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Xiaoning Cen,1,&ast; Yunmei Huang,2,&ast; Zhuangnian Lu,3,&ast; Wenjun Shao,4 Chenyi Zhuo,1 Chongchan Bao,5 Shi Feng,5 Cheng Wei,5 Xiqiang Tang,5 Lijun Cen,5 Wenwen Guo,5 Xinru Tian,5 Qianli Tang,5 Xusen Huang1 1General Surgery, Affiliated Hospital of YouJiang Medical University for Nationalities, Baise, 533000, Guangxi, People’s Republic of China; 2Department of Pathology, Affiliated Hospital of YouJiang Medical University for Nationalities, Baise, 533000, Guangxi, People’s Republic of China; 3Department of Pediatrics, Affiliated Hospital of YouJiang Medical University for Nationalities, Baise, 533000, Guangxi, People’s Republic of China; 4Medical college of Soochow University, Suzhou, Jiangsu, 215000, People’s Republic of China; 5YouJiang Medical University for Nationalities, Baise, 533000, Guangxi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qianli TangYouJiang Medical University for Nationalities, Baise, 533000, Guangxi, People’s Republic of ChinaEmail htmgx@163.comXusen HuangGeneral Surgery, Affiliated Hospital of YouJiang Medical University for Nationalities, Baise, 533000, Guangxi, People’s Republic of ChinaEmail hxsfy@163.comBackground: LncRNAs play an important role in tumor initiation and development. However, the underlying involvement of lncRNA expression in colorectal carcinoma remains to be clarified.Methods: All analyses were performed in R software v4.0, SPSS v13.0, and GraphPad Prism 8. The “limma” package was used to identify differentially expressed lncRNAs between two groups with the threshold of |logFC| > 1 and P < 0.05. The “Survival” package was used to conduct survival analysis. HCT8 and SE480 cell lines were used to conduct further phenotype experiments, including transwell, wound-healing, CCK8 and colony formation assay. Gene set enrichment analysis was used to explore the biological pathway difference in high and low IGFL2-AS1 patients.Results: The lncRNA IGFL2-AS1 was highly expressed in colon adenocarcinoma (COAD) tissue and cell lines (HCT116, HCT8, HCT129, and SW480). The COAD patients with high IGFL2-AS1 were associated with a worse prognosis. Meanwhile, the knockdown of IGFL2-AS1 could significantly suppress the proliferation and invasion of COAD cells. Gene set enrichment analysis showed that the top five biological pathways involving IGFL2-AS1 were angiogenesis, epithelial–mesenchymal transition, KRAS signaling, myogenesis, and coagulation. Western blot results showed that the inhibition of IGFL2-AS1 could significantly reduce the N-cadherin, HIF1A and KRAS protein expression, yet increase the E-cadherin protein level. IGFL2-AS1 was also positively correlated with M0 macrophages, M2 macrophages, and neutrophils but negatively correlated with CD4+ memory T cells and CD8+ T cells.Conclusion: IGFL1-AS1 could seriously worsen patient outcomes and facilitate COAD progression, thus serving as an independent tumor marker.Keywords: IGFL2-AS1, lncRNA, colon cancer, immune

Ye Shen,* Jinping Ou,* Bingjie Wang, Lihong Wang, Junhui Xu, Xinan Cen Department of Hematology, Peking University First Hospital, Beijing, 100034, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xinan CenDepartment of Hematology, Peking University First Hospital, No. 8, Xishiku Street, Xicheng District, Beijing, 100034, People’s Republic of ChinaEmail cenxn@bjmu.edu.cnBackground: This study assessed the clinical characteristics of gastrointestinal bleeding (GIB), obstruction (GIO), and perforation (GIP) in patients with primary gastrointestinal diffuse large B-cell lymphoma (PGI-DLBCL) and the influence on long-term survival.Methods: A retrospective analysis was performed of 148 patients with PGI-DLBCL admitted to Peking University First Hospital from August 1994 to May 2018. The clinical characteristics of GIB, GIO, and GIP before and after chemotherapy were recorded. The associated overall survival and progression-free survival were analyzed.Results: Among 148 patients, 56.8% had gastrointestinal complications (GICs), including GIB, GIO, GIP, and multiple complications, and 22.6% of them occurred after chemotherapy, mostly during the first 4 cycles. The most common clinical manifestations of patients with GICs were abdominal pain or discomfort (79.8%), hematemesis or melena (22.6%), and abnormal bowel habits (17.9%). Patients with Eastern Cooperative Oncology Group (ECOG) score ≥ 2, tumor mass ≥ 10 cm, or intestinal involvement had significantly higher risk of severe GICs as initial manifestations. Among 130 patients who received chemotherapy, B symptoms, tumor mass ≥ 10 cm, and Lugano stage (IIE, IV) strongly correlated with GICs after chemotherapy (P < 0.05). Rituximab did not increase the risk of GICs. GICs which occurred before or after chemotherapy reduced the objective response rate at the end of chemotherapy. The prognosis of patients was significantly worsened by GIP, GIB, or multiple complications after chemotherapy (P < 0.05). GIB at presentation or GIO before or after chemotherapy had no prognostic value (both P > 0.05).Conclusion: GICs adversely affect the quality of life, prolong the length of hospitalization, and shorten the long-term survival of patients with PGI-DLBCL.Keywords: diffuse large B-cell lymphoma, gastrointestinal complication, bleeding, obstruction, perforation

