Natural products as a potential modulator of microglial polarization in neurodegenerative diseases.

Neurodegenerative diseases (NDs) are characterized by the progressive loss of structure and function of neurons most common in elderly population, mainly including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). Neuroinflammation caused by microglia as the resident macrophages of the central nervous system (CNS) plays a contributory role in the onset and progression of NDs. Activated microglia, as in macrophages, to be heterogeneous, can polarize into M1 (pro-inflammatory) and M2 (anti-inflammatory) functional phenotypes. The former elaborate pro-inflammatory mediators promoting neuroinflammation and neuronal damage. In contrast, the latter generate anti-inflammatory mediators and neurotrophins that inhibit neuroinflammation and promote neuronal healing. Consistently, the regulation of microglial polarization from M1 to M2 phenotype appears as an outstanding therapeutic and preventive approach for NDs treatment. Although non-steroidal anti-inflammatory drugs (NSAIDs) currently used to alleviate M1 microglia-associated neuroinflammation responsible for the development of NDs, these drugs have different degrees of adverse effects and limited efficacy. As the advantages of novel structure, multi-target, high efficiency and low toxicity, natural products as the modulators of microglial polarization have attracted considerable concerns in the therapeutic areas of NDs. In this review, we mainly summarized the therapeutic potential of natural products and their various molecular mechanisms for NDs treatment through modulating microglial polarization. The aim of the current review is expected to be useful to develop innovative modulators of microglial polarization from natural products for the amelioration and treatment of NDs.

Increased BBB permeability contributes to EGCG-caused cognitive function improvement in natural aging rats: pharmacokinetic and distribution analyses.

Previous studies report that (-)-epigallocatechin-3-gallate (EGCG), the most abundant polyphenolic ingredient in green tea, has high efficacy against Alzheimer's disease (AD) in various in vivo and in vitro models. However, as a water-soluble component, how EGCG exerts its anti-AD effects in the brain was not elucidated. In the present study, we investigated the anti-AD mechanisms of EGCG in natural aging rats with cognitive impairments (CIs) assessed using Morris water maze. The rats were treated with EGCG (100 mg/kg per day, intragastrically) for 4 weeks. The expression of ß-amyloid (Aß1-42) in the brain was detected with immunohistochemical staining. We showed that EGCG administration significantly ameliorated the CI in the aging rats with CI and decreased Aß1-42 plaque formation in their brains. Then we used an efficient ultra-performance liquid chromatography-tandem mass spectrometer method to evaluate EGCG concentrations in rat plasma and tissue distribution. We found that EGCG absorption was significantly increased in the aging with CI group compared with control young rats. After oral administration of EGCG (100 mg), EGCG could not be detected in the brain tissues of control young rats, but it was found in the brain tissue of aging rats with CI. By using Evans Blue assay, transmission electron microscopy, and Western blotting assay, we demonstrated that the permeability of blood-brain barrier (BBB) was significantly increased in aging rats with CI. These results suggest that the permeability change of BBB is the physiological structural basis for EGCG treatment to improve learning and memory, thus providing a solid evidence for EGCG druggability in anti-AD therapeutic field.

Schisandrin ameliorates cognitive impairment and attenuates Aß deposition in APP/PS1 transgenic mice: involvement of adjusting neurotransmitters and their metabolite changes in the brain.

Neurotransmitters (NTs) in the brain are involved in neurodegenerative diseases, such as Alzheimer's disease (AD). Schisandrin is a major ingredient of Schisandra chinensis (Turcz.) Baill and has been used for the treatment of AD. In this study we examined the therapeutic effects of schisandrin in APP/PS1 transgenic mice, and correlated the beneficial effects on cognitive impairment with the adjustments in NTs and their metabolites in the mouse brains. APP/PS1 mice were treated with schisandrin (2 mg·kg-1·d-1, ip) for 2 weeks. In Morris Water Maze test; untreated APP/PS1 mice displayed significant cognitive impairment compared with normal mice; schisandrin administration ameliorated the cognitive impairment and significantly decreased Aß deposition in the hippocampus. In order to assess the effects of schisandrin on NTs and their metabolites, we developed a rapid and sensitive UPLC-MS/MS method for simultaneous determination of serotonin, 5-hydroxyindole acetic acid, dopamine, norepinephrine, γ-aminobutyric acid, glutamic acid, homovanillic acid, 3,4-dihydroxyphenylacetic acid and acetylcholine in mouse brains. This method conformed to methodology validation requirements. We found that there were statistically significant differences in these NTs and their metabolites between untreated APP/PS1 mice and normal mice, whereas schisandrin administration restored the abnormal NTs and their metabolites levels. These results suggest that schisandrin could alter the levels of these NTs and their metabolites in the brain, thus ameliorating learning and memory impairments in APP/PS1 mice.

