Dose-Response最新文献

{"title":"Mechanism Study on Radiosensitization Effect of Curcumin in Bladder Cancer Cells Regulated by Filamin A","authors":"Zhenfan Wang, S. He, Minjun Jiang, Xue-Hua Li, Na Chen","doi":"10.1177/15593258221100997","DOIUrl":"https://doi.org/10.1177/15593258221100997","url":null,"abstract":"Objective To study the radiosensitization effect of curcumin, a natural product with anti-inflammatory and anti-cancer properties, in bladder cancer cells and identify the specific role of FLNA gene in that process. Methods CCK-8 method was initially adopted to identify the proper interventional concentration of curcumin. T24 bladder cancer cells were subjected to CCK-8, flow cytometry, and colony formation assay to study the cell biological behaviors under different interventions. γ-H2AX test was performed to test the level of damage in T24 cells. RT-qPCR and Western blot were conducted to measure FLNA mRNA and protein levels. Results Low-dose curcumin (10, 20 μM) following X-ray exposure resulted in increased DNA damage, augmented apoptosis, and reduced proliferation of T24 cells. Certain radiosensitization was demonstrated when curcumin was applied at 10 μM. Additionally, elevation of FLNA gene and protein levels was also indicated upon combination treatment. Conclusion Low-dose curcumin has certain radiosensitization effect in bladder cancer, where FLNA plays a certain regulatory role.","PeriodicalId":11285,"journal":{"name":"Dose-Response","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2022-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47943015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Feasibility of Enhancing Skin Permeability of Acyclovir through Sterile Topical Lyophilized Wafer on Self-Dissolving Microneedle-Treated Skin","authors":"Uzair Nagra, K. Barkat, Muhammad Aleem Ashraf, M. Shabbir","doi":"10.1177/15593258221097594","DOIUrl":"https://doi.org/10.1177/15593258221097594","url":null,"abstract":"Acyclovir is an antiviral drug that is frequently prescribed for the herpes virus. However, the drug requires frequent dosing due to limited bioavailability (10–26.7%). The rationale of the present study was to develop a self-dissolving microneedle system for local and systemic delivery of acyclovir using a topical lyophilized wafer on microneedle-treated skin to provide the drug at the site of infection. The microneedles prepared with hydroxypropyl methylcellulose (HPMC) (8% w/w) or HPMC (8% w/w)-polyvinyl pyrrolidone (PVP) (30% w/w) penetrated excised rat skin, showing sufficient mechanical strength and rapid polymer dissolution. The topical wafer was prepared with acyclovir (40% w/w; equivalent to 200 mg of drug), gelatin (10% w/w), mannitol (5% w/w), and sodium chloride (5% w/w). The uniform distribution of acyclovir within the wafer in an amorphous form was confirmed by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). No polymer–drug interaction was evident in the lyophilized wafer as per Fourier transform infrared spectroscopy (FTIR) analysis. The wafer showed a sufficiently porous structure for rapid hydration as per scanning electron microscopy (SEM) analysis. During ex-vivo analysis, the skin was pre-treated with a self-dissolving microneedle array for 5 minutes, and the wafer was placed on this microporated-skin. Topical wafer provided ∼7–11 times higher skin concentration than the ID99 reported with a lower lag-time. Based on in-vivo testing, ∼2.58 µg/ml of Cmax was achieved in rabbit plasma during 24 hours’ study. Our findings suggest that the self-dissolving microneedle-assisted topical wafer, proposed for the first time, would be efficacious against the infection residing in the skin layer and for systemic therapy.","PeriodicalId":11285,"journal":{"name":"Dose-Response","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2022-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46058895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of Diclofenac and Andrographolide Combination on Carrageenan-Induced Paw Edema and Hyperalgesia in Rats","authors":"Augustine Tandoh, C. Danquah, C. Benneh, D. W. Adongo, Eric Boakye-Gyasi, E. Woode","doi":"10.1177/15593258221103846","DOIUrl":"https://doi.org/10.1177/15593258221103846","url":null,"abstract":"Studies into drug combination at low doses are a promising approach to the management of pain and inflammation. The aim of this study was to evaluate the anti-edema and anti-hyperalgesic effects of a combination of diclofenac and andrographolide. Male Sprague-Dawley rats were first treated with diclofenac or andrographolide alone (3–100 mg/kg), as well as a combination of the 2 drugs. Carrageenan was then injected into the right hind paw of rats, and changes in paw volume and sensitivity to mechanical (von Frey) and thermal (Hargreaves test) stimuli measured. Results showed drug combination produced synergistic effects at reducing paw edema especially at lower doses, with a Loewe synergy score of 13.02 ± 8.75 in SynergyFinder and a combination index of .41 ± .18 after isobolographic analysis. Again synergy scores for decreasing response to 1.0 and 3.6 g force application of von Frey filaments after drug combination were 10.127 ± 5.68 and 8.554 ± 6.53, respectively, in