Junhui Xu,* Mangju Wang,* Ye Shen, Miao Yan, Weiwei Xie, Bingjie Wang, Huihui Liu, Xinan Cen Department of Hematology, Peking University First Hospital, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xinan CenDepartment of Hematology, Peking University First Hospital, No. 8 Xi Shi Ku Street, Xi Cheng District, Beijing, 100034, People’s Republic of ChinaTel +86-10-83575746Email cenxn@bjmu.edu.cnBackground: Amyloid light-chain amyloidosis (AL amyloidosis) is commonly associated with multiple myeloma. However, the clinical characteristics and prognosis of symptomatic and smoldering multiple myeloma with AL amyloidosis are not particularly clear.Methods: Patients with symptomatic and smoldering multiple myeloma in the Peking University First Hospital registry from 2010 to 2018 were studied. The clinical and laboratory information was collected from first presentation to death or until the last available clinical follow-up. The patients’ survival and outcomes were analyzed, and the relationship between the clinical parameters and survival was also assessed.Results: Compared with symptomatic multiple myeloma patients without AL amyloidosis, patients with AL amyloidosis had higher incidence of BNP≧700pg/mL (P< 0.001), ALP> 187.5IU/L (P=0.032) and ALB< 25g/L (P< 0.001). Similarly, compared with smoldering multiple myeloma patients without AL amyloidosis, patients with AL amyloidosis had higher incidence of BNP≧700pg/mL (P=0.030) and Alb< 25g/L (P=0.024). The existence of AL amyloidosis, especially those with the heart involvement, was related to shorter long-term survival of symptomatic and smoldering multiple myeloma according to univariate analyses. Renal involvement and gastrointestinal tract involvement had an impact on the prognosis of smoldering multiple myeloma but not on the symptomatic multiple myeloma. Cox regression model for overall survival detected BNP≧700pg/mL in symptomatic multiple myeloma having independent poorer prognostic significance (HR=2.455, P=0.004). Interestingly, BNP at diagnosis was significantly correlated with cardiac amyloidosis (r=0.496, P< 0.001). Cox regression model for overall survival detected the presence of AL amyloidosis in smoldering multiple myeloma having independent poorer prognostic significance (HR=8.741, P=0.002).Conclusion: AL amyloidosis is an independent poor prognostic factor for not only symptomatic multiple myeloma but also smoldering multiple myeloma. It is mainly because of involvement of important organs, especially the heart. AL amyloidosis probably has a greater impact on the prognosis of smoldering multiple myeloma than on the symptomatic multiple myeloma.Keywords: symptomatic multiple myeloma, smoldering multiple myeloma, AL amyloidosis, poor prognostic factor

Abstract Background Obesity is a global health issue with detrimental effects on various human organs, including the reproductive system. Observational human data and several lines of animal experimental data suggest that maternal obesity impairs ovarian function and early embryo development, but the precise pathogenesis remains unclear. Methods We established a high-fat diet (HFD)-induced obese female mouse model to assess systemic metabolism, ovarian morphology, and oocyte function in mice. For the first time, this study employed single-cell RNA sequencing to explore the altered transcriptomic landscape of preimplantation embryos at different stages in HFD-induced obese mice. Differential gene expression analysis, enrichment analysis and protein-protein interactions network analysis were performed. Results HFD-induced obese female mice exhibited impaired glucolipid metabolism and insulin resistance. The ovaries of HFD mice had a reduced total follicle number, an increased proportion of atretic follicles, and irregular granulosa cell arrangement. Furthermore, the maturation rate of embryonic development by in vitro fertilization of oocytes was significantly decreased in HFD mice. Additionally, the transcriptional landscapes of preimplantation embryos at different stages in mice induced by different diets were significantly distinguished. The maternal-to-zygotic transition was also affected by the failure to remove maternal RNAs and to turn off zygotic genome expression. Conclusions HFD-induced obesity impaired ovarian morphology and oocyte function in female mice and further led to alterations in the transcriptional landscape of preimplantation embryos at different stages of HFD mice.