Development of a UPLC-MS/MS Method for Simultaneous Determination of Six Flavonoids in Rat Plasma after Administration of Maydis stigma Extract and Its Application to a Comparative Pharmacokinetic Study in Normal and Diabetic Rats.

Maydis stigma is an important medicine herb used in many parts of the world for treatment of diabetes mellitus, which main bioactive ingredients are flavonoids. This paper describes for the first time a study on the comparative pharmacokinetics of six active flavonoid ingredients of Maydis stigma in normal and diabetic rats orally administrated with the decoction. Therefore, an efficient and sensitive ultra high performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) method for the simultaneous determination of six anti-diabetic ingredients (cynaroside, quercetin, luteolin, isorhamnetin, rutin and formononetin) of Maydis stigma in rat plasma has been developed and validated in plasma samples, which showed good linearity over a wide concentration range (r² > 0.99), and gave a lower limit of quantification of 1.0 ng·mL-1 for the analytes. The intra- and interday assay variability was less than 15% for all analytes. The mean extraction recoveries and matrix effect of analytes and IS from rats plasma were all more than 85.0%. The stability results showed the measured concentration for six analytes at three QC levels deviated within 15.0%. The results indicated that significant differences in the pharmacokinetic parameters of the analytes were observed between the two groups of animals, whereby the absorptions of these analytes in the diabetic group were all significantly higher than those in the normal group, which provides an experimental basis for the role of Maydis stigma in anti-diabetic treatment.

Association of serum interleukin-2 with severity and prognosis in hospitalized patients with community-acquired pneumonia: a prospective cohort study.

The prior studies have shown that interleukin-2 (IL-2) exerts important roles in the pathological and physiological processes of lung diseases. However, the role of IL-2 in community-acquired pneumonia (CAP) is still uncertain. Through a prospective cohort study, our research will explore the correlations between serum IL-2 levels and the severity and prognosis in CAP patients. There were 267 CAP patients included. Blood samples were obtained. Serum IL-2 were tested by enzyme-linked immunosorbent assay (ELISA). Demographic traits and clinical characteristics were extracted. Serum IL-2 were gradually elevated with increasing severity scores in CAP patients. Correlation analyses revealed that serum IL-2 were connected with physiological parameters including liver and renal function in CAP patients. According to a logistic regression analysis, serum IL-2 were positively correlated with CAP severity scores. We also tracked the prognostic outcomes of CAP patients. The increased risks of adversely prognostic outcomes, including mechanical ventilation, vasoactive agent usage, ICU admission, death, and longer hospital length, were associated with higher levels of IL-2 at admission. Serum IL-2 at admission were positively associated with severe conditions and poor prognosis among CAP patients, indicated that IL-2 may involve in the initiation and development of CAP. As a result, serum IL-2 may be an available biomarker to guide clinicians in assessing the severity and determining the prognosis of CAP.

The diagnostic value of lncRNA HOTAIR for cervical carcinoma in vaginal discharge and serum.

There is a lower incidence of cervical carcinoma compared with other common carcinomas, however, the mortality rate of cervical carcinoma is higher, suggesting that the treatment and prognosis of cervical carcinoma are relatively poor. Therefore, cervical carcinoma patients urgently need to find new diagnostic markers for early detection and treatment. One hundred and fifty cervical carcinoma and 100 benign cervical disease patients from 2019 January to 2021 December in Tianjin Central Hospital of Gynecology Obstetrics were selected and 100 healthy women were as normal group. The expression of HOX transcript antisense RNA (HOTAIR) in cervical carcinoma and paracancerous tissue, serum sample was measured by realtime PCR assay. The receiver operating characteristic of HOTAIR for cervical carcinoma was analyzed. The study found that the expression level of HOTAIR in primary cervical carcinoma is closely related to tumor metastasis and prognosis. The expression level of HOTAIR in paracancerous tissue was significantly lower than that in cancer tissue, and the expression level of HOTAIR in vaginal discharge and serum was higher than that in cervical carcinoma patients which was positively correlated with tumor malignancy, meanwhile, HOTAIR was significantly reduced after surgery 3 months both in vaginal discharge and serum. In order to examine the diagnostic efficiency of HOTAIR for cervical carcinoma, we found that the area under curve of vaginal discharge was 0.9723, sensitivity was 92%, specificity was 98%, the area under curve of serum was 0.8518, sensitivity was 79%, and specificity was 94% by receiver operating characteristic analysis. The accuracy were 92.7% and 89.3% in vaginal discharge and serum via certified by cervical carcinoma and benign cervical disease patient and healthy people. The above results show that the diagnostic performance of HOTAIR in vaginal discharge is higher than that of serum, and it is expected to become a marker for cervical carcinoma diagnosis and treatment.

