American journal of physiology. Endocrinology and metabolism最新文献

{"title":"Circulating interleukin-33 levels in obesity and type 2 diabetes: a systematic review and meta-analysis.","authors":"Ghalia Missous, Nicholas Van Panhuys","doi":"10.1152/ajpendo.00157.2024","DOIUrl":"10.1152/ajpendo.00157.2024","url":null,"abstract":"<p><p>Obesity and type 2 diabetes (T2D) are increasingly prevalent worldwide, and there is a critical need for novel interventions. Interleukin-33 (IL-33), an anti-inflammatory cytokine that regulates metabolism, is a promising biomarker for these conditions. The goal of this systematic review and meta-analysis is to examine the role of IL-33 in obesity and T2D, assessing its potential in predicting disease progression. A systematic search was performed on Scopus, Web of Science, and PubMed up until May 30, 2023. Each study was assessed for quality and sources of bias using the relevant critical appraisal checklists. Meta-analyses were conducted to compare IL-33 levels in individuals with obesity and T2D versus healthy controls (HC), and in obesity alone versus HC. Eighteen studies were included in the systematic review, and nine qualified for meta-analyses. The analyses showed insufficient evidence to suggest a significant difference in IL-33 levels between individuals with T2D and HC (mean difference, MD = -79.95, 95% CI [-241.38; 81.48]), with substantial heterogeneity across the studies observed (<i>I</i>² = 97.1%, τ² = 33,549.15). Similarly, there was insufficient evidence to suggest a significant difference between nondiabetic individuals with obesity and HC (MD = -7.31, 95% CI [-25.74; 11.13]), and heterogeneity was noted (<i>I</i>² = 86.2%, τ² = 342.45). There is insufficient evidence to indicate significant differences in IL-33 levels in individuals with T2D or obesity compared with HC. The results suggest a need for improved IL-33 measurement methods to reduce heterogeneity, enhancing understanding of the role of IL-33 in obesity and T2D, and informing future research and therapeutic strategies.<b>NEW & NOTEWORTHY</b> Our research finds an inconclusive relationship between IL-33 serum levels in individuals with type 2 diabetes (T2D) and nondiabetic individuals with obesity. In addition, we note a potential gender association with IL-33 serum levels. Further studies with larger cohorts are required to assess the significance of serum IL-33 in T2D and obesity. Urgent standardization is needed in IL-33 quantification and reporting methods for reliable comparisons.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E686-E699"},"PeriodicalIF":5.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Arginine vasopressin induces analgesic effects and inhibits pyramidal cells in the anterior cingulate cortex in spared nerve injured mice.","authors":"Hua-Xing Si, Xiao-Die Liu, Chao-Yi Sun, Shan-Ming Yang, Han Zhao, Xian-Xia Yan, Tao Chen, Pan Wang","doi":"10.1152/ajpendo.00361.2024","DOIUrl":"10.1152/ajpendo.00361.2024","url":null,"abstract":"<p><p>Neuropathic pain (NP) is a severe disease caused by a primary disease or lesion affecting the somatosensory nervous system. It is reported that NP is related to the increased activity of glutamatergic pyramidal cells and changed neural oscillations in the anterior cingulate cortex (ACC). Arginine vasopressin (AVP), a neurohypophyseal hormone, has been shown to cause pain-alleviating effects when applied to the peripheral system. However, the extent to which, and the mechanisms by which, AVP induces analgesic effects in the central nervous system remains unclear. In the present study, we observed that intranasal delivery of AVP inhibited mechanical pain, thermal pain, and spontaneous pain sensitivity in mice with spared nerve injury. Meanwhile, AVP application exclusively reduced the FOS expression in the pyramidal cells but not interneurons in the ACC. In vivo electrophysiological recording of the ACC further showed that AVP application not only inhibited the theta oscillation in local field potential analysis but also reduced the firing rate of spikes of pyramidal cells in the ACC in neuropathic pain mice. In summary, AVP induces analgesic effects by inhibiting neural theta oscillations and the spiking of pyramidal cells of the ACC in mice with neuropathic pain, which should provide new potential noninvasive methods for clinical treatment of chronic pain.<b>NEW & NOTEWORTHY</b> Following intranasal administration of arginine vasopressin (AVP), the pain thresholds for mechanical and thermal nociception significantly increased in the spared nerve injury (SNI) group; exogenous intranasal delivery of AVP improved the physical coordination of SNI mice, resulting in an analgesic effect; AVP treatment significantly reduced the increased firing rate of PYR^ACC of the SNI group; AVP treatment significantly inhibited the elevated theta oscillation in the anterior cingulate cortex (ACC) in SNI mice.