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1.
Cell Mol Gastroenterol Hepatol ; 9(1): 145-160, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31562937

RESUMO

BACKGROUND & AIMS: Toll-like receptor 2 (TLR2) and TLR3 regulate hepatic immunity under pathological conditions, but their functions and potential drug targets in alcoholic liver disease (ALD) remain poorly understood. METHODS: ALD-associated liver injury were induced in TLR2 knockout (TLR2-/-), TLR3-/-, TLR2-/- bone marrow transplanted (BMT), TLR3-/- BMT, IL-10-/- mice, and their wild-type littermates through ethanol challenge with or without co-administered epigallocatechin-3-gallate (EGCG). Moreover, Kupffer cells were depleted by GdCl3 injection to evaluate their pathogenic roles in ALD. RESULTS: We identified that deficiency of TLR2 and TLR3 significantly alleviated and aggravated ALD-induced liver injury, respectively. Mechanistically, Kupffer cell inactivation, M1 to M2 polarization, and IL-10 production via STAT3 activation contributed to hepatic protection mediated by concurrent TLR2 inhibition and TLR3 agonism. These findings were further confirmed in TLR2 and TLR3 BMT mice. We also identified a novel ALD-protective agent EGCG which directly interacted with Kupffer cell TLR2/3 to induce IL-10 production. Deficiency of IL-10 aggravated ALD injury and blunted EGCG-mediated hepatoprotection while depletion of Kupffer cells partially recovered liver injury but abolished EGCG's actions. CONCLUSIONS: Altogether, our results illustrate the divergent roles of Kupffer cells TLR2/3 in ALD progression via anti-inflammatory cytokine IL-10 production.

2.
Brain Behav Immun ; 83: 192-199, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31614176

RESUMO

Neuro-inflammation might impact on clinical manifestations and cognition function via changing the volumes of key brain structures such as the anterior cingulate cortex (ACC) in bipolar disorder (BD). In this study, we investigated the interrelations among interleukin (IL)-6 cytokine level, grey matter (GM) volume of the anterior cingulated cortex (ACC), and attention function among offspring of parents diagnosed with BD. The offspring were categorized as being either asymptomatic or symptomatic based on whether they manifested pre-defined sub-threshold mood symptoms. We found that the symptomatic offspring showed significantly higher serum levels of IL-6 than the asymptomatic offspring (F(1, 59) = 67.65, p < 0.001). On the brain level, we obtained significant interactive effect of group and IL6 level on the ACC GM (PFWE = 0.017). Specifically, the GM volume of the rostral ACC was negatively associated with the levels of IL-6 in the asymptomatic offspring (PFWE = 0.021), but not the symptomatic offspring (PFWE > 0.05). Mediation analyses revealed that the GM volume of the rostral ACC significantly mediated the negative association between the IL-6 levels and attention performance in the asymptomatic offspring (bootstrapping Confidence Interval (CI) = -6.0432 to -0.0731) but not the symptomatic offspring (bootstrapping CI = -0.3197 to 1.3423). Our data suggest that the asymptomatic and symptomatic bipolar offspring may exhibit different neurocognitive-inflammatory profiles, which could be further validated as viable biosignatures for BD risk and resilience.

3.
J Ethnopharmacol ; 248: 112357, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-31693919

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Gogi berry is a traditional food supplement and medical herbal which has been widely used in Eastern Asian countries. Lycium barbarum polysaccharides (LBP) are the major active components of Gogi berry and have been proved to possess a lot of biological activities. AIM OF THE STUDY: We aimed to delineate the protective effect and mechanism of LBP on hepatic encephalopathy (HE). MATERIALS AND METHODS: We investigated the protective mechanism of LBP in a thioacetamide (TAA, intraperitoneally injected, 400 mg/kg) induced acute HE mice model. Key phenotypes of clinical HE were phenocopied in the mice model, including high mortality, severe hepatic histology injury, increased hepatic oxidative stress, apoptosis, enhanced circulating levels of pro-inflammatory cytokines and ammonia, suppressed tryptophan hydroxylase activity, and deficits in locomotor activity. RESULTS: The pathological alterations were effectively ameliorated by the oral administration with LBP (5 mg/kg, oral gavage, everyday), which were mediated by regulating MAPK pathways in both the liver and brain. Knockout of pro-inflammatory cytokines TNF-α or IL-6 effectively ameliorated impaired mice locomotor activity and MAPK activation in the brain. In an in vitro TNF-α-, IL-6-, or ammonia-induced microglia damaged cell model, cell injuries were evidently protected by the co-administration with LBP (50 µg/ml). CONCLUSION: LBP ameliorated the hepatic/brain injuries and impaired locomotor activities in a HE mice model. Pro-inflammatory cytokines may serve as communicating molecules linking the liver and brain for the HE pathogenesis, partly through MAPK regulation.