[Research on EGCG improving the degenerative changes of the brain in AD model mice induced with chemical drugs].

OBJECTIVE: To study the effect and mechanism of (-)-Epigallocatechin-3-gallate (EGCG) on the degeneretive changes of the brain in Alzheimer's disease (AD) model mice induced with chemical drugs. METHODS: AD model mice were established by subcutaneously injecting with 3% D-gal at the dose of 150 mg/kg body weight once daily for 6 weeks. From the third week, the mice of D-gal + V(E) 280 U/kg group, D-gal + EGCG 2 mg/(kg x d) group and D-gal + EGCG 6 mg/(kg x d) group were intragastricly given with 5.6% V(E) at the dose of 280 IU/kg and EGCG at the dose of 2 mg/kg x d or 6 mg/kg x d respectively after injection of D-gal. The mice of control group, D-gal + dd H2O group and D-gal + oil group were administered with same volume vehicle distilled water and soybean oil respectively. The pathological changes of the brain in AD model mice were observed by HE staining analysis, the immunohistochemical analysis of beta-amyloid (Abeta) and evaluating the expression of amyloid precursor protein (APP) in the hippocampus of mice by Western blot analysis. RESULTS: EGCG 2 mg/(kg x d) or 6 mg/(kg x d) 4 weeks, ig evidently released neuronal injury in the hippocampus of the AD mice induced by D-gal, and significantly reduced the express of Abeta and APP in the hippocampus of AD model mice induced by D-gal (P < 0.01). CONCLUSION: EGCG has a protective effect on AD model mice induced by D-gal by decreasing the expression of APP and beta-Amyloid in the hippocampus of mice.

Association of Circulating Apolipoprotein AI Levels in Patients With Alzheimer's Disease: A Systematic Review and Meta-Analysis.

With the development of medicine, our research on Alzheimer's disease (AD) has been further deepened, but the mechanism of its occurrence and development has not been fully revealed, and there is currently no effective treatment method. Several studies have shown that apolipoprotein AI (ApoA-I) can affect the occurrence and development of Alzheimer's disease by binding to amyloid ß (Aß). However, the association between circulating levels of ApoA-I and AD remains controversial. We conducted a meta-analysis of 18 studies published between 1992 and 2017 to determine whether the ApoA-I levels in the blood and cerebrospinal fluid (CSF) are abnormal in AD. Literatures were searched in PubMed, EMBASE and Web of Science databases without language limitations. A pooled subject sample including 1,077 AD patients and 1,271 healthy controls (HCs) was available to assess circulating ApoA-I levels; 747 AD patients and 680 HCs were included for ApoA-I levels in serum; 246 AD patients and 456 HCs were included for ApoA-I levels in plasma; 201 AD patients and 447 HCs were included for ApoA-I levels in CSF. It was found that serum and plasma levels of ApoA-I were significantly reduced in AD patients compared with HCs {[standardized mean difference (SMD) = -1.16; 95% confidence interval (CI) (-1.72, -0.59); P = 0.000] and [SMD = -1.13; 95% CI (-2.05, -0.21); P = 0.016]}. Patients with AD showed a tendency toward higher CSF ApoA-I levels compared with HCs, although this difference was non-significant [SMD = 0.20; 95% CI (-0.16, 0.56); P = 0.273]. In addition, when we analyzed the ApoA-I levels of serum and plasma together, the circulating ApoA-I levels in AD patients was significantly lower [SMD = -1.15; 95% CI (-1.63, -0.66); P = 0.000]. These results indicate that ApoA-I deficiency may be a risk factor of AD, and ApoA-I has the potential to serve as a biomarker for AD and provide experimental evidence for diagnosis of AD. Systematic Review Registration: PROSPERO, identifier: 325961.

Association of Circulating Magnesium Levels in Patients With Alzheimer's Disease From 1991 to 2021: A Systematic Review and Meta-Analysis.

