Objective(s): Rheumatoid arthritis (RA) is a chronic autoimmune disease with progressive cartilage erosion and joint destruction. CD73 plays a critical role in regulating inflammatory responses. This study aims to investigate the effects of CD73 blockade on RA progression and explore the potential mechanism. Materials and Methods: Soluble CD73 levels were determined by enzyme-linked immunosorbent assay. Immunohistochemistry (IHC) was used to detect CD73 expression in tissues. A collagen-induced arthritis (CIA) rat model was used to evaluate the effect of CD73 inhibitors in vivo. Hematoxylin and eosin staining was used to evaluate synovial tissue inflammation. Safranin O/Fast Green staining and Micro-CT were used to evaluate cartilage erosion and bone destruction. A live cell imaging system was used to analyze cell proliferation. Cell invasion experiments were performed using Transwell chambers. Results: Our data showed that CD73 expression was significantly increased in synovial tissues and serum from RA patients. The increased CD73 expression may be attributed to the hypoxic microenvironment via the hypoxia-inducible factor pathway in synovial tissues. Using CIA rats, our data demonstrated that CD73 blockade alleviated bone destruction and synovial inflammation. CD73 blockade inhibited synovioblast proliferation, invasion, and pro-inflammatory cytokine production. Moreover, transcriptome analysis revealed that differentially expressed genes (DEGs) in synovioblasts induced by CD73 blockade were primarily enriched for inflammatory responses, neutrophil chemotaxis, and integrin-mediated signaling pathways. Conclusion: CD73 blockade alleviated RA disease progression by regulating the activity of synovial fibroblasts. CD73 blockade is a potential therapeutic approach for patients with RA.

Background:CD73, a pivotal enzyme in the purinergic signaling cascade, modulates the concentrations of adenosine and inosine. These metabolites are involved in immune responses and inflammatory processes. This study aims to investigate the function of CD73 in the pathogenesis of inflammatory bowel disease (IBD) and explore the potential mechanism. Methods:Dextran-Sodium-Sulfate (DSS)-induced colitis mice models were established by orally administering 3% DSS. CD73 was blocked by intraperitoneal injection of Adenosine 5'- (α, β-methylene) diphosphate (APCP). Inosine was supplemented by intraperitoneal injection. Hematoxylin-eosin (H&E), PAS and Alcian blue staining were used to evaluate the inflammation infiltration and colon damage. Serum IL-6 levels were detected by ELISA assay. High-performance liquid chromatography-mass spectrometry (LC-MS) was used to investigate the level of inosine. Results:Blockade of CD73 by APCP aggravated disease severity in DSS-induced colitis mice models, characterized by increased weight loss, colon shortening and pathological damage, increased disease activity and IL-6 production. Blocking CD73 impairs intestinal barrier function and integrity by reducing the expression of tight junction proteins (claudin-1, occludin and ZO-1), both in colon tissues and intestinal epithelial cell-MODE-K. In addition, APCP increased oxidative stress in colon tissue and MODE-K (increased MDA level, decreased SOD and GSH activities). Moreover, blocking CD73 reduced inosine levels in vivo and in vitro. We found that inosine treatment significantly ameliorated DSS-induced colitis in mice, as demonstrated by decreased weight loss, less colon shortening and histological injury, reduced disease activity and IL-6 production. Notably, the effects of inosine on MODE-K cells were opposite to those of APCP, including the effects on the expression of oxidative stress molecules and tight junction proteins. Conclusion:This study indicates that CD73 exerts a protective effect in the progress of DSS-induced colitis. Inosine supplementation might be a potential therapeutic strategy for colitis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that can lead to multiple complications. Sjögren's syndrome (SS) is another autoimmune condition that may occur as a primary disorder or in conjunction with other autoimmune diseases, including RA. This study aimed to investigate the shared gene signatures between RA and SS. Gene expression datasets for RA (GSE15573, GSE93776) and SS (GSE48378, GSE94510, GSE93683) were obtained and analyzed to identify differentially expressed genes (DEGs) in peripheral blood mononuclear cells (PBMCs) and T cells. Gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed on the DEGs identified. Quantitative real-time PCR (qRT-PCR) was used to validate the expression levels of DEGs in PBMCs from patients with RA and SS. A total of 244 DEGs were identified from the RA PBMC dataset, comprising 142 upregulated genes and 102 downregulated genes. These DEGs were significantly enriched in biological processes related to immune responses, including cellular response to lipopolysaccharide, defense response against fungi, inflammatory responses, and antibacterial humoral responses. In contrast, 335 DEGs were identified from the SS PBMC dataset; among these, 320 genes were upregulated, while 15 were downregulated. The DEGs associated with SS showed strong involvement in defense responses against viruses, innate immune responses, viral responses, as well as cellular reactions to lipopolysaccharide. Moreover, we identified 12 shared DEGs between RA and SS PBMCs: RNASE2, NDUFB3, LY96, ANKRD22, EIF2AK2, RNASE3, CLEC4D, TNFAIP6, DYNLT1, RPS27L, LILRA5, and F5. Validation through qRT-PCR confirmed increased expression levels of RNASE2, RNASE3, NDUFB3, and EIF2AK2 in PBMCs. This study successfully delineated key DEGs along with their associated biological processes within the context of RA and SS PBMCs. Through bioinformatics analyses combined with qRT-PCR validation, we have identified four critical genes that may serve as potential biomarkers or therapeutic targets for further investigation.

