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1.
Brain Behav Immun ; 82: 264-278, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31476414

RESUMO

Isorhynchophylline (IRN) has been demonstrated to have distinct anti-Alzheimer's disease (AD) activity in several animal models of AD. In this study, we aimed at evaluating the preventive effect of IRN on the cognitive deficits and amyloid pathology in TgCRND8 mice. Male TgCRND8 mice were administered with IRN (20 or 40 mg/kg) by oral gavage daily for 4 months, followed by assessing the spatial learning and memory functions with the Radial Arm Maze (RAM) test. Brain tissues were determined immunohistochemically or biochemically for changes in amyloid pathology, tau hyperphosphorylation and neuroinflammation. Our results revealed that IRN (40 mg/kg) significantly ameliorated cognitive deficits in TgCRND8 mice. In addition, IRN (40 mg/kg) markedly reduced the levels of Aß40, Aß42 and tumor necrosis factor (TNF-α), interleukin 6 (IL-6) and IL-1ß, and modulated the amyloid precursor protein (APP) processing and phosphorylation by altering the protein expressions of ß-site APP cleaving enzyme-1 (BACE-1), phosphorylated APP (Thr668), presenilin-1 (PS-1) and anterior pharynx-defective-1 (APH-1), as well as insulin degrading enzyme (IDE), a major Aß-degrading enzyme. IRN was also found to inhibit the phosphorylation of tau at the sites of Thr205 and Ser396. Immunofluorescence showed that IRN reduced the Aß deposition, and suppressed the activation of microglia (Iba-1) and astrocytes (GFAP) in the cerebral cortex and hippocampus of TgCRND8 mice. Furthermore, IRN was able to attenuate the ratios of p-c-Jun/c-Jun and p-JNK/JNK in the brains of TgCRND8 mice. IRN also showed marked inhibitory effect on JNK signaling pathway in the Aß-treated rat primary hippocampus neurons. We conclude that IRN improves cognitive impairment in TgCRND8 transgenic mice via reducing Aß generation and deposition, tau hyperphosphorylation and neuroinflammation through inhibiting the activation of JNK signaling pathway, and has good potential for further development into pharmacological treatment for AD.

2.
Free Radic Biol Med ; 143: 454-470, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31472247

RESUMO

Brachial plexus avulsion (BPA) occurs when the spinal nerve roots are pulled away from the surface of the spinal cord and disconnects neuronal cell body from its distal downstream axon, which induces massive motoneuron death, motor axon degeneration and de-innervation of targeted muscles, thereby resulting in permanent paralysis of motor functions in the upper limb. Avulsion injury triggers oxidative stress and intense local neuroinflammation at the lesioned site, leading to the death of most motoneurons. Berberine (BBR), a natural isoquinoline alkaloid derived from medicinal herbs of Berberis and Coptis species, has been reported to possess neuro-protective, anti-inflammatory and anti-oxidative effects in various animal models of central nervous system (CNS)-related disorders. In this study, we aimed to investigate the effect of BBR on motoneuron survival and axonal regeneration following spinal root avulsion plus re-implantation in rats. Our results indicated BBR significantly accelerated motor function recovery in the forelimb as revealed by the increased Terzis grooming test score, facilitated motor axon regeneration as evidenced by the elevated number of Fluoro-Gold-labeled and P75-positive regenerative motoneurons. The survival of motoneurons was notably promoted by BBR administration presented with boosted ChAT-immunopositive and neutral red-stained neurons. BBR treatment efficiently alleviated muscle atrophy, attenuated functional motor endplates loss in biceps and prevented the reduction of motor axons in the musculocutaneous nerve. Additionally, BBR treatment markedly mitigated the avulsion-induced neuroinflammation via inhibiting microglial and astroglial reactivity, up-regulated the expression of antioxidative indicator Cu/Zn SOD, and down-regulated the levels of nNOS, 3-NT, lipid peroxidation and NF-κB, as well as promoted SIRT1, PI3K and Akt activation. Collectively, BBR might be a promising therapy to assist re-implantation surgery for the treatment of BPA.

3.
J Ethnopharmacol ; 234: 44-56, 2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-30610932

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Chrysanthemum indicum Linne (C. indicum), a healthy food and folk medicine in China for thousands of years, has been reported to exert heat-clearing and detoxifying effects and extensively applied to treat various symptoms such as inflammation diseases, hepatitis and headache. AIM OF THIS STUDY: The purpose of the present study was to investigate the protective effect of the supercritical carbon dioxide fluid extract from flowers and buds of C. indicum (CISCFE) on D-galactose-induced brain and liver damage during aging process and to illuminate the underlying mechanisms. MATERIALS AND METHODS: Mice were orally administrated with CISCFE (100, 150 and 300 mg/kg) after injection with D-galactose. 24 h after the last administration, the blood samples, whole brain and liver tissues were collected for biochemical analysis, histological examination and western blot analysis. The body weight, spleen and thymus indexes, alanine transaminase (ALT), aspartate transaminase (AST), total antioxidant capacity (T-AOC), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), malondialdehyde (MDA) in brain and liver, interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and necrosis factor-α (TNF-α) were detected. Besides, the expressions of Bax, Bcl-2 and cleaved caspase-3 were determined by western blot assay. RESULTS: The results indicated that CISCFE effectively increased the suppressed body weight, attenuated the decline of thymus and spleen indexes, and reduced the elevated levels of ALT and AST induced by D-gal. Furthermore, CISCFE might notably alleviate D-gal-induced abnormal alterations in structure and function of brain and liver dose-dependently via renewing normal antioxidant enzymes activities (SOD, CAT, GSH-Px), reducing MDA accumulation, decreasing inflammatory cytokines productions (IL-1ß, IL-6, TNF-α), as well as attenuating the increase of Bax/Bcl-2 ratio and cleaved caspase-3 activation in the liver and brain. CONCLUSIONS: Taken together, our present results suggested that CISCFE treatment could effectively mitigate the D-gal-induced hepatic and cerebral injury, and the underlying mechanism might be tightly related to the decreased oxidative stress, inflammation and apoptosis, indicating CISCFE might be an alternative and promising agent for the treatment of aging and age-associated brain and liver diseases.