Alzheimer's disease (AD) remains a medical and social challenge worldwide. Magnesium (Mg) is one of the most frequently evaluated essential minerals with diverse biological functions in human body. However, the association between circulating Mg levels and AD remains controversial. We conducted a meta-analysis of 21 studies published between 1991 and 2021 to determine whether the Mg levels in the blood and cerebrospinal fluid (CSF) are abnormal in AD. Literatures were searched in PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), and Wanfang Data without language limitations. A pooled subject sample including 1,112 AD patients and 1,001 healthy controls (HCs) was available to assess Mg levels in serum and plasma; 284 AD patients and 117 HCs were included for Mg levels in CSF. It was found that serum and plasma levels of Mg were significantly reduced in AD patients compared with HCs (standardized mean difference [SMD] = -0.89; 95% confidence interval [CI] [-1.36, -0.43]; P = 0.000). There was statistically non-significant for Mg level in CSF between AD and HCs, whereas a decreased tendency were detected (SMD = -0.16; 95% CI [-0.50, 0.18]; P = 0.364). .In addition, when we analyzed the Mg levels of serum, plasma and CSF together, the circulating Mg levels in AD patients was significantly lower (SMD = -0.74, 95% CI [-1.13; -0.35]; P = 0.000). These results indicate that Mg deficiency may be a risk factor of AD and Mg supplementation may be a potentially valuable adjunctive treatment for AD. Systematic Review Registration: www.crd.york.ac.uk/PROSPERO/, registration number CRD42021254557.

Natural products as pharmacological modulators of mitochondrial dysfunctions for the treatments of Alzheimer's disease: A comprehensive review.

Alzheimer's disease (AD) is the most common progressive neurodegenerative disorder characterized by neuronal loss and cognitive impairment that harshly affect the elderly individuals. Currently, the available anti-AD pharmacological approaches are purely symptomatic to alleviate AD symptoms, and the curative effects of novel anti-AD drugs focused on Aß target are disappointing. Hence, there is a tremendous need to adjust AD therapeutic targets and discover novel anti-AD agents. In AD, mitochondrial dysfunction gradually triggers neuronal death from different aspects and worsens the occurrence and progress of AD. Consequently, it has been proposed that the intervention of impaired mitochondria represents an attractive breakthrough point for AD treatments. Due to chemical diversity, poly-pharmacological activities, few adverse effects and multiple targeting, natural products (NPs) have been identified as a valuable treasure for drug discovery and development. Multiple lines of studies have scientifically proven that NPs display ameliorative benefits in AD treatment in relation to mitochondrial dysfunction. This review surveys the complicated implications for mitochondrial dysregulation and AD, and then summarizes the potentials of NPs and their underlying molecular mechanisms against AD via reducing or improving mitochondrial dysfunction. It is expected that this work may open the window to speed up the development of innovative anti-AD drugs originated from NPs and improve upcoming AD therapeutics.

Pharmacokinetic properties and bioequivalence of two formulations of arbidol: an open-label, single-dose, randomized-sequence, two-period crossover study in healthy Chinese male volunteers.

BACKGROUND: Arbidol is an antiviral drug indicated for the prevention and treatment of all types of influenza infection and some other kinds of acute respiratory infections, specifically against influenza groups A and B, and severe acute respiratory syndrome. It is used to help prevent influenza infection as long as necessary with little risk for influenza mutation rendering it less effective. OBJECTIVE: The aim of this study was to compare the pharmacokinetic properties and tolerability, and to determine bioequivalence, of a newly developed generic dispersible tablet formulation (test) and a branded capsule formulation (reference) of arbidol 200 mg in healthy Chinese fasted male volunteers. METHODS: This open-label, single-dose, randomized-sequence, 2-period crossover study was conducted in healthy native Chinese male volunteers. Eligible subjects were randomly assigned in a 1:1 ratio to receive a single 200-mg dose of the test or reference formulation, followed by a 1-week washout period and administration of the alternate formulation. The study drugs were administered after a 12-hour overnight fast. After the study drug administration, serial blood samples were collected for 72 hours after administration. Plasma drug concentrations were determined using high-performance liquid chromatography coupled with tandem mass spectrometry. Several pharmacokinetic pararameters, including C(max), T(max), t((1/2)), AUC(0-t), and AUC(0-infinity), were determined from the plasma concentrations of the 2 formulations of arbidol using noncompartmental analysis. The formulations were to be considered bioequivalent if the log-transformed ratios of C(max) and AUC were within the predetermined bioequivalence range of 80% to 125% established by the State Food and Drug Administration (SFDA) of the People's Republic of China. Tolerability was assessed by monitoring vital signs (blood pressure, heart rate, temperature, and electrocardiography), laboratory analysis (hematology, blood biochemistry, hepatic function, and urinalysis), and subject interview on adverse events. RESULTS: Twenty subjects were enrolled and completed the study (mean [SD] age, 21.1 [1.1] years; weight, 64.7 [5.1] kg; and height, 172.3 [3.1] cm). Neither period nor sequence effect was observed. The main pharmacokinetic properties with the test and reference formulations were as follows: C(max), 417.4 (107.6) and 414.8 (95.1) ng/mL, respectively (P = NS); median (range) T(max), 0.63 (0.25-1.0) and 0.75 (0.5-1.5) hours (P = 0.035); AUC(0-t), 2033.6 (564.9) and 1992.0 (483.3) ng/mL/h (P = NS); AUC(0-infinity), 2285.4 (597.7) and 2215.2 (604.0) ng/mL/h (P = NS); and t(1/2), 6.9 (4.2) and 6.1 (5.2) hours (P = NS). The 90% CIs for the log-transformed ratios of C(max), AUC(0-t), and AUC(0-infinity) were 91.7% to 109.7%, 91.0% to 112.8%, and 92.0% to 116.3%, respectively (all, P < 0.05), which were within the predetermined range for bioequivalence. No adverse events were found on analysis of vital signs or laboratory tests or reported by subjects in this study. CONCLUSION: In this study in healthy Chinese male volunteers, the dispersible tablet formulation and the 200-mg capsule formulation of arbidol met the SFDA's regulatory definition of bioequivalence based on the rate and extent of absorption.