Flavonoids are widely found in plants and diets and are considered to possess a variety of biological activities. Therefore, in this study, 8 novel compounds derivating from the precursor compound 1a, were designed and synthesized, and their activities against ulcerative colitis(UC) were evaluated to provide the most active molecule 2d. Both a cellular inflammation model by LPS(Lipopolysaccharide)-induced RAW 264.7 cells and the UC model in 2 % Dextran Sulfate Sodium(DSS) intragastrically injected mice were established and employed to detect and validate the effects and mechanisms of compound 2d on ulcerative colitis. Cell experiments showed that compound 2d possesses the best anti-UC activity among all derivatives (2a-d, 3a-d). Compound 2d could significantly inhibit the release of inflammatory cytokines such as TNF-α, IL-6, IL-1β and IL-8 in RAW264.7 cells induced by LPS at 10 μM. RAW264.7 cells. In vivo experiments further demonstrated that compound 2d could effectively treat UC in mice induced by DSS. The results indicated that compound 2d restored MPO oxidative stress, reduced the secretion of inflammatory factors, and regulated the expression of NF-κB and MAPK pathway-related proteins, which was consistent with the results at the cellular level. The results of the relevant intestinal flora showed that compound 2d could normalize the intestinal flora of mice with ulcerative colitis. In summary, compound 2d may inhibit inflammation and oxidative stress by regulating NF-κB and MAPK pathways, and restore the diversity of intestinal microbiota to treat ulcerative colitis. It provides a new approach for the clinical application of flavonoids.

Abstract Nonalcoholic fatty liver disease (NAFLD) is usually characterized with disrupted bile acid (BA) homeostasis. However, the exact role of certain BA in NAFLD is poorly understood. Here we show levels of serum hyodeoxycholic acid (HDCA) decrease in both NAFLD patients and mice, as well as in liver and intestinal contents of NAFLD mice compared to their healthy counterparts. Serum HDCA is also inversely correlated with NAFLD severity. Dietary HDCA supplementation ameliorates diet-induced NAFLD in male wild type mice by activating fatty acid oxidation in hepatic peroxisome proliferator-activated receptor α (PPARα)-dependent way because the anti-NAFLD effect of HDCA is abolished in hepatocyte-specific Pparα knockout mice. Mechanistically, HDCA facilitates nuclear localization of PPARα by directly interacting with RAN protein. This interaction disrupts the formation of RAN/CRM1/PPARα nucleus-cytoplasm shuttling heterotrimer. Our results demonstrate the therapeutic potential of HDCA for NAFLD and provide new insights of BAs on regulating fatty acid metabolism.

Autophagy, an efficient and effective approach to clear rapidly damaged organelles, macromolecules, and other harmful cellular components, enables the recycling of nutrient materials and supply of nutrients to maintain cellular homeostasis. Ubiquitination plays an important regulatory role in autophagy. This paper summarizes the most recent progress in ubiquitin modification in various stages of autophagy, including initiation, elongation, and termination. Moreover, this paper shows that ubiquitination is an important way through which selective autophagy achieves substrate specificity. Furthermore, we note the distinction between monoubiquitination and polyubiquitination in the regulation of autophagy. Compared with monoubiquitination, polyubiquitination is a more common strategy to regulate the activity of the autophagy molecular machinery. In addition, the role of ubiquitination in the closure and fusion of autophagosomes warrants further study. This article not only clarifies the regulatory mechanism of autophagy but also contributes to a deeper understanding of the importance of ubiquitination modification.

Objectives. To compare four DNA extraction methods for recovering bacterial DNA from mammalian faecal samples. Methods and Results. Three commercial kits from QIAamp, TIANamp, and MAGEN, together with the classic cetyltrimethylammonium bromide (CTAB) method, were evaluated for their performance in extracting bacterial DNA from the gut microbiota of five mammals, including humans (Homo sapiens), macaques (Macaca mulatta), dogs (Canis lupus familiaris), golden hamsters (Mesocricetus auratus), and mice (Mus musculus). First, we assessed the efficiency of the four methods based on DNA yield, purity, and integrity. Then, we investigated the impact of these methods on microbial composition and diversity and examined the relative abundance of dominant phyla bacteria based on 16S rRNA gene sequencing and real-time quantitative PCR. Our results showed that the CTAB method yielded relatively larger amounts of DNA, while the MAGEN kit yielded more Firmicutes DNA and reflected the true status of the microbiota more accurately. Conclusions. Of the four methods tested, the traditional CTAB method and commercial MAGEN kit accomplished the best performance in terms of DNA concentration and Firmicutes abundance across most of the tested species. As the CTAB method and MAGEN kit exhibited different advantages, we further tested and compared their DNA extraction performance on a defined microbiota comprising six strains from four dominant phyla to see which one better reflected the true status of the microbiota. In conclusion, the MAGEN kit was found to be superior to the CTAB method, as the testing results were closer to that of the defined microbiota.

