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.

Regulation of human cardiac Kv1.5 channels by extracellular acidification.

Human Kv1.5 channels (hKv1.5) conduct the ultra-rapid delayed rectifier potassium current (I Kur), which plays an important role in action potential repolarization of atrial myocytes. The present study was undertaken to examine the effects of acidic pH on hKv1.5 wild-type (WT) and its pore mutant channels heterologously expressed in Chinese hamster ovary (CHO) cells using site-directed mutagenesis combined with whole-cell patch-clamp technique. Both extracellular and intracellular acidifications equally and reversely reduced the amplitude of hKv1.5 currents. The extracellular acidification significantly shifted the voltage dependence of current activation to more depolarized potentials and accelerated deactivation kinetics of the current. The ancillary ß subunits Kvß1.3 and Kvß1.2, known to modify the pharmacological sensitivities of hKv1.5, enhanced the extracellular proton-induced inhibitory effect on hKv1.5 current. In addition, several mutants (T462C, T479A, T480A, and I508A) exhibited significantly higher sensitivity to acidic pH-induced inhibition compared with WT channel, whereas the inhibitory effect of acidic pH was markedly reduced in H463G mutant. These observations indicate that (1) extracellular acidification modifies hKv1.5 gating and activity, (2) ß subunits and several residues (T462, T479, T480, and I508) play critical roles in determining the sensitivity of the channel to acidic exposure, and (3) H463 may be a critical sensor for the channel inhibition by extracellular protons.

[Research progress on targeting effect and regulating mechanisms of the stemness of cancer stem cells].

Cancer stem cells(CSCs) have become an important target to overcome the obstacle of tumor therapy. In recent years, many reports have shown that the heterogenicity and plasticity of CSCs, and the microenvironment interact with each other, which become important factors affecting the dynamic conversion of CSCs. Therefore, we should not only focus on the stem characteristics of CSCs, but also consider the factors related to the regulation of the dynamic transformation of CSCs stemness. The signaling pathways, epithelial- mesenchymal transition(EMT) and the niche of CSCs, are proved to play an important role in the regulation of stemness of CSCs. The aspects are important in the studies of tumor therapy by targeting CSCs. This article summarizes the mechanisms for regulation of the stemness of cancer stem cells and the progress in the studies of targeting cancer stem cells with a focus on the CSCs dynamic regulation.

Biological factors driving colorectal cancer metastasis.

Approximately 20% of colorectal cancer (CRC) patients present with metastasis at diagnosis. Among Stage I-III CRC patients who undergo surgical resection, 18% typically suffer from distal metastasis within the first three years following initial treatment. The median survival duration after the diagnosis of metastatic CRC (mCRC) is only 9 mo. mCRC is traditionally considered to be an advanced stage malignancy or is thought to be caused by incomplete resection of tumor tissue, allowing cancer cells to spread from primary to distant organs; however, increasing evidence suggests that the mCRC process can begin early in tumor development. CRC patients present with high heterogeneity and diverse cancer phenotypes that are classified on the basis of molecular and morphological alterations. Different genomic and nongenomic events can induce subclone diversity, which leads to cancer and metastasis. Throughout the course of mCRC, metastatic cascades are associated with invasive cancer cell migration through the circulatory system, extravasation, distal seeding, dormancy, and reactivation, with each step requiring specific molecular functions. However, cancer cells presenting neoantigens can be recognized and eliminated by the immune system. In this review, we explain the biological factors that drive CRC metastasis, namely, genomic instability, epigenetic instability, the metastatic cascade, the cancer-immunity cycle, and external lifestyle factors. Despite remarkable progress in CRC research, the role of molecular classification in therapeutic intervention remains unclear. This review shows the driving factors of mCRC which may help in identifying potential candidate biomarkers that can improve the diagnosis and early detection of mCRC cases.

The novel HLA-A*02:405 allele characterized by sequencing-based typing.

HLA-A*02:405 differs from HLA-A*02:06:01:01 by one nucleotide substitution in codon 161 in exon 3.

DNA repair genes XPC, XPG polymorphisms: relation to the risk of colorectal carcinoma and therapeutic outcome with Oxaliplatin-based adjuvant chemotherapy.

