Xue-Mei Wang

Schizandrin A Inhibits Microglia-Mediated Neuroninflammation through Inhibiting TRAF6-NF-κB and Jak2-Stat3 Signaling Pathways.

Microglial-mediated neuroinflammation has been established as playing a vital role in pathogenesis of neurodegenerative disorders. Thus, rational regulation of microglia functions to inhibit inflammation injury may be a logical and promising approach to neurodegenerative disease therapy. The purposes of the present study were to explore the neuroprotective effects and potential molecular mechanism of Schizandrin A (Sch A), a lignin compound isolated from Schisandra chinesnesis. Our observations showed that Sch A could significantly down-regulate the increased production of nitric oxide (NO), tumor necrosis factor (TNF)-α and interleukin (IL)-6 induced by lipopolysaccharide (LPS) both in BV-2 cells and primary microglia cells. Moreover, Sch A exerted obvious neuroprotective effects against inflammatory injury in neurons when exposed to microglia-conditioned medium. Investigations of the mechanism showed the anti-inflammatory effect of Sch A involved the inhibition of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) expression levels and inhibition of the LPS-induced TRAF6-IKKβ-NF-κB pathway. Furthermore, inhibition of Jak2-Stat3 pathway activation and Stat3 nuclear translocation also was observed. In conclusion, SchA can exert anti-inflammatory and neuroprotective effects by alleviating microglia-mediated neuroinflammation injury through inhibiting the TRAF6-IKKβ-NF-κB and Jak2-Stat3 signaling pathways.

Resokaempferol-mediated anti-inflammatory effects on activated macrophages via the inhibition of JAK2/STAT3, NF-κB and JNK/p38 MAPK signaling pathways

The excessive or prolonged production of inflammatory mediators can result in numerous chronic diseases, such as rheumatoid arthritis, atherosclerosis, diabetes, and cancer. Therefore, for many inflammatory-related diseases, pharmaceutical intervention is required to restrain the excessive release of such inflammatory mediators. Novel therapeutics and mechanistic insight are sought for the management of chronic inflammatory diseases. Resokaempferol (RES) is a type of flavonoid recently reported to demonstrate anti-cancer properties. However, the anti-inflammatory capacity of RES has not been studied to date. Therefore, this study investigated whether RES is capable of suppressing the inflammatory response to lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and the mechanism by which this is achieved. We found that RES attenuated the LPS-induced production of nitric oxide (NO), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), interleukin (IL)-1β, tumor necrosis factor-α (TNF-α), monocyte chemotactic protein 1 (MCP-1) and IL-6. RES also inhibited the nuclear translocation of signal transducer and activator of transcription (STAT) 3 and reduced the LPS-mediated phosphorylation of Janus kinase (JAK) 2 and STAT3 at the sites of Ser727 and Tyr705. RES also inhibited the activation of NF-κB and JNK/p38 MAPK signaling pathways in LPS-induced RAW264.7 cells. Additionally, RES inhibited the activation of the JAK2/STAT3 pathway in exogenous IL-6-activated RAW264.7 macrophages. We conclude that RES inhibits the inflammatory response in activated macrophages by blocking the activation of the JAK2/STAT3 pathway by both LPS and IL-6 signaling.

A randomized double-blind placebo-controlled study of Pu’er tea (普洱茶) extract on the regulation of metabolic syndrome

ObjectiveTo explore the regulative efficacy of Pu’er tea (普洱茶) extract on metabolic syndrome.MethodsNinety patients with metabolic syndrome were randomly divided into two groups, the intervention group administered with Pu’er tea extract, and the placebo group with placebo capsules. After 3 months’ treatment, body mass index, waist hip ratio, blood lipids, blood sugar, immune and inflammatory index, and oxidation index of the patients with metabolic syndrome were tested and analyzed.ResultsIn the intervention group, the body mass index, waist-hip ratio, fasting and 2 h postprandial blood glucose, serum total cholesterol, triglycerides, low density lipoprotein and apolipoprotein B-100 all decreased in the patients with metabolic syndrome, and also the high-density lipoprotein level increased and apolipoprotein A-1 showed the tendency to increase. Serum C-reactive protein, tumor necrosis factor-α, and interleukin-6 were decreased in the intervention group. Interleukin-10 level was increased, MDA was decreased and superoxide dismutase was increased. Compared with before treatment and the placebo group, there were significant differences (P<0.05, P<0.01).ConclusionsPu’er tea demonstrated excellent potential in improving central obesity, adjusting blood lipid, lowering blood sugar, regulating immunity and resisting oxidation. It can adjust the metabolic syndrome of different clinical phenotypes to different degrees, and is ideally fit for early prevention of metabolic syndrome.