OBJECTIVE: To evaluate the effectiveness of case-based learning (CBL) in medical students’ education through meta-analysis. MATERIALS AND METHODS: PubMed, Cochrane Library, Elsevier and other databases were searched to find randomized controlled trials (RCTs) of CBL teaching methods and other teaching methods published from January 1, 1995, to October 1, 2020. All included studies used the Cochrane risk bias assessment tool, and Review Manager software, version 5.3 (Copenhagen, Denmark), was used for the meta-analysis and systematic review. RESULTS: A total of 8 studies were included with a total of 939 students, including 480 in the CBL group and 459 in the control group. Compared with other teaching methods, CBL teaching can improve medical students’ academic performance (p=0.03) and case analysis ability (p<0.001). CONCLUSIONS: CBL is an active teaching method that is effective for educating medical students and helps to improve their performance and case analysis ability. [ABSTRACT FROM AUTHOR]

Renal interstitial fibrosis (RIF), a progressive process affecting the kidneys in chronic kidney disease (CKD), currently lacks an effective therapeutic intervention. Traditional Chinese medicine (TCM) has shown promise in reducing RIF and slowing CKD progression. In this study, we demonstrated the dose-dependent attenuation of RIF by Ootheca mantidis (SPX), a commonly prescribed TCM for CKD, in a mouse model of unilateral ureteral obstruction (UUO). RNA-sequencing analysis suggested that SPX treatment prominently downregulated apoptosis and inflammation-associated pathways, thereby inhibiting the fibrogenic signaling in the kidney. We further found that transplantation of fecal microbiota from SPX-treated mice conferred protection against renal injury and fibrosis through suppressing apoptosis in UUO mice, indicating that SPX ameliorated RIF via remodeling the gut microbiota and reducing apoptosis in the kidneys. Further functional exploration of the gut microbiota combined with fecal metabolomics revealed increased levels of some probiotics, including Akkermansia muciniphila (A. muciniphila), and modulations in glutamine-related amino acid metabolism in UUO mice treated with SPX. Subsequent colonization of A. muciniphila and supplementation with glutamine effectively mitigated cell apoptosis and RIF in UUO mice. Collectively, these findings unveil a functionally A. muciniphila- and glutamine-involved gut–renal axis that contributes to the action of SPX, and provide important clue for the therapeutic potential of SPX, A. muciniphila, and glutamine in combatting RIF.

This paper proposes an idea of pouring gasification ash into the underground goaf as a grouting fire prevention and extinguishing material. In order to effectively solve the problem that the gasification ash slurry of coal-based oil tends to block the pipeline in the process of grouting, the influence of three suspension agents such as xanthan gum, carboxymethyl cellulose(CMC) and sodium soil on the suspension rate and fluidity of gasification ash slurry was studied through a series of experiments. The results showed that with the increase of the amount of suspension agent, the suspension rate of slurry increased gradually, and its fluidity decreased gradually. More specifically, when the addition amount of xanthan gum, CMC and sodium-soil was 0.25%, 1.5%and 3%, respectively, the suspension rate reached the maximum with 81.82%, 72.73% and 53.24%, respectively. Among the three suspending agents, xanthan gum has the best suspending effect on gasification ash, followed by CMC and sodium-soil. The fluidity experiment showed that the fluidity of the slurry was the worst with adding xanthan gum to the slurry, which is not beneficial for the pipeline transportation of the slurry. While sodium-clay is added to slurry, the fluidity of the slurry is the best. But it is prone to water-cement separation and blockage of the pipe. Hence, considering suspension rate and flow, CMC was selected as suspension agent.

Abstract Objective High intake of caffeoylquinic acid (CQA)-rich dietary supplements, such as green coffee bean extracts, offers health-promoting effects on maintaining metabolic homeostasis. Similar to many active herbal ingredients with high pharmacological activities but low bioavailability, CQA has been reported as a promising thermogenic agent with anti-obesity properties, which contrasts with its poor oral absorption. Intestinal tract is the first site of CQA exposure and gut microbes might react quickly to CQA. Thus, it is of interest to explore the role of gut microbiome and microbial metabolites in the beneficial effects of CQA on obesity-related disorders. Results Oral CQA supplementation effectively enhanced energy expenditure by activating browning of adipose and thus ameliorated obesity-related metabolic dysfunctions in high fat diet-induced obese (DIO) mice. Here, 16S rRNA gene amplicon sequencing revealed that CQA treatment remodeled the gut microbiota to promote its anti-obesity actions, as confirmed by antibiotic treatment and fecal microbiota transplantation. CQA enriched the gut commensal species Limosilactobacillus reuteri (L. reuteri) and stimulated the production of short-chain fatty acids, especially propionate. Mono-colonization of L. reuteri or low-dose CQA treatment did not reduce adiposity in DIO mice, while their combination elicited an enhanced thermogenic response, indicating the synergistic effects of CQA and L. reuteri on obesity. Exogenous propionate supplementation mimicked the anti-obesity effects of CQA alone or when combined with L. reuteri, which was ablated by the monocarboxylate transporter (MCT) inhibitor 7ACC1 or MCT1 disruption in inguinal white adipose tissues to block propionate transport. Conclusions Our data demonstrate a functional axis among L. reuteri, propionate, and beige fat tissue in the anti-obesity action of CQA through the regulation of thermogenesis. These findings provide mechanistic insights into the therapeutic use of herbal ingredients with poor bioavailability via their interaction with the gut microbiota. Video Abstract