4.
Restor Neurol Neurosci ; 37(6): 571-581, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31796710

RESUMO

Many ocular diseases (such as glaucoma, diabetic retinopathy, age-related macular degeneration, and traumatic eye injuries) can result in the degeneration of retinal cells and the subsequent loss of vision. Some kinds of treatments, such as drugs, stem cell transplantation and surgery are reported to be effective in certain patients. However, no confirmatively effective, convenient and low-price intervention has been available so far. Physical exercise has been reported to exert neuroprotective effects on several neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease. Studies investigating the potential impacts of exercise on retinal diseases are rapidly emerging. Here we review these up-to-date findings from both human and animal studies, and discuss the possible mechanisms underlying exercise-elicited protection on retina.

5.
Invest Ophthalmol Vis Sci ; 60(14): 4606-4618, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31756254

RESUMO

Purpose: To investigate the neuroprotective effects of Lycium barbarum polysaccharides (LBP) against chronic ocular hypertension (OHT) in rats and to consider if effects differed when treatment was applied before (pretreatment) or during (posttreatment) chronic IOP elevation. Methods: Sprague-Dawley rats (10-weeks old) underwent suture implantation around the limbus for 15 weeks (OHT) or 1 day (sham). Four experimental groups were studied, three OHT groups (n = 8 each) treated either with vehicle (PBS), LBP pretreatment or posttreatment, and a sham control (n = 5) received no treatment. LBP (1 mg/kg) pre- and posttreatment were commenced at 1 week before and 4 weeks after OHT induction, respectively. Treatments continued up through week 15. IOP was monitored twice weekly for 15 weeks. Optical coherence tomography and ERG were measured at baseline, week 4, 8, 12, and 15. Eyes were collected for ganglion cell layer (GCL) histologic analysis at week 15. Results: Suture implantation successfully induced approximately 50% IOP elevation and the cumulative IOP was similar between the three OHT groups. When compared with vehicle control (week 4: -23 ± 5%, P = 0.03), LBP pretreatment delayed the onset of retinal nerve fiber layer (RNFL) thinning (week 4, 8: -2 ± 7%, -11 ± 3%, P > 0.05) and arrested further reduction up through week 15 (-10 ± 4%, P > 0.05). LBP posttreatment intervention showed no significant change in rate of loss (week 4, 15: -25 ± 4.1%, -28 ± 3%). However, both LBP treatments preserved the retinal ganglion cells (RGC) and retinal functions up to week 15, which were significantly reduced in vehicle control. Conclusions: LBP posttreatment arrested the subsequent neuronal degeneration after treatment commencement and preserved RGC density and retinal functions in a chronic OHT model, which was comparable with pretreatment outcomes.


Assuntos
Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/uso terapêutico , Degeneração Neural/prevenção & controle , Fármacos Neuroprotetores/uso terapêutico , Hipertensão Ocular/tratamento farmacológico , Animais , Doença Crônica , Eletrorretinografia , Feminino , Pressão Intraocular/fisiologia , Degeneração Neural/metabolismo , Degeneração Neural/fisiopatologia , Fibras Nervosas/patologia , Hipertensão Ocular/metabolismo , Hipertensão Ocular/fisiopatologia , Ratos , Ratos Sprague-Dawley , Retina/fisiopatologia , Células Ganglionares da Retina/patologia , Tomografia de Coerência Óptica
6.
Int Rev Neurobiol ; 147: 199-217, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31607355