SynergyFinder. Synergistic effects were also seen after drug combination in the Hargreaves test with a synergy score of 5.136 ± 16.38. In conclusion, combination of diclofenac with andrographolide showed better pharmacologic effects after carrageenan injection and was more synergistic at low-dose combinations.","PeriodicalId":11285,"journal":{"name":"Dose-Response","volume":"20 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2022-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41339117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exaggerated Risk Perception of Low-Dose Radiation: Motives and Mechanisms","authors":"Sergei V. Jargin","doi":"10.1177/15593258221103378","DOIUrl":"https://doi.org/10.1177/15593258221103378","url":null,"abstract":"Radiation is a known carcinogen because of the world-wide health scare that was created in 1960. However, there is no evidence that radiation is a carcinogen below some threshold. Prof. Edward Calabrese pursued the emergence of the linear no-threshold theory (LNT) and questioned whether it ever had a scientific basis. After the Chernobyl accident many publications appeared with LNT-based prognostications, for example, of millions of victims from nuclear accidents, reviewed previously. Apparently, certain writers’ exaggeration of medical and ecological consequences of the moderate anthropogenic increase in the background radiation contributed to a strangulation of the atomic energy, which was in the interests of fossil fuel producers. Some dose-effect correlations may be attributed to a dosedependent selection, self-selection and recall bias noticed in exposed cohorts. It can be reasonably assumed that individuals, knowing that they had higher doses would be more motivated to undergo medical examinations being at the same time given more attention. Therefore, diagnosis of diseases would be on the average more likely in people with higher doses. For example, the dose-dependent increase in incidence of cardioand cerebrovascular diseases among Mayak Production Association (MPA) workers was not accompanied by a corresponding elevation of mortality, which can be attributed to a more frequent recording of mild cases in people with higher doses. The excess relative risk per unit dose for leukemia amongMPAworkers, using incidence data, has been considerably higher than that using mortality data. A more efficient detection of latent leukemia with occasional registration of unverified cases is a probable explanation. Elevated risks of non-malignant diseases have been found in Chernobyl, MPA, and Techa River populations. For example, the excess relative risk of cerebrovascular diseases, per unit dose, among MPAworkers was reportedly higher than in the atomic bomb survivors, where the exposure was acute and thus would be expectedly higher. Remarkably, the dosedependent incidence increase in cerebrovascular and ischemic heart disease among MPA workers was not accompanied by any increase in mortality, which can be explained by a dosedependent diagnostic efficiency with recording of mild and borderline cases in people with higher dose estimates. According to the same researchers, the incidence of cerebrovascular diseases was significantly increased among MPA workers with cumulative external doses ≥ 0.1 Gy. For comparison, UNSCEAR could not make any conclusions about immediate causal relationships between doses ≤ 1–2 Gy and excess incidence of cardiovascular or generally of non-malignant diseases. The value 1–2 Gy may be an undervaluation due to bias in epidemiological studies. Doubtful correlations between low-dose exposures and nonmalignant conditions call into question the cause–effect character of such correlations for malignancies reported by the same resear","PeriodicalId":11285,"journal":{"name":"Dose-Response","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2022-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43113314","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stimulation of Erythrocyte Membrane Blebbing by Bifenthrin Induced Oxidative Stress","authors":"F. Mukhtar, K. Jilani, I. Bibi, Zahid Mushataq, Maham Abdul Bari Khan, María Fátima","doi":"10.1177/15593258221076710","DOIUrl":"https://doi.org/10.1177/15593258221076710","url":null,"abstract":"Background Bifenthrin is an insecticide and anti-estrogenic compound primarily used to control residential pests by depolarizing sodium gated voltage channels in the nervous system. Eryptosis, the suicidal death of erythrocytes, featured by PS exposure, membrane blebbing and cell shrinkage. Anemia is an outcome of uncontrolled eryptosis. Research Design In this study, erythrocytes were treated with different concentrations (.5-1-1.5 μM) of bifenthrin over a period of 48 hours. In order to investigate the oxidative stress induced by bifenthrin, catalase, superoxide dismutase, and glutathione peroxidase activities were investigated. Results Obtained data indicated the decrease in the enzymes (superoxide dismutase, glutathione peroxidase, and catalase) activities in bifenthrin treated cells at 1 μM concentration. In addition, measurement of cell size and confirmation of the role of calcium in the stimulation of the eryptotic activity of