Abnormal adenosine metabolism of neutrophils inhibits airway inflammation and remodeling in asthma model induced by Aspergillus fumigatus.

BACKGROUND: Neutrophils consume a large amount of energy when performing their functions. Compared with other white blood cells, neutrophils contain few mitochondria and mainly rely on glycolysis and gluconeogenesis to produce ATP. The inflammatory site is hypoxic and nutrient poor. Our aim is to study the role of abnormal adenosine metabolism of neutrophils in the asthmatic airway inflammation microenvironment. METHOD: In this study, an asthma model was established by intratracheal instillation of Aspergillus fumigatus extract in Ecto-5'-Nucleotidase (CD73) gene-knockout and wild-type mice. Multiple analyses from bronchoalveolar lavage fluid (BALF) were used to determine the levels of cytokines and chemokines. Immunohistochemistry was used to detect subcutaneous fibrosis and inflammatory cell infiltration. Finally, adenosine 5'-(α, ß-methylene) diphosphate (APCP), a CD73 inhibitor, was pumped subcutaneously before Aspergillus attack to observe the infiltration of inflammatory cells and subcutaneous fibrosis to clarify its therapeutic effect. RESULT: PAS staining showed that CD73 knockout inhibited pulmonary epithelial cell proliferation and bronchial fibrosis induced by Aspergillus extract. The genetic knockdownof CD73 significantly reduced the production of Th2 cytokines, interleukin (IL)-4, IL-6, IL-13, chemokine (C-C motif) ligand 5 (CCL5), eosinophil chemokine, neutrophil IL-17, and granulocyte colony-stimulating factor (G-CSF). In addition, exogenous adenosine supplementation increased airway inflammation. Finally, the CD73 inhibitor APCP was administered to reduce inflammation and subcutaneous fibrosis. CONCLUSION: Elevated adenosine metabolism plays an inflammatory role in asthma, and CD73 could be a potential therapeutic target for asthma.

Effects of Juhongtanke oral solution on alleviating the symptoms of community-acquired pneumonia: A multicenter, prospective, randomized controlled trial.

Introduction: The timely alleviation of symptoms is essential for managing community-acquired pneumonia (CAP). Juhongtanke oral solution is a traditional marketed Chinese patent medicine believed to ease CAP symptoms. The currently available evidence is based on a few retrospective studies of patients with various types of pneumonia, whereas robust randomized controlled trials (RCTs) that support this notion are lacking. Material and methods: In this multi-center, prospective RCT, patients were randomly allocated to receive routine treatment alone or a combination of Juhongtanke oral solution (20 mL q8h) for 5 days and maintained for an additional 3-day safety observation period. The primary outcome was Breathlessness, Cough, and Sputum Scale (BCSS) score evaluated on day 5. Secondary outcomes included the evaluation of cough and dyspnea items in the Visual Analogue Scale (VAS) from days 1-5, remission rate in BCSS and VAS during the treatment course, and the length of hospitalization and in-hospital mortality. Results: Of 272 patients assessed for eligibility, 240 were enrolled in the study (n =120 per group). The mean difference in BCSS evaluated on day 5 was a median 1 point [95%CI (1.00, 2.00)], significantly lower in the treatment group compared with the control group (p < 0.001). Similar results were observed in VAS on day 5, with statistics of a median 2 points [95%CI (1.40, 2.50)] in the cough item and a median 1 point [95%CI (0.50, 2.00)] in the dyspnea item, significantly lower in the treatment group compared with the control group (both p < 0.001). The treatment group had a favorable outcome in BCSS and VAS remission rate assessments compared with the control group, with 99.50% vs. 89.17% in BCSS (p = 0.01), 98.33% vs. 75% in the cough item of VAS (p < 0.001), and 88.33% vs. 62.50% in the dyspnea item of VAS (p < 0.001), respectively. No notable adverse effects were observed during the study. No differences were observed in the length of hospitalization between groups (with a median of 7 days for both groups, p = 0.871). Conclusion: Juhongtanke oral solution may be considered to alleviate the clinical symptoms of CAP.

[Two new sucrose cinnamates from Polygonum lapathifolium var. salicifolium].