B-cell acute lymphoblastic leukemia (B-ALL) is a hematological malignancy characterized by the aberrant accumulation of malignant and immature B cells in the bone marrow. Recent reports including ours have demonstrated that RNA modifications play pivotal roles in B-ALL progression and drug resistance. In the current study, we show that fat mass and obesity-associated protein (FTO), a demethylase of N6-methyladenosine (m6A) RNA modifications, is highly expressed in relapsed or refractory (R/R) B-ALL patients and B-ALL cell lines. In human B-ALL cells, FTO knockdown inhibited proliferation and cell cycle progression in vitro, while FTO overexpression exhibited opposite effects. Moreover, FTO knockdown significantly attenuated tumorigenesis in vivo after transplantation into immune-compromised mice as shown by reduced tumor burden and extended mouse survival. Interestingly, our research suggested that FTO overexpression resulted in altered cytoplasmic and mitochondrial ribosome biogenesis, and FTO knockdown led to a nucleolar stress-like morphologic change and mitochondrial dysfunction in B-ALL cells. Mechanistically, we found that FTO upregulated the expression of a group of ribosomal proteins via m6A-modification, among which RPS15a, RPL9, MRPS16 and MRPL44 were the most prominent ones and confirmed at the mRNA and protein levels. FTO upregulates RPS15a, RPL9, MRPS16 and MRPL44 by mitigating YTHDF2-mediated m6A-mRNA decay. Comparatively, although FTO knockdown induced B-ALL cell apoptosis mildly, it synergized with Doxorubicin to promote apparent B-ALL cell death. Furthermore, we found that the FTO inhibitor FB23-2 combined with Doxorubicin markedly repressed B-ALL progression in vivo, accompanied by nucleolar stress-like changes and mitochondrial dysfunction. In summary, our data suggest that FTO is a critical RNA epigenetic promotor of B-ALL, and targeted FTO blockade synergizing with Doxorubicin could be a potential therapy for B-ALL, likely by inhibiting cytoplasmic and mitochondrial ribosome biogenesis.

