Targeting the aryl hydrocarbon receptor with FICZ regulates IL-2 and immune infiltration to alleviate Hashimoto's thyroiditis in mice.

Hashimoto's thyroiditis (HT) is the most frequent autoimmune disorder. Growing work points to the involvement of aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor, in the regulation of immune homeostasis. However, the roles of AhR and its ligands in HT remains unclear. In this study, we leveraged public human database analyses to postulate that the AhR expression was predominantly in thyroid follicular cells, correlating significantly with the thyroid infiltration levels of multiple immune cells in HT patients. Using a thyroglobulin-induced HT mouse model and in vitro thyroid follicular epithelial cell cultures, we found a significant downregulation of AhR expression in thyrocytes both in vivo and in vitro. Conversely, activating AhR by FICZ, a natural AhR ligand, mitigated inflammation and apoptosis in thyrocytes in vitro and conferred protection against HT in mice. RNA sequencing (RNA-seq) of thyroid tissues indicated that AhR activation moderated HT-associated immune or inflammatory signatures. Further, immunoinfiltration analysis indicated that AhR activation regulated immune cell infiltration in the thyroid of HT mice, such as suppressing cytotoxic CD8+ T cell infiltration and promoting anti-inflammatory M2 macrophage polarization. Concomitantly, the expression levels of interleukin-2 (IL-2), a lymphokine that downregulates immune responses, were typically decreased in HT but restored upon AhR activation. In silico validation substantiated the binding interaction between AhR and IL-2. In conclusion, targeting the AhR with FICZ regulates IL-2 and immune infiltration to alleviate experimental HT, shedding new light on the therapeutic intervention of this prevalent disease.

Facile room-temperature synthesis of a spherical mesoporous covalent organic framework for capillary electrochromatography.

Herein, a spherical covalent organic framework COF TAPB-DMTP was facilely synthesized from 2,5-dimethoxyterephthalaldehyde (DMTP) and 1,3,5-tri-(4-aminophenyl)benzene (TAPB) as monomers. COF TAPB-DMTP with regular mesoporous and excellent mass transfer ability was first introduced into the capillary and immobilized on the inner wall of the capillary through a simple in situ growth method. Through various characterization results, COF TAPB-DMTP was successfully prepared and modified onto the capillary inner wall. The separation performance and potential of COF TAPB-DMTP modified capillary column was explored. The new developed COF modified column achieved a highly efficiency and selective separation between analytes with different properties, including halogeno benzenes, alkylbenzenes, phenols and sulfonamides. Satisfactory stability and reproducibility were observed on COF TAPB-DMTP modified columns. The intraday, interday and three batch columns relative standard deviations were all less than 1.85 % for the retention time. The separation performance of prepared column has no significant change after 90 continuous runs. Additionally, the COF TAPB-DMTP modified capillary column was successfully used for separation and detection of triazole antifungal drugs in human plasma, and the recoveries of three antifungal drugs (fluconazole, isavuconazole and posaconazole) in spiked samples were in the range of 98.6-100.8 %, 92.4-102.1 % and 99.9-107.5 %, respectively. This self-made column showed excellent application potential in chromatography separation science.

Anti-inflammatory effect and component analysis of Chaihu Qingwen granules.

