{"title":"Cancer-specific cytotoxicity of Ringer's acetate solution irradiated by cold atmospheric pressure plasma.","authors":"Camelia Miron, Kenji Ishikawa, Satoshi Kashiwagura, Yuki Suda, Hiromasa Tanaka, Kae Nakamura, Hiroaki Kajiyama, Shinya Toyokuni, Masaaki Mizuno, Masaru Hori","doi":"10.1080/10715762.2023.2201390","DOIUrl":"https://doi.org/10.1080/10715762.2023.2201390","url":null,"abstract":"<p><p>Cold atmospheric pressure plasmas are promising medical tools that can assist in cancer treatment. While the medical pathology mechanism is substantially understood, knowledge of the contribution of reactive species formed in plasma and the mode of activation of biochemical pathways is insufficient. Herein, we present a concept involving antitumoral plasma-activated organics, which is envisaged to increase cytotoxicity levels against cancer cells. Ringer's acetate solution was irradiated by low-temperature plasma at atmospheric pressure and possible reaction pathways of the compound generation are presented. The chemical compounds formed by plasma treatment and their effects on non-tumorigenic breast epithelial cells (MCF-10A) and breast cancer cells (MCF-7) were investigated. The cell viability results have shown that plasma-derived compounds have both, stimulatory and inhibitory effects on cell viability, depending on the concentration of the generated compounds in the irradiated liquids. Previous studies have shown that oxidative stresses involving reactive oxygen and nitrogen species (RONS) can be used to kill cancer cells. Hence, while RONS offers promising first-step killing effects, cell viability results have shown that plasma-derived compounds, such as acetic anhydride and ethyl acetate, have the potential to play important roles in plasma-based cancer therapy.</p>","PeriodicalId":12411,"journal":{"name":"Free Radical Research","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2023-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9622168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Emil L Larsen, Andreas Andersen, Laura K Kjaer, Mie K Eickhoff, Marie Frimodt-Møller, Frederik Persson, Peter Rossing, Jens Lykkesfeldt, Filip K Knop, Tina Vilsbøll, Jørgen Rungby, Henrik E Poulsen
{"title":"Effects of two- and twelve-weeks sodium-glucose cotransporter 2 inhibition on DNA and RNA oxidation: two randomized, placebo-controlled trials.","authors":"Emil L Larsen, Andreas Andersen, Laura K Kjaer, Mie K Eickhoff, Marie Frimodt-Møller, Frederik Persson, Peter Rossing, Jens Lykkesfeldt, Filip K Knop, Tina Vilsbøll, Jørgen Rungby, Henrik E Poulsen","doi":"10.1080/10715762.2023.2213820","DOIUrl":"https://doi.org/10.1080/10715762.2023.2213820","url":null,"abstract":"<p><p>Animal studies have shown that SGLT2 inhibition decreases oxidative stress, which may explain the cardiovascular protective effects observed following SGLT2 inhibition treatment. Thus, we investigated the effects of two and twelve weeks SGLT2 inhibition on DNA and RNA oxidation. Individuals with type 2 diabetes (<i>n</i> = 31) were randomized to two weeks of treatment with the SGLT2 inhibitor empagliflozin treatment (25 mg once daily) or placebo. The primary outcome was changes in DNA and RNA oxidation measured as urinary excretion of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo), respectively. In another trial, individuals with type 2 diabetes (<i>n</i> = 35) were randomized to twelve weeks of dapagliflozin treatment (10 mg once daily) or placebo in a crossover study. Changes in urinary excretion of 8-oxodG and 8-oxoGuo were investigated as a <i>posthoc</i> analysis. Compared with placebo treatment, two weeks of empagliflozin treatment did not change urinary excretion of 8-oxodG (between-group difference: 0.3 nmol/24-hour (95% CI: -4.2 to 4.8)) or 8-oxoGuo (1.3 nmol/24-hour (95% CI: -4.7 to 7.3)). From a mean baseline 8-oxodG/creatinine urinary excretion of 1.34 nmol/mmol, dapagliflozin-treated individuals changed 8-oxodG/creatinine by -0.17 nmol/mmol (95% CI: -0.29 to -0.04) following twelve weeks of treatment, whereas placebo-treated individuals did not change 8-oxodG/creatinine (within-group effect: 0.10 nmol/mmol (95% CI: -0.02 to 0.22)) resulting in a significant between-group difference (<i>p</i> = 0.01). Urinary excretion of 8-oxoGuo was unaffected by dapagliflozin treatment. In conclusion, two weeks of empagliflozin treatment did not change DNA or RNA oxidation. However, a <i>posthoc</i> analysis revealed that longer-term dapagliflozin treatment decreased DNA oxidation. <b>Clinicaltrials.gov:</b> NCT02890745 and NCT02914691.HighlightsPlasma ferritin correlated with DNA and RNA oxidation in individuals with T2D.Twelve weeks dapagliflozin treatment decreased DNA oxidation.Dapagliflozin and empagliflozin treatment did not change RNA oxidation.Lipid peroxidation was unaffected by two weeks empagliflozin treatment.</p>","PeriodicalId":12411,"journal":{"name":"Free Radical Research","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2023-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9980737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ankit Mittal, Vinod Kumar Vashistha, Dipak Kumar Das
