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Ulcerative colitis (UC) is a chronic inflammatory bowel disease worldwide. Infiltration of pro-inflammatory macrophages (M1 macrophages) contributes to the occurrence of bowel inflammation. Transplantation of mesenchymal stem cells (MSCs) is a promising therapeutic strategy for UC, but the exact mechanism remains unknow yet. Here, we treated DSS-induced colitis mice with adipose‐derived mesenchymal stem cells (ADMSCs) and revealed that ADMSCs alleviated colon inflammation by reducing the infiltration of M1 macrophages. Moreover, ADMSCs exerted this therapeutic effect by inhibiting succinate accumulation, increasing PHD2 to prevent M1 macrophages from overexpressing HIF-1α and thereby reprogramming the glycolytic pathway of M1 macrophages. Meanwhile, the succinate secreted by M1 macrophages triggered ADMSCs to secrete PGE2 in return, which could also shift macrophages from M1 phenotype to M2. Our work demonstrated an immunomodulatory effect of ADMSCs and provided a novel perspective on UC therapy.

ABSTRACT Nonalcoholic fatty liver disease (NAFLD) is a prevalent and progressive disease spectrum ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), yet there is no effective treatment and efficient noninvasive diagnostic method for NASH. The present study investigated the longitudinal alternations of gut microbiota in the Western diet (WD) induced murine NAFLD model using 16S rRNA sequencing. Evident steatosis and inflammation were detected in the liver at the 8th and 12th week, while prompted hepatic oxidative injury and fibrosis were found at the 16th week. In this progressive process, impaired bile acid (BA) metabolism plays a vital part. Long-term WD intervention alters microbial richness and composition in the intestine, shaping characteristic microbial feature correspondence to each NAFLD stage. Descending abundances of Clostridia and Ruminococcaceae were found in NAFLD progression, while inflammation-related microbes [Eubacterium]_fissicatena_group, Romboutsia, and Erysipelatoclostridium were verified to identify borderline NASH at 8th and 12th week, and BA-associated taxa Dubosiella, Bosea, Helicobacter, and Alistipes were recognized as special symbols reflecting the state of oxidative damage and fibrosis in NASH at 16th week. Further, feces and colon abundances of Akkermansia were verified to be depleted in the process of borderline NASH progressed to NASH, and exhibited substantial correlations with NAFLD indexes ALT, AST, TC, and TBA. These characteristic taxa were effective to identify NAFLD and NASH, and microbiota-derived predictive models for NAFLD and NASH exhibited great potential (AUC 0.983 and 0.784). These findings demonstrate that a core set of gut microbiome especially BA-related taxa may be adopted as a noninvasive diagnostic tool for NAFLD and NASH. IMPORTANCE This study concentrates on longitudinal alternations of gut microbiota in NAFLD progression and discovers the interrelationships between them. These findings may uncover the role of gut microbiota in NAFLD progression and identify novel noninvasive diagnostic tools for NAFLD based on microbial biomarkers.

The protein ISG15 encoded by interferon-stimulated gene (ISG) 15 is the first identified member of the ubiquitin-like protein family and exists in the form of monomers and conjugated complexes. Like ubiquitin, ISG15 can mediate an ubiquitin-like modification by covalently modifying other proteins, known as ISGylation. There is growing evidence showing that both the free and conjugated ISG15 are involved in multiple key cellular processes, including autophagy, exosome secretion, DNA repair, immune regulation, and cancer occurrence and progression. In this review, we aim to further clarify the function of ISG15 and ISGylation in cancer, demonstrate the important relationship between ISG15/ISGylation and cancer, and emphasize new insights into the different roles of ISG15/ISGylation in cancer progression. This review may contribute to therapeutic intervention in cancer. However, due to the limitations of current research, the regulation of ISG15/ISGylation on cancer progression is not completely clear, thus further comprehensive and sufficient correlation studies are still needed.