Abstract Nonalcoholic steatohepatitis (NASH) is a rapidly developing pathology around the world, with limited treatment options available. Some farnesoid X receptor (FXR) agonists have been applied in clinical trials for NASH, but side effects such as pruritus and low‐density lipoprotein elevation have been reported. Intestinal FXR is recognized as a promising therapeutic target for metabolic diseases. Glycine‐β‐muricholic acid (Gly‐MCA) is an intestine‐specific FXR antagonist previously shown to have favorable metabolic effects on obesity and insulin resistance. Herein, we identify a role for Gly‐MCA in the pathogenesis of NASH, and explore the underlying molecular mechanism. Gly‐MCA improved lipid accumulation, inflammatory response, and collagen deposition in two different NASH models. Mechanistically, Gly‐MCA decreased intestine‐derived ceramides by suppressing ceramide synthesis–related genes via decreasing intestinal FXR signaling, leading to lower liver endoplasmic reticulum (ER) stress and proinflammatory cytokine production. The role of bile acid metabolism and adiposity was excluded in the suppression of NASH by Gly‐MCA, and a correlation was found between intestine‐derived ceramides and NASH severity. This study revealed that Gly‐MCA, an intestine‐specific FXR antagonist, has beneficial effects on NASH by reducing ceramide levels circulating to liver via lowering intestinal FXR signaling, and ceramide production, followed by decreased liver ER stress and NASH progression. Intestinal FXR is a promising drug target and Gly‐MCA a novel agent for the prevention and treatment of NASH.

Thyroid hormones regulate systemic glucose metabolism through incompletely understood mechanisms. Here the authors report that hepatic thyroid hormone receptor β mediates the effects of the thyroid hormone T3 on systemic glucose homeostasis by modulating GLP-1 levels through suppression of hepatic CYP8B1 expression and bile acid mediated inhibition of intestinal FXR signalling.

BackgroundThe debate over the impact of vitamin D in assisted reproduction continues. The purpose of our study was to assess embryo quality and pregnancy outcomes among groups with different levels of vitamin D after the first in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycle in patients with normal ovarian reserve (NOR).MethodsPatients in this retrospective cohort study were divided into three groups: severe vitamin D deficiency group (25OH-D < 10 ng/ml), vitamin D deficiency group (10 ng/ml ≤ 25OH-D < 20 ng/ml), and non-vitamin D deficiency group (25OH-D ≥ 20 ng/ml). The primary outcome was clinical pregnancy, while the secondary outcomes were mature oocytes, oocyte fertilization, available cleavage embryos, available blastocysts, biochemical pregnancy, early abortion, and embryo implantation. A modified Poisson regression model and multiple linear regression analysis were conducted for the multivariate analysis.Results264 NOR patients undergoing the first IVF/ICSI cycles were included. For the primary outcome, there was no significant difference in clinical pregnancy between the severe vitamin D deficiency group and the other two groups (vitamin D deficiency group: adjusted RR = 1.026; 0.780 - 1.350; P = 0.854; non-vitamin D deficiency group: adjusted RR = 1.092; 0.743 - 1.605; P = 0.652). For all secondary outcomes, no significant differences were observed among the severe vitamin D deficiency, vitamin D deficiency, and non-vitamin D deficiency groups (P > 0.05). Exploratory subgroup analyses concerning the season of embryo transfer, phase of embryo transferred, and endometrial thickness, as well as the sensitivity analysis using logistic regression models for the primary outcome, revealed comparable clinical pregnancy rates among the groups (P > 0.05). Subgroup analysis concerning ovarian stimulation protocol indicated that in the subgroup of gonadotrophin-releasing hormone (GnRH) antagonist protocol, the clinical pregnancy rate of the non-vitamin D deficiency group was significantly higher than that of the other two groups (P < 0.05).ConclusionSerum vitamin D level was not associated with embryo quality and pregnancy outcomes for patients with NOR. Further studies with greater sample sizes and a longer follow-up period are needed to elucidate the relationships between vitamin D levels and IVF outcomes.

