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Polysaccharides are biologically essential macromolecules, widely exist in plants, which are used in food, medicine, bioactives' encapsulation, targeted delivery and other fields. Suitable extraction technology can not only improve the yield, but also regulate the physicochemical, improve the functional property, and is the basis for the research and application of polysaccharide. High pressure (HP) extraction (HPE) induces the breakage of raw material cells and tissues through rapid changes in pressure, increases extraction yield, reduces extraction time, and modifies structure of polysaccharides. However, thus far, literature review on the mechanism of extraction, improved yield and modified structure of HPE polysaccharide is lacking. Therefore, the present work reviews the mechanism of HPE polysaccharide, increasing extraction yield, regulating physicochemical and functional properties, modifying structure and improving activity. This review contributes to a full understanding of the HPE or development of polysaccharide production and modification methods and promotes the application of HP technology in polysaccharide production.
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Medicina , Polissacarídeos , Polissacarídeos/farmacologia , Polissacarídeos/química , Extratos Vegetais/química , Substâncias Macromoleculares , Antioxidantes/químicaRESUMO
Objective: To observe the effect of implementing standardized flow management in enteral nutrition therapy for critically ill patients. Methods: We selected 241 critically ill patients admitted to our hospital from January 2020 to January 2023. Patients with enteral nutrition without standard process management were set as the control group (n = 109), while those with enteral nutrition and standard process management were set as the observation group (n = 132). The total protein, albumin, prealbumin, and hemoglobin were compared between the two groups on the 7th and 14th day of nutritional therapy. Immune indicators (IgM, IgA, and IgG), NUTRIC score, and the incidence of infectious complications were compared between the two groups. Results: On the 7th and 14th day of treatment, the total protein, albumin, prealbumin, hemoglobin, and immune indicators in the observation group were higher than those in the control group, and the differences were statistically significant (P < .05). On the 7th and 14th day of treatment, the NUTRIC score of the observation group was higher than that in the control group, with a statistically significant difference (P < .05). The incidence of infectious complications in the observation group was lower than that in the control group, and the difference was statistically significant (P < .05). Conclusion: Implementing standardized process management of EN for critically ill patients improves total protein, albumin, prealbumin, hemoglobin, immune indexes, NUTRIC score, and nutritional status, while reducing the incidence of infectious complications. These findings offer valuable insights for clinical practice and advocate for practical application.
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LGALS12, also known as galectin12, belongs to the galectin family with ß-galactoside-binding activity. We previously reported that LGALS12 is an important regulator of adipogenesis in porcine adipocytes in vitro, but its value in pig breeding needed to be explored in vivo. In this study, we used CRISPR/Cas9 to construct porcine fetal fibroblasts (PFFs) with a 43 bp deletion in LGALS12 exon 2. Using these PFFs as donor cells, a LGALS12 knockout pig model was generated via somatic cell nuclear transfer. Primary cultures of porcine intramuscular (IM) and subcutaneous (SC) adipocytes were established using cells from LGALS12 knockout pigs and wild-type pigs. A comparison of these cells proved that LGALS12 deficiency suppresses cell proliferation via the RAS-p38MAPK pathway and promotes lipolysis via the PKA pathway in both IM and SC adipocytes. In addition, we observed AKT activation only in IM adipocytes and suppression of the Wnt/ß-catenin only in SC adipocytes. Our findings suggest that LGALS12 deficiency affects the adipogenesis of IM and SC adipocytes through different mechanisms.