Baicalin mitigates cognitive impairment and protects neurons from microglia-mediated neuroinflammation via suppressing NLRP3 inflammasomes and TLR4/NF-κB signaling pathway.

AIMS: Baicalin (BAI), a flavonoid compound isolated from the root of Scutellaria baicalensis Georgi, has been established to have potent anti-inflammation and neuroprotective properties; however, its effects during Alzheimer's disease (AD) treatment have not been well studied. This study aimed to investigate the effects of BAI pretreatment on cognitive impairment and neuronal protection against microglia-induced neuroinflammation and to explore the mechanisms underlying its anti-inflammation effects. METHODS: To determine whether BAI plays a positive role in ameliorating the memory and cognition deficits in APP (amyloid beta precursor protein)/PS1 (presenilin-1) mice, behavioral experiments were conducted. We assessed the effects of BAI on microglial activation, the production of proinflammatory cytokines, and neuroinflammation-mediated neuron apoptosis in vivo and in vitro using Western blot, RT-PCR, ELISA, immunohistochemistry, and immunofluorescence. Finally, to elucidate the anti-inflammation mechanisms underlying the effects of BAI, the protein expression of NLRP3 inflammasomes and the expression of proteins involved in the TLR4/NF-κB signaling pathway were measured using Western blot and immunofluorescence. RESULTS: The results indicated that BAI treatment attenuated spatial memory dysfunction in APP/PS1 mice, as assessed by the passive avoidance test and the Morris water maze test. Additionally, BAI administration effectively decreased the number of activated microglia and proinflammatory cytokines, as well as neuroinflammation-mediated neuron apoptosis, in APP/PS1 mice and LPS (lipopolysaccharides)/Aß-stimulated BV2 microglial cells. Lastly, the molecular mechanistic study revealed that BAI inhibited microglia-induced neuroinflammation via suppression of the activation of NLRP3 inflammasomes and the TLR4/NF-κB signaling pathway. CONCLUSION: Overall, the results of the present study indicated that BAI is a promising neuroprotective compound for use in the prevention and treatment of microglia-mediated neuroinflammation during AD progression.

Pharmacokinetics of single-dose and multiple-dose memantine in healthy chinese volunteers using an analytic method of liquid chromatography-tandem mass spectrometry.

