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Jing Huang, Zhijian Lin, Yu Wang, Xueli Ding, Bing Zhang School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, People’s Republic of ChinaCorrespondence: Bing Zhang, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, People’s Republic of China, Email zhangb@bucm.edu.cnBackground: Hyperuricemia (HUA) is a major public health issue with a high prevalence worldwide. Wuling San (WLS) is an effective treatment for HUA. However, the active compounds and the related mechanism are unclear. In this study, we aimed to explore the active compounds and the underlying pharmacological mechanisms of WLS against HUA.Methods: First, a network pharmacology approach was used to detect active compounds of WLS, and potential targets and signaling pathways involved in the treatment of HUA were predicted. Then, a molecular docking strategy was used to predict the affinity between active compounds and key targets. Finally, to verify the prediction, the HUA rat model was established.Results: 49 active compounds with 108 common targets were obtained. Besides, cerevisterol, luteolin, ergosterol peroxide, beta-sitosterol, and sitosterol were identified as key active compounds. In PPI analysis, TNF, IL6, CASP3, PPARG, STAT3, and other 12 core targets were obtained. GO enrichment analysis indicated that WLS was likely to interfere with oxidative stress in the treatment of HUA, and KEGG enrichment analysis indicated multiple inflammation-related signaling pathways possibly involved in the treatment of HUA by WLS, including TNF, and NOD-like receptor, HIF-1, PI3K-Akt, and IL-17 signaling pathways. The results of molecular docking indicated that the active compounds had good binding properties to their key targets. In the validation experiments, WLS significantly reduced the levels of serum uric acid (SUA) and serum malondialdehyde (MDA). Moreover, WLS not only significantly increased the levels of total antioxidant capacity (T-AOC) and superoxide dismutase (SOD), but also inhibited the expression of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6).Conclusion: In the present study, we demonstrate that WLS has multicomponent, multitarget, and multi-pathway properties in the treatment of HUA. Its potential capability to reduce SUA could be ascribed to oxidative stress improvement and inflammation inhibition.Keywords: hyperuricemia, Wuling San, oxidative stress, inflammation

Patients with inflammatory bowel disease tend to have malnutrition, frailty, and low muscle mass, which impact on poor clinical outcomes. Abdominal computed tomography is frequently used to assess body composition. This study aimed to evaluate the association of low muscle mass and readmission within 1 year in patients with inflammatory bowel disease during hospitalization and follow-up.A total of 211 patients with inflammatory bowel disease who had undergone computed tomography scans were included retrospectively. They were divided into subgroups based on disease activity. The male patients with skeletal muscle index ≤45.4 cm2/m2 and the female patients with skeletal muscle index ≤ 34.3 cm2/m2 were considered to have low muscle mass. Sociodemographic, clinical, and prognostic data were recorded. The analyses were done using the Statistical Package for the Social Sciences 25.0 software.The prevalence rate of low muscle mass was 64.7%. Low body mass index and hemoglobin, high erythrocyte sedimentation rate, smoking, and gastrointestinal surgery history were risk factors for low muscle mass (P.05). Patients using steroids and biologics and using them more than 7 months were prone to develop low muscle mass and readmission (P.05), while patients using immunomodulators were not. Inflammatory bowel disease patients with visceral fat area/subcutaneous fat area ≥0.71 were likely to readmit within 1 year than those with visceral fat area/subcutaneous fat area0.71 (P.05). Overweight or obese inflammatory bowel disease patients with low muscle mass had a shorter time to readmission than those without low muscle mass (P.05).Overweight/obese inflammatory bowel disease patients with low muscle mass and patients using steroids and biologics have shorter time to readmission within 1 year regardless of disease activity.

