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1.
Adv Exp Med Biol ; 1155: C1, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31605371

RESUMO

Affiliations of authors Muhammad Shahbaz and Shahid Alam were incorrect in the published book. This has now been corrected as below.

2.
Exp Cell Res ; 383(2): 111557, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31415759

RESUMO

Diabetic peripheral neuropathy is a common complications of Type 2 Diabetes and its main pathological feature is myelin sheath damage of peripheral nerve that was induced by Schwann cells (SCs) apoptosis. Increasing evidence suggested that taurine might play a role in improving DPN because of its ability to prevent SCs apoptosis. In this study, we explore the effect of taurine on preventing SCs apoptosis and its underlying mechanism. Sprague Dawley rats were treated with streptozotocin to establish the diabetes model. Rats were randomly divided into control, diabetes, taurine treatment (as giving 0.5%, 1% and 2% taurine in drinking water) groups. RSC96 cell (a rat SCs line) was used for intervention experiments in vitro. Results showed that taurine significantly corrected morphology of damaged myelin sheath and inhibited SCs apoptosis in sciatic nerve of diabetic rats. Moreover, taurine prevented apoptosis of RSC96 cells exposed to high glucose. Mechanistically, taurine up-regulated NGF expression and phosphorylation levels of Akt and GSK3ß, while, blocking activation of NGF and phosphorylation of Akt and GSK3ß increased apoptosis of high glucose-exposed RSC96 cells with taurine supplement. These results revealed taurine improved the myelin sheath damage of sciatic nerve in diabetic rats by controlling SCs apoptosis via NGF/Akt/GSK3ß signaling pathways, which provides some clues that taurine might be effective and feasible candidate for the treatment of DPN.

3.
Adv Exp Med Biol ; 1155: 13-24, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468382

RESUMO

Taurine is a sulfur-containing amino acid which has strong activities in enhancing immunity. Gut microbiota is closely interrelated with intestinal mucosal immunity, but the effects and mechanisms of taurine on intestinal microbiota and mucosal immune cells under an immunosuppressive condition remain unclear. This study was conducted to investigate the effect of taurine on gut microbiota and immune cells in Peyer's patches (PPs) of dexamethasone (Dex)-induced immunosuppressive mice. Mice (4-week-old, Male) were randomly divided into three groups: the Control group (n = 12), the Dex-induced immunosuppressive model group (n = 12) and the taurine intervention group (n = 12). The model was established by Dex injection for 7 days and the taurine intervention group was gavaged 100 mg/kg soluble taurine for 30 days. The changes of intestinal microbiota and immune cells in PPs were tested by denaturing gradient gel electrophoresis (DGGE) and flow cytometry, respectively. Results showed that the microbiota in immunosuppressive mice was obvious different compared with control group, in which, the Lachnospiraceae and Ruminococcaceae groups were significantly reduced, and their reduction were reversed after taurine intervention. Compared to the control group, the total cell number in PPs, as well as the subsets of CD3+ cells (T cells), CD19+ cells (B cells) in model groups were significantly lower, and they were dramatically improved after taurine treatment. Our results suggested that taurine has a positive effect on i ntestinal homeostasis of the immunosuppressive mice.


Assuntos
Microbioma Gastrointestinal/efeitos dos fármacos , Tolerância Imunológica , Nódulos Linfáticos Agregados/efeitos dos fármacos , Taurina/farmacologia , Animais , Homeostase , Masculino , Camundongos , Distribuição Aleatória
4.
Adv Exp Med Biol ; 1155: 381-390, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468416

RESUMO

Taurine (2-aminoethanesulfonic acid) has positive effects on the formation of immune systems. In this study, we evaluated the effects of taurine on the development of T lymphocyte subpopulations in thymus of immunosuppresive mice. The immunosuppressed mice model was established by intraperitoneal injection of dexamethasone (Dex) for 7 days. Mice (male, Kunming strain) were randomly divided into three groups, the normal control group (Cont.), the Dex-induced immunosuppressive model group (Dex + PBS), and the taurine intervention group (Dex + TAU). Taurine was administered at a dose of 200 mg/kg for 30 days or until euthanasia. Total cell numbers in the thymi of mice were evaluated by cell count, and the flow cytometry was used to determine the proportion of different cell subsets. Our results showed that the size and weight of thymi of Dex + PBS group were significantly smaller than those of Cont. group, and taurine administration efficiently increased the thymus index. Taurine also significantly increased the number of CD4- CD8- double negative (DN), CD4+ CD8+ double positive (DP), CD4+ single positive (CD4+) and CD8+ SP (CD8+) cells compared with the Dex + PBS group, but did not affect the CD4+/CD8+ cell ratio in thymus of Dex-induced immunoseppressive mice. Our results suggested that taurine has a positive effect on thymus differentiation in Dex-induced immunosuppressive mice.