OBJECTIVE: This study consisted of 2 phases: development of a liquid chromatography-tandem mass spectrometry (LC/MS) method for determination of memantine in human plasma and characterization of single-dose and multiple-dose pharmacokinetic profiles of memantine in healthy Chinese volunteers using the LC/MS method. METHODS: An analytic method of LC/MS for determination of memantine in human plasma was developed and validated and was applied to this single-center, open-label, single-dose and multiple-dose pharmacokinetic study conducted in healthy native Chinese volunteers. Subjects were randomized to receive a single dose of 5, 10, or 20 mg of memantine to study the linear characteristics of pharmacokinetics, or a multiple dose of 5 mg once daily for 14 days to study the drug accumulation. The pharmacokinetic parameters calculated included C(max), T(max), AUC, t(1/2),mean residence time (MRT), maximum steady-state plasma concentration (C(ssmax)), minimum steady-state plasma concentration ((ssmin)), average steady-state plasma concentration (C(ssav)), and fluctuation percentage (DF). All values were expressed as mean (SD). Sequential blood samples were collected from 0 to 360 hours for single-dose pharmacokinetic determinations after the dose on day 1; in the multiple-dose pharmacokinetic arm, the sequential blood samples were also obtained from 0 to 360 hours on day 14 after collecting the predose samples at 0 hour on days 11, 12, and 13. Memantine concentrations in plasma were determined by LC/MS method. A calibration curve was constructed by 7 memantine concentrations and processed by least-squares linear regression analysis (w=1/x(2)). Safety assessments, including adverse events (AEs), were performed at all study visits. RESULTS: The LC/MS method for determination of memantine in human plasma was developed and validated. The standard calibration curve for spiked human plasma containing memantine was linear in the concentration range of 0.2 to 200.0 ng/mL. The correlation coefficient was greater than 0.9960 (n = 6). The lower limit of quantification for memantine in human plasma was 0.2 ng/mL, and the intraday and interday coefficients of variation were all lower than 15%. The mean recoveries of the 0.4, 20.0, and 180.0 ng/mL levels were 78.87%, 81.55%, and 81.98%, respectively. The coefficients of variation were all lower than 15% after being treated at room temperature for 24 hours, for 45 days at -40 degrees , and within 3 freeze-and-thaw cycles in plasma samples. Forty native Chinese subjects (10 [5 men, 5 women] subjects per group; mean [SD] age, 21.6 [1.6] [range, 19-27] years; weight, 63.0 [7.7] [range, 52-82] kg; height, 170.0 [7.0] [range, 155-185] cm) were enrolled in the study. After single-dose oral administration, the main pharmacokinetic parameters found for memantine at doses of 5, 10, and 20 mg were as follows: C(max), 6.20 (0.75), 11.60 (1.95), and 25.34 (8.34) ng/mL, respectively; T(max), 5.70 (1.64), 6.00 (1.33), and 6.89 (1.41) h; AUC(0-t), 486.19 (80.00), 889.32 (239.49), and 1772.91 (784.07) ng x h/mL; AUC(0-infinity), 540.05 (89.68), 932.07 (230.82), and 1853.29 (776.85) ng x h/mL; t(1/2), 66.86 (11.75), 63.57 (12.58), and 62.06 (9.26) h; and MRT, 99.37 (16.96), 91.73 (18.16), and 89.56 (13.77) h. The main pharmacokinetic parameters found for memantine at doses of 5 mg once daily for 14 days were as follows: T(max), 6.80 (2.46) h; C(ssmax), 19.69 (2.00) ng/mL; C(ssmin), 12.76 (2.80) ng/mL; C(ssav), 16.10 (2.46) ng/mL; t(1/2), 64.57 (15.78) h; MRT, 93.17 (23.38) h; AUC(ss),386.37 (59.00) ng x h/mL; and DF, 44.47% (15.27%). One female subject withdrew from the study after a single 20-mg dose due to an AE (dizziness and vomiting); no other subjects experienced an AE. CONCLUSIONS: In these healthy Chinese subjects, the t(1/2) and MRT values were fixed and did not increase following the increased dose, and the AUC(infinity) and C(max) values increased following the increasing dosage of memantine. Linear pharmacokinetics was found at doses from 5 to 20 mg. The multiple-dose pharmacokinetic parameters (other than C(max)) were nearly similar compared with the single-dose administration. The maximum plasma concentration of memantine after multiple-dose administration was greater than that after a single-dose administration, suggesting memantine accumulation with multiple-dose administration of 5 mg and requiring further confirmation in larger studies.

Elevated circulating magnesium levels in patients with Parkinson's disease: a meta-analysis.

BACKGROUND: The association between circulating magnesium (Mg) and Parkinson's disease (PD) remains ambiguous and controversial. Thus, a meta-analysis was conducted to evaluate the circulating Mg levels in PD patients and to clarify whether high circulating Mg levels should be considered as a potential risk factor for PD. METHODS: In this study, 17 case-control published studies were selected in our meta-analysis by searching the electronic databases of Web of Science, PubMed, and China National Knowledge Infrastructure (CNKI) before June 1, 2018. Overall, 848 PD cases and 784 healthy controls (HC), 1,023 PD cases and 911 HC, and 180 PD cases and 144 HC met the inclusion criteria for this study Mg levels in serum, peripheral blood, and cerebrospinal fluid (CSF), respectively. Standardized mean difference (SMD) in random-effects model and 95% CI were used to assess the correlation strength through the comparison of the two groups. RESULTS: Meta-analysis showed that the serum Mg levels in PD cases were significantly higher than those in HC individuals (SMD =1.09, 95% CI =0.52, 1.66). Furthermore, this result was further confirmed by the combined analysis of serum and whole blood studies together (SMD =0.64, 95% CI =0.10, 1.19). In addition, the higher CSF Mg levels in patients of PD were observed in comparison with normal range (SMD =0.55, 95% CI =0.21, 0.88). However, this data did not further discuss and analyze because of the smaller sample size of CSF studies. CONCLUSION: Our findings supported the notion that the increase of circulating Mg levels appears in the patients with PD.