ETHNOPHARMACOLOGICAL RELEVANCE: As prevalent acute respiratory condition in clinical practice, acute lung injury has a quick start and severe symptoms which can harm patients physically. Chaihu Qingwen granules (CHQW) is a classic formula for the treatment of respiratory diseases. Clinical observation shows that CHQW has good efficacy in treating colds, coughs, and fevers. AIM OF THE STUDY: The aim of this study was to investigate the anti-inflammatory effect of CHQW on lipopolysaccharide (LPS)-induced acute lung injury (ALI) model in rats and to explore its potential mechanism, as well as to clarify its substance composition. MATERIALS AND METHODS: Male SD rats were randomly divided into the blank group, the model group, the ibuprofen group, the Lianhua Qingwen capsule group and the CHQW group (2, 4 and 8 g/kg, respectively). The LPS-induced acute lung injury (ALI) model in rats was established after pre-administration. The histopathological changes in the lung and the levels of inflammatory factors in bronchoalveolar lavage fluid (BALF) and serum of ALI rats were observed. The inflammation-related proteins toll-like receptor 4 (TLR4), inhibitory kappa B alpha (IκBα), phospho-IκBα (p-IκBα), nuclear-factor-kappa B (NF-κB), and NLR family pyrin domain containing 3(NLRP3) expression levels were measured by western blotting analysis and immunohistochemical analysis. The chemical composition of CHQW was identified by liquid chromatography-quadrupole-time of flight-mass spectrometry (LC-Q-TOF-MS). RESULTS: CHQW significantly ameliorated lung tissue pathological injury in LPS-induced ALI rats and decreased the release of inflammatory cytokines (interleukin-1ß, interleukin-17 and tumor necrosis factor-α) in BALF and serum. In addition, CHQW decreased the expression of TLR4, p-IκBα and NF-κB proteins, increased the level of IκBα, regulated the TLR4/NF-κB signaling pathway, and inhibited the activation of NLRP3. The chemical components of CHQW were analyzed by LC-Q-TOF-MS, and a total of 48 components were identified by combining information from the literature, mainly flavonoids, organic acids, lignans, iridoids and phenylethanoid glycosides. CONCLUSION: The results of this study showed that the pretreatment of CHQW had a strong protective effect on LPS-induced ALI in rats, reducing lung tissue lesions and decreasing inflammatory cytokines released in BALF and serum. The protective mechanism of CHQW may be related to the inhibition of the TLR4/NF-κB signaling pathway and NLRP3 activation. The main active ingredients of CHQW are flavonoids, organic acids, lignans, iridoids and phenylethanoid glycosides.

In situ growth of imine-based covalent organic framework as stationary phase for high-efficiency electrochromatographic separation.

Design of the smart stationary phases, which can improve the separation efficiency is an essential work in the capillary electrochromatography (CEC). Owing to good excellent properties, covalent organic frameworks (COFs) have showed promising potential in the area of separation science. Here, a micro- and mesoporous COF TAPB-BTCA with adequate available interaction sites and outstanding mass transfer performance was first exploited as a stationary phase for high-efficiency in capillary electrochromatography. Through in situ growth approach, the COF TAPB-BTCA coated capillary column was facilely prepared at room temperature. The separation ability of the COF TAPB-BTCA coated capillary column was studied. The fabricated column showed high efficiency for the separation of six types of small molecular compounds, including alkylbenzenes, chlorobenzenes, phenols, parabens, vanillin and related phenolic compounds, and non-steroidal anti-inflammatory drugs (NSAIDs). The maximum theoretical plates reached up to 293,363 N/m for phloroglucinol, showing significantly improved column efficiency in comparison to previous reported COFs-based columns. In addition, the mass loadability for methylbenzene was achieved to 1.44 mg/mL. Also, excellent reproducibility and stability were obtained on the COF TAPB-BTCA coated columns. The relative standard deviations of intra-day (n = 3), inter-day (n = 3) and three batch tubes were all less than 2%, and no obvious change was presented in separation performance after the column was used 120 runs. This COF TAPB-BTCA-based stationary phase would be a promising candidate for high-efficiency chromatographic separation.

Physiologically-based pharmacokinetic modeling-guided rational combination of tacrolimus and voriconazole in patients with different CYP3A5 and CYP2C19 alleles.