Assuntos
Diferenciação Celular , Imunossupressão , Subpopulações de Linfócitos T/efeitos dos fármacos , Taurina/farmacologia , Timo/efeitos dos fármacos , Animais , Relação CD4-CD8 , Dexametasona , Citometria de Fluxo , Masculino , Camundongos , Distribuição Aleatória , Subpopulações de Linfócitos T/citologia
5.
Adv Exp Med Biol ; 1155: 747-754, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468445

RESUMO

Arsenate, a well known toxicant, can induce injury in nerve system via oxidative stress and apoptosis. This study was designed to explore the protective effect of taurine against arsenite-induced neurotoxicity and its related mechanism in primary cortical neurons. The cells were treated with arsenite with or without taurine. Twenty-Four hours later, cell viability was examined using the MTT assay. The activity of caspase-3 was analyzed and the level of Akt and p-Akt were examined by western blot. The results show that taurine treatment significantly attenuates the decrease in cell viability of arsenite-exposed primary cortical neurons. Taurine also reversed the arsenite-induced increase in caspase-3 activity. The decrease in p-Akt levels induced by arsenite exposure was prevented by taurine treatment. Thus, taurine attenuated the effect of arsenite on primary cortical neurons, an effect that may involve the Akt pathway.


Assuntos
Apoptose , Arsênico/toxicidade , Neurônios/efeitos dos fármacos , Taurina/farmacologia , Caspase 3 , Humanos , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais
6.
Adv Exp Med Biol ; 1155: 787-799, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468448

RESUMO

It was reported that apoptosis of Schwann cells could increase in the diabetic rats. The studies showed that taurine inhibited apoptosis in a variety of cells. However, there were few reports on studying the protection of taurine against apoptosis of Schwann cells induced by high glucose (HG) and the underlying mechanism. In our study, the cells were divided into five groups: Control: the normal medium; HG group: 50 mM high glucose; T1: 50 mM high glucose+Taurine (10 mM) group; T2: 50 mM high glucose+Taurine (20 mM) group; T3: 50 mM high glucose+Taurine (40 mM) group. We used MTT and Tunel assays to measure the cell viability and apoptosis, respectively. Then, we also used western blotting to detect the protein levels of apoptosis-related protein. The results demonstrate that taurine promoted cell viability and decreased apoptosis in RSC96 cells exposed to HG. Furthermore, taurine markedly improved imbalance of Bax and Bcl-2, inhibited the translocation of Cytochrome C (Cyt C) from mitochondria to cytosol and reduced caspase-3 activity in HG-induced RSC96 cells. Our results indicate that taurine protect against apoptosis of Schwann cells induced by HG via inhibiting mitochondria-dependent caspase-3 pathway.


Assuntos
Apoptose , Células de Schwann/efeitos dos fármacos , Taurina/farmacologia , Animais , Células Cultivadas , Diabetes Mellitus Experimental , Glucose/efeitos adversos , Ratos , Células de Schwann/citologia
7.
Adv Exp Med Biol ; 1155: 869-874, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468453

RESUMO

Our group previously reported that taurine has a protective capacity on the hippocampus and cerebellum of arsenic (As)-exposed mouse. In the present study, we explore whether taurine demonstrates protection against As toxicity in primary cortical neurons. Primary cortical neurons were exposed to various concentrations of arsenite and cell viability was assessed to confirm the toxicity of As on cortical neurons. The protection of taurine was examined after primary cortical neurons were treating with arsenite and taurine for 24 h. The cell viability was examined by MTT and caspase-3 activity assay. The expression of Bax and Bcl-2 was determined by western blot. The results showed that As exposure reduced cell viability and enhanced the activity of caspase-3, which were markedly inhibited by taurine treatment. The expression of Bax and Bcl-2 were disturbed by As exposure, which were reversed by taurine. These results indicated that taurine expose protective effect on As-exposed primary cortical neurons and its mechanism maybe involved the regulation of Bax/Bcl-2.