Two new sucrose cinnamates(1 and 2) along with nine known compounds(3-11) were isolated from ethanol extract of Polygonum lapathifolium var. salicifolium by silica gel column chromatography, ODS column chromatography and semi-preparative HPLC. Their structures were elucidated by extensive spectroscopic methods including 1 D-and 2 D-NMR experiments, as well as HR-ESI-MS analysis. Eleven compounds(7 sucrose cinnamates, 3 phenylpropanoids and 1 lactone) were obtained and their structures were identified as(1,3-O-di-p-coumaroyl)-ß-D-fructofuranosyl-(2→1)-α-D-glucopyranoside(1),(1,3-O-di-p-coumaroyl)-ß-D-fructofuranosyl-(2→1)-(6-O-acetyl)-α-D-glucopyranoside(2),(3-O-feruloyl)-ß-D-fructofuranosyl-(2→1)-(6-O-p-coumaroyl)-α-D-glucopyranoside(3), hydropiperoside(4), vanicoside C(5),(1,3-O-di-p-coumaroyl)-ß-D-fructofuranosyl-(2→1)-(6-O-feruloyl)-α-D-glucopyranoside(6), vanicoside B(7),trans-p-hydroxycinnamic acid methyl ester(8), trans-p-hydroxycinnamic acid ethyl ester(9), methyl ferulate(10) and dimethoxydimethylphthalide(11), respectively. Compounds 1 and 2 were two new sucrose cinnamates, and compounds 1-11 were isolated from this plant for the first time. The antioxidant activities of the isolated compounds 1-9 were investigated by an oxygen radical absorbance capacity(ORAC) assay, and all nine compounds were found to show strong antioxidant activities. Among them, compound 6(10 µmol·L~(-1)) was the supreme one in antioxidant activities, with its ORAC value equivalent to(1.60±0.05) times of 50 µmol·L~(-1) Trolox.

Heat-sensitive moxibustion self-administration in patients in the community with primary hypertension: A protocol for a multi-center, pragmatic, non-randomized trial.

BACKGROUND: Although the efficacy of antihypertensive drugs has been well established for primary hypertension, their effectiveness is always limited by side effects and poor compliance. Heat-sensitive moxibustion is an innovative acupoint stimulation therapy that is promising as a community health care intervention for hypertension. AIMS: This study aims to evaluate the pragmatic effectiveness and safety of heat-sensitive moxibustion self-administration by patients in the community with primary hypertension. METHODS: This study will adopt a multi-center, pragmatic, nonrandomized design. Six hundred patients with primary hypertension will be recruited from 4 communities. Each patient will choose to either receive heat-sensitive moxibustion self-administration + original antihypertensive drugs or maintain their original antihypertensive drugs without heat-sensitive moxibustion for 1 year. EXPECTED OUTCOMES: The primary outcome will be changes in systolic and diastolic blood pressures and the percentage changes in the doses of antihypertensive drugs. The secondary outcomes will be changes in quality of life assessed by a validated patient-reported outcome scale and the levels of fasting blood glucose, glycated hemoglobin, total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, urinary albumin, and serum creatinine. The proportion of patients with poor compliance with the heat-sensitive moxibustion regimen will also be evaluated as a secondary outcome. The safety of heat-sensitive moxibustion will be considered by analyzing the incidence of all and serious adverse events and their correlation with heat-sensitive moxibustion. DISCUSSION: The findings of this study will provide pragmatic evidence for heat-sensitive moxibustion self-administration in patients in the community with primary hypertension and may also establish an ethical basis for further randomized controlled trials. TRIAL REGISTRATION: The protocol of this trial was registered in ClinicalTrials.gov at May 11, 2020 (No. NCT04381520).

Effects of Notch Signaling Pathway in Cervical Cancer by Curcumin Mediated Photodynamic Therapy and Its Possible Mechanisms in Vitro and in Vivo.