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E700-E710"},"PeriodicalIF":5.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantifying protein kinetics in vivo: Influence of precursor dynamics on product labeling.","authors":"Huifang Yao, Seamus Kelley, Dan Zhou, Sophie VanSickle, Sheng-Ping Wang, Jennifer Piesvaux, Haihong Zhou, Hao Chen, David McKenney, David G McLaren, Jeanine E Ballard, Stephen F Previs","doi":"10.1152/ajpendo.00323.2024","DOIUrl":"https://doi.org/10.1152/ajpendo.00323.2024","url":null,"abstract":"<p><p>Protein kinetics can be quantified by coupling stable isotope tracer methods with mass spectrometry readouts; however, inter-connected decision points in the experimental design affect the complexity of the workflow and impact data interpretations. For example, choosing between a single bolus (pulse-chase) or a continuous exposure protocol influences subsequent decisions regarding when to measure and how to model the temporal labeling of a target protein. Herein, we examine the merits of in vivo tracer protocols, we direct attention towards stable isotope tracer experiments that rely on administering a single bolus since these are generally more practical to use as compared to continuous administration protocols. We demonstrate how the interplay between precursor and product kinetics impacts downstream analytics and calculations by contrasting fast vs slow turnover precursors (e.g. ¹³C-leucine vs ²H-water, respectively). Although the data collected here underscore certain advantages of using longer lived precursors (e.g. ²H- or ¹⁸O-water) the results also highlight the influence of tracer recycling on measures of protein turnover. We discuss the impact of tracer recycling and consider how the sampling interval is critical for interpreting studies. Finally, we demonstrate that tracer recycling does not limit the ability to perform back-to-back studies of protein kinetics. It is possible to run experiments in which subjects are used as their own controls even though the precursor and product remain labeled following an initial tracer dosing.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The roles of the gut microbiota, metabolites, and epigenetics in the effects of maternal exercise on offspring metabolism.","authors":"Jing Ren, Liyuan Zhou, Shunhua Li, Qian Zhang, Xinhua Xiao","doi":"10.1152/ajpendo.00200.2024","DOIUrl":"https://doi.org/10.1152/ajpendo.00200.2024","url":null,"abstract":"<p><p>Metabolic diseases, including obesity, dyslipidemia, and type 2 diabetes, have become severe challenges worldwide. The developmental origins of health and disease (DOHaD) hypothesis suggests that an adverse intrauterine environment can increase the risk of metabolic disorders in offspring. Studies have demonstrated that maternal exercise is an effective intervention for improving the offspring metabolic health. However, the pathways through which exercise works are unclear. It has been reported that the gut microbiota mediates the effect of maternal exercise on offspring metabolism, and epigenetic modifications have also been proposed to be important molecular mechanisms. Microbial metabolites can influence epigenetics by providing substrates for DNA or histone modifications, binding to G-protein coupled receptors to affect downstream pathways, or regulating the activity of epigenetic modifying enzymes. This review aims to summarize the intergenerational effect of maternal exercise and proposes that gut microbiota-metabolites-epigenetic regulation is an important mechanism by which maternal exercise improves offspring metabolism, which may yield novel targets for the early prevention and intervention of metabolic diseases.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early Exposure to a Cholinergic Receptor Blocking Agent Mitigates Adult Obesity and Protects Pancreatic Islet Function in Male Rats.","authors":"Ananda Malta, Camila Cristina Ianoni Matiusso, Lucas da Silva de Lima, Tatiane Aparecida Ribeiro, Laize Peron Tófolo, Douglas Lopes Almeida, Veridiana Mota Moreira, Isabela Peixoto Martins, Audrei Pavanello, Paulo Cezar de Freitas Mathias","doi":"10.1152/ajpendo.00191.2024","DOIUrl":"https://doi.org/10.1152/ajpendo.00191.2024","url":null,"abstract":"<p><p><i>Background:</i> We tested the hypothesis that attenuation of the circulating insulin level in rats during early life can provide sustained protection against diet-induced obesity and metabolic dysfunction in adulthood. <i>Methods:</i> Male Wistar rats received intraperitoneal scopolamine butylbromide (SB) during the first 12 days of suckling, whereas control rats received 0.9% saline injections. The animals were weaned on day 21 and fed a normal chow diet. At 60 days of age, the control and SB groups were fed a normal chow diet (ND; 4.5% fat) or a high-fat diet (HF; 35% fat) until 90 days of age to induce obesity and metabolic dysfunction. Insulin