Assuntos
Arsênico/toxicidade , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Taurina/farmacologia , Animais , Apoptose , Sobrevivência Celular , Células Cultivadas , Camundongos , Neurônios/citologia , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína X Associada a bcl-2/metabolismo
8.
Adv Exp Med Biol ; 1155: 875-887, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468454

RESUMO

Diabetes mellitus (DM) is a condition characterized by chronic hyperglycemia, which leads to diabetic neuropathy and apoptosis in the spinal cord. Taurine has been found to ameliorate the diabetic neuropathy and control apoptosis in various tissues. However, there are few reports that discuss the direct relationship between spinal cord and anti-apoptotic effect of taurine. In this study, DM was induced in male SD rats with STZ @ 25 mg/Kg of body weight in combination with high fat diet. After 2 weeks, they were divided into four groups as DM: diabetic rats, T1 (0.5%), T2 (1%) and T3 (2%) taurine solution, while control group was non-diabetic rats (no treatment). The results showed that DM increased apoptosis, decreased phosphorylated Akt and Bad. DM decreased expression of Bcl-2 and increased the Bax. Moreover, the release of cytochrome c into cytosol was increased in DM and activation of caspase-3 was also increased. However, taurine reversed all these abnormal changes in a dose dependent manner. Our results suggested the involvement of Akt/Bad signaling pathway and mitochondrial apoptosis pathway in protective effect of taurine against apoptosis in the spinal cord of diabetic rats. Therefore, taurine may be a potential medicine against diabetic neuropathy by controlling apoptosis.


Assuntos
Apoptose , Neuropatias Diabéticas , Medula Espinal/efeitos dos fármacos , Taurina/farmacologia , Animais , Diabetes Mellitus Experimental , Masculino , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Medula Espinal/citologia
9.
Adv Exp Med Biol ; 1155: 923-934, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468457

RESUMO

Diabetic neuropathy (DN) is the most common chronic complication of DM and its major pathological changes show axonal dysfunction, atrophy and loss. However, there are few reports that taurine promotes neurite growth of dorsal root ganglion (DRG) cells. In current study, DRG neurons were exposed to high glucose (HG) with or without taurine. The neurite outgrowth of DRG neurons was observed by fluorescent immunohistochemistry method. Expression of Gap-43, Akt, phosphorylated Akt, mTOR and phosphorylated mTOR was determined by Western blot assay. Our results showed that HG significantly decreased the neurite outgrowth and expression of Gap-43 in DRG neurons. Moreover, phosphorylated levels of Akt and mTOR were downregulated in DRG neurons exposed to HG. On the contrary, taurine supplementation significantly reversed the decreased neurite outgrowth and Gap-43 expression, and the downregulated phosphorylated levels of Akt and mTOR. However, the protective effects of taurine were blocked in the presence of PI3K antagonists LY294002 or Akt antagonists Perifosine. These results indicate that taurine promotes neurite outgrowth of DRG neurons exposed to HG via activating Akt/mTOR signal pathway.


Assuntos
Gânglios Espinais/citologia , Neurônios/efeitos dos fármacos , Taurina/farmacologia , Células Cultivadas , Proteína GAP-43/metabolismo , Glucose , Humanos , Neuritos/efeitos dos fármacos , Neurônios/citologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo
10.
Adv Exp Med Biol ; 1155: 935-947, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468458

RESUMO

Taurine protect against diabetic neuropathy. However, the protective mechanism of taurine has been poorly understood. It has been demonstrated that microRNAs (miRNAs) are involved in regulating gene expression. Therefore, it is interested in whether taurine affects miRNAs expression profile in peripheral nerve tissue of diabetic neuropathy. In the present study, rats were treated as three group: (1) control (Con) group, (2) diabetic mellitus (DM) group and (3) taurine treatment (Tau) group. Sciatic nerve tissue was harvested and miRNA expression was determined using sequencing. The results showed that 80 miRNAs showed significant difference in DM group compared to Con group, of which 20 miRNAs showed up-regulating, as well as, 60 miRNAs showed down-regulating. On the other hand, 215 differential miRNAs were found between DM and Tau groups. Moreover, the numbers of up-regulated and down-regulated miRNAs were 1 and 214, respectively. Twelve specific miRNAs were screened out and the target genes were obtained by target analysis software. GO and KEGG enrichment analyses showed that these potential target genes for the miRNAs might be involved in axon guidance, generation of neurons, nervous system development and neurogenesis. Our results provided a miRNA profile for further exploring protective mechanisms of taurine against diabetic peripheral neuropathy.


