Deqi Jiang

SIRT3 in Neural Stem Cells Attenuates Microglia Activation-Induced Oxidative Stress Injury Through Mitochondrial Pathway

Sirtuin 3 (SIRT3), a mitochondrial protein, is involved in energy metabolism, cell apoptosis and mitochondrial function. However, the role of SIRT3 in neural stem cells (NSCs) remains unknown. In previous studies, we found that microglia activation-induced cytotoxicity negatively regulated survival of NSCs, along with mitochondrial dysfunction. The aim of this study was to investigate the potential neuroprotective effects of SIRT3 on the microglia activation-induced oxidative stress injury in NSCs and its possible mechanisms. In the present study, microglia-NSCs co-culture system was used to demonstrate the crosstalk between both cell types. The cytotoxicity of microglia activation by Amyloid-β (Aβ) resulted in the accumulation of reactive oxygen species (ROS) and down-regulation of SIRT3, manganese superoxide dismutase (MnSOD) gene expression in NSCs, concomitant to cell cycle arrest at G0/G1 phase, increased cell apoptosis rate and opening of the mitochondrial permeability transition pore (mPTP) and enhanced mitochondrial membrane potential (ΔΨm) depolarization. Furthermore, SIRT3 knockdown in NSCs via small interfering RNA (siRNA) accelerated cell injury, whereas SIRT3 overexpression provided resistance to microglia activation-induced oxidative stress cellular damage. The mechanisms of SIRT3 attenuated activated microglia-induced NSC dysfunction included the decreased mPTP opening and cyclophilin D (CypD) protein expression, inhibition of mitochondrial cytochrome C (Cyt C) release to cytoplasm, declined Bax/B-cell lymphoma 2 (Bcl-2) ratio and reduced caspase-3/9 activity. Taken together, these data imply that SIRT3 ameliorates microglia activation-induced oxidative stress injury through mitochondrial apoptosis pathway in NSCs, these results may provide a novel intervention target for NSC survival.

Nicotine contributes to the neural stem cells fate against toxicity of microglial-derived factors induced by Aβ via the Wnt/β-catenin pathway

Recent studies have demonstrated that the molecules secreted from microglias play important roles in the cell fate determination of neural stem cells (NSCs), and nicotinic acetylcholine receptor agonist treatment could reduce neuroinflammation in some neurodegenerative disease models, such as Alzheimers disease (AD). However, it is not clear how nicotine plays a neuroprotective role in inflammation-mediated central nervous diseases, and its possible mechanisms in the process remain largely elusive. The aim of this study is to improve the survival microenvironment of NSCs co-cultured with microglias in vitro by weakening inflammation that mediated by accumulation of β-amyloid peptide (Aβ). The viability, proliferation, differentiation, apoptosis of NSCs and underlying mechanisms associated with Wnt signaling pathway were investigated. The results showed that Aβ could directly damage NSCs. Furthermore, concomitant to elevated levels of TNF-α, IL-1β derived from microglias, the NSCs had been damaged more severely with the upregulation of Axin 2, p-β-catenin and the downregulation of β-catenin, p-GSK-3β, microtubule-associated protein-2, choline acetyltransferase. However, addition of 10 μmol/L nicotine before microglias treated with Aβ was beneficial to protect the NSCs against neurotoxicity of microglial-derived factors induced by Aβ, which partially rescued proliferation, differentiation and inhibited apoptosis of NSCs via activation of Wnt/β-catenin pathway. Taken together, these data imply that low concentration nicotine attenuates NSCs injury induced by microglial-derived factors via Wnt signaling pathway. Thus, treatment with nicotinic acetylcholine receptor agonist provides a promising research field for neural stem cell fate and therapeutic intervention in neuroinflammation diseases.

Efficacy and safety of prostaglandin E1 plus lipoic acid combination therapy versus monotherapy for patients with diabetic peripheral neuropathy.

