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BackgroundIntrahepatic cholangiocarcinoma (iCCA) is a highly aggressive cancer with a dismal prognosis and few effective therapeutic approaches. This study aimed to investigate the efficacy, safety, and predictive biomarkers of hepatic arterial infusion chemotherapy (FOLFOX-HAIC) in combination with lenvatinib and PD-1 inhibitor for patients with advanced iCCA.MethodsLocally advanced or metastatic iCCA patients receiving the triple combination therapy of lenvatinib, PD-1 inhibitor, and FOLFOX-HAIC were included in this retrospective study. Primary endpoint was the progression-free survival, evaluated using the RECIST criterion. The secondary endpoints included overall survival, objective response rate, and safety. Whole exome and RNA sequencing of tumor biopsy tissues were performed for biomarker exploration.ResultsBetween May, 2019 and December 2022, a total of 46 patients were included in this study. The primary endpoint showed a median progression-free survival of 9.40 months (95% CI: 5.28-13.52), with a 6-month progression-free survival rate of 76.1%. The median overall survival was 16.77 months (95% CI, 14.20-19.33), with an objective response rate of 47.8% and disease control rate of 91.3% per RECIST. In addition, 4.3% and 8.7% of patients achieved complete response of all lesions and intrahepatic target lesions per mRECIST, respectively. The most common treatment-related adverse events were neutropenia, thrombocytopenia, elevated aspartate aminotransferase and alanine aminotransferase level. Furthermore, integrated analysis of genetic, transcriptomic, and immunohistochemistry data revealed that pre-existing immunity (high expression level of immune-related signatures and intra-tumoral CD8+ T cell density) in baseline tumor tissues was associated with superior clinical benefits. However, the evaluation of tumor mutation burden did not show potential predictive value in this triple combination.ConclusionFOLFOX-HAIC in combination with lenvatinib and PD-1 inhibitor demonstrated a promising antitumor activity with manageable safety profiles in patients with advanced iCCA. Moreover, our study also revealed new perspectives on potential biomarkers for clinical efficacy.

BackgroundEpididymal leiomyosarcoma is an extremely rare tumor. In this study, we describe the sonographic features of this uncommon tumor.MethodsA case of epididymal leiomyosarcoma diagnosed at our institute was retrospectively analyzed. Ultrasonic images, noted clinical manifestations, treatment procedures, and pathology results were collected for this patient. The same information was collected from a systematic literature search on epididymal leiomyosarcoma, including the PUBMED, Web of Science and Google Scholar databases.ResultsThe literature search resulted in 12 articles; we were able to extract data from 13 cases of epididymal leiomyosarcomatosis. The median patient age was 66 (35–78) years, and the average tumor diameter was 2–7 cm. All patients had unilateral epididymal involvement. The lesions were all solid, irregular-shaped in almost half of the cases, featured clear borders in six cases, and had unclear borders in four cases. The internal echogenicity was heterogeneous in the majority of lesions: six cases were hypoechoic (7/11) and three cases moderately echoic (3/10). Information on blood flow within the mass was provided in four cases, but all were noted with significant vascularity. Surrounding tissue invasion was discussed in 11 cases, with 4 featuring peripheral invasion or metastasis.ConclusionEpididymal Leiomyosarcoma demonstrates sonographic characteristics common to many malignant tumors, such as increased density, irregular shape, heterogeneous internal echogenicity, and hypervascular. Ultrasonography is helpful to differentiate benign epididymal lesions, and can provide some reference for clinical diagnosis and treatment. However, compared with other malignant tumors of the epididymis, it has no characteristic sonographic features,and pathological confirmation is required.

The breakthrough in the discovery of immune checkpoint PD-1/PD-L1 inhibitors, such as the series of Bristol Myers Squibb synthetic compounds, boosted the research of small molecules with blockade effects on the interaction of PD-1/PD-L1. However, the search for natural products derived PD-1/PD-L1 inhibitors can be impeded by the false positive and/or negative results from the screening assays. Herein, we combined a PD-1/PD-L1 blockade assay (pair ELISA) and a PD-L1/PD-L1 binding assay (surface plasmon resonance; SPR) to evaluate a panel of natural compounds previously reported to show anti-PD-1/PD-L1 activity. The test compounds included kaempferol, cosmosiin, tannic acid, pentagalloyl glucose, ellagic acid, resveratrol, urolithin A, and rifubutin. Based on the analyses of their responses to the combined screening assays, these compounds were categorized into four groups: I) PD-1/PD-L1 inhibitors that can bind to PD-1 and PD-L1; II) PD-1/PD-L1 inhibitors selectively bind to PD-L1 protein; III) PD-1/PD-L1 inhibitors without binding capacity, and IV) PD-1/PD-L1 binders without blockade effect. Discrimination of positive responders in the PD-1/PD-L1 blockade and binding assays can provide useful insights to avoid false outcomes. Examples demonstrated in this study suggest that it is crucial to adopt proper evaluation methods (including using multiple-facet functional assays and target binding techniques) for the search for natural products derived PD-1/PD-L1 inhibitors.

Immune checkpoint blockade and MAPK-targeted combined therapy is a promising regimen for advanced melanoma patients. However, the clinical benefit from this combo regimen remains limited, especially in patients who acquired resistance to MAPK-targeted therapy. Here, we systematically characterized the immune landscape during MAPK-targeted therapy in patients and mouse melanoma models. We observed that both the abundance of tumor-infiltrated T cells and the expression of immune-related genes were upregulated in the drug-responsive period, but downregulated in the resistance period, implying that acquired drug resistance dampens the antitumor immune response. Further transcriptomic dissection indicated that loss of MHC-I antigen presentation on tumor cells plays a critical role in the reduction of T cell infiltration during drug resistance. Survival analysis demonstrates that loss of antigen presentation and reduction of T-cell infiltration during acquired drug resistance are associated with poorer clinical response and prognosis of anti-PD-1 therapy in melanoma patients. In addition, we identified that alterations in the MAPK inhibitor resistance-related oncogenic signaling pathway closely correlated with deficiency of MHC-I antigen presentation, including activation of the PI3K-mTOR, MAPK, and Wnt pathways. In conclusion, our research illuminates that decreased infiltration of T cells is associated with acquired drug resistance during MAPK-targeted therapy, which may underlie the cross-resistance to immune checkpoint blockade.

The HLA class Ib molecule is an alloantigen that causes transplant rejection on behalf of individual human and plays an important role in maternal-fetal immune tolerance. Early studies on HLA class Ib focused on the mechanism of HLA-G-induced immune escape, but in recent years, studies on the mechanism of HLA-G have deepened and gradually explored the mechanism of HLA-E and HLA-F, which are also HLA class Ib molecules. In the maternal-fetal interface, trophoblast cells express HLA class Ib molecules to protect the fetus from maternal immune cells by binding to inhibitory receptors of decidual immune cells (DICs) and shifting Th1/Th2 balance toward Th2 bias. Further studies on the molecular mechanism of HLA class Ib molecules provide a reference for its application in the field of clinical assisted reproduction.