Background The significance of endoscopic evaluation in the diagnosis and management of ulcerative colitis (UC) has been widely recognized. Over the years, scholars have established several endoscopic scores. Herein, we assessed the clinical application value of the Mayo Endoscopic Subscore (Mayo ES), the Degree of Ulcerative Colitis Burden of Luminal Inflammation (DUBLIN) score, and the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) score in UC patients, by comparing their correlation with disease activity and their predictive potential for treatment response and clinical outcomes. Methods UC patients hospitalized from September 2015 to September 2019 were retrospectively analysed. We employed Spearman's rank correlation coefficient to assess the linear association of the assessed endoscopic scores with the clinical parameters. The receiver-operating characteristic curve was applied to evaluate the predictive capabilities of the endoscopic scores for treatment escalation and 1-year readmission. Results A total of 178 patients were enrolled; most of them (82%) suffered moderate or severe colitis. Among them, 48 (27%) patients received treatment escalation and 59 (33%) were readmitted within 1 year. The DUBLIN and UCEIS scores demonstrated higher correlations with clinical parameters than the Mayo ES. The DUBLIN scores significantly differed between patients with mild, moderate, and severe colitis (all P 0.05). Conclusion This study demonstrates that both the DUBLIN and UCEIS scores outperform the Mayo ES in assessing disease severity and predicting treatment response and clinical outcomes in UC patients.

The effect of grassland conversion to cropland on the incorporation of N into microbial residues remains unclear. We analyzed for amino sugars, as a microbial residue biomarker, and adopted stable-isotope-probing technique to trace the assimilation of 15NH4+-N (added in the form of 15 N-labelled ammonium sulphate) into amino sugars with or without organic C sources (glucose and crop residue) in native grassland and converted cropland soils over a 65-day period. Total 15 N-amino sugars in the cropland were significantly decreased by 16–29% compared to grassland regardless of C source. This suggests that the microbial assimilation of available N into microbial residues was decreased, after conversion, and that stronger responses to substrate inputs occurred in the grassland soils. The addition of available and complex C substrates triggered divergent accumulation patterns of 15 N-amino sugars, indicating that C availability was a major driver for microbial N immobilization. Meanwhile, the conversion of grassland led to suppressed N immobilization activity of both fungi and bacteria. These results suggest that long-term land-use change could considerably affect the N utilization by fungi and bacteria during their anabolic processes, which may exert long-lasting impacts on soil organic N storage.

In the traditional viewpoint, inhibitory and excitatory effects always induce opposite responses. In the present study, the enhanced bursting activities induced by excitatory autapses, which are consistent with the recent experimental observations, and those induced by inhibitory autapses, which is a paradoxical phenomenon, were simulated using the Chay model. The same bifurcations and different ionic currents for the same responses were acquired with fast-slow variable dissection and current decomposition, respectively. As the inhibitory or excitatory autaptic conductance increased, the ending phase of the burst related to a homoclinic bifurcation of the fast subsystem changed to widen the burst duration to contain more spikes, which was induced by an elevated minimal potential (Vmin) of spiking of the fast subsystem. Larger inhibitory and excitatory autaptic conductances induced smaller and larger maximal potentials (Vmax) of spiking, respectively. During the downstroke, a weaker potassium current induced by the smaller Vmax played a dominant role for the inhibitory autapse, and the stronger potassium current induced by the larger Vmax became weaker due to the opposite autaptic current of the excitatory autapse, which induced the Vmin elevated. The results present the nonlinear and biophysical mechanisms of the same responses to opposite effects, which extends nonlinear dynamics knowledge and provides potential modulation measures for the nervous system.

Background Lymphangiomatosis is a multisystem disorder that is rarely localized to the gastrointestinal tract. Lymphangiomatosis usually has no specific clinical presentation and is easily misdiagnosed. A case report and review of the literature on lymphangiomatosis associated with protein-losing enteropathy will help to improve the overall understanding of this disease. Case summary We report a case of lymphangiomatosis of the bowel and other solid organs. A 78-year-old man presented with recurrent bowel bleeding and protein-losing enteropathy, as well as cystic lesions in the spleen, liver, and kidney. Imaging examinations revealed many cystic lesions on the spleen, liver, kidney, and thickened wall of the ascending colon, as well as pleural effusion and ascites. Colonoscopy revealed a strawberry mucosa, variable spontaneous bleeding, and surface erosion located in the terminal ileum. Several cystic masses with a translucent and smooth surface as well as diffuse white spots were located in the colon. A laterally spreading tumor (LST) was located in the ascending colon. Pathology indicated highly differentiated adenocarcinoma (LST) and lymphangiomatoid dilation, and D2-40 was positive. The final diagnosis was lymphangiomatosis. The patient underwent surgery for LST and then was administered thalidomide 75-150 mg/d. His condition, however, did not improve. He eventually died 6 mo after the initial diagnosis. Conclusion Lymphangiomatosis usually occurs diffusely and can involve many organs, such as the spleen, kidney, liver, lung, mesentery, and bowel. Recurrent bowel bleeding or protein-losing enteropathy is an important indicator that should alert clinicians about the possibility of this disease when it afflicts the bowel. Doctors should improve the medical understanding of lymphangiomatosis.

