Tortuosity Engineering of Water Channels to Customized Water Supply for Enhancing Hydrogel Solar Evaporation.

Hydrogel as a solar evaporator shows great potential in freshwater production. However, hydrogels often lead to an imbalance between solar energy input and water supply management due to their excessively high saturated water content. Thus, achieving a stable water-energy-balance in hydrogel evaporators remains challenging. Here, by tortuosity engineering designed water transport channels, a seamless high-tortuosity/low-tortuosity/high-tortuosity structured hydrogel (SHLH structure hydrogel) evaporator is developed, which enables the hydrogel with customized water transport rate, leading to the controlled water supply at the evaporator interface. An excellent equilibrium between the photothermal conversion and water supply is established, and the maximum utilization of solar energy is realized, thereby achieving an excellent evaporation rate of 3.64 kg m-2 h-1 under one solar illumination. This tortuosity engineering controlled SHLH structured evaporator provides a novel strategy to attain water-energy-balance and expands new approaches for constructing hydrogel-based evaporators with tailored water transportation capacity.

A Nanoparticle Vaccine Displaying Conserved Epitopes of the Preexisting Neutralizing Antibody Confers Broad Protection against SARS-CoV-2 Variants.

The rapid development of the SARS-CoV-2 vaccine has been used to prevent the spread of coronavirus 2019 (COVID-19). However, the ongoing and future pandemics caused by SARS-CoV-2 variants and mutations underscore the need for effective vaccines that provide broad-spectrum protection. Here, we developed a nanoparticle vaccine with broad protection against divergent SARS-CoV-2 variants. The corresponding conserved epitopes of the preexisting neutralizing (CePn) antibody were presented on a self-assembling Helicobacter pylori ferritin to generate the CePnF nanoparticle. Intranasal immunization of mice with CePnF nanoparticles induced robust humoral, cellular, and mucosal immune responses and a long-lasting immunity. The CePnF-induced antibodies exhibited cross-reactivity and neutralizing activity against different coronaviruses (CoVs). CePnF vaccination significantly inhibited the replication and pathology of SARS-CoV-2 Delta, WIV04, and Omicron strains in hACE2 transgenic mice and, thus, conferred broad protection against these SARS-CoV-2 variants. Our constructed nanovaccine targeting the conserved epitopes of the preexisting neutralizing antibodies can serve as a promising candidate for a universal SARS-CoV-2 vaccine.

An interpretable machine learning model for predicting 28-day mortality in patients with sepsis-associated liver injury.

Sepsis-Associated Liver Injury (SALI) is an independent risk factor for death from sepsis. The aim of this study was to develop an interpretable machine learning model for early prediction of 28-day mortality in patients with SALI. Data from the Medical Information Mart for Intensive Care (MIMIC-IV, v2.2, MIMIC-III, v1.4) were used in this study. The study cohort from MIMIC-IV was randomized to the training set (0.7) and the internal validation set (0.3), with MIMIC-III (2001 to 2008) as external validation. The features with more than 20% missing values were deleted and the remaining features were multiple interpolated. Lasso-CV that lasso linear model with iterative fitting along a regularization path in which the best model is selected by cross-validation was used to select important features for model development. Eight machine learning models including Random Forest (RF), Logistic Regression, Decision Tree, Extreme Gradient Boost (XGBoost), K Nearest Neighbor, Support Vector Machine, Generalized Linear Models in which the best model is selected by cross-validation (CV_glmnet), and Linear Discriminant Analysis (LDA) were developed. Shapley additive interpretation (SHAP) was used to improve the interpretability of the optimal model. At last, a total of 1043 patients were included, of whom 710 were from MIMIC-IV and 333 from MIMIC-III. Twenty-four clinically relevant parameters were selected for model construction. For the prediction of 28-day mortality of SALI in the internal validation set, the area under the curve (AUC (95% CI)) of RF was 0.79 (95% CI: 0.73-0.86), and which performed the best. Compared with the traditional disease severity scores including Oxford Acute Severity of Illness Score (OASIS), Sequential Organ Failure Assessment (SOFA), Simplified Acute Physiology Score II (SAPS II), Logistic Organ Dysfunction Score (LODS), Systemic Inflammatory Response Syndrome (SIRS), and Acute Physiology Score III (APS III), RF also had the best performance. SHAP analysis found that Urine output, Charlson Comorbidity Index (CCI), minimal Glasgow Coma Scale (GCS_min), blood urea nitrogen (BUN) and admission_age were the five most important features affecting RF model. Therefore, RF has good predictive ability for 28-day mortality prediction in SALI. Urine output, CCI, GCS_min, BUN and age at admission(admission_age) within 24 h after intensive care unit(ICU) admission contribute significantly to model prediction.