The aim of this report was to evaluate the efficacy and safety of prostaglandin E1 (PGE1) plus lipoic acid (LA) for the treatment of diabetic peripheral neuropathy (DPN) compared with that of PGE1 or LA monotherapy. Randomized controlled trials (RCT) published up to 3 August 2014 were reviewed. A random or fixed effect model was used to analyze outcomes expressed as risk ratios (RR) or mean difference (MD) with a 95% confidence interval (CI). I(2) statistic was used to assess heterogeneity. Subgroup and sensitivity analyses were performed. The outcomes measured were as follows: clinical efficacy, median motor nerve conduction velocity (MNCV), median sensory nerve conduction velocity (SNCV), peroneal MNCV, peroneal SNCV and adverse effects. Thirty-one RCT with 2676 participants were included. Clinical efficacy of PGE1+LA combination therapy was significantly better than monotherapy (p<0.00001, RR=1.32, 95% CI 1.26 to 1.38). Compared with monotherapy, PGE1+LA combination therapy led to significant improvements in median MNCV (p<0.00001, MD=4.69, 95% CI 3.16 to 6.23), median SNCV (p<0.00001, MD=5.46, 95% CI 4.04 to 6.88), peroneal MNCV (p<0.00001, MD=5.19, 95% CI 3.71 to 6.67) and peroneal SNCV (p<0.00001, MD=5.50, 95% CI 3.30 to 7.70). There were no serious adverse events associated with drug intervention. PGE1+LA combination therapy is superior to PGE1 or LA monotherapy for improvement of neuropathic symptoms and nerve conduction velocities in patients with DPN. These findings should be further validated by larger well-designed and high-quality RCT.

Effects of prostaglandin E1 plus methylcobalamin alone and in combination with lipoic acid on nerve conduction velocity in patients with diabetic peripheral neuropathy: A meta-analysis.

This report was to evaluate the efficacy of lipoic acid, prostaglandin E1 and methylcobalamin (L+P+M) for the treatment of diabetic peripheral neuropathy (DPN) in comparison with that of prostaglandin E1 plus methylcobalamin (P+M), in order to provide the basis and reference for clinical rational drug use. Randomized controlled trials (RCTs) of L+P+M for DPN published up to 3rd August, 2014 were searched. A random or fixed effect model was used to analyze outcomes which were expressed as risk ratios (RRs) or mean difference (MD) with a 95% confidence interval (CI). Eighteen RCTs with 1410 participants were included. Clinical efficacy of L+P+M therapy was significantly better than P+M therapy (fifteen trials; RR 1.32, 95% CI 1.24-1.41, P<0.00001, I(2)=32%). As compared with P+M therapy, the pooled effects of L+P+M therapy on nerve conduction velocities (NCVs) were (fifteen trials; MD 4.70, 95% CI 3.77-5.63, P<0.00001, I(2)=79%) for median MNCV, (thirteen trials; MD 4.73, 95% CI 3.69-5.77, P<0.00001, I(2)=85%) for median SNCV, (sixteen trials; MD 4.22, 95% CI 3.32-5.12, P<0.00001, I(2)=83%) for peroneal MNCV, (fourteen trials; MD 3.09, 95% CI 2.04-4.14, P<0.00001, I(2)=82%) for peroneal SNCV. There was no serious adverse events associated with drugs intervention. L+P+M therapy was superior to P+M therapy for improvement of clinical efficacy and NCVs in DPN patients. These findings should be further verified by high-quality RCTs.

Overexpression of mitochondrial Hsp75 protects neural stem cells against microglia-derived soluble factor-induced neurotoxicity by regulating mitochondrial permeability transition pore opening in vitro

Microglia (MG)-induced neurotoxicity, a major determinant of Alzheimers disease, is closely related to the survival of neural stem cells (NSCs). Heat shock protein 75 (Hsp75) has been reported to exert protective effects against environmental stresses; however, whether or not it protects NSCs against MG-derived soluble factor-induced neurotoxicity remains unclear. In the present study, we constructed NSCs that overexpressed human Hsp75 protein and established a co-culture system in order to elucidate the role of Hsp75 in NSC-MG interactions. The results obtained indicated that Hsp75 expression increased after 12 h of soluble factor induction and continued to increase for up to 36 h of treatment. The overexpression of Hsp75 decreased NSC apoptosis and preserved mitochondrial membrane potential. Further experiments revealed that the overexpression of Hsp75 inhibited the formation of cyclophilin D (CypD)-dependent mitochondrial permeability transition pore (mPTP) involvement in neurotoxicity-mediated mitochondrial dysfunction and suppressed the activation of the mitochondrial apoptotic cascade, as demonstrated by the inhibition of the release of cytochrome c (Cytc) and the activation of caspase-3. The findings of this study demonstrate that Hsp75 overexpression prevents the impairment of NSCs induced by MG-derived soluble factors by regulating the opening of mPTP. Thus, Hsp75 warrants further investigation as a potential candidate for protection against neurotoxicity.