Assuntos
Neuropatias Diabéticas/genética , MicroRNAs/genética , Nervo Isquiático/metabolismo , Taurina/farmacologia , Animais , Diabetes Mellitus Experimental , Ratos , Nervo Isquiático/efeitos dos fármacos
11.
Adv Exp Med Biol ; 1155: 889-903, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468455

RESUMO

Diabetes causes memory loss. Hippocampus is responsible for memory and increased apoptosis was found in diabetes patients. Taurine improved memory in diabetes condition. However, mechanism is unclear. In current study, hippocampal cell line HT-22 cells were subjected to analysis as five groups i.e. Control, High glucose (HG) at concentration of 150 mM, HG + 10 mM (T1), 20 mM (T2) and 40 mM (T3) taurine solution. TUNEL assay showed that HG increased the number of apoptotic cell significantly while taurine reduced apoptosis. Taurine increased phosphorylation of Akt in HT-22 cell treated with HG, and increased phosphorylation of Bad (p-Bad) was seen suggesting involvement of Akt/Bad signaling pathway. Expression of Bcl-2 was reduced in HG group but taurine improved this. Bax expression showed opposite trend. This indicated that taurine may reduce apoptosis by controlling balance of Bcl-2 and Bax. When the activation of Akt was blocked by using of perifosine, the effect of taurine disappears either partially or altogether. Thus, it was clear that taurine reduces apoptosis via Akt/Bad pathway in HT-22 cells exposed to HG which further improves downstream balance of Bcl-2 and Bax. This mechanism may be involved in apoptosis of hippocampus cells in diabetic condition.


Assuntos
Apoptose , Neurônios/efeitos dos fármacos , Taurina/farmacologia , Animais , Linhagem Celular , Glucose , Hipocampo/citologia , Camundongos , Fosforilação , Transdução de Sinais
12.
ACS Chem Neurosci ; 10(5): 2243-2249, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30817108

RESUMO

MicroRNAs (miRNAs) are small and evolutionary conserved noncoding RNAs that are involved in post-transcriptional gene regulation. Differential expression levels of miRNAs can be used as potential biomarkers of disease. Previous animal studies have indicated that the expression level of miR-132 is negatively correlated with its downstream molecule nuclear receptor related 1 protein (Nurr1), which is one of the key factors for the maintenance of dopaminergic function and is particularly vulnerable in Parkinson's disease (PD). However, this correlation has not been confirmed in human patients with PD. Moreover, the possible involvement of miR-132 during the pathogenesis and progression of PD is not fully investigated. Therefore, in the present study, we determined the peripheral circulation levels of miR-132 and Nurr1 in patients with PD, neurological disease controls (NDC) and healthy controls (HC) by reverse transcription real-time quantitative PCR (RT-qPCR). Our data clearly demonstrated that the plasma miR-132 level in PD was significantly higher than those in HC (178%, p < 0.05) and NDC (188%, p < 0.001). When adjusted for gender and age, higher level of miR-132 expression was associated with the significantly increased risk for PD in males and was closely related with the disease stages and disease severity. Furthermore, peripheral Nurr1 was significantly decreased in PD compared with HC (56%, p < 0.001) and NDC (58%, p < 0.001). Much more interestingly, further analysis revealed a negative correlation between the decreased Nurr1 level and the elevated miR-132 level in PD. All these findings indicated that the combination of a high miR-132 level with the low level of its downstream Nurr1 might be a potential biomarker aiding in the diagnosis of PD and monitoring disease progression.