The drug-drug interactions (DDIs) between tacrolimus and voriconazole are highly variable among individuals. We aimed to develop a physiologically based pharmacokinetic (PBPK) model to predict the DDIs in people with different CYP3A5 and CYP2C19 alleles. First, pharmacokinetic data of humans receiving tacrolimus with or without voriconazole from the literature were used to construct and validate the PBPK model. Thereafter, we developed a model incorporating the metabolism of voriconazole mediated by CYP2C19 and the inhibitory effect of voriconazole on CYP3A4/5. Finally, the model was used to evaluate the dose adjustment of tacrolimus in people with different CYP3A5 and CYP2C19 alleles. When tacrolimus was administered alone (3 mg PO, single dose), the predicted AUC0-∞ of tacrolimus in CYP3A5 nonexpressers (19.22) was 3.5-fold higher than that in expressers (5.48). Following voriconazole (200 mg PO, bid) administration in human with different CYP2C19 genotypes, the AUC0-∞ of tacrolimus increased by 5.1- to 8.3-fold in CYP3A5 expressers and by 5.3- to 10.2-fold in CYP3A5 nonexpressers. The lower the gene expression level of CYP2C19 in the population, the higher the exposure to tacrolimus. When tacrolimus was combined with voriconazole (200 mg, bid; 400 mg, bid, on Day 1), the final model simulations suggested that the dose regimen of tacrolimus should be regulated to 0.15 mg/kg/day (qd) in CYP3A5 expressers with different CYP2C19 genotypes. For CYP3A5 nonexpressers, the dosing schedule of tacrolimus should be modified to 0.05 mg/kg/24 h for patients with 2C19 EM, 0.05 mg/kg/48 h for 2C19 IM and 0.05 mg/kg/72 h for 2C19 PM. In conclusion, a PBPK model with CYP3A5 and CYP2C19 polymorphisms was successfully established, providing more insights regarding the DDIs between tacrolimus and voriconazole to guide the clinical use of tacrolimus.

Structural characterization and anti-lipotoxicity effects of a pectin from okra (Abelmoschus esculentus (L.) Moench).

Okra (Abelmoschus esculentus (L.) Moench) is rich in various bioactive ingredients and used as a medicinal plant in traditional medicine. In the present study, to find the polysaccharide with anti-lipotoxicity effects from okra and clarify its structure, a pectin OP-1 was purified from okra, which had a backbone containing →4)-α-GalpA-(1 â†’ residues, and 1,5-Ara linked the main chain through the O-3 of the residue →3,4)-α-GalpA-(1→, and the C-6 of residue 1, 4-α-GalpA replaced by methyl ester. In vitro experiments showed that OP-1 pretreatment alleviated oleic acid (OA)-induced lipid accumulation, ROS generation, apoptosis, transaminase leakage, and inflammatory cytokine secretion in HepG2 cells, resulting in reduced lipotoxicity. Further molecular results revealed that OP-1 increased Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) phosphorylation and affected the expression of AMPK downstream targets, including inhibit SREBP1c and FAS, as well as activate CPT-1A. Impressively, AMPK inhibitor dorsomorphin (Compound C) blocked the effects of OP-1 against lipotoxicity. The effects of OP-1 on lipid metabolism were also diminished by dorsomorphin. Our results demonstrated that OP-1 possesses a potent function in preventing lipotoxicity via regulating AMPK-mediated lipid metabolism and provide a novel insight into the future utilization of okra polysaccharide.

Nor-triterpenoids from the fruiting bodies of Ganoderma lucidum and their inhibitory activity against FAAH.

Two new nor-triterpenoids ganodrenol A (1), B (2), and a new natural product ganodrenol C (3), along with three known nor-triterpenoids (4-6) were isolated from the fruiting bodies of Ganoderma lucidum. The chemical structures of these isolates were determined by 1 D and 2 D NMR, HRESIMS, and X-ray crystallography analysis. The inhibitory effects of isolated triterpenoids (1-6) against FAAH were evaluated by an in vitro assay, and compound 4 showed an inhibition rate of 70.27%. In addition, the cytotoxic effect of compounds (1-6) was evaluated against LOVO, MCF-7, and RAW264.7 cells, which displayed no significant cytotoxicity.

Design and Preparation of Polyimide/TiO2@MoS2 Nanofibers by Hydrothermal Synthesis and Their Photocatalytic Performance.

