Neuroprotective and mechanistic study of GJ-4 on okadaic acid-induced memory impairment in mice / 药学学报

GJ-4 is crocin enrichments extracted from Gardenia jasminoides J. Ellis, and our previous studies have shown that GJ-4 significantly improved learning and memory impairment induced by Aβ in mice. Herein, a memory deficit model was developed by injecting okadaic acid (OA) into the lateral ventricle of mice, and the neuroprotection and underlying mechanism of GJ-4 on neuronal injury caused by Tau hyperphosphorylation were investigated. The Animal Care & Welfare Committee, Institute of Materia Medica, CAMS & PUMC has approved all procedures (No.00000318). GJ-4 at different doses was intragastric administration to mice for 16 days. Step-down test and Morris water maze test showed that GJ-4 could significantly improve OA-induced memory impairment in mice, and reduced the loss of Nissl bodies in the hippocampus of mice. GJ-4 could also decrease the phosphorylation level of Tau protein at Ser396, Thr231 and Ser404 via increasing protein phosphatase 2A (PP2A) activity and inhibiting glycogen synthase kinase-3β (GSK-3β) activity. Besides, further researches indicated that GJ-4 could inhibit the level of oxidative stress in the brain of OA mice, reduce neuronal apoptosis and inhibit the neuroinflammation mediated by activation of astrocytes in the hippocampus of mice, and eventually achieve its effects in improving learning and memory impairment in mice. According to these findings, we anticipated that GJ-4 might be a potential therapeutic drug for Alzheimer's disease.

Novel compound FLZ alleviates rotenone-induced PD mouse model by suppressing TLR4/MyD88/NF-

Parkinson's disease (PD) is the second most common neurodegenerative disease, but none of the current treatments for PD can halt the progress of the disease due to the limited understanding of the pathogenesis. In PD development, the communication between the brain and the gastrointestinal system influenced by gut microbiota is known as microbiota-gut-brain axis. However, the explicit mechanisms of microbiota dysbiosis in PD development have not been well elucidated yet. FLZ, a novel squamosamide derivative, has been proved to be effective in many PD models and is undergoing the phase I clinical trial to treat PD in China. Moreover, our previous pharmacokinetic study revealed that gut microbiota could regulate the absorption of FLZ

Mechanisms of ferroptosis and its involvement in Parkinson's disease / 药学学报

Ferroptosis is a novel type of regulated cell death with morphology, biochemistry and mechanisms differing from traditional cell death types such as apoptosis, necrosis and pyroptosis. The regulatory mechanisms of ferroptosis mainly involve iron metabolism, amino acid metabolism and lipid metabolism. It has been found that ferroptosis plays a key role in the pathogenesis of diseases including neurodegenerative diseases, malignant tumors and ischemic reperfusion injury. Parkinson's disease (PD) is one of the most common neurodegenerative diseases and its etiology and pathogenesis remains unclear. Recent studies revealed that ferroptosis might be involved in the pathogenesis of PD, as evidenced by high iron content, depletion of reduced form of glutathione and elevated levels of lipid peroxides detectable in the midbrain of PD patients. Both in vitro and in vivo models of PD have shown that some ferroptosis inhibitors have the ability of attenuating the symptoms and one iron chelator is undergoing a clinic trial. We here summarize the mechanisms of ferroptosis and its association with PD, in an effort to suggest potential novel targets for therapies of PD.

Lipopolysaccharide potentiates dopaminergic neuronal dysfunction in α-synuclein transgenic mice / 药学学报

Parkinson's disease (PD) is the most prevalent neurodegenerative disorder, with several risk factors contributing to the onset, such as aging, genetics, oxidative stress and neuroinflammation. There are several PD animals that mimics different risk factor. α-Synuclein mutation mice and systemic lipopolysaccharide (LPS) injection mice are two kinds of most common animal models that replicate genetic mutation and neuroinflammation, respectively. However, in these two animal models, the pathogenesis occurred after a long period of stimulation. In the present study, four-month-old α-synucleintransgenic mice (A53T) were intraperitoneally injected with LPS once a week for continuous 8 weeks to simulate the inflammatory response. The behavioral results showed that the time of mice staying on the rod and the performance score were markedly decreased, indicating motor dysfunction. Dopaminergic neuronal function also decreased. It was noted that the movement dysfunction and pathological changes were aggravated in LPS plus α-synuclein challenged mice compared with LPS or α-synuclein stimulated alone, suggesting that the double attack had synergistic effects. Mechanistic study demonstrated that LPS and α-synuclein combined challenge led to obvious neuroinflammatory response and apoptosis, which might contribute to motor and dopaminergic neuronal dysfunction. In addition, differential proteomic study showed that the expression of CD99L2 and COX7RP significantly increased in the midbrain of LPS plus α-synuclein challenged mice, which were closely related to inflammation and apoptosis, and might be involved in the pathogenesis of PD. In conclusion, the present study demonstrated that LPS could potentiate dopaminergic neuronal function in α-synuclein transgenic mice, which might be an ideal method to develop PD animal model.

Mechanism of Non-receptor Tyrosine Kinase Src Regulating Neuroinflammation Through Phosphatase and Tensin Homology Protein in Microglia / 中国医学科学院学报

Objective To investigate the mechanism of non-receptor tyrosine kinase Src regulating neuroinflammation through phosphatase and tensin homology protein(PTEN)in microglia. Methods BV2 cells were incubated with PTEN inhibitor bpv(HOpic)for 2 hours,and then added with lipopolysaccharide(LPS)to induce neuroinflammation,Western blot was performed to determine the expression of phosphorylated protein kinase B(Akt)to investigate the activity of PTEN. Enzyme-linked immunosorben assay(ELISA)was used to determine the release of tumor necrosis factor α(TNF-α)to assess neuroinflammation.After PTEN inhibitor or Src specific small interfering RNA was added,the change of neuroinflammation was evaluated to study the mechanism of Src regulating neuroinflammation. Results LPS induced significant neuroinflammation in BV2 cells,as indicated by significantly increased expression of p-Akt and release of TNF-α(P<0.001).The PTEN inhibitor signficantly increased Akt phosphorylation(P<0.05)and TNF-α release(P<0.001)in LPS-induced BV2 cells compared to simply LPS-induced cells.The Src small interfering RNA significantly decreased the release of TNF-α(P<0.001)and inhibited PTEN(P<0.001)and Akt(P<0.001)phosphorylation. Conclusion Src kinase may regulate neuroinflammtion response in BV2 cells by regulating the phosphorylation of PTEN.

Recent advances in study of dihydroceramide / 药学学报

Sphingolipids are a class of lipids that have important signaling functions. The most widely studied bioactive shingolipids include ceramides, sphingosine-1-phosphate and so on. In contrast, dihydroce­ramides have received poor attention. However, recent reports indicate that dihydroceramides are in fact bioactive lipids. The biological activity of dihydroceramide derivatives have been proven in the biophysical, genetic and pharmacological models by decreasing dihydroceramide desaturase activity. Current research shows that dihydroceramides are involved in a variety of important physiological and pathological processes, including the response of autophagy, apoptosis and cell cycle arrest. In this review article, we summarizes the recent advances in study of dihydroceramide in the metabolism pathway, the key metabolic enzymes and biological funcitons.

The role of neuroinflammation-related regulatory targets in the treatment for Parkinson's disease / 药学学报

Parkinson's disease (PD) is a neurodegenerative disease characterized by the degeneration of dopaminergic neurons. The present therapeutic drugs for PD can only alleviate the patients' symptoms, but cannot prevent or delay progression of the disease. Great efforts have been made in the identification of new molecular targets that can prevent or delay the loss of dopaminergic neurons. Growing evidences support the key role of neuroinflammation in the pathogenesis of PD, featured by the activation of glial cells and many enzymes and receptors. This review will provide an overview of the enzymes and receptors closely related to neuroinflammation, which have a potential in the prevention or treatment of the disease.

Microglial Phagocytosis in the Neurodegenerative Diseases / 中国医学科学院学报

Microglia are the resident innate immune cells in the brain. Under endogenous or exogenous stimulates, they become activated and play an important role in the neurodegenerative diseases. Microglial phagocytosis is a process of receptor-mediated engulfment and degradation of apoptotic cells. In addition, microglia can phagocyte brain-specific cargo, such as myelin debris and abnormal protein aggregation. However, recent studies have shown that microglia can also phagocyte stressed-but-viable neurons, causing loss of neurons in the brain. Thus, whether microglial phagocytosis is beneficial or not in neurodegenerative disease remains controversial. This article reviews microglial phagocytosis related mechanisms and its potential roles in neurodegenerative diseases, with an attempt to provide new insights in the treatment of neurodegenerative diseases.

Recent advances in study of sphingolipids on liver diseases / 药学学报

Sphingolipids, especially ceramide and S1P, are structural components of biological membranes and bioactive molecules which participate in diverse cellular activities such as cell division, differentiation, gene expression and apoptosis. Emerging evidence demonstrates the role of sphingolipids in hepatocellular death, which contributes to the progression of several liver diseases including ischaemia-reperfusion liver injury, steatohepatitis or hepatocarcinogenesis. Furthermore, some data indicate that the accumulation of some sphingolipids contributes to the hepatic dysfunctions. Hence, understanding of sphingolipid may open up a novel therapeutic avenue to liver diseases. This review focuses on the progress in the sphingolipid metabolic pathway with a focus on hepatic diseases and drugs targeting the sphingolipid pathway.

Research progress in the study of protective effect of tanshinone IIA on cerebral ischemic stroke / 药学学报

Danshen is one of the traditional Chinese herbal medicines and nas a long history or being used clinically in the treatment of cardiovascular and cerebrovascular conditions such as coronary heart disease and angina pectoris. Tanshinone IIA is a derivative of phenanthrene-quinone isolated from Danshen. It has been reported to be the major bioactive compound of Danshen and has diverse biological effects. Recent studies demonstrated that tanshinone IIA had neuroprotective effects on experimental ischemic stroke through its antiinflammatory, anti-oxidant, anti-apoptosis effects and its inhibitory effect on excitatory amino acid toxicity. In this review, we summarized all the recent progresses on the protective effect of tanshinone IIA on cerebral ischemic stroke. Hopefully, this article will throw some light on further study and application of tanshinone IIA.

The role of heat shock protein 70 in regulating neuroinflammation / 药学学报

Neurodegenerative disease is characterized by progressive loss of neurons in specific brain regions that results in neuronal dysfunction of the central nervous system. Although the pathological mechanism is not fully established, the activation of glial cells mediated neuroinflammation appears to be involved. Heat shock protein 70 (HSP70) is originally described as intracellular chaperone, which plays an important role in protein quality control in cells. However, recent study showed that up-regulation of HSP70 had anti-inflammatory effects in the brain. HSP70 protected neurons from damage and improved neurological function by decreasing inflammatory response as indicated by inactivation of glial cells and inhibition of pro-inflammatory cytokine release. So it is of great significance to find new compounds targeting at HSP70 as neuroprotective agents to delay the progress of neurodegenerative disease. This review will focus on the role of HSP70 in neuroinflammation and the recent advances in using HSP70 as a target for the treatment of neurodegenerative disease.

Scavenger receptor on astrocytes and its relationship with neuroinflammation / 中国医学科学院学报

Neuroinflammation in central nervous system, featured by glial cells activation, can always be found during the development of neurodegenerative diseases. Astrocytes, the most abundant glial cells in the brain, can release both pro-inflammatory and anti-inflammatory factors, thus playing a crucial role in the neuroinflammation. A variety of pattern-recognition receptors on astrocytes are involve d in the inflammatory response, particularly the scavenger receptor. Scavenger receptor is a cell surface glycoprotein and can identify diverse ligands. With a variety of biological functions, it may activate many signal pathways related to neuroinflammation, regulate the host defense and the development of neuroinflammation, and eventually regulate the process of neuroinflammation. Thus, it play a key role in the development of neurodegenerative diseases and many other conditions. This review summarizes the scavenger receptor expressed on astrocytes and how it regulates signal transduction pathways associated with neuroinflammation and thus participates in regulating neuroinflammation.

Therapeutic effect of a natural squamosamide derivative FLZ on Parkinson's disease model mice induced by LPS plus MPTP / 药学学报

The aim of this study is to investigate the protective effect of N-[2-(4-hydroxyphenyl)ethyl]-2-(2, 5-dimethoxyphenyl)-3-(3-methoxy-4-hydroxyphenyl)acrylamide (FLZ), a novel synthetic squamosamide cyclic derivative, against Parkinson's disease (PD) model mice induced by the inflammatory bacterial endotoxin, lipopolysaccharides (LPS) and the neurotoxin 1-methy-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP). C57/BL mice were ip injected LPS (5 mg x kg(-1)) once. One week following the LPS injection, mice received a subcutaneous injection of MPTP (25 mg x kg(-1)) once daily for 2 days. Eight weeks later, FLZ (25, 50 and 75 mg x kg(-1)) was orally administered to mice once daily for 60 days. The motor ability of the mice was evaluated by rod climbing test and footprint test. The dopamine (DA) levels in mouse striatum were determined by high performance liquid chromatography system. The tyrosine hydroxylase (TH)-positive cells were showed by immunohistochemical analysis. FLZ treatment significantly improved motor dysfunction of mice challenged by LPS plus MPTP. The increase of TH-positive cell numbers and elevation of DA levels may be contributed to the beneficial effects of FLZ on motor behavior. This study showed FLZ has significant therapeutic effect on LPS plus MPTP induced chronic PD model, which indicates its potential as a new candidate drug to treat PD.

Research progress of the relationship between microglia and cerebral ischemia / 药学学报

Microglia are the principal immune effectors in brain and participate in a series ofneurodegenerative diseases. The microglial shapes are highly plastic. The morphology is closely related with their activation status and biological functions. Cerebral ischemia could induce microglial activation, and microglial activation is subjected to precise regulation. Microglia could play either protective or neurotoxic roles in cerebral ischemia. Therefore, regulating the expression of receptors or protein molecules on microglia, inhibiting the excessive activation of microglia and production of pro-inflammatory factors, promoting the release of neuroprotective substances might be beneficial to the treatment of cerebral ischemia. The study about relationship between microglia and cerebral ischemia will shed a light on the treatment of cerebral ischemia. This paper is a review of microglial activation and regulation during cerebral ischemia as well as related therapeutic methods.

Neurodegenerative conformational disease and heat shock proteins / 药学学报

Many major neurodegenerative diseases are associated with proteins misfolding and aggregation, which are also called "neurodegenerative conformational disease". The interaction of gene mutation and environmental factors are probably primary events resulting in oligomer and aggregate formations of proteins. Moreover, the dysfunctions of protein control systems, i.e. the ubiquitin-proteasome system and autophagy-lysosomal system, also contribute to the neurodegenerative process. The present review mainly summarizes protein misfolding and aggregation in the development of neurodegenerative conformational disease and the underling mechanisms, as well as upregulation of heatshock proteins as a promising treatment method for this kind of disease.

The role of vitagene in aging and Alzheimer's disease and relevant advances of pharmacological study / 药学学报

Free radical hypothesis of aging emphasized that the age-related accumulation of free radicals results in cell injury. Alzheimer's disease (AD) is the most common form of neurodegenerative disease characterized by impaired cognition and memory of the elderly. Aging is a key risk factor in AD. Substantial evidence suggests that imbalance between free radical formation and clearance promotes AD pathogenesis. The brain overcomes oxidative stress by inducing expression of a set of genes called vitagenes. The protein products of vitagenes include heat shock proteins, heme oxygenases and thioredoxin systems, which serve as endogenous lifeguard of cells. This paper is a review of the expression and function of vitagenes in aging and AD brain, as well as relevant pharmacological study.

Heat shock proteins: new target in cytoprotective and tumor therapy / 药学学报

Heat shock proteins (HSPs) form the most ancient defense system in all living organisms. These proteins act as molecular chaperones by helping the refolding of misfolded proteins and assisting their elimination if they become irreversibly damaged. HSPs interact with a number of cellular systems and form efficient cytoprotective mechanisms. HSPs allow cells to adapt to gradual changes in their environment and to survive in otherwise lethal conditions. The events of cell stress and cell death are linked, and HSPs induced in response to stress appear to function at key regulatory points in the control of apoptosis. HSPs include antiapoptotic and proapoptotic proteins that interact with a variety of cellular proteins. Their expression levels can determine the fate of the cell in response to death stimulus. On the other hand, HSPs are overexpressed in tumor cells, and the inhibition of HSP90 has recently been regarded as a very promising tool to combat various cancers. HSPs can be secreted to circulatory system from a variety of cell types in response to stress. The secreted exogenous proteins act as cytokines and have potential modulatory functions in immune system. Cell surface-bound HSP70 can render tumor cell more sensitive to natural killer cell-mediated cytolytic attack. Therefore, modulator of chaperone activities is becoming a new target of drug development, such as in apoptosis and tumor immunity fields.

Effects of extremely low magnetic field on acute and chronic arthritis of rats / 中国应用生理学杂志

<p><b>AIM</b>To investigate the effects of extremely low magnetic field on acute and chronic arthritis of rats.</p><p><b>METHODS</b>The acute arthritis animal models were built by the right thenar hypodermic injection of carrageenan. Then they were exposed to magnetic field for 6 hours and 8 hours, respectively. The chronic arthritis animal models were built by the right thenar hypodermic injection of complete freund's adjuvant. They were exposed to magnetic field for 7 days and 6 hours each day after the secondary affection appeared 15 days later. The swelling and inflammatory cytokine were observed in both the acute and chronic arthritis models.</p><p><b>RESULTS</b>The ankle and thenar swellings decreased in both the acute and chronic arthritis models after different time exposure. The cytokine of serum and articular lixivium did not change in 6 hours exposed groups of acute arthritis models. The serum IL-6 and articular lixivium IL-6, TNF-alpha decreased compared with sham groups. Though the rest indexes were unchanged, they had the tendency of decrease.</p><p><b>CONCLUSION</b>The extremely low magnetic field has the effects of restraining acute and chronic arthritis of rats, and can also partially restrain the cytokines when the rats were exposed for 8 hours. The mechanisms need to be further investigated.</p>

Effects of Tiaoxin and Zishen prescription on hippocampus neurotransmitters in Alzheimer's disease rats / 中国应用生理学杂志

<p><b>AIM</b>A method of stereotaxic apparatus was employed to damage the nucleus basalis of Meynert, and the effects of Tiao-xinzishen prescriptions on neurotransmitters such as ACh, 5-HT and NE in hippocampus were observed.</p><p><b>METHODS</b>Rats were placed on the brain stereotaxic apparatus and received a bilateral lesion of Meynert by IA injection, according to the atlas of Daxinos and Watson. After seven days of lesion, AD rats were selected. Rats were treated with Tiaoxin or/and Zishen prescription for 20 days, respectively. Hippocampus ACh was measured by spectrophotometer and 5-HT and NE by high performance liquid chromatography (HPLC).</p><p><b>RESULTS</b>The contents of hippocampus ACh, 5-HT and NE of AD rats were significantly increased after the treatment with the three prescriptions, respectively.</p><p><b>CONCLUSION</b>These prescriptions had some up regulating effects on hippocampus neurotransmitters in rats, which had already decreased due to dementia.</p>