Tat-dependent conditionally replicating adenoviruses expressing diphtheria toxin A for specifically killing HIV-1-infected cells.

HIV-1 infection remains a public health problem with no cure. Although antiretroviral therapy (ART) is effective for suppressing HIV-1 replication, it requires lifelong drug administration due to a stable reservoir of latent proviruses and may cause serious side effects and drive the emergence of drug-resistant HIV-1 variants. Gene therapy represents an alternative approach to overcome the limitations of conventional treatments against HIV-1 infection. In this study, we constructed and investigated the antiviral effects of an HIV-1 Tat-dependent conditionally replicating adenovirus, which selectively replicates and expresses the diphtheria toxin A chain (Tat-CRAds-DTA) in HIV-1-infected cells both in vitro and in vivo. We found that Tat-CRAds-DTA could specifically induce cell death and inhibit virus replication in HIV-1-infected cells mediated by adenovirus proliferation and DTA expression. A low titer of progeny Tat-CRAds-DTA was also detected in HIV-1-infected cells. In addition, Tat-CRAds-DTA showed no apparent cytotoxicity to HIV-1-negative cells and demonstrated significant therapeutic efficacy against HIV-1 infection in a humanized mouse model. The findings in this study highlight the potential of Tat-CRAds-DTA as a new gene therapy for the treatment of HIV-1 infection.

Recombinant neutralizing secretory IgA antibodies for preventing mucosal acquisition and transmission of SARS-CoV-2.

Passive delivery of antibodies to mucosal sites may be a valuable adjunct to COVID-19 vaccination to prevent infection, treat viral carriage, or block transmission. Neutralizing monoclonal IgG antibodies are already approved for systemic delivery, and several clinical trials have been reported for delivery to mucosal sites where SARS-CoV-2 resides and replicates in early infection. However, secretory IgA may be preferred because the polymeric complex is adapted for the harsh, unstable external mucosal environment. Here, we investigated the feasibility of producing neutralizing monoclonal IgA antibodies against SARS-CoV-2. We engineered two class-switched mAbs that express well as monomeric and secretory IgA (SIgA) variants with high antigen-binding affinities and increased stability in mucosal secretions compared to their IgG counterparts. SIgAs had stronger virus neutralization activities than IgG mAbs and were protective against SARS-CoV-2 infection in an in vivo murine model. Furthermore, SIgA1 can be aerosolized for topical delivery using a mesh nebulizer. Our findings provide a persuasive case for developing recombinant SIgAs for mucosal application as a new tool in the fight against COVID-19.

Hepatoprotective efficacy and interventional mechanism of the panaxadiol saponin component in high-fat diet-induced NAFLD mice.