RESUMO

Body-weight-supported locomotor training is an activity-based therapy used frequently to train individuals with spinal cord injury (SCI) for restoring walking ability. Locomotor training after SCI is developed on the basic scientific findings of activity-dependent neuroplasticity. Based on the research from animal SCI models, there exists a spinal neural networks for locomotion which can be reactivated by intense repetitive locomotor training. Notably, the effectiveness of locomotor training depends largely on the severity of injury and time after injury. Locomotor training, using body-weight-supported walking overground or on a treadmill, with assistance manually or robotically, with a variety of training intensity and training programs, has been shown to elicit improvements in locomotor function for incomplete SCI individuals. For chronic and motor complete SCI, other interventions with proven effectiveness such as epidural stimulation might be applied in addition to locomotor training to improve the chance of locomotor recovery. In this chapter, we review the factors that influence the functional outcomes of locomotor training. We also summarize the circuitry, cellular and molecular levels of mechanisms underlying the positive role of locomotor training in inducing neuroplasticity and functional recovery following SCI.

7.
Int Rev Neurobiol ; 147: 281-294, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31607358

RESUMO

Adiponectin, one kind of adipokines, has been shown to be neuroprotective in different neurodegenerative diseases. Adiponectin exerts its role through combination with its receptors and activates downstream molecular pathways. In the retinas, the expression of adiponectin can be detected and adiponectin receptors (AdipoRs) locate in different retinal cells. Adiponectin is mainly produced by adipose tissue, enters the circulation and passes through blood-brain barrier (BBB) without injury. It can also be produced locally in the brains as well as in the retinas. Therefore, it is possible that adiponectin from blood as well as that produced locally in the retinas take part in defense of different eye diseases. Here we have summarized the published data about the protective effects of adiponectin in eye diseases. Because exercise can increase the production of adiponectin systemically in the whole body and locally in the brain although no evidence has shown that exercise can increase the production of adiponectin in the eyes until now, we hypothesize that exercise will have a potential protective effect for the eyes via increasing the levels of adiponectin which needs further investigation.

8.
Int Rev Neurobiol ; 147: 323-360, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31607360

RESUMO

Exercise training improves mental and cognitive functions by enhancing neurogenesis and neuroprotection. Recent studies suggest the facilitation of spinogenesis across different brain regions including hippocampus and cerebral cortex by physical activity. In this article we will summarize major findings for exercise effects on synaptogenesis and spinogenesis, in order to provide mechanisms for exercise intervention of both psychiatric diseases and neurodegenerative disorders. We will also revisit major findings for molecular mechanism governing exercise-related spinogenesis, and will discuss the screening for novel factors, or exerkines, whose levels are correlated with endurance training and affect neural plasticity. We believe that further studies focusing on the molecular mechanism of exercise-mediate spinogenesis should benefit the optimization of exercise therapy in clinics and the evaluation of treatment efficiency using specific biomarkers.

9.
Int Rev Neurobiol ; 147: xiii-xiv, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31607365
10.
Brain Behav Immun ; 82: 178-187, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31437533

RESUMO

Minimal hepatic encephalopathy (MHE) is characterized as cognitive deficits including memory and learning dysfunctions after liver injuries or hepatic diseases. Our understandings of neurological mechanisms of MHE-associated cognitive syndromes, however, are far from complete. In the current study we generated a mouse MHE model by repetitive administrations of thioacetamide (TAA), which induced hyperammonemia plus elevated proinflammatory cytokines in both the general circulation and motor cortex. MHE mice presented prominent motor learning deficits, which were associated with excess dendritic spine pruning in the motor cortex under 2-photon in vivo microscopy. The pharmaceutical blockade of glucocorticoid receptor or suppression of its biosynthesis further rescued motor learning deficits and synaptic protein loss. Moreover, MHE mice presented microglial activation, which can be alleviated after glucocorticoid pathway inhibition. In sum, our data demonstrates corticosterone-induced microglial activation, synaptic over-pruning and motor learning impairments in MHE, providing new insights for MHE pathogenesis and potential targets of clinical interventions.

11.
iScience ; 17: 230-241, 2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31307003

RESUMO

Adult dendritic spines present structural and functional plasticity, which forms the basis of learning and memory. To provide in vivo evidence of spine plasticity under neurotoxicity, we generated an acute motor deficit model by single injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into adult mice. Acute MPTP infusion impairs motor learnings across test paradigms. In vivo two-photon imaging further revealed MPTP-induced prominent dendritic spine loss and substantially increased calcium spikes in apical tufts of layer 5 pyramidal neurons in the motor cortex. MPTP infusion also decreased the activity of somatostatin (SST)-expressing inhibitory interneurons. Further chemogenetic re-activation of SST interneurons reversed MPTP-induced hyperactivation of dendrites, rescued spine loss, and enhanced motor learning. Taken together, our study reports MPTP-induced structural and functional deficits of dendritic spines and suggests the potency of modulating local inhibitory transmission to relieve neurological disorders.