Organic-inorganic nanocomposite fibers can avoid the agglomeration of single nanoparticles and reduce the cost (nanoparticles assembled on the surface of nanofibers), but also can produce new chemical, electrical, optical, and other properties, with a composite synergistic effect. Aromatic polyimide (PI) is a high-performance polymer with a rigid heterocyclic imide ring and an aromatic benzene ring in its macromolecular framework. Due to its excellent mechanical properties, thermal stability, and easy-to-adjust molecular structure, PI has been widely used in electronics, aerospace, automotive, and other industries related to many applications. Here, we report that TiO2 nanorods were grown on polyimide nanofibers by hydrothermal reaction, and MoS2 nanosheets were grown on TiO2 nanorods the same way. Based on theoretical analysis and experimental findings, the possible growth mechanism was determined in detail. Further experiments showed that MoS2 nanosheets were uniformly coated on the surface of TiO2 nanorods. The TiO2 nanorods have photocatalytic activity in the ultraviolet region, but the bandgap of organic/inorganic layered nanocomposites can redshift to visible light and improve their photocatalytic performance.

Effects of high-fat diet on thyroid autoimmunity in the female rat.

BACKGROUND: While contributions of dyslipidemia to autoimmune diseases have been described, its impact on thyroid autoimmunity (TA) is less clear. Programmed cell death 1(PD-1)/PD-ligand 1 (PD-L1) immune checkpoint is crucial in preventing autoimmune attack while its blockade exacerbates TA. We thus unveiled the effect of high-fat diet (HFD) on TA, focusing on the contribution of PD-1/PD-L1. METHODS: Female Sprague Dawley (SD) rats were randomly fed with a regular diet or HFD (60% calories from fat) for 24 weeks. Then, thyroid ultrasonography was performed and samples were collected for lipid and thyroid-related parameter measure. RESULTS: HFD rats exhibited hyperlipemia and abnormal biosynthesis of the unsaturated fatty acid in serum detected by lipidomics. These rats displayed a relatively lower echogenicity and increased inflammatory infiltration in thyroid accompanied by rising serum thyroid autoantibody levels and hypothyroidism, mimicking human Hashimoto's thyroiditis. These alterations were concurrent with decreased mRNA and immunostaining of intrathyroidal PD-1 and also serum PD-1 levels but not the PD-L1 expression, suggesting a role of a PD-1 pathway. Meanwhile, the infiltration of B and T cell, a key cellular event inhibited by the PD-1 signals, was enhanced in the thyroid of HFD rats, along with thyroid fibrosis and apoptosis. CONCLUSIONS: Our data suggest that HFD triggers TA through a mechanism possibly involving downregulation of PD-1-related immunosuppression, providing a novel insight into the link between dyslipidemia and autoimmune toxicities.

Epifriedelanol enhances adriamycin-induced cytotoxicity towards K562/ADM cells by down regulating of P-gp and MRP2.

1. Multidrug resistance (MDR) is a critical issue during chemotherapy of cancers. Epifriedelanol (Epi) is the effective compounds from the Root Bark of Ulmus davidiana. This study aims to investigate the effect of Epi on MDR and its potential mechanism in the adriamycin (Adr)-resistant K562/ADM cells.2. The effect of Epi on MDR, P-glycoprotein (P-gp) and multidrug resistance-associated proteins (MRPs) were investigated in the adriamycin (Adr)-resistant K562/ADM cells. In addition, the alterations of nuclear receptor pregnane X receptor (PXR) and constitutive androstane receptor (CAR) mRNA expression levels in K562/ADM cells after Epi treatment were also examined.3. Epi significantly enhanced Adr-induced cytotoxicity towards K562/ADM cells. Combination of Epi and Adr can significantly reduce the 50% inhibitory concentration (IC50) of K562/ADM cells to Adr. The reversal fold was 1.83 and 3.64 after treated with Epi at 10 and 20 µM, respectively. The intracellular accumulation of Adr was significant increased after exposure to Epi at 5-20 µM compared with the control group. Furthermore, Epi treatment significantly decreased the mRNA and protein expression of P-gp and MRP2 in K562/ADM cells.4. The present study demonstrated that Epi could enhance Adr-induced cytotoxicity towards K562/ADM cells accompanied by the down-regulation of P-gp and MRP2.