{"title":"Free radical scavenging activity of gallic acid toward various reactive oxygen, nitrogen, and sulfur species: a DFT approach.","authors":"Ankit Mittal, Vinod Kumar Vashistha, Dipak Kumar Das","doi":"10.1080/10715762.2023.2197556","DOIUrl":"https://doi.org/10.1080/10715762.2023.2197556","url":null,"abstract":"<p><p>Gallic acid is a well-recognized naturally occurring compound possessing antioxidant activities. The free radical scavenging ability of gallic acid for fifty reactive species, such as oxygen, nitrogen, and sulfur-containing species, has been studied using the formal hydrogen atom transfer mechanism. The theoretical studies have been conducted in the gas phase and aqueous solution at M05-2X/6-311++G** level using the density functional theory (DFT) calculations. The relative damaging potential of all the reactive species has been compared by investigating their hydrogen atom and electron affinity. Furthermore, a comparison of their relative reactivity was made by evaluating several global chemical reactivity descriptors. Additionally, the feasibility of scavenging the species by gallic acid has been studied by computing the redox potentials and equilibrium constants for the overall process in the aqueous solution.</p>","PeriodicalId":12411,"journal":{"name":"Free Radical Research","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2023-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9615960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Hypoxia induces dichotomous and reversible attenuation of T cell responses through reactive oxygen species-dependent phenotype redistribution and delay in lymphoblast proliferation.","authors":"Dharmendra Kumar Maurya, Deepak Sharma, Santosh Kumar Sandur","doi":"10.1080/10715762.2023.2178918","DOIUrl":"https://doi.org/10.1080/10715762.2023.2178918","url":null,"abstract":"<p><p>As T cells transit between blood, lymphoid organs, and peripheral tissues, they experience varied levels of oxygen/hypoxia in inflamed tissues, skin, intestinal lining, and secondary lymphoid organs. Critical illness among COVID-19 patients is also associated with transient hypoxia and attenuation of T cell responses. Hypoxia is the fulcrum of altered metabolism, impaired functions, and cessation of growth of a subset of T cells. However, the restoration of normal T cell functions following transient hypoxia and kinetics of their phenotype-redistribution is not completely understood. Here, we sought to understand kinetics and reversibility of dichotomous T cell responses under sustained and transient hypoxia. We found that a subset of activated T cells accumulated as lymphoblasts under hypoxia. Further, T cells showed the normal expression of activation markers CD25 and CD69 and inflammatory cytokine secretion but a subset exhibited delayed cell proliferation under hypoxia. Increased levels of reactive oxygen species (ROS) in cytosol and mitochondria were seen during dichotomous and reversible attenuation of T cell response under hypoxia. Cell cycle analysis revealed maximum levels of cytosolic and mitochondrial ROS in dividing T cells (in S, G2, or M phase). Hypoxic T cells also showed specific attenuation of activation induced memory phenotype conversion without affecting naïve and activated T cells. Hypoxia-related attenuation of T cell proliferation was also found to be reversible in an allogeneic leukocyte specific mixed lymphocyte reaction assay. In summary, our results show that hypoxia induces a reversible delay in proliferation of a subset of T cells which is associated with obliteration of memory phenotype and specific increase in cytosolic/mitochondrial ROS levels in actively dividing subpopulation. Thus, the transient reoxygenation of hypoxic patients may restore normal T cell responses.</p>","PeriodicalId":12411,"journal":{"name":"Free Radical Research","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9234601","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Growth acceleration of Nile tilapia at 21 to 31 weeks of age with plasma-treated air-supplied water.","authors":"Yoshihisa Ikeda, Ryo Fukushima, Kazuki Tange, Hideki Motomura, Taiju Saito, Masafumi Jinno","doi":"10.1080/10715762.2023.2185124","DOIUrl":"https://doi.org/10.1080/10715762.2023.2185124","url":null,"abstract":"<p><p>This study aimed to develop a technique to accelerate fish growth without using genetic modification or genome editing. We have prepared a reactor with four pairs of opposed electrodes and a high-voltage power supply for the discharge. An arc discharge generates a plasma-treated gas in the reactor. Plasma-treated gas containing active species such as nitric oxide (NO) was generated <i>via</i> an arc discharge in the atmosphere and inserted into an aquarium containing Nile tilapia. No ozone was detected in the plasma-treated gas. Plasma treatment gas was supplied to the 20 L tank at a flow rate of 10 L per minute for varying supply times. The supply duration of plasma-treated air to the