Association of circulating manganese levels with Parkinson's disease: A meta-analysis.

Whether systemic manganese (Mn) dysfunctions in Parkinson's Disease (PD) is still under ongoing debate. The recent reported studies on the circulating Mn levels in PD showed inconsistent results. A meta-analysis study was conducted to evaluate the association of circulating Mn levels with PD, and to clarify whether Mn should be considered as a potential risk factor for PD. A systematic searching was performed based on PubMed, web of science, and China National Knowledge Infrastructure (CNKI). Finally, 22 studies were identified, involving 637 PD patients and 802 health controls (HC) individuals for serum Mn, 1258 PD patients and 1304 HC individuals for peripheral blood Mn, and 195 PD patients and 196 HC individuals for cerebrospinal fluid (CSF) Mn. Forest plots were adopted to represent the comparison of the groups by assessing standardized mean difference with random effects model. This meta-analysis revealed a significantly increased serum Mn levels in PD patients (SMD=0.78; 95% CI [0.32, 1.24]; P=0.001), and it was further confirmed when serum, plasma and whole blood studies were analyzed together (SMD=0.58; 95% CI [0.25, 0.91]; P=0.001). Instead, no significant differences of CSF Mn were observed between PD patients and HC individuals (SMD=-0.09; 95% CI [-0.47, 0.29]; P=0.644). These results supported the notion that elevated Mn level should be a potential risk factor for PD, although the high heterogeneity and methodological limitations recommended caution in the interpretations for the present findings.

The clinical significance of the combined detection of serum Smac, HE4 and CA125 in endometriosis-associated ovarian cancer.

OBJECTIVE: This study aims to investigate the clinical significance of serum Smac, HE4 and CA125 alone or combined for detecting endometriosis-associated ovarian cancer (EAOC). METHODS: The level of serum Smac, HE4 and CA125 in 40 healthy controls, 40 cases of benign endometriosis ovarian tumor, and 60 cases of EAOC were detected by ELISA and electrochemical immune method. RESULTS: Serum Smac expression level was significantly lower in the EAOC group than in the control group and benign ovarian tumor group (P< 0.05), while HE4 and CA125 expression levels were significantly higher in the EAOC group than the other two groups. The sensitivity of Smac single detection was up to 91.67%, and the specificity of HE4 was up to 98.75%. Furthermore, the sensitivity of Smac + HE4 + CA125 combined was the highest, which reached up to 98.33%; but the specificity was low, which reached up to 75%. The serum expression level differences before and after surgery were statistically significant. As the number of chemotherapies increases, the Smac level increased, and HE4 and CA125 levels gradually decreased. Furthermore, Smac increased to normal at the end of the 2nd period of chemotherapy, while HE4 and CA125 decreased to normal in 2nd and 3rd period of chemotherapy, respectively. CONCLUSION: Serum Smac, HE4 and CA125 may play an important role in predicting EAOC and in monitoring the prognosis of postoperative EAOC.

Association of interleukin-33 gene polymorphisms with susceptibility to late onset Alzheimer's disease: a meta-analysis.

The association between interleukin-33 (IL-33) gene polymorphisms and late onset Alzheimer's disease (LOAD) remains controversial in previous studies. Thus, a meta-analysis was conducted to assess the association between the IL-33 polymorphisms (rs11792633 and rs7044343) and LOAD susceptibility. Crude odds ratio (OR) and 95% confidence interval (CI) were used to investigate the relationship strength. Sensitivity analysis was performed, and publication bias was estimated by the Begg's and Egger's tests. Overall, six independent studies involving 2,589 patients and 8,414 control samples met our inclusion criteria and were included in this meta-analysis. The results showed that IL-33 rs11792633 polymorphism had statistically significant correlation with a decreased risk of LOAD in heterozygous comparison model (OR =0.64, 95% CI =0.48-0.83), homozygote comparison model (OR =0.83, 95% CI =0.74-0.93), dominant model (OR =0.78, 95% CI =0.67-0.91), recessive model (OR =0.70, 95% CI =0.59-0.84), and allelic model (OR =0.79, 95% CI =0.69-0.91), which were also validated by stratified subgroup analysis. Additionally, there was an apparent association between the IL-33 rs7044343 variant and LOAD risk under four genetic models for overall population (heterozygous comparison model: OR =0.75, 95% CI =0.63-0.89; dominant model: OR =0.83, 95% CI =0.70-0.98; recessive model: OR =0.80, 95% CI =0.68-0.94; allelic model: OR =0.86, 95% CI =0.79-0.94) as well as Caucasian subgroup. In summary, our meta-analysis implicated that IL-33 gene polymorphisms rs11792633 and rs7044343 were significantly associated with the susceptibility of LOAD.