B-cell acute lymphocytic leukemia (B-ALL) is a malignant hematological disorder marked by the aberrant proliferation of abnormal B lymphocytes. Although recent advancements have highlighted the pivotal role of ribosomes in the progression of B-ALL, the specific function of ribosomal protein L9 (RPL9), a key component of ribosomal structural protein, still unclear. In this study, we observed a significant upregulation of RPL9 in human B-ALL cells compared to normal B cells, suggesting RPL9’s potential key role in B-ALL progression. Enforced RPL9 knockdown (KD) led to decreased proliferation and increased apoptosis in B-ALL cells compared to the control group. Furthermore, RPL9 KD significantly extended the survival time of NCG mice bearing B-ALL cells in vivo compared to controls. Mechanistically, our findings indicate that RPL9 KD triggers nucleolar stress, disrupts ribosome biosynthesis, and activates the p53 signaling pathway. Building upon our recent investigation into the positive regulatory influence of FTO on m6A-modified RPL9, we discovered that FTO overexpression can mitigate the activation of p53 signaling induced by RPL9 KD. Our findings further suggest that RPL9 KD increases MICA/B mRNA and protein expression in B-ALL cells, which serves as crucial ligands of NK cell’s NKG2D, potentially heightening their sensitivity to NK cell-mediated cytotoxicity. In summary, our study suggests that RPL9 KD suppresses B-ALL proliferation and upregulates immunotherapy targets, highlighting the important role of RPL9 as a potential target for conventional and immunotherapy of B-ALL.

ETHNOPHARMACOLOGICAL RELEVANCE:Chronic Obstructive Pulmonary Disease (COPD) is a progressive respiratory disorder with complex pathogenesis and multiple contributing factors. Modified Fangji Huangqi decoction (MFJHQ), a traditional Chinese medicine formula, has demonstrated clinical efficacy in COPD treatment. However, the pharmacological roles and underlying mechanisms of MFJHQ in treating COPD remain unclear. AIM OF STUDY:To investigate the therapeutic effects and molecular mechanisms of MFJHQ in the treatment of COPD. METHODS:COPD models were established in vitro using alveolar organoid (AOs) and 16 Human Bronchial Epithelial (16HBE) cells separately, induced by porcine pancreatic elastase (PPE) and in vivo in PPE-induced COPD mice. MFJHQ was administered via gavage for three weeks. RNA-sequencing and network pharmacology were employed to elucidate potential mechanisms of action. RESULTS:In vitro, MFJHQ enhanced epithelial barrier integrity by reducing permeability and upregulating zonula occludens-1 (ZO-1) expression. In vivo, MFJHQ effectively improved pulmonary function, alleviated emphysema and airway obstruction, and protected the lung structure from damage. Mechanistically, based on the results of RNA-sequencing and network pharmacology and subsequent experiments MFJHQ inhibited IL-33 and its downstream NF-κB signaling and CXCL5 expression, thereby reducing neutrophil recruitment in lung tissues. CONCLUSION:MFJHQ ameliorates COPD progression by inhibiting neutrophil infiltration through suppression of IL-33 and CXCL5, providing a new therapeutic strategy for COPD.

Oral squamous cell carcinoma (OSCC) is a major global health concern with a 5-year survival rate of approximately 50%, driven by high recurrence and metastasis. N6-methyladenosine (m6A) RNA modification, regulated by METTL3, plays a critical role in cancer progression, yet its mechanisms in OSCC remain underexplored. This study investigates the METTL3/HNRNPA2B1/FOXQ1 axis in OSCC tumorigenesis. m6A RNA immunoprecipitation sequencing (MeRIP-Seq) and motif analysis were performed to identify m6A modification sites in OSCC cell lines. METTL3, HNRNPA2B1, and FOXQ1 expression levels were assessed in OSCC and normal tissues using immunohistochemistry as a retrospectively registered. METTL3 was modulated in CAL27 cells to evaluate its effects on m6A levels, HNRNPA2B1/FOXQ1 expression, and mRNA stability via RT-qPCR, Western blotting, and RNA immunoprecipitation (RIP)-PCR. Functional assays (EdU, wound healing, Transwell) assessed proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT). Xenograft models validated in vivo effects. MeRIP-Seq identified the "GGAC" motif as a predominant m6A site. METTL3, HNRNPA2B1, and FOXQ1 were significantly overexpressed in OSCC tissues (p < 0.05). METTL3 silencing reduced m6A levels, HNRNPA2B1/FOXQ1 expression, and mRNA stability, attenuating proliferation, migration, invasion, and EMT, while overexpression enhanced these phenotypes. RIP-PCR confirmed METTL3 binding to HNRNPA2B1/FOXQ1 mRNA. In vivo, METTL3 silencing decreased tumor growth and FOXQ1 expression. METTL3-mediated m6A modification promotes OSCC progression by stabilizing HNRNPA2B1 and FOXQ1 mRNA, driving EMT and malignancy. The METTL3/HNRNPA2B1/FOXQ1 axis is a potential diagnostic and therapeutic target for OSCC, offering novel insights into epigenetic regulation and treatment strategies.