12.
Neural Regen Res ; 14(11): 1845-1850, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31290433

RESUMO

Glaucoma is a chronic, progressive optic neuropathy characterized by the loss of peripheral vision first and then central vision. Clinically, normal tension glaucoma is considered a special subtype of glaucoma, in which the patient's intraocular pressure is within the normal range, but the patient experiences typical glaucomatous changes. However, increasing evidence has challenged the traditional pathophysiological view of normal tension glaucoma, which is based only on intraocular pressure, and breakthroughs in central nervous system imaging may now greatly increase our knowledge about the mechanisms underlying normal tension glaucoma. In this article, we review the latest progress in understanding the pathogenesis of normal tension glaucoma and in developing imaging techniques to detect it, to strengthen the appreciation for the connection between normal tension glaucoma and the brain.

13.
Sci Adv ; 5(7): eaaw1888, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31281888

RESUMO

Physical exercise improves learning and memory, but little in vivo evidence has been provided to illustrate the molecular mechanisms. Here, we show that chronic treadmill exercise activates the mechanistic target of rapamycin (mTOR) pathway in mouse motor cortex. Both ex vivo and in vivo recordings suggest that mTOR activation leads to potentiated postsynaptic excitation and enhanced neuronal activity of layer 5 pyramidal neurons after exercise, in association with increased oligodendrogenesis and axonal myelination. Exercise training also increases dendritic spine formation and motor learning. Together, exercise activates mTOR pathway, which is necessary for spinogenesis, neuronal activation, and axonal myelination leading to improved motor learning. This model provides new insights for neural network adaptations through exercises and supports the intervention of cognitive deficits using exercise training.

14.
Hum Brain Mapp ; 40(12): 3452-3463, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31282606

RESUMO

Aberrant structural (diffusion tensor imaging [DTI]) and resting-state functional magnetic resonance imagining connectivity are core features of bipolar disorder. However, few studies have explored the integrity agreement between structural and functional connectivity (SC-FC) in bipolar disorder. We examine SC connectivity coupling index whether could potentially provide additional clinical predictive value for bipolar disorder spectrum disorders besides the intramodality network measures. By examining the structural (DTI) and resting-state functional network properties, as well as their coupling index, among 57 euthymic bipolar disorder patients (age 13-28 years, 18 females) and 42 age- and gender-matched healthy controls (age 13-28 years, 16 females), we found that compared to controls, bipolar disorder patients showed increased structural rich-club connectivity as well as decreased functional modularity. Importantly, the coupling strength between structural and functional connectome was decreased in patients compared to controls, which emerged as the most powerful feature discriminating the two groups. Our findings suggest that structural-functional coupling strength could serve as a valuable biological trait-like feature for bipolar disorder over and above the intramodality network measures. Such measure can have important clinical implications for early identification of bipolar disorder individuals, and inform strategies for prevention of bipolar disorder onset and relapse.