Xeroderma pigmentosum complementation group C and G (XPC, XPG) play important roles in DNA damage repairing machinery. Genetic variations in the XPC and XPG may be associated with increased risk for colorectal carcinoma (CRC). In this study, we evaluated the relation between the XPC Lys939Gln, XPG Asp1104His polymorphisms, and CRC susceptibility in a population-based case-control study, which included 1,028 CRC cases and 1,085 controls. Compared with the corresponding wild genotypes, we found that individuals with at least one copy of the XPC Lys939Gln (AC or CC genotype) and XPG Asp1104His (GC or CC genotype) had an increased risk for CRC. In addition, the variant genotypes of the XPC Lys939Gln AC/CC (P = 0.027) or XPG Asp1104His GC/CC (P = 0.003) reduced the elevation of preoperative carcinoembryonic antigen (CEA) level. Moreover a significantly longer progression-free survival (PFS) after Oxaliplatin-based adjuvant chemotherapy was observed in patients with XPG Asp1104His wide-type GG genotype (n = 432, Log-rank test: P = 0.033). Cox proportional hazards analyses demonstrated that variant genotypes of XPG Asp1104His [hazard ratio (HR) = 1.692, 95% confidence interval (95%CI): 1.202-2.383, P = 0.003] as well as pathology grade (HR = 2.545, 95%CI: 2.139-3.030, P < 0.001), and lymph node metastases (HR = 1.851, 95%CI: 1.306-2.625, P < 0.001) were predictive of shorter PFS for the CRC patients with Oxaliplatin-based adjuvant chemotherapy. In conclusion, the current data suggested that XPC Lys939Gln and XPG Asp1104His polymorphisms might contribute to the identification of patients with increased risk for CRC.

Promoter methylation status and expression of estrogen receptor alpha in familial breast cancer patients.

The hypermethylation of estrogen receptor alpha (ERα) promoter is a common molecular alteration in sporadic breast cancer (BC), but its involvement in familial BC remains largely unknown. In the present study, we analyzed the methylation statuses of four regions (ER1, ER3, ER4, and ER5) of the ERα promoter and the ERα expression levels of 113 familial BC patients in a Han Chinese Population from northeastern China and evaluated the association between major clinicopathological features and the hypermethylation statuses of the ERα gene. Tumor samples were analyzed for ERα methylation status by the methylation-specific polymerase chain reaction for ERα, PR, p53, BRCA-1, and BRCA-2 by immunohistochemical (IHC) staining and for Her-2 status by IHC and fluorescence in situ hybridization (FISH). ERα methylation was observed in tumor tissues in 47/113 (41.6%) familial BC patients. There were no significant differences in the methylation statuses among ER1 (20.4%), ER3 (18.6%), ER4 (17.7%), and ER5 (19.5%; χ (2) = 3.89, p > 0.05). An association between ERα expression level and its promoter methylation level was found. In addition, ERα methylation was significantly correlated with tumor size, PR expression, p53 nuclear accumulation, and BRCA-1 and BRCA-2 statuses. In conclusion, in familial BC patients, the level of ERα gene promoter methylation correlates with ERα expression, PR, p53 nuclear accumulation, and BRCA-1 and BRCA-2 statuses. Epigenetic alteration of ERα gene may play an important role in the pathogenesis of familial BC.

Reversing multidrug resistance by tyrosine kinase inhibitors.

Recently, a large number of tyrosine kinase inhibitors(TKIs) have been developed as anticancer agents. These TKIs can specifically and selectively inhibit tumor cell growth and metastasis by targeting various tyrosine kinases and thereby interfering with cellular signaling pathways. The therapeutic potential of TKIs has been hindered by multidrug resistance(MDR), which is commonly caused by overexpression of ATP-binding cassette(ABC) membrane transporters. Interestingly, some TKIs have also been found to reverse MDR by directly inhibiting the function of ABC transporters and enhancing the efficacy of conventional chemotherapeutic drugs. In this review, we discuss ABC transporter-mediated MDR to TKIs and MDR reversal by TKIs.

[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.

[Corrigendum] MicroRNA-148a inhibits breast cancer migration and invasion by directly targeting WNT-1.