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Adipócitos , Sistemas CRISPR-Cas , Suínos , Animais , Técnicas de Inativação de Genes , Adipócitos/metabolismo , Adipogenia/genética , Proliferação de CélulasRESUMO
Increasing evidence shows that SARS-CoV-2 can infect kidneys and cause acute kidney injury (AKI) in critically ill COVID-19 patients. However, mechanisms through which COVID-19 induces AKI are largely unknown, and treatment remains ineffective. Here, we report that kidney-specific overexpressing SARS-CoV-2 N gene can cause AKI, including tubular necrosis and elevated levels of serum creatinine and BUN in 8-week-old diabetic db/db mice, which become worse in those with older age (16 weeks) and underlying diabetic kidney disease (DKD). Treatment with quercetin, a purified product from traditional Chinese medicine (TCM) that shows effective treatment of COVID-19 patients, can significantly inhibit SARS-CoV-2 N protein-induced AKI in diabetic mice with or without underlying DKD. Mechanistically, quercetin can block the binding of SARS-CoV-2 N protein to Smad3, thereby inhibiting Smad3 signaling and Smad3-mediated cell death via the p16-dependent G1 cell-cycle arrest mechanism in vivo and in vitro. In conclusion, SARS-CoV-2 N protein is pathogenic and can cause severe AKI in diabetic mice, particularly in those with older age and pre-existing DKD, via the Smad3-dependent G1 cell-cycle arrest mechanism. Importantly, we identify that quercetin may be an effective TCM compound capable of inhibiting COVID-19 AKI by blocking SARS-CoV-2 N-Smad3-mediated cell death pathway.
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Injúria Renal Aguda , COVID-19 , Diabetes Mellitus Experimental , Camundongos , Animais , SARS-CoV-2 , COVID-19/complicações , Quercetina/farmacologia , Diabetes Mellitus Experimental/complicações , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/patologia , Camundongos Endogâmicos , Pontos de Checagem do Ciclo CelularRESUMO
Ovarian cancer has become an urgent threat to global female healthcare. Cisplatin, as the traditional chemotherapeutic agent against ovarian cancer, retains several limitations, such as drug resistance and dose-limiting toxicity. In order to solve the above problems and promote the therapeutic effect of chemotherapy, combining chemotherapy and phototherapy has aroused wide interest. In this study, we constructed a versatile cisplatin prodrug-conjugated therapeutic platform based on ultrasmall CuS-modified Fe(III)-metal-organic frameworks (MIL-88) (named M-Pt/PEG-CuS) for tumor-specific enhanced synergistic chemo-/phototherapy. After intravenous injection, M-Pt/PEG-CuS presented obvious accumulation in tumor and Fe(III)-MOFs possessed magnetic resonance imaging (MRI) to guide synergy therapy. Both in vitro and in vivo experimental results showed that M-Pt/PEG-CuS could not only successfully inhibit tumor growth by combining chemotherapy and NIR-II PTT but also avoid the generation of liver damage by the direct treatment of cisplatin(II). Our work presented the development of the nanoplatform as a novel NIR-II photothermal agent, as well as gave a unique combined chemo-photothermal therapy strategy, which might provide new ways of ovarian cancer therapy for clinical translation.
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Nanopartículas , Neoplasias Ovarianas , Pró-Fármacos , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Doxorrubicina/farmacologia , Feminino , Compostos Férricos , Humanos , Imageamento por Ressonância Magnética , Neoplasias Ovarianas/diagnóstico por imagem , Neoplasias Ovarianas/tratamento farmacológico , Fototerapia , Terapia Fototérmica , Pró-Fármacos/farmacologiaRESUMO
Triple negative breast cancer (TNBC) is highly malignant and prone to recurrence and metastasis. Patients with TNBC usually have poor prognosis. Hence, it is urgent to develop new comprehensive treatments for TNBC. The combination of heat shock protein (HSP) inhibitor and the photothermal agent can reduce the temperature required to kill tumor cells, thus achieving mild-temperature photothermal therapy (PTT). Compared with traditional PTT, mild-temperature PTT not only decreases tumor thermoresistance introduced by the overexpression of HSP, but also reduces the damage to normal tissues. Meanwhile, Azo initiator 2,2-azobis[2-(2-imidazolin-2-yl) propane]-dihydroch-loride (AIPH) can be thermally decomposed to generate oxygen-independent free radicals. Herein, a new therapeutic multifunctional nanoplatform (M-17AAG-AIPH) by loading heat shock protein 90 (HSP90) inhibitor (17AAG) and AIPH incorporated into mesoporous polydopamine (MPDA) was successfully constructed for mild-temperature PTT combined with oxygen-independent cytotoxic free radicals against TNBC. Under 808 nm laser irradiation, the mild-temperature PTT arising from the combined effects of 17AAG and MPDA induced a rapid release and decomposition of AIPH, promoting the apoptosis of cancer cells in hypoxic microenvironments. Both in vitro and in vivo results showed that the designed nanoplatform can significantly inhibit tumor growth and provided an efficient new therapeutic strategy for TNBC. STATEMENT OF SIGNIFICANCE: There is still an urgent need for new strategies for the treatment of triple negative breast cancer (TNBC). In this work, we successfully constructed a new therapeutic multifunctional nanoplatform (M-17AAG-AIPH) by co-carrying heat shock protein 90 (HSP90) inhibitor (17AAG) and AIPH on mesoporous polydopamine (MPDA). MPDA owned good biocompatibility and outstanding photothermal-conversion ability. The loading of 17AAG can reduce the heat resistance of tumor cells via specifically inhibiting the activity of HSP90, so as to achieve mild-temperature PTT. Meanwhile, 17AAG and MPDA mediated mild-temperature PTT promoted the decomposition of AIPH into oxygen-independent cytotoxic free radicals. Both in vitro and in vivo results showed that M-17AAG-AIPH can significantly inhibit tumor growth and provided an efficient new therapeutic strategy for TNBC.