Curcumin, as a high effect and low toxicity anti-cancer drug and photosensitiser, has synergistic and complementary effects with photodynamic therapy (PDT). However, due to its unclear mechanism, PDT's application and efficacy were limited. Notch signaling pathway, which is highly correlates with carcinogenesis and development of cervical cancer, could be a potential therapeutic targets to improve the effectiveness of PDT. Therefore, in this study, we explored the effects of Notch signaling pathway in cervical cancer by curcumin mediated PDT with/without Notch receptor blocker (DAPT), and hope to elucidate its mechanism. Firstly, the effect on the proliferation of cervical cancer Me180 cells were detected with MTT assay, and apoptosis were detected with Annexin V-FITC/PI combined with flow cytometry. Secondly, after establishment of nude mice model, dividing the experimental animals into model group, curcumin PDT group, simple DAPT group, and curcumin-PDT+DAPT group, and analyzing tumor volume changes as well as HE staining in each group. mRNA and protein expression of gene Notch-1 and its downstream NF-κB and VEGF were observed with RT-PCR, immunohistochemical staining and Western-blot with/without inhibition of Notch signaling pathway by DAPT, both in vivo and in vitro experiments. We found both DAPT and curcumin-PDT can inhibit the proliferation and induce apoptosis of cervical cancer cell. The two have synergistic effect in vitro and in vivo. This effect can effectively block the conduction of Notch signaling pathway, which is associated with down-regulation of the expression of Notch1 and NF-κB. Notch signaling pathway could be one of the targets of curcumin-PDT photodynamic therapy.

Effects of biomass pyrolysis derived wood vinegar on microbial activity and communities of activated sludge.

The effects of wood vinegar (WVG) on microbial activity and communities of activated sludge were investigated in a sequencing batch reactor (SBR) process. Results showed that the optimal WVG concentration was 4 µL/L when the pollutants removal efficiency and microbial activity were promoted by a WVG dilution factor of 1000. WVG could reduce the increase in microbial species richness, which led to a more notable variety of microbial species diversity. The enhanced microbial activity and communities were addressed to the promotion of 7 main classes of microbes in Proteobacteria, Bacteroidetes, Acidobacteria, and Nitrospirae phyla. The growth of ammonia-oxidizing bacteria (AOB), nitrite-oxidizing bacteria (NOB), and main genera of denitrifying bacteria (DNB), phosphorus-accumulating organisms (PAOs), and glycogen-accumulating organisms (GAOs) could be promoted by WVG, which improved the sewage treatment effectiveness in a SBR.

The origin of high hydrocarbon groundwater in shallow Triassic aquifer in Northwest Guizhou, China.

Original high hydrocarbon groundwater represents a kind of groundwater in which hydrocarbon concentration exceeds 0.05 mg/L. The original high hydrocarbon will significantly reduce the environment capacity of hydrocarbon and lead environmental problems. For the past 5 years, we have carried out for a long-term monitoring of groundwater in shallow Triassic aquifer in Northwest Guizhou, China. We found the concentration of petroleum hydrocarbon was always above 0.05 mg/L. The low-level anthropogenic contamination cannot produce high hydrocarbon groundwater in the area. By using hydrocarbon potential, geochemistry and biomarker characteristic in rocks and shallow groundwater, we carried out a comprehensive study in Dalongjing (DLJ) groundwater system to determine the hydrocarbon source. We found a simplex hydrogeology setting, high-level water-rock-hydrocarbon interaction and obviously original hydrocarbon groundwater in DLJ system. The concentration of petroleum hydrocarbon in shallow aquifer was found to increase with the strong water-rock interaction. Higher hydrocarbon potential was found in the upper of Guanling formation (T2g3) and upper of Yongningzhen formation (T1yn4). Heavily saturated carbon was observed from shallow groundwater, which presented similar distribution to those from rocks, especially from the deeper groundwater. These results indicated that the high concentrations of original hydrocarbon in groundwater could be due to the hydrocarbon release from corrosion and extraction out of strata over time.

Herbal Medicines for Asthmatic Inflammation: From Basic Researches to Clinical Applications.

Asthma is one of the most common chronic inflammatory disorders, associated with reversible airflow obstruction, airway hyperresponsiveness, and airway remodeling. This disease has a significant impact on individuals, their families, and society. Standardized therapeutics such as inhaled corticosteroid in combination with long acting ß2 agonist have been applied for asthma control; however, complementary and alternative medicines, especially herbal medicines, are still widely used all over the world. A growing body of literature suggests that various herbals or related products might be effective in inhibiting asthmatic inflammation. In this review, we summarize recent advances about the mechanistic studies of herbal medicines on allergic airway inflammation in animal models and their potential application into clinic for asthma control.