Blocking mPTP on Neural Stem Cells and Activating the Nicotinic Acetylcholine Receptor α7 Subunit on Microglia Attenuate Aβ-Induced Neurotoxicity on Neural Stem Cells

Abstractβ-Amyloid (Aβ) can stimulate microglia to release a variety of proinflammatory cytokines and induce neurotoxicity. Nicotine has been reported to inhibit TNF-α, IL-1, and ROS production in microglia. Mitochondrial permeability transition pore (mPTP) plays an important role in neurotoxicity as well. Here, we investigated whether activating the microglial α7-nAChR has a neuroprotective role on neural stem cells (NSCs) and the function of mPTP in NSCs in this process. The expression of α7-nAChR in rat NSCs was detected by immunocytochemistry and RT-PCR. The viability of microglia and NSCs was examined by MTT assay. The mitochondrial membrane potential (ΔΨm) and morphological characteristics of NSCs was measured by JC-1 staining and transmission electron microscopy respectively. The distribution of cytochrome c in the subcellular regions of NSCs was visualized by confocal laser scanning microscopy, and the expression levels of cyclophilin D and cleaved caspase-3 were assayed by western blot. The apoptotic rate of NSCs was measured by flow cytometry. The expression of α7-nAChR was detected in microglial cells, but no expression was found in NSCs. The viability of rat microglial cells and NSCs was not affected by reagents or coculture itself. Aβ1–42-mediated microglial activation impaired the morphology and the ΔΨm of mitochondria of NSCs as well as increased cell apoptosis. However, the damage was attenuated when the α7-nAChRs on microglial cells were activated or the mPTPs on NSCs were blocked. Blockade of mPTPs on NSCs and activation of α7-nAChRs on microglia exhibit neuroprotective roles in Aβ-induced neurotoxicity of NSCs.

Theophylline: a review of population pharmacokinetic analyses

Numerous population pharmacokinetic studies of theophylline have been conducted in paediatric and adult patients. The purpose of this review was to summarize the published studies concerning population pharmacokinetics of theophylline in patients of different ages and discuss factors that might cause the large variability in the pharmacokinetics of theophylline.

Correlation between MCP-1-2518A/G polymorphism and the risk of Alzheimer’s disease

The -2518A/G polymorphism in monocyte chemotactic protein-1 (MCP-1) has been extensively investigated for association with Alzheimer’s disease (AD); however, the results from different studies are inconsistent. The aim of this study was to draw an accurate conclusion of the association. All eligible case–control studies were searched in PubMed, Embase, Chinese National Knowledge Infrastructure, China Biological Medicine Databases, and Wanfang Databases. Eight case–control studies with a total of 2370 cases and 2413 controls were eligible to be included in this meta-analysis. The association was evaluated by calculating the odds ratios (ORs) with the corresponding 95% confidence intervals (CIs). Overall, there was no significant association between MCP-1-2518A/G polymorphism and AD risk in all genetic models (the allele model G vs. A: OR = 1.15, 95% CI 0.92–1.45, p = 0.22; the co-dominant model GG vs. AA: OR = 1.38, 95% CI 0.80–2.36, p = 0.25; the dominant model AG + GG vs. AA: OR = 1.14, 95% CI 0.89–1.46, p = 0.31; the recessive model GG vs. AG + AA: OR = 1.35, 95% CI 0.87–2.09, p = 0.18). In subgroup analysis by ethnicity, a significant difference was not detected in both Caucasians and Asians. In allele model (G vs. A), the required sample size of 31858 was calculated by applying trial sequential analysis. Cumulative z curve is always below the trial sequential monitoring boundary and is nominally statistically significant (Z = 1.96). A consistent result was obtained in other genetic models. In summary, the present meta-analysis suggests that MCP-1-2518A/G polymorphism may not be associated with genetic susceptibility of AD in general population, but the association remains indeterminate due to the insufficient evidence.

Comment on Kuyper et al.—Atenolol vs Nonatenolol β-Blockers for the Treatment of Hypertension: A Meta-analysis

To the Editor: We read with great interest the article by Kuyper et al. entitled “Atenolol vs Nonatenolol b-Blockers for the Treatment of Hypertension: A Meta-analysis” published in the May 2014 issue of the Canadian Journal of Cardiology. The authors performed a meta-analysis of randomized controlled trials to compare the efficacy of atenolol vs nonatenolol b-blockers in clinical trials enrolling young (< 60 years) and older patients with hypertension. The study is of profound academic importance; however, there are still some queries that we would like to communicate with the authors.