Background: Diazoxide is a selective mitochondrial-sensitive potassium channel opening agent that has a definite effect on reducing myocardial ischemia/reperfusion injury (MIRI). However, the exact effects of diazoxide postconditioning on the myocardial metabolome remain unclear, which might contribute to the cardioprotective effects of diazoxide postconditioning.Methods: Rat hearts subjected to Langendorff perfusion were randomly assigned to the normal (Nor) group, ischemia/reperfusion (I/R) group, diazoxide (DZ) group and 5-hydroxydecanoic acid + diazoxide (5-HD + DZ) group. The heart rate (HR), left ventricular developed pressure (LVDP), left ventricular end-diastolic pressure (LVEDP), and maximum left ventricular pressure (+dp/dtmax) were recorded. The mitochondrial Flameng scores were analysed according to the ultrastructure of the ventricular myocardial tissue in the electron microscopy images. Rat hearts of each group were used to investigate the possible metabolic changes relevant to MIRI and diazoxide postconditioning.Results: The cardiac function indices in the Nor group were better than those in the other groups at the end point of reperfusion, and the HR, LVDP and +dp/dtmax of the Nor group at T2 were significantly higher than those of the other groups. Diazoxide postconditioning significantly improved cardiac function after ischaemic injury, and the HR, LVDP and +dp/dtmax of the DZ group at T2 were significantly higher than those of the I/R group, which could be abolished by 5-HD. The HR, LVDP and +dp/dtmax of the 5-HD + DZ group at T2 were significantly lower than those of the DZ group. The myocardial tissue in the Nor group was mostly intact, while it exhibited considerable damage in the I/R group. The ultrastructural integrity of the myocardium in the DZ group was higher than that in the I/R and 5-HD + DZ groups. The mitochondrial Flameng score in the Nor group was lower than that in the I/R, DZ and 5-HD + DZ groups. The mitochondrial Flameng score in the DZ group was lower than that in the I/R and 5-HD + DZ groups. Five metabolites, namely, L-glutamic acid, L-threonine, citric acid, succinate, and nicotinic acid, were suggested to be associated with the protective effects of diazoxide postconditioning on MIRI.Conclusion: Diazoxide postconditioning may improve MIRI via certain metabolic changes. This study provides resource data for future studies on metabolism relevant to diazoxide postconditioning and MIRI.

Although the functions of metabolic enzymes and nuclear receptors in controlling physiological homeostasis have been established, their crosstalk in modulating metabolic disease has not been explored. Genetic ablation of the xenobiotic-metabolizing cytochrome P450 enzyme CYP2E1 in mice markedly induced adipose browning and increased energy expenditure to improve obesity. CYP2E1 deficiency activated the expression of hepatic peroxisome proliferator-activated receptor alpha (PPARα) target genes, including fibroblast growth factor (FGF) 21, that upon release from the liver, enhanced adipose browning and energy expenditure to decrease obesity. Nineteen metabolites were increased in Cyp2e1-null mice as revealed by global untargeted metabolomics, among which four compounds, lysophosphatidylcholine and three polyunsaturated fatty acids were found to be directly metabolized by CYP2E1 and to serve as PPARα agonists, thus explaining how CYP2E1 deficiency causes hepatic PPARα activation through increasing cellular levels of endogenous PPARα agonists. Translationally, a CYP2E1 inhibitor was found to activate the PPARα–FGF21–beige adipose axis and decrease obesity in wild-type mice, but not in liver-specific Ppara-null mice. The present results establish a metabolic crosstalk between PPARα and CYP2E1 that supports the potential for a novel anti-obesity strategy of activating adipose tissue browning by targeting the CYP2E1 to modulate endogenous metabolites beyond its canonical role in xenobiotic-metabolism.

The aims of the present study were to investigate the anti-inflammatory function of two flavonoids apigenin and genistein in rat intestinal epithelial (IEC-6) cells stimulated by tumor necrosis factor-alpha (TNF-α) and to clarify whether the heat treatment of the flavonoids might affect flavonoid activity. The flavonoids at lower dosage (e.g. 5 μmol/L) had no toxic effect but growth promotion on the cells. Meanwhile, the flavonoid pretreatment of the cells before TNF-α stimulation could maintain cellular morphology, decrease the production of prostaglandin E2 and two pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-6, but increase the production of two anti-inflammatory cytokines IL-10 and transforming growth factor-β. Additionally, the flavonoids could block off the nuclear translocation of nuclear factor-kappaB (NF-κB) p65, and suppress the expression of phosphorylated IκBα and p65 induced by TNF-α. Meanwhile, the NF-κB inhibitor BAY 11–7082 shared a similar function with the flavonoids to mediate the production of IL-6/IL-10. Furthermore, in silico analysis also declared that the flavonoids could interact with the IκBα–NF–κB complex at the binding pockets to yield the binding energies ranging from −31.7 to −34.0 kJ/mol. However, the heated flavonoids were consistently less effective than the unheated counterparts to perform these anti-inflammatory effects. It is thus proposed that both apigenin and genistein have anti-inflammatory potential to the TNF-α-stimulated IEC-6 cells by inactivating the NF-κB pathway, while heat treatment of the flavonoids caused a negative impact on these assessed anti-inflammatory effects.