This study aim to investigate the effects of inosine on rheumatoid arthritis (RA) disease and explore the potential mechanism. Collagen-Induced Arthritis (CIA) rats were used to investigate the effects of inosine on bone destruction and inflammation. Micro-CT scan was used to detect the bone injury. H&E and Safranin O staining were used to evaluate the synovial inflammation and cartilage damage. RANKL-induced osteoclasts differentiation assay was used to investigate the effects of inosine on osteclastogenesis. CCK-8 and transwell experiments were performed to investigate the RA synovioblast (RASFs) proliferation and invasion. We observed that inosine intraperitoneal injection led to significant reduction in arthritis score of CIA rats. Micro-CT scan showed the decreased degree of bone destruction and increased bone mass in inosine treated CIA-rats. H&E and Safranin O staining showed that inosine significantly inhibited the inflammation and cartilage erosion in CIA-rats. The IL-6 and IL-8 levels in synovial tissues were lower in inosine treated CIA-rats than that in vehicle group. Furthermore, TRAP staining showed that the osteoclasts numbers were decreased in inosine treated CIA-rats. In vitro, inosine led to the decrease of osteoclasts numbers, F-actin ring and the expression of osteoclasts-specific markers. Furthermore, we found that inosine inhibited osteoclastogenesis via down-regulating OPN. OPN supplementation could counteract the inhibiting effect of inosine on osteoclastogenesis. Additionally, we observed that inosine significantly inhibited proliferation, invasion and inflammatory cytokines secretion of RASFs. In conclusion, inosine alleviated bone destruction and inflammation in CIA-rats by inhibiting osteoclastogenesis and RASFs activation. Hence, inosine supplementation may be a potential strategy for RA therapy.

M2 macrophages play a pivotal role in promoting the growth and metastasis of lung cancer cells. Inhibiting M2 macrophage polarization represents an effective immunotherapeutic approach against tumors. Although (-)-Guaiol has been shown to exert potent inhibitory effects on M2 macrophage polarization, its underlying molecular mechanism remains unclear. This study aimed to elucidate the effects of (-)-Guaiol on M2 macrophage polarization and to explore the potential molecular mechanisms involved. Bone marrow-derived macrophages (BMDMs) from mice were polarized toward the M2 phenotype using IL-4 and M-CSF. Both ex vivo and in vivo experiments were performed to determine whether (-)-Guaiol suppresses M2 macrophage polarization through the PPAR-γ-related signaling pathway. PPAR-γ agonists and inhibitors were applied to confirm the involvement of PPAR-γ in the effects of (-)-Guaiol. A co-culture system of M2 macrophages and Lewis lung carcinoma (LLC) cells was established. Wound healing, Transwell invasion, and plate cloning experiments were performed to determine the effects of (-)-Guaiol on the metastasis and development of lung cancer cells. (-)-Guaiol markedly downregulated the expression of CD206, a characteristic surface marker of M2-polarized macrophages. It also significantly inhibited the proliferation, invasion, and metastatic potential of LLC cells co-cultured with M2 macrophages. Animal experiments revealed that (-)-Guaiol treatment significantly decreased the tumor volume and weight, as well as CD206 expression. Moreover, integrated in vitro and in vivo analyses revealed that (-)-Guaiol inhibited M2 macrophage polarization primarily by suppressing the PPAR-γ signaling pathway. These findings demonstrate that (-)-Guaiol inhibits M2 macrophage differentiation via targeted suppression of the PPAR-γ-related signaling pathway, thereby reducing the proliferation, migration, and invasion of lung cancer cells.

