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Objectives Cervical alignment and range of motion (ROM) changes after cervical spine surgery are related to cervical biomechanical and functions. Few studies compared these parameters between posterior laminoplasty and anterior 3‐level hybrid surgery incorporating anterior cervical discectomy and fusion (ACDF) with cervical disc replacement (CDR). This study is aimed to detect the differences of cervical alignment and ROM changes of the two surgeries in a matched‐cohort study. Methods From January 2018 and May 2020, 51 patients who underwent 3‐level hybrid surgery incorporating ACDF with ACDR were included. A 1:1 match of the patients who underwent cervical laminoplasty based on age, gender, duration of symptoms, body mass index, and cervical alignment type was utilized as control group. General data (operative time, blood loss, etc.), Japanese Orthopaedic Association (JOA) score, VAS (Visual Analog Score), NDI (The Neck Disability Index), cervical sagittal alignment, and cervical range of motion (ROM) were recorded and compared. Results Both groups gained significant improvement in JOA, VAS, NDI scores postoperatively (p

Objective(s): To investigate whether 3-methyladenine (3-MA) can protect the kidney of streptozotocin (STZ) - induced diabetes mice, and explore its possible mechanism. Materials and Methods: STZ was used to induce diabetes in C57BL/6J mice. The mice were divided into normal control group (NC), diabetes group (DM), and diabetes+3-MA intervention group (DM+3-MA). Blood glucose, water consumption, and body weight were recorded weekly. At the end of the 6th week of drug treatment, 24-hour urine was collected. Blood and kidneys were collected for PAS staining to evaluate the degree of renal injury. Sirius red staining was used to assess collagen deposition. Blood urea nitrogen (BUN), serum creatinine, and 24-hour urine albumin were used to evaluate renal function. Western blot was used to detect fibrosis-related protein, inflammatory mediators, high mobility group box 1 (HMGB1)/NF-κB signal pathway molecule, vascular endothelial growth factor (VEGF), and podocin, and immunohistochemistry (IHC) was used to detect the expression and localization of autophagy-related protein and fibronectin.Results: Compared with the kidney of normal control mice, the kidney of diabetes control mice was more pale and hypertrophic. Hyperglycemia induces renal autophagy and activates the HMGB1/NF-κB signal pathway, leading to the increase of inflammatory mediators, extracellular matrix (ECM) deposition, and proteinuria in the kidney. In diabetic mice treated with 3-MA, blood glucose decreased, autophagy and HMGB1/NF-κB signaling pathways in the kidneys were inhibited, and proteinuria, renal hypertrophy, inflammation, and fibrosis were improved. Conclusion: 3-MA can attenuate renal injury in STZ-induced diabetic mice through inhibition of autophagy and HMGB1/NF-κB signaling pathway.

Abstract Background Environmental temperature is critical in regulating biological functions in fish. S. prenanti is a kind of cold-water fish, but of which we have little knowledge about the metabolic adaptation and physiological responses to long-term cold acclimation. Results In this study, we determined the physiological responses of S. prenanti serum after 30 days of exposure to 6℃. Compared with the control group, the levels of TC, TG, and LDL-C in the serum were significantly (P

Milk was a source of important nutrients for humans and was especially important for children and adolescents. The modern dairy animal production pattern had contributed to residual sex steroid hormones in milk. When this milk was consumed by humans, these hormones entered the body leading to hormonal disruptions and potentially increasing the risk of various types of cancers. This article reviewed the presence of residual sex steroid hormones in milk, their potential risks on human health, and their possible association with the incidence of breast and prostate cancer. The potential linkage between dairy consumption and these cancers were described in detail. The hormones present in dairy products could affect the development and progression of these types of cancer. Sex steroid hormones could interact with different signaling pathways, influencing carcinogenic cascades that could eventually lead to tumorigenesis. Given these potential health risks, the article suggested appropriate consumption of dairy products. This included being mindful not just of the amount of dairy consumed, but also the types of dairy products selected. More scientific exploration was needed, but this review provided valuable insights for health-conscious consumers and contributed to the ongoing discussion on dietary guidelines and human health.

Introduction: Current anti-rheumatic drugs are primarily modulating immune cell activation, yet their effectiveness remained suboptimal. Therefore, novel therapeutics targeting alternative mechanisms, such as synovial activation, is urgently needed. Objectives: To explore the role of Midline-1 (Mid1) in synovial activation. Methods: NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice were used to establish a subcutaneous xenograft model. Wild-type C57BL/6, Mid1-/-, Dpp4-/-, and Mid1-/- Dpp4-/- mice were used to establish a collagen-induced arthritis model. Cell viability, cell cycle, qPCR and western blotting analysis were used to detect MH7A proliferation, dipeptidyl peptidase-4 (DPP4) and Mid1 levels. Co-immunoprecipitation and proteomic analysis identified the candidate protein of Mid1 substrates. Ubiquitination assays were used to determine DPP4 ubiquitination status. Results: An increase in Mid1, an E3 ubiquitin ligase, was observed in human RA synovial tissue by GEO dataset analysis, and this elevation was confirmed in a collagen-induced mouse arthritis model. Notably, deletion of Mid1 in a collagen-induced arthritis model completely protected mice from developing arthritis. Subsequent overexpression and knockdown experiments on MH7A, a human synoviocyte cell line, unveiled a previously unrecognized role of Mid1 in synoviocyte proliferation and migration, the key aspects of synovial activation. Co-immunoprecipitation and proteomic analysis identified DPP4 as the most significant candidate of Mid1 substrates. Mechanistically, Mid1 promoted synoviocyte proliferation and migration by inducing ubiquitin-mediated proteasomal degradation of DPP4. DPP4 deficiency led to increased proliferation, migration, and inflammatory cytokine production in MH7A, while reconstitution of DPP4 significantly abolished Mid1-induced augmentation of cell proliferation and activation. Additionally, double knockout model showed that DPP4 deficiency abolished the protective effect of Mid1 defect on arthritis. Conclusion: Overall, our findings suggest that the ubiquitination of DPP4 by Mid1 promotes synovial cell proliferation and invasion, exacerbating synovitis in RA. These results reveal a novel mechanism that controls synovial activation, positioning Mid1 as a promising target for therapeutic intervention in RA.

High mobility group protein 1 (HMGB1) plays a complex role in tumor biology. When released into the extracellular space, it binds to the receptor for advanced glycation end products (RAGE) located on the cell membrane, playing an important role in tumor development by regulating a number of biological processes and signal pathways. In this review, we outline the multifaceted functions of the HMGB1/RAGE axis, which encompasses tumor cell proliferation, apoptosis, autophagy, metastasis, and angiogenesis. This axis is instrumental in tumor progression, promoting tumor cell proliferation, autophagy, metastasis, and angiogenesis while inhibiting apoptosis, through pivotal signaling pathways, including MAPK, NF-κB, PI3K/AKT, ERK, and STAT3. Notably, small molecules, such as miRNA-218, ethyl pyruvate (EP), and glycyrrhizin exhibit the ability to inhibit the HMGB1/RAGE axis, restraining tumor development. Therefore, a deeper understanding of the mechanisms of the HMGB1/RAGE axis in tumors is of great importance, and the development of inhibitors targeting this axis warrants further exploration.

