Brain structure alterations and cognitive impairment following repetitive mild head impact: An in vivo MRI and behavioral study in rat.

Mild traumatic brain injury (mTBI) or concussion is a common health issue. Several people repeatedly experience head impact milder than that causing concussion. The present study aimed to confirm the effects of such repeated impact on the brain structure and cognitive abilities. Rat models were established by closed skull weight-drop injury. The animals were anesthetized, subjected to single (s)-sham, s-mTBI, repetitive (r)-sham, and r-mTBI, and recovery times were recorded. MRI, including T2-weighted and diffusion tensor imaging (DTI), as well as, neurological severity scores (mNSS) were assessed for the dynamics of the brain structure and neurological function. Morris water maze (MWM) was used to evaluate the cognitive function. The histological examination of r-mTBI rats revealed the basis of structural changes in the brain. There was no significant difference in the recovery time, MRI, mNSS, and MWM between the s-sham and the s-mTBI groups. Compared with r-sham, r-mTBI induced significant differences in the following aspects. The recovery time was prolonged and beam balance test (BBT) in mNSS increased from day 5. MWM performances were worse even after the BBT was recovered. The volumes of the cortex (CT), hippocampus (HP), and lateral ventricle had changed from day 5, which reached a maximum at day 14. Abnormal DTI parameters were observed in CT, corpus callosum, and HP. Histological analyses showed that both in CT and HP, neuron counts reduced at the end of the experiment. Altogether, these findings indicate that non-symptomatic head injury may result in brain atrophy and cognitive impairment when occurred repeatedly.

Synthesis of 3-acyloxyxanthone derivatives as α-glucosidase inhibitors: A further insight into the 3-substituents' effect.

Considerable interest has been attracted in xanthone and its derivatives because of their important biological activities. In this paper, a series of novel 3-arylacyloxyxanthone derivatives 2a-p were synthesized and evaluated for their biological activities toward α-glucosidase. In comparison to the parent 1,3-dihydroxylxanthone 1a, 3-arylacyloxy derivatives 2a-p with additional aromatic ester groups at 3-position show up to 13.7-fold higher inhibitory activities. In particular, the IC50 values of compounds 2i, 2m, 2p reach 13.3, 10.6, 11.6 µM, respectively. These results suggest that addition of aromatic moieties by esterification at the 3-OH of the parent 1,3-dihydroxylxanthone is an efficient way to increase the inhibition against α-glucosidase. Different from previous multi-hydroxylxanthones, these 3-arylacyloxyxanthone derivatives show efficient inhibitory activities may due to the π-stacking or hydrophobic effects of the additional aromatic moieties rather than the H-bonding donor interaction of 3-OH. Structure-activity relationship analysis shows that the substituents on the additional aromatic ring also influence the inhibition. All the oxygen or nitrogen-containing groups, like hydroxyl, methoxy, methaminyl, and alkylsilyloxy, can enhance the inhibitory activities. In addition, the kinetics of enzyme inhibition measured by using Lineweaver-Burk plots shows that selected compounds 2i, 2m and 2p are non-competitive inhibitors. Docking simulations further support our structure-activity relationship analysis that additional aromatic moieties enhance inhibitory activities via hydrophobic effects. The new developed 3-arylacyloxyxanthone derivatives probably bind with α-glucosidase in an allosteric site different from traditional multi-hydroxylxanthones.

Cerebral vasospasm and corticospinal tract injury induced by a modified rat model of subarachnoid hemorrhage.

OBJECTIVE: Double-hemorrhage rat models of subarachnoid hemorrhages (SAH) are most effective at simulating delayed cerebral vasospasms (CVS). The present study modified the models to minimize additional trauma and investigated injury of the corticospinal tract (CST) using diffusion tensor imaging (DTI). METHODS: On the first day, 0.3ml of autologous arterial blood was collected by puncturing the caudal artery and injected into the cisterna magna via percutaneous puncture; and the operation was repeated on the third day. The diameters of the basilar artery (BA), middle cerebral artery (MCA), and anterior cerebral artery (ACA) were measured by magnetic resonance angiography on days 3, 5, 7, 9, and 11 post-SAH. Meanwhile, on days 3, 7, 11, 15 and 19, DTI was performed to evaluate the injury of the CST at cerebral peduncle (CP) and pyramidal tract (Py) by measuring fractional anisotropy (FA) value. RESULTS: Blood was deposited mainly in the basal cistern. Diameters of BA, MCA, and ACA were significantly reduced. FA value of the CP was lower in the SAH group than in the control group; but FA value of Py wasn't different between the two groups. CONCLUSION: This is a minimally-invasive and high performance rat model of SAH. Additionally, the occurrence of CVS is firm and the axons in CP are injured.

Diallyl trisufide protects against oxygen glucose deprivation -induced apoptosis by scavenging free radicals via the PI3K/Akt -mediated Nrf2/HO-1 signaling pathway in B35 neural cells.