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Antineoplásicos , Hipertermia Induzida , Nanopartículas , Neoplasias de Mama Triplo Negativas , Linhagem Celular Tumoral , Radicais Livres , Proteínas de Choque Térmico , Humanos , Hipertermia Induzida/métodos , Nanopartículas/química , Oxigênio , Fototerapia/métodos , Terapia Fototérmica , Temperatura , Neoplasias de Mama Triplo Negativas/terapia , Microambiente TumoralRESUMO
BACKGROUND: Mitogen-activated protein kinases (MAPKs) plays essential roles in the development, hormone regulation and abiotic stress response of plants. Nevertheless, a comprehensive study on MAPK family members has thus far not been performed in Tartary buckwheat. RESULTS: Here, we identified 16 FtMAPKs in the Fagopyrum tataricum genome. Phylogenetic analysis showed that the FtMAPK family members could be classified into Groups A, B, C and D, in which A, B and C members contain a Thr-Glu-Tyr (TEY) signature motif and Group D members contain a Thr-Asp-Tyr (TDY) signature motif. Promoter cis-acting elements showed that most ProFtMAPks contain light response elements, hormone response elements and abiotic stress response elements, and several ProFtMAPks have MYB-binding sites, which may be involved in the regulation of flavonoid biosynthesis-related enzyme gene expression. Synteny analysis indicated that FtMAPKs have a variety of biological functions. Protein interaction prediction suggested that MAPKs can interact with proteins involved in development and stress resistance. Correlation analysis further confirmed that most of the FtMAPK genes and transcription factors involved in the stress response have the same expression pattern. The transient transformation of FtMAPK1 significantly increased the antioxidant enzymes activity in Tartary buckwheat leaves. In addition, we also found that FtMAPK1 can respond to salt stress by up-regulating the transcription abundance of downstream genes. CONCLUSIONS: A total of 16 MAPKs were identified in Tartary buckwheat, and the members of the MAPK family containing the TDY motif were found to have expanded. The same subfamily members have relatively conserved gene structures and similar protein motifs. Tissue-specific expression indicated that the expression of all FtMAPK genes varied widely in the roots, stems, leaves and flowers. Most FtMAPKs can regulate the expression of other transcription factors and participate in the abiotic stress response. Our findings comprehensively revealed the FtMAPK gene family and laid a theoretical foundation for the functional characterization of FtMAPKs.
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Fagopyrum , Fagopyrum/genética , Fagopyrum/metabolismo , Regulação da Expressão Gênica de Plantas , Filogenia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismoRESUMO
Key enzymes play a vital role in plant growth and development. However, the evolutionary relationships between genes encoding key enzymes in the metabolic pathway of Tartary buckwheat flavonoids are poorly understood. Based on the published Tartary buckwheat genome sequence and related Tartary buckwheat transcriptome data, 48 key enzyme-encoding genes involved in flavonoid metabolism were screened from the Tartary buckwheat genome in this study; the chromosome localization, gene structure and promoter elements of these enzyme-encoding gene were also investigated. Gene structure analysis revealed relatively conserved 5' exon sequences among the 48 genes, indicating that the structural diversity of key enzyme-encoding genes is low in Tartary buckwheat. Through promoter analysis, these key enzyme-encoding genes were found to contain a large number of light-response elements and hormone-response elements. In addition, some genes could bind MYB transcription factors, participating in the regulation of flavonoid biosynthesis. The transcription level of the 48 key enzyme-encoding gene varied greatly among tissues. In this study, we identified 48 key enzyme-encoding genes involved in flavonoid metabolic pathways, and elucidated the structure, evolution and tissue-specific expression patterns of these genes. These results lay a foundation for further understanding the functional characteristics and evolutionary relationships of key enzyme-encoding genes involved in the flavonoid metabolic pathway in Tartary buckwheat.