Triterpenoids from the fruiting bodies of Ganoderma lucidum and their inhibitory activity against FAAH.

Seventeen triterpenoids including four new lanostane triterpenoids (1-3 and 5) were isolated from the fruiting bodies of Ganoderma lucidum by various chromatographic techniques. Their chemical structures were determined by extensive spectroscopic data, including 1D-NMR, 2D-NMR, and HRESIMS. In addition, the spectral data of compound 4 was reported for the first time. In an in vitro bioassay, most isolated triterpenoids could inhibit the hydrolysis activity of fatty acid amide hydrolase (FAAH). Furthermore, there is no cytotoxicity observed for these isolated triterpenoids. Therefore, G. lucidum showed the potential application for anti-neuroinflammation and more FAAH inhibitors may be explored from G. lucidum.

The flavonoids of okra insulates against oxidative stress, neuroinflammation and restores BDNF levels in Aß1-42 induced mouse model of Alzheimer's disease.

Okra (Abelmoschus esculentus [L.] Moench.) has been used as a natural drug in East or West Africa for many centuries, as well as consumed in most areas of the world as a tropical vegetable. The study aimed to evaluate whether the flavonoids of okra fruit (FOF) administration influence Aß1-42-induced learning and memory impairment, and explore the underlying mechanisms. The Y-maze task and the Morris water maze test were used for evaluating cognition processes. The levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), superoxide dismutase (SOD), total antioxidant capacity (T-AOC), and glutathione peroxidase (GSH-Px) were detected by ELISA kits. The expressions of nuclear factor kappa-light chain-enhancer of activated B (NF-κB), brain-derived neurotrophic factor (BDNF), cAMP-response element-binding protein (CREB), extracellular signal-regulated kinase (ERK), phosphatidylinositol 3 kinase (PI3K), protein kinase B (AKT), glycogen synthase kinase-3ß (GSK-3ß) were studied by western blot. Histopathological changes were observed by H.E. straining. The results showed that intracerebroventricular injection of Aß1-42 was effective in producing memory deficits in mice. Besides, Aß1-42 exposure could significantly increase the levels of NF-κB, TNF-α, IL-1ß, and decreased T-AOC, the activities of SOD and GSH-Px in the hippocampus and cortex. Furthermore, the level of BDNF was also reduced, accompanied by down-regulated CREB/ERK and PI3K/AKT/GSK-3ß signaling pathways in the hippocampus and cortex. Nevertheless, chronic administration of FOF (100 or 300 mg/kg, i.g.) significantly prevented Aß1-42-induced behavioral and biochemical alterations. It also suggested that FOF could improve the cognitive deficits in AD-like model mice, which might be mediated by regulation of BDNF levels in cortex and hippocampus and up-regulating of CREB/ERK and PI3K/AKT/GSK3ß pathways, as well as alleviation of oxidative stress and neuroinflammation.

Antidepressant effects of a polysaccharide from okra (Abelmoschus esculentus (L) Moench) by anti-inflammation and rebalancing the gut microbiota.

The present study aimed to evaluate the antidepressant-like effect of a polysaccharide (OP), which is isolated from okra (Abelmoschus esculentus (L) Moench), in CUMS-induced mice and its possible mechanisms. OPT, FST and TST were employed to examine the anxiety and depressive behavior in CUMS-induced mice and fecal microbiota transplantation (FMT) CUMS-induced mice, while proinflammatory cytokines, TLR4/NF-κB pathway and MAPKs signaling were detected in both CUMS-induced mice and LPS-induced BV2 cells. The results showed that anxiety- and depressive-like behaviors, gut microbiota dysbiosis and changes of SCFAs, and activation of inflammatory reactions in the colon, serum, and hippocampus of CUMS-induced mice, as well as activation of inflammatory reactions in BV2 cells, could be alleviated by the treatment of OP. The mice that were colonized by OP microbiota showed improved anxiety and depressive behaviors and lower inflammatory response. Furthermore, OP inhibited the expression of TLR4, the nuclear translocation of NF-κB and high levels of proinflammatory cytokines, and enhanced the MAPKs signaling, these effects of OP also observed in LPS-induced BV2 cells. Above all, suggested that the potential mechanism of the antidepressant-like effects of OP was closely correlated with the bidirectional communication of microbiota-gut-brain axis via regulation of inflammation response.

The impact of particulate matter (PM2.5) on skin barrier revealed by transcriptome analysis: Focusing on cholesterol metabolism.

Accumulating evidence suggests that particulate matter (PM2.5), as a major air pollutant, imposes a certain degree of destruction and toxicity to the skin. It particularly impairs the structure and function of the epidermis. To study the impact of PM2.5 on the skin, transcriptome analysis was performed on PM2.5-exposed human primary keratinocytes. Functional annotation analysis demonstrates that PM2.5 significantly up-regulates cholesterol-metabolism-related genes. Via lipid extraction from PM2.5 treated three-dimensional epidermis tissue model (3D-ETM) and subsequent characterization via mass spectrometry, it was confirmed that PM2.5 significantly increases epidermal cholesterol levels in vitro. Conversely, the amount of squalene in 3D-ETM was significantly reduced by PM2.5. Interestingly, neither cholesterol nor squalene showed significant fluctuations in the green tea extract (GTE) treated epidermis tissue model under PM2.5 exposure. This study shows that PM2.5 may cause barrier disorders by increasing cholesterol synthesis, leading to transient accumulation of epidermal cholesterol and decrease of squalene. It was suggested that cholesterol and squalene, which are the key substances affecting skin barrier function, can be used as new biomarkers of skin damage induced by PM2.5. Moreover, it was demonstrated that GTE can reduce damage caused by PM2.5 exposure by not only anti-inflammatory and antioxidant mechanisms, but also by off-setting the disturbance to epidermal lipid homeostasis. This study demonstrates the strong potential of GTE as an active ingredient to be utilized in cosmetic products to effectively reduce the damage PM2.5 induces in skin.

The anti-nephritic activity of a polysaccharide from okra (Abelmoschus esculentus (L.) Moench) via modulation of AMPK-Sirt1-PGC-1α signaling axis mediated anti-oxidative in type 2 diabetes model mice.

Diabetic nephropathy (DN) with high morbidity and mortality is one of the most severe diabetes complications and affects nearly one-third of people with diabetes. Our present experiment was designed to assess the potential therapeutic of a polysaccharide purified from okra (OP) on DN in high-fat diet-fed and streptozotocin (STZ)-induced diabetic mice. We found that an 8-week treatment with OP could significantly decrease the 24-h urine protein (24-h UP), serum creatinine (Scr), serum urea nitrogen (SUN) and glycosylated hemoglobin (HbA1c) levels, which are regard as the biomarkers of renal injury. The results of immunohistochemical analysis and histopathological examination showed that the diabetic-induced microstructural changes and fibrosis in kidney can be alleviated by the administration of OP (400 mg/kg). Our immunofluorescences results demonstrated that OP (400 mg/kg) could greatly reduce the level of reactive oxygen species (ROS) in kidney. In addition, we also studied the level of SOD, GSH, CAT, HO-1, Nrf2, p-AMPK, PGC-1α, Sirt1, Bcl-2, cleaved caspase-3 and Bax in renal tissue by assay kit and western blot. Our results suggested that OP ameliorated DN in diabetic mice, which is possibly related to suppressing apoptosis and oxidative stress through activating AMPK-Sirt1-PGC-1α signaling axis.

Polysaccharide from Okra (Abelmoschus esculentus (L.) Moench) Improves Antioxidant Capacity via PI3K/AKT Pathways and Nrf2 Translocation in a Type 2 Diabetes Model.

Polysaccharide extracted from okra (Abelmoschus esculentus (L.) Moench), a traditional functional food, is a biologically active substance reported to possess hypoglycemic and anti-oxidative qualities. However, it is unknown which polysaccharides play a role and have the potential mechanism. This present study is to assess the possible impacts of a novel polysaccharide isolated from okra (OP) on mice fed with a high-fat diet (HFD) combined with an intraperitoneal injection (i.p.) of 100 mg/kg streptozotocin (STZ) twice, to induce type 2 diabetes mellitus (T2DM). We found that an eight-week administration of OP at 200 or 400 mg/kg body weight significantly alleviated the symptoms, with elevations in blood glucose, triglyceride (TG), total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C), as well as reducing high-density lipoprotein cholesterol (HDL-C), body weight, food, and water consumption. The OP treatment increased the hepatic glycogen and decreased the mussy hepatic cords and liver fibrosis in the T2DM mice. The decreases of ROS and MDA and the increases of SOD, GSH-Px and CAT in liver were observed after administration of OP. OP alleviated the T2DM characteristics through the activation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/glycogen synthase kinase 3 beta (GSK3ß) pathway, and enhanced the nuclear factor erythroid-2 (Nrf2) expression and promoted Nrf2-medicated heme oxygenase-1(HO-1) and superoxide dismutase 2 (SOD2) expression. OP also relieved mitochondrial dysfunction by inhibiting NOX2 activation. Taken together, these findings suggest that a polysaccharide isolated from okra exerts anti-T2DM effects partly by modulating oxidative stress through PI3K/AKT/GSK3ß pathway-medicated Nrf2 transport. We have determined that a polysaccharide possesses hypoglycemic activity, as well as its underlying mechanism.

Intracerebroventricular injection of resveratrol ameliorated Aß-induced learning and cognitive decline in mice.

Resveratrol (RSV) is a natural plant polyphenol compound which consists in red grape skins and wine in general. Plenty of previous studies have shown that resveratrol has neuroprotective effects. The primary object of this research was to study the effects of RSV on improving the cognitive function and neurodegeneration in the mouse model of Alzheimer's disease induced by Aß1-42, and the possible mechanism about targeting on Sirt1, which results in attenuating inflammatory response and mitochondrial dysfunction. We established the AD model of intracerebroventricular (i.c.v.) injection of Aß1-42 and it was observed that the significant decrease in alternately of Y Maze and the quadrant dwell time percentage of Morris water maze test. Furthermore, there were significant upregulations of AMPK/ PGC-1α and downregulations of NF-κB/ IL-1ß/ NLRP3 signaling pathways in the hippocampus and prefrontal cortex in AD mice. The treatments with RSV and Donepezil could significantly ameliorate all the behavioral and biochemical changes induced by Aß1-42. It also noticeably improved the histopathological changes in the hippocampus and cortex. The results suggested that RSV might protect against cognitive deficits and neurodegeneration induced by Aß1-42, and serve as a potential agent in treatment of AD.

The effect of Schisandra chinensis extracts on depression by noradrenergic, dopaminergic, GABAergic and glutamatergic systems in the forced swim test in mice.

Schisandra chinensis (Turcz.) Baill., as a Chinese functional food, has been widely used in neurological disorders including insomnia and Alzheimer's disease. The treatment of classical neuropsychiatric disorder depression is to be developed from Schisandra chinensis. The antidepressant-like effects of the Schisandra chinensis extracts (SCE), and their probable involvement in the serotonergic, noradrenergic, dopaminergic, GABAergic and glutamatergic systems were investigated by the forced swim test (FST). Acute administration of SCE (600 mg kg(-1), i.g.), a combination of SCE (300 mg kg(-1), i.g.) and reboxetine (a noradrenalin reuptake inhibitor, 2.5 mg kg(-1), i.p.) or imipramine (a TCA, 2 mg kg(-1), i.p.) reduced the immobility time in the FST. Pretreatment with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4, a selective noradrenergic neurotoxin, 50 mg kg(-1), i.p., 4 days), haloperidol (a non-selective D2 receptor antagonist, 0.2 mg kg(-1), i.p.), SCH 23390 (a selective D1 receptor antagonist, 0.03 mg kg(-1), i.p.), bicuculline (a competitive GABA antagonist, 4 mg kg(-1), i.p.) and N-methyl-d-aspartic acid (NMDA, an agonist at the glutamate site, 75 mg kg(-1), i.p.) effectively reversed the antidepressant-like effect of SCE (600 mg kg(-1), i.g.). However, p-chlorophenylalanine (pCPA, an inhibitor of 5-HT synthesis, 100 mg kg(-1), i.p., 4 days,) did not eliminate the reduced immobility time induced by SCE (600 mg kg(-1), i.g.). Moreover, the treatments did not change the locomotor activity. Altogether, these results indicated that SCE produced antidepressant-like activity, which might be mediated by the modification of noradrenergic, dopaminergic, GABAergic and glutamatergic systems.

Brain-derived Neurotrophic Factor Signaling Mediates the Antidepressant-like Effect of the Total Flavonoids of Alpiniae Oxyphyllae Fructus in Chronic Unpredictable Mild Stress Mice.

The present study verified the antidepressant-like effects of the total flavonoids of Alpinia oxyphylla Miq. (AOF) using the chronic unpredictable mild stresses paradigm and explored the mechanism that underlies antidepressant-like effects of AOF in mice. Previous research has shown that tropomyosin-related kinase B (TrkB) receptor-mediated extracellular regulated protein kinases (ERK) signaling pathways participate in depression pathophysiology. Therefore, we aimed to explore whether AOF improved depression-like behaviors by increasing activity of ERK pathways mediated by TrkB. Results showed that AOF significantly reduced the immobility time in the forced swimming test and increased the sucrose preference in sucrose preference test. In addition, decreased phosphorylated cyclic adenosine monophosphate response element-binding protein (pCREB)/CREB, pERK/ERK, and pTrkB/TrkB levels in the hippocampus induced by chronic unpredictable mild stresses were reversed by intragastric administration of AOF. Results suggested that AOF increased pCREB/CREB, pERK/ERK, and pTrkB/TrkB levels by acting on the TrkB receptor. To verify this hypothesis, mice were pretreated with the TrkB inhibitor K252a (or 0.1% dimethyl sulfoxide, intraperitoneally, 2 weeks), before the intragastric administration of AOF. This resulted in an absence of antidepressant-like effects, as well as no activation of pERK/pCREB/BDNF signaling pathways. Results demonstrated that AOF might exert antidepressant-like effects by targeting TrkB receptor-mediated pERK/pCREB/BDNF signal systems, which could help to identify the AOF receptor. Copyright © 2016 John Wiley & Sons, Ltd.

Schisandrin C Ameliorates Learning and Memory Deficits by Aß1-42 -induced Oxidative Stress and Neurotoxicity in Mice.

Schisandrin C (SCH-C) is a main and typical antioxidative lignan isolated from the fruits of Schisandra chinensis (Trucz.) Baill (a widely used traditional Chinese medicine). The present study aimed to characterize the effect of SCH-C on memory impairment and further research on pathological changes in Aß1-42 -induced Alzheimer's disease mice. Mice were administration with SCH-C daily for 5 days in the lateral cerebral ventricles using sterotaxically implanted cannula. Cognitive functions were assessed by Y-maze test, active avoidance test and Morris water maze test in all groups, and the level of Aß1-42 and neuronal injury induced by Aß1-42 were reversed remarkably following SCH-C treatment compared with sham group; meanwhile the impairment of short-term or working memory was dramatically improved. In addition, SCH-C significantly inhibited total cholinesterase (ChEtotal), and increased superoxide dismutase (SOD) and glutathione peroxidase (GSH-px) activity glutathione (GSH) levels in the hippocampus and cerebral cortex. It can be speculated that SCH-C offers protection against Aß1-42 -induced dysfunction in learning and memory by inhibiting ChEtotal and its antioxidant action. Copyright © 2015 John Wiley & Sons, Ltd.