The viscoelasticity of mechanically sensitive tissues such as periodontal ligaments (PDLs) is key in maintaining mechanical homeostasis. Unfortunately, PDLs easily lose viscoelasticity (e.g., stress relaxation) during periodontitis or dental trauma, which disrupt cell–extracellular matrix (ECM) interactions and accelerates tissue damage. Here, Pluronic F127 diacrylate (F127DA) hydrogels with PDL‐matched stress relaxation rates and high elastic moduli are developed. The hydrogel viscoelasticity is modulated without chemical cross‐linking by controlling precursor concentrations. Under cytomechanical loading, F127DA hydrogels with fast relaxation rates significantly improved the fibrogenic differentiation potential of PDL stem cells (PDLSCs), while cells cultured on F127DA hydrogels with various stress relaxation rates exhibited similar fibrogenic differentiation potentials with limited cell spreading and traction forces under static conditions. Mechanically, faster‐relaxing F127DA hydrogels leveraged cytomechanical loading to activate PDLSC mechanotransduction by upregulating integrin–focal adhesion kinase pathway and thus cytoskeletal rearrangement, reinforcing cell–ECM interactions. In vivo experiments confirm that faster‐relaxing F127DA hydrogels significantly promoted PDL repair and reduced abnormal healing (e.g., root resorption and ankyloses) in delayed replantation of avulsed teeth. This study firstly investigated how matrix nonlinear viscoelasticity influences the fibrogenesis of PDLSCs under mechanical stimuli, and it reveals the underlying mechanobiology, which suggests novel strategies for PDL regeneration. [ABSTRACT FROM AUTHOR]

In the field of lightweight structures, foldcore sandwich structure is regarded as a promising replacement for conventional honeycomb sandwich structure. In this study, a new M-type glass fiber foldcore structure was fabricated by hot-pressing molding technology, and the effects of various factors on the low-velocity impact characteristics were investigated. In addition, a 3 D progressive damage numerical model matching the experimental results was established. The results showed that the impact energy exerted a certain influence on the response characteristics of the sandwich structure, but did not change the development trend of the load curve. The sandwich panel was able to achieve the overall load-carrying potential for the impactor whose size was longer than the foldcore span (25 mm). In addition, as the sharpness of the impactor increased, the damage range of the sandwich panel became concentrated and the load-bearing capacity gradually decreased. As revealed by the findings, the maximum load and specific energy absorption of laminated sandwich panels were improved by 150 and 40% respectively compared to single sandwich panel at base position. Therefore, it is beneficial to appropriately reduce the core span and increase the number of laminations to improve impact resistance of foldcore sandwich in practical applications. [ABSTRACT FROM AUTHOR]

Morinda officinalis is a traditional Chinese tonic herb, and have been used in the treatment of multiple diseases. Here, three iridoid glycosides isolated from M. officinalis were evaluated for their roles in the autophagy-lysosomal pathway. All three iridoid glycosides could induce TFEB/TFE3-mediated lysosomal biogenesis and trigger autophagy. Interestingly, they promoted the nuclear import of TFEB/TFE3 without affecting their nuclear export, suggesting their role in the maintenance of lysosomal homeostasis. The results from this study shed light on the identification of autophagy activators from M. officinalis and provide a basis for developing them in the treatment of oxidative stress-involved diseases. [ABSTRACT FROM AUTHOR]