Oxidative stress contributes to development of ischemic brain damage. Many antioxidants have been proven effective in ameliorating cerebral ischemia injury by inhibiting oxidative stress. DATS, an organosulfuric component of garlic oil, exhibits antioxidative effects. In present study, we used OGD model to investigate the neuroprotective effects of DATS and the mechanisms related to these effects. B35 neural cells exposed to OGD caused a decrease in cell viability and increases in the percentage of apoptotic cells and the level of intracellular cleaved caspase-3, all of which were markedly attenuated by DATS. Further, DATS treatment significantly increased Nrf2 expression and nuclear translocation, upregulated downstream gene HO-1 and inhibited intracellular ROS and MDA generation, all of which were markedly attenuated in cells transfected with Nrf2-specific siRNA. In addition, inhibition of PI3K/Akt signaling by PI3K-specific siRNA not only decreased the expression level of Nrf2 and HO-1 proteins, but also diminished the antioxidative and neuroprotective effect of DATS. Taken together, these results indicate that DATS protects B35 neural cells against OGD-induced cell injury by inhibiting ROS production via upregulating the PI3K/Akt-mediated Nrf2 pathway, which further activates HO-1. Based on our results, DATS may be a potential candidate for intervention in hypoxic-ischemic brain injuries such as stroke.

Analysis of protein-protein interaction network and functional modules on primary osteoporosis.

BACKGROUND: Primary osteoporosis is an age-related disease, and the main cause of this disease is the failure of bone homeostasis. Previous studies have shown that primary osteoporosis is associated with gene mutations.To explore the functional modules of the PPI (protein-protein interaction) network of differentially expressed genes (DEGs), and the related pathways participating in primary osteoporosis. METHODS: The gene expression profile of primary osteoporosis GSE35956 was downloaded from the GEO (Gene Expression Omnibus) database and included five MSC (mesenchymal stem cell) specimens of normal osseous tissue and five MSC specimens of osteoporosis. The DEGs between the two types of MSC specimens were identified by the samr package in R language. In addition, the functions and pathways of DEGs were enriched. Then the DEGs were mapped to String to acquire PPI pairs and the PPI network was constructed with by these PPI pairs. Topological properties of the network were calculated by Network Analyzer, and modules in the network were screened by Cluster ONE software. Subsequently, the fronting five modules whose P-value was less than 1.0e-05 were identified and function analysis was conducted. RESULTS: A total of 797 genes were filtered as DEGs from these ten specimens of GSE35956 with 660 up-regulated genes and 137 down-regulated genes. Meanwhile, up-regulated DEGs were mainly enriched in functions and pathways related to cell cycle and DNA replication. Furthermore, there were 4,135 PPI pairs and 377 nodes in the PPI network. Four modules were enriched in different pathways, including cell cycle and DNA replication pathway in module 2. CONCLUSIONS: In this paper, we explored the genes and pathways involved in primary osteoporosis based on gene expression profiles, and the present findings have the potential to be used clinically for the future treatment of primary osteoporosis.

Entecavir plus adefovir rescue therapy for chronic hepatitis B patients after multiple treatment failures in real-life practice.

AIM: To evaluate the efficacy and safety of Entecavir (ETV) plus adefovir (ADV) for chronic hepatitis B (CHB) patients after multiple nucleos(t)ide analogue (NAs) failure treatment. METHODS: Hepatitis B e antigen (HBeAg)-positive patients who had a suboptimal response or developed resistance to two or more previous NAs treatments were included, and all subjects were treated with ETV in combination with ADV for ≥ 24 months. Complete virologic response (CVR) was defined as an undetectability of serum hepatitis B virus (HBV) DNA level during treatment. Safety assessment was based on the increasing of serum creatinine and creatine kinase levels. RESULTS: A total of 45 eligible patients were included. Twenty-five patients had been treated with lamivudine (LAM) or telbivudine (LdT) and developed genotypic resistance. Resistance to ADV was present in 18 patients and 4 patients had a suboptimal response to ETV. Two patients had a resistance to both LAM and ADV. The cumulative probabilities of CVR at 12 and 24 months of ETV + ADV treatment were 88.9% (40/45) and 97.8% (44/45), respectively. Although one patient failed to achieve CVR, its serum HBV DNA level decreased by 3.3 log copies/mL after 24 months of combination therapy. The cumulative probability of HBeAg seroconversion was 15.6% (7/45) and 26.7% (12/45) at 12 and 24 months of treatment, respectively. History of prior exposure to specific NAs did not make a difference to ETV + ADV treatment outcome. There were no significant adverse events related to ETV + ADV therapy observed in the study subjects. CONCLUSION: ETV + ADV can be used as an effective and safe rescue therapy in patients after multiple NA therapy failures, especially in the areas where tenofovir is not yet available.

Gold-mediated selective cysteine modification of peptides using allenes.

A new approach for selective modification of cysteine-containing peptides through gold-mediated oxidative allene-thiol coupling reaction in aqueous medium is developed.

Multifunctional bioconjugation by Morita-Baylis-Hillman reaction in aqueous medium.

An efficient approach for modular assembly of multifunctional bioconjugates from oligosaccharides, peptides and proteins with fluorescent probes/affinity tags based on Morita-Baylis-Hillman (MBH) reaction in aqueous medium has been developed.

