Epstein-Barr virus (EBV)-related hemophagocytic lymphohistiocytosis (EBV-HLH) and infectious mononucleosis (IM) are characterized by fever, hepatomegaly, and splenomegaly, but HLH has a 50% lethality rate. Therefore, this study aimed to compare the laboratory findings in differentiating EBV-HLH children from IM children who have fever, hepatomegaly, or splenomegaly. A total of 131 IM patients and 29 EBV-HLH pediatric patients with fever, hepatomegaly, or splenomegaly were enrolled in our study. The clinical traits and laboratory findings were analyzed, and a predictive regression analysis was also performed. EBV-HLH patients had a lower set of diagnostic markers, which included fibrinogen (FIB), white blood cells (WBC), hemoglobin (Hb), and platelet (PLT), compared to IM patients. Triglyceride (TG) and ferritin were elevated obviously in EBV-HLH patients compared to IM patients. CD4dimCD8+ T cells are highly activated T cells. EBV-HLH patients experienced a significant decrease in the absolute number and ratio of CD4dimCD8+T cells (CD4dimCD8+T#, CD4dimCD8+T%) compared to IM patients in our study. The AUC of CD4dimCD8+ T # in the diagnosis of EBV-HLH was 0.920 with a sensitivity of 86.2% and a specificity of 90.1%. A logistic regression analysis was developed to improve sensitivity. The results revealed that lower levels of Hb, FIB, and CD4dimCD8+T cells were risk factors for EBV-HLH. The regression model for separating EBV-HLH from EBV-IM had an AUC of was 0.996 with a sensitivity of 100% and a specificity of 95.3%. The ratio and absolute number of CD4dimCD8+T cells were decreased in IM and EBV-HLH patients. EBV-HLH can be identified in IM patients with fever, hepatomegaly, or splenomegaly by detecting Hb, FIB, and the absolute number of CD4dimCD8+T cells.

Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1) is necessary to maintain stability of EBV episomes, EBV replication, and causes host genomic instability and promotes tumor cells survival. Recent studies have shown that viruses utilize liquid-liquid phase separation (LLPS) within host cells to form sub-cellular compartments known as "virus factories". Prion-like domains (PrLDs), which resemble structural domains of low complexity, are shown to drive LLPS in vivo. In the current study, a PrLD is identified in EBNA1 and aggregation of EBNA1 proteins is observed in EBV-positive tumors. EBNA1 condensate interacting molecules are examined and are found that EBNA1 interacts with the splicing factor SRSF1 to regulate alternative splicing of SRRM1 and promote tumor progression. Deleting the EBNA1 PrLD results in defects in protein aggregation, LLPS, alternative splicing regulation, and nasopharyngeal carcinoma cells proliferation. Targeting the PrLD of EBNA1 inhibits the formation of protein aggregation, promotes alternative splicing of SRRM1, and inhibits the progression of nasopharyngeal carcinoma. Here, we report for the first time that EBNA1, a protein from the human oncogenic virus EBV, is a prion-like protein, combining algorithm prediction and experimental validation. That implies a possible molecular pathogenic mechanism of EBNA1 in neurodegenerative diseases.

Background/Objectives: Retinal ischemia–reperfusion (I/R) injury is a common mechanism in glaucoma, diabetic retinopathy, and retinal vein occlusion, leading to progressive loss of retinal ganglion cells (RGCs). This study investigates the regulatory role of miR-21-5p and its interaction with Signal Transducer and Activator of Transcription 3 (STAT3) in retinal I/R injury. Methods: An acute intraocular hypertension (AIH) rat model was used to induce retinal I/R. The interaction between miR-21-5p and STAT3 was examined by dual-luciferase reporter assays. miR-21-5p and STAT3 expression were quantified by qRT-PCR and Western blotting. Retinal morphology, microglial polarization, and RGC survival were assessed by H&E staining and immunofluorescence. In vitro, microglia and RGCs were subjected to oxygen–glucose deprivation/reperfusion (OGD/R), and microglial-conditioned media (MCM) were applied to RGCs. Results: (1) miR-21-5p ameliorated AIH-induced retinal damage in vivo. (2) Overexpression of miR-21-5p inhibits M1 polarization of RM cultured in vitro. (3) MCM from miR-21-5p-overexpressing microglia attenuated OGD/R-induced RGC death. (4) miR-21-5p downregulates STAT3 expression to inhibit RM M1 polarization. (5) miR-21-5p down-regulation of STAT3 levels inhibits M1 polarization and reduces apoptosis of RGCs in retinal microglia of AIH rats. Conclusions: miR-21-5p alleviates retinal I/R injury by restraining microglial M1 polarization through direct repression of STAT3, thereby promoting RGC survival. These findings identify the miR-21-5p/STAT3 axis as a potential therapeutic target for ischemic retinal diseases.