Dietary administration is a promising strategy for intervention in non-alcoholic fatty liver disease (NAFLD). Our research team has identified a biologically active component, the panaxadiol saponin component (PDS-C) isolated from total saponins of panax ginseng, which has various pharmacological and therapeutic functions. However, the efficacy and mechanism of PDS-C in NAFLD were unclear. This study aimed to elucidate the hepatoprotective effects and underlying action mechanism of PDS-C in NAFLD. Mice were fed a high-fat diet (HFD) for 8 weeks to induce NAFLD and treated with PDS-C and metformin as the positive control for 12 weeks. PDS-C significantly alleviated liver function, hepatic steatosis and blood lipid levels, reduced oxidative stress and inflammation in NAFLD mice. In vitro, PDS-C has been shown to reduce lipotoxicity and ROS levels while enhancing the antioxidant and anti-inflammatory capabilities in HepG2 cells induced by palmitic acid. PDS-C induced AMPK phosphorylation, leading to upregulation of the Nrf2/HO1 pathway expression and downregulation of the NFκB protein level. Furthermore, our observations indicate that PDS-C supplementation improves insulin resistance and glucose homeostasis in NAFLD mice, although its efficacy is not as pronounced as metformin. In conclusion, these results demonstrate the hepatoprotective efficacy of PDS-C in NAFLD and provide potential opportunities for developing functional products containing PDS-C.

Fndc5/irisin deficiency leads to dysbiosis of gut microbiota contributing to the depressive-like behaviors in mice.

BACKGROUND: Depression is one of the most common mental diseases and the leading cause of disability worldwide. A dysfunctional gut microbiota-brain axis is one of the main pathological bases of depression. Irisin, an exercise-related myokine, reduces depression-like behaviors and may guide the relief of depressive symptoms by exercise. However, its underlying mechanism remains unclear. METHODS: Fibronectin type III domain containing 5 (Fndc5)/Irisin was knocked out in male wide-type C57BL/6N mice using CRISPR-cas9. The depression and anxiety symptoms were examined in irisin knockout and control mice with or without chronic unpredictable mild stress by sucrose preference test (SPT), forced swimming test (FST), and tail suspension test (TST). Fecal microbiota was assessed by 16S rRNA sequencing and microbiota-related metabolites using liquid chromatography with tandem mass spectrometry. Differential metabolites were analyzed with the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. RESULTS: The knockout mice showed anxiety- and depression-like behaviors and altered diversity and richness of gut microbiota. At the phylum level, these mice had decreased Firmicutes and increased Bacteroidota populations, while at the genus level, they exhibited a low relative abundance of Lactobacillus and Bifidobacterium. Moreover, knocking out of Irisin gene in these mice significantly reduced N-desmethyl-mifepristone (RU 42633) and elevated (-)-stercobilin levels. The KEGG results showed that the microbiota-related metabolites affected by irisin mainly clustered into arginine and proline metabolism and affected the mechanistic target of rapamycin kinase (mTOR) signaling pathway. CONCLUSION: Our findings show that Fndc5/irisin deficiency causes depression in mice by inducing dysbiosis of gut microbiota and changes in microbiota-related metabolites.

Advances in saRNA Vaccine Research against Emerging/Re-Emerging Viruses.

Although conventional vaccine approaches have proven to be successful in preventing infectious diseases in past decades, for vaccine development against emerging/re-emerging viruses, one of the main challenges is rapid response in terms of design and manufacture. mRNA vaccines can be designed and produced within days, representing a powerful approach for developing vaccines. Furthermore, mRNA vaccines can be scaled up and may not have the risk of integration. mRNA vaccines are roughly divided into non-replicating mRNA vaccines and self-amplifying RNA (saRNA) vaccines. In this review, we provide an overview of saRNA vaccines, and discuss future directions and challenges in advancing this promising vaccine platform to combat emerging/re-emerging viruses.

Pentagalloyl Glucose: A Review of Anticancer Properties, Molecular Targets, Mechanisms of Action, Pharmacokinetics, and Safety Profile.