Abstract Background Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. In traditional anti-cancer therapy, epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI) have been proven to be beneficial for patients with EGFR mutations. However, patients with EGFR wild-type NSCLC were usually not respond to EGFR-TKIs. Enhancer of zeste homolog 2 (EZH2) is a key molecular in the PRC2 complex and plays an important role in epigenetic regulation and is overexpressed in variant tumors. EZH2 inhibitors have been reported to sensitize variant tumor cells to anticancer drugs. This study aimed to investigate whether the EZH2 inhibitors, GSK343 and DZNep when combined with gefitinib can reverse EGFR-TKIs resistance in EGFR wild-type NSCLC cells. Methods The RNA-sequencing data of patients with NSCLC [502 patients with lung squamous cell carcinoma, including 49 paracancerous lung tissues and 513 patients with lung adenocarcinoma (LUAD), including 59 paracancerous lung tissues] from the Cancer Genome Atlas (TCGA), were analyzed for EZH2 expression. EZH2 expression was verified in 40 NSCLC tissue cancer samples and their corresponding paracancerous tissues from our institute (TJMUGH) via RT-PCR. A549 and H1299 cells treated with siRNA or EZH2 inhibitors were subjected to cell viability and apoptosis analyses as well to EGFR pathway proteins expression analyses via western blotting. Results EZH2 was upregulated in human NSCLC tissues and correlated with poor prognosis in patients with LUAD based on data from both TCGA and TJMUGH. Both GSK343 and DZNep sensitized EGFR wild-type LUAD cells (A549 and H1299) to gefitinib and suppressed cell viability and proliferation in vitro by downregulating the phosphorylation of EGFR and AKT and by inducing cell apoptosis. Co-administration of EZH2 inhibitors (GSK343 or DZNep) with gefitinib exerted a stronger inhibitory effect on tumor activity, cell proliferation and cell migration than single drug administration in vitro and in vivo. Conclusions These data suggest that the combination of EZH2 inhibitors with EGFR-TKIs may be an effective method for treating NSCLC-patients with EGFR-wild type, who do not want to undergo traditional treatment with chemotherapy.

Iron is a critical element for living cells in terrestrial life. Although iron metabolism is strictly controlled in the body, disturbance of iron homeostasis under certain type of condition leads to innate and adaptive immune response. In innate immunity, iron regulates macrophage polarizations, neutrophils recruitment, and NK cells activity. In adaptive immunity, iron had an effect on the activation and differentiation of Th1, Th2, and Th17 and CTL, and antibody response in B cells. In this review, we focused on iron and immune regulation and listed the specific role of iron in macrophage polarization, T-cell activation, and B-cells antibody response. In addition, correlations between iron and several diseases such as cancer and aging degenerative diseases and some therapeutic strategies targeting those diseases are also discussed.

Nowadays, lung cancer has the highest mortality worldwide. The emergence of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has greatly improved the survival of patients with non-small cell lung cancer (NSCLC) having EGFR-TKI-sensitive mutations. Unfortunately, acquired resistance happens for most patients. In the present research, we found that EGFR-TKIs (such as gefitinib and osimertinib) can induce autophagy in NSCLC cell lines. Compared with parental sensitive cells, drug-resistant cells have higher autophagy activity. The use of an autophagy inhibitor could enhance the toxicity of gefitinib and osimertinib, which indicates that the enhancement of protective autophagy might be one of the mechanisms of EGFR-TKI resistance in NSCLC. In addition, increased autophagy activity is associated with decreased enhancer of zeste homolog 2 (EZH2) expression. Knockdown of EZH2 or EZH2 inhibitor treatment could lead to increased autophagy in NSCLC cells, indicating that EZH2 is a negative regulator of autophagy. We revealed that the increase in autophagy caused by the reduction of EZH2 was reversed in vitro and in vivo when combining gefitinib or osimertinib with suberoylanilide hydroxamic acid (SAHA), a broad-spectrum histone deacetylase inhibitor (HDACi). In conclusion, our results indicated that the combination of EGFR-TKIs and SAHA may be a new strategy to overcome EGFR-TKIs acquired resistance.