High altitude alpine grasslands in the Qinghai-Tibetan Plateau (QTP) contain high soil organic C (SOC) stocks that are extremely vulnerable to climate warming. Microbial residues are increasingly recognized as a major source of SOC, however, how climate warming affects this component of SOC in this region remains largely unknown. In this study, we examined the response of microbial residues to a 3-year experimental warming and the degree to which they contributed to SOC storage in two Tibetan ecosystems—alpine steppe (AS) and swamp meadow (SM). The number of microbial residues was indicated by amino sugar analysis. Our results revealed that warming yielded divergent microbial residue accumulation that significantly altered their contribution to SOC storage in the two alpine grasslands. Warming increased microbial residue abundance by approximately 17.6% across 0 to 20 cm depth in SM soils, while causing a significant decline (about 6.2%) in AS soils. The higher microbial residue accumulation in SM could lessen potential positive feedbacks from climate warming, while the decrease in microbial residues in AS may indicate greater loss of microbial-derived C inputs in warmed soils. Moreover, we found that warming selectively increased fungal residues as compared with bacterial despite inconsistent responses to warming in the two grasslands. These changes were accompanied by significant shifts in fungal to bacterial residue C ratios and their contribution to SOC pool, indicating an alteration of SOC composition and stability in alpine grassland ecosystems. These findings demonstrate that a microbial-derived C feedback to climate change is ecosystem-specific that alters the direction and magnitude of the microbial community.

Purpose Fucoidan is a natural bioactive product with broad therapeutic applications. Hepatocellular carcinoma (HCC) is a common malignancy of the liver associated with a relatively high mortality rate; thus, effective treatments are urgently needed. Here, the effects of fucoidan on HCC and the underlying mechanism were explored. Methods The proliferation and apoptosis of two HCC cell lines (BEL-7402 and LM3) treated with different concentrations of fucoidan or saline were assessed. The levels of proliferating cell nuclear antigen (PCNA) and CCK8 assay were used to determine proliferative capabilities of BEL-7402 and LM3 cells. Apoptosis of LM3 cells was assessed by Hoechst 33342 staining, Western blotting and flow cytometry. The capability of fucoidan to inhibit the growth of LM3 cells was investigated by monitoring of the p38 MAPK/ERK pathways and the upstream kinases, PI3K/Akt. LM3 xenograft tumors were used for in vivo verification. Results Cell proliferation and apoptosis assays consistently showed that fucoidan has an inhibitory effect on cell growth. Fucoidan significantly promoted apoptosis of LM3 cells through a mechanism involving activation of caspases 8, 9, and 3 accompanied by changes in B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein (Bax), as well as changes in the phosphorylation of p38 MAPK and ERK. Fucoidan also altered the phosphorylation of its upstream kinase, Akt. Fucoidan treatment markedly reduced the growth of LM3 xenograft tumors, consistent with the in vitro results. Conclusion Fucoidan conveys antitumor effects and, thus, should be further explored as a potential treatment option for HCC.

BACKGROUND This study retrospectively explored body composition changes and related factors in patients with ulcerative colitis (UC). MATERIAL AND METHODS Patients with UC and healthy individuals who served as the healthy control at the Affiliated Hospital of Qingdao University September 2017 to August 2018 were retrospectively analyzed. Clinical data and laboratory examination indexes were collected. The skeletal muscle area (SMA) of the third lumbar vertebra cross-section, the subcutaneous fat area (SFA), and the visceral fat area (VFA) at the umbilical level were measured by computed tomography (CT), and the skeletal muscle index (SMI) was calculated to evaluate the loss of muscle mass. RESULTS Data from a total of 80 patients (median age, 49.49 years; 44 [55%] men) with active UC in the UC group and 80 healthy people age- and sex-matched in the healthy control group were collected. The incidence of low SMI and malnutrition was remarkably higher in the UC group than in the healthy control group (P0.05). Low SMI was observed in 62.5% of UC patients who had a normal body mass index. Based on classification by the Truelove and Witts' criteria, the prevalence of malnutrition in severe UC patients was remarkably higher than that in mild and moderate UC patients (P0.05). Based on the disease extent, the prevalence of low SMI in E3 type UC was dramatically higher than that in E2 type (P=0.028). CONCLUSIONS Loss of muscle mass was related to disease extent in patients with UC. Loss of muscle mass is more likely to be associated with malnutrition.

