such as tumor necrosis factor (TNF)-α, interleukin (IL)-6 and leptin. The low-grade chronic inflammation associated with obesity increases the susceptibility to infections, which results in changes in host homeostasis capable of promoting effector responses in order to protect it from the pathogen. One of the main responses triggered during the systemic inflammation is the body temperature variation, defined as a controlled increase in Tc due to the production of peripheral and central inflammatory mediators such as systemically produced IL-1β, IL-6, TNF-α. In order to minimize the harmful effects of systemic inflammation, drugs such as non-steroidal anti-inflammatories drugs (NSAIDs) are used in current therapy, but the indiscriminate and chronic use can cause significant harm to users, such as the formation of gastric ulcers. This project presents data on the action of citral, a monoterpene found in different essential oils of medicinal plants with anti-inflammatory action, antipyretic and antihyperlipidemic reported in the literature. For this, we used male Swiss mice, fed for 12 weeks with standard diet (SD) and high-fat diet (HFD). We evaluated the action of citral (25, 100 and 300 mg/kg) on LPS-induced systemic inflammation. After LPS-injetion intraperitoneal i.p., we obtained Tc data and collected samples of serum and gastric mucosa for biochemical and molecular dosages. Our results confirm the induction of obesity with HFD, with the significant increase in body weight and adipose tissue (epididymal, retroperitoneal and visceral) and organs (liver, spleen and kidneys) when compared with SD mice. Citral showed dose dependent action on body temperature profile in animals SD and HFD. The thermal index of citral-treated animals (300 mg/kg) was significantly lower in HFD-treated obese animals when compared to SD animals, indicating an effective cryogenic action of this essential oil in the obese group. Citral treatment reduced the peripheral inflammatory signaling of TNF-α in SD and HFD animals and reduced the plasma leptin concentration in HFD animals after LPS challenge by 90 minutes. Also, the citral reduced the concentration of IL-6 levels in the hypothalamus of obese mice. We also characterize renal (urea and creatinine) and hepatic (AST, ALT, alkaline phosphatase and γ-GT) biochemical parameters of animals exposed to LPS and treated with citral and ibuprofen (IBU), a classic NSAIDs. Biochemical parameters indicate that the HFD diet reduced the alkaline phosphatase levels of obese animals compared to SD animals. Citral (100 mg/kg) also reduced the alkaline phosphatase levels of the SD animals and raised the ALT levels in the HFD animals compared to their respective control animals (Tween 80 + Saline). In the evaluation of gastric mucosa of SD and HFD animals treated with citral or IBU it was possible to characterize that there was no change in the levels of markers for oxidative stress (malondialdehyde - MDA and reduced glutathione - GSH) and local inflammation (myeloperoxidase - MPO). The results obtained so far demonstrate that the citral acts to effectively reduce body temperature during systemic inflammation, with a different action profile in HFD animals when compared to SD.
Obesity is considered a public health problem, which has growing in many countries around the world. Ingestion of a rich fat diet leads to a progressive increase in adipose tissue and triggers changes in immune system modulation, increasing the concentration of systemic biomarkers such as tumor necrosis factor (TNF)-α, interleukin (IL)-6 and leptin. The low-grade chronic inflammation associated with obesity increases the susceptibility to infections, which results in changes in host homeostasis capable of promoting effector responses in order to protect it from the pathogen. One of the main responses triggered during the systemic inflammation is the body temperature variation, defined as a controlled increase in Tc due to the production of peripheral and central inflammatory mediators such as systemically produced IL-1β, IL-6, TNF-α. In order to minimize the harmful effects of systemic inflammation, drugs such as non-steroidal anti-inflammatories drugs (NSAIDs) are used in current therapy, but the indiscriminate and chronic use can cause significant harm to users, such as the formation of gastric ulcers. This project presents data on the action of citral, a monoterpene found in different essential oils of medicinal plants with anti-inflammatory action, antipyretic and antihyperlipidemic reported in the literature. For this, we used male Swiss mice, fed for 12 weeks with standard diet (SD) and high-fat diet (HFD). We evaluated the action of citral (25, 100 and 300 mg/kg) on LPS-induced systemic inflammation. After LPS-injetion intraperitoneal i.p., we obtained Tc data and collected samples of serum and gastric mucosa for biochemical and molecular dosages. Our results confirm the induction of obesity with HFD, with the significant increase in body weight and adipose tissue (epididymal, retroperitoneal and visceral) and organs (liver, spleen and kidneys) when compared with SD mice. Citral showed dose dependent action on body temperature profile in animals SD and HFD. The thermal index of citral-treated animals (300 mg/kg) was significantly lower in HFD-treated obese animals when compared to SD animals, indicating an effective cryogenic action of this essential oil in the obese group. Citral treatment reduced the peripheral inflammatory signaling of TNF-α in SD and HFD animals and reduced the plasma leptin concentration in HFD animals after LPS challenge by 90 minutes. Also, the citral reduced the concentration of IL-6 levels in the hypothalamus of obese mice. We also characterize renal (urea and creatinine) and hepatic (AST, ALT, alkaline phosphatase and γ-GT) biochemical parameters of animals exposed to LPS and treated with citral and ibuprofen (IBU), a classic NSAIDs. Biochemical parameters indicate that the HFD diet reduced the alkaline phosphatase levels of obese animals compared to SD animals. Citral (100 mg/kg) also reduced the alkaline phosphatase levels of the SD animals and raised the ALT levels in the HFD animals compared to their respective control animals (Tween 80 + Saline). In the evaluation of gastric mucosa of SD and HFD animals treated with citral or IBU it was possible to characterize that there was no change in the levels of markers for oxidative stress (malondialdehyde - MDA and reduced glutathione - GSH) and local inflammation (myeloperoxidase - MPO). The results obtained so far demonstrate that the citral acts to effectively reduce body temperature during systemic inflammation, with a different action profile in HFD animals when compared to SD.
Descrição
Palavras-chave
Obesidade, Inflamação Sistêmica, LPS, Citral