LY01005 is an investigational new drug product of goserelin acetate which is formulated as extended-release microspheres for intramuscular injection. To support the proposed clinical trials and marketing application of LY01005, pharmacodynamics, pharmacokinetics and toxicity studies were performed in rats. In the pharmacological study in rats, LY01005 induced an initial supra-physiological level increase of testosterone at 24 h post-dosing which then rapidly fell to castration level. The potency of LY01005 was comparable to the comparator Zoladex® but its effect lasted longer and more stable. A single-dose pharmacokinetics study in rats demonstrated that the Cmax and AUClast of LY01005 increased in a dose-proportional manner in the range of 0.45–1.80 mg/kg and the relative bioavailability was 101.0% between LY01005 and Zoladex®. In the toxicity study, almost all of the positive findings of LY01005 in rats including the changes in hormones (follicle-stimulating hormone, luteinizing hormone, testosterone, progestin) and in reproductive system (uterus, ovary, vagina, cervix uteri, mammary gland, testis, epididymis and prostate) were related to the direct pharmacological effects of goserelin. Mild histopathological changes in foreign body removal reaction induced by excipient were also observed. In conclusion, LY01005 displayed a sustained-release profile of goserelin, and exerted a continuous efficacy in vivo in animal models, which had a comparable potency but with a more sustained effect than that of Zoladex®. The safety profile of LY01005 was largely the same with Zoladex®. These results strongly support the planned LY01005 clinical trials.

The TID (total ionizing dose) in-situ experiments of LC1020B, an anti-fuse FPGA (Field Programmable Gate Array) device, were designed and carried out under different dose rates, and the influence of dose rate on the TID effect of FPGA was studied. The experimental results show that: 1) the TID irradiation failure of the FPGA under different dose rates has nothing to do with the input voltage parameter exceeding the standard. 2) with the decrease of cobalt source irradiation dose rate [171, 26.83, and 2.68 mGy(Si)/s], the TID effect failure dose threshold [168, 229, and 334 Gy(Si), respectively] of the FPGA gradually increased, showing obvious attenuation of low dose rate damage. Theoretical analysis suggests that, compared with the space charge limitation effect, the oxide charge annealing effect plays a dominant role, and longer irradiation time is beneficial to the oxide charge annealing. And based on the experimental data, an FPGA TID analytical model with power consumption current as the damage characterization parameter is established, which lays a foundation for scientific evaluation of radiation effect of anti-fuse FPGAs.

Zi-Shan Lin,1,* Xiao-Juan Yu,1,* Xu Zhang,1,2 Su-Xia Wang,1,2 Xi-Nan Cen,3 Fu-De Zhou,1 Ming-Hui Zhao1,4 1Renal Division, Department of Medicine, Peking University First Hospital; Institute of Nephrology, Peking University, Renal Pathology Center, Institute of Nephrology, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, People’s Republic of China; 2Laboratory of Electron Microscopy, Pathological Centre, Peking University First Hospital, Beijing, People’s Republic of China; 3Department of Hematology, Peking University First Hospital, Beijing, People’s Republic of China; 4Peking-Tsinghua Center for Life Sciences, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Fu-De ZhouRenal Division, Department of Medicine, Peking University First Hospital, Institute of Nephrology, Peking University; Renal Pathology Center, Institute of Nephrology, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, No. 8 Xishiku Street, Xicheng District, Beijing, 100034, People’s Republic of ChinaTel +86-13501162527Fax +86-10-83575694Email zhoufude1801@vip.sina.comBackground: Monoclonal immunoglobulin-associated renal lesions in patients with newly diagnosed myeloma vary. We aimed to determine the pathological spectrum and analyze associated prognostic factors.Methods: Fifty-six patients with newly diagnosed multiple myeloma and biopsy-proven renal lesions were enrolled. Kidney biopsies were reanalyzed, and the baseline clinical characteristics, treatments and outcomes were recorded.Results: Fifty-one patients had monoclonal immunoglobulin-associated renal lesions, with myeloma cast nephropathy (MCN) being the most common pattern. We divided our cohort into pure MCN, MCN+ other pathologies and non-MCN. Patients with MCN had more severe renal injury than those with non-MCN. In our cohort, none of the patients with pure MCN or MCN + other pathologies presented with nephrotic syndrome. Patients with non-MCN had better renal and overall survival than those with pure MCN but similar survivals to those with MCN + other pathologies. Number of myeloma casts (HR 1.08, p = 0.012) was the only independent prognostic factor for renal survival. Male sex (HR: 3.64; p = 0.015) and number of casts (HR: 1.17; p = 0.001) were independent prognostic factors for overall survival.Conclusion: Patients with MCN had more severe renal injury than those with non-MCN. Patients with non-MCN had better renal and overall outcomes than those with pure MCN, but their outcomes were similar to those with MCN + other pathologies. The independent predictors of overall survival were male sex and number of myeloma casts.Keywords: kidney biopsy, multiple myeloma, myeloma cast nephropathy, monoclonal immunoglobulin, prognosis