13.
Mol Cell Biochem ; 457(1-2): 133-143, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30911955

RESUMO

Mesenchymal stem cell transplantation has been proposed as a promising therapy for regeneration of damaged tissues-especially, bone marrow mesenchymal stem cell (BMSC) transplantation therapy is considered to be an effective strategy for treating various injures in recent years. However, poor viability of transplanted BMSCs in injured tissues has limited their therapeutic efficiency. Nerve growth factor (NGF) has been reported to be a pro-survival factor in series of cells. Moreover, NGF could improve BMSC viability and activate anti-apoptotic pathway. Therefore, we are interested to know whether NGF promoted BMSC survival in transplanted tissue. In this study, we investigated the protective effect and potential mechanisms of NGF against apoptosis of BMSCs in vitro. 2,5-hexanedione (HD) was the apoptosis inducer. BMSCs were treated with 40 mM HD and different concentrations of NGF (0, 50, 100, 200 µg/L) together for 24 h. Results showed that NGF treatment increased the viability of BMSCs exposed to HD. Moreover, NGF effectively suppressed HD-induced apoptosis which was characterized by inhibiting caspase-3 activity, as well as mitochondrial transmembrane potential depolarization. Mechanistically, it was found that NGF promoted phosphorylation of Akt and Bad, which is TrkA dependent. However, K252a and MK-2206 (TrkA and Akt inhibitor, respectively) suppressed the anti-apoptosis of NGF, indicating the protective effect of NGF on BMSCs apoptosis via a novel Akt/Bad pathway. The findings suggested that NGF may be used as an effective protective agent against BMSC apoptosis so as to promote the survival rate of transplanted BMSCs and their tissue repair capability.


Assuntos
Apoptose/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Hexanonas/farmacologia , Células-Tronco Mesenquimais/metabolismo , Fator de Crescimento Neural/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína de Morte Celular Associada a bcl/metabolismo , Animais , Células-Tronco Mesenquimais/patologia , Ratos , Ratos Sprague-Dawley
14.
Biosci Rep ; 39(2)2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30670632

RESUMO

Because precise mechanism for 2,5-hexanedione (HD)-induced neuronal apoptosis largely remains unknown, we explored the potential mechanisms both in vivo and in vitro Rats were intraperitoneally exposed to HD at different doses for 5 weeks, following which the expression levels of nerve growth factor (NGF), phosphorylation of Akt and Bad, dimerization of Bad and Bcl-xL, as well as the release of cytochrome c and the caspase-3 activity were measured. Moreover, these variables were also examined in vitro in HD-exposed VSC4.1 cells with or without a PI3K-specific agonist (IGF-1), and in HD-exposed VSC4.1 cells with or without a PI3K-specific inhibitor (LY294002) in the presence or absence of NGF. The data indicate that, as the concentration of HD increased, rats exhibited progressive gait abnormalities, and enhanced neuronal apoptosis in the rat sciatic nerve, compared with the results observed in the control group. Furthermore, HD significantly down-regulated NGF expression in the rat sciatic nerve. Moreover, suppression of NGF expression inhibited the phosphorylation of Akt and Bad. Meanwhile, an increase in the dimerization of Bad and Bcl-xL in mitochondria resulted in cytochrome c release and caspase-3 activation. In contrast, HD-induced apoptosis was eliminated by IGF-1. Additionally, NGF supplementation reversed the decrease in phosphorylation of Akt and Bad, as well as reversing the neuronal apoptosis in HD-exposed VSC4.1 cells. However, LY294002 blocked these effects of NGF. Collectively, our results demonstrate that mitochondrial-dependent apoptosis is induced by HD through NGF suppression via the PI3K/Akt pathway both in vivo and in vitro.