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Fagopyrum , Fagopyrum/genética , Fagopyrum/metabolismo , Flavonoides , Regulação da Expressão Gênica de Plantas , Redes e Vias Metabólicas/genética , Filogenia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismoRESUMO
Qufengtongluo (QFTL) decoction is an effective treatment for diabetic nephropathy (DN). However, the underlying molecular mechanism is still unclear. In this study, we try to investigate whether QFTL decoction acts via inhibiting PI3K/Akt signaling pathway. Twenty-four GK rats were randomly divided into 3 groups: blank group, sham-operated group, and QFTL group. After model establishment, rats in QFTL group were given QFTL decoction by gavage, while the rest were given pure water. During the 8-week intervention, 24 hr urinal protein was measured every 2-3 weeks. After intervention, kidneys were removed for pathological smear, quantitative real-time PCR, and western blotting to detect expression levels of p-PI3K, p-Akt, PTEN, TGF-ß, PI3K mRNA, Akt mRNA, PTEN mRNA, and TGF-ß mRNA. QFTL group showed a slighter degree of renal fibrosis in Masson and PASM staining and a greater reduction of 24 hr urinal protein than blank group. Compared to blank group, expression levels of p-PI3K, p-Akt, PI3K mRNA, and Akt mRNA were lower in QFTL group, while expression levels of PTEN and PTEN mRNA were higher. Besides, TGF-ß was downregulated by QFTL decoction. In conclusion, this study suggests that QFTL decoction might inhibit PI3K/Akt signaling pathway via activating PTEN and inhibiting TGF-ß.
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Title. Chemotherapy-induced myelosuppression lowers the quality of life in breast cancer patients and causes many complications. Traditional Chinese Medicine (TCM) is a widely used complementary and alternative medicine therapies. Objective. To study whether TCM can reduce the incidence of chemotherapy-induced leukopenia, neutropenia, and febrile neutropenia (FN) in breast cancer patients. Methods. The data were analyzed retrospectively between patients who received TCM treatment (group 1, n = 453) and patients who did not receive TCM treatment (group 2, n = 359). Significant risk factors associated with the occurrence of chemotherapy-induced leukopenia, neutropenia, and FN were identified using multivariate analysis. Propensity score-matched patients were analyzed to adjust for any baseline differences. Results. Group 1 patients had a significantly lower rate of chemotherapy-induced severe leukopenia, neutropenia, and FN, compared with group 2 (43% versus 71%, P < 0.0001, 72% versus 78%, P = 0.005, 6% versus 24%, P < 0.0001, resp.). Multivariate analysis revealed that chemotherapy regimens containing anthracyclines combined with paclitaxel or docetaxel were the most significant predictor. Subgroup analysis indicated that TCM treatment showed benefit in relieving chemotherapy-induced leukopenia and FN in most chemotherapy regimens. Conclusions. TCM treatment could lower the risk of severe chemotherapy-induced leukopenia, neutropenia, and FN in breast cancer patients.