Pentagalloyl glucose (PGG) is a natural hydrolyzable gallotannin abundant in various plants and herbs. It has a broad range of biological activities, specifically anticancer activities, and numerous molecular targets. Despite multiple studies available on the pharmacological action of PGG, the molecular mechanisms underlying the anticancer effects of PGG are unclear. Here, we have critically reviewed the natural sources of PGG, its anticancer properties, and underlying mechanisms of action. We found that multiple natural sources of PGG are available, and the existing production technology is sufficient to produce large quantities of the required product. Three plants (or their parts) with maximum PGG content were Rhus chinensis Mill, Bouea macrophylla seed, and Mangifera indica kernel. PGG acts on multiple molecular targets and signaling pathways associated with the hallmarks of cancer to inhibit growth, angiogenesis, and metastasis of several cancers. Moreover, PGG can enhance the efficacy of chemotherapy and radiotherapy by modulating various cancer-associated pathways. Therefore, PGG can be used for treating different human cancers; nevertheless, the data on the pharmacokinetics and safety profile of PGG are limited, and further studies are essential to define the clinical use of PGG in cancer therapies.

IV Vitamin C in Sepsis: A Latest Systematic Review and Meta-Analysis.

Sepsis is a high-incidence disease and demands intensive care. Finding effective treatment is the key to cure sepsis. Studies have shown a lower level of vitamin C in patients with sepsis. Therefore, vitamin C supplementation has become one of the measures to treat sepsis. However, the clinical studies of vitamin C in the treatment of sepsis have been controversial. We performed a meta-analysis to evaluate vitamin C's efficacy and safety in the treatment of sepsis. We searched four electronic databases: PubMed, Embase, Web of Science, and the Cochrane Library, and two researchers independently screened 24 eligible RCTs published in English. Our review demonstrates that intravenous (IV) vitamin C might improve short-term mortality (RR, 0.82; 95% CI, 0.65-1.02; P=0.07; and I 2 = 45%) and overall mortality (RR, 0.86; 95% CI, 0.74-1.01; P=0.06; and I 2 = 51%) of patients with sepsis. Moreover, the SOFA score of patients with sepsis improved significantly after treatment with vitamin C for over 72 hours (RR, 0.26; 95% CI, 0.09-0.42; P=0.002; and I 2 = 0%). The main results of our study were moderate-quality evidence. More high-quality, multicenter RCTs are needed to provide more substantial evidence on the efficacy and safety of IV vitamin C for sepsis.

Ginsenoside Rk3 Inhibits the Extramedullary Infiltration of Acute Monocytic Leukemia Cell via miR-3677-5p/CXCL12 Axis.

Background: Acute monocytic leukemia belongs to type M5 of acute myeloid leukemia (AML) classified by FAB, which appears a high incidence of extramedullary infiltration (EMI) and poor prognosis. In this study, we observed the inhibitory effect of ginsenoside Rk3 on the EMI of monocytic leukemia cells and initially explored its related mechanism of targeting the miR-3677-5p/CXCL12 axis. Methods: The MTT assay and colony formation assay were used to detect the inhibitory effect of Rk3 on proliferation. Both cellular migration and invasion were observed by the Transwell assay. The expression levels of miR-3677-5p, CXCL12, and CXCR4 were detected by RT-qPCR and Western blot, as well as overexpression of miR-3677-5p by transfected with lentivirus and detection of a dual luciferase reporter gene. The expression of MMP2 and TIMP2 was detected by immunofluorescence. Results: Rk3 effectively inhibits the proliferation, migration, and invasion associated with EMI of leukemia. The leukemia cells of M5 patients with EMI showed low expression of miR-3677-5p but high expression of the mRNA of CXCL12 and CXCR4. Overexpression of miR-3677-5p or intervention of CXCL12 effectively inhibited the proliferation, migration, and invasion of SHI-1 cells. The luciferase assay showed that CXCL12 was the downstream target gene of miR-3677-5p. After overexpression of miR-3677-5p or intervention of CXCL12 in combination with Rk3, the inhibitory effect on the proliferation, migration, and invasion of SHI-1 cells was more obvious. Importantly, Rk3 significantly regulated the expression levels of miR-3677-5p, CXCL12, CXCR4, and EMI-related functional proteins including MMP2 and TIMP2. Overexpression of miR-3677-5p or intervention of CXCL12 also regulated the expression of MMP2 and TIMP2. Conclusions: The leukemia cells of M5 patients with EMI appeared to have low expression of miR-3677-5p and high expression of the mRNA of CXCL12 and CXCR4, which may be used as indicators of EMI and poor prognosis. Rk3 is effective in inhibiting the EMI of SHI-1 cells by targeting the miR-3677-5p/CXCL12 axis.

