Asthma aggravates alzheimer's disease by up-regulating NF- κB signaling pathway through LTD4.

Clinical studies have shown that asthma is a risk factor for dementia or Alzheimer's disease (AD). To investigate whether asthma aggravates AD in APP/PS1 mice and explore the potential mechanisms, an asthma model was established using six-month-old APP/PS1 mice, and montelukast was used as a therapeutic agent in APP/PS1 mice with asthma. The Morris water maze test showed that asthma aggravates spatial learning and memory abilities. Asthma also upregulates the NF-κB inflammatory pathway in APP/PS1 mice and promotes the expression of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), amyloid-ß (Aß) deposition, neuronal damage, synaptic plasticity deficiency, activation of microglia and astrocytes. The level of LTD4 and its receptor CysLT1R in the hippocampus of APP/PS1 mice after the asthma modeling was established was higher than that in APP/PS1 mice, suggesting that asthma may affect the pathology of AD through LTD4 and its receptor Cys-LT1R. Montelukast ameliorates these pathological changes and cognitive impairment. These results suggest that asthma aggravates AD pathology and cognitive impairment of APP/PS1 mice via upregulation of the NF-κB inflammatory pathway, and montelukast ameliorates these pathological changes.

Clinical efficacy and safety of tigecycline based on therapeutic drug monitoring for carbapenem-resistant Gram-negative bacterium pneumonia in intensive care units.

BACKGROUND: We investigated the associations between the different doses of tigecycline, its efficacy and safety, and the role of tigecycline therapeutic drug monitoring for patients in the intensive care unit. METHODS: This study was a single-center cohort including patients infected with multidrug-resistant Acinetobacter baumannii (MDR-AB) and multidrug-resistant Klebsiella pneumoniae (MDR-KP) causing pulmonary infections. The steady-state plasma concentration after tigecycline administration was determined by High-Performance Liquid Chromatography (HPLC) in patients admitted to the ICU between October 2020 and December 2021. Multivariate analyses of tigecycline's clinical efficacy and safety were performed to control confounding factors. RESULTS: For this study, we included 45 patients and 45 blood samples to determine steady-state trough concentrations of tigecycline. All patients were divided into the High Dose (HD) and Standard Dose (SD) groups. The median trough concentration of tigecycline was 0.56 µg/mL in the HD group, which was higher than in the SD group (0,21 µg/mL), p = 0.000. There was no significant difference between the two groups of patients in terms of bacterial eradication rate, mortality rate, and clinical efficacy. Multiple regression analysis showed that the ICU days were correlated with mortality OR 1.030(1.005-1.056), p = 0.017. APACHE II was significantly associated with clinical efficacy OR 0.870(0.755-1.002), p = 0.045. The level of fibrinogen decline in the HD group was significantly higher than in the SD group (-3.05 ± 1.67 vs -1.75 ± 1.90), p = 0.038. We identified that age and tigecycline treatment duration influenced fibrinogen decline. CONCLUSIONS: Tigecycline plasma concentrations are significantly increased when using a high dose. However, the plasma concentration of tigecycline is not correlated with clinical efficacy and adverse reactions. Fibrinogen decline appears to be related to the patient's age and days of tigecycline. Large sample data are still needed to confirm the clinical guidance significance of tigecycline TDM.

Altered plasma glutamate and glutamine levels in patients with drug-resistant and drug-responsive symptomatic focal epilepsy.

OBJECTIVES: To compare the levels of plasma glutamate and glutamine in drug-resistant or drug-responsive symptomatic focal epilepsy. Dysfunctional glutamate neurotransmission plays an essential role in epilepsy pathophysiology. METHODS: This cross-sectional study included 80 drug-resistant and 42 drug-responsive symptomatic focal epileptic patients and 132 healthy controls from June 2017 to February 2018. Plasma glutamate and glutamine levels were assessed via high-performance liquid chromatography. RESULTS: Patients with drug-resistant symptomatic focal epilepsy had significantly higher plasma glutamate levels than healthy controls, whereas those with the drug-responsive disease had higher plasma glutamine levels than healthy controls. These results indicate that plasma glutamate and glutamine levels can discriminate patients with drug-resistant and drug-responsive symptomatic focal epilepsy from control individuals with the areas under the curve values of 0.931 and 0.72, respectively. CONCLUSION: Elevated plasma glutamate levels are associated with drug-resistant symptomatic focal epilepsy and may aid the diagnosis of drug-resistant symptomatic focal epilepsy.