15.
Brain Res ; 1696: 1-9, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-29705604

RESUMO

We aimed to investigate the effects of bone marrow mesenchymal stem cell conditioned medium (BMSC-CM) in preventing 2,5-hexanedione (HD)-induced damage to motoneurons, and examined the molecular mechanisms that mediate these effects. VSC4.1 cells were exposed to 25 mM HD for 24 h followed by incubation with DMEM for 24 h. HD-treated cells were incubated with BMSC-CM at varied concentrations. Incubation with BMSC-CM ameliorated the decreased cell viability and reduced LDH release from cells exposed to HD. BMSC-CM suppressed the elevated number of autophagic vacuoles, cells with LC3 puncta, increased LC3-II/LC3-I ratio, and decreased p62 caused by HD exposure. BMSC-CM elevated NGF and p-TrkA expressions in HD-treated cells. Administration of NGF inhibited autophagy, an effect that was similar to that observed after BMSC-CM treatment; this effect was abolished by the addition of NGF-neutralizing antibodies. BMSC-CM or NGF elevated p-protein kinase B (Akt) and p-mammalian target of rapamycin (mTOR) in HD-exposed cells, which was interrupted by TrkA inhibitor, K252a and mTOR inhibitor, rapamycin. BMSC-CM prevented HD-induced autophagic cell damage in VSC4.1 cells. The neuroprotective effect of BMSC-CM appeared to be at least partly associated with its ability to trigger the NGF-phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR signaling pathway.

16.
Amino Acids ; 50(5): 487-502, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29492671

RESUMO

Diets in rats and humans have shown promising results. Taurine improved glucagon activity, promoted glycemic stability, modified glucose levels, successfully addressed hyperglycemia via advanced glycation end-product control, improved insulin secretion and had a beneficial effect on insulin resistance. Taurine treatment performed well against oxidative stress in brain, increased the secretion of required hormones and protected against neuropathy, retinopathy and nephropathy in diabetes compared with the control. Taurine has been observed to be effective in treatments against diabetic hepatotoxicity, vascular problems and heart injury in diabetes. Taurine was shown to be effective against oxidative stress. The mechanism of action of taurine cannot be explained by one pathway, as it has many effects. Several of the pathways are the advanced glycation end-product pathway, PI3-kinase/AKT pathway and mitochondrial apoptosis pathway. The worldwide threat of diabetes underscores the urgent need for novel therapeutic measures against this disorder. Taurine (2-aminoethane sulfonic acid) is a natural compound that has been studied in diabetes and diabetes-induced complications.

17.
Cell Death Dis ; 9(4): 435, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29568078

RESUMO

Microglia-mediated neuroinflammation is implicated in multiple neurodegenerative disorders, including Parkinson's disease (PD). Hence, the modulatioein of sustained microglial activation may have therapeutic potential. This study is designed to test the neuroprotective efficacy of taurine, a major intracellular free ß-amino acid in mammalian tissues, by using paraquat and maneb-induced PD model. Results showed that mice intoxicated with paraquat and maneb displayed progressive dopaminergic neurodegeneration and motor deficits, which was significantly ameliorated by taurine. Taurine also attenuated the aggregation of α-synuclein in paraquat and maneb-intoxicated mice. Mechanistically, taurine suppressed paraquat and maneb-induced microglial activation. Moreover, depletion of microglia abrogated the dopaminergic neuroprotective effects of taurine, revealing the role of microglial activation in taurine-afforded neuroprotection. Subsequently, we found that taurine suppressed paraquat and maneb-induced microglial M1 polarization and gene expression levels of proinflammatory factors. Furthermore, taurine was shown to be able to inhibit the activation of NADPH oxidase (NOX2) by interfering with membrane translocation of cytosolic subunit, p47phox and nuclear factor-kappa B (NF-κB) pathway, two key factors for the initiation and maintenance of M1 microglial inflammatory response. Altogether, our results showed that taurine exerted dopaminergic neuroprotection through inactivation of microglia-mediated neuroinflammation, providing a promising avenue and candidate for the potential therapy for patients suffering from PD.

18.
Sci Rep ; 8(1): 4516, 2018 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-29540747

RESUMO

Chronic exposure to n-hexane, a widely used organic solvent in industry, induces central-peripheral neuropathy, which is mediated by its active metabolite, 2,5-hexanedione (HD). We recently reported that transplantation of bone marrow-mesenchymal stem cells (BMSC) significantly ameliorated HD-induced neuronal damage and motor deficits in rats. However, the mechanisms remain unclear. Here, we reported that inhibition of HD-induced autophagy contributed to BMSC-afforded protection. BMSC transplantation significantly reduced the levels of microtubule-associated protein 1 light chain 3-II (LC3-II) and the degradation of sequestosome-1 (p62) in the spinal cord and sciatic nerve of HD-intoxicated rats. Downregulation of autophagy by BMSC was also confirmed in VSC4.1 cells exposed to HD. Moreover, inhibition of autophagy by PIK III mitigated the neurotoxic effects of HD and, meanwhile, abolished BMSC-afforded neuroprotection. Furthermore, we found that BMSC failed to interfere with Beclin 1, but promoted activation of mammalian target of rapamycin (mTOR). Unc-like kinse 1 (ULK1) was further recognized as the downstream target of mTOR responsible for BMSC-mediated inhibition of autophagy. Altogether, BMSC transplantation potently ameliorated HD-induced autophagy through beclin 1-independent activation of mTOR pathway, providing a novel insight for the therapeutic effects of BMSC against n-hexane and other environmental toxicants-induced neurotoxicity.