water tank was 0.5, 2, 5, and 15 min. Tanks were prepared for each of these four conditions, and gas was supplied daily at the same time. We observed that on supplying plasma-treated gas to tilapia from the 16th week of age for 5 min daily, the average length of the fish at 31 weeks of age was ∼1.5 times longer than that of the control fish. All other supply time conditions were also found to grow acceleration over the control. In the 15-minute supply time condition, individual differences in body length were more significant. A sample had more growth suppression than controls. In other words, the results suggest that an excess supply of active species can cause growth inhibition. These results suggest that an optimal supply of plasma-treated gas has a growth-promoting effect on fish.Key policy highlightsThe fish growth was accelerated by supplying plasma-treated air to the tank.The amount of ozone in the plasma-treated air was below the detection limit, and a large amount of RNS, such as nitric oxide, was generated.After an experimental period of 16 to 31 weeks, the average length of fish in the most significant growth condition was 1.5 times that of the control fish.</p>","PeriodicalId":12411,"journal":{"name":"Free Radical Research","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9602330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Plasma activated Ringer's lactate solution.","authors":"Hiromasa Tanaka, Masaaki Mizuno, Kenji Ishikawa, Camelia Miron, Yasumasa Okazaki, Shinya Toyokuni, Kae Nakamura, Hiroaki Kajiyama, Masaru Hori","doi":"10.1080/10715762.2023.2182663","DOIUrl":"https://doi.org/10.1080/10715762.2023.2182663","url":null,"abstract":"<p><p>Low-temperature plasma (LTP) has been widely used in life science. Plasma-activated solutions were defined as solutions irradiated with LTP, and water, medium, and Ringer's solutions have been irradiated with LTP to produce plasma-activated solutions. They contain chemical compounds produced by reactions among LTP, air, and solutions. Reactive oxygen and nitrogen species (RONS) are major components in plasma-activated solutions and recent studies revealed that plasma-activated organic compounds are produced in plasma-activated Ringer's lactate solution (PAL). Many <i>in vitro</i> and <i>in vivo</i> studies demonstrated that PAL exhibits anti-tumor effects on cancers, and biochemical analyses revealed intracellular molecular mechanisms of cancer cell death by PAL.</p>","PeriodicalId":12411,"journal":{"name":"Free Radical Research","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9586584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mengna Zuo, Ruiying Tong, Xiaoying He, Yang Liu, Jiwei Liu, Shujun Liu, Ying Liu, Junwei Cao, Libing Ma
{"title":"FOXO signaling pathway participates in oxidative stress-induced histone deacetylation.","authors":"Mengna Zuo, Ruiying Tong, Xiaoying He, Yang Liu, Jiwei Liu, Shujun Liu, Ying Liu, Junwei Cao, Libing Ma","doi":"10.1080/10715762.2023.2190862","DOIUrl":"https://doi.org/10.1080/10715762.2023.2190862","url":null,"abstract":"<p><p>High concentrations of antioxidants can exert pro-oxidative effects, elevate the level of intracellular reactive oxygen species (ROS), and cause oxidative stress in cells. We previously found that high concentrations of curcumin, a natural polyphenol antioxidant, elevated ROS levels and upregulated the expression of histone deacetylase 1 (HDAC1) in human gastric cancer cells (hGCCs); however, its potential mechanisms and subsequent functions have not been elucidated. In the present study, we treated hGCCs with high concentrations of curcumin, detected several indicators of oxidative stress, and investigated the mechanism of curcumin-treatment-mediated HDAC1 upregulation and its effect on histone acetylation. The results showed that curcumin treatment caused oxidative stress in hGCCs and upregulated HDAC1/2 expression <i>via</i> the forkhead box O (FOXO) signaling pathway, ultimately leading to the deacetylation of histones in hGCCs. Moreover, HDAC1/2 mediates the deacetylation of FOXOs and promotes their transcription activities, implying a positive feedback loop between FOXOs and HDAC1/2. These findings present a mechanism by which oxidative stress induces histone deacetylation in hGCCs.</p>","PeriodicalId":12411,"journal":{"name":"Free Radical Research","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9239061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Low-temperature plasma as magic wand to differentiate between the good and the evil.","authors":"Shinya Toyokuni, Hao Zheng, Yingyi Kong, Kotaro Sato, Kae Nakamura, Hiromasa Tanaka, Yasumasa Okazaki","doi":"10.1080/10715762.2023.2190860","DOIUrl":"https://doi.org/10.1080/10715762.2023.2190860","url":null,"abstract":"<p><p>Plasma is the fourth physical state of matter, characterized by an ionized gaseous mixture, after solid, liquid, and gas phases, and contains a wide array of components such as ions, electrons, radicals, and ultraviolet ray. Whereas the sun and thunder are typical natural plasma, recent progress