We previously reported that the structural modifications of pentacyclic triterpenoids including oleanolic acid resulted in enhanced hyaluronidase inhibitory activity but whether this applies to other pentacyclic triterpenoids such as betulinic acid (BA) is unknown. Herein, we synthesized BA derivatives with an α,β-unsaturated ketene moiety and evaluated for their: 1) hyaluronidase inhibitory activity and, 2) anti-inflammatory effects against lipopolysaccharides (LPS) induced inflammation. Compared to BA, the BA derivatives exerted improved anti-hyaluronidase activity (26.3%–72.8% vs. 22.6%) and anti-inflammatory effects by reducing nitrite production in BV2 cells (3.9%–46.8% vs. 3.4%) and RAW264.7 cells (22.7%–49.2% vs. 20.4%). BA derivatives inhibited LPS-induced production of pro-inflammatory cytokines in THP-1 cells (15.2%–22.4%). BA derivatives also exerted promising anti-inflammatory effects against hyaluronic acid fragment induced nitrite production (8.6%–35.6%) in THP-1 cells. BA derivatives showed augmented anti-hyaluronidase and anti-inflammatory effects but further biological evaluations using in vivo models are warranted to confirm their efficacy.

Ocean acidification, as one of the major consequences of global climate change, markedly affects multiple ecosystem functions in disparate marine environments from coastal habitats to the deep ocean. Evaluation of the responses of marine microbial community to the increasing partial pressure of CO2 (pCO2) is crucial to explore the microbe-driven biogeochemical processes in the future ocean. In this study, a microcosm incubation of eutrophic coastal water from Xiamen Bay under elevated pCO2 (about 1,000 μatm) and control (ambient air, about 380–410 μatm) conditions was conducted to investigate the effect of ocean acidification on the natural bacterioplankton community. During the 5-day incubation period, the chlorophyll a concentration and bacterioplankton abundance were not significantly affected by increased pCO2. Hierarchical clustering and non-metric multidimensional scaling analysis based on Bray-Curtis similarity among the bacterioplankton community derived from the 16S rRNA genes revealed an inconspicuous impact of elevated pCO2 on the bacterial community. During the incubation period, Proteobacteria, Bacteroidetes, Actinobacteria, Cyanobacteria, and Epsilonbacteraeota were predominant in all microcosms. Despite the distinct temporal variation in the composition of the bacterioplankton community during the experimental period, statistical analyses showed that no significant difference was found on bacterioplankton taxa between elevated pCO2 and control, indicating that the bacterioplankton at the population-level were also insensitive to elevated pCO2. Our results therefore suggest that the bacterioplankton communities in the fluctuating and eutrophic coastal ecosystems appear to be adaptable to the short-term elevated pCO2.

Objective: The objective of the study was to evaluate the relationship between frequency of exposure to general anesthesia before the age of 3 and subsequent risk of diagnosis for attention-deficit hyperactivity disorder (ADHD).Method: We searched PubMed, Embase, Web of Science, and Cochrane Library database for eligible inclusion in the meta-analysis. The indicated outcomes were extracted from the included studies, and the combined effects were calculated using the RevMan software 5.3.Results: Compared with no exposure to general anesthesia, single exposure to general anesthesia did not increase the risk of ADHD for children before the age of 3 [hazard ratio (HR): 1.14, 95%; confidence intervals (CI): 0.97–1.35; p = 0.11; I2 = 0%], while multiple exposures to general anesthesia did increase the risk of ADHD (HR: 1.83; 95% CIs: 1.00–3.32; p = 0.05; I2 = 81%).Conclusion: Multiple, but not single, exposures to general anesthesia in children before age of 3 increased the risk of ADHD.

Obesity, a chronic low-grade inflammatory state, not only promotes bone loss, but also accelerates cell senescence. However, little is known about the mechanisms that link obesity, bone loss, and cell senescence. Interleukin-6 (IL-6), a pivotal inflammatory mediator increased during obesity, is a candidate for promoting cell senescence and an important part of senescence-associated secretory phenotype (SASP). Here, wild type (WT) and (IL-6 KO) mice were fed with high-fat diet (HFD) for 12 weeks. The results showed IL-6 KO mice gain less weight on HFD than WT mice. HFD induced trabecular bone loss, enhanced expansion of bone marrow adipose tissue (BMAT), increased adipogenesis in bone marrow (BM), and reduced the bone formation in WT mice, but it failed to do so in IL-6 KO mice. Furthermore, IL-6 KO inhibited HFD-induced clone formation of bone marrow cells (BMCs), and expression of senescence markers (p53 and p21). IL-6 antibody inhibited the activation of STAT3 and the senescence of bone mesenchymal stem cells (BMSCs) from WT mice in vitro, while rescued IL-6 induced senescence of BMSCs from IL-6 KO mice through the STAT3/p53/p21 pathway. In summary, our data demonstrated that IL-6 KO may maintain the balance between osteogenesis and adipogenesis in BM, and restrain senescence of BMSCs in HFD-induced bone loss.

The intestinal microbiome influences the health of animals. However, little is known about the impact of indoor conditions and sex on intestinal microbiome diversity and composition in ducks. The present study aimed to investigate differences in the cecal microbiome between male and female ducks reared on the floor (PY group) or in cages (LY group). We also determined the relationships between cecal microbiota composition and slaughter traits, and the expression levels of mucosal and intestinal structural genes in ducks. There was a slight difference in slaughter traits among the groups, with cecum weight being significantly lighter in the LY compared with the PY group, especially in females (p < 0.05). Analysis of the alpha diversity of the cecal microbiota between males and females in the LY and PY groups showed that LY males had significantly lower diversity and richness. Beta diversity analysis demonstrated differences in the microbiota composition in relation to rearing conditions, and a significant difference between the sexes in the PY groups. The dominant bacterial phyla in duck cecum were Bacteroidetes, Firmicutes, Proteobacteria, and Fusobacteria. The relative abundances of the most common bacteria revealed that the intestinal microbiota diversity and composition were affected by both feeding conditions and sex. Several bacterial genera were detected differentially among the groups. These genera were correlated with slaughter traits and expression levels of mucosal and cecal structural genes in ducks. In conclusion, rearing conditions, sex, and associated changes in the cecal microbiota are thus associated with gut barrier functions in ducks.

Divalent metal transporter 1 (DMT1) is a key transporter of iron uptake and delivering in human and animals. However, post-transcriptional regulation of DMT1 is poorly understood. In this study, bioinformatic algorithms (TargetScan, PITA, miRanda, and miRDB) were applied to predict, screen, analyze, and obtain microRNA-16 family members (miR-16, miR-195, miR-497, and miR-15b) targeting DMT1, seed sequence and their binding sites within DMT1 3′ untranslated region (3′ UTR) region. As demonstrated by dual-luciferase reporter assays, luciferase activity of DMT1 3′ UTR reporter was impaired/enhanced when microRNA-16 family member over-expression plasmid/its inhibitor was transfected to HCT116 cells. Corroboratively, co-transfection of microRNA-16 family member over-expression plasmid and DMT1 3′ UTR mutant reporter repressed the luciferase activity in HCT116 cells. In addition, over-expression microRNA-16 family member augmented its expression and diminished DMT1 protein expression in HCT116 cells. Interestingly, tail vein injection of miR-16 assay revealed reduced plasma iron levels, higher miR-16 expression, and lower DMT1 protein expression in the duodenum of mice. Taken together, we provide evidence that microRNA-16 family (miR-16, miR-195, miR-497, and miR-15b) is confirmed to repress intestinal DMT1 expression in vitro and in vivo, which will give valuable insight into post-transcriptional regulation of DMT1.

The mechanisms of adaptive resistance of Escherichia coli to aminoglycosides remain unclear. Our RNA-Seq study found that expression of yhjX was markedly upregulated during initial exposure to subinhibitory concentrations of gentamicin. The expression of yhjX was then downregulated dramatically during a second exposure to gentamicin compared to the first exposure. YhjX encodes a putative transporter of the major facilitator superfamily, which is known to be the sole target of the YpdA/YpdB two-component system, the expression of which is highly and specifically induced by pyruvate. To investigate the effect of yhjX on the adaptive resistance of E. coli, in the present study, we constructed yhjX deletion and complemented strains of E. coli ATCC25922. Changes in extracellular pyruvate levels of wide-type and yhjX mutant were measured to determine whether YhjX functions as a pyruvate transporter. The results showed that yhjX deletion improved the growth of E. coli in medium containing subinhibitory concentrations of gentamicin. The yhjX deletion mutant did not exhibit adaptive resistance to subinhibitory concentrations of gentamicin. YhjX might not function as a pyruvate efflux pump in E. coli but was associated with the decrease following a sharp increase in the extracellular pyruvate level. Our findings indicate that yhjX regulates the growth of E. coli in the presence of a subinhibitory concentration of gentamicin and mediates the adaptive resistance to gentamicin.

BackgroundMetagenomic next-generation sequencing (mNGS) has been widely reported to identify pathogens in infectious diseases (IDs). In this work, we intended to investigate the diagnostic value and clinical acceptance of paired-samples mNGS as compared to the culture method.MethodsA total of 361 patients with suspected infection were retrospectively included. With reference to the clinical diagnosis, we compared the diagnostic performance and clinical acceptance in pathogen detection between mNGS and culture tests. Moreover, the pathogen concordance of paired blood and respiratory tract (RT) samples in mNGS assay was investigated.ResultsAmong 511 samples, 62.04% were shown to be pathogen positive by mNGS, and that for clinical diagnosis was 51.86% (265/511). When compared to culture assay (n = 428), mNGS had a significantly higher positivity rate (51.87% vs. 33.18%). With reference to the clinical diagnosis, the sensitivity of mNGS outperformed that of culture (89.08% vs. 56.72%). Importantly, mNGS exhibited a clinically accepted rate significantly superior to that of culture. In addition, the mNGS result from 53 paired blood and RT samples showed that most pairs were pathogen positive by both blood and RT, with pathogens largely being partially matched.ConclusionThrough this large-scale study, we further illustrated that mNGS had a clinically accepted rate and sensitivity superior to those of the traditional culture method in diagnosing infections. Moreover, blood and paired RT samples mostly shared partial-matched positive pathogens, especially for pathogens with abundant read numbers in RT, indicating that both blood and RT mNGS can aid the identification of pathogens for respiratory system infection.

Hepatitis B infection is substantially associated with the development of liver cancer globally, with the prevalence of hepatocellular carcinoma (HCC) cases exceeding 50%. Hepatitis B virus (HBV) encodes the Hepatitis B virus X (HBx) protein, a pleiotropic regulatory protein necessary for the transcription of the HBV covalently closed circular DNA (cccDNA) microchromosome. In previous studies, HBV-associated HCC was revealed to be affected by HBx in multiple signaling pathways, resulting in genetic mutations and epigenetic modifications in proto-oncogenes and tumor suppressor genes. In addition, transforming growth factor-β (TGF-β) has dichotomous potentials at various phases of malignancy as it is a crucial signaling pathway that regulates multiple cellular and physiological processes. In early HCC, TGF-β has a significant antitumor effect, whereas in advanced HCC, it promotes malignant progression. TGF-β interacts with the HBx protein in HCC, regulating the pathogenesis of HCC. This review summarizes the respective and combined functions of HBx and TGB-β in HCC occurrence and development.

Infectious diseases pose a severe threat to human health and are accompanied by significant economic losses. Studies of urban outbreaks of infectious diseases are diverse. However, previous studies have neglected the identification of critical events and the evaluation of scenario-based modeling of urban infectious disease outbreak emergency management mechanisms. In this paper, we aim to conduct an empirical analysis and scenario extrapolation using a questionnaire survey of 18 experts, based on the CIA-ISM method and scenario theory, to identify the key factors influencing urban infectious disease outbreaks. Subsequently, we evaluate the effectiveness of urban infectious disease outbreak emergency management mechanisms. Finally, we compare and verify the actual situation of COVID-19 in China, drawing the following conclusions and recommendations. (1) The scenario-based urban infectious disease emergency management model can effectively replicate the development of urban infectious diseases. (2) The establishment of an emergency command center and the isolation and observation of individuals exposed to infectious diseases are crucial factors in the emergency management of urban outbreaks of infectious disease.

Cancer, ranks as the secondary cause of death, is a group of diseases that are characterized by uncontrolled tumor growth and distant metastasis, leading to increased mortality year-on-year. To date, targeted therapy to intercept the aberrant proliferation and invasion is crucial for clinical anticancer treatment, however, mutant expression of target genes often leads to drug resistance. Therefore, it is essential to identify more molecules that can be targeted to facilitate combined therapy. Previous studies showed that death associated protein 3 (DAP3) exerts a pivotal role in regulating apoptosis signaling of tumors, meanwhile, aberrant DAP3 expression is associated with the tumorigenesis and disease progression of various cancers. This review provides an overview of the molecule structure of DAP3 and the discrepant roles played by DAP3 in various types of tumors. Considering the molecular mechanism of DAP3-regulated cancer development, new potential treatment strategies might be developed in the future.

BackgroundLower respiratory tract infections are the leading cause of morbidity and mortality in children worldwide. Timely and accurate pathogen detection is crucial for proper clinical diagnosis and therapeutic strategies. The low detection efficiency of conventional methods and low specificity using respiratory samples seriously hindered the accurate detection of pathogens.MethodsIn this study, we retrospectively enrolled 1,032 children to evaluate the performance of metagenomics next-generation sequencing (mNGS) using bronchoalveolar lavage fluid (BALF) sample and protected bronchial brushing (BB) sample in diagnosing pneumonia in children. In addition, conventional tests (CTs) were also performed.ResultsThe specificity of BB mNGS [67.3% (95% CI 58.6%–75.9%)] was significantly higher than that of BALF mNGS [38.5% (95% CI 12.0%–64.9%)]. The total coincidence rate of BB mNGS [77.6% (95% CI 74.8%–80.5%)] was slightly higher than that of BALF mNGS [76.5% (95% CI 68.8%–84.1%)] and CTs [38.5% (95% CI 35.2%–41.9%)]. During the epidemics of Mycoplasma pneumoniae, the detection rate of M. pneumoniae in the >6-year group (81.8%) was higher than that in the 3–6-year (78.9%) and 6-year, and 3–6-year groups, respectively. mNGS detection should be performed at the duration of 5–7 days after the start of continuous anti-microbial therapy or at the duration of 6–9 days from onset to mNGS test.ConclusionsThis is the first report to evaluate the performance of BB mNGS in diagnosing pulmonary infections in children on a large scale. Based on our findings, extensive application of BB mNGS could be expected.

Psoriasis is a chronic inflammatory skin disease. The histopathological features of psoriasis include excessive proliferation of keratinocytes and infiltration of immune cells. The S100 proteins are a group of EF-hand Ca2+-binding proteins, including S100A2, -A7, -A8/A9, -A12, -A15, which expression levels are markedly upregulated in psoriatic skin. These proteins exert numerous functions such as serving as intracellular Ca2+ sensors, transduction of Ca2+ signaling, response to extracellular stimuli, energy metabolism, and regulating cell proliferation and apoptosis. Evidence shows a crucial role of S100 proteins in the development and progress of inflammatory diseases, including psoriasis. S100 proteins can possibly be used as potential therapeutic target and diagnostic biomarkers. This review focuses on the pathogenic role of S100 proteins in psoriasis.

Background and Objective: Cardiovascular disease is a high-fatality health issue. Accurate measurement of cardiovascular function depends on precise segmentation of physiological structure and accurate evaluation of functional parameters. Structural segmentation of heart images and calculation of the volume of different ventricular activity cycles form the basis for quantitative analysis of physiological function and can provide the necessary support for clinical physiological diagnosis, as well as the analysis of various cardiac diseases. Therefore, it is important to develop an efficient heart segmentation algorithm.Methods: A total of 275 nuclear magnetic resonance imaging (MRI) heart scans were collected, analyzed, and preprocessed from Huaqiao University Affiliated Strait Hospital, and the data were used in our improved deep learning model, which was designed based on the U-net network. The training set included 80% of the images, and the remaining 20% was the test set. Based on five time phases from end-diastole (ED) to end-systole (ES), the segmentation findings showed that it is possible to achieve improved segmentation accuracy and computational complexity by segmenting the left ventricle (LV), right ventricle (RV), and myocardium (myo).Results: We improved the Dice index of the LV to 0.965 and 0.921, and the Hausdorff index decreased to 5.4 and 6.9 in the ED and ES phases, respectively; RV Dice increased to 0.938 and 0.860, and the Hausdorff index decreased to 11.7 and 12.6 in the ED and ES, respectively; myo Dice increased to 0.889 and 0.901, and the Hausdorff index decreased to 8.3 and 9.2 in the ED and ES, respectively.Conclusion: The model obtained in the final experiment provided more accurate segmentation of the left and right ventricles, as well as the myocardium, from cardiac MRI. The data from this model facilitate the prediction of cardiovascular disease in real-time, thereby providing potential clinical utility.

BackgroundImmunotherapy plays an increasingly critical role in the systemic treatment of HCC. This current study aimed to establish a novel prognostic predictor of Programmed death 1 (PD-1) inhibitor therapy in hepatocellular carcinoma (HCC) independent of Child-Pugh grade.MethodsOur study screened patients with HCC who received PD-1 inhibitors at Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology from January 2018 to December 2020. ALG grade was determined by the patient’s serum ALP and GGT levels before the initiation of PD-1 inhibitors. The endpoints of our study were overall survival (OS) and progression free survival (PFS). Follow-up ended at May 31, 2022.ResultsEighty- five patients (77 with Child−Pugh grade A, 8 with Child−Pugh grade B at baseline) were enrolled according to the inclusion criteria. Patients with Child−Pugh grade A achieved longer PFS and OS than those with Child−Pugh grade B. Patients with ALG grade 3 at baseline showed worse tumor response and poorer survival, and ALG grade could stratify patients with Child−Pugh grade A into subgroups with significantly different prognosis.ConclusionsALG grade, combining ALP and GGT, is a novel and readily available prognostic marker and the predictive effect of ALG grade on patient prognosis is independent of Child−Pugh grade.

Ischemic stroke, mostly caused by thromboembolic or thrombotic arterial occlusions, is a primary leading cause of death worldwide with high morbidity and disability. Unfortunately, no specific medicine is available for the treatment of cerebral I/R injury due to its limitation of therapeutic window. Hydroxysafflor yellow A, a natural product extracted from Carthamus tinctorius, has been extensively investigated on its pharmacological properties in cerebrovascular diseases. However, review focusing on the beneficial role of HSYA against cerebral I/R injury is still lacking. In this paper, we reviewed the neuroprotective effect of HSYA in preclinical studies and the underlying mechanisms involved, as well as clinical data that support the pharmacological activities. Additionally, the sources, physicochemical properties, biosynthesis, safety and limitations of HSYA were also reviewed. As a result, HSYA possesses a wide range of beneficial effects against cerebral I/R injury, and its action mechanisms include anti-excitotoxicity, anti-oxidant stress, anti-apoptosis, anti-inflammation, attenuating BBB leakage and regulating autophagy. Collectively, HSYA might be applied as one of the promising alternatives in ischemic stroke treatment.

Coronavirus disease 2019 (COVID-19) is currently a severe threat to global public health, and the immune response to COVID-19 infection has been widely investigated. However, the immune status and microecological changes in the respiratory systems of patients with COVID-19 after recovery have rarely been considered. We selected 72 patients with severe COVID-19 infection, 57 recovered from COVID-19 infection, and 65 with non-COVID-19 pneumonia, for metatranscriptomic sequencing and bioinformatics analysis. Accordingly, the differentially expressed genes between the infected and other groups were enriched in the chemokine signaling pathway, NOD-like receptor signaling pathway, phagosome, TNF signaling pathway, NF-kappa B signaling pathway, Toll-like receptor signaling pathway, and C-type lectin receptor signaling pathway. We speculate that IL17RD, CD74, and TNFSF15 may serve as disease biomarkers in COVID-19. Additionally, principal coordinate analysis revealed significant differences between groups. In particular, frequent co-infections with the genera Streptococcus, Veillonella, Gemella, and Neisseria, among others, were found in COVID-19 patients. Moreover, the random forest prediction model with differential genes showed a mean area under the curve (AUC) of 0.77, and KCNK12, IL17RD, LOC100507412, PTPRT, MYO15A, MPDZ, FLRT2, SPEG, SERPINB3, and KNDC1 were identified as the most important genes distinguishing the infected group from the recovered group. Agrobacterium tumefaciens, Klebsiella michiganensis, Acinetobacter pittii, Bacillus sp. FJAT.14266, Brevundimonas naejangsanensis, Pseudopropionibacterium propionicum, Priestia megaterium, Dialister pneumosintes, Veillonella rodentium, and Pseudomonas protegens were selected as candidate microbial markers for monitoring the recovery of COVID patients. These results will facilitate the diagnosis, treatment, and prognosis of COVID patients recovering from severe illness.

Various studies have described the roles of myeloid-derived suppressor cells (MDSCs) in pathological conditions, but relatively few have described them under normal physiological conditions. Accumulation of MDSCs is important creating an anti-inflammation environment, which is essential for fertilized egg implantation. This study was designed to record the dynamic changes in MDSC-like cells composition during the menstrual period (MP) and ovulation period (OP) in healthy volunteers over the course of a single menstrual cycle to explore the association between MDSCs and the menstrual cycle under normal physiological conditions. The ratio of MDSC-like cells was higher in MP samples, whereas the activity of Arg-1 was higher during the OP window. There was a negative correlation between the ratio of MDSC-like cells and the percentage of lymphocytes and a positive correlation between MDSC-like cells and prostaglandin E2 (PGE2). Furthermore, regular changes in the ratio and function of MDSC-like cells in the peripheral blood were observed during menstruation, all of which corresponded to the cycle stage. During menstruation, MDSCs may promote endometrial repair, whereas they promote pregnancy during the OP. These findings may help to better understand the pathophysiology of pregnancy-related complications and lay a foundation for improving perinatal outcomes.

This case study aimed to investigate the changes in student teachers’ (STs) interactional language during their internship at local schools. The student teacher interactive language was measured using the analytical tool of improved Flanders interactive analysis system (iFIAS), and an intervention and interview were conducted afterward. The study found that the student teacher’s interactive language keeps changing: the ratio of teacher language (TL) is increasing, while the ratio of student language (SL) and silence are decreasing; the teacher’s direct instruction gradually shifts to indirect instruction; the number of positive integration grids (PIG) grows larger, while the number of defect grids is getting smaller; and the teacher asks more valid questions and makes more positive comments. The overall change did not come naturally, but due to the mentor’s instruction, the ST’s self-reflection, and the researchers’ prompt feedback of the iFIAS after each lesson. The study quantified the ST’s classroom language using iFIAS to provide a visualized understanding of the language. The findings can provide a reference value for future research on the interactive language of student teachers.

Anti-PD-1/PD-L1 therapy has shown significant benefits in the treatment of a variety of malignancies. However, not all cancer patients can benefit from this strategy due to drug resistance. Therefore, there is an urgent need for methods that can effectively improve the efficacy of anti-PD-1/PD-L1 therapy. Combining anti-PD-1/PD-L1 therapy with regorafenib has been demonstrated as an effective method to enhance its therapeutic effect in several clinical studies. In this review, we describe common mechanisms of resistance to anti-PD-1/PD-L1 therapy, including lack of tumor immunogenicity, T cell dysfunction, and abnormal expression of PD-L1. Then, we illustrate the role of regorafenib in modifying the tumor microenvironment (TME) from multiple aspects, which is different from other tyrosine kinase inhibitors. Regorafenib not only has immunomodulatory effects on various immune cells, but can also regulate PD-L1 and MHC-I on tumor cells and promote normalization of abnormal blood vessels. Therefore, studies on the synergetic mechanism of the combination therapy may usher in a new era for cancer treatment and help us identify the most appropriate individuals for more precise treatment.

Hypoxia is an important feature of the tumor microenvironment(TME) and is closely associated with cancer metastasis, immune evasion, and drug resistance. However, the precise role of hypoxia in hepatocellular carcinoma(HCC), as well as its influence on the TME, and drug sensitivity remains unclear. We found the excellent survival prediction value of Hypoxia_DEGs_Score model. In hypoxic HCC, somatic mutation, copy number variation, and DNA methylation were closely related to hypoxic changes and affected tumorigenesis, progression, metastasis, and drug resistance. In HCC, aggravated hypoxic stress was found to be accompanied by an immune exclusion phenotype and increased infiltration of immunosuppressive cells. In the validation cohort, patients with high Hypoxia_DEGs_Score were found to have worse immunotherapeutic outcomes and prognoses, and may benefit from drugs against cell cycle signaling pathways rather than those inhibiting the PI3K/mTOR pathway. Hypoxia_DEGs_Score has an excellent predictive capability of changes in the TME, the efficacy of immunotherapy, and the response of drugs. Therefore, Hypoxia_DEGs_Score can help develop personalized immunotherapy regimens and improve the prognosis of HCC patients.

Novel pyrazolecarbamide derivatives bearing a sulfonate fragment were synthesized to identify potential antifungal and antiviral agents. All the structures of the key intermediates and target compounds were confirmed by nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS). The single-crystal X-ray diffraction of the compound T22 showed that pyrazole carbamide is a sulfonate. The in vitro antifungal activities of the target compounds against Colletotrichum camelliae, Pestalotiopsis theae, Gibberella zeae, and Rhizoctonia solani were evaluated at 50 μg/ml. Among the four pathogens, the target compounds exhibited the highest antifungal activity against Rhizoctonia solani. The compound T24 (EC50 = 0.45 mg/L) had higher antifungal activity than the commercial fungicide hymexazol (EC50 = 10.49 mg/L) against R. solani, almost similar to bixafen (EC50 = 0.25 mg/L). Additionally, the target compounds exhibited protective effects in vivo against TMV. Thus, this study reveals that pyrazolecarbamide derivatives bearing a sulfonate fragment exhibit potential antifungal and antiviral activities.

Loess is a ubiquitous, silty aeolian sediment common across the semiarid to subhumid regions in the Northern Hemisphere. As such, the physical characteristics of loess sediment, such as modal grain size and quartz crystallinity index, have the potential to inform us about dust transport pathways and corresponding atmospheric circulation responsible for entrainment, transport, and deposition. In this article, we combine detailed granularity analyses and non-parametric end-member modeling with investigations of the quartz crystallinity index of three loess deposits, extending from East to Central Asia, with the aim of identifying dust transport processes and the climate subsystems responsible for them. We find marked differences in the grain size characteristics of Eastern and Central Asian loess. Given potential linkages of fine particles to the westerly jet stream, here we focused on the fine-grained end-members in the loess. The fine-grained components of the Central Asian Bishkek (BSK) and Chashmanigar (CMG) loess may be derived from individual particles carried at high altitude by major climate subsystems such as the westerlies. However, similar quartz crystallinity indexes of fine- and coarse-grained components in the Central Asian loess indicated that surface-level wind strength might influence the releases from proximal-sourced regions and abundances in the upper atmosphere for the fine particles. By contrast, the fine-grained component of the East Asian [Fanshan18 (FS18)] loess seems to yield physical similarities to the Tertiary Red Clays underlying many loess stratigraphies, and has been interpreted to relate to transport associated with the East Asian winter monsoon. It was further supported by quartz crystallinity indexes of the

Respiratory syncytial virus (RSV) is the most common and critical viral pathogen causing acute lower respiratory tract infection in infants and young children and has a huge disease burden worldwide. At present, there are many studies on RSV transcriptomics exploring the mechanism of disease, but different studies show different gene expression patterns and results due to different sample collection platforms and data analysis strategies. A meta-analysis was performed on eight whole blood transcriptome datasets containing 436 children with acute RSV infection and 241 healthy children. A total of 319 differentially expressed genes (DEGs) (P value

PurposeFungal keratitis is a sight-threatening corneal infection caused by fungal pathogens, and the pathogenic mechanisms have not been fully elucidated. The aim of this study was to determine whether NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated pyroptosis contributes to Candida albicans (C. albicans) keratitis and explore the underlying mechanism.MethodsAn in vivo mouse model of C. albicans keratitis and an in vitro culture model of human corneal epithelial cells (HCECs) challenged with heat-killed C. albicans (HKCA) were established in this study. The degree of corneal infection was evaluated by clinical scoring. Gene expression was assessed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis or immunofluorescence staining was performed to evaluate protein expression. TdT-mediated dUTP nick end labeling (TUNEL) staining was performed to examine the pyroptotic cell death. A lactate dehydrogenase (LDH) release assay was performed to assess cytotoxicity.ResultsCompared with the mock-infected group, we observed that the mRNA levels of NLRP3, caspase-1 (CASP1), interleukin (IL)−1β and gasdermin-D (GSDMD) in C. albicans-infected mice cornea was significantly increased. Our data also demonstrated that the protein expression of NLRP3 and the pyroptosis-related markers apoptosis-associated speck-like protein containing a CARD (ASC), cleaved CASP1, N-GSDMD, cleaved IL-1β and cleaved IL-18 as well as pyroptotic cell death were dramatically elevated in the mouse model of C. albicans keratitis. More importantly, NLRP3 knockdown markedly alleviated pyroptosis and consequently reduced corneal inflammatory reaction in C. albicans keratitis. In vitro, the presence of activated NLRP3 inflammasome and pyroptotic cell death were validated in HCECs exposed to HKCA. Furthermore, the potassium (K+) channel inhibitor glyburide decreased LDH release and suppressed NLRP3 inflammasome activation and pyroptosis in HCECs exposed to HKCA.ConclusionIn conclusion, the current study revealed for the first time that NLRP3 inflammasome activation and pyroptosis occur in C. albicans-infected mouse corneas and HCECs. Moreover, NLRP3 inflammasome-mediated pyroptosis signaling is involved in the disease severity of C. albicans keratitis. Therefore, This NLRP3 inflammasome-dependent pathway may be an attractive target for the treatment of fungal keratitis.

ObjectiveThis study aimed to explore the use of the Omaha System in rehabilitation and nursing methods and the effects on patients within the community who had experienced stroke and previous falls.MethodsThis study enrolled 42 patients who had experienced stroke and previous falls and had returned to the community after being discharged from the Department of Neurology and Rehabilitation of the Affiliated Hospital of Nanchang University from January to July 2018. The patients were randomly divided into two groups: an experimental group (n = 21) and a control group (n = 21). Patients in the control group received routine community rehabilitation care, and patients in the experimental group received community rehabilitation care on the basis of the Omaha System. Intervention lasted for 1 year. The Omaha outcome score, the ability to perform activities of daily living (ADL) (measured via the Modified Barthel Index [MBI]), and the incidence of falls for each group were compared before and after the intervention.ResultsAfter 1 year of intervention, the Omaha outcome score and MBI of both groups were higher than before; the Omaha outcome score and MBI of the experimental group were higher than those of the control group; the differences were statistically significant (P < 0.05). No fall occurred in either of the two groups.ConclusionThe Omaha System can comprehensively evaluate the health problems of patients, guide nursing intervention, and quantitatively evaluate the effect of nursing intervention; it is therefore worthy of promotion.

Arbuscular mycorrhizal fungi (AMF) can form symbiotic relationships with most terrestrial plants and regulate the uptake and distribution of antimony (Sb) in rice. The effect of AMF on the uptake and transport of Sb in rice was observed using pot experiments in the greenhouse. The results showed that AMF inoculation increased the contact area between roots and metals by forming mycelium, and changed the pH and Eh of the root soil, leading to more Sb entering various parts of the rice, especially at an Sb concentration of 1,200 mg/kg. The increase in metal toxicity further led to a decrease in the rice chlorophyll content, which directly resulted in a 22.7% decrease in aboveground biomass, 21.7% in underground biomass, and 11.3% in grain biomass. In addition, the antioxidant enzyme results showed that inoculation of AMF decreased 22.3% in superoxide dismutase, 9.9% in catalase, and 20.7% in peroxidase compared to the non-inoculation groups, further verifying the negative synergistic effect of AMF inoculation on the uptake of Sb in rice. The present study demonstrated the effect of AMF on the uptake and transport of Sb in the soil–rice system, facilitating future research on the related mechanism in the soil–rice system under Sb stress.

BackgroundGuangdong is a hyperepidemic area of dengue, which has over 0.72 million cumulative cases within the last four decades, accounting for more than 90% of cases in China. The local epidemic of dengue in Guangdong is suspected to be triggered by imported cases and results in consequent seasonal transmission. However, the comprehensive epidemiological characteristics of dengue in Guangdong are still unclear.MethodsThe epidemiology, seroprevalence, molecular evolution of dengue virus, and the development of policies and strategies on the prevention and control of dengue were analyzed in Guangdong, China from 1978 to 2017.FindingsSeasonal transmission of dengue virus in Guangdong, China was mainly sustained from July to October of each year. August to September was the highest risk period of local dengue outbreaks. Most of the dengue cases in Guangdong were young and middle-aged adults. Five hundred and three fatal cases were recorded, which declined within the last two decades (n = 10). The serological test of healthy donors' serum samples showed a positive rate of 5.77%. Dengue virus 1–4 (DENV 1–4) was detected in Guangdong from 1978 to 2017. DENV 1 was the dominant serotype of dengue outbreaks from 1978 to 2017, with an increasing tendency of DENV 2 since 2010. Local outbreaks of DENV 3 were rare. DENV 4 was only encountered in imported cases in Guangdong, China. The imported cases were the main source of outbreaks of DENV 1–2. Early detection, management of dengue cases, and precise vector control were the key strategies for local dengue prevention and control in Guangdong, China.InterpretationDengue has not become an endemic arboviral disease in Guangdong, China. Early detection, case management, and implementation of precise control strategies are key findings for preventing local dengue transmission, which may serve for countries still struggling to combat imported dengue in the west pacific areas.

Introduction: Congenital muscular dystrophy (CMD) is a group of early-onset disorders with clinical and genetic heterogeneity. Patients always present with muscle weakness typically from birth to early infancy, delay or arrest of gross motor development, and joint and/or spinal rigidity. There are various genes related to the development of CMD. Among them, mutations in integrin alpha 7 (ITGA7) is a rare subtype. The identification of disease-causing genes facilitates the diagnosis and treatment of CMD.Methods: We screened ITGA7 mutations in four people by whole exome sequencing and targeted sequencing from a consanguineous family. We then carried out electromyography and neuroelectrophysiological examinations to clarify a clinical picture of the patient diagnosed with CMD.Results: We report a Chinese boy diagnosed with CMD who carries a homozygous variant (c.1088dupG, p.H364Sfs*15) of the ITGA7 gene. According to the genotype analysis of his family members, this is an autosomal recessive inheritance.Conclusions: Our case further shows that ITGA7 mutation is related to CMD. Genetic counseling and multidisciplinary management of CMD play an important role in helping patients and their family. Further elucidation of the significant clinical and genetic heterogeneity, therapeutic targets, and the clinical care for patients remains our challenge for the future.

The Tibetan population has lived and successfully reproduced at high altitude for many generations. Studies have shown that Tibetans have various mechanisms for protection against high-altitude hypoxia, which are probably due, at least in part, to placental adaptation. However, comprehensive in silico analyses of placentas in Tibetans are lacking. We performed a microarray-based comparative transcriptome analysis of 10 Tibetan women from Yushu, Qinghai, CHN (∼3,780 m) and 10 European women living in Leadville, CO, United States (∼3,100 m) for less than three generations. Expression of HIF-1α, STAT3, EGFR, HSP5A, XBP1, and ATF6A mRNA was less in the Tibetan placentas as compared with European placentas. A total of 38 miRNAs were involved in regulating these genes. Differentially expressed genes were enriched for HIF1α signaling pathways, protein processing in the endoplasmic reticulum, PI3K-AKT signaling pathways, and MAPK signaling pathways. Based on the transcriptome profiles, the Tibetan population was distinct from the European population; placental tissues from the Tibetan population are lacking hypoxic responses, and “passivation” occurs in response to hypoxic stress. These results provide insights into the molecular signature of adaptation to high altitudes in these two populations.

Immunosuppressive molecules are valuable prognostic biomarkers across different cancer types. Leukocyte immunoglobulin like receptor subfamily B1 (LILRB1) is considered to be an immunosuppressive molecule, which is an important receptor of human leukocyte antigen G. However, the clinical significance of LILRB1 expression in gastric cancer remains unexplored. We analyzed the immunohistochemistry data of 166 gastric cancer patients to determine the clinicopathologic and survival significance of LILRB1. Immunofluorescence was conducted to detect the co-localization of LILRB1 with infiltrating immune cells. Additionally, we also assessed the immune contexture, immune cell functions and tumor microenvironment state related to LILRB1. We found that LILRB1 was mainly present in tumor stroma which was higher in tumor tissues compared with matched adjacent tissues. High-LILRB1 expression was associated with more advanced tumor stage, higher recurrence risk and worse survival. Immunohistochemistry and bioinformatic analysis showed that LILRB1 had a significant positive correlation with M2 tumor-associated macrophages (TAMs) infiltration. Immunofluorescence confirmed that M2 TAMs were the primary immune cells expressing LILRB1. Dense infiltration of LILRB1+ M2 TAMs yielded an immunosuppressive microenvironment manifested as enriched exhausted CD8+ T cells and increased immunosuppressive cytokines. Moreover, patients with high infiltration of both LILRB1+ cells and M2 TAMs indicated poor prognosis and inferior therapeutic responsiveness to adjuvant chemotherapy. In conclusion, LILRB1+ M2 TAMs were associated with a pro-tumor immune contexture and determine poor prognosis in gastric cancer. Further studies are essential to explore therapeutic targeting LILRB1+ M2 TAMs.

Living at high altitudes is extremely challenging as it entails exposure to hypoxia, low temperatures, and high levels of UV radiation. However, the Tibetan population has adapted to such conditions on both a physiological and genetic level over 30,000–40,000 years. It has long been speculated that fetal growth restriction is caused by abnormal placental development. We previously demonstrated that placentas from high-altitude Tibetans were protected from oxidative stress induced by labor compared to those of European descent. However, little is known about how placental mitochondria change during high-altitude adaptation. In this study, we aimed to uncover the mechanism of such adaptation by studying the respiratory function of the placental mitochondria of high-altitude Tibetans, lower-altitude Tibetans, and lower-altitude Chinese Han. We discovered that mitochondrial respiration was greater in high-altitude than in lower-altitude Tibetans in terms of OXPHOS via complexes I and I+II, ETSmax capacity, and non-phosphorylating respiration, whereas non-ETS respiration, LEAK/ETS, and OXPHOS via complex IV did not differ. Respiration in lower-altitude Tibetans and Han was similar for all tested respiratory states. Placentas from high-altitude Tibetan women were protected from acute ischemic/hypoxic insult induced by labor, and increased mitochondrial respiration may represent an acute response that induces mitochondrial adaptations.

Schistosomiasis is a parasitic disease endemic to freshwater areas of Southeast Asia, Africa, and South America that is capable of causing serious damage to the internal organs. Recent studies have linked exosomes to the progression of schistosomiasis. These structures are important mediators for intercellular communication, assist cells to exchange proteins, lipids, and genetic material and have been shown to play critical roles during host–parasite interactions. This review aims to discuss the pathophysiology of exosomes in schistosomiasis and their roles in regulating the host immune response. Understanding how exosomes are involved in the pathogenesis of schistosomiasis may provide new perspectives in diagnosing and treating this neglected disease.

Teacher questions have long been considered important in mediating students’ learning in language classrooms. This paper examined the mediated-learning behaviors involved in teacher questions during whole-class instruction in high schools of China. Five lessons of different topics were observed. Conversation analytic approach was applied to analyze teachers’ verbal interactions with students during whole-class teaching. Teachers’ questions and students’ responses were transcribed and categorized as display questions or referential questions. The mediated-learning behaviors involved in the two types of questions were discussed by presenting six sessions of interaction. The study investigated which question type initiated the interaction involving more variety of mediated-learning behaviors and what pedagogical implications this may have for teacher questioning techniques that enhance student learning. The study found the interactions initiated by referential questions contain more varieties of mediated-learning behaviors. This study suggests that teachers need to be encouraged to use referential questions more frequently whether in display interactions or in referential interactions.

Hepatocellular carcinoma (HCC) has been recognized as the third leading cause of cancer-related deaths worldwide. There is increasing evidence that the abnormal expression of autophagy-related genes plays an important role in the occurrence and development of HCC. Therefore, the study of autophagy-related genes can further elucidate the genetic drivers of cancer and provide valuable therapeutic targets for clinical treatment. In this study, we used 232 autophagy-related genes extracted from the Human Autophagy Database (HADb) and Molecular Signatures Database (MSigDB) to construct 1884 autophagy-related gene pairs. On this basis, we developed a prognostic model based on autophagy-related gene pairs using least absolute shrinkage and selection operator (LASSO) Cox regression to evaluate the prognosis of patients after liver cancer resection. We then used 845 liver cancer samples from three different databases to test the reliability of the risk signature through survival analysis, receiver operating characteristic (ROC) curve analysis, univariate and multivariate analysis. To further explore the underlying biological mechanisms, we conducted an enrichment analysis of autophagy-related genes. Finally, we combined the signature with independent prognostic factors to construct a nomogram. Based on the autophagy-related gene pair (ARGP) signature, we can divide patients into high- or low-risk groups. Survival analysis and ROC curve analysis verified the validity of the signature (AUC: 0.786—0.828). Multivariate Cox regression showed that the risk score can be used as an independent predictor of the clinical outcomes of liver cancer patients. Notably, this model has a more accurate predictive effect than most prognostic models for hepatocellular carcinoma. Moreover, our model is a powerful supplement to the HCC staging indicator, and a nomogram comprising both indicators can provide a better prognostic effect. Based on pairs of multiple autophagy-related genes, we proposed a prognostic model for predicting the overall survival rate of HCC patients after surgery, which is a promising prognostic indicator. This study confirms the importance of autophagy in the occurrence and development of HCC, and also provides potential biomarkers for targeted treatments.

Hyperlipidemia is a common metabolic disorder and regarded as one of the main risk factors for cardiovascular disease. The gut microbiota has been identified as a potential contributor to hyperlipidemia as it can greatly regulate bile acid metabolism. Linderae radix is a natural medicine widely used in the treatment of a variety of diseases and is also a common drug for hyperlipidemia. Recently, the lipid-lowering effect of Linderae radix are receiving increasing attention but the underlying mechanism remains unknown. The study aimed to investigate the effects of Linderae radix ethanol extract (LREE) on gut microbiota in rats with hyperlipidemia syndrome. We established a hyperlipidemia rat model using a high-fat diet and used LREE as the intervention. Blood lipid levels and pathological examination were measured to assess the effects of LREE on hyperlipidemia. The gut microbiota was determined by 16s rDNA sequencing and the bile acid metabolism-related proteins were detected by western blot to discover the underlying correlations. The results show that LREE lowered TC, TG, and LDL levels effectively, and it also alleviated liver injury by reducing ALT and AST activity. Meanwhile, LREE improved gut microbiota disturbance caused by HFD via increasing intestinal microbiota diversity and changing the abundance of the Firmicutes, Bacteroidetes, and Actinobacteria. In addition, LREE can increase bile acid reabsorption and promote fecal excretion through farnesoid X receptor (FXR), apical sodium-dependent bile acid transporter (ASBT), organic solute transporter alpha (OST-α), and cytochrome P450 family 7 Subfamily A Member 1 (CYP7A1) thus restoring abnormal bile acid metabolism caused by hyperlipidemia.

Exosomes are small membranous vesicles released by many kinds of cells, and are indispensable in cell-to-cell communication by delivering functional biological components both locally and systemically. Long non-coding RNAs (lncRNAs) are long transcripts over 200 nucleotides that exhibit no or limited protein-coding potentials. LncRNAs are dramatic gene expression regulators, and can be selectively sorted into exosomes. Exosomal lncRNAs derived from cancer cells and stromal cells can mediate the generation of pre-metastatic niches (PMNs) and thus promote the progression of cancer. In this review, we summarized the fundamental biology and characteristics of exosomal lncRNAs. Besides, we provided an overview of current research on functions of exosomal lncRNAs between cancer cells and non-cancer cells. A deep understanding of exosomal lncRNAs’ role in cancer will be facilitated to find important implications for cancer development and treatment.

MicroRNAs (miRNAs) have been reported to play critical roles in the pathological development of hepatocellular carcinoma (HCC), one of the most common cancers in the world. Our study aims to explore the expression, function and mechanism of miR-631 in HCC. Our findings are that expression of miR-631 is significantly down-regulated in HCC tissue compared with that in adjacent non-cancerous tissue, and low expression of miR-631 in HCC tissue is associated with cirrhosis, multiple tumors, incomplete tumor encapsulation, poor tumor differentiation, and high TNM stage. Our test results showed that miR-631 could inhibit migration, invasion, epithelial–mesenchymal transition (EMT) and intrahepatic metastasis of HCC. Receptor-type protein tyrosine phosphatase epsilon (PTPRE) as a downstream target of miR-631 could promote migration, invasion and EMT of HCC cells. Besides, the expression of PTPRE had a negative correlation with the expression of miR-631 both in vivo and in vitro, and increasing expression of PTPRE could reverse inhibitory effects of miR-631 in HCC cells. In sum, our study first demonstrated that miR-631 targeted PTPRE to inhibit intrahepatic metastasis in HCC. We gain insights from these findings into the mechanism of miRNAs regulation in HCC metastasis and further introduce a novel therapeutic target for HCC treatment.

Chronic inflammation is part of the pathological process during atherosclerosis (AS). Due to the abundance of monocytes/macrophages within the arterial plaque, monocytes/macrophages have become a critical cellular target in AS studies. In recent decades, a number of long noncoding RNAs (lncRNAs) have been found to exert regulatory roles on the macrophage metabolism and macrophage plasticity, consequently promoting or suppressing atherosclerotic inflammation. In this review, we provide a comprehensive overview of lncRNAs in macrophage biology, highlighting the potential role of lncRNAs in AS based on recent findings, with the aim to identify disease biomarkers and future therapeutic interventions for AS.

Britanin has been reported to have therapeutic effects on neurodegenerative and inflammation-based diseases. However, whether it is involved in the regulation of triple-negative breast cancer development has not been elucidated. In this study, we investigated the anti-tumor activity against triple-negative breast cancer tumor of Britanin by bioluminescence imaging in vivo using athymic (nu/nu) mice implanted with MDA-MB-231 and SUM-159 cells expressing a luciferase reporter gene, and explored the anti-tumor mechanism of Britanin. The results showed that Britanin treatment inhibited triple-negative breast cancer cell proliferation in vivo, and Cell Counting Kit-8 (IC50 values are 4.27 and 5.05 μM) and colony formation tests (P < 0.001) confirmed this result. Transwell assays were conducted to verify that Britanin treatment inhibited cell migration and invasion (P < 0.001). Apoptosis was determined by TdT-mediated dUTP nick-end labeling method. Western blot and qRT-PCR analysis showed that Britanin treatment caused a decrease in the member expression of NF-kappa B signaling pathway. Computational modeling showed that Britanin could directly bind to a p-65 core region composed of Cys38, Cys120, and Gln128 residues. The results showed that the inhibitory mechanisms of Britanin on cancer cells may be by ways of inhibiting the NF-kappa B pathway. In addition, bioluminescence imaging screening system is useful for accelerating the application of Britanin in the antitumor field, and provides a useful tool for evaluating the phytochemicals efficacy in inhibiting cancer cell proliferation in animal models.

Transcriptional intermediary factor 1 γ (TIF1γ), also known as TRIM33, RFG7, PTC7, or Ectodermin, is an E3 ubiquitin-ligase family member with a ring-box-coiled-coil region. It can regulate TGF-β/Smad signaling in two different ways in different cellular contexts. On one hand, TIF1γ can monoubiquitinate Smad4 to inhibit the formation of Smad2/3/4 nuclear complexes. On the other hand, TIF1γ can function as a cofactor of phosphorylated (p)-Smad2/3, competing with Smad4 to inhibit the formation of the Smad2/3/4 complex. In addition, TIF1γ has been reported to play a role in transcription elongation, cellular differentiation, embryonic development, and mitosis. As transforming growth factor-β (TGF-β) superfamily signaling plays an important role in the occurrence and development of cancer, and TIF1γ was reported to be involved in the regulation of TGF-β superfamily signaling, studies on TIF1γ during the last decade have focused on its role in the development of cancer. However, TIF1γ can function either as a tumor suppressor or promoter in different cellular contexts, yet there are few reviews focusing on the roles of TIF1γ in cancer. Hence, in this paper we systematically review and discuss the roles of TIF1γ in cancer. Firstly, we review the biological features, the regulatory mechanisms and the related signaling pathways of TIF1γ. Next, we illustrate the roles of TIF1γ in different tumors. We then provide a tentative hypothesis that explains the dual roles of TIF1 γ in cancer. Finally, we provide our viewpoint regarding the future developments of cancer research focusing on TIF1γ, especially in relation to the effects of TIF1γ on tumoral immunity.

Doxorubicin (Dox), an antitumor antibiotic, has therapeutic effects on many kinds of tumors. However, Dox can produce some serious side effects that limit its clinical application. Thus, exploration of effective drug targets or active lead compounds against Dox-induced organ damage is necessary. Dioscin, one natural product, has potent effects against Dox-induced renal injury and cardiotoxicity. However, the effects of dioscin on Dox-induced hepatotoxicity have not been reported. In this study, the results showed that dioscin significantly ameliorated Dox-induced cell injury, reduced reactive oxygen species (ROS) level, and suppressed cell apoptosis in alpha mouse liver 12 (AML-12) cells caused by Dox. In vivo, dioscin evidently decreased the levels of alanine transaminase (ALT), aspartate transaminase (AST), malondialdehyde (MDA); increased the levels of superoxide dismutase (SOD), glutathione (GSH), and glutathione peroxidase (GSH-Px); and alleviated liver injury. Mechanism study showed that dioscin remarkably up-regulated the expression levels of silent information regulator 1 (Sirt1) and heme oxygenase-1 (HO-1) via increase of the nuclear translocation of NF-E2-related factor 2 (Nrf2) and suppressed the expression levels of forkhead box protein O1 (FOXO1) and kelch-like ECH-associated protein-1 (Keap1) to inhibit oxidative stress. Furthermore, dioscin obviously decreased the nuclear translocation of nuclear factor κB (NF-κB) and the mRNA levels of tumor necrosis factor alpha (TNF-α), interleukin 1β (IL-1β), and interleukin 6 (IL-6) to suppress inflammation. Meanwhile, dioscin significantly regulated tumor suppressor P53 (P53) expression level and BCL-2-associated X (BAX)/BCL-2 apoptosis regulator (BCL-2) ratio to inhibit cell apoptosis. These results were further validated by knockdown of Sirt1 using siRNA silencing in AML-12 cells, which confirmed that the target of dioscin against Dox-induced hepatotoxicity was Sirt1/FOXO1/NF-κB signal. In short, our findings showed that dioscin exhibited protective effects against Dox-induced liver damage via suppression of oxidative stress, inflammation, and apoptosis, which should be developed as one new candidate for the prevention of Dox-induced liver injury in the future.