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BACKGROUND: To evaluate the refractive outcomes for the correction of low to moderate astigmatism up to 1 year following small incision lenticule extraction (SMILE) surgery. METHODS: This retrospective study enrolled 98 eyes from 98 patients who underwent SMILE surgery for the correction of myopia and astigmatism. Only right eyes were included in this study to avoid the bias of orientation errors. The vector method was used to analyze the outcomes of astigmatism at 1 month, 6 months and 12 months after the procedure, including the double-angle plots, correction index (CI), index of success (IOS), angle of error (AofE) and magnitude of error (MofE). The effectiveness, safety, stability and predictability were also investigated during the 12-month follow-up. RESULTS: The preoperative cylinder ranged from -2.75 D to -0.25 D (average of -0.90±0.68 D), and the mean postoperative cylinder values were -0.24±0.29 D, -0.24±0.29 D, and -0.20±0.27 D at 1 month, 6 months, and 12 months, respectively. The mean astigmatism in vector form was -0.14 D×27.19° at 1 month, -0.13 D×27.29° at 6 months, and -0.10 D×28.63° at 12 months after surgery. The CI was 1.00±0.32 and IOS was 0.29±0.44 at the 12-month follow-up. Significant negative correlations were found between the CI and absolute target induced astigmatism (TIA) value, and positive correlations were found between the IOS and absolute AofE value (P<0.05). The MofE was limited within ±1.00 D at the 12-month follow-up. Fifty-six eyes (57.1%) gained one line in corrected distance visual acuity (CDVA) and five eyes (5.1%) gained two lines. There were no significant differences observed in the refractive outcomes among time points. CONCLUSIONS: SMILE surgery was effective and safe in correcting low to moderate astigmatism, and stable refractive outcomes were observed at the long-term follow-up. The undercorrection of astigmatism could possibly be influenced by attempted astigmatism correction preoperatively, the axis rotation during the surgery or wound healing postoperatively. This study suggested that nomograms should be adjusted in correcting astigmatism with SMILE surgery.
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Astigmatismo/cirurgia , Miopia/cirurgia , Procedimentos Cirúrgicos Refrativos/métodos , Adolescente , Adulto , Astigmatismo/patologia , Feminino , Humanos , Terapia com Luz de Baixa Intensidade/métodos , Masculino , Estudos Retrospectivos , Adulto JovemRESUMO
OBJECTIVE: To explore the distribution characteristics of basic syndromes and its related factors in patients with chronic functional constipation (CFC). METHODS: The complete data of 538 patients with CFC were collected and initial database was established with Epidata 3. 0. TCM syndrome typing was performed. The distribution characteristics of basic syndromes were analyzed using SPSS 17. 0 Software. The univariate and multivariate Logistic regression analyses were performed with SPSS 17. 0 Software to determine basic syndrome related factors such as age, engaged professionals, sleep quality, depression, mental stress, interpersonal relations, work fatigue, stimulating beverage, exercise conditions, Western medicine type of constipation, and so on. RESULTS: The TCM syndrome frequency of CFC patients was sequenced from high to low as qi deficiency syndrome (380 cases, 70.6%), qi stagnation syndrome (337 cases, 62.6%), blood deficiency syndrome (234 cases, 43.5%), yin deficiency syndrome (220 cases, 40.9%), yang deficiency syndrome (197 cases, 36.6%), and others(58 cases, 10. 8%) . Most patients were complicated with complex syndromes, and the most common complex syndromes were qi deficiency complicated qi stagnation syndrome (275 cases, 51.1%) and qi deficiency complicated blood deficiency syndrome (222 cases, 41.3%). Aging, work fatigue, and exercise conditions were main related factors for qi deficiency syndrome (P <0. 01, P <0. 05). Poor emotional (depression and anxiety tendencies), mental stress, interpersonal relations, defecation barriers constipation were main related factors for qi stagnation syndrome (P <0.01). Sleep quality and poor emotional (depression and anxiety tendencies) were main related factors for blood deficiency syndrome (P <0. 01, P < 0.05). Stimulating beverages were main related factor for yin deficiency syndrome (P <0.05). Engaged in mental work and slow transit constipation were main related factors for yang deficiency syndrome (P < 0. 01, P <0. 05). CONCLUSIONS: CFC is featured as complex syndromes. The most common complex syndromes were qi deficiency complicated qi stagnation syndrome and qi deficiency complicated blood deficiency syndrome. Basic syndrome related factors such as age, engaged professionals, sleep quality, poor emotional (depression and anxiety tendencies), mental stress, interpersonal relations, work fatigue, stimulating beverage, exercise conditions, Western medicine type of constipation were associated with the distribution of CFC syndromes.