Background. The cholinergic anti-inflammatory pathway connects the immune response system and the nervous system via the vagus nerve. The key regulatory receptor is the α7-subtype of the nicotinic acetylcholine receptor (α7nAChR). Cholinergic anti-inflammatory pathway has been proved to be effective in suppressing the inflammation responses in acute lung injury (ALI). Dendritic cells (DCs), the important antigen-presenting cells, also express the α7nAChR. Past studies have indicated that reducing the quantity of mature conventional DCs and inhibiting the maturation of pulmonary DCs may prove effective for the treatment of ALI. However, the effects of cholinergic anti-inflammatory pathway on maturation, function, and quantity of DCs and conventional DCs in ALI remain unclear. Objective. It was hypothesized that cholinergic anti-inflammatory pathway may inhibit the inflammatory response of ALI by regulating maturation, phenotype, and quantity of DCs and conventional DCs. Methods. GTS-21 (GTS-21 dihydrochloride), an α7nAchR agonist, was prophylactically administered in sepsis-induced ALI mouse model and LPS-primed bone marrow-derived dendritic cells. The effects of GTS-21 were observed with respect to maturation, phenotype, and quantity of DCs, conventional DCs, and conventional DCs2 (type 2 conventional DCs) and the release of DC-related proinflammatory cytokines in vivo and in vitro. Results. The results of the present study revealed that GTS-21 treatment decreased the maturation of DCs and the production of DC-related proinflammatory cytokines in vitro and in sepsis-induced ALI mouse model; it reduced the quantity of CD11c+MHCII+ conventional DCs and CD11c+CD11b+ conventional DCs2 in vivo experiment. Conclusions. Cholinergic anti-inflammatory pathway contributes to the reduction in the inflammatory response in ALI by regulating maturation, phenotype, and quantity of DCs, conventional DCs, and conventional DCs2.

Abstract Background To investigate the distribution of peripheral anterior chamber depth (ACD) and the relationship between peripheral ACD and gonioscopy compared to other ocular parameters for primary angle closure disease (PACD) screening. We performed a population-based survey in Pudong New District of Shanghai, China, in 2011. Methods Cross-sectional study. Adults 50 and older were enrolled from a population-based study using cluster random sampling in Pudong New District, Shanghai. Remote ocular screening was performed with digital anterior eye structure photography. Van Herrick measurements were used to evaluate the peripheral ACD, the depth of the peripheral anterior chamber, and corneal thickness (CT), and the ACD to CT ratio was calculated. Subjects with peripheral ACD less than 0.5 CT were made follow-up appointments for clinical examination with gonioscopy. Receiver operating characteristic curves (ROC) were generated to show the performance of different tests in screening for primary angle closure disease (PACD). Results Two thousand five hundred twenty-eight adults participated in the study with 91 patients diagnosed with PACD. Two thousand four hundred sixty-three subjects had valid data in the right eye available for analysis. The mean peripheral ACD values for men and women were significantly different: 1.04 ± 0.46 (range 0.11–2.93) CT and 0.87 ± 0.41 (range 0.12–2.96) CT respectively (t = − 4.18; P

Abstract Background Iron metabolism disorder is closely associated with several malignant tumors, however the mechanisms underlying iron and the carcinogenesis in osteosarcoma are not yet well understood. Methods Cell proliferation ability of osteosarcoma cell lines was measured by CCK-8, EdU incorporation and colony formation assays. Cell cycle analysis was detected by flow cytometry. The carcinogenesis of osteosarcoma was measured by soft-agar formation, trans-well and Wound healing-scratch assay. Warburg effect was detected by Seahorse respirometry assays. Reactive oxygen species (ROS) level was measured by Dichlorodihydrofluorescein diacetate (DCFH-DA) fluorescent probes. Western blotting was used to measure the expression of mitoferrin 1 (SLC25A37) and mitoferrin 2 (SLC25A28). Iron level in vitro and vivo was detected by iron assay kit. RNAi stable cell lines was generated using shRNA. Results Iron promoted proliferation, carcinogenesis and Warburg effect of osteosarcoma cells. Iron-induced reactive oxygen species (ROS) played an important role in these processes. Iron accumulated more in mitochondrion than in cytoplasm, suggesting mitochondrion-mediated iron accumulation was involved in the development of osteosarcoma. Moreover, iron upregulated the expression of mitoferrin 1 (SLC25A37) and mitoferrin 2 (SLC25A28). Knock-down of mitoferrin 1 (SLC25A37) and mitoferrin 2 (SLC25A28) decreased the production of ROS. In addition, iron increased the expression of Warburg key enzymes HK2 and Glut1, and affected AMPK/mTORC1 signaling axis. Conclusions Mitochondrion-mediated iron accumulation promotes carcinogenesis and Warburg effect of osteosarcoma cells. Meanwhile, iron deprivation might be a novel effective strategy in the treatment of osteosarcoma.