Gold-catalyzed amide synthesis from aldehydes and amines in aqueous medium.

An efficient gold-catalyzed amide synthesis from aldehydes and amines in aqueous medium under mild reaction conditions has been developed.

Gold-mediated bifunctional modification of oligosaccharides via a three-component coupling reaction.

An efficient modular approach for single-site incorporation of two independent functionalities (amines and alkynes) into aldehyde-containing oligosaccharides concurrently by using a one-pot gold-mediated three-component coupling reaction in aqueous medium under mild conditions has been developed.

Toward potent α-glucosidase inhibitors based on xanthones: a closer look into the structure-activity correlations.

A series of novel xanthone derivatives 6-16 having non-coplanar and flexible structures were synthesized as potent α-glucosidase inhibitors. Biological evaluation indicated that compounds 6-12 bearing one or two naphthol moieties exhibited up to 30-fold enhanced activities compared with their corresponding parent compounds 2-5, whereas compounds 13-16 bearing one dihydroxylnaphthalenyl group showed decreased activities compared with their corresponding analogs 6-9 having one naphthol group. Among them, compounds 7-8, 10-12 and 15 were more active than 1-deoxynojirimycin, a well-known inhibitor for α-glucosidase. The structure-activity correlations suggested that inhibiting of α-glucosidase was a result of multiple interactions with the enzyme, including π-stacking, hydrophobic effect and conformational flexibility due to the structural non-coplanarity. In addition, compounds 4, 8 and 15 showed non-competitive inhibition.

Morphological evidence for existence of IL-6 receptor alpha in the glomus cells of rat carotid body.

The carotid body (CB) senses changes in arterial blood PO2 and modulates respiratory movement. It is generally accepted that the dopaminergic type I cells in the CB are chemoreceptors. However, it has not been clarified whether the carotid body has the ability to perceive the stimulation of proinflammatory cytokines. Interleukin 6 (IL-6) as a multifunctional cytokine plays a pivotal role in host defense mechanism. In the present study, we observed the expression of IL-6Ralpha mRNA and protein in the carotid body using immunohistochemistry, Western blots, and in situ hybridization. The results confirmed the presence of IL-6Ralpha proteins and mRNAs in the glomus cells of rat carotid body. These results suggest that the function of the carotid body may be influenced by the proinflammatrory cytokines through their receptors.

[The effect of copolymer-1 on the apoptosis and the IL-6R expression of the retinal ganglion cells in chronic elevated intraocular pressure rat model].

AIM: To observe the effect of autoimmune response induced by copolymer-1 (COP-1) on apoptosis of retinal ganglion cells (RGCs) and IL-6R expression on the RGCs in chronic elevated intraocular pressure (EIOP) rat models. METHODS: Thirty SD rats were randomly divided into 3 groups, namely normal control group, mock-immunized EIOP group and COP-1-immunized EIOP group. Cauterization of episcleral vein was used to set up rat's EIOP model. The normal control rats were not immunized, whereas the rats in the other two groups were immunized via i.p injection with normal saline and COP-1 at hindfeet, respectively. The expression of the IL-6R on RGCs was detected by immunohistochemical staining. The apoptosis of the RGCs was examined by TUNEL staining. RESULTS: The number of the apoptotic RGCs in the COP-1- immunized EIOP group was notably lower than that in mock-immunized EIOP group (P<0.05). IL-6R were expressed on RGCs in all 3 groups, and expression level of IL-6R increased in the following order: normal control group, mock-immunized EIOP group and COP-1-immunized EIOP group (P<0.05). CONCLUSION: The autoimmune response induced by COP-1 protects the RGCs from apoptosis under the condition of chronic EIOP and results in increased IL-6R expression on RGCs. These results suggest that increased IL-6R expression on RGCs induced by COP-1 immunization with the protection of neurons resulted from autoimmune response is related.

Extravasation of blood-borne immunoglobulin G through blood-brain barrier during adrenaline-induced transient hypertension in the rat.

The effect of transient hypertension on blood-brain barrier (BBB) permeability, particularly on extravasation of immunoglobulin G (IgG), has not been fully understood. In the present experiment, we investigated the time course of endogenous albumin and IgG extravasation through BBB and the localization of extravasated IgG in brain parenchyma during adrenaline(AD)-induced transient hypertension in the rat by using Evans blue fluorescence, immunohistochemistry, and Western blot. The results showed that a bolus injection of AD (10 microg/kg) induced a transient elevation of arterial pressure lasting about 1 min. The endogenous albumin and IgG entered the brain parenchyma via BBB only when hypertension occurred. Electron microscopically, the IgG-like immunoreactivities were predominantly seen in the cytoplasm of endothelia of capillaries, pericytes, extracellular space of parenchyma, and the cytoplasm of glial cells. The results suggest that circulating IgG or antibodies might contact the structures of brain parenchyma through passage of BBB when its permeability is temporally changed by transient hypertension. This phenomenon implies a possible mechanism of pathogenesis for immune-mediated diseases in the brain.