Objective Although direct isthmic repair, such as PSVPH, did not affect the mobility of the fixed segment and adjacent segment, it has a relatively low rate of isthmic fusion compared with conventional fusion. The Isobar TTL dynamic internal fixation system has been widely used in clinical practice and has achieved satisfactory clinical results. However, the use of the Isobar TTL system in combination with direct isthmic repair for lumbar spondylolysis has rarely been reported. The aim of this study was to compare the clinical and radiologic outcomes between patients who underwent Isobar TTL system and PSVPH with direct repair of defect for lumbar spondylolysis. Methods Stepwise propensity score matching (PSM) for age and sex were performed to keep comparable clinical data between groups in this retrospective and matched‐pair case control study. A total of 50 patients diagnosed with lumbar spondylolysis underwent surgical implantation of the Isobar TTL group (n = 25) or PSVPH group (n = 25) from June 2009 to June 2016. Clinical outcomes were assessed using the Oswestry disability index (ODI), and visual analog score (VAS). Radiographic evaluations included range of motion (ROM) and the disc heights of stabilized segment and adjacent segment, adjacent segment degeneration (ASD) and bony fusion. Three‐dimensional reconstruction of lumbar CT scan was obtained to evaluate bone fusion of the isthmic at final follow‐up. The independent Student's t test and chi‐square test were applied to compare the differences between groups. Results A total of 25 patients from TTL group were matched to 25 patients in PSVPH group for age, sex, body mass index (BMI), defect side, spondylolisthesis meyerding, and follow‐up duration. The intervertebral space height (IH) of stabilized segment at postoperative 1 week and final follow‐up in the TTL group was higher than those in the PSVPH group, respectively (P = 0.030; P = 0.013). The ROM of stabilized segment at final follow‐up in the TTL group was significantly lower than that in the PSVPH group (P

Objective At present, the influence of Modic changes (MCs) on postoperative fusion rate of lumbar interbody fusion (LIF) is mainly focused on the medium‐ and long‐term fusion rate, while the short‐term fusion rate has not been reported. The aim of this study was to compare the short‐term fusion rate of lumbar degenerative disease patients with and without MCs after single level transforaminal lumbar interbody fusion (TLIF). Methods In this retrospective and matched‐pair case control study, we included 100 patients who underwent TLIF from January 2017 to January 2020 and had at least two follow‐up visits over a two‐year period. Fifty patients with MCs (MCs group) were matched with 50 patients without MCs (non MCs group) for age, sex, surgical level, diagnosis, operative time, and intraoperative blood loss. We collected the X‐ray and computed tomography (CT) data of patients from 3 months to 2 years after the operation to assess bony fusion and the cage union ratio. According to the type of cage, the MCs group was further divided into the nano‐hydroxyapatite/polyamide 66 (n‐HA/PA66) group and polyetheretherketone (PEEK) group, and the fusion performance between the two groups was compared. Finally, age, sex, body mass index (BMI), smoking and cage type were included in the logistic regression model for risk factor analysis. Results The bony fusion rates in the MCs group at 3 months, 6 months, 1 year and 2 years after surgery were significantly lower than those in the non MCs group (P

AIM: To investigate the role of autophagy inhibitor 3-methyladenine (3-MA) on a diabetic mice model (DM) and the potential mechanism. METHODS: Male C57BL/6J mice were randomly divided into a normal control group (NC group) and an DM group. DM were induced by multiple low-dose intraperitoneal injection of streptozotocin (STZ) 60 mg/kg●d for 5 consecutive days. DM mice were randomly subdivided into untreated group (DM group), 3-MA (10 mg/kg●d by gavage) treated group (DM+3-MA group) and chloroquine (CQ; 50 mg/kg by intraperitoneal injection) treated group (DM+CQ group). The fasting blood glucose (FBG) levels were recorded every week. At the end of experiment, retinal samples were collected. The expression levels of pro-apoptotic proteins cleaved caspase-3, cleaved poly ADP-ribose polymerase 1 (PARP1) and Bax, anti-apoptotic protein Bcl-2, fibrosis-associated proteins Fibronectin and type 1 collagen α1 chain (COL1A1), vascular endothelial growth factor (VEGF), inflammatory factors interleukin (IL)-1β and tumor necrosis factor (TNF)-α, as well as autophagy related proteins LC3, Beclin-1 and P62 were determined by Western blotting. The oxidative stress indicators 8-hydroxydeoxyguanosine (8-OHdG) and malondialdehyde (MDA) were detected by commercial kits. RESULTS: Both 3-MA and CQ had short-term hypoglycemic effect on FBG and reduced the expression of VEGF and inflammatory factors IL-1β and TNF-α in DM mice. 3-MA also significantly alleviated oxidative stress indicators 8-OHdG and MDA, decreased the expression of fibrosis-related proteins Fibronectin and COL1A1, pro-apoptotic proteins cleaved caspase-3, cleaved PARP1, as well as the ratio of Bax/Bcl-2. CQ had no significant impact on the oxidative stress indicators, fibrosis, and apoptosis related proteins. The results of Western blotting for autophagy related proteins showed that the ratio of LC3 II/LC3 I and the expression of Beclin-1 in the retina of DM mice were decreased by 3-MA treatment, and the expression of P62 was further increased by CQ treatment. CONCLUSION: 3-MA has anti-apoptotic and anti-fibrotic effects on the retina of DM mice, and can attenuate retinal oxidative stress, VEGF expression and the production of inflammatory factors in the retina of DM mice. The underlying mechanism of the above effects of 3-MA may be related to its inhibition of early autophagy and hypoglycemic effect.

Folate is a water-soluble B vitamin involved in the synthesis of purines and pyrimidines and is one of the essential vitamins for human growth and reproduction. Folate deficiency due to low dietary intake, poor absorption of folate, and alterations in folate metabolism due to genetic defects or drug interactions significantly increases the risk of diseases such as neural tube defects, cardiovascular disease, cancer, and cognitive dysfunction. Recent studies have shown that folate deficiency can cause hyperhomocysteinemia, which increases the risk of hypertension and cardiovascular disease, and that high homocysteine levels are an independent risk factor for liver fibrosis and cirrhosis. In addition, folate deficiency results in increased secretion of pro-inflammatory factors and impaired lipid metabolism in the liver, leading to lipid accumulation in hepatocytes and fibrosis. There is substantial evidence that folate deficiency contributes to the development and progression of a variety of liver diseases, including non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic liver disease (ALD), viral hepatitis, hepatic fibrosis, and liver cancer. Here we review key studies on the role of folate in the pathophysiology of liver diseases, summarize the current status of studies on folate in the treatment of liver diseases, and speculate that folate may be a potential therapeutic target for liver diseases.

Abstract Background Accumulating data indicate that N6-methyladenosine (m6A) RNA methylation and lncRNA deregulation act crucial roles in cancer progression. Heterogeneous nuclear ribonucleoprotein A2B1 (HNRNPA2B1) as an m6A “reader” has been reported to be an oncogene in multiple malignancies. We herein aimed to elucidate the role and underlying mechanism by which HNRNPA2B1-mediated m6A modification of lncRNAs contributes to non-small cell lung cancer (NSCLC). Methods The expression levels of HNRNPA2B1 and their association with the clinicopathological characteristics and prognosis in NSCLC were determined by RT-qPCR, Western blot, immunohistochemistry and TCGA dataset. Then, the role of HNRNPA2B1 in NSCLC cells was assessed by in vitro functional experiments and in vivo tumorigenesis and lung metastasis models. HNRNPA2B1-mediated m6A modification of lncRNAs was screened by m6A-lncRNA epi-transcriptomic microarray and verified by methylated RNA immunoprecipitation (Me-RIP). The lncRNA MEG3-specific binding with miR-21-5p was evaluated by luciferase gene report and RIP assays. The effects of HNRNPA2B1 and (or) lncRNA MEG3 on miR-21-5p/PTEN/PI3K/AKT signaling were examined by RT-qPCR and Western blot analyses. Results We found that upregulation of HNRNPA2B1 was associated with distant metastasis and poor survival, representing an independent prognostic factor in patients with NSCLC. Knockdown of HNRNPA2B1 impaired cell proliferation and metastasis in vitro and in vivo, whereas ectopic expression of HNRNPA2B1 possessed the opposite effects. Mechanical investigations revealed that lncRNA MEG3 was an m6A target of HNRNPA2B1 and inhibition of HNRNPA2B1 decreased MEG3 m6A levels but increased its mRNA levels. Furthermore, lncRNA MEG3 could act as a sponge of miR-21-5p to upregulate PTEN and inactivate PI3K/AKT signaling, leading to the suppression of cell proliferation and invasion. Low expression of lncRNA MEG3 or elevated expression of miR-21-5p indicated poor survival in patients with NSCLC. Conclusions Our findings uncover that HNRNPA2B1-mediated m6A modification of lncRNA MEG3 promotes tumorigenesis and metastasis of NSCLC cells by regulating miR-21-5p/PTEN axis and may provide a therapeutic target for NSCLC.