secretion, food intake, and body weight were measured. Pancreatic islet function, autonomic nervous system function, and glucose homeostasis were evaluated at 90 days of age. <i>Result:</i> During lactation, the plasma insulin concentration was significantly lower in the SB groups than in the control group. SB rats also exhibited reduced body weight. The HF diet resulted in obesity, glucose intolerance, insulin resistance, disruption of insulin secretion, and vagal hyperactivity in adult control rats. Remarkably, SB-treated HF diet rats showed attenuated body weight and adiposity, and did not develop diet-induced glucose/insulin imbalance. Additionally, vagal activity and adequate pancreatic islet insulin secretion were preserved. <i>Conclusion:</i> Offspring exposed to SB during early life are provided with long-lasting protection against obesity and metabolic complications induced by an HF diet. An attenuated circulating insulin level in early life may have far-reaching consequences on metabolic programming.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adipose Tissue Insulin Resistance in Children and Adolescents: Linking Glucose and Free Fatty Acid Metabolism to Hepatic Injury Markers.","authors":"J Bonet, Ram Weiss, Alfonso Galderisi, Chiara Dalla Man, Sonia Caprio, Nicola Santoro","doi":"10.1152/ajpendo.00270.2024","DOIUrl":"10.1152/ajpendo.00270.2024","url":null,"abstract":"<p><p>Obesity is one of the leading causes of the development of insulin resistance, diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD) in children. With the progression of insulin resistance, both glucose and free fatty acid (FFA) plasma levels are elevated, leading to cardiometabolic complications such as impaired glucose tolerance (IGT), type 2 diabetes and liver fat accumulation. Oral minimal models were used to estimate insulin sensitivity indexes (SI and SI_FFA) in 375 adolescents with obesity. Differences between NGT and IGT were assessed by using Mann-Whitney test, while the relationship between insulin sensitivities and plasma alanine transaminase (ALT) by using Spearman correlation and linear regression model of the log transformed variables. Also, 48 youth repeated the OGTT and the measurement of liver function test after ~1.3 years of follow-up. Insulin sensitivity indexes resulted to be statistically different in NGT compared to IGT (P<10^-6) and correlated to each other (ρ=0.7, P<10^-6). Lipolysis was completely suppressed after 30min in NGT, compared to 120min in IGT. SI and SI_FFA were both statistically correlated with ALT ρ= -0.19 (P<10^-3). Also, the percentages of variation of SI_FFA and ALT between the first and second visit correlated significantly (ρ= -0.47, P=0.002). FFA minimal model can be used to estimate adipose tissue lipolysis in youth with obesity. The relationship of SI and SI_FFA and with ALT, along with the progression of the impairment of adipose tissue insulin sensitivity, showed a systemic insulin resistance state, underlying the interrelationship of glucose and FFA metabolism and with hepatic damage.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pompe disease, a new approach to clearing out the trash.","authors":"Ann Louise Olson","doi":"10.1152/ajpendo.00379.2024","DOIUrl":"10.1152/ajpendo.00379.2024","url":null,"abstract":"","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E653-E654"},"PeriodicalIF":4.2,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142387265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Class B1 GPCRs: insights into multireceptor pharmacology for the treatment of metabolic disease.","authors":"Panjamaporn Sangwung, Joseph D Ho, Tessa Siddall, Jerry Lin, Alejandra Tomas, Ben Jones, Kyle W Sloop","doi":"10.1152/ajpendo.00371.2023","DOIUrl":"10.1152/ajpendo.00371.2023","url":null,"abstract":"<p><p>The secretin-like, class B1 subfamily of seven transmembrane-spanning G protein-coupled receptors (GPCRs) consists of 15 members that coordinate important physiological processes. These receptors bind peptide ligands and use a distinct mechanism of activation that is driven by evolutionarily conserved structural features. For the class B1 receptors, the C-terminus of the cognate ligand is initially recognized by the receptor via an N-terminal extracellular domain that forms a hydrophobic ligand-binding groove. This binding enables the N-terminus of the ligand to engage deep into a large volume, open transmembrane pocket of the receptor. Importantly, the phylogenetic basis of this ligand-receptor activation mechanism has provided opportunities to engineer analogs of several class B1 ligands for therapeutic use. Among the most accepted of these are drugs targeting the glucagon-like peptide-1 (GLP-1) receptor for the treatment of type 2 diabetes and obesity. Recently, multifunctional agonists possessing activity at the GLP-1 receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor, such as tirzepatide, and others that also contain glucagon receptor activity, have been developed. In this article, we review members of the class B1 GPCR family with focus on receptors for GLP-1, GIP, and glucagon, including their signal transduction and receptor trafficking characteristics. The metabolic importance of these receptors is also highlighted, along with the benefit of polypharmacologic ligands. Furthermore, key structural features and comparative analyses of high-resolution cryogenic electron microscopy structures for these receptors in active-state complexes with either native ligands or multifunctional agonists are provided, supporting the pharmacological basis of such therapeutic agents.