Effect of modified Wuzi Yanzong Granule (加味五子衍宗颗粒) on patients with mild cognitive impairment from oxidative damage aspect

ObjectiveTo observe the effects of modified Wuzi Yanzong Granule (加味五子衍宗颗粒, WYG) on memory function and the activity of serum superoxide dismutase (SOD), malondialdehyde (MDA) levels, leukocyte mitochondrial DNA (mtDNA) deletion rate and β-amyloid protein1–28 (A β1–28) in patients with mild cognitive impairment (MCI).MethodsThirty-six patients with MCI were selected based on the internationally recognized Petersen’s criteria, and equally and randomly assigned to two groups. The treated group was treated with WYG and the control group was treated with placebo for 3 months. In addition, 20 healthy subjects were included in the study as the normal control group. Changes of memory function, SOD activity, MDA content, leukocyte mtDNA deletion rate and A β1–28 content were observed before and after treatment.ResultsCompared with the normal control group, the memory quotient and SOD activity in patients with MCI decreased significantly (P < 0.01), while MDA, A β1–28 levels and the leukocyte mtDNA deletion rate increased significantly (P < 0.01). After treatment, levels of memory quotient and serum SOD activity increased while the serum MDA level, leukocyte mtDNA deletion rate and A β1–28 level decreased in the treated group compared with those before treatment (P<0.01, P<0.05). Meanwhile, leukocyte mtDNA deletion rate and A β1–28 content in the treated group were all lower than those in the control group (P<0.05).ConclusionWYG could improve memory function in patients with MCI and the therapeutic mechanism is possibly related to the increased activity of anti-oxidase, the improved free radical metabolism and the alleviation of leukocyte mtDNA oxidation damage. WYG shows clinical significance in delaying the progression of MCI.

Modified Wu-Zi-Yan-Zong prescription, a traditional Chinese polyherbal formula, suppresses lipopolysaccharide-induced neuroinflammatory processes in rat astrocytes via NF-κB and JNK/p38 MAPK signaling pathways.

Neuroinflammation plays an important role in several neurodegenerative diseases. In this study, we investigated the anti-inflammatory properties of modified Wu-Zi-Yan-Zong prescription (MWP), a traditional Chinese polyherbal formula, in primary cultured rat astrocytes treated with lipopolysaccharide (LPS). The results showed that MWP significantly inhibited release of nitric oxide (NO) and prostaglandin E (PGE), as well as expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 in LPS-induced rat astrocytes. Mechanism study indicated that MWP significantly inhibited nuclear factor-kappa B (NF-κB) inflammatory signaling pathway through attenuating inhibitor of nuclear factor-κB (IκB) degradation and down-regulating IκB kinases (IKKs) phosphorylation level. Moreover, MWP also decreased c-Jun NH(2)-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK) phosphorylation, which play an important role in the induction of proinflammatory gene expressions. At last, MWP protected neurons from LPS-activated astrocytes in neuron-astrocyte co-culture system. Taken together, our results suggest that MWP may act to suppress neuroinflammatory response in LPS-stimulated rat astrocytes via NF-κB and JNK/p38 MAPK signaling cascades, and MWP may be a useful agent for prevention and treatment of neuroinflammatory disease.