Leucine-rich repeat kinase 2 (Lrrk2) has received widespread attention as a risk gene associated with Parkinson's disease. As the immune response attributes of Parkinson's disease have been gradually revealed, the link between Lrrk2 and the immune system has emerged. Here, we demonstrated that Lrrk2 regulates macrophage function by promoting M1 polarization. Transcriptome and immunological analyses revealed that deletion of Lrrk2 in macrophages leads to blunted interferon (IFN)-γ and lipopolysaccharide (LPS)-stimulated M1 macrophage-associated gene expression and function. Mechanistically, Lrrk2 supports M1-associated immune effector signatures, including chemokines and inducible nitric oxide synthase (iNOS) expression, by enhancing signal transducer and activator of transcription 1 (STAT1) transcription factor signaling. The effect of Lrrk2 on macrophages is dependent on its kinase activity. These results revealed a previously uncharacterized role of Lrrk2 in M1 macrophage polarization by modulating cellular responses to cytokines and toll-like receptors (TLRs), such as IFN-γ and LPS.

Wetland virus (WELV), a newly identified Orthonairovirus phylogenetically related to the Crimean-Congo hemorrhagic fever virus (CCHFV), has recently been shown to cause human infections. A portion of patients infected with WELV usually present with febrile diseases, accompanied by hemorrhagic and neurological symptoms. Currently, there are no reports demonstrating effective therapeutic drugs for the treatment of WELV. In this study, we evaluated the anti-WELV efficacy of five nucleoside analogs: four clinically approved drugs-ribavirin, remdesivir, molnupiravir, and sofosbuvir; and a clinical candidate 4'-fluorouridine. Ribavirin and 4'-fluorouridine strongly inhibited WELV replication in vitro. Remdesivir and molnupiravir showed limited antiviral activity against WELV in Huh7 cells but not in Vero cells, while sofosbuvir did not exhibit inhibitory effects. Utilizing a lethal immunocompetent mouse model of WELV infection, we found that oral administration of relatively low doses of ribavirin (25 mg/kg/day) or 4'-fluorouridine (2.5 mg/kg/day) significantly reduced the mortality of WELV-infected mice by decreasing viral titers in tissues and alleviating pathological damage. This treatment strategy retained significant efficacy even when initiated 2-4 days after infection. Additionally, we identified mutations G3033R and A3756V in the C-terminal region of the WELV L protein, which may be associated with viral resistance to ribavirin and 4'-fluorouridine. This study revealed varying degrees of anti-WELV efficacy among different nucleoside analogs and identified 4'-fluorouridine as a promising therapeutic candidate and ribavirin as a priority treatment option for WELV infection.

Spinal cord injury (SCI) triggers a complex cascade of events, including myelin loss, neuronal damage, neuroinflammation, and the accumulation of damaged cells and debris at the injury site. Infiltrating bone marrow derived macrophages (BMDM phi) migrate to the epicenter of the SCI lesion, where they engulf cell debris including abundant myelin debris to become pro-inflammatory foamy macrophages (foamy M phi), participate neuroinflammation, and facilitate the progression of SCI. This study aimed to elucidate the cellular and molecular mechanisms underlying the functional changes in foamy M phi and their potential implications for SCI. Contusion at T10 level of the spinal cord was induced using a New York University (NYU) impactor (5 g rod from a height of 6.25 mm) in male mice. ABCA1, an ATP-binding cassette transporter expressed by M phi, plays a crucial role in lipid efflux from foamy cells. We observed that foamy M lacking ABCA1 exhibited increased lipid accumulation and a higher presence of lipid-accumulated foamy M as well as elevated pro-inflammatory response in vitro and in injured spinal cord. We also found that both genetic and pharmacological enhancement of ABCA1 expression accelerated lipid efflux from foamy M phi, reduced lipid accumulation and inhibited the pro-inflammatory response of foamy M phi, and accelerated clearance of cell debris and necrotic cells, which resulted in functional recovery. Our study highlights the importance of understanding the pathologic role of foamy M in SCI progression and the potential of ABCA1 as a therapeutic target for modulating the inflammatory response, promoting lipid metabolism, and facilitating functional recovery in SCI.