Cancer cell membrane-derived nanoparticle drug delivery system enables precise drug delivery to tumor tissues and is a new effective way to treat solid tumors. The aim of this study is to develop a safe and effective cancer cell membrane-derived nano-delivery system targeting gastric cancer. We previously reported that EPH receptor A2 (EphA2) is an important target for gastric cancer. RNA m6A methyltransferases METTL3 is upregulated in multiple cancers and promotes cancer development by increasing the expression of multiple oncogenes. We design a new nano-delivery system PLGA-STM-TAT: nanoparticles PLGA (poly lactic acid-hydroxyacetic acid) loaded with METTL3 inhibitor STM2457 and cell-penetrating peptide TAT, and then covered with gastric cancer cell membranes equipped with YSA peptides by means of click chemistry, which targeting EphA2. The nanoparticles are specifically enriched in gastric cancer tissues, significantly increased drug accumulation, and inhibited cancer cell proliferation by decreasing key oncogenes c-MYC and BRD4. During drug administration, we found that the expression of the immune checkpoint molecule PD-L1 was suppressed, and the anti-tumor immune effect was enhanced by the nano-delivery system in combination with anti-PD1. This cancer cell membrane-derived nano-delivery system provides a new biological strategy to treat gastric cancer through effective m6A modulation and EphA2 targeting. Statement of significance M6A modifications have important biological roles, especially in tumors. Targeting highly modified m6A in gastric cancer becomes a challenge. We developed a nano-drug delivery system for modulating m6A that could produce an effective anti-cancer therapeutic effect and that the nanoparticles enhanced antitumor immunity when combined with anti-PD1.This cancer cell membrane-derived new nano-drug delivery system shows great promise as an antitumor approach by modulating m6A modification and targeting EphA2 in gastric cancers.

Rationale: Acute high intraocular pressure (IOP) induces retinal ischemia/reperfusion (RI/R) that further initiates neuroinflammatory responses. This event can cause retinal tissue damage and neuronal death, ultimately resulting in irreversible blindness worldwide that lacks effective therapies, validated treatment targets and underlying mechanisms. We sought to explore the potential mechanisms on the causal link between the neuroinflammatory response and neurodegeneration following acute high IOP. Methods: A rat model of RI/R induced by acute high IOP was used to investigate the spatiotemporal profiles of blood-retinal barrier (BRB) disruption, peripheral immune cell infiltration, and innate immune cell response following acute glaucomatous injury. RNA sequencing and in vivo transfection with adeno-associated virus (AAV) were used to explore the pathogenic mechanisms of acute high IOP-induced neuroinflammation. Results: Disruption of the inner BRB and infiltration of macrophages and lymphocytes occurred during the early stage after acute high IOP. These events were accompanied by an innate immune response. RNA sequencing revealed that Lipocalin-2 (Lcn2) was one of the most significantly up-regulated inflammation-related genes. Lcn2 knockdown ameliorated inner BRB disruption, peripheral immune cell infiltration, and innate immune cell response, resulting in neuroprotective effects. Furthermore, we found that acute glaucomatous injury triggers high expression of LCN2 in the peripheral serum, which is strongly associated with the severity of the neuroinflammatory response in the retina. Conclusions: A "neuroinflammatory cascade" characterized by breakdown of inner BRB, peripheral immune cell infiltration, and innate immune cell response occurs during the initial stage following glaucomatous injury. We also identified a novel mechanism for LCN2 in acute high IOP-induced neuroinflammation. LCN2 has the potential to serve as a candidate biomarker for predicting the severity of the neuroinflammatory response following acute glaucoma, which may provide new evidence to retinal repair strategies for better visual function recovery at intervention time points and new targets.