Tetrahydroxystilbene glucoside protects against sodium azide-induced mitochondrial dysfunction in human neuroblastoma cells.

Objective: Mitochondrial dysfunction is evident in the early stage of Alzheimer's disease (AD). Therefore development of drugs that protect mitochondrial function is a promising strategy for AD. The present work was to investigate the effects of 2, 3, 5, 4'-Tetrahydroxystilbene-2-O-ß-d-glucosides (TSG) on a mitochondrial dysfunction cell model induced by sodium azide and elucidate the underlying mechanisms. Methods: Mitochondrial membrane potential (MMP) was detected by a fluorescence method. Cellular adenosine triphosphate (ATP) level was measured using a firefly luciferase-based kit. Reactive oxygen species (ROS) was detected using dichlorofluorescin diacetate (DCFH-DA). The expression levels of Bcl-2 and Bax were measured by Western blotting assay. Flow cytometry was utilized to measure apoptosis. Results: Pretreatment of TSG (25-200 µmol/L) for 24 h significantly elevated MMP and ATP content, reduced ROS level and Bax/Bcl-2 ratio, and inhibited apoptosis in SH-SY5Y cells exposed to sodium azide. Conclusion: These results suggest that TSG protects SH-SY5Y cells against sodium azide-induced mitochondrial dysfunction and apoptosis. These findings are helpful to understand the protective effect of TSG on mitochondria, which are involved in the early stage of AD.

Beta-Asarone Alleviates Myocardial Ischemia-Reperfusion Injury by Inhibiting Inflammatory Response and NLRP3 Inflammasome Mediated Pyroptosis.

Beta-asarone (ß-Asarone), the major component of Acorus tatarinowii Rhizoma, has been proved to be muti-pharmacological activities including anti-inflammation, and which is effective in protecting the central nervous system. However, the effect of ß-Asarone on myocardial ischemia-reperfusion (I/R) injury is not yet clear. This study used a rat model with 45 min occlusion and 24 h releasing of proximal segment of left anterior descending coronary artery. The effects of ß-Asarone on cardiac histopathology, myocardial infarction size, levels of cardiac troponin T (cTNT), myeloperoxidase (MPO) and interleukin-1ß (IL-1ß), protein expressions of apoptosis-associated speck-like protein containing a CARD (ASC), Nod-like receptor protein 3 (NLRP3), caspase-1 and Gasdermin D (GSDMSD), and left ventricular performance were studied respectively. Our results showed that administration of ß-Asarone significantly improved the heart outcome after myocardial ischemia and reperfusion in terms of less infarction size and lower serum cTNT concentration. Further, ß-Asarone treatment evidently inhibited inflammatory response with less granulocyte infiltration, mild tissue edema and lower tissue MPO content, it also suppressed NLRP3 signal pathway and cardiac cell's pyroptosis for less protein expressions of ASC and NLRP3, lower level cleavage activation of caspase-1 and GSDMSD, and lower serum IL-1ß concentration. Finally, ß-Asarone treatment well preserved the left ventricular performance with higher ejection fraction and fractional shortening. The experimental results suggested that ß-Asarone was protective against myocardial ischemia-reperfusion injury, in which inhibition of inflammatory response and suppression of NLRP3 inflammasome mediated pyroptosis were supposed to play a vital role.

Recognition and Optimization of Ingredients Treating Nitroglycerin-Induced Migraine Rats from Wuzhuyu Decoction.

Wuzhuyu decoction (WZYD) has been clinically used to treat migraine effectively since Eastern Han Dynasty of ancient China. However, its antimigrainic ingredients remain unclear. In present study, the antimigrainic ingredients of WZYD were explored and optimized in nitroglycerin-induced migraine rats through correlation analysis of decoction spectra-pharmacological effects and absorption spectra-pharmacological using entropy-weighted partial least squares regression method. The decoction spectra and absorption spectra were obtained through the determination of nine main ingredients in ten kinds of WZYDs and WZYDs' single-pass intestinal perfusion samples using high performance liquid chromatography-diode array detector. The pharmacodynamics indexes related to migraine model rats were detected using high performance liquid chromatography method and kits after oral administration of WZYDs. Then, the key ingredients influencing indexes were achieved through the correlation analysis. And the optimization of key ingredients was acquired through uniform design experiment. The pharmacodynamic verification test was used to clarify the advantages of the optimized sample. The results showed that the final optimized sample, in which the concentrations of rutaecarpine, evodiamine, ginsendside Rb1, 6-gingerol, ginsendside Rg1, rutaevine, and limonin were 0.081, 0.565, 1.455, 0.159, 0.871, 0.178, and 0.009 mg·mL-1, respectively, provided the best comprehensive effect than another optimized sample and the best uniform design sample. Therefore, a new reliable method for rapidly recognizing and optimizing the effective constituents of WZYD treating migraine was established.