Rationale: Familial adenomatous polyposis (FAP) associated with desmoids tumors (DTs) complicated by abscess formation is rare. The management is not easy and the choice of the best treatment may be controversial. Patient concerns: A 33-year-old man was admitted to our hospital for abdominal pain, fever, chills, nausea, and vomiting. He had a family history of FAP, and history of abdominal surgery. Diagnoses: An abdominal enhanced chest computed tomography (CT) scan revealed a soft tissue mass in the abdominal wall and an irregular mesenteric soft tissue mass with internal fistula and intra-abdominal abscess. A CT-guided biopsy of the abdominal wall mass revealed DTs. Interventions: The patient was given oral antibiotics for 6 months, and ultimately underwent surgery. Outcomes: The patient had no evidence of recurrence on follow-up at 10 months. Lessons: This case indicates that for patients with FAP who have a history of abdominal surgery and a progressively enlarging mass and abscess in the abdomen, it is necessary to consider the possibility of DTs. FAP-related DTs are rarely complicated by abscess formation. Antibiotic therapy plus surgical resection of the tumor may be effective and make good prognosis.

Recently, microRNA-498 (miR-498) plays important effect in human cancers. Nonetheless, the role of miR-498 is still unclear in gastric cancer (GC). Therefore, this study was designed to investigate the function of miR-498 in GC tissues and cell lines (SGC-7901, BGC-823, MGC-803). The expressions of miR-498 and BMI-1 were examined in GC tissues via the RT-qPCR assay. The function of miR-498 was investigated through MTT and transwell assays. The relationship between miR-498 and BMI-1 was testified by dual luciferase assay. The protein expression of EMT markers, AKT pathway markers and BMI-1 was measured through western blot. The expression of miR-498 was decreased in GC tissues which predicted poor prognosis of GC patients. Moreover, functional analyses show that the overexpression of miR-498 inhibited the progression of GC. Furthermore, BMI-1 was a direct target of miR-498 which was upregulated in GC. Especially, the upregulation of BMI-1 recovered the suppressive effect of miR-498 in GC. In addition, miR-498 inhibited the metastasis and proliferation of GC cells through blocking EMT and AKT pathway. MiR-498, by targeting BMI-1, presents a plethora of tumor suppressor activities in GC cells.

We evaluated how microbial residues and their contributions to soil carbon (C) stocks changed with long-term (50 years) conversion of native grassland to cropland in the profiles (0–15, 15–30, 30–60, 60–90 cm) of chernozem. The conversion of grassland into arable land led to substantial depletion of microbial residues down to 90-cm depth, indicating the potential vulnerability of the microbial-derived C due to land-use change. Moreover, losses of microbial residue C at depths below 30 cm were much higher than that of total soil C after several decades’ cultivation. This demonstrated that the decline of total soil C pool after grassland conversion was selectively removing microbial residue C. Lower ratio of fungal to bacterial residue C after grassland conversion suggested a shift in the composition of microbial residue C, with potential consequences for changes in soil C quality and stock associated with land cultivation. Collectively, our findings foster the importance of microbial-derived organic C for soil C stock maintenance and emphasize the necessity to take subsurface soils into account when evaluating the role of microbial-derived C to soil C losses under land-use change.