Subsequently to the publication of the above article, an interested reader drew to the authors' attention that the data panel for the MDA­MB­231/migration/NC experiment in Fig. 2B on p. 1428 was strikingly similar to the data shown for the MDA­MB­231/invasion/Blank experiment in Fig. 2C, such that these data appeared to have been derived from the same original source. The authors have referred back to their original data, and realize that the data panel was selected incorrectly for Fig. 2B. The corrected version of Fig. 2, showing the correct data for the MDA­MB­231/migration/NC experiment in Fig. 2B, is shown on the next page. The authors regret the error that was made during the preparation of this figure, and can confirm that the error in the assembly of this figure did not adversely affect the conclusions reported in the study. The authors are grateful to the Editor of Oncology Reports for allowing them the opportunity to publish a Corrigendum, and all the authors agree to this Corrigendum. Furthermore, they apologize to the readership for any inconvenience caused. [the original article was published in Oncology Reports 35: 1425­1432, 2016; DOI: 10.3892/or.2015.4502].

Advances of research of Fc-fusion protein that activate NK cells for tumor immunotherapy.

The rapid development of bioengineering technology has introduced Fc-fusion proteins, representing a novel kind of recombinant protein, as promising biopharmaceutical products in tumor therapy. Numerous related anti-tumor Fc-fusion proteins have been investigated and are in different stages of development. Fc-fusion proteins are constructed by fusing the Fc-region of the antibody with functional proteins or peptides. They retain the bioactivity of the latter and partial properties of the former. This structural and functional advantage makes Fc-fusion proteins an effective tool in tumor immunotherapy, especially for the recruitment and activation of natural killer (NK) cells, which play a critical role in tumor immunotherapy. Even though tumor cells have developed mechanisms to circumvent the cytotoxic effect of NK cells or induce defective NK cells, Fc-fusion proteins have been proven to effectively activate NK cells to kill tumor cells in different ways, such as antibody-dependent cell-mediated cytotoxicity (ADCC), activate NK cells in different ways in order to promote killing of tumor cells. In this review, we focus on NK cell-based immunity for cancers and current research progress of the Fc-fusion proteins for anti-tumor therapy by activating NK cells.

[Corrigendum) RNA interference­mediated FANCF silencing sensitizes OVCAR3 ovarian cancer cells to adriamycin through increased adriamycin­induced apoptosis dependent on JNK activation.

After the publication of the article, an interested reader drew to the authors' attention that there appeared to be a pair of overlapping data panels in Fig. 4C on p. 1726 [specifically, the 'Untransfected' and 'Control shRNA' data panels for the ADM (24 h) experiments]. The authors have consulted their original data, and have realized that this figure was inadvertently assembled incorrectly. Furthermore, they have noticed that Fig. 1 on p. 1724 also contained errors that arose during its assembly; essentially, several of the data panels in Fig. 1C, showing the detection of FANCD2 focus formation via immunofluorescence experiments, were selected inappropriately. The corrected versions of Figs. 1 and 4, containing the corrected data panels for Figs. 1C and 4C respectively, are shown on the next page. Note that these errors did not affect the results or the conclusions reported in this work. The authors all agree to this Corrigendum, and are grateful to the Editor of Oncology Reports for allowing them to have the opportunity to correct these mistakes. Lastly, the authors apologize to the readership for any inconvenience these errors may have caused. [Oncology Reports 29: 1721­1729, 2013; DOI: 10.3892/or.2013.2295].

BRAF and KRAS mutations in metastatic colorectal cancer: future perspectives for personalized therapy.

Colorectal cancer (CRC) is one of the most commonly diagnosed cancers worldwide and 30% of patients with CRC experience metastasis. Patients with metastatic colorectal cancer (mCRC) have a 5-year overall survival rate of <10%. V-raf murine sarcoma viral oncogene homolog B1 (BRAF) and V-Ki-ras2 Kirsten ratsarcoma viral oncogene homolog (KRAS) mutations are mostly studied in mCRC, as clinical trials found that first-line chemotherapy with anti-epidermal growth factor receptor agent confers limited efficacy for mCRC. Treatment decisions for early-stage mCRC do not consider BRAF or KRAS mutations, given the dramatically poor prognosis conferred by these mutations in clinical trials. Thus, it is necessary to identify patients with mCRC harboring BRAF or KRAS mutations to formulate rational therapeutic strategies to improve prognosis and survival. BRAF and KRAS mutations occur in ∼10% and ∼44% of patients with mCRC, respectively. Although the survival rate of patients with mCRC has improved in recent years, the response and prognosis of patients with the aforementioned mutations are still poor. There is a substantial unmet need for prospective personalized therapies for patients with BRAF- or KRAS-mutant mCRC. In this review, we focus on BRAF and KRAS mutations to understand the mechanisms underlying resistance and improving the response rate, outcomes, and prognosis of patients with mCRC bearing these mutations and to discuss prospective personalized therapies for BRAF- and KRAS-mutant mCRC.