Exosomes derived from human umbilical cord mesenchymal stromal cells deliver exogenous miR-145-5p to inhibit pancreatic ductal adenocarcinoma progression.

The roles of miRNAs in the development of cancer have made them promising tools for novel therapeutic approaches. However, the successful delivery of miRNAs to cancer cells has been hampered by difficulties in developing an effective and sustainable delivery mechanism. Exosomes are small endogenous membrane vesicles that mediate communication between cells by delivering genetic materials. Thus, given their intrinsic properties, exosomes have been a focus for use as biological delivery vehicles for miRNAs transfer. Whether exosomes can effectively deliver exogenous miRNAs to pancreatic ductal adenocarcinoma (PDAC) cells has not been thoroughly investigated. Here, we used exosomes from human umbilical cord mesenchymal stromal cells (hucMSCs) to deliver exogenous miR-145-5p, which inhibited PDAC cell proliferation and invasion and increased apoptosis and cell cycle arrest, concomitant with decreased Smad3 expression in vitro. Using a mouse model, we also demonstrated that overexpressing miR-145-5p significantly reduced the growth of xenograft tumors in vivo. Our findings provide novel insights that exosomes might be an attractive therapeutic vehicle for the clinical administration of miRNAs in patients with PDAC.

Dopaminergic precursors differentiated from human blood-derived induced neural stem cells improve symptoms of a mouse Parkinson's disease model.

Autologous neural stem cells (NSCs) may offer a promising source for deriving dopaminergic (DA) cells for treatment of Parkinson's disease (PD). Methods: By using Sendai virus, human peripheral blood mononuclear cells (PBMNCs) were reprogrammed to induced NSCs (iNSCs), which were then differentiated to dopaminergic neurons in vitro. Whole-genome deep sequencing was performed to search for mutations that had accumulated during the reprogramming and expansion processes. To find the optimal differentiation stage of cells for transplantation, DA precursors obtained at various differentiation time points were tested by engraftment into brains of naïve immunodeficient mice. At last, the safety and efficacy of iNSC-derived DA precursors were tested by transplantation into the striatum of immunodeficient PD mouse models. Results: PBMNC-derived iNSCs showed similar characteristics to fetal NSCs, and were able to specifically differentiate to DA neurons with high efficiency in vitro. The sequencing data proved that no harmful SNVs, Indels and CNVs were generated during the reprogramming and expansion processes. DA precursors obtained between differentiation day 10 to 13 in vitro were most suitable for transplantation when a balanced graft survival and maturation were taken into account. Two weeks after transplantation of DA precursors into mouse PD models, the motor functions of PD mice started to improve, and continued to improve until the end of the experiments. No graft overgrowth or tumor was observed, and a significant number of A9-specific midbrain DA neurons were surviving in the striatum. Conclusion: This study confirmed the efficacy of iNSC-derived DA precursors in a mouse PD model, and emphasized the necessity of genomic sequencing and vigorous safety assessment before any clinical translation using iNSCs.

The Distribution of Urinary Alzheimer-Associated Neuronal Thread Protein and Its Association with Common Chronic Diseases in the General Population.