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E600-E615"},"PeriodicalIF":5.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11559640/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141562433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic shifts in ratio of ucOcn to cOcn towards bone resorption contribute to age-dependent bone loss in male mice.","authors":"Matthew Bernhard, Obinna Okorie, Wei-Ju Tseng, Mengcun Chen, Julia Danon, Mingshu Cui, Elisabeth Lashbrooks, Yanmei Yang, Bin Wang","doi":"10.1152/ajpendo.00294.2024","DOIUrl":"https://doi.org/10.1152/ajpendo.00294.2024","url":null,"abstract":"<p><p>The study of the senile osteoporosis in men still lags significantly behind in women. The changes of protein molecule levels and their relationships with bone loss remain poorly understood. In the present study, we used C57BL/6J male mice at ages from 3 to 24 months to delineate the mechanisms of aging effects on bone loss. We employed the micro-computed tomography, mechanical testing, histomorphometry assays, and detection of serum levels of undercarboxylated osteocalcin (ucOcn) and carboxylated osteocalcin (cOcn) to assess bone mass changes and their relationships with ratios of ucOcn to cOcn in mice from different age groups. The results showed that mouse trabecular bone mass reduced gradually with age while cortical bone loss and mechanical property changes mostly occurred in advanced age. Our findings further demonstrated that the increase in osteoclast activity and the decrease in osteoblast function were significantly corelated with blood levels of ucOcn and cOcn, respectively. The dynamic metabolic changes of ucOcn to cOcn ratio were correlated with age-dependent bone loss in mice. In summary, metabolic shifts in ratio of ucOcn to cOcn towards bone resorption from young adult to elderly mice contribute to the pathogenesis of age-related bone loss. Simultaneously monitoring blood ratios of ucOcn to cOcn may be useful to predict the status of bone mass <i>in vivo</i>.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492943","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Postnatal surge of adipose-secreted leptin is a robust predictor of fat mass trajectory in mice.","authors":"Olga Horakova, Petra Janovska, Ilaria Irodenko, Jana Buresova, Inge van der Stelt, Sara Stanic, Eliska Haasova, Nivasini Shekhar, Tatyana Kobets, Jaap Keijer, Petr Zouhar, Martin Rossmeisl, Jan Kopecky, Kristina Bardova","doi":"10.1152/ajpendo.00237.2024","DOIUrl":"https://doi.org/10.1152/ajpendo.00237.2024","url":null,"abstract":"<p><p>The transient postnatal increase in circulating leptin levels, known as leptin surge, may increase later susceptibility to diet-induced obesity in rodents. However, the source of leptin during the surge needs to be better characterized, and the long-term effects of leptin are contradictory. Characterization of the interaction of leptin with the genetic background, sex, and other factors is required. Here, we focused on the impact of circulating leptin levels and several related variables, measured in 2- and 4-week-old (i) obesity-prone C57BL/6 (B6) and (ii) obesity-resistant A/J mice. In total, 264 mice of both sexes were used. Posttranscriptionally controlled leptin secretion from subcutaneous white adipose tissue, the largest adipose tissue depot in mice pups, was the primary determinant of plasma leptin levels. When the animals were randomly assigned standard chow or high-fat diet (HFD) between 12 - 24 weeks of age, the obesogenic effect of HFD-feeding was observed in B6 but not A/J mice. Only leptin levels at 2 weeks, i.e., close to the maximum in the postnatal leptin surge, correlated with both body weight (BW) trajectory throughout the life and adiposity of the 24-week-old mice. Leptin surge explained 13 and 7 % of the variance in BW and adiposity of B6 mice and 9 and 35 % of the variance in these parameters in A/J mice, with a minor role of sex. Our results prove the positive correlation between the leptin surge and adiposity in adulthood, reflecting the fundamental biological role of leptin. This role could be compromised in obese subjects.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}