LncRNA C9orf139 can regulate the growth of pancreatic cancer by mediating the miR-663a/Sox12 axis.

BACKGROUND: Recent studies have proved the important role of many oncogenic long non-coding RNAs (lncRNAs) in the progression of pancreatic cancer, but little is known about the mechanisms of tumor suppression in pancreatic cancer. AIM: To evaluate the function of tumor suppressor lncRNA C9orf139 in pancreatic cancer progression and to study the underlying mechanism. METHODS: We assigned 54 patients with pancreatic ductal adenocarcinoma treated at our hospital to the patient group and 30 normal subjects undergoing physical examination to the control group. RT-qPCR was used to measure the relative expression of C9orf139 in the tissue and serum of patients, in an attempt to investigate the prognostic value of C9orf139 in pancreatic cancer patients. The luciferase reporter gene assay was performed to determine the interaction between C9orf139 and miR-663a. The biological function of C9orf139 was assessed by in vitro assays and in vivo subcutaneous tumor formation tests in animal models. To figure out the molecular mechanism of C9orf139 to act on miR-663a/Sox12, RNA pull-down, Western blot assay, RNA immunoprecipitation assay, and co-immunoprecipitation assay were performed. RESULTS: C9orf139 level significantly increased in the tissue and serum of patients, which had clinical diagnostic value for pancreatic cancer. Patients with high C9orf139 expression had a higher risk of progressing to stage III + IV, lymph node metastasis, and poor differentiation. Cox regression analysis suggested that C9orf139, tumor-node-metastasis stage, and lymph node metastasis were independent prognostic factors in patients. The underlying mechanism of C9orf139 was that it promoted the growth of pancreatic cancer cells by modulating the miR-663a/Sox12 axis. CONCLUSION: C9orf139 is highly expressed in pancreatic cancer, qualified to be used as a potential diagnostic and prognostic marker for pancreatic cancer. Its promotion of pancreatic cancer cell growth is achieved by mediating the miR-663a/Sox12 axis.

LncRNA SNHG4 Attenuates Inflammatory Responses by Sponging miR-449c-5p and Up-Regulating STAT6 in Microglial During Cerebral Ischemia-Reperfusion Injury.

BACKGROUND: Inflammatory response mediated by microglia plays a key role in cerebral ischemia-reperfusion injury. This study intends to probe the role of lncRNA SNHG4 in regulating the inflammatory response of the microglia during cerebral ischemia reperfusion. MATERIALS AND METHODS: Blood samples and cerebrospinal fluid samples were collected from acute cerebral infarction (ACI) patients and healthy controls. The middle cerebral artery occlusion (MCAO) models were constructed with rats. LPS induction and oxygen-glucose deprivation methods were respectively applied to simulate the activation of microglia in vitro. qRT-PCR was employed to determine the expressions of SNHG4, miR-449c-5p and related inflammatory factors in vivo and in vitro. The inflammatory responses of the microglia subject to the varied expressions of SNHG4 and miR-449c-5p were detected. Luciferase assays were conducted to verify the crosstalk involving SNHG4, miR-449c-5p and STAT6. RESULTS: Compared with the control group, the expression of SNHG4 derived from the samples of ACI patients and the microglia of MCAO group were remarkably down-regulated, but the expression of miR-449c-5p was dramatically up-regulated. Overexpression of SNHG4 and knock-down of miR-449c-5p could inhibit the expression of pro-inflammatory cytokine in the microglia and promote the expression of anti-inflammatory factors. Meanwhile, the phospho-STAT6 was up-regulated, whereas the knock-down of SNHG4 and over-expression of miR-449c-5p in microglia had the opposite effects. Luciferase assay confirmed that SNHG4 could target miR-449c-5p, while miR-449c-5p could target STAT6. CONCLUSION: SNHG4 can regulate STAT6 and repress inflammation by adsorbing miR-449c-5p in microglia during cerebral ischemia-reperfusion injury.

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.