The contribution of microbial residues to soil organic carbon (SOC) is a process highly influenced by soil properties. We evaluated the presence of microbial amino sugar residues in soil (0–50 cm) of control and warmed plots in an alpine meadow on the Qinghai-Tibet Plateau. Alpine grasslands in the Qinghai-Tibet Plateau store large amounts of soil C and are highly vulnerable to climate change. Results showed that warming significantly increased total microbial residues across the 0–50 cm soil depth. The proportion of microbial-derived C to SOC significantly increased in warmed plots (52% on average) by soil depth compared to the control (38%). Higher microbial turnover and selective preservation into organo-mineral complexes likely explains the observed result. Given insignificant change in total SOC, our results infer an alteration of the SOC source configuration (microbial-derived vs. plant-derived). The observed greater magnitude of warming effects on fungal residues compared to bacterial illustrate a distinct community response to warming. We conclude that warming has the potential to influence soil C sequestration through increased microbial residue inputs, consequently altering its composition and source configuration. Our work provides valuable insights at the molecular level to identify mechanisms of microbial-mediated C processes that are influenced by climate change in high elevation ecosystems.

In contrast to the traditional viewpoint that inhibitory effect can often induce the reduction of neural firing activities, negative self-feedback current mediated by inhibitory autapse is identified to enhance neuronal bursting activities in the Chay model composed of fast and slow subsystems. With increasing autaptic strength of the autapse, bursting patterns exhibit period-adding bifurcations, which leads to the increase in the mean firing frequency. Such a phenomenon can be well interpreted with fast–slow variable dissection and bifurcation analysis to the bursting patterns. The initial and termination phases of the burst correspond to a saddle-node bifurcation and a saddle-homoclinic (SH) bifurcation of the fast subsystem, respectively. With increasing the autaptic strength, the termination phase of the burst delays and the initial phase remains nearly unchanged. Therefore, the width of the burst becomes wider to contain more spikes, which leads to the period-adding bifurcations and the increases of mean firing frequency. The detailed relationship between the delay of termination phase (SH point) and the characteristic of the inhibitory autaptic current is identified. Moreover, the distinction between the present paper and the previous investigations of the enhancement of bursting activities induced by inhibitory current with time delay is discussed. Based on the results that inhibitory autapse without time delay can enhance bursting activities via bifurcation mechanism, a novel case of nonlinear dynamics in contrast to the traditional viewpoint of the inhibitory effect, a possible function of the autapse, a novel potential measure to modulate bursting activities are present.

Urbanization, industrialization and their associated water shortage pressures have brought great challenges to agricultural development and water security. Understanding the virtual water flow involved in the grain trade is critical to ensuring water security and agricultural production. However, there are few studies on the comprehensive benefits provided by virtual water flow in the grain trade. This paper proposes a linear optimization model to fill this gap. The model is used to estimate the virtual water flow via interregional grain trade within China in 2015 and corresponding benefits to resources, the economy, and the environment from both outflow and inflow comparative perspectives. Three results characterize the virtual water flow pattern of interprovincial grain trade in China in 2015: (1) In terms of resource benefit, 31. billion cubic meters of water resources were saved, accounting for approximately 39.7% of the total virtual water flow. (2) A positive economic benefit was realized, with an increase of 6.4 trillion yuan in industrial value added. (3) Certain regions with a high crop green water occupation index account for a considerable proportion of the green water of the local agricultural ecosystem. Simultaneously, massive output of virtual water would aggravate the destruction of terrestrial ecosystems. Finally, the results suggest that promoting the marketization of water resources, improving water productivity, exploring regional compensation mechanisms and improving green water conservation capacity should be considered for water security policies.

Intestinal stricture and obstruction are rare complications of ulcerative colitis (UC). Currently, there are only a few studies on the treatment of UC with intestinal stenosis, however there are no reports on the treatment of UC with benign intestinal stenosis with ustekinumab (UST).A 22-year-old woman was admitted to our hospital due to a 3-year history of recurrent bloody mucous in stool with intermittent abdominal pain and distension developed in the past month. She was steroid-dependent and had developed a secondary loss of response to infliximab.She was diagnosed with UC combined with incomplete intestinal obstruction due to stenosis. The stricture had a mixed pattern with both inflammatory and fibrotic components, with the former covering a larger section of the intestine.The patient was given UST for 56 weeks.The patient's symptoms subsided after treatment with UST. The ulcers healed, and the stenosis was reduced.UST is effective against UC with benign intestinal stenosis. It is thought that UST inhibits the production of transforming growth factor-β and interleukin-17, leading to the suppression of myofibroblast proliferation, ultimately alleviating intestinal stenosis.