Assuntos
Chrysanthemum/química , Inflamação/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Envelhecimento/patologia , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Dióxido de Carbono/química , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Flores , Galactose/toxicidade , Inflamação/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos , Extratos Vegetais/administração & dosagem , Superóxido Dismutase/metabolismo
4.
Oncotarget ; 6(3): 1790-805, 2015 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-25595897

RESUMO

Increasing appreciation of tumor heterogeneity and the tumor-host interaction has stimulated interest in developing novel therapies that target both tumor cells and tumor microenvironment. Bone marrow derived cells (BMDCs) constitute important components of the tumor microenvironment. In this study, we aim to investigate the significance of VEGFR1- and VEGFR2-expressing non-tumor cells, including BMDCs, in esophageal cancer (EC) progression and in VEGFR1/VEGFR2-targeted therapies. Here we report that VEGFR1 or VEGFR2 blockade can significantly attenuate VEGF-induced Src and Erk signaling, as well as the proliferation and migration of VEGFR1⁺ and VEGFR2⁺ bone marrow cells and their pro-invasive effect on cancer cells. Importantly, our in vivo data show for the first time that systemic blockade of VEGFR1⁺ or VEGFR2⁺ non-tumor cells with neutralizing antibodies is sufficient to significantly suppress esophageal tumor growth, angiogenesis and metastasis in mice. Moreover, our tissue microarray study of human EC clinical specimens showed the clinicopathological significance of VEGFR1 and VEGFR2 in EC, which suggest that anti-VEGFR1/VEGFR2 therapies may be particularly beneficial for patients with aggressive EC. In conclusion, this study demonstrates the important contributions of VEGFR1⁺ and VEGFR2⁺ non-tumor cells in esophageal cancer progression, and substantiates the validity of these receptors as therapeutic targets for this deadly disease.


Assuntos
Anticorpos Neutralizantes/farmacologia , Neoplasias Esofágicas/terapia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Anticorpos Neutralizantes/imunologia , Neoplasias Esofágicas/irrigação sanguínea , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Nus , Terapia de Alvo Molecular , Estadiamento de Neoplasias , Neovascularização Patológica/terapia , Microambiente Tumoral , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/biossíntese , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/imunologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/biossíntese , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Neurobiol Dis ; 45(1): 219-33, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21871565

RESUMO

PDSS2 is a gene that encodes one of the two subunits of trans-prenyl diphosphate synthase that is essential for ubiquinone biosynthesis. It is known that mutations in PDSS2 can cause primary ubiquinone deficiency in humans and a similar disease in mice. Cerebellum is the most often affected organ in ubiquinone deficiency, and cerebellar atrophy has been diagnosed in many infants with this disease. In this study, two Pdss2 conditional knockout mouse lines directed by Pax2-cre and Pcp2-cre were generated to investigate the effect of ubiquinone deficiency on cerebellum during embryonic development and in adulthood, respectively. The Pdss2(f/-); Pax2-cre mouse recapitulates some symptoms of ubiquinone deficiency in infants, including severe cerebellum hypoplasia and lipid accumulation in skeletal muscles at birth. During early cerebellum development (E12.5-14.5), Pdss2 knockout initially causes the delay of radial glial cell growth and neuron progenitor migration, so the growth of mutant cerebellum is retarded. During later development (E15.5-P0), increased ectopic apoptosis of neuroblasts and impaired cell proliferation result in the progression of cerebellum hypoplasia in the mutant. Thus, the mutant cerebellum contains fewer neurons at birth, and the cells are disorganized. The developmental defect of mutant cerebellum does not result from reduced Fgf8 expression before E12.5. Electron microscopy reveals mitochondrial defects and increased autophagic-like vacuolization that may arise in response to abnormal mitochondria in the mutant cerebellum. Nevertheless, the mutant mice die soon after birth probably due to cleft palate and micrognathia, which may result from Pdss2 knockout caused by ectopic Pax2-cre expression in the first branchial arch. On the other hand, the Pdss2(f/-); Pcp2-cre mouse is healthy at birth but gradually loses cerebellar Purkinje cells and develops ataxia-like symptoms at 9.5 months; thus this conditional knockout mouse may serve as a model for ubiquinone deficiency in adult patients. In conclusion, this study provides two mouse models of Pdss2 based ubiquinone deficiency. During cerebellum development, Pdss2 knockout results in severe cerebellum hypoplasia by impairing cell migration and eliciting ectopic apoptosis, whereas Pdss2 knockout in Purkinje cells at postnatal stages leads to the development of cerebellar ataxia.


Assuntos
Alquil e Aril Transferases/genética , Ataxia Cerebelar/genética , Cerebelo/embriologia , Cerebelo/crescimento & desenvolvimento , Marcha/fisiologia , Células de Purkinje/metabolismo , Alquil e Aril Transferases/metabolismo , Animais , Apoptose/fisiologia , Movimento Celular/fisiologia , Proliferação de Células , Ataxia Cerebelar/metabolismo , Cerebelo/metabolismo , Camundongos , Camundongos Knockout , Ubiquinona/metabolismo , Caminhada/fisiologia
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