Relationship between Endogenous Hydrogen Sulfide and Blood Stasis Syndrome Based on the Qi-Blood Theory of Chinese Medicine

Abstract“Qi” and “blood” are two essential concepts in Chinese medicine (CM). As qi is intangible, the concept of qi is still controversial between CM and Western medicine. However, the endogenous hydrogen sulfide (H2S) and other gaseous signaling molecules provides a new approach for understanding the essence of qi in CM. Blood stasis syndrome is a common syndrome in CM. According to the CM theory, the incidence of blood stasis syndrome is closely correlated to the reckless movement of qi, as qi and blood are inseparable in regulating physiological functions. In recent years, more and more evidences suggest a close correlation between blood stasis syndrome and microcirculation dysfunction. In this paper, we discuss the relationship between endogenous H2S and blood stasis syndrome based on qi-blood theory of CM. We found that endogenous H2S maybe a material basis in concept of qi in CM, while dysfunctional microcirculation is the pathological basis of the blood stasis syndrome. As qi is closely associated with incidence and progression of blood stasis syndrome, endogenous H2S may play an important role in preventing and treating the blood stasis syndrome by improving the function of microcirculation.

Ginsenoside Rk1 suppresses pro-inflammatory responses in lipopolysaccharide-stimulated RAW264.7 cells by inhibiting the Jak2/Stat3 pathway

The saponin ginsenoside Rk1 is a major compound isolated from ginseng. Ginsenoside Rk1 has been reported to have anti-inflammatory and anti-tumor properties and to be involved in the regulation of metabolism. However, the effect and mechanism of anti-inflammatory action of ginsenoside Rk1 has not been fully clarified. We investigated whether ginsenoside Rk1 could suppress the inflammatory response in lipopolysaccharide-stimulated RAW264.7 macrophages and to explore its mechanism of the action. RAW264.7 cells were treated with LPS (1 μg·mL-1) in the absence or the presence of Ginsenoside Rk1 (10, 20, and 40 μmol·L-1). Then the inflammatory factors were tested with Griess reagents, ELISA, and RT-PCR. The proteins were analyzed by Western blotting. Ginsenoside Rk1 inhibited lipopolysaccharide-induced expression of nitric oxide (NO), interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α, and monocyte chemotactic protein (MCP)-1. Ginsenoside Rk1 inhibited the lipopolysaccharide-stimulated phosphorylation of NF-κB and janus kinase (Jak)2 and signal transducer and activator of transcription (Stat)3 at Ser727 and Tyr705. These data suggested that ginsenoside Rk1 could inhibit expression of inflammatory mediators and suppress inflammation further by blocking activation of NF-κB and the Jak2/Stat3 pathway in LPS-stimulated RAW264.7 cells.

Icariin Protects SH-SY5Y Cells from Formaldehyde-Induced Injury through Suppression of Tau Phosphorylation

ObjectiveTo investigate the neuroprotective effects of icariin on formaldehyde (FA)-treated human neuroblastoma SH-SY5Y cells and the possible mechanisms involved.MethodsSH-SY5Y cells were divided into FA treatment group, FA treatment group with icariin, and the control group. Cell viability, apoptosis, and morphological changes were determined by cell counting kit-8 (CCK 8), flow cytometry, and confocal microscopy, respectively. The phosphorylation of Tau protein was examined by western blotting.ResultsFA showed a half lethal dose (LD50) of 0.3 mmol/L in SH-SY5Y cells under the experimental conditions. Icariin (1–10 µmol/L) prevented FA-induced cell death in SH-SY5Y cells in a dose-dependent manner, with the optimal effect observed at 5 µmol/L. After FA treatment, the absorbance in FA group was 1.31±0.05, while in the group of icariin (5 µmol/L) was 1.63±0.05. Examination of cell morphology by confocal microscopy demonstrated that 5 µmol/L icariin significantly attenuated FA-induced cell injury (P <0.05). Additionally, Icariin inhibited FA-induced cell apoptosis in SH-SY5Y cells. Results from western blotting showed that icariin suppressed FA-induced phosphorylation at Thr 181 and Ser 396 of Tau protein, while having no effect on the expression of the total Tau protein level. Furthermore, FA activated Tau kinase glycogen synthase kinase 3 beta (GSK-3β) by enhancement of Y216 phosphorylation, but icariin reduced Y216 phosphorylation and increased Ser 9 phosphorylation.ConclusionIcariin protects SH-SY5Y cells from FA-induced injury poßsibly through the inhibition of GSK-3β-mediated Tau phosphorylation.