Rapid healing of wounds infected by bacteria, especially multidrug-resistant bacteria, is a common clinical challenge. Local bacterial infection causes excessive reactive oxygen species (ROS) that further induce oxidative stress and inflammatory responses, which impairs cell migration, angiogenesis and delays cutaneous regenera-tion. Herein, we designed a novel type of carbon quantum dots (CQDs) derived from herbal medicines. The CQDs are able to against gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA), and possessed SOD-like as well as CAT-like activities for scavenging ROS. The biocompatible CQDs could protect HUVECs migration and angiogenesis from oxidative stress damage. Moreover, the expression of NO and pro -inflammatory cytokines (TNF-alpha and IL-6) of LPS-induced macrophages could be downregulated by the CQDs. Besides, the self-healing hydrogel decorated with multifunctional CQDs were prepared via the reaction between OSA and CMCS through Schiff base linkage for better wound management. The CQDs/hydrogel could contin-uously eliminate bacteria and scavenge ROS to modulate the complex oxidative stress microenvironment. The results of animal experiments demonstrated that the CQDs/hydrogel exerted the effects of eliminating MRSA, anti-inflammation, and promoting angiogenesis, which was manifested in enhancing wound healing, epithelial regeneration and collagen disposition. Therefore, the CQDs/hydrogel is excellent candidate for MRSA-infected skin wound healing.

Chediak-Higashi syndrome (CHS) is a life-threatening autosomal recessive immunodeficiency disease presenting with recurrent infections, hypopigmentation, progressive neurodegeneration, and hemophagocytic lymphohistiocytosis (HLH), known as the accelerated stage. Two-thirds of patients experience a fatal accelerated phase. CHS is caused by lysosomal transport regulator (LYST) gene mutations. We report the case of CHS, who was born with pale skin and silver hair. Bone marrow aspirate revealed large inclusions in granulocytes, monocytes, and lymphocytes. Genetic analysis revealed a new nonsense mutation in the LYST gene: c.8186G > A (W2729Ter). The child presented with fever, hepatosplenomegaly, and lymphadenectasis. Laboratory tests showed pancytopenia, hypofibrinogenemia, and high serum ferritin, indicating an accelerated phase of CHS. She underwent allogeneic hematopoietic stem cell transplantation (HCST) combined with umbilical cord blood transplantation (UCBT) after HLH-related chemotherapy. The patient has been alive for nine months without recurrence. We have identified a novel nonsense mutation in the LYST gene that correlates with a severe phenotype, and HSCT combined with UCBT is an effective treatment.

The search for effective combination therapy with immune checkpoint inhibitors (ICI) has become important for cancer patients who do not respond to the ICI well. Histone deacetylases (HDACs) inhibitors have attracted wide attention as anti-tumor agents. ACY-1215 is a selective inhibitor of HDAC6, which can inhibit the growth of a variety of tumor. We previously revealed that HDAC family is highly expressed in colorectal cancer specimens and mouse models. In this study, ACY-1215 was combined with anti-PD1 to treat tumor-bearing mice associated with colorectal cancer. ACY-1215 combined with anti-PD1 effectively inhibited the colorectal tumor growth. The expression of PD-L1 in tumor of mice were inhibited by ACY-1215 and anti-PD1 combination treatment, whereas some biomarkers reflecting T cell activation were upregulated. In a co-culture system of T cells and tumor cells, ACY-1215 helped T cells to kill tumor cells. Mechanically, HDAC6 enhanced the acetylation of STAT1 and inhibited the phosphorylation of STAT1, thus preventing STAT1 from entering the nucleus to activate PD-L1 transcription. This study reveals a novel regulatory mechanism of HDAC6 on non-histone substrates, especially on protein acetylation. HDAC6 inhibitors may be of great significance in tumor immunotherapy and related combination strategies.