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Constipação Intestinal/complicações , Ansiedade/complicações , Constipação Intestinal/diagnóstico , Constipação Intestinal/psicologia , Constipação Intestinal/terapia , Depressão/complicações , Diagnóstico Diferencial , Análise Fatorial , Fadiga , Humanos , Medicina Tradicional Chinesa , Qi , Estresse Psicológico/complicações , Síndrome , Deficiência da Energia Yang/diagnóstico , Deficiência da Energia Yin/diagnósticoRESUMO
BACKGROUND: Previous studies have demonstrated that structural deficits and functional connectivity imbalances might underlie the pathophysiology of obsessive-compulsive disorder (OCD). The purpose of the present study was to investigate gray matter deficits and abnormal resting-state networks in patients with OCD and further investigate the association between the anatomic and functional alterations and clinical symptoms. METHODS: Participants were 33 treatment-naïve OCD patients and 33 matched healthy controls. Voxel-based morphometry was used to investigate the regions with gray matter abnormalities and resting-state functional connectivity analysis was further conducted between each gray matter abnormal region and the remaining voxels in the brain. RESULTS: Compared with healthy controls, patients with OCD showed significantly increased gray matter volume in the left caudate, left thalamus, and posterior cingulate cortex, as well as decreased gray matter volume in the bilateral medial orbitofrontal cortex, left anterior cingulate cortex, and left inferior frontal gyrus. By using the above morphologic deficits areas as seed regions, functional connectivity analysis found abnormal functional integration in the cortical-striatum-thalamic-cortical (CSTC) circuits and default mode network. Subsequent correlation analyses revealed that morphologic deficits in the left thalamus and increased functional connectivity within the CSTC circuits positively correlated with the total Y-BOCS score. CONCLUSION: This study provides evidence that morphologic and functional alterations are seen in CSTC circuits and default mode network in treatment-naïve OCD patients. The association between symptom severity and the CSTC circuits suggests that anatomic and functional alterations in CSTC circuits are especially important in the pathophysiology of OCD.
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Córtex Cerebral/fisiopatologia , Corpo Estriado/fisiopatologia , Vias Neurais , Transtorno Obsessivo-Compulsivo/patologia , Transtorno Obsessivo-Compulsivo/fisiopatologia , Adolescente , Adulto , Comportamento , Mapeamento Encefálico , Estudos de Casos e Controles , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Reprodutibilidade dos Testes , Tálamo/fisiopatologia , Adulto JovemRESUMO
OBJECTIVE: To observe the effects of Huzhang Gout Granule (HZGG), a compound traditional Chinese herbal medicine, on cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) activities, the two important oxidases in the course of inflammation, so as to investigate the possible anti-inflammatory mechanism of HZGG. METHODS: After stimulating the blood sample of healthy volunteer with calcium ionophore A23187, concentration of thromboxane B(2) (TXB(2)) in the healthy volunteer's blood was detected by enzyme-linked immunosorbent assay (ELISA) to observe the effects of HZGG at low- and high-dose on the activity of COX-1, with aspirin as control drug. The concentration of prostaglandin I(2) (PGI(2)) in the healthy volunteer's blood sample, in which aspirin was added to destroy activity of COX-1 beforehand and which was stimulated with lipopolysaccharide, was detected by ELISA method to observe the effects of HZGG on the activity of COX-2, with celecoxib as control drug. In the animal experiment, 40 rats were implanted with sponges soaking in 0.5% arachidonic acid solution in the back to induce inflammatory effusion. Content of leukotriene B4 (LTB4) in the polymorphonuclear leukocytes (PMNs) from the inflammatory effusions was detected with reversed-phase high-performance liquid chromatography (RP-HPLC) to observe the impacts of different doses of HZGG on the activity of 5-LOX, with dexamethasone as control drug. RESULTS: The concentration of TXB(2) in the low-dose HZGG group was higher than those in the high-dose HZGG group and the aspirin group (P<0.05). The concentrations of PGI2 in the low- and high-dose HZGG groups were higher than that in the celecoxib group (P<0.05), but there was no significant difference between the low-dose HZGG group and the high-dose HZGG group (P>0.05). The content of LTB4 in the blank control group was higher than those in the low-dose HZGG group, the high-dose HZGG group or the dexamethasone group (P<0.05) CONCLUSION: HZGG can reduce the releasing of inflammatory mediators, such as TXB2, PGI2 and LTB4, by inhibiting the activities of COX and 5-LOX.