Antineuroinflammatory Effects of Modified Wu-Zi-Yan-Zong Prescription in β-Amyloid-Stimulated BV2 Microglia via the NF-κB and ERK/p38 MAPK Signaling Pathways

Modified Wu-Zi-Yan-Zong prescription (MWP), a traditional Chinese medicinal decoction, has possessed the neuroprotective and anti-inflammatory properties. The mechanisms associated with these properties, however, are not completely understood. We designed the experiments to elucidate the antineuroinflammatory property of MWP in BV2 microglia activated by β-amyloid (Aβ), which is a characteristic feature of Alzheimers disease (AD). The composition of MWP was studied using HPLC. BV2 microglia cells were then treated with Aβ in the presence or absence of MWP. The effects of MWP treatment on Aβ-activated neuroinflammation were determined using PCR, western blotting, and immunofluorescence staining. MWP significantly inhibited the mRNA expression of inflammatory mediators such as IL-1β, IL-6, TNF-α, and MCP-1, as well as the expression of inducible nitric oxide synthase (iNOS) in Aβ-activated BV2 microglia. MWP also inhibited the nuclear translocation and signaling pathway of nuclear factor kappa B (NF-κB) by suppressing inhibitor of nuclear factor-κB (IκB) degradation and downregulating IκB kinase β (IKKβ) phosphorylation. Moreover, MWP decreased extracellular regulated protein kinase (ERK)/p38 mitogen-activated protein kinase (MAPK) phosphorylation, which is an important signaling pathway for proinflammatory gene expression. We concluded that MWP could suppress neuroinflammatory responses in Aβ-activated BV2 microglia via the NF-κB and ERK/p38 MAPK signaling cascades and could prove an effective therapeutic agent for the prevention and treatment of neuroinflammatory diseases such as AD.

Uncovering potential anti-neuroinflammatory components of Modified Wuziyanzong Prescription through a target-directed molecular docking fingerprint strategy

Graphical abstract Figure. No caption available. HighlightsA TMDF strategy was proposed to identify the potential anti‐neuroinflammatory components of MWP.120 possible structures were characterized by the SASC strategy.The prenylated flavonoids showed broad‐spectrum anti‐neuroinflammatory activities.IKK&bgr; and p38‐&agr; were the major anti‐neuroinflammatory targets.The Western blotting assay reinforced the reliability of the proposed TMDF strategy. ABSTRACT Neuroinflammation is a main factor in the pathogenesis of neurodegenerative diseases, such as Alzheimer disease. Our previous studies indicated that the modified Wuziyanzong Prescription (MWP) can suppress neuroinflammatory responses via nuclear factor‐kappa B (NF‐&kgr;B) and mitogen‐activated protein kinases (MAPKs) signaling pathways. However, the anti‐neuroinflammatory components of MWP remain unclear. Herein, a target‐directed molecular docking fingerprint (TMDF) strategy, via integrating the chemical profiling and molecular docking approaches, was developed to identify the potential anti‐neuroinflammatory components of MWP. First, as many as 120 possible structures, including 49 flavonoids, 28 phenylpropionic acids, 18 amides, 10 carotenoids, eight phenylethanoid glycosides, four lignans, two iridoids, and one triterpenoid were deduced by the source attribution and structural classification‐assisted strategy. Then, their geometries were docked against five major targets of the NF‐&kgr;B and MAPKs signaling cascades, including p38‐&agr;, IKK&bgr;, ERK1, ERK2, and TRAF6. The docking results revealed diverse contributions of different components towards the protein targets. Collectively, prenylated flavonoids showed intensive or moderate anti‐neuroinflammatory activities, while phenylpropanoids, amides, phenylethanoid glycosides, lignans, and triterpenoids exhibited moderate or weak anti‐neuroinflammatory effects. The anti‐neuroinflammatory activities of four retrieved prenylated flavonoids were tested by Western blotting assay, and the results mostly agreed with those predicted by the docking method. These gained information demonstrates that the established TMDF strategy could be a rapid and feasible methodology to investigate the potential active components in herbal compound prescriptions.