This paper analyzes the elements and chemical components contained in the gasification ash through elemental analysis and X-ray fluorescence spectroscopy, and proposes that the gasification ash should be poured into underground goaf as grouting fire prevention material. In order to solve the problem that the gasification ash slurry is easy to block the pipeline during the long-distance transportation process, the polymer surfactant carboxymethyl cellulose（ＣＭＣ） is used as the suspending agent. Water separation rate and fluidity of the slurry are tested by suspension and flow experiments under different water-cement ratios and suspending agent additions. The results show that the gasification ash contains a variety of metal elements and non-metal elements. These elements mainly exist in the form of oxides. The oxides with higher content are SiO2, Fe2O3, CaO and Al2O3. When the amount of gasification ash and CMC increased, the water extraction rate and fluidity of grout decreased gradually. Through the suspension test, when the slurry water-cement ratio is 1∶0.2, the CMC addition amount should be greater than 1.25%. When the water-cement ratio is 1∶0.4, 1∶0.6 or 1∶0.8, the CMC addition amount should be greater than 0.5%. If the water-cement ratio is 1∶1, the addition amount of CMC should be greater than 0.25%. If the water-cement ratio exceeds 1∶1, the slurry appears as paste, which does not meet the requirements of grouting.

Nonalcoholic fatty liver disease (NAFLD), characterized by extensive triglyceride accumulation in hepatocytes, may progress to nonalcoholic steatohepatitis (NASH) with liver fibrosis and inflammation and increase the risk of cirrhosis, cancer, and death. It has been reported that physical exercise is effective in ameliorating NAFLD and NASH, while skeletal muscle dysfunctions, including lipid deposition and weakness, are accompanied with NAFLD and NASH. However, the molecular characteristics and alterations in skeletal muscle in the progress of NAFLD and NASH remain unclear. In the present study, we provide a comprehensive analysis on the similarity and heterogeneity of quadriceps muscle in NAFLD and NASH mice models by RNA sequencing. Importantly, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway functional enrichment analysis revealed that NAFLD and NASH led to impaired glucose and lipid metabolism and deteriorated functionality in skeletal muscle. Besides this, we identified that myokines possibly mediate the crosstalk between muscles and other metabolic organs in pathological conditions. Overall, our analysis revealed a comprehensive understanding of the molecular signature of skeletal muscles in NAFLD and NASH, thus providing a basis for physical exercise as an intervention against liver diseases.

Objective To investigate the clinical efficacy and adverse reactions of CEAC conditioning regimen combined with autologous hematopoietic stem cell transplantation for treatment of non-Hodgkin lymphoma. Methods We conducted a retrospective analysis of 102 patients with non-Hodgkin lymphoma, who underwent autologous hematopoietic stem cell transplantation after CEAC conditioning regimen in our hospital from 2011 to 2017. The factors affecting the patients' survival, clinical efficacy of the treatment, neutrophil and platelet reconstitution time, and adverse events associated with the conditioning regimen were analyzed. Results Hematopoietic reconstruction was achieved successfully in 100 of the 102 patients. The median time of neutrophil and platelet reconstitution time was 10 d (7~17 d) and 12 d (7~33 d) in these cases, respectively. The main adverse reactions included nausea, vomit, fever, liver toxicity and diarrhea. The patients were followed up for a median of 42 months, during which disease progression occurred in 25 (24.5%) cases; death occurred in 18 (17.6%) cases, and 9 (8.8%) of these cases resulted from disease progression. The overall 3-year survival rate of the patients was 81.3%, with an overall 3-year progression-free survival rate of 77.5%. Univariate analysis showed that the disease type was a prognostic factor for the overall survival (P < 0.001) and progression-free survival (P < 0.001), and IPI score was a prognostic factor for progression-free survival (P=0.041). Multivariate analysis showed that the disease type (HR=0.144, 95%CI: 0.052~0.400, P < 0.001) was an independent prognostic factor for the overall survival; the disease type (HR=0.291, 95%CI: 0.133~0.637, P=0.002) and the pretransplant status (HR=1.940, 95%CI: 1.192~3.159, P=0.008) were independent prognostic factors for progression-free survival. The toxic reactions related with the conditioning regimen included nausea, vomiting, diarrhea, fever, and infections, and the transplant-related mortality rate was 1.96%. Conclusion CEAC conditioning regimen can achieve a good efficacy with tolerable adverse reactions in patients undergoing autologous hematopoietic stem cell transplantation for non-Hodgkin lymphoma.