Suhuang antitussive capsule at lower doses attenuates airway hyperresponsiveness, inflammation, and remodeling in a murine model of chronic asthma.

Suhuang antitussive capsule (Suhuang), a traditional Chinese medication, is found effective in treating chronic cough and cough variant asthma (CVA). This study aimed to determine the possible effects and underlying mechanisms of Suhuang on chronic ovalbumin (OVA)-induced airway hyperresponsiveness (AHR), inflammation, and remodeling in mice. Mice were randomly assigned to six experimental groups: control, OVA model with or without Suhuang (low dose: 3.5 g/kg, middle dose: 7.0 g/kg, high dose: 14.0 g/kg), or dexamethasone (2.5 mg/kg). AHR, inflammatory cells, cytokines in bronchoalveolar lavage fluid (BALF), lung pathology, mucus production, and airway remodeling were examined. We found Suhuang treated at lower doses effectively inhibited OVA-induced AHR, airway inflammation, mucus production and collagen deposition around the airway. High dose of Suhuang reduced most of the inflammatory hallmarks while exerted inconsiderable effects on the number of macrophages in BALF and AHR. At all doses, Suhuang significantly reduced the levels of interlukin (IL) -13 and transforming growth factor (TGF)-ß1, but had little effects on IL-4, IL-5, IL-17A and interferon (IFN)-γ. Thus, Suhuang administration alleviates the pathological changes of chronic asthma likely through inhibition of IL-13 and TGF-ß1. Suhuang might be a promising therapy for patients with allergic asthma in the future.

Exogenous interleukin-17A inhibits eosinophil differentiation and alleviates allergic airway inflammation.

IL-17 is known to play important roles in immune and inflammatory disease, such as in asthma, but its functions in allergic airway inflammation are still controversial, and the molecular mechanisms mediating these functions remain unclear. Increased production of eosinophils in bone marrow and their emergence in the airway have been linked to the onset and progression of allergic asthma. In this study, we investigated the effects of exogenous IL-17 on allergic airway inflammation and explored the underlying molecular mechanisms through eosinophil generation. Exogenous IL-17 significantly attenuated the features of allergic inflammation induced by ovalbumin in mice. It inhibited eosinophil differentiation both in vivo and in vitro, accompanied by down-regulated expression of CC chemokine receptor 3, GATA binding protein 1 (GATA-1), and GATA binding protein 2 (GATA-2), as well as reduced formation of common myeloid progenitors and eosinophil progenitors, but without influencing eosinophil apoptosis. IL-17 also significantly decreased the number of eosinophils in IL-5-transgenic mice, although it notably increased the levels of IL-3, IL-5, and granulocyte/macrophage colony-stimulating factor. In addition, IL-17 had little effect on secretion of the inflammatory cytokines by eosinophils. Neutralization of endogenous IL-17 significantly augmented eosinophil recruitment in the airways. Together, these findings suggest that exogenous IL-17 protects against allergic airway inflammation, most likely through inhibition of the eosinophil differentiation in bone marrow.

Prevention of allergic airway hyperresponsiveness and remodeling in mice by Astragaliradix antiasthmatic decoction.

BACKGROUND: Astragali radix Antiasthmatic Decoction (AAD), a traditional Chinese medication, is found effective in treating allergic diseases and chronic cough. The purpose of this study is to determine whether this medication could suppress allergen-induced airway hyperresponsiveness (AHR) and remodeling in mice, and its possible mechanisms. METHODS: A mouse model of chronic asthma was used to investigate the effects of AAD on the airway lesions. Mice were sensitized and challenged with ovalbumin (OVA), and the extent of AHR and airway remodeling were characterized. Cells and cytokines in the bronchoalveolar lavage fluid (BALF) were examined. RESULTS: AAD treatment effectively decreased OVA-induced AHR, eosinophilic airway inflammation, and collagen deposition around the airway. It significantly reduced the levels of IL-13 and TGF-ß1, but exerted inconsiderable effect on INF-γ and IL-10. CONCLUSIONS: AAD greatly improves the symptoms of allergic airway remodeling probably through inhibition of Th2 cytokines and TGF-ß1.