BACKGROUND: Alzheimer-associated neuronal thread protein (AD7c-NTP) has been found to be a biomarker for Alzheimer's disease (AD). OBJECTIVE: The aim of the present study was to investigate the distribution of Alzheimer-associated neuronal thread protein and its relationship to common chronic diseases in the general population. METHODS: Urine samples of 1,805 participants were collected from four districts (Xi Cheng, Fang Shan, Tong Zhou, and Yan Qing) in Beijing. The assessment in this study included a questionnaire that captured participants' demographic information, use of medication and histories of disease, neurological examinations, psychometric evaluations, physical and clinical examinations, and laboratory tests. RESULTS: Urine AD7c-NTP level was increased among the population over 60 years old and females exhibited higher levels than males. These results controlled for other demographic factors such as education levels, employment status, body mass index and current residence. The urine AD7c-NTP levels exhibited no association with non-neurological diseases (0.3346±0.4482 ng/ml), such as hypertension (0.3445±0.4187), stroke (0.3652±0.4010), diabetes (0.3319±0.4371), dyslipidemia (0.3440±0.4314), renal insufficiency (0.3223±0.3909), cancer (0.5055±1.0006), chronic lung disease (0.2911±0.2852), chronic liver disease (0.5579±0.6726), severe depression symptoms (0.5186±0.7040), and mild depression symptoms (0.3669±0.3811). CONCLUSIONS: Cut-off values for urine AD7c-NTP levels for different age groups and genders should be established. AD7c-NTP levels proved relatively stable in the body and were not impacted by demographic factors or common chronic diseases.

[Difference in intestinal absorption of Wuzhuyu decoction between normal and migraine model rats].

To compare the intestinal absorption of Wuzhuyu decoction(WZYD) between normal rats and migraine model rats, and investigate the optimized WZYD from aspect of absorption. The rat single pass intestinal perfusion test(SPIP) was adopted for optimized sample and un-optimized sample in normal and migraine model rats induced by nitroglycerin and reserpine. The contents of 8 ingredients were determined by high performance liquid chromatography(HPLC), and 4 absorption parameters for each ingredient were calculated and compared: unit area absorption(Mper area), absorption rate constant(Ka), apparent coefficient(Papp) and relative absorption rate(RA). The results showed that there was a great difference between normal rats and model rats in the intestinal absorption of the same WZYD. As compared with normal rats, the absorption parameters of most ingredients in optimized sample were increased in migraine model rats induced by nitroglycerin; Similar phenomena were also found in migraine model rats induced by reserpine. However, the absorption parameters of most ingredients were decreased in un-optimized sample. Therefore, pathological model rats shall be used for effective ingredient recognition based on the correlation between intestinal absorption spectra and pharmacological effects. As compared with the un-optimized samples, the absorption of effective ingredients was faster, easier and more adequate in the optimized samples, revealing their mechanism on better efficacy from the aspect of absorption.

Some Methodological Characteristics of Alzheimer-Associated Urine Neuronal Thread Protein Detected by Enzyme-Linked Immunosorbent Assay.

BACKGROUND: Alzheimer-associated neuronal thread protein (AD7c-NTP) has been found to be a candidate biomarker of Alzheimer's disease (AD). OBJECTIVE: To investigate the effects of urine collected time, different preservatives addition, and storage condition on the measurement of urine AD7c-NTP by enzyme-linked immunosorbent assay (ELISA). METHODS: Three hundred urine samples were collected from 20 participants at three time points on five consecutive days. These samples were immediately placed at 4°C and detected within 2 h. The single spot samples of the first day morning were split into eleven duplicate aliquots (a-k) of 1 ml each, (a) without any preservative (untreated), (b) containing boric acid (2 g/L), (c) containing NaHCO3 (5 g/L), (a-c) were detected at six different time points. For the other eight preservative-free samples, (d-g) were stored at -20°C and (h-k) were stored at -70°C, respectively, detected at different time points. All of the results were compared with the baseline urine. RESULTS: The urine AD7c-NTP levels at different time points behaved stably (p > 0.05). Urine samples without any preservative increased over time, and compared with the NaHCO3 addition group, boric acid addition group behaved stably. Samples stored at -20°C and -70°C led to an obviously false positive. CONCLUSIONS: AD7c-NTP can be tested using random urine instead of the first morning urine. If the specimen cannot be tested in time, boric acid appears to be an acceptable preservative with storage at 4°C, freezing is not recommended.

Increased central dopaminergic activity might be involved in the behavioral abnormality of cuprizone exposure mice.