in the electronics enabled the generation of body-temperature plasma, designated as low-temperature plasma (LTP) or non-thermal plasma since the 1990s. LTP has attracted the attention of researchers for possible biological and medical applications. All the living species on earth utilize water as essential media for solvents and molecular transport. Thus, biological application of LTP naturally intervenes water whether LTP is exposed directly or indirectly, where plasma-activated lactate (PAL) is a standard, containing H<sub>2</sub>O<sub>2</sub>, NO<sub>2</sub><sup>-</sup> and other identified molecules. Electron spin resonance and immunohistochemical studies demonstrated that LTP exposure is a handy method to load local oxidative stress. Cancer cells are characterized by persistent self-replication and high cytosolic catalytic Fe(II). Therefore, both direct exposure of LTP and PAL can provide higher damage to cancer cells in comparison to non-tumorous cells, which has been demonstrated in a variety of cancer types. The cell death mode is either apoptosis or ferroptosis, depending on the cancer-type. Thus, LTP and PAL are expected to work as an additional cancer therapy to the established guideline protocols, especially for use in somatic cavities or surgical margins.</p>","PeriodicalId":12411,"journal":{"name":"Free Radical Research","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9239056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Exposure of low-temperature plasma after vaccination in tongue promotes systemic IgM induction against spike protein of SARS-CoV-2.","authors":"Kotaro Sato, Kouki Fujii, Hiromasa Tanaka, Masaru Hori, Hideharu Hibi, Shinya Toyokuni","doi":"10.1080/10715762.2023.2190486","DOIUrl":"https://doi.org/10.1080/10715762.2023.2190486","url":null,"abstract":"<p><p>COVID-19 has been pandemic since 2020 with persistent generation of new variants. Cellular receptor for SARS-CoV-2 is angiotensin-converting enzyme 2 (ACE2), where transmembrane serine protease-2 (TMPRSS2) is essential for viral internalization. We recently reported abundant expression of ACE2 and TMPRSS2 in the oral cavity of humans and mice. Therefore, oral cavity may work for COVID-19 infection gates. Here we undertook to evaluate whether vaccination in the tongue harbors any merit in comparison to subcutaneous injection. Low-temperature plasma (LTP) is the fourth physical state of matters with ionization above gas but at body temperature. LTP provides complex chemistry, eventually supplying oxidative and/or nitrosative stress on the interface. LTP-associated cellular death has been reported to cause apoptosis and/or ferroptosis. However, there is few data available on immunogenicity retention after LTP exposure. We therefore studied the effect of LTP exposure after the injection of keyhole limpet hemocyanin (KLH) or spike 2 protein of SARS-CoV-2 to the tongue of six-week-old male <i>BALB/c</i> mice, compared to subcutaneous vaccination. Whereas LTP did not change the expression of ACE2 and TMPRSS2 in the tongue, repeated LTP exposure after tongue vaccination significantly promoted systemic and specific IgM production at day 11. In contrast, repeated LTP exposure after subcutaneous vaccination of KLH decreased systemic IgM production. Of note, tongue injection produced significantly higher titer of IgM and IgG in the case of KLH. In conclusion, LTP significantly reinforced humoral immunity by IgM after tongue injection. Vaccination to the tongue can be a novel strategy to acquire immediate immunity.</p>","PeriodicalId":12411,"journal":{"name":"Free Radical Research","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9239057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Iron-loaded extracellular vesicles: angel or demon?","authors":"Huimin Chen, Yuhan Tang","doi":"10.1080/10715762.2023.2191813","DOIUrl":"https://doi.org/10.1080/10715762.2023.2191813","url":null,"abstract":"<p><p>Extracellular vesicles (EVs) are identified as a non-classical way to mediate iron efflux except ferroportin. Interestingly, recent studies indicated that EVs pathway is a novel way involved in iron efflux. Mitochondria-derived vesicles (MDVs) are the potential mediator to load mitochondrial iron into EVs. Additionally, iron-replete cells resist excess iron-induced damage by secreting iron-loaded EVs, and the uptake of these EVs induces oxidative damage in the recipient cell. Importantly, iron-loaded EVs play a key role in aberrant iron distribution, which drives the progress of diseases like nonalcoholic fatty liver disease (NAFLD) and neurodegenerative diseases. Herein, we summarize extant research on intracellular iron export with an emphasis on EVs and put our eyes on the relationship between iron-loaded EVs with both parent and target cells. Iron-loaded EVs will be an important avenue for later research on their vital role in iron redistribution.</p>","PeriodicalId":12411,"journal":{"name":"Free Radical Research","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9232951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}