bifenthrin were performed. A significant increase in mean cell volume was found in the presence of bifenthrin and a decrease in mean cell volume in the presence of calcium channel blocker was observed. Similarly, there was also a significant increase in the percentage of hemolysis indicating the necrotic activity of bifenthrin. Conclusions It is concluded that the indicated doses of bifenthrin triggered oxidative stress which may lead to early cell death by eryptosis and hemolysis.","PeriodicalId":11285,"journal":{"name":"Dose-Response","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44283684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Green Synthesis of Silver Nanoparticles (AgNPs), Structural Characterization, and their Antibacterial Potential","authors":"Muhammad Asif, R. Yasmin, R. Asif, Ana Ambreen, Madiha Mustafa, Shehla Umbreen","doi":"10.1177/15593258221088709","DOIUrl":"https://doi.org/10.1177/15593258221088709","url":null,"abstract":"Background In the field of nanotechnology, the metallic nanoparticles are of remarkable interest because of their unique electronic, magnetic, chemical, and mechanical properties. Purpose: In the present work, silver nanoparticles (AgNPs) were synthesized using bio-reduction method. Research Design: Silver nitrate was used as metallic precursor and the extract of Moringa oleifera leaves with different concentrations was used as reducing as well capping agent. The extract exhibited strong potential in rapid reduction of silver ions for the synthesis of silver nanoparticles. The synthesized silver nanoparticles were characterized by UV-visible spectroscopy, X-ray diffraction (XRD), and scanning electron microscopy (SEM) techniques. Results: The absorption SPR peaks appeared in the range of 415 to 439 nm. SEM analysis exhibited that particles were spherical in shape with size distribution range from 10 nm to 25 nm. The synthesized silver nanoparticles were pure crystalline in nature as confirmed by the XRD spectra with average crystallite size 7 nm. In vitro antibacterial activity of the prepared silver nanoparticles colloidal samples as well the extract was studied using different concentrations of AgNPs (C1 = 100 μg/ml, C2 = 50 μg/ml, C3 = 25 μg/ml) by well diffusion method against Gram negative Escherichia coli. The antibacterial performance was assessed by measuring the zone of inhibition (ZOI). Conclusions The results suggested that AgNPs prepared by green approach can be considered as an alternative antibacterial agent.","PeriodicalId":11285,"journal":{"name":"Dose-Response","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46222191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dose-dependent Spasmolytic, Bronchodilator, and Hypotensive Activities of Panicum miliaceum L.","authors":"F. Saqib, Arwa A. Al-Huqail, Memona Asma, L. Chicea, M. Hogea, M. Irimie, C. Gavris","doi":"10.1177/15593258221079592","DOIUrl":"https://doi.org/10.1177/15593258221079592","url":null,"abstract":"Panicum miliaceum L. is a medicinally effective plant used in indigenous system of medicine for a variety of ailments. However, there is no comprehensive study explaining its effectiveness in gastrointestinal tract, respiratory, and cardiovascular system ailments. This study was designed to validate the pharmacological basis for the folkloric use of Panicum miliaceum L. in diarrhea, asthma, and hypertension. Panicum miliaceum extract was analyzed to detect the presence of bioactive compounds by HPLC. The isolated rabbit jejunum, trachea, and aorta were used for in vitro experiments using tissue bath assembly coupled with Power Lab data acquisition system to explore their relative effects. In-vivo experiments were performed for anti-diarrheal activity. HPLC analysis revealed the presence of gallic acid, butylated hydroxytoluene, catechin, and quercetin. Concentration dependent activities were observed by relaxing K+ (low) induced contractions having spasmolytic effect with EC50 = .358 ± .052, bronchodilator (EC50 = 2.483 ± .05793), and vasorelaxant (EC50 = .383 ± .063), probably due to the ATP dependent potassium channel activation. It was confirmed through pre-exposure of glibenclamide (specific ATP-dependent K+ channel blocker) having similarities with cromakalim. Pm.Cr revealed its antidiarrheal via in vivo experiments on rats. This study indicates that Panicum miliaceum has antidiarrheal, spasmolytic, bronchodilator, and vasorelaxant activities probably due to the ATP dependent K+ channel activation.","PeriodicalId":11285,"journal":{"name":"Dose-Response","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46502463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Revisiting the Paradox of Smoking: Radioactivity in Tobacco Smoke or Suppressing the SARS-CoV-2 Receptor, Angiotensin-Converting Enzyme 2, via Aryl-Hydrocarbon Receptor Signal?","authors":"S. Mortazavi, J. Bevelacqua, Payman Rafiepour, A. Ghadimi-Moghadam, Pooya Saraie, Najmeh Jooyan, Seyedeh Hanieh Mortazavi, S. M. Javad Mortazavi, J. Welsh","doi":"10.1177/15593258221075111","DOIUrl":"https://doi.org/10.1177/15593258221075111","url":null,"abstract":"Despite current controversies, some reports show a paradoxical mitigating effect associated with smoking