Epstein-Barr virus (EBV) is a human tumor virus associated with a variety of malignancies, including nasopharyngeal carcinoma, gastric cancers, and B-cell lymphomas. N6-methyl- adenosine (m6A) modifications modulate a wide range of cellular processes and participate in the regulation of virus-host cell interactions. Here, we discovered that EBV infection downregulates toll-like receptor 9 (TLR9) m6A modification levels and thus inhibits TLR9 expression. TLR9 has multiple m6A modification sites. Knockdown of METTL3, an m6A " writer " , decreases TLR9 protein expression by inhibiting its mRNA stability. Mechanistically, Epstein-Barr nuclear antigen 1 increases METTL3 protein degradation via K48-linked ubiquitin-proteasome pathway. Additionally, YTHDF1 was identified as an m6A " reader " of TLR9, enhancing TLR9 expression by promoting mRNA translation in an m6A-depen- dent manner, which suggests that EBV inhibits TLR9 translation by " hijacking " host m6A modification mechanism. Using the METTL3 inhibitor STM2457 inhibits TLR9-induced B cell proliferation and immunoglobulin secretion, and opposes TLR9-induced immune responses to assist tumor cell immune escape. In clinical lymphoma samples, the expression of METTL3, YTHDF1, and TLR9 was highly correlated with immune cells infiltration. This study reveals a novel mechanism that EBV represses the important innate immunity molecule TLR9 through modulating the host m6A modification system.

In recent years, the role of mitochondrial dynamics in neurodegenerative diseases has becoming increasingly important. More and more evidences have shown that in pathological conditions, abnormal mitochondrial divisions, especially Drp1-Fis1-mediated divisions, play an important role in the occurrence and development of Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease, glaucoma, and other neurodegenerative diseases. This review highlights several new mechanisms of physiological fission of mitochondria and the difference/connection of physiological/pathological mitochondrial fission. In addition, we described the relationship between abnormal mitochondrial dynamics and neurodegenerative diseases in detail and emphatically summarized its detection indicators in basic experiments, trying to provide references for further mechanism exploration and therapeutic targets.

The development and progression of nasopharyngeal carcinoma (NPC) is closely associated with Epstein -Barr virus (EBV) infection. NPC is usually asymptomatic until it spreads to other sites, and more than 70% of cases are classified as locally advanced disease at diagnosis. EBV-positive nasopharyngeal cancer tissues express only limited viral latent proteins, but express high levels of the EBV-encoded BamHI-A rightward transcript (BART) miRNA molecules. Here, we report that EBV-miRNA-BART2-5p (BART2-5p) promotes NPC cell invasion and metastasis in vivo and in vitro but has no effect on NPC cell proliferation and apoptosis. In addition, BART2-5p altered the mRNA and miRNA expression profiles of NPC cells. The development of human tumors has been reported to be associated with altered miRNAs expression, and overall miRNAs expression is reduced in many types of tumors. We found that BART2-5p downregulated the expression of several miRNAs that could exert oncogenic functions. Mechanistically, BART2-5p directly targets the RNase III endonuclease DICER1, inhibiting its function of cleaving double-stranded stem-loop RNA into short double-stranded RNA, which in turn causes altered expression of a series of key epithelialmesenchymal transition molecules, and reverting DICER1 expression can rescue this phenotype. Furthermore, analysis from clinical samples showed a negative correlation between BART2-5p and DICER1 expression. According to our study, high expression of BART2-5p in tissues and plasma of patients with NPC is associated with poor prognosis. Our results suggest that, BART2-5p can accelerate NPC metastasis through modulating miRNA profiles which are mediated by DICER1, implying a novel role of EBV miRNAs in the pathogenesis of NPC.

Colonies formed by bacteria, archaea, fungi, and viral groups and their genomes, metabolites, and expressed proteins constitute complex human microbiomes. An increasing evidences showed that carcinogenesis and disease progression were link to microbiomes. Different organ sources, their microbial species, and their metabolites are different; the mechanisms of carcinogenic or procancerous are also different. Here, we summarize how microbiomes contribute to carcinogenesis and disease progression in cancers of the skin, mouth, esophagus, lung, gastrointestinal, genital, blood, and lymph malignancy. We also insight into the molecular mechanisms of triggering, promoting, or inhibiting carcinogenesis and disease progress induced by microbiomes or/and their secretions of bioactive metabolites. And then, the strategies of application of microorganisms in cancer treatment were discussed in detail. However, the mechanisms by which human microbiomes function are still poorly understood. The bidirectional interactions between microbiotas and endocrine systems need to be clarified. Probiotics and prebiotics are believed to benefit human health via a variety of mechanisms, in particular, in tumor inhibition. It is largely unknown how microbial agents cause cancer or how cancer progresses. We expect this review may open new perspectives on possible therapeutic approaches of patients with cancer.