Decreased circulating Zinc levels in Parkinson's disease: a meta-analysis study.

There is no consensus on the involvement of zinc (Zn) dysfunctions in Parkinson's Disease (PD). We performed a meta-analysis to evaluate whether circulating Zn levels in the serum, plasma, and cerebrospinal fluid (CSF) are altered in PD. Twenty-three published studies were selected by searching the databases of PubMed and China National Knowledge Infrastructure (CNKI). A total of 803 PD patients and 796 controls, 342 PD patients and 392 controls, and 135 PD patients and 93 controls were included to study Zn levels in the serum, plasma, and CSF, respectively. Our meta-analysis showed that the serum Zn levels were significantly lower in PD patients compared with health controls (SMD = -0.59; 95% CI [-1.06, -0.12]; P = 0.014). A reduced Zn levels in PD patients were found when serum and plasma studies were analyzed together (SMD = -0.60, 95% CI [-0.98; -0.22]; p = 0.002). PD patients had a tendency toward reduced CSF Zn levels compared with health controls (SMD = -0.50; 95% CI [-1.76, 0.76]; P = 0.439), but no statistical significance was obtained and this data did not allow conclusions due to a small sample size of CSF studies. This study suggests that reduced Zn levels in the serum and plasma are associated with an increased risk for PD.

[The progress of the concentration technology of extract of traditional Chinese medicine].

The concentration of extract of traditional Chinese medicine (TCM) is one of the important unit operations that affect the quality of the pharmaceutical products. However, there are some problems to be solved. The concentration process has the shortages of relatively high temperature, relatively long time or low efficient, some losses of active and volatile ingredients, more operation steps, easy fouling and emission of waste water. In order to solve these problems, many new technologies and installations have been developed in the past thirty years, including suspension freeze-concentration, progressive freeze-concentration, single- or multi-effect evaporation with an external natural circulating flow, on-line preventing fouling evaporation with vapor-liquid-solid flow, reverse osmosis concentration, membrane distillation, osmotic distillation, macro-porous resin adsorption etc. The system of the extract of TCM is very complex. The extract includes water and alcohol extracts. The composition of TCM is made of active and inactive ingredients. Hence, it is necessary to master the features of every concentration technologies and installations, including their merits and demerits, flexibilities, degree of maturations of techniques and so on to get a wise choice for the industry applications. New concentration technologies and installations of the extract of TCM developed recently are reviewed in this paper. The characteristics of each method are analyzed and discussed in order to guide the industry applications. At the same time, the further research directions of concentration techniques of extract of TCM are also given.

Association between ABCB1 polymorphisms and haplotypes and Alzheimer's disease: a meta-analysis.

Although several epidemiological studies have investigated the association between ATP-binding cassette subfamily B member 1 (ABCB1) gene polymorphisms and Alzheimer's disease (AD) susceptibility, controversial results exist. Here, we performed a meta-analysis to assess whether ABCB1 polymorphisms 3435C > T (rs1045642), 2677G > T/A (rs2032582), 1236C > T (rs1128503) and haplotypes were associated with AD risk. Nine independent publications were included and analyzed. Crude odds ratio (OR) and 95% confidence interval (CI) were applied to investigate the strength of the association. Sensitivity analysis was conducted to measure the robustness of our analysis. A funnel plot and trim and fill method were used to test and adjust for publication bias. The results showed a significant association between the 3435C > T single nucleotide polymorphism (SNP) and AD susceptibility (CT vs. CC: OR = 1.24, 95% CI = 1.06-1.45, P = 0.01; CT + TT vs. CC: OR = 1.21, 95% CI = 1.04-1.41, P = 0.01) in the total population, as well as in Caucasian subgroup. The 2677G > T/A SNP was related to a decreased AD risk in Caucasian subgroup (TT + TA + AA vs. GT + GA + GG: OR = 0.68, 95% CI = 0.47-0.98, P = 0.04). Moreover, the ABCB1 haplotype analysis showed that the 1236T/2677T/3435C haplotype was associated with a higher risk of AD (OR = 1.99, 95% CI = 1.24-3.18, P = 0.00). Our results suggest that the ABCB1 3435C > T SNP, the 2677G > T/A SNP and 1236T/2677T/3435C haplotype are significantly associated with AD susceptibility.