in individuals with symptomatic COVID-19 compared to the general population. To explain the potential mechanisms behind the lower number of hospitalized COVID-19 patients, it has been hypothesized that cigarette smoking may reduce the odds of cytokine storm and related severe inflammatory responses through cholinergic-mediated anti-inflammatory mechanisms. Japanese scientists have recently identified a potential mechanism behind the lower numbers of COVID-19 cases amongst smokers compared to non-smokers. However, we believe that this mitigative effect may be due to the relatively high concentration of deposited energy of alpha particles emitted from naturally occurring radionuclides such as Po-210 in cigarette tobacco. Regarding COVID-19, other researchers and our team have previously addressed the anti-inflammatory and immune-modulating effects of low doses of ionizing radiation. MC-simulation using the Geant4 Monte Carlo toolkit shows that the radiation dose absorbed in a spherical cell with a radius of .9 μm for a single 5.5 MeV alpha particle is about 5.1 Gy. This energy deposition may trigger both anti-inflammatory and anti-thrombotic effects which paradoxically lower the risk of hospitalization due to COVID-19 in smokers.","PeriodicalId":11285,"journal":{"name":"Dose-Response","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47164837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Positive Cofactor 4 as a Potential Radiation Biodosimeter for Early Assessment","authors":"Le Ma, Q. Gong, Gaoyu Liu, Jieping Chen, Yu Wang, P. Luo, C. Shi","doi":"10.1177/15593258221081317","DOIUrl":"https://doi.org/10.1177/15593258221081317","url":null,"abstract":"During a major radiation event, a large number of people need to be rapidly assessed for radiation damage to ensure effective medical treatment and efficient use of medical resources. However, current techniques cannot meet the requirement of rapid detection of large quantities of samples in an emergency. It is essential to develop rapid and accurate radiation biodosimeters in peripheral blood. Here, we identified radiation sensitive genes in mice by RNA sequencing and evaluated their utility as radiation biodosimeters in human cell lines. Mice were subjected to gamma-irradiation with different doses (0–8 Gy, .85 Gy/min), and the tail venous blood was analyzed by RNA sequencing. We have identified 5 genes with significantly differential expression after radiation exposure. We found that positive cofactor 4(PC4) had well correlation with radiation dose in human lymphoblastoid cell line after irradiation. The relative expression of PC4 gene showed a good linear correlation with the radiation dose after 1–5 Gy irradiation (.85 Gy/min). PC4 gene can be rapidly recruited to the DNA damage sites faster than γ-H2AX after radiation in immunofluorescence detection. In conclusion, PC4 may be represented as new radiation biological dosimeter for early assessment.","PeriodicalId":11285,"journal":{"name":"Dose-Response","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46032326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dexmedetomidine Protects Against Kidney Fibrosis in Diabetic Mice by Targeting miR-101-3p-Mediated EndMT","authors":"Li Song, Songling Feng, Hao Yu, Sen Shi","doi":"10.1177/15593258221083486","DOIUrl":"https://doi.org/10.1177/15593258221083486","url":null,"abstract":"Objective: Our main purpose is to explore the effect and mechanism of Dexmedetomidine (DEX) in diabetic nephropathy fibrosis. Methods: Diabetic model was established by intraperitoneal injection of streptozotocin (STZ) treated CD-1 mice and high glucose cultured human dermal microvascular endothelial cells (HMVECs). Immunofluorescence was used to detect renal endothelial-mesenchymal transition (EndMT); Hematoxylin and Eosin (HE) staining and Masson’s Trichrome Staining (MTS) was used to analyze renal fibrosis; CCK-8 was used to evaluate cell viability; Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to assess the expression of miR-101-3p; Western blots were utilized to judge the protein expression levels of EndMT, extracellular matrix and TGF-β1/Smad3 signal pathway. Results: In this study, we first found that the protective effect of DEX on DN was related to EndMT. DEX alleviated kidney fibrosis by inhibiting EndMT in diabetic CD-1 mice. DEX could also inhibit high glucose-induced HMVECs EndMT. Then, we confirmed that miR-101-3p was the regulatory target of DEX. The expression of miR-101-3p was decreased in diabetic CD-1 mice and high glucose-induced HMVECs. After DEX treatment, the miR-101-3p increased, and the inhibition of miR-101-3p could counteract the protective effect of DEX and aggravate the EndMT. Finally, we found that the TGF- β1/Smad3 signal pathway was involved in the protective effect of DEX on DN. DEX inhibited the activation of TGF-β1/Smad3 signal pathway. On the contrary, inhibiting miR-101-3p promoted the expression of TGF-β1/Smad3. Conclusion: DEX protects kidney fibrosis in diabetic mice by targeting miR-101-3p-mediated EndMT.","PeriodicalId":11285,"journal":{"name":"Dose-Response","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48487125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}