Endoplasmic reticulum stress (ERS) is a kind of cell response for coping with hypoxia and other stresses. Pieces of evidence show that continuous stress can promote the occurrence, development, and drug resistance of tumors through the unfolded protein response. Therefore, the abnormal ac-tivation of ERS and its downstream signaling pathways not only can regulate tumor growth and metastasis but also profoundly affect the efficacy of antitumor therapy. Therefore, revealing the molecular mechanism of ERS may be expected to solve the problem of tumor multidrug resistance (MDR) and become a novel strategy for the treatment of refractory and recurrent tumors. This re-view summarized the mechanism of ERS and tumor MDR, reviewed the relationship between ERS and tumor MDR, introduced the research status of tumor tissue and ERS, and previewed the prospect of targeting ERS to improve the therapeutic effect of tumor MDR. This article aims to provide researchers and clinicians with new ideas and inspiration for basic antitumor treatment.

CRKL (CRK Like Proto-Oncogene) belongs to the Crk family and is a 39-kDa adapter protein that encodes SH2 and SH3 (src homologs) domains. To identify its oncogenic role in malignant melanoma, we investigated the association between CRKL and mutation, prognosis, tumor mutation burden, immune cell infiltration of mela-noma, and explored the associations between CRKL and immunotherapy response. Our results showed that abnormal CRKL expression is associated with poor prognosis in melanoma and is significantly correlated with immune-activated pathways and processes, immune cell infiltrations, and expression of immunoregulators. Importantly, we found that CRKL expression is a predictive biomarker for anti-PD1 therapy response in mela-noma patients. Furthermore, inhibiting CRKL expression in melanoma cell lines suppressed their proliferation and metastasis, as well as activated the pyroptosis-related pathway. Our study provides potential mechanisms of melanoma pathogenesis, which may suggest new avenues for targeted therapy in this disease.

To summarise research studies on scar laser therapy since the 21st century using bibliometric methods, and to speculate on the possible development in the future. The literature about scar laser therapy in Web of Science database was searched. CiteSpace and VOSviewer were used to analyse main countries, institutions, journals，subject hotspots and trends, etc. A total of 884 papers have been published since the 21st century. These publications were written by 653 authors from 515 institutions in 58 countries. The United States published 287 papers in this field and ranks first. Laser in Surgery and Medicine is the most widely published journal, with Shumaker as the core author. The main keyword clustering includes terms such as combination therapy, wound healing, fractional photothermolysis, experience, scar formation, etc. CiteSpace and VOSviewer were used to sort out and summarise the countries, institutions, authors, journals, research hotspots and frontier topics of related literature about scar laser therapy since the 21st century. The current situation of its application and basic scientific research in clinical treatments were summarised briefly. This provides a new idea for the development and research of scar laser therapy in the future.

The present study focused on the effect of miR-93-5p on apoptosis of retinal neurons in acute ocular hypertension (AOH) model by regulating PDCD4 and explored its related mechanism. We detected that miR-93-5p expression was decreased and PDCD4 expression was increased in the AOH retina by qRT-PCR. Therefore, we explored the role of miR-93-5p and PDCD4. MiR-93-5p overexpression inhibited the apoptosis of retinal neurons and the expression of PDCD4 in vivo and in vitro. Inhibiting the expression of PDCD4 via transfected interfering RNA decreased the apoptosis of retinal cells and increased the expression of PI3K/Akt pathway-related proteins in vitro. However, the addition of PI3K protein inhibitor LY294002 reversed this effect, leading to a decrease of PI3K/Akt pathway protein expression and an increase of apoptosis-related protein Bax/Bcl-2 expression ratio. Finally, up-regulating miR-93-5p or down-regulating PDCD4 increased the expression of PI3K/Akt pathway protein in vivo. In conclusion, under the condition of AOH injury, miR-93-5p-inhibiting PDCD4 expression reduced the apoptosis of retinal neurons by activating PI3K/Akt pathway.