Parkinson's disease (PD) affects millions of people's lives worldwide. The main pathogenesis of PD is dopaminergic neuron necrosis and neuroinflammation mediated by activated microglia cells. In recent years, the anti-inflammatory ability and neuroprotective effects of miR-124 in PD models were well proved, but the in vivo delivery of miR-124 remains challenging. Herein, we report a protein nanosystem modified with a brain-targeting peptide ApoE that could efficiently deliver miR-124 across the blood-brain barrier (BBB). This nanosystem showed good cell viability on brain endothelial cells and microglia cells, and administration of this nanosystem significantly decreased the neuroinflammation and dopaminergic neuron loss, as well as recovered parts of neurobehavioral deficits. This ApoE peptide-based protein nanosystem holds great promise for the delivery of RNA therapeutics to the brain and for realizing neuron protection in PD treatment.

Sepsis-associated encephalopathy (SAE) is a common and severe complication of sepsis, which causes long-term neurological deficits, such as cognitive impairment. Despite extensive research, there is still lack of specific treatments for SAE. Chaperone-mediated autophagy (CMA), a selective type of autophagy, has been reported to be related to cognitive dysfunctions in many neurodegenerative diseases. The aim of this study was to investigate the alteration of CMA activity in the hippocampus of SAE mice and explore the neuroprotective effect of enhanced CMA. Cecal ligation and puncture (CLP) was conducted to induce SAE. In the contextual fear conditioning test, the ratio of freezing time of CLP mice significantly decreased compared with that of the mice in the Sham group, indicating cognitive impairment in SAE mice. The expression of lysosome-associated membrane protein type 2A (Lamp2a) and chaperone heat shock cognate 71 kDa protein (Hsc70), positive markers for CMA activity, decreased in hippocampal neurons of SAE mice. Although overexpression of Lamp2a in neurons via adeno-associated virus injection in the hippocampus had little effect on the mortality of septic mice, this intervention significantly alleviated the memory impairments in contextual fear conditioning test, Y-maze test and novel objective recognition test, and attenuated the neural death observed in SAE mice. We further demonstrated that the overexpression of Lamp2a in the hippocampus increased the expression of phosphorylated cyclic-AMP response element binding protein (p-CREB), brain-derived neurotrophic factor (BDNF) and B-cell lymphoma-2 (Bcl-2), and suppressed the expression of cleaved caspase-3. Taken together, our study results suggested that the upregulation of CMA activity ameliorated cognitive impairments and neuron loss in SAE mice partially through the p-CREB-BDNF/Bcl-2 signaling pathways, providing a potential therapeutic target for SAE.