The neurotoxican cuprizone (CPZ, a copper chelator) has been used extensively to create a mouse model of demyelination. However, the effects on behavior of CPZ treatment have not been reported in C57BL/6 mice given a diet containing 0.4% CPZ within 3weeks. Behavioral abnormalities were assessed using a range of test: Y-maze, spontaneous locomotor activity, rota-rod test, novel object recognition, climbing. Mice exposed to CPZ displayed more arm entrance, locomotor movements, and climbing behavior, suggesting an increase in central nervous system activity. However, no significant differences either in spontaneous alternation or latency to fall from the rotating drum were observed, demonstrating that spatial working memory or motor coordination and balance didn't impair by CPZ short-term exposure. In addition, they showed higher dopamine levels and dopamine transporter expression in the cortex. Our findings indicate that increased central dopaminergic activity may relate to the behavioral abnormality in mice, and this CPZ short-term exposure with higher dose may offer a model to study some aspects of biology relevant to schizophrenia and other related disorders.

Optimization of combinations of ginsenoside-Rg1, ginsenoside-Rb1, evodiamine and rutaecarpine for effective therapy of mouse migraine.

Wuzhuyu decoction (WZYD) is a classic traditional Chinese medicine (TCM) formula. It has been extensively used for treating migraine for thousands of years in TCM. Four potential active ingredients from WZYD, ginsenoside-Rg1 (Rg1), ginsenoside-Rb1 (Rb1), evodiamine (Ev) and rutaecarpine (Ru), were found to have positive correlations with pharmacodynamic indicators involving mouse migraine in our previous study. To find a better therapeutic effect on migraine, this research was carried out to optimize the combinations of Rg1, Rb1, Ev and Ru using the uniform design method. The results showed that Rb1 and Ev played key roles in improving the therapeutic effect on mouse migraine by strongly ameliorating pharmacodynamic indicators associated with migraine. They significantly increased the contents of 5-hydroxytryptamine, noradrenaline and dopamine in brain tissues, and reduced the content of nitric oxide in brain tissues and the activities of nitric oxide synthase in both brain tissues and blood serum. The optimal concentrations of Rb1 and Ev were 1057.4 mg/L and 312.5 mg/L, respectively. Rg1 and Ru contributed less to the overall desirability, suggesting that they had reverse effects on some pharmacodynamic indicators of this type of migraine. The verification test demonstrated by the immunohistochemical method that the optimal combination inhibited the expression of c-fos and c-jun in periaqueductal gray of mice, and strongly ameliorated pharmacodynamic indicators. These results suggested that the therapeutic effect of the optimal combination of the four ingredients was strong, and the optimal results were proven to be reliable and accurate.

Indoleamine 2,3-dioxygenase is upregulated in the brain of rats with acute pancreatitis.

BACKGROUND: Acute pancreatitis (AP) has an effect on both inflammatory/autoimmune processes and psychological states, but the pathophysiological causes of pancreatic encephalopathy in the brain are unclear. We hypothesized that the peripheral immune/inflammatory response during AP can affect indolamine 2,3-dioxygenase (IDO) expression and serotonin content in the brain. METHODS: About 210 male Sprague Dawley rats were randomly divided into five groups: control (0 h) and 6 h, 24 h, 48 h and 72 h experimental groups. Acute pancreatitis was induced by an injection of a sodium taurocholate solution via a cannulated bile-pancreatic duct. We measured the plasma TNF-α and IL-6 levels; serotonin, 5-HIAA and the protein concentration levels of IDO and monoamine oxidase A (MAO-A) were evaluated in the striatum, hippocampus and left prefrontal cortex. RESULTS: The IL-6 and the TNF-α levels increased in the 24 h, 48 h and 72 h groups. The IDO concentrations of both the 72 h group in the hippocampus and 48 h, 72 h groups in the prefrontal cortex increased; in the corpus striatum, the IDO concentrations fluctuated without statistical significance. The MAO-A protein concentration of the 6 h and 24 h groups decreased in the striatum, hippocampus and prefrontal cortex. There were no statistically significant differences found in the serotonin and 5-HIAA concentrations. CONCLUSIONS: During the process of AP, cytokines, such as IL-6 and TNF-α, may play a role in activation of neuronal pathways utilizing the metabolic enzyme IDO, which may play an important role in determining the mental symptomatology accompanying AP.

Identification of active ingredients in Wuzhuyu decoction improving migraine in mice by spectral efficiency association.