BackgroundSarcopenia is a poor prognostic factor in patients with esophageal cancer (EC). It can be aggravated by neoadjuvant therapy (NAT) that improves the prognosis of patients with EC. Until now, the impact of preoperative sarcopenia on survival prognosis in patients receiving NAT for EC remains unclear.MethodsWe systematically researched relevant studies in the PubMed, EMBASE, Web of Science, the Cochrane Library databases up to March 8, 2020. Prevalence of sarcopenia before and after NAT, overall survival (OS) and disease-free survival (DFS) were collected for analysis. Finally, eleven cohort studies were included.ResultsPooled analysis indicated that preoperative sarcopenia was negatively associated with OS. (HR = 1.290; 95% CI [1.078–1.543]; P = 0.005; I2 = 0.0%) and DFS (HR = 1.554; 95% CI [1.177–2.052]; P = 0.002; I2 = 0.0%) in the patients with EC receiving NAT. The prevalence of sarcopenia increased by 15.4% following NAT (95%CI [12.9%-17.9%]). Further subgroup analysis indicated that sarcopenia diagnosed following NAT (HR = 1.359; 95% CI [1.036–1.739]; P = 0.015; I2 = 6.9%) and age >65 years (HR = 1.381; 95% CI [1.090– 1.749]; P = 0.007; I2 = 0.0%) were the independent risk factors for decreased OS.ConclusionsClinicians should strengthen the screening of preoperative sarcopenia in patients of EC both receiving NAT and older than 65 years and give active nutritional support to improve the prognosis of patients.Systematic Review RegistrationInternational Platform of Registered Systematic Review and Meta-Analysis Protocols (INPLASY), identifier INPLASY202050057.

Granular cell tumor (GCT) represents a less frequently seen tumor originating from Schwann cells. Although GCT develops in various locations in the human body, GCT of the mediastinum is extremely uncommon. A case of mediastinal GCT diagnosed by aspiration using a fine needle assisted by endoscopic ultrasound (EUS-FNA) via a modified technique based on wet suction was reported. An asymptomatic 28-year-old man was referred for assessment of a mass in the mediastinum that was found incidentally via chest computed tomography (CT) at health screening. EUS demonstrated a hypoechoic lesion with a distinct boundary, which was derived from the upper posterior mediastinum and partly located close to the posterior wall of the esophagus. Therefore, EUS-FNA with a modified wet suction technique was performed to harvest adequate specimens for the diagnosis of GCT. Minimally invasive tumor removal was performed, and histological examination of the specimen harvested surgically verified GCT, consistent with histological findings of the specimen obtained by EUS-FNA. The case highlights that a good accuracy of histological diagnosis and specimen quality are achieved for the modified wet-suction technique in EUS-FNA, and a preoperative diagnosis of mediastinal GCT can be made with certainty.

Colon cancer is a common malignancy and its poor outcome mainly attributes to chemotherapy resistance. AMP-activated protein kinase (AMPK) is noted to mediate development of and chemotherapy resistance in colon cancer. This study aims to explore the mechanism regarding AMPK-mediated β-catenin degradation in chemotherapy resistance in colon cancer. β-catenin was upregulated in colon cancer tissues and cells, as it was positively correlated with the malignancy and poor prognosis, and chemotherapy resistance of colon cancer. As colon cancer cells were exposed to cisplatin and tamoxifen, functional experiment revealed that AMPK activated by its agonist metformin inhibited the proliferation and chemotherapy resistance of colon cancer cells by regulating β-catenin. Co-immunoprecipitation assay confirmed the interaction between β-catenin, E3 ubiquitin ligase Parkin and AMPK. Finally, we xenografted tumors in nude mice and validated the effects of AMPK and β-catenin on tumor growth and chemotherapy resistance in vivo. Parkin induced ubiquitination and degradation of β-catenin while AMPK downregulated β-catenin by elevating the phosphorylation of Parkin. Taken together, AMPK phosphorylates Parkin to promote the ubiquitination and degradation of β-catenin, thereby downregulating β-catenin, which inhibits the proliferation of colon cancer cells and reverses the chemotherapy resistance in colon cancer.