Background: CD5L (CD5 molecular-like) plays an important role in lipid metabolism and immune regulation. This study aimed to investigate the roles of CD5L on liver hepatocellular carcinoma (LIHC).Methods: We analyzed the CD5L mRNA expression and its potential prognostic value based on The Cancer Genome Atlas and Gene Expression Omnibus databases. Immunohistochemical analysis was used to investigate the CD5L levels in LIHC tissues. Serum CD5L levels in LIHC were detected by enzyme-linked immunosorbent assay. Cell Counting Kit-8 (CCK-8) assay was used to investigate the effect of CD5L treatment on HepG2 and QSG-7701 cell proliferation. CD5L expression correlated genes were exhumed based on the LinkedOmics. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses for CD5L associated genes were performed. The correlation between CD5L and tumor immune infiltration was analyzed by using Tumor Immune Estimation Resource (TIMER) 2.0.Results: CD5L mRNA and protein levels were significantly decreased in LIHC tumor tissue compared with non-tumor control tissues. Moreover, serum CD5L levels were significantly lower in LIHC patients than that in healthy subjects. Gene Expression Profiling Interactive Analysis 2 and Kaplan-Meier plotter analysis showed that a high-CD5L expression was correlated with favorable overall survival in LIHC patients, except the LIHC patients with hepatitis virus. CCK-8 results showed that CD5L treatment significantly decreased HepG2 cell proliferation in a concentration-dependent manner, and CD5L treatment had no effect on the proliferation of non-tumor hepatocyte line QSG-7701. CD5L associated genes were enriched in the immune response biological process, and CD5L expression levels were positively correlated with the immune infiltrates of CD8(+) T cell and M1 macrophage cells but negatively correlated with CD4(+) T cells and M0 macrophage cell infiltration.Conclusions: Exogenous CD5L inhibits cell proliferation of hepatocellular carcinoma. CD5L may act as a role of prognostic marker.

Spinal cord injury (SCI) results in severe motor and sensory dysfunction with no effective therapy. Spinal cord debris (sp) from injured spinal cord evokes secondary SCI continuously. We and other researchers have previously clarified that it is mainly bone marrow derived macrophages (BMDMs) infiltrating in the lesion epicenter to clear sp, rather than local microglia. Unfortunately, the pro-inflammatory phenotype of these infiltrating BMDMs is predominant which impairs wound healing. Hydralazine, as a potent vasodilator and scavenger of acrolein, has protective effects in many diseases. Hydralazine is also confirmed to promote motor function and hypersensitivity in SCI rats through scavenging acrolein. However, few studies have explored the effects of hydralazine on immunomodulation, as well as spontaneous pain and emotional response, the important syndromes in clinical patients. It remains unclear whether hydralazine affects infiltrating BMDMs after SCI. In this study, we targeted BMDMs to explore the influence of hydralazine on immune cells in a mouse model of SCI, and also investigated the contribution of polarized BMDMs to hydralazine-induced neurological function recovery after SCI in male mice. The adult male mice underwent T10 spinal cord compression. The results showed that in addition to improving motor function and hypersensitivity, hydralazine relieved SCI-induced spontaneous pain and emotional response, which is a newly discovered function of hydralazine. Hydralazine inhibited the recruitments of pro-inflammatory BMDMs and educated infiltrated BMDMs to a more reparative phenotype involving in multiple biological processes associated with SCI pathology, including immune/inflammation response, neurogenesis, lipid metabolism, oxidative stress, fibrosis formation, and angiogenesis, etc. As an overall effect, hydralazine-treated BMDMs loaden with sp partially rescued neurological function after SCI. It is concluded that hydralazine plays an immunomodulation role of educating pro-inflammatory BMDMs to a more reparative phenotype; and hydralazine-educated BMDMs contribute to hydralazine-induced improvement of neurological function in SCI mice, which provides support for drug and cell treatment options for SCI therapy.