15.
Neural Regen Res ; 14(10): 1755-1764, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31169193

RESUMO

Soluble Nogo66 receptor-Fc protein (sNgR-Fc) enhances axonal regeneration following central nervous system injury. However, the underlying mechanisms remain unclear. In this study, we investigated the effects of sNgR-Fc on the proliferation and differentiation of neural progenitor cells. The photothrombotic cortical injury model of ischemic stroke was produced in the parietal cortex of Sprague-Dawley rats. The rats with photothrombotic cortical injury were randomized to receive infusion of 400 µg/kg sNgR-Fc (sNgR-Fc group) or an equal volume of phosphate-buffered saline (photothrombotic cortical injury group) into the lateral ventricle for 3 days. The effects of sNgR-Fc on the proliferation and differentiation of endogenous neural progenitor cells were examined using BrdU staining. Neurological function was evaluated with the Morris water maze test. To further examine the effects of sNgR-Fc treatment on neural progenitor cells, photothrombotic cortical injury was produced in another group of rats that received transplantation of neural progenitor cells from the hippocampus of embryonic Sprague-Dawley rats. The animals were then given an infusion of phosphate-buffered saline (neural progenitor cells group) or sNgR-Fc (sNgR-Fc + neural progenitor cells group) into the lateral ventricle for 3 days. sNgR-Fc enhanced the proliferation of cultured neural progenitor cells in vitro as well as that of endogenous neural progenitor cells in vivo, compared with phosphate-buffered saline, and it also induced the differentiation of neural progenitor cells into neurons. Compared with the photothrombotic cortical injury group, escape latency in the Morris water maze and neurological severity score were greatly reduced, and distance traveled in the target quadrant was considerably increased in the sNgR-Fc group, indicating a substantial improvement in neurological function. Furthermore, compared with phosphate-buffered saline infusion, sNgR-Fc infusion strikingly improved the survival and differentiation of grafted neural progenitor cells. Our findings show that sNgR-Fc regulates neural progenitor cell proliferation, migration and differentiation. Therefore, sNgR-Fc is a potential novel therapy for stroke and neurodegenerative diseases, The protocols were approved by the Committee on the Use of Live Animals in Teaching and Research of the University of Hong Kong (approval No. 4560-17) in November, 2015.

16.
Invest Ophthalmol Vis Sci ; 60(6): 2023-2033, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31067322

RESUMO

Purpose: To investigate the posttreatment neuronal rescue effects of Lycium barbarum polysaccharides (LBP) in an acute ocular hypertensive (AOH) model. Methods: Intraocular pressure (IOP) was elevated manometrically to 80 mm Hg (AOH) or 15 mm Hg (sham) for 120 minutes in adult Sprague-Dawley rats. Five experimental groups were considered: Three AOH groups were pretreated with PBS (vehicle) (n = 9), LBP 1 mg/kg (n = 8), or 10 mg/kg (n = 13), and one AOH group was posttreated with LBP 10 mg/kg (n = 8), once daily. The sham cannulation group (n = 5) received no treatment. Pretreatments commenced 7 days before and posttreatment 6 hours after AOH, and continued up through postcannulation day 28. All the animals underwent optical coherence tomography and electroretinogram measurements at baseline and postcannulation days 10 and 28. The ganglion cell layer (GCL) densities were quantified at day 28. Results: Both inner retinal layer thickness (IRLT) and positive scotopic threshold response (pSTR) underwent significant reduction (≥50% of thickness and amplitude) in the vehicle group (P < 0.05). Pretreatment with LBP 1 and 10 mg/kg retained 77 ± 11% and 89 ± 8% of baseline IRLT, respectively, and preserved pSTR functions. The posttreatment group showed a significant reduction in IRLT (-35 ± 8%, P < 0.001) and pSTR (∼48% of baseline, P < 0.001) on day 10. By day 28, there was an improvement in functional pSTR (∼72% of baseline, P > 0.05) with no significant further thinning (-40 ± 8%, P = 0.15) relative to day 10. GCL density was reduced in vehicle control (P = 0.0001), but did not differ between sham and pre- and posttreated AOH groups. Conclusions: The rescue effect of LBP posttreatment was observed later, which arrested the secondary degeneration and improved the retinal function.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Pressão Intraocular/fisiologia , Hipertensão Ocular/tratamento farmacológico , Células Ganglionares da Retina/patologia , Campos Visuais/fisiologia , Animais , Modelos Animais de Doenças , Eletrorretinografia , Feminino , Seguimentos , Pressão Intraocular/efeitos dos fármacos , Hipertensão Ocular/diagnóstico , Hipertensão Ocular/fisiopatologia , Ratos , Ratos Sprague-Dawley , Células Ganglionares da Retina/efeitos dos fármacos , Tomografia de Coerência Óptica , Resultado do Tratamento , Campos Visuais/efeitos dos fármacos
17.
Chem Commun (Camb) ; 55(44): 6221-6224, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31080975

RESUMO

Triangeliphthalides A-D (1-4), four novel phthalide trimers with two new linkage styles, were isolated from Angelica sinensis, together with two related phthalide dimers (5-6). Their structures including absolute configurations were determined. The production mechanism of phthalide polymers was proposed, and their bioactivities were also evaluated.