Wuzhuyu decoction is a traditional Chinese medicine used for the effective treatment of migraines, termed 'Jueyin headache', in China. However, there have been few investigations to clarify the composition of Wuzhuyu decoction for the treatment of migraines. In the present study, 10 types of Wuzhuyu decoction were analyzed by chromatograms. 5-hydroxytryptamine (5-HT)-depletion mouse models of migraine were prepared by subcutaneous injection of reserpine and placement of autologous blood clots in the cerebral cortex. The levels of 5-HT, noradrenaline (NE), dopamine (DA), nitric oxide (NO) and nitric oxide synthase (NOS) in the brain tissues and sera of the mice were determined. The ingredients and pharmacodynamic indices of the Wuzhuyu decoctions were analyzed using spectral efficiency association by partial least squares regression. The levels of 5-HT, NE and DA in the mouse brain tissues were reduced to 337.785 ± 84.504, 171.173 ± 65.172 and 242.075 ± 158.621 mg/g brain tissue, respectively. The level of NO in the brain tissues increased to 0.425 ± 0.184 µmol/g protein and the activities of NOS in the brain tissues and sera increased to 0.719 ± 0.477 U/mg and 50.688 ± 8.132 U/ml, respectively. Regarding the ingredients of the Wuzhuyu decoction, those with significant regression coefficients were ginsenoside-Rg1, Re, Rb1, rutaevine (Rv), limonin (Li), evodiamine (Ev), rutaecarpine (Ru) and substance X (awaiting identification). Rg1, Re, Rb1, Rv, Li, Ev, Ru and X in the Wuzhuyu decoction were observed to yield the pharmacological effects, whereas Rb1, Rv and Ev were important in index improvement.

The level of Alzheimer-associated neuronal thread protein in urine may be an important biomarker of mild cognitive impairment.

Increased levels of Alzheimer-associated neuronal thread protein (AD7c-NTP) are often detected in urine in the early course of Alzheimer's disease (AD), which makes it a promising biomarker for AD. However, whether the concentration of urinary AD7c-NTP is increased in patients with mild cognitive impairment (MCI) remains unclear. The aim of this study was to explore the value of urinary AD7c-NTP to assist in the diagnosis of cognitive impairment by comparing differences in urinary AD7c-NTP among normal controls, MCI patients and AD patients. One hundred and seventy patients from the Xuan wu Hospital, Capital Medical University were divided into three groups according to their clinical diagnosis: an AD group (n=45), an MCI group (n=60) and a normal group (n=65). The Mini Mental State Examination and the Montreal Cognitive Assessment scale were used to screen for the diagnosis of AD and MCI, and patients met the diagnostic criteria of the National Institute of Neurological Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association. The level of urinary AD7c-NTP was determined using the enzyme-linked immunosorbent assay method. The urinary levels of AD7c-NTP in the AD group (median 2.14 [range 0.49-6.39] ng/ml) and the MCI group (median 1.57 [range 0.4-4.15] ng/ml) were significantly higher than those of the normal group (median 0.53 [range 0.04-2.07] ng/ml). To our knowledge our study is the first to show that the level of urinary AD7c-NTP in MCI patients is higher than in healthy people, which suggests that the level of urinary AD7c-NTP may be an important biomarker for early diagnosis of MCI.

Lmx1a enhances the effect of iNSCs in a PD model.

Lmx1a plays a central role in the specification of dopaminergic (DA) neurons, which potentially could be employed as a key factor for trans-differentiation to DA neurons. In our previous study, we have converted somatic cells directly into neural stem cell-like cells, namely induced neural stem cells (iNSCs), which further can be differentiated into subtypes of neurons and glia in vitro. In the present study, we continued to test whether these iNSCs have therapeutic effects when transplanted into a mouse model of Parkinson's disease (PD), especially when Lmx1a was introduced into these iNSCs under a Nestin enhancer. iNSCs that over-expressed Lmx1a (iNSC-Lmx1a) gave rise to an increased yield of dopaminergic neurons and secreted a higher level of dopamine in vitro. When transplanted into mouse models of PD, both groups of mice showed decreased ipsilateral rotations; yet mice that received iNSC-Lmx1a vs. iNSC-GFP exhibited better recovery. Although few iNSCs survived 11weeks after transplantation, the improved motor performance in iNSC-Lmx1a group did correlate with a greater tyrosine hydroxylase (TH) signal abundance in the lesioned area of striatum, suggesting that iNSCs may have worked through a non-autonomous manner to enhance the functions of remaining endogenous dopaminergic neurons in brain.