Purpose. Aloperine (ALO), an alkaloid isolated from Sophora alopecuroides L., possesses multiple pharmacological activities and holds a promise potential for the treatment of various clinical conditions, including skin hypersensitivity, cancer, and inflammatory disorders. The purpose of this study was to investigate the role of ALO in acetaminophen (N-acetyl-para-aminophenol (APAP))-induced acute liver injury and its underlying mechanisms. Materials and Methods. An animal model of acute liver injury was induced by intraperitoneal injection of APAP (150 mg/kg). Prior to APAP injection, ALO (40 mg/kg) was administered daily for 7 consecutive days. Serum alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase levels were then measured using an automated chemical analyzer. Histopathological changes were evaluated using hematoxylin and eosin staining. Oxidative stress levels were measured by detecting superoxide dismutase (SOD), glutathione (GSH), and malondialdehyde (MDA). Pro-inflammatory cytokines were detected in serum and liver tissues using ELISA and quantitative real-time polymerase chain reaction (q-PCR). The expression of members of the HMGB1/TLR4/NF-κB signaling pathway and NLRP3 inflammasome were determined by Western blot and/or q-PCR. In addition, the expression and location of NLRP3, cleaved caspase-1, high-mobility group box 1 (HMGB1), and phosphorylated p65 (p-p65) were detected by immunofluorescence. Results. Pretreatment with ALO significantly protected mice from APAP-induced acute liver injury, with decreased MDA content, and significantly increased GSH and SOD activities. Furthermore, ALO pretreatment reduced the release of pro-inflammatory cytokines (IL-1β and TNF-α) and decreased the expression of caspase-1, cleaved caspase-1, and NLRP3. In addition, ALO pretreatment also inhibited the activation of the HMGB1/TLR4/NF-κB signaling pathway. Conclusion. Taken together, ALO can ameliorate APAP-induced acute liver injury by inhibiting oxidative stress, inflammation by inhibiting the HMGB1/TLR4/NF-κB, and NLRP3/inflammasome pathway.

Abstract Background The bone-implant gap resulted from morphological mismatch between cervical bony endplates and implant footprint may have adverse impact on bone-implant interfacial osseointegration of cervical disc arthroplasty (CDA). The purpose of the study was to evaluate the impact of bone-implant gap size on the interfacial osseointegration in a rabbit animal model. Methods A series of round-plate implants with different teeth depth (0.5 mm, 1.0 mm, 1.5 mm and 2.0 mm) was specifically designed. A total of 48 New Zealand white rabbits were randomly categorized into four groups by the implants they received (0.5 mm: group A, 1.0 mm: group B, 1.5 mm: group C, 2.0 mm: group D). At 4th and 12th week after surgery, animals were sacrificed. Micro-CT, acid fuchsin and methylene blue staining and hematoxylin and eosin (HE) staining were conducted. Results At 4th week and 12th week after surgery, both micro-CT and HE staining showed more new bone formation and larger bone coverage in group A and group B than that in group C and group D. At 12th week, the bone biometric parameters were significantly superior in group C when compared with group D (p

Abstract Background Maintaining osmotic equilibrium plays an important role in the survival of cold-water fishes. Heat stress has been proven to reduce the activity of Na+/K+-ATPase in the gill tissue, leading to destruction of the osmotic equilibrium. However, the mechanism of megatemperature affecting gill osmoregulation has not been fully elucidated. Results In this study, Siberian sturgeon (Acipenser baerii) was used to analyze histopathological change, plasma ion level, and transcriptome of gill tissue subjected to 20℃, 24℃and 28℃. The results showed that ROS level and damage were increased in gill tissue with the increasing of heat stress temperature. Plasma Cl− level at 28℃ was distinctly lower than that at 20℃ and 24℃, while no significant difference was found in Na+ and K+ ion levels among different groups. Transcriptome analysis displayed that osmoregulation-, DNA-repair- and apoptosis-related terms or pathways were enriched in GO and KEGG analysis. Moreover, 194 osmoregulation-related genes were identified. Amongst, the expression of genes limiting ion outflow, occluding (OCLN), and ion absorption, solute carrier family 4, member 2 (AE2) solute carrier family 9, member 3 (NHE3) chloride channel 2 (CLC-2) were increased, while Na+/K+-ATPase alpha (NKA-a) expression was decreased after heat stress. Conclusions This study reveals for the first time that the effect of heat stress on damage and osmotic regulation in gill tissue of cold-water fishes. Heat stress increases the permeability of fish’s gill tissue, and induces the gill tissue to keep ion balance through active ion absorption and passive ion outflow. Our study will contribute to research of global-warming-caused effects on cold-water fishes.

Abstract Ischemia/reperfusion (I/R)-induced liver injury with severe cell death is a major complication of liver transplantation. Transmembrane member 16A (TMEM16A), a component of hepatocyte Ca2+-activated chloride channel, has been implicated in a variety of liver diseases. However, its role in hepatic I/R injury remains unknown. Here, mice with hepatocyte-specific TMEM16A knockout or overexpression were generated to examine the effect of TMEM16A on hepatic I/R injury. TMEM16A expression increased in liver samples from patients and mice with I/R injury, which was correlated with liver damage progression. Hepatocyte-specific TMEM16A knockout alleviated I/R-induced liver damage in mice, ameliorating inflammation and ferroptotic cell death. However, mice with hepatic TMEM16A overexpression showed the opposite phenotype. In addition, TMEM16A ablation decreased inflammatory responses and ferroptosis in hepatocytes upon hypoxia/reoxygenation insult in vitro, whereas TMEM16A overexpression promoted the opposite effects. The ameliorating effects of TMEM16A knockout on hepatocyte inflammation and cell death were abolished by chemically induced ferroptosis, whereas chemical inhibition of ferroptosis reversed the potentiated role of TMEM16A in hepatocyte injury. Mechanistically, TMEM16A interacted with glutathione peroxidase 4 (GPX4) to induce its ubiquitination and degradation, thereby enhancing ferroptosis. Disruption of TMEM16A–GPX4 interaction abrogated the effects of TMEM16A on GPX4 ubiquitination, ferroptosis, and hepatic I/R injury. Our results demonstrate that TMEM16A exacerbates hepatic I/R injury by promoting GPX4-dependent ferroptosis. TMEM16A–GPX4 interaction and GPX4 ubiquitination are therefore indispensable for TMEM16A-regulated hepatic I/R injury, suggesting that blockades of TMEM16A–GPX4 interaction or TMEM16A inhibition in hepatocytes may represent promising therapeutic strategies for acute liver injury.

Summary: To analyze the differences between different-sized Acipenser dabryanus, we randomly selected 600 3-month-old A. dabryanus juveniles. Four months later, the blood and white muscle of these fish were analyzed. The results showed no significant difference in the length-weight relationship (LWR) b value between the large and small A. dabryanus. The levels of serum growth hormone (gh) and insulin-like growth factor 1 (igf1) in the large A. dabryanus were significantly lower than those in the small, whereas the activity levels of Total superoxide dismutase (T-sod) and catalase (cat) were opposite to the results of gh and igf1. A total of 212 and 245 metabolites showed significant changes in the positive and negative polarity mode, respectively. Among 3,308 proteins identified, 69 proteins showed upregulated expression, and 185 proteins showed downregulated expression. These results indicated that the growth advantage of A. dabryanus was closely related to glycolysis, protein synthesis, and antioxidant function.

Hepatitis B has become one of the major global health threats, especially in developing countries and regions. Hepatitis B virus infection greatly increases the risk for liver diseases such as cirrhosis and cancer. However, treatment for hepatitis B is limited when considering the huge base of infected people. The immune response against hepatitis B is mediated mainly by CD8+ T cells, which are key to fighting invading viruses, while regulatory T cells prevent overreaction of the immune response process. Additionally, follicular T helper cells play a key role in B-cell activation, proliferation, differentiation, and formation of germinal centers. The pathogenic process of hepatitis B virus is generally the result of a disorder or dysfunction of the immune system. Therefore, we present in this review the critical functions and related biological processes of regulatory T cells and follicular T helper cells during HBV infection.