Background Cervical cancer ranks third in cancer incidence worldwide and is the most frequent gynecological cancer in developing countries. To expore the molecular mechanism of cervical cancer and to find effective treatment have become the focus of medical workers. CD73 has been implicated in the progression of many cancers. However, the study of CD73 in cervical cancer has not been reported. The aim of this study was to identify the effect and mechanism of CD73 overexpression on cervical cancer growth in vitro and in vivo. Methods Cervical cancer cell models with CD73 overexpression were construction by using lentiviruses infection in Hela and SiHa cells. Cell’s proliferation was investigated by using xCELLigence real-time cell analysis (RTCA) system. Murine xenograft models were used to evaluate the effect of CD73 overexpression on tumor growth in vivo. Small interfering RNA (siRNA) transfection were used to suppress expression levels of EGFR and AKT1. Cell cycle and apoptosis were evaluated by flow cytometry (FCM). Results CD73 overexpression significantly promoted cervical cancer cells proliferation in vitro and tumor growth in vivo. The expression levels of EGFR and AKT1 were significantly increased in cell models and transplanted tumor tissues with CD73 overexpression. And moreover, knockdown of EGFR and AKT1 could inhibit proliferation of CD73 overexpressed cell models via inducing cell apoptosis and cell cycles increased in G2/M phase and reduction of G1 phase. Furthermore, the expression levels of CDK2, CDK3 and CDKN1A, which are cell cycle regulated molecules, were significantly increased in CD73 overexpressed cells with EGFR/AKT1 knockdown. Conclusions Our data demonstrated that CD73 overexpression promote cervical cancer growth in vitro and in vivo, via activating EGFR/AKT1 pathway.

Abstract Background Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect multiple systems. Sjögren's syndrome (SS) is an autoimmune disease that may be primary SS (pSS) or occur together with other autoimmune diseases, including SLE. This study aimed to explore the shared gene signatures in SLE and pSS. Methods Gene expression data sets of SLE (GSE50772 and GSE81622) and pSS (GSE84844 and GSE48378) were obtained and analyzed for differentially expressed genes (DEGs) in peripheral blood mononuclear cells (PBMCs). A protein–protein interaction (PPI) network was constructed. Gene ontology (GO) and KEGG pathway enrichment analysis were carried out for the DEGs. Results We screened 232 and 110 DEGs from the SLE and pSS data sets, respectively. We found 32 shared DEGs, which were all upregulated in patients compared with controls. Among these 32 DEGs, 11 genes showed a more than twofold change in all data sets (IFI27, IFI44L, RSAD2, IFIT1, IFI44, USP18, IFI6, HERC5, EPSTI1, OAS1, and OAS3). PPI analysis showed that 29 genes interacted with each other. GO analysis showed that these 32 shared DEGs were mainly enriched in biological processes associated with the type I interferon signaling pathway, defense response to viruses, response to viruses, negative regulation of viral genome replication, and the immune response. Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that these 32 DEGs were related to virus infection. Conclusion This study showed that alterations to biological processes associated with the response to virus infection play critical roles in both SLE and pSS.

Abstract Background The fifth wave of H7N9 avian influenza virus caused a large number of human infections and a large number of poultry deaths in China. Since September 2017, mainland China has begun to vaccinate poultry with H5 + H7 avian influenza vaccine. We investigated the avian influenza virus infections in different types of live poultry markets and samples before and after genotype H5 + H7 vaccination in Nanchang, and analyzed the changes of the HA subtypes of AIVs. Methods From 2016 to 2019, we monitored different live poultry markets and collected specimens, using real-time reverse transcription polymerase chain reaction (RT-PCR) technology to detect the nucleic acid of type A avian influenza virus in the samples. The H5, H7 and H9 subtypes of influenza viruses were further classified for the positive results. The χ2 test was used to compare the differences in the separation rates of different avian influenza subtypes. Results We analyzed 5,196 samples collected before and after vaccination and found that the infection rate of AIV in wholesale market (21.73%) was lower than that in retail market (24.74%) (P < 0.05). Among all the samples, the positive rate of sewage samples (33.90%) was the highest (P < 0.001). After vaccination, the positive rate of H5 and H7 subtypes decreased, and the positive rate of H9 subtype and untypable HA type increased significantly (P < 0.001). The positive rates of H9 subtype in different types of LPMs and different types of samples increased significantly (P < 0.01), and the positive rates of untypable HA type increased significantly in all environmental samples (P < 0.05). Conclusions Since vaccination, the positive rates of H5 and H7 subtypes have decreased, but the positive rates of H9 subtypes have increased to varying degrees in different testing locations and all samples. This results show that the government should establish more complete measures to achieve long-term control of the avian influenza virus.