The human gut microbiota is a complex ecosystem regulating the host's environmental interaction. The same functional food or drug may have varying bioavailability and distinct effects on different individuals. Drugs such as antibiotics can alter the intestinal flora, thus affecting health. However, the relationship between intestinal flora and non-antibiotic drugs is bidirectional: it is not only affected by drugs; nevertheless, it can alter the drug structure through enzymes and change the bioavailability, biological activity, or toxicity of drugs to improve their efficacy and safety. This review summarizes the roles and mechanisms of antibiotics, antihypertensive drugs, nonsteroidal anti-inflammatory drugs, lipid-lowering drugs, hypoglycemic drugs, virus-associated therapies, metabolites, and dietary in modulating the colorectal cancer gut microbiota. It provides a reference for future antitumor therapy targeting intestinal microorganisms.

背景与目的:脓毒症相关肝损伤(SRLI)发病机制尚不清楚,细菌内毒素(LPS)对肝脏血管内皮细胞的炎症损害可能是重要环节.前期研究提示,RNA特异性腺苷脱氨酶1(ADAR1)可能通过调控内皮细胞功能相关蛋白Caveolin 1(Cav-1)在参与血管内皮应激中的局部和全身炎症反应.因此,本研究初步探讨ADAR1与Cav-1在SRLI中的作用,以期为SRLI的早期防治寻找新的方法.方法:取ADAR1基因敲除小鼠(ADAR1ECKO)与野生型小鼠(ADAR1flox/flox)各20只,腹腔注射LPS(20mg/kg)诱导脓毒症小鼠模型脓毒症模型,6 h后每组小鼠各取10只,获取肝脏组织,并分离肝窦内皮细胞(LSECs),通过HE染色观察其肝脏病理学改变,用细胞免疫荧光法观察LSECs中Cav-1及其下游蛋白VE-cadherin的表达,两组其余小鼠用于生存率分析;用ADAR1 siRNA转染正常野生型小鼠的LSECs后,通过内皮细胞成管实验观察转染后LSECs的增殖情况、Western blot检测Cav-1下游相关蛋白的表达.结果:生存观察结果显示,注射LPS后,ADAR1ECKO小鼠死亡时间早于ADAR1flox/flox小鼠,存活率低于ADAR1flox/flox小鼠(均P＜0.05);组织病理学观察显示,注射LPS6h后,ADAR1ECKO小鼠的肝损伤比ADAR1flox/flox小鼠更严重;细胞免疫荧光观察显示,注射LPS6h后,ADAR1ECKO小鼠LSECs中Cav-1与VE-cadherin 的表达低于ADAR1flox/flox小鼠.正常野生型小鼠的LSECs转染ADAR1 siRNA后,成管能力明显减弱,Cav-1下游蛋白VE-cadherin的表达下调,但β-Catenin的表达无明显变化.结论:ADAR1的下调或功能缺失会导致SRLI加重,机制可能涉及其调控Cav-1/VE-cadherin通路的活性.因此,激活ADAR1/Cav-1/VE-cadherin通路可能是防治SRLI的有效策略.

Lactoferrin (Lf), a multiple functional natural immune protein, is widely distributed in mammalian milk and glandular secretions (bile, saliva, tears and nasal mucosal secretions, etc.). In the previous study, we found that Lf plays an anti-inflammatory and anti-tumorigenesis role in AOM/DSS (azoxymethane/dextran sulfate sodium) induced mouse colitis-associated colon cancer model. Although we found that Lf has anti-inflammatory effects in chronic inflammation, its specific role and mechanisms in acute inflammation have not been clarified. Here, we reported that the expression levels of Lf were significantly increased when the organism was infected by Gram-negative bacteria. We then explored the role and potential mechanism of Lf in lipopolysaccharide (LPS)-induced acute inflammation. In the LPS-induced acute abdominal inflammation model, Lf deficiency aggravated inflammatory response and promoted macrophage chemotaxis to the inflammation site. Lf inhibited macrophage chemotaxis by suppressing the expression of macrophage-associated chemokines Ccl2 and Ccl5. Highly activated NF-κB signaling in Lf−/− mice was responsible for the high expression of Ccl2 and Ccl5. Our results suggested that the anti-inflammatory effect of Lf offers a new potential treatment for acute inflammatory diseases.