Macrophages, as central components of innate immunity, feature significant heterogeneity. Numerus studies have revealed the pivotal roles of macrophages in the pathogenesis of liver fibrosis induced by various factors. Hepatic macrophages function to trigger inflammation in response to injury. They induce liver fibrosis by activating hepatic stellate cells (HSCs), and then inflammation and fibrosis are alleviated by the degradation of the extracellular matrix and release of anti-inflammatory cytokines. MicroRNAs (miRNAs), a class of small non-coding endogenous RNA molecules that regulate gene expression through translation repression or mRNA degradation, have distinct roles in modulating macrophage activation, polarization, tissue infiltration, and inflammation regression. Considering the complex etiology and pathogenesis of liver diseases, the role and mechanism of miRNAs and macrophages in liver fibrosis need to be further clarified. We first summarized the origin, phenotypes and functions of hepatic macrophages, then clarified the role of miRNAs in the polarization of macrophages. Finally, we comprehensively discussed the role of miRNAs and macrophages in the pathogenesis of liver fibrotic disease. Understanding the mechanism of hepatic macrophage heterogeneity in various types of liver fibrosis and the role of miRNAs on macrophage polarization provides a useful reference for further research on miRNA-mediated macrophage polarization in liver fibrosis, and also contributes to the development of new therapies targeting miRNA and macrophage subsets for liver fibrosis.

Abstract T cells play a crucial role in atherosclerosis, with its infiltration preceding the formation of atheroma. However, how T‐cell infiltration is regulated in atherosclerosis remains largely unknown. Here, this work demonstrates that dipeptidyl peptidase‐4 (DPP4) is a novel regulator of T‐cell motility in atherosclerosis. Single‐cell ribonucleic acid (RNA) sequencing and flow cytometry show that CD4+ T cells in atherosclerotic patients display a marked increase of DPP4. Lack of DPP4 in hematopoietic cells or T cells reduces T‐cell infiltration and atherosclerotic plaque volume in atherosclerosis mouse models. Mechanistically, DPP4 deficiency reduces T‐cell motility by suppressing the expression of microtubule associated protein midline‐1 (Mid1) in T cells. Deletion of either DPP4 or Mid1 inhibits chemokine‐induced shape change and motility, while restitution of Mid1 in Dpp4−/− T cell largely restores its migratory ability. Thus, DPP4/Mid1, as a novel regulator of T‐cell motility, may be a potential inflammatory target in atherosclerosis.

Background: There is increasing evidence that long non-coding RNAs (lncRNAs) can be used as potential prognostic factors for cancer. This study aimed to develop a prognostic model for lung adenocarcinoma (LUAD) using angiogenesis-related long non-coding RNAs (lncRNAs) as potential prognostic factors.Methods: Transcriptome data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were analyzed to identify aberrantly expressed angiogenesis-related lncRNAs in LUAD. A prognostic signature was constructed using differential expression analysis, overlap analysis, Pearson correlation analysis, and Cox regression analysis. The model’s validity was assessed using K-M and ROC curves, and independent external validation was performed in the GSE30219 dataset. Prognostic lncRNA-microRNA (miRNA)-messenger RNA (mRNA) competing endogenous RNA (ceRNA) networks were identified. Immune cell infiltration and mutational characteristics were also analyzed. The expression of four human angiogenesis-associated lncRNAs was quantified using quantitative real-time PCR (qRT-PCR) gene arrays.Results: A total of 26 aberrantly expressed angiogenesis-related lncRNAs in LUAD were identified, and a Cox risk model based on LINC00857, RBPMS-AS1, SYNPR-AS1, and LINC00460 was constructed, which may be an independent prognostic predictor for LUAD. The low-risk group had a significant better prognosis and was associated with a higher abundance of resting immune cells and a lower expression of immune checkpoint molecules. Moreover, 105 ceRNA mechanisms were predicted based on the four prognostic lncRNAs. qRT-PCR results showed that LINC00857, SYNPR-AS1, and LINC00460 were significantly highly expressed in tumor tissues, while RBPMS-AS1 was highly expressed in paracancerous tissues.Conclusion: The four angiogenesis-related lncRNAs identified in this study could serve as a promising prognostic biomarker for LUAD patients.

Abstract Background Cervical cancer is a common malignant tumor in women, with a high mortality rate, has great harm to women’s health. Long-term and persistent infection of high-risk human papillomavirus (HR-HPV) is the main reason of the occurrence and development of cervical cancer. Methods The infection rate of HPV-58 is higher in the Jingzhou area. In this study, 172 complete HPV-58 E6-E7 sequences were amplified by polymerase chain reaction (PCR), the amplified products were sequenced, and the gene variations of HPV-58 E6-E7 were analyzed. A Neighbor-Joining phylogenetic tree was constructed by MEGA 11. The secondary structure of E6 and E7 protein was investigated. PAML X was used to analyze the selective pressure. The B cell epitopes of E6 and E7 proteins in HPV-58 were predicted by ABCpred server. Results In E6 sequences, 10 single nucleotide variants were observed, including 7 synonymous and 3 non-synonymous variants. In E7 sequences, 12 single nucleotide variants were found, including 3 synonymous variants and 9 non-synonymous variants. There are 5 novel variants. The phylogenetic analysis showed that all the E6-E7 sequences were distributed in A lineage. No positively selected site was found in E6 sequence, but G63 in E7 sequences was identified as positively selected site. Some amino acid substitutions affected multiple B cell epitopes. Conclusion Various E6 and E7 mutational data may prove useful for development of better diagnostic and vaccines for the region of Jingzhou, Hubei province of central China.

Acipenser dabryanus is an ancient living fossil and a flagship species of the Yangtze River. However, A. dabryanus was listed as a critically endangered species due to the dramatic decrease in its population, and disease outbreaks occurring during captive breeding have hindered the protection of this species. Here, we investigated the effect of the pathogenic bacterium Edwardsiella tarda and poly(I:C) on A. dabryanus at the histopathological and transcriptomic levels. After 48 h of infection with E. tarda, A. dabryanus exhibited marked pathological changes in the intestine and liver. We then conducted full-length transcriptome sequencing of the spleen by SMRT sequencing technology. Using the full-length transcriptome data as a reference, transcriptomic results obtained through Illumina sequencing technology revealed that a total of 894 and 963 unigenes were differentially expressed between the PBS and bacterial infection groups and between the PBS and poly(I:C) challenge groups, respectively. E3 ubiquitin ligases family members, T-cell receptor and clusters of differentiation were significantly upregulated by bacteria or poly(I:C) treatment, while the complement was significantly downregulated, suggesting that they might participate in multiple immune pathways in the response to pathogen invasion. Pathogen infection also induced changes in some key rate-limiting enzymes involved in energy metabolism. Our study can provide important information on the molecular mechanisms underlying the immune response of fish to pathogenic microbial infections and help explore the antibacterial and antiviral immunity of A. dabryanus.

Temperature fluctuations caused by climate change and global warming pose a great threat to various species. Most fish are particularly vulnerable to elevated temperatures. Understanding the mechanism of high-temperature tolerance in fish can be beneficial for proposing effective strategies to help fish cope with global warming. In this study, we systematically studied the effects of high temperature on Acipenser dabryanus, an ancient living fossil and flagship species of the Yangtze River, at the histological, biochemical, transcriptomic and metabolomic levels. Intestinal and liver tissues from the control groups (18 °C) and acute heat stress groups (30 °C) of A. dabryanus were sampled for histological observation and liver tissues were assessed for transcriptomic and metabolomic profiling. Histopathological analysis showed that the intestine and liver tissues were damaged after heat stress. The plasma cortisol content and the levels of oxidative stress markers (catalase/glutathione reductase) and two aminotransferases (aspartate aminotransferase/alanine aminotransferase) increased significantly in response to acute heat stress. Transcriptomic and metabolomic methods showed 6707 upregulated and 4189 downregulated genes and 64 upregulated and 78 downregulated metabolites in the heat stress group. Heat shock protein (HSP) genes showed striking changes in expression under heat stress, with 21 genes belonging to the HSP30, HSP40, HSP60, HSP70 and HSP90 families significantly upregulated by short-term heat stress. The majority of genes associated with ubiquitin and various immune-related pathways were also markedly upregulated in the heat stress group. In addition, the combined analysis of metabolites and gene profiles suggested an enhancement of amino acid metabolism and glycometabolism and the suppression of fatty acid metabolism during heat stress, which could be a potential energy conservation strategy for A. dabryanus. To the best of our knowledge, the present study represents the first attempt to reveal the mechanisms of heat stress responses in A. dabryanus, which can provide insights into improved cultivation of fish in response to global warming.

Abstract The SARS-CoV-2 infection causes severe immune disruption. However, it is unclear if disrupted immune regulation still exists and pertains in recovered COVID-19 patients. In our study, we have characterized the immune phenotype of B cells from 15 recovered COVID-19 patients, and found that healthy controls and recovered patients had similar B-cell populations before and after BCR stimulation, but the frequencies of PBC in patients were significantly increased when compared to healthy controls before stimulation. However, the percentage of unswitched memory B cells was decreased in recovered patients but not changed in healthy controls upon BCR stimulation. Interestingly, we found that CD19 expression was significantly reduced in almost all the B-cell subsets in recovered patients. Moreover, the BCR signaling and early B-cell response were disrupted upon BCR stimulation. Mechanistically, we found that the reduced CD19 expression was caused by the dysregulation of cell metabolism. In conclusion, we found that SARS-CoV-2 infection causes immunodeficiency in recovered patients by downregulating CD19 expression in B cells via enhancing B-cell metabolism, which may provide a new intervention target to cure COVID-19.

Platypharodon extremus is an endemic species on the Qinghai–Tibet Plateau. As a secondary protected species in China, the basic genomic information of this species has not yet been reported. Here, through third-generation sequencing, the full-length transcriptome of P. extremus was obtained. We identified 323,290 CCS sequences, and a total of 50,083 unigenes were extracted after correction with second-generation sequencing data and the removal of redundant reads. A total of 50,067 transcripts were annotated with the various databases. Based on the sequence information, three members in the bone morphogenetic proteins (bmps) family and their receptors, were identified. We found that the special structures of these proteins (zinc-dependent metalloproteinase domain, CUB domains, EGF-like domains and TGF-β domain) are highly conserved in fish and that they are closely evolutionarily related to the bmps and bmp receptors of Cyprinidae fishes. This is the first study to sequence the full-length transcriptome of P. extremus, which will help us to further understand its biology.

B cells are the core components of humoral immunity. A mature B cell can serve in multiple capacities, including antibody production, antigen presentation, and regulatory functions. Forkhead box P3 (FoxP3)-expressing regulatory T cells (Tregs) are key players in sustaining immune tolerance and keeping inflammation in check. Mounting evidence suggests complex communications between B cells and Tregs. In this review, we summarize the yin-yang regulatory relationships between B cells and Tregs mainly from the perspectives of T follicular regulatory (Tfr) cells and regulatory B cells (Bregs). We discuss the regulatory effects of Tfr cells on B cell proliferation and the germinal center response. Additionally, we review the indispensable role of B cells in ensuring homeostatic Treg survival and describe the function of Bregs in promoting Treg responses. Finally, we introduce a new subset of Tregs, termed Treg-of-B cells, which are induced by B cells, lake the expression of FoxP3 but still own immunomodulatory effects. In this article, we also enumerate a sequence of research from clinical patients and experimental models to clarify the role of Tfr cells in germinal centers and the role of convention B cells and Bregs to Tregs in the context of different diseases. This review offers an updated overview of immunoregulatory networks and unveils potential targets for therapeutic interventions against cancer, autoimmune diseases and allograft rejection.

Abstract Background The surgical outcomes of anterior cervical discectomy and fusion (ACDF) in female patients according to menopausal status remain unclear. The objective of this study was to investigate the differences in these outcomes among female patients with different menopausal statuses. Methods Ninety-one patients undergoing single-level or consecutive two-level ACDF with a minimum 12-month postoperative follow-up were included in this study. There were 38 patients in the premenopausal group, 28 patients in the early postmenopausal group, and 25 patients in the late postmenopausal group. The clinical outcomes were evaluated by means of the neck disability index (NDI) scores, Japanese Orthopedic Association (JOA) scores, and visual analog scale (VAS) scores. Radiological parameters included cervical lordosis (CL), the functional spinal unit (FSU) angle, range of motion (ROM) of the total cervical spine, ROM of the FSU, anterior and posterior FSU height, implant subsidence, adjacent segment degeneration (ASD), and Hounsfield unit (HU) values. Results All groups showed significant improvements in their JOA, VAS, and NDI scores (P < 0.05). The differences in preoperative and final follow-up CL, ROM of C2-7, FSU angle, and ROM of FSU were not statistically significant among the three groups (P > 0.05). The anterior FSU height loss rate showed a significant difference (P = 0.043), while there was no difference in the posterior FSU height loss rate (P = 0.072). The fusion rates in the early and late postmenopausal groups were consistently lower than those in the premenopausal group during the follow-up period. All patients had satisfactory outcomes at the final follow-up. Conclusion There were no significant differences in clinical or other related outcomes of single-level or consecutive two-level ACDF in the long term among female patients with different menopausal statuses. However, the early bony fusion rates and anterior FSU height loss rates were poorer in late postmenopausal patients than in premenopausal or early postmenopausal patients. Hence, importance should be attached to the protection of late postmenopausal patients in the early postoperative period to guarantee solid bony fusion.

Abstract Background CCR2 is involved in maintaining immune homeostasis and regulating immune function. This study aims to elucidate the mechanism by which CCR2 regulates B‐cell signalling. Methods In Ccr2‐knockout mice, the development and differentiation of B cells, BCR proximal signals, actin movement and B‐cell immune response were determined. Besides, the level of CCR2 in PBMC of SLE patients was analysed by bioinformatics. Results CCR2 deficiency reduces the proportion and number of follicular B cells, upregulates BCR proximal signalling and enhances the oxidative phosphorylation of B cells. Meanwhile, increased actin filaments aggregation and its associated early‐activation events of B cells are also induced by CCR2 deficiency. The MST1/mTORC1/STAT1 axis in B cells is responsible for the regulation of actin remodelling, metabolic activities and transcriptional signalling, specific MST1, mTORC1 or STAT1 inhibitor can rescue the upregulated BCR signalling. Glomerular IgG deposition is obvious in CCR2‐deficient mice, accompanied by increased anti‐dsDNA IgG level. Additionally, the CCR2 expression in peripheral B cells of SLE patients is decreased than that of healthy controls. Conclusions CCR2 can utilise MST1/mTORC1/STAT1 axis to regulate BCR signalling. The interaction between CCR2 and BCR may contribute to exploring the mechanism of autoimmune diseases.

Liver is an important organ for glucose and lipid metabolism, immunity, and detoxification in fish. However, the gene regulatory network of postnatal liver development still remains unknown in teleost fish. In this study, we performed transcriptome analysis on the liver of S. prenanti at three stages. A total of 1692 differentially expressed genes (DGEs) were identified across three liver developmental stages. The oil red O staining and PAS staining revealed that the lipid content of liver was increased and the glycogen content of liver was decreased during liver development. The fatty acids biosynthesis related genes were upregulated in adult and young stages compared with juvenile stage, while lipid degradation related genes were downregulated. The genes related to glycolysis, gluconeogenesis and glycogenolysis were upregulated in juvenile or young stages compared with adult stage. Further pathway analysis indicated that the CYP450 pathway, cell cycle and amino acid metabolic pathway were induced in the process of liver maturation. Our study presents the gene expression pattern in different liver development stages of S. prenanti and may guide future studies on metabolism of S. prenanti liver.