Feasibility study of high-temperature thermoseed inductive hyperthermia in melanoma treatment.

Current treatment modalities for melanoma do not offer satisfactory efficacy. We have developed a new, minimally invasive hyperthermia technology based on radio-frequency hyperthermia. Herein, we investigated the feasibility of using a nickel-copper thermoseed for inductive hyperthermia at a relatively high temperature (46-55 ˚C). In vitro, the thermoseed showed good thermal effects and effective killing of B16/F10 melanoma cells. Temperatures of 53.1 ± 0.5 ˚C were achieved for a single thermoseed and 56.5 ± 0.5 ˚C for two in parallel (spacing 5 mm). No B16/F10 melanoma cells survived with heating time longer than 20 min in the parallel thermoseed group. Magnetic fields or thermoseeds alone did not affect the survival rate of B16/F10 cells (P>0.05). In vivo, B16/F10 melanoma cells were subcutaneously injected into the right axilla of C57BL/6 mice. After the tumors grew to ~11-13 mm, two thermoseeds (spacing 5 mm) were implanted into the tumors and the mice were subjected to an alternating magnetic field (100-250 kHz, 15 kA/m) to induce hyperthermia. The temperature at the center of the tumor reached 46 ˚C at 5 min and plateaued at 50 ˚C. Thermoseed treatment produced large necrotic areas, inhibited tumor growth in 60% (6 of 10) of animals and prolonged survival time (P<0.05). Thus, with further optimization and testing, high-temperature thermoseed inductive hyperthermia may have therapeutic potential for melanoma.

Acceleration of age-related changes in the retina in alpha-tocopherol transfer protein null mice fed a Vitamin E-deficient diet.

PURPOSE: To assess the role of vitamin E (VE) in age-related changes in the retinal tissues by using a mouse model of severe VE deficiency. METHODS: Pups of alpha-tocopherol transfer protein null (a-TTP(-)(/)(-)) mice were fed a VE-deficient diet for 4 or 18 months (VE (-) group). Wild-type C57BL/6 mice were fed a 0.002% alpha-tocopherol-supplemented diet (VE (+) group). In various ocular tissues, the VE levels were measured by high-performance liquid chromatography; the fatty acid composition by gas chromatography (GC); and the hydroxyoctadecadienoic acid and 8-iso-prostaglandin F(2)(alpha) levels, which are biomarkers for lipid peroxidation, by GC-mass spectrometry. The retinal structure was assessed by light, electron, and fluorescence microscopy. RESULTS: The alpha-tocopherol level in the retinas obtained from 4-month-old VE (-) animals was 71-fold lower than that in the retinas obtained from the VE (+) group. In addition, gamma-tocopherol was not detected; thus, the VE (-) group demonstrated a more severe VE deficiency than ever reported. In this group, the concentration of n-3 polyunsaturated fatty acids decreased (0.3- to 0.9-fold), whereas that of other classes of fatty acids was unchanged or increased. At 18 months of age, the number of the outer nuclear layer (ONL) nuclei was observed to be 17% lower in the VE (-) than in the VE (+) group (P < 0.05). Electron microscopy revealed larger amounts of matrix between the ONL nuclei indicating the Müller cell hypertrophy, greatly expanded rod outer segment discs, and a larger number of inclusion bodies in the retinal pigment epithelium (RPE; P < 0.05) in the VE (-) group. Fluorescence microscopy revealed that the autofluorescence signal was increased in the RPE layer in this group. When the observations of the 18-month-old animals were compared to those of the 4-month-old animals, the hydroxyoctadecadienoic acid and 8-iso-prostaglandin F(2)(alpha) levels were found to be increased in the retina and RPE obtained from both the VE (-) and VE (+) groups; however, the age-related increases were more remarkable in the VE (-) group (2.6- to 43.5-fold) than in the VE (+) group (0.8- to 8.7-fold). CONCLUSIONS: The combined use of a-TTP(-)(/)(-) mice and a VE-deficient diet leads to a severe deficiency of VE, enhances lipid peroxidation in the retina, and accelerates degenerative damage of the retina with age.