[Study on pharmacological ingredients of wuzhuyu tang treating migraine by correlating absorption ingredients in everted intestinal sac and pharmacodynamics].

Wuzhuyu Tang is a classical formula for treating migraine, but its' pharmacological ingredients is unclear yet. Present study employed the everted intestinal sac model to collect the absorption samples of 10 kinds of Wuzhuyu decoction, and then analyzed the contents of 9 ingredients in Wuzhuyu Tang and absorption samples quantitatively or semi-quantitatively by HPLC-DAD method. Reserpine was used to establish the mice model of migraine, and then the contents and activities of 5-hydroxytryptamine, noradrenaline, dopamine, nitric oxide and nitricoxide synthase in brain tissues and serums were determined respectively after oral administration of Wuzhuyu Tang. Using the partial least squares regression method to correlate the total absorption quantity of 9 ingredients and pharmacodynamics. The result shows that limocitrin-3-O-beta-D-glucoside, ginsenoside Rg1 and Rb1, rutaevine, limonin, evodiamine and rutaecarpine are the main ingredients influenced the effects in absorption samples in everted intestinal sacs, especially ginsenoside Rg1, rutaevine, evodiamine and rutaecarpine among them have obvious improving effects to most pharmacodynamics index, might be the pharmacological ingredients influenced the therapeutical effects of Wuzhuyu Tang treating migraine.

Rutile TiO2 particles exert size and surface coating dependent retention and lesions on the murine brain.

The rising commercial use and large-scale production of engineered nanoparticles (NPs) may lead to unintended exposure to humans. The central nervous system (CNS) is a potential susceptible target of the inhaled NPs, but so far the amount of studies on this aspect is limited. Here, we focus on the potential neurological lesion in the brain induced by the intranasally instilled titanium dioxide (TiO2) particles in rutile phase and of various sizes and surface coatings. Female mice were intranasally instilled with four different types of TiO2 particles (i.e. two types of hydrophobic particles in micro- and nano-sized without coating and two types of water-soluble hydrophilic nano-sized particles with silica surface coating) every other day for 30 days. Inductively coupled plasma mass spectrometry (ICP-MS) were used to determine the titanium contents in the sub-brain regions. Then, the pathological examination of brain tissues and measurements of the monoamine neurotransmitter levels in the sub-brain regions were performed. We found significant up-regulation of Ti contents in the cerebral cortex and striatum after intranasal instillation of hydrophilic TiO2 NPs. Moreover, TiO2 NPs exposure, in particular the hydrophilic NPs, caused obvious morphological changes of neurons in the cerebral cortex and significant disturbance of the monoamine neurotransmitter levels in the sub-brain regions studied. Thus, our results indicate that the surface modification of the NPs plays an important role on their effects on the brain. In addition, the difference in neurotoxicity of the two types of hydrophilic NPs may be induced by the shape differences of the materials. The present results suggest that physicochemical properties like size, shape and surface modification of the nanomaterials should be considered when evaluating their neurological effects.

Effects of cysteamine on MPTP-induced dopaminergic neurodegeneration in mice.

Cysteamine is a degradation product of the amino acid cysteine and a reduced form of cystamine. Cysteamine exhibits strong antioxidant activity and has been implicated in the treatment of neurodegenerative disorders such as Huntington's disease. In the present study, we investigated whether cysteamine confers protection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced toxicity in the dopaminergic neurons in a mouse model for Parkinson's disease (PD). The loss of dopaminergic (DA) neurons and reduction in striatal DA concentrations induced by MPTP was ameliorated to a significant extent by pretreatment with low (20mg/kg/day), but not high (75mg/kg/day), dose of cysteamine 4days prior to and subsequently along with the MPTP treatment. Consistently, the increased production of pro-oxidants, such as reactive oxygen species (ROS) and malondialdehyde (MDA), was significantly suppressed by low dose of cysteamine. Conversely, the reduction in GSH level caused by MPTP exposure was significantly attenuated by pretreatment of cysteamine. In addition, the inhibited secretion of the brain-derived neurotrophic factor (BDNF) by neurons derived from substantia nigra pars compact (SNpc) of MPTP-treated mice was significantly restored by cysteamine administration. Our results demonstrate that cysteamine at low dose confers potent neuroprotection against MPTP-induced toxicity of dopaminergic neurons, and may become a potential therapeutic strategy for PD.