Remimazolam: An Updated Review of a New Sedative and Anaesthetic.

Remimazolam (CNS7056) is a novel benzodiazepine for intravenous sedation; it has an ultra-short duration of action and was recently approved for use in procedural sedation and general anaesthesia. It acts on γ-aminobutyric acid type A receptors and is rapidly converted into an inactive metabolite by tissue esterase enzymes. Remimazolam has been successfully used in endoscopic inspection or surgery and general anaesthesia induction and maintenance with fast and predictable onset and recovery times, high procedure success rates, and minor respiratory and hemodynamic fluctuations and without serious drug-related adverse reactions. If needed, the effects of remimazolam can be reversed by flumazenil, which allows prompt termination of sedation. Although remimazolam has great potential for sedation in patients admitted to intensive care units, future studies are needed to evaluate its efficacy and safety in patients requiring sedation for a long period, and numerous studies are warranted to explore the optimal dose in different application scenarios. The review aimed to provide an introduction to the process of remimazolam synthesis and its current clinical uses and future clinical developments.

Herpes simplex virus type 2 inhibits TNF-α-induced NF-κB activation through viral protein ICP22-mediated interaction with p65.

Herpes simplex virus type 2 (HSV-2) is a prevalent human pathogen and the main cause of genital herpes. After initial infection, HSV-2 can establish lifelong latency within dorsal root ganglia by evading the innate immunity of the host. NF-κB has a crucial role in regulating cell proliferation, inflammation, apoptosis, and immune responses. It is known that inhibition of NF-κB activation by a virus could facilitate it to establish infection in the host. In the current study, we found that HSV-2 inhibited TNF-α-induced activation of NF-κB-responsive promoter in a dose-dependent manner, while UV-inactivated HSV-2 did not have such capability. We further identified the immediate early protein ICP22 of HSV-2 as a vital viral element in inhibiting the activation of NF-κB-responsive promoter. The role of ICP22 was confirmed in human cervical cell line HeLa and primary cervical fibroblasts in the context of HSV-2 infection, showing that ICP22 deficient HSV-2 largely lost the capability in suppressing NF-κB activation. HSV-2 ICP22 was further shown to suppress the activity of TNF receptor-associated factor 2 (TRAF2)-, IκB kinase α (IKK α)-, IKK ß-, IKK γ-, or p65-induced activation of NF-κB-responsive promoter. Mechanistically, HSV-2 ICP22 inhibited the phosphorylation and nuclear translocation of p65 by directly interacting with p65, resulting in the blockade of NF-κB activation. Furthermore, ICP22 from several alpha-herpesviruses could also inhibit NF-κB activation, suggesting the significance of ICP22 in herpesvirus immune evasion. Findings in this study highlight the importance of ICP22 in inhibiting NF-κB activation, revealing a novel mechanism by which HSV-2 evades the host antiviral responses.

CCL28 Enhances HSV-2 gB-Specific Th1-Polarized Immune Responses against Lethal Vaginal Challenge in Mice.

Plasmid DNA (pDNA) represents a promising "genetic vaccine platform" capable of overcoming major histocompatibility complex barriers. We previously demonstrated that low-to-moderate doses of mucosae-associated epithelial chemokine (MEC or CCL28) as an immunomodulatory adjuvant can trigger effective and long-lasting systemic and mucosal HSV-2 gD-specific immune responses, whereas mice immunized with gD in combination with high-dose CCL28 showed toxicity and lost their immunