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Context-dependent role of sirtuin 2 in inflammation

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Neural Regeneration Research 2025年第3期20卷 682-694页

作者： NoemíSola-Sevilla Maider Garmendia-Berges MCarmen Mera-Delgado Elena Puerta department of Pharmaceutical Sciences Division of PharmacologySchool of Pharmacy and NutritionUniversity of NavarraPamplonaSpain Navarra Institute for Health Research(IdiSNA) PamplonaSpain

Sirtuin 2 is a member of the sirtuin family nicotinamide adenine dinucleotide(NAD~+)-dependent deacetylases, known for its regulatory role in different processes, including inflammation. In this context, sirtuin 2 has been involved in the modulation of key inflammatory signaling pathways and transcription factors by deacetylating specific targets, such as nuclear factor κB and nucleotide-binding oligomerization domain-leucine-rich-repeat and pyrin domain-containing protein 3(NLRP3). However, whether sirtuin 2-mediated pathways induce a pro-or an anti-inflammatory response remains controversial. Sirtuin 2 has been implicated in promoting inflammation in conditions such as asthma and neurodegenerative diseases, suggesting that its inhibition in these conditions could be a potential therapeutic strategy. Conversely, arthritis and type 2 diabetes mellitus studies suggest that sirtuin 2 is essential at the peripheral level and, thus, its inhibition in these pathologies would not be recommended. Overall, the precise role of sirtuin 2 in inflammation appears to be context-dependent, and further investigation is needed to determine the specific molecular mechanisms and downstream targets through which sirtuin 2 influences inflammatory processes in various tissues and pathological conditions. The present review explores the involvement of sirtuin 2 in the inflammation associated with different pathologies to elucidate whether its pharmacological modulation could serve as an effective strategy for treating this prevalent symptom across various diseases.

关键词： interferon inflammation lipopolysaccharide neuroinflammation NLRP3 nuclear factorκB sirtuin 2

Potassium and calcium channels in different nerve cells act as therapeutic targets in neurological disorders

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Neural Regeneration Research 2025年第5期20卷 1258-1276页

作者： Qing Qiu Mengting Yang Danfeng Gong Haiying Liang Tingting Chen department of pharmacology School of PharmacyNantong UniversityNantongJiangsu ProvinceChina Jiangsu Province Key Laboratory of Inflammation and Molecular Drug Target NantongJiangsu ProvinceChina department of pharmacy Longyan First Affiliated Hospital of Fujian Medical UniversityLongyanFujian ProvinceChina

The central nervous system, information integration center of the body, is mainly composed of neurons and glial cells. The neuron is one of the most basic and important structural and functional units of the central nervous system, with sensory stimulation and excitation conduction functions. Astrocytes and microglia belong to the glial cell family, which is the main source of cytokines and represents the main defense system of the central nervous system. Nerve cells undergo neurotransmission or gliotransmission, which regulates neuronal activity via the ion channels, receptors, or transporters expressed on nerve cell membranes. Ion channels, composed of large transmembrane proteins, play crucial roles in maintaining nerve cell homeostasis. These channels are also important for control of the membrane potential and in the secretion of neurotransmitters. A variety of cellular functions and life activities, including functional regulation of the central nervous system, the generation and conduction of nerve excitation, the occurrence of receptor potential, heart pulsation, smooth muscle peristalsis, skeletal muscle contraction, and hormone secretion, are closely related to ion channels associated with passive transmembrane transport. Two types of ion channels in the central nervous system, potassium channels and calcium channels, are closely related to various neurological disorders, including Alzheimer's disease, Parkinson's disease, and epilepsy. Accordingly, various drugs that can affect these ion channels have been explored deeply to provide new directions for the treatment of these neurological disorders. In this review, we focus on the functions of potassium and calcium ion channels in different nerve cells and their involvement in neurological disorders such as Parkinson's disease, Alzheimer's disease, depression, epilepsy, autism, and rare disorders. We also describe several clinical drugs that target potassium or calcium channels in nerve cells and could be u

关键词： astrocytes calcium channels central nervous system extracellular ion concentration microglia neurological disorders neurons potassium channels

Houttuynia cordata polysaccharide alleviated intestinal injury and modulated intestinal microbiota in H1N1 virus infected mice

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Chinese Journal of Natural Medicines 2019年第3期17卷 187-197页

作者： CHEN Mei-Yu LI Hong LU Xiao-Xiao LING Li-Jun WENG Hong-Bo SUN Wei CHEN Dao-Feng ZHANG Yun-Yi department of pharmacology School of Pharmacy Fudan University department of Pharmacognosy School of Pharmacy Fudan University

Houttuynia cordata polysaccharide(HCP) is extracted from Houttuynia cordata, a key traditional Chinese medicine. The study was to investigate the effects of HCP on intestinal barrier and microbiota in H1N1 virus infected mice. Mice were infected with H1N1 virus and orally administrated HCP at a dosage of 40 mg×kg^(–1)×d^(–1). H1N1 infection caused pulmonary and intestinal injury and gut microbiota imbalance. HCP significantly suppressed the expression of hypoxia inducible factor-1α and decreased mucosubstances in goblet cells, but restored the level of zonula occludens-1 in intestine. HCP also reversed the composition change of intestinal microbiota caused by H1N1 infection, with significantly reduced relative abundances of Vibrio and Bacillus, the pathogenic bacterial genera. Furthermore, HCP rebalanced the gut microbiota and restored the intestinal homeostasis to some degree. The inhibition of inflammation was associated with the reduced level of Toll-like receptors and interleukin-1β in intestine, as well as the increased production of interleukin-10. Oral administration of HCP alleviated lung injury and intestinal dysfunction caused by H1N1 infection. HCP may gain systemic treatment by local acting on intestine and microbiota. This study proved the high-value application of HCP.

关键词： H1N1 influenza virus Houttuynia cordata Inflammation Intestinal Barrier Microbiota Polysaccharide

Beneficial effects of Houttuynia cordata polysaccharides on “two-hit” acute lung injury and endotoxic fever in rats associated with anti-complementary activities

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Acta Pharmaceutica Sinica B 2018年第2期8卷 218-227页

作者： Yan Lu Yun Jiang Lijun Ling Yunyi Zhang Hong Li Daofeng Chen department of Pharmacognosy School of Pharmacy Fudan University department of pharmacology School of Pharmacy Fudan University

Houttuynia cordata Thunb. is a traditional herb used for clearing heat and eliminating toxins,and has also been used for the treatment of severe acute respiratory syndrome(SARS). In vitro, the crude H. cordata polysaccharides(CHCP) exhibited potent anti-complementary activity through both the classical and alternative pathways by acting on components C3 and C4 of the complement system without interfering with the coagulation system. This study was to investigate the preventive effects of CHCP on acute lung injury(ALI) induced by hemorrhagic shock plus lipopolysaccharide(LPS) instillation(two-hit)and LPS-induced fever in rats. CHCP significantly attenuated pulmonary injury in the "two-hit" ALI model by reducing pulmonary edema and protein exudation in bronchoalveolar lavage fluid(BALF). In addition, it reduced the deposit of complement activation products in the lung and improved oxidantantioxidant imbalance. Moreover, CHCP administration inhibited fever in rats, reduced the number of leukocytes and restored serum complement levels. The inhibition on the inappropriate activation of complement system by CHCP may play an important role in its beneficial effects on inflammatory diseases. The anti-complementary polysaccharides are likely to be among the key substances for the heatclearing function of H. cordata.

关键词： Houttuynia cordata Polysaccharides Fever Acute lung injury Anti-complementary

Induction of systemic lupus erythematosus syndrome in BALB/c mice by immunization with active chromatin

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Acta Pharmacologica Sinica 2004年第6期25卷 105-109页

作者： Hong LI, Yun-yi ZHANG, Ya-nan SUN, Xi-yi HUANG, Yong-feng JIA, Duan LI2 department of pharmacology, schoolof pharmacy, fudan university, Shanghai 200032, China department of pharmacology School of Pharmacy Fudan University Shanghai 200032 China

AIM: To establish an animal model for systemic lupus erythematosus (SLE)-like syndrome in mice. METHODS: BALB/c mice were immunized with active chromatin isolated from ConA-actived syngeneic spleno-lymphocytes. Plasma samples of mice were tested by enzyme-linked immunosorbent assays (ELISA) for the presence of IgG anti-dsDNA, -ssDNA, and anti-histone antibodies. Tumor necrosis factor-α (TNF-α) in serum was measured by ELISA. Spleno-lymphocyte proliferation assays and the levels of interferon-γ (IFN-γ) in supernatants were tested respectively. Proteinuria was measured. Kidneys were examined by direct immunohistochemical method and light microscopy. RESULTS: Anti-ds DNA, ssDNA, and histone antibodies were induced in active chromatin-immu- nized mice, the proliferation response of splenocytes to ConA and LPS were reduced, levels of interferon-γ in supernatants and TNF-α in serum were lowered. Lupus nephritis was assessed by the presence of Ig deposits, glomerular pathology and proteinuria. CONCLUSION: The active chromatin-induced SLE-like mouse model was similar to idiopathic SLE in human.

关键词： systemic lupus erythematosus chromatin autoantibody tumor necrosis factor interferon type II B-lymphocytes T-lymphocytes female enzyme-linked immunosorbent assay

Polymyxin B as an inhibitor of lipopolysaccharides contamination of herb crude polysaccharides in mononuclear cells

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Chinese Journal of Natural Medicines 2017年第7期15卷 487-494页

作者： LU Xiao-Xiao JIANG Yi-Fan LI Hong OU Ying-Ye ZHANG Zhi-De DI Hong-Ye CHEN Dao-Feng ZHANG Yun-Yi department of pharmacology School of Pharmacy Fudan University Shanghai 201203 China department of Pharmacognosy School of Pharmacy Fudan University Shanghai 201203 China

Lipopolysaccharides(LPS) contamination in herbal crude polysaccharides is inevitable. The present study was performed to explore the effect of polymyxin B on abolishing the influence of LPS contamination in mononuclear cells. LPS was pretreated with polymyxin B sulfate(PB) at different concentrations for 1, 5 or 24 h, and then used to stimulate RAW264.7 and mouse peritoneal macrophages(MPMs). The nitric oxide(NO) and tumor necrosis factor-α(TNF-α) in cell culture supernatant, as the indications of cell response, were assayed. Bupleurum chinensis polysaccharides(BCPs) with trace amount contamination of LPS was treated with PB. 30 μg·mL^(–1) of PB, treating LPS(10 and 1000 ng·mL^(–1) in stimulating RAW264.7 and MPMs respectively) at 37 ℃ for 24 h, successfully abolished the stimulating effect of LPS on the cells. When the cells were stimulated with LPS, BCPs further promoted NO production. However, pretreated with PB, BCPs showed a suppression of NO production in MPMs and no change in RAW264.7. In the in vitro experiments, LPS contamination in polysaccharide might bring a great interference in assessing the activity of drug. Pretreatment with PB(30 μg·mL^(–1)) at 37 °C for 24 h was sufficient to abolish the effects of LPS contamination(10 and 1 000 ng·mL^(–1)).

关键词： Lipopolysaccharide Polymyxin B Bupleurum chinensis polysaccharides Mouse peritoneal macrophages RAW264.7 cells

Development of a C3c-based ELISA method for the determination of anti-complementary potency of Bupleurum polysaccharides

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Acta Pharmaceutica Sinica B 2015年第4期5卷 316-322页

作者： Mulu Wu Hong Li Yunyi Zhang Daofeng Chen department of pharmacology School of Pharmacy Fudan University department of Microbiology Yong Loo Lin School of Medicine National University of Singapore department of Pharmacognosy School of Pharmacy Fudan University

Traditionally, determination of inhibitory potency of complement inhibitors is performed by the hemolytic assay. However, this assay is not applicable to the lectin pathway, thus impeding the understanding of complement inhibitors against the overall function of the complement system. The main objective of our study was to develop a specific enzyme-linked immunosoihent assay (ELISA) as an alternative method to assess the anti-complement activity, particularly against the lectin pathway. By using respective coating substrates against different activation pathways, followed by capturing the stable C3c fragments, our ELBA method can be used to screen complement inhibitors against the classical pathway and the lectin pathway. The inhibitory effect of sununin on the classical pathway, as measured by our hemolytic assay is consistent with previous reports. Further assessment of suramin and Bupleurum polysaccharides against the lectin pathway showed a good reproducibility of the method. Comparison of the lectin pathway IC5is between *** var, purviPliam polysaccharides (1.055 ingtmE) and Buplcurann chinense polysaccharides (0.98 ing/mL) showed that similar to the classical and alterative pathway, these two Bupleurum polysaccharides had comparable anti complementary properties against the lectin pathway. The results demonstrate that the described EIASA assay can compensate for he shortcomings of the hemolytic assay in lectin pathway. (C) 2015 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://***/licenses/by-nc-nd/4.0/).

关键词： ELISA Complement C3c Suramin Bupleurum smithti var. parvifolium Bupleurum chinense Polysaccharides

Polysaccharides extracted from the roots of Bupleurum chinense DC modulates macrophage functions

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Chinese Journal of Natural Medicines 2017年第12期15卷 889-898页

作者： ZHANG Zhi-De LI Hong WAN Fen SU Xiao-Yu LU Yan CHEN Dao-Feng ZHANG Yun-Yi department of pharmacology School of Pharmacy Fudan University Shanghai 201203 China department of Pharmacognosy School of Pharmacy Fudan University Shanghai201203 China

The present study aimed to investigate the effects of polysaccharides extracted from Bupleurum chinense DC(BCPs) on macrophage functions. In the in vivo experiment, 1 m L of 5% sodium thioglycollate was injected into the abdomen of the mice on Day 0 and macrophages were harvested on Day 4. The macrophages were cultured in plates and treated with different concentrations of BCPs and stimulus. Effects of BCPs on macrophage functions were assessed by chemotaxis assay, phagocytosis assay and Enzyme-Linked Immunosorbent Assay(ELISA). Our results showed the enhanced chemotaxis, phagocytosis and secretion of nitric oxide(NO) and inflammatory cytokines by macrophages when treated with BCPs. However, when chemotaxis and phagocytosis were up-regulated by complement components or opsonized particles, BCPs inhibited these effects. Also, the NO production induced by lipopolysaccharides(LPS) was suppressed by BCPs mildly. Moreover, BCPs had an inhibitory effect on the [Ca^(2+)]i elevation of macrophages. These results suggested that BCPs exerted modulatory effects on macrophage functions, which may contribute to developing novel approaches to treating inflammatory diseases.

关键词： Bupleurum chinense DC Polysaccharides Macrophage functions [Ca^2+]i

Distribution of nimodipine in brain following intranasal administration in rats

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Acta Pharmacologica Sinica 2004年第4期25卷 124-129页

作者： Qi-zhi ZHANG, Xin-guo JIANG2, Chun-hua WU department of Pharmaceutics, school ofpharmacy, fudan university, Shanghai 200032, China department of Pharmaceutics School of Pharmacy Fudan University

AIM: To determine whether nasally applied nimodipine (NM) could improve its systemic bioavailability and be transported directly from the nasal cavity to the brain. METHODS: NM was administered nasally, intravenously (iv), and orally to male Sprague-Dawley rats. At different times post dose, blood, cerebrospinal fluid (CSF), and brain tissue samples were collected, and the concentrations of NM in the samples were analyzed byHPLC. RESULTS: Oral systemic bioavailability of NM in rats was 1.17 %, nasal dosing improved bioavailibility to 67.4 %. Following intranasal administration, NM concentrations in olfactory bulb (OB) within 30 min post dose were found significant higher than in the other brain tissues. However, similar NM levels in different brain regions were observed after iv injection. AUC in CSF and OB from the nasal route was 1.26 and 1.39 fold compared with the iv route, respectively. The brain-to-plasma AUC ratios were significantly higher after nasal administration than after iv administration (P<0.01). CONCLUSION: Nasally administered NM could markedly improve the bioavailability and a fraction of the NM dose could be transported into brain via the olfactory pathway in rats.

关键词： intranasal administration nimodipine olfactory bulb olfactory pathways