19.
Neurochem Res ; 43(4): 948-958, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29478199

RESUMO

Epidemiological investigations and experimental studies indicate that chronic arsenic exposure can reduce learning and memory function. However, the underlying mechanism of this effect remains largely unknown. Emerging evidence suggests that microRNA (miRNA) play an important role in toxicant exposure and a regulatory role in cognitive function. In this study, we observed that subchronic arsenic exposure induced impairment of learning and memory and significantly up-regulated miRNA-219 (miR-219) expression in the mouse hippocampus. Furthermore, the expression of CaMKII, an experimentally validated target of miR-219, was decreased in the mice exposed to arsenic. Suppression of miR-219 by adeno-associated viral (AAV)-delivered anti-miR-219 prevented the arsenic-induced impairment of learning and memory and relieved the pathological changes in the synaptic structure of the hippocampus. Furthermore, we observed that the NMDA receptor subunit 2 (NR2) and the memory-related proteins c-Fos and c-Jun were up-regulated by inhibition of miR-219 in the mouse hippocampus. Taken together, the results of this study indicate that inhibition of miR-219 regulates arsenic-induced damage in the structure of the hippocampus and impairment of learning and memory, possibly by targeting CaMKII. Suppression of miR-219 may be a potential strategy to ameliorate arsenic-induced neurotoxicity.


Assuntos
Arsênico/toxicidade , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/biossíntese , Hipocampo/metabolismo , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/metabolismo , MicroRNAs/metabolismo , Sinapses/metabolismo , Animais , Dependovirus/metabolismo , Hipocampo/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Camundongos , MicroRNAs/antagonistas & inibidores , Sinapses/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologia
20.
J Cell Biochem ; 119(4): 3732-3743, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29236316

RESUMO

2,5-Hexanedione (HD) is an important bioactive metabolite of n-hexane and mediates the neurotoxicity of parent compound. Studies show that HD induces apoptotic death of neural progenitor cells. However, its underlying mechanism remains unknown. Mesenchymal stem cells (MSCs) are multipotential stem cells with the ability to differentiate into various cell types and have been used as cell model for studying the toxic effects of chemicals on stem cells. In this study, we exposed rat bone marrow MSCs to 0, 10, 20, and 40 mM HD in vitro. Apoptosis and disruption of mitochondrial transmembrane potential were estimated by immunochemistry staining. The expression of Akt, Bad, phosphorylated Akt (p-Akt), and Bad (p-Bad) as well as cytochrome c in mitochondria and cytosol were examined by Western blot. Moreover, caspase 3 activity, viability, and death of cells were measured by spectrophotometry. Our results showed that HD induced cell apoptosis and increased caspase 3 activity. HD down-regulated the expression levels of p-Akt, p-Bad and induced MMP depolarization, followed by cytochrome c release. Moreover, HD led to a concentration-dependent increase in the MSCs death, which was relative to MSCs apoptosis. However, these toxic effects of HD on the MSCs were significantly mitigated in the presence of IGF, which could activate PI3 K/Akt pathway. These results indicated that HD induced mitochondria-mediated apoptosis in the MSCs via inhibiting Akt/Bad signaling pathway and apoptotic death of MSCs via the signaling pathway. These results might provide some clues for studying further the mechanisms of HD-induced stem cell apoptosis and adverse effect on neurogenesis.


Assuntos
Hexanonas/farmacologia , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína de Morte Celular Associada a bcl/metabolismo , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Caspase 3/metabolismo , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Ratos , Transdução de Sinais/efeitos dos fármacos
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