The Western Sichuan Plateau (WSP), located in the eastern margin of the Qinghai–Tibet Plateau, is the most strongly deformed region of the continental crust in China. Frequent tectonic movements shape the unique topography and landform of the WSP and have also produced abundant geological heritage resources. Based on the existing geological heritage survey data in Sichuan Province, the nearest index analysis method of employing a regional spatial point model was used to reveal the distribution rules and the genetic mechanism of typical geological relics in the WSP for the first time. Results indicate that the formation and distribution of geological relics in the WSP are generally controlled by tectonic movement and supplemented by the comprehensive action of external forces such as flowing water. Their distribution shows a condensed spatial distribution pattern and extends along the strike of a fault zone and river strike strip. Finally, based on the characteristics of geological relics in the WSP, some suggestions on the protection and development of regional geological relics were put forward.

Abstract Background The global numbers of confirmed cases and deceased critically ill patients with COVID-19 are increasing. However, the clinical course, and the 60-day mortality and its predictors in critically ill patients have not been fully elucidated. The aim of this study is to identify the clinical course, and 60-day mortality and its predictors in critically ill patients with COVID-19. Methods Critically ill adult patients admitted to intensive care units (ICUs) from 3 hospitals in Wuhan, China, were included. Data on demographic information, preexisting comorbidities, laboratory findings at ICU admission, treatments, clinical outcomes, and results of SARS-CoV-2 RNA tests and of serum SARS-CoV-2 IgM were collected including the duration between symptom onset and negative conversion of SARS-CoV-2 RNA. Results Of 1748 patients with COVID-19, 239 (13.7%) critically ill patients were included. Complications included acute respiratory distress syndrome (ARDS) in 164 (68.6%) patients, coagulopathy in 150 (62.7%) patients, acute cardiac injury in 103 (43.1%) patients, and acute kidney injury (AKI) in 119 (49.8%) patients, which occurred 15.5 days, 17 days, 18.5 days, and 19 days after the symptom onset, respectively. The median duration of the negative conversion of SARS-CoV-2 RNA was 30 (range 6–81) days in 49 critically ill survivors that were identified. A total of 147 (61.5%) patients deceased by 60 days after ICU admission. The median duration between ICU admission and decease was 12 (range 3–36). Cox proportional-hazards regression analysis revealed that age older than 65 years, thrombocytopenia at ICU admission, ARDS, and AKI independently predicted the 60-day mortality. Conclusions Severe complications are common and the 60-day mortality of critically ill patients with COVID-19 is considerably high. The duration of the negative conversion of SARS-CoV-2 RNA and its association with the severity of critically ill patients with COVID-19 should be seriously considered and further studied.

Abstract Background Dietary fiber is effective for colorectal cancer (CRC) treatment. Interleukin-6 (IL-6) and its adaptors are potential targets for CRC therapy. Butyrate, a metabolite of dietary fiber, is a new, highly safe type of targeted drug. Methods In this study, Cell Counting Kit-8 cell viability and wound healing assays, western blot analysis, immunofluorescence staining, and xenograft tumor mouse models were used to evaluate the anticancer effect of butyrate and its possible mechanism in vivo and in vitro. Results Dietary fiber and sodium butyrate (NaB) decreased CRC burden by decreasing IL-6 receptor gp130 and blocking IL-6/JAK2/STAT3 axis activation in vitro and in vivo. Furthermore, NaB reduced the gp130 protein level by regulating its degradation rate via targeting TRAF5. Conclusions The fiber metabolite butyrate inhibits CRC development by reducing gp130 via TRAF5.