Assuntos
Angelica sinensis/química , Benzofuranos/química , Biopolímeros/química , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Estrutura Molecular
18.
Neural Regen Res ; 14(9): 1494-1498, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31089038

RESUMO

Artemisinin, also called qinghaosu, is originally derived from the sweet wormwood plant (Artemisia annua), which is used in traditional Chinese medicine. Artemisinin and its derivatives (artemisinins) have been widely used for many years as anti-malarial agents, with few adverse side effects. Interestingly, evidence has recently shown that artemisinins might have a therapeutic value for several other diseases beyond malaria, including cancers, inflammatory diseases, and autoimmune disorders. Neurodegeneration is a challenging age-associated neurological disorder characterized by deterioration of neuronal structures as well as functions, whereas neuroinflammation has been considered to be an underlying factor in the development of various neurodegenerative disorders, including Alzheimer's disease. Recently discovered properties of artemisinins suggested that they might be used to treat neurodegenerative disorders by decreasing oxidation, inflammation, and amyloid beta protein (Aß). In this review, we will introduce artemisinins and highlight the possible mechanisms of their neuroprotective activities, suggesting that artemisinins might have therapeutic potential in neurodegenerative disorders.

19.
Phytochemistry ; 164: 60-66, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31096077

RESUMO

Fifteen phenylpropanoid glycosides, including six undescribed compounds were isolated from the fruit of Lycium barbarum L. (Solanaceae) (goji or wolfberry). Their structures were identified by detailed spectroscopic analyses. Seven known compounds were firstly isolated from the genus Lycium, in which the 1D and 2D NMR data of one compound were reported for the first time. Notably, two undescribed compounds were a pair of rare tautomeric glycoside anomers characterized by the presence of free anomeric hydroxy. Antioxidant and hypoglycemic activities of all these compounds were assessed using DPPH radical scavenging, oxygen radical absorbance capacity (ORAC), and α-glucosidase inhibitory assays, respectively. These compounds showed different levels of oxygen radical absorbance capacity, and some isolates exhibited potent antioxidant activity with greater ORAC values than the positive control (EGCG).


Assuntos
Antioxidantes/farmacologia , Frutas/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Glicosídeos/farmacologia , Lycium/química , Fenilpropionatos/farmacologia , Antioxidantes/química , Antioxidantes/isolamento & purificação , Compostos de Bifenilo/antagonistas & inibidores , Relação Dose-Resposta a Droga , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Glicosídeos/química , Glicosídeos/isolamento & purificação , Conformação Molecular , Fenilpropionatos/química , Fenilpropionatos/isolamento & purificação , Picratos/antagonistas & inibidores , Espécies Reativas de Oxigênio/antagonistas & inibidores , Relação Estrutura-Atividade , alfa-Glucosidases/metabolismo
20.
Mol Nutr Food Res ; 63(11): e1801339, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30938072

RESUMO

SCOPE: Besides abstinence and nutritional support, there is no proven clinical treatment for patients with alcoholic fatty liver disease (AFLD). Here, the therapeutic effects and mechanisms of action of wolfberry-derived zeaxanthin dipalmitate (ZD) on AFLD models are demonstrated. METHODS AND RESULTS: The hepatoprotective effects of ZD are evaluated in vitro and in vivo. Direct interacting receptors of ZD on cell membranes are identified by liver-specific knockdown and biophysical measurements. Downstream signaling pathways are delineated using molecular and cellular biological methods. It is demonstrated that ZD attenuates hepatocyte and whole-liver injury in ethanol-treated cells (dose: 1 µm) and a chronic binge AFLD rat model (dose: 10 mg kg-1 ), respectively. The direct targets of ZD on the cell membrane include receptor P2X7 and adiponectin receptor 1 (adipoR1). Signals from P2X7 and adipoR1 modulate the phosphatidylinositide 3-kinase-Akt and/or AMP-activated protein kinase-FoxO3a pathways, to restore mitochondrial autophagy (mitophagy) functions suppressed by ethanol intoxication. In addition, ZD alleviates hepatic inflammation partially via the inhibition of Nod-like receptor 3 inflammasome, whose activation is a direct consequence of suppressed mitophagy. Liver-specific inhibition of receptors or mitophagy significantly impairs the beneficial effects of ZD. CONCLUSIONS: ZD is an effective and promising agent for the potential treatment of AFLD.

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