Abstract Fish culture in paddy fields is a traditional aquaculture mode, which has a long history in East Asia. Large-scale loach (Paramisgurnus dabryanus) fast growth is suitable for paddy fields aquaculture in China. The objective of this study was to identify differential expression genes (DEGs) in the brain, liver and muscle tissues between large (LG, top 5% of maximum total length) and small (SG, top 5% of minimum total length) groups using RNA-seq. In total, 150 fish were collected each week and 450 fish were collected at twelfth week from three paddy fields for all the experimental. Histological observation found that the muscle fibre diameter of LG loaches was greater than that of SG loaches. Transcriptome results revealed that the high expression genes (HEGs) in LG loaches (fold change ≥ 2, p

Heat stress induced by global warming has damaged the well-being of aquatic animals. The skin tissue plays a crucial role as a defense barrier to protect organism, however, little is known about the effect of heat stress on fish skin, particularly in cold-water fish species. Here, we investigated the effects of mild heat stress (24°C, MS) and high heat stress (28°C, HS) on Siberian sturgeon skin using RNA-seq, histological observation, and microbial diversity analysis. In RNA-seq, 8,819 differentially expressed genes (DEGs) in MS vs. C group and 12,814 DEGs in HS vs. C group were acquired, of which the MS vs. C and HS vs. C groups shared 3,903 DEGs, but only 1,652 DEGs were successfully annotated. The shared DEGs were significantly enriched in pathways associating with mucins synthesis. Histological observation showed that the heat stresses significantly reduced the number of skin mucous cells and induced the damages of epidermis. The microbial diversity analysis elicited that heat stress markedly disrupted the diversity and abundance of skin microbiota by increasing of potential pathogens (Vibrionimonas, Mesorhizobium, and Phyllobacterium) and decreasing of probiotics (Bradyrhizobium and Methylovirgula). In conclusion, this study reveals that heat stress causes adverse effects on sturgeon skin, reflecting in decreasing the mucus secretion and disordering the mucosal microbiota, which may contribute to develop the preventive strategy for heat stress caused by global warming.

Background The aim of this study was to determine the function of long non‐coding RNA small nucleolar RNA host gene 6 (SNHG6) in non‐small cell lung cancer (NSCLC) and its underlying mechanisms. Methods The association of SNHG6 or miR‐101‐3p with clinicopathological characteristics and prognosis in patents with NSCLC was assessed by TCGA dataset. Cell proliferation and invasion were evaluated by MTT and Transwell assays and SNHG6‐specific binding with miR‐101‐3p was verified by bioinformatic analysis, luciferase gene report and RNA immunoprecipitation assays. qRT‐PCR and Western blot was used to assess the effects of SNHG6 on the expression of miR‐101‐3p and chromodomain Y like (CDYL) in NSCLC cells. A xenograft tumor model in vivo was established to observe the effects of SNHG6 knockdown on tumor growth. Results We found that increased expression of SNHG6 was associated with pathological stage and lymph node infiltration, and acted as an independent prognostic factor of tumor recurrence in patients with NSCLC. Silencing SNHG6 expression repressed cell growth and invasion in vitro and in vivo, but overexpression of SNHG6 reversed these effects. Furthermore, SNHG6 was identified to act as a sponge of miR‐101‐3p, which could reduce cell proliferation and attenuate SNHG6‐induced CDYL expression. Low expression of miR‐101‐3p or high expression of CDYL was related to poor survival in patients with NSCLC. Conclusions Our findings demonstrated that lncRNA SNHG6 contributed to the proliferation and invasion of NSCLC by downregulating miR‐101‐3p.

Background Nephrotoxicity, especially acute kidney injury (AKI), is the main dose-limiting toxicity of cisplatin. Although recent studies showed that curcumin prevented cisplatin-induced AKI effectively, further studies to understand the mechanism are required. Methods We established an AKI mouse model. Male C57BL/6 mice were assigned to three groups: saline group (control), cisplatin group (CP), and curcumin + cisplatin group (CP + Cur). The CP group received a single intraperitoneal (i.p.) injection of cisplatin, while the control group received saline. The CP + Cur group received i.p. curcumin three days before cisplatin injection and curcumin administered for another three days until the day before euthanization. Renal injury was assessed by serological and histological analysis. Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) were used to detect the phosphatase and tensin homolog (PTEN), and microRNA (miR)-181a expression in the renal tissues. Bioinformatics prediction and western blotting methods validated the targets of miR-181a in vitro. Results Curcumin treatment alleviated cisplatin-induced nephrotoxicity as validated by the blood urea nitrogen (BUN) values, and histological analysis of kidneys. At the molecular level, curcumin treatment decreased miR-181a expression level, which was induced by cisplatin and restored the in vivo expression of PTEN, which was suppressed by cisplatin. We verified the direct regulation of PTEN by miR-181a in cultured human embryonic kidney 293T cells. Conclusions We showed the involvement of miR-181a/PTEN axis in the renoprotective effect of curcumin against cisplatin-induced AKI, and provide new evidence on the ability of curcumin to alleviate cisplatin-induced nephrotoxicity.

Abstract Schistosomiasis is a prevalent parasitic disease worldwide. The main pathological changes of hepatosplenic schistosomiasis are hepatic granuloma and fibrosis due to worm eggs. Portal hypertension and ascites induced by hepatic fibrosis are usually the main causes of death in patients with chronic hepatosplenic schistosomiasis. Currently, no effective vaccine exists for preventing schistosome infections. For quite a long time, praziquantel (PZQ) was widely used for the treatment of schistosomiasis and has shown benefit in treating liver fibrosis. However, drug resistance and chemical toxicity from PZQ are being increasingly reported in recent years; therefore, new and effective strategies for treating schistosomiasis-induced hepatic fibrosis are urgently needed. MicroRNA (miRNA), a non-coding RNA, has been proved to be associated with the development of many human diseases, including schistosomiasis. In this review, we present a balanced and comprehensive view of the role of miRNAs in the pathogenesis, grading, and treatment of schistosomiasis-associated hepatic fibrosis. The multiple regulatory roles of miRNAs, such as promoting or inhibiting the development of liver pathology in murine schistosomiasis are also discussed in depth. Additionally, miRNAs may serve as candidate biomarkers for diagnosing liver pathology of schistosomiasis and as novel therapeutic targets for treating schistosomiasis-associated hepatic fibrosis.

Acipenser dabryanus is an endemic species restricted to the upper reaches of the Yangtze River and is listed as a national first-class protected animal in China. In the present study, two lipid metabolism-associated genes, namely, lipoprotein lipase (LPL) and apolipoprotein E (apoE), were identified from the full-length transcriptome analysis of A. dabryanus. The full-length genes encoded polypeptides with typical conserved motifs and functional sites shared with their homologues in other fish. Gene expression profile analysis showed that the LPL and apoE genes were constitutively expressed in A. dabryanus. The highest expression level of LPL was found in the muscle, while apoE was predominantly expressed in the liver. In the fasting and refeeding experiment, one hundred twenty fish were randomly assigned to four groups (fasting 0, 3, 7 or 14 d and then refed for 14 d). Fasting and refeeding significantly regulated the expression level of LPL with various expression patterns in different tissues, whereas starvation showed little effect on apoE expression. In addition, the expression levels of LPL and apoE were significantly affected by feeding frequency. The fish were bred for eight weeks at six different feeding frequencies groups (once a day, two times a day, three times a day, four times a day, five times a day and six times a day). Both LPL and apoE expression levels were significantly upregulated in the liver in the highest feeding frequency group. Our study suggests potential roles for LPL and apoE in lipid metabolism in A. dabryanus and will be useful for further study of nutrition regulation in fish.

Immunoglobin G4-related disease (IgG4-RD) is one of the newly discovered autoimmune diseases characterized by elevated serum IgG4 concentrations and multi-organ fibrosis. Despite considerable research and recent advances in the identification of underlying immunological processes, the etiology of this disease is still not clear. Adaptive immune cells, including different types of T and B cells, and cytokines secreted by these cells play a vital role in the pathogenesis of IgG4-RD. Antigen-presenting cells are stimulated by pathogens and, thus, contribute to the activation of naïve T cells and differentiation of different T cell subtypes, including helper T cells (Th1 and Th2), regulatory T cells, and T follicular helper cells. B cells are activated and transformed to plasma cells by T cell-secreted cytokines. Moreover, macrophages, and some important factors (TGF-β, etc.) promote target organ fibrosis. Understanding the role of these cells and cytokines implicated in the pathogenesis of IgG4-RD will aid in developing strategies for future disease treatment and drug development. Here, we review the most recent insights on IgG4-RD, focusing on immune dysregulation involved in the pathogenesis of this autoimmune condition.

With the expansion of our knowledge on inborn errors of immunity (IEI), it gradually becomes clear that immune dysregulation plays an important part. In some cases, autoimmunity, hyperinflammation and lymphoproliferation are far more serious than infections. Thus, immune dysregulation has become significant in disease monitoring and treatment. In recent years, the wide application of whole-exome sequencing/whole-genome sequencing has tremendously promoted the discovery and further studies of new IEI. The number of discovered IEI is growing rapidly, followed by numerous studies of their pathogenesis and therapy. In this review, we focus on novel discovered primary immune dysregulation diseases, including deficiency of SLC7A7, CD122, DEF6, FERMT1, TGFB1, RIPK1, CD137, TET2 and SOCS1. We discuss their genetic mutation, symptoms and current therapeutic methods, and point out the gaps in this field.

Abstract. B lymphocytes produce antibodies under the stimulation of specific antigens, thereby exerting an immune effect. B cells identify antigens by their surface B cell receptor (BCR), which upon stimulation, directs the cell to activate and differentiate into antibody generating plasma cells. Activation of B cells via their BCRs involves signaling pathways that are tightly controlled by various regulators. In this review, we will discuss three major BCR mediated signaling pathways (the PLC-γ2 pathway, PI3K pathway and MAPK pathway) and related regulators, which were roughly divided into positive, negative and mutual-balanced regulators, and the specific regulators of the specific signaling pathway based on regulatory effects.

Background. Novel coronavirus disease 2019 (COVID-19), an acute respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), rapidly progressed to a global pandemic. Currently, there are limited effective medications approved for this deadly disease. Objective. To investigate the potential predictors of COVID-19 mortality and risk factors for hyperinflammation in COVID-19. Methods. Retrospective analysis was carried out in 1,149 patients diagnosed with COVID-19 in Tongji Hospital, Wuhan, China, from 1/13/2020 to 3/15/2020. Results. We found significant differences in the rates of hyperuricemia (OR: 3.17, 95% CI: 2.13-4.70; p

The parasitic worms, Schistosoma mansoni and Schistosoma japonicum, reside in the mesenteric veins, where they release eggs that induce a dramatic granulomatous response in the liver and intestines. Subsequently, infection may further develop into significant fibrosis and portal hypertension. Over the past several years, uncovering the mechanism of immunopathology in schistosomiasis has become a major research objective. It is known that T lymphocytes, especially CD4+ T cells, are essential for immune responses against Schistosoma species. However, obtaining a clear understanding of how T lymphocytes regulate the pathological process is proving to be a daunting challenge. To date, CD4+ T cell subsets have been classified into several distinct T helper (Th) phenotypes including Th1, Th2, Th17, T follicular helper cells (Tfh), Th9, and regulatory T cells (Tregs). In the case of schistosomiasis, the granulomatous inflammation and the chronic liver pathology are critically regulated by the Th1/Th2 responses. Animal studies suggest that there is a moderate Th1 response to parasite antigens during the acute stage, but then, egg-derived antigens induce a sustained and dominant Th2 response that mediates granuloma formation and liver fibrosis. In addition, the newly discovered Th17 cells also play a critical role in the hepatic immunopathology of schistosomiasis. Within the liver, Tregs are recruited to hepatic granulomas and exert an immunosuppressive role to limit the granulomatous inflammation and fibrosis. Moreover, recent studies have shown that Tfh and Th9 cells might also promote liver granulomas and fibrogenesis in the murine schistosomiasis. Thus, during infection, T-cell subsets undergo complicated cross-talk with antigen presenting cells that then defines their various roles in the local microenvironment for regulating the pathological progression of schistosomiasis. This current review summarizes a vast body of literature to elucidate the contribution of T lymphocytes and their associated cytokines in the immunopathology of schistosomiasis.

Superoxide dismutase and catalase are two major antioxidant enzymes in the fish antioxidant defense system, which can remove excess reactive oxygen species and protect fish from stress-induced oxidative damage. The present study aimed to clone the sequences of Yangtze sturgeon, Acipenser dabryanus, Cu/Zn superoxide dismutase (AdCu/Zn-SOD) and catalase (AdCAT), and to explore changes of gene expression in the liver and intestine during fasting and refeeding. A total of 120 fish were exposed to four fasting and refeeding protocols (fasting for 0, 3, 7, or 14 d and then refeeding for 14 d). The coding sequences of AdCu/Zn-SOD and AdCAT encoded 155 and 526 amino acid proteins, respectively, both of which were expressed mainly in the liver. During fasting, when compared to the control group, liver AdCu/Zn-SOD expression was significantly higher in the 3- and 14-d groups, whereas its intestinal expression increased significantly only in the 7-d group. Liver AdCAT expression increased significantly in the 3-, 7-, and 14-d groups. During refeeding, liver AdCu/Zn-SOD expression increased significantly in the 3-, 7-, and 14-d groups compared with those in the control group. Similarly, intestinal AdCu/Zn-SOD expression increased significantly in the 3- and 7-d groups. Moreover, intestinal AdCAT expression was significantly higher in the 3-d group than in the control group, but decreased significantly in the 14-d group. Our findings indicated that AdCu/Zn-SOD and AdCAT play important roles in protecting fish against starvation-induced oxidative stress. Yangtze sturgeon exhibited the potential to adapt to a starvation and refeeding regime.

Abstract Objectives The intention of our study was to investigate the relationship between miR‐144‐3p and EZH2 as well as the effects of their interaction on cell propagation and invasiveness in lung adenocarcinoma (LUAD). Methods The expression levels of miR‐144‐3p and EZH2 in LUAD tissues and normal tissues were determined by qRT‐PCR. The dual‐luciferase reporter assay was utilized to validate the targeting relationship between miR‐144‐3p and EZH2. MTT assay and colony formation assay were performed to evaluate the viability and propagation of LUAD cells, while the effects of miR‐144‐3p and EZH2 on LUAD cell invasiveness were confirmed by transwell assay. Protein expression levels of VEGFA, MMP2, and MMP9 were measured by Western blot. Furthermore, xenograft tumor models were established to verify the effects of miR‐144‐3p on tumor formation and EZH2, VEGFA, MMP2 and MMP9 expressions in vivo. Results miR‐144‐3P was downregulated in LUAD tissues, and overexpression of miR‐144‐3p inhibited propagation and invasiveness of LUAD cells. EZH2 was a target of miR‐144‐3p and was highly expressed in LUAD cells. Knockdown of EZH2 could suppress the propagation and invasion of LUAD cells. Increased miR‐144‐3p expression exerted an inhibitory effect on LUAD tumor formation in vivo. Conclusion Overexpression of miR‐144‐3p impeded the propagation and invasiveness of LUAD cells by targeting EZH2.

Abstract Background Most of the current available cervical disc prostheses present a flat surface instead of an arcuate surface which is most similar to the morphology of cervical endplate. Therefore, we designed a novel prosthesis (Pretic-I, Trauson) based on the physiological curvature of the cervical endplate. Biomechanical evaluation of cervical disc replacement (CDR) with this novel prosthesis was performed and compared with the Prestige LP prosthesis. Methods Three motion segments of 18 cadaveric cervical specimens (C2-C7) were evaluated with a 75 N follower load. Overall, the biomechanics of three models, intact specimen, CDR with the novel prosthesis and CDR with the Prestige LP prosthesis, were studied to gain insight into the effective function of the novel prosthesis. The range of motion (ROM) of all three segments and intradiscal pressure (IDP) on adjacent levels were measured and analysed. Results Compared to the intact condition, the ROM of all three segments showed no significant difference in the replacement group. Moreover, there was also no significant difference in the ROM between the two prostheses. Besides, the IDP on the cranial adjacent level showed no obvious difference between the two prostheses; nevertheless, the IDP on the caudal adjacent level of the novel prosthesis was significantly less than the Prestige LP prosthesis. Conclusions In summary, the novel disc prosthesis was effective to maintain the ROM at the target segment and adjacent segments. Besides, CDR with the novel prosthesis could reduce the IDP on the caudal adjacent level to a certain extent, compared with the Prestige LP prosthesis.

Fibrosis is responsible for approximately 45% of deaths in the industrialized world and has been a major global healthcare burden. Excessive fibrosis is the primary cause of organ failure. However, there are currently no approved drugs available for the prevention or treatment of fibrosis-related diseases. It has become evident that fibrosis is characterized by inflammation. In a large number of studies of various organs in mice and humans, pyroptosis has been found to play a significant role in fibrosis. Pyroptosis is a form of programmed cell death mediated by the N-terminal fragment of cysteinyl aspartate-specific proteinase (caspase)-1-cleaved gasdermin D (GSDMD, producing GSDMD-N) that gives rise to inflammation via the release of some proinflammatory cytokines, including IL-1β, IL-18 and HMGB1. These cytokines can initiate the activation of fibroblasts. Inflammasomes, an important factor upstream of GSDMD, can activate caspase-1 to trigger the maturation of IL-1β and IL-18. Moreover, the inhibition of inflammasomes, proinflammatory cytokines and GSDMD can prevent the progression of fibrosis. This review summarizes the growing evidence indicating that pyroptosis triggers fibrosis, and highlights potential novel targets for antifibrotic therapies.

Ammonia-N is toxic to many aquatic animals and serves as a key stress factor in aquatic environments. The effects of ammonia-N stress on the immune response of darkbarbel catfish Pelteobagrus vachellii were investigated in this study. Changes in overall histology, and in the expression of complement C3 and immunoglobulin M (IgM) in spleen and head kidney, and lysozyme and C3 in serum, were measured in 1 and 5 mg/L ammonia-N. Hyperemia, melano-macrophage assembly and loose splenosis were evident in spleen tissue. Both lysozyme and component C3 were significantly reduced in serum (P 0.05). IgM expression also increased significantly at 6–12 h in spleen and 6–24 h in head kidney after the 1 mg/L treatment (P

Dipeptidyl peptidase-4 (DPP-4) is an important protease that is widely expressed on the surface of human cells and plays a key role in immune-regulation, inflammation, oxidative stress, cell adhesion, and apoptosis by targeting different substrates. DPP-4 inhibitors (DPP-4i) are commonly used as hypoglycemic agents. However, in addition to their hypoglycemic effect, DPP-4i have also shown potent activities in the cardiovascular system, particularly in the regulation of blood pressure (BP). Previous studies have shown that the regulatory actions of DPP-4i in controlling BP are complex and that the mechanisms involved include the functional activities of the nerves, kidneys, hormones, blood vessels, and insulin. Recent work has also shown that inflammation is closely associated with the elevation of BP, and that the inhibition of DPP-4 can reduce BP by regulating the function of the immune system, by reducing inflammatory reactions and by improving oxidative stress. In this review, we describe the potential anti-hypertensive effects of DPP-4i and discuss potential new anti-hypertensive therapies. Our analysis indicated that DPP-4i treatment has a mild anti-hypertensive effect as a monotherapy and causes a significant reduction in BP when used in combined treatments. However, the combination of DPP-4i with high-dose angiotensin converting enzyme inhibitors (ACEI) can lead to increased BP. We suggest that DPP-4i improves vascular endothelial function in hypertensive patients by suppressing inflammatory responses and by alleviating oxidative stress. In addition, DPP-4i can also regulate BP by activating the sympathetic nervous system, interfering with the renin angiotensin aldosterone system (RAAS), regulating Na/H2O metabolism, and attenuating insulin resistance (IR).

Type 1 diabetes (T1D) is an autoimmune disease characterized by the immune cell-mediated progressive destruction of pancreatic β-cells. High-mobility group box 1 protein (HMGB1) has been recognized as a potential immune mediator to enhance the development of T1D. So we speculated that HMGB1 inhibitors could have anti-diabetic effect. Sodium butyrate is a short fatty acid derivative possessing anti-inflammatory activity by inhibiting HMGB1. In the current study, we evaluated the effects of sodium butyrate in streptozotocin (STZ)-induced T1D mice model. Diabetes was induced by multiple low-dose injections of STZ (40 mg/kg/day for 5 consecutive days), and then sodium butyrate (500 mg/kg/day) was administered by intraperitoneal injection for 7 consecutive days after STZ treatment. Blood glucose, incidence of diabetes, body weight, pancreatic histopathology, the amounts of CD4+T cell subsets, IL-1β level in serum and pancreatic expressions levels of HMGB1, and NF-κB p65 protein were analyzed. The results showed that sodium butyrate treatment decreased blood glucose and serum IL-1β, improved the islet morphology and decreased inflammatory cell infiltration, restored the unbalanced Th1/Th2 ratio, and down-regulated Th17 to normal level. In addition, sodium butyrate treatment can inhibit the pancreatic HMGB1 and NF-κB p65 protein expression. Therefore, we proposed that sodium butyrate should ameliorate STZ-induced T1D by down-regulating NF-κB mediated inflammatory signal pathway through inhibiting HMGB1.

Background Acipenser dabryanus, an endemic Chinese species, has been listed as a first-class protected animal in China. Sturgeons are among the oldest and most primitive group of existing fish in the world and occupy a special place in the evolutionary history of fish. Thus, a study of the reproduction and sex differentiation of sturgeon will be of great value for fish as well as the whole vertebrate group. Methods In this study, we conducted comparative analysis of the testes and ovaries transcriptomes of A. dabryanus to screen for sex-differentiation and sexual development-related genes. Results The transcriptome sequencing of six cDNA libraries generated 265 million clean reads, encompassing 79 Gb of sequences. The N50 and mean length of the identified 91,375 unigenes were 1,718 and 989 bp, respectively. A total of 6,306, 9,961, 13,170, 15,484, and 23,588 unigenes were annotated in the clusters of orthologous groups, gene ontology categories, Kyoto Encyclopedia of Genes and Genomes Pathway, euKaryotic orthologous groups, and NCBI non-redundant protein databases, respectively. A total of 5,396 differentially expressed genes were found between the two sexes, with 1,938 predicted to be up-regulated in ovaries and 3,458 in testes. A total of 73 candidate genes known to be involved in sex differentiation and sexual development were searched in the transcriptome of A. dabryanus of which 52 showed significant similarity. We highlighted six genes that are differentially expressed between the two sexes and may play important roles in sex differentiation and gonad maintenance. In addition, 24,271 simple sequence repeats (SSRs) and 550,519 single-nucleotide polymorphisms (SNPs) were detected. Discussion This work represents the first transcriptome study comparing the ovary and testis in A. dabryanus. The putative differentially expressed genes between the gonads provide an important source of information for further study of the sex-differentiation related genes and the sex-differentiation mechanism in sturgeons. The SSRs or SNPs identified in this study will be helpful in the discovery of sex-related markers in A. dabryanus.

B-cell formation, development, and differentiation are complex processes regulated by several mechanisms. Recently, there has been growing evidence indicating that microRNAs (miRNAs) are important for normal B-cell lineage development. miRNAs are small non-coding RNA molecules, about 20–22 nucleotide in length, that play an important role in regulating gene expression. They pair with specific messenger RNAs (mRNAs), resulting in mRNAs translational repression or degradation. Here, we review current research about the function of miRNAs in the aspects of B-cell physiology and pathology. We start by introducing the process of miRNA biogenesis. We will then focus on the role of miRNAs during B-cell lineage commitment and development in the bone marrow, followed by a discussion of miRNAs’ role in subsequent peripheral B-cell activation, proliferation, and final differentiation (including B-cell central tolerance and autoimmunity). We list and describe several examples to illustrate miRNAs’ role in the development of B-cell lymphoma, both as oncogenes and tumor suppressor genes. Finally, we delineate the potential value of miRNAs in diagnosing B-cell lymphoma, predicting clinical outcomes, and modulating the efficiency of anticancer treatments. Despite the vast amount of research conducted on miRNAs in recent years, it is still necessary to increase and further strengthen studies on miRNAs and their targets to promote a better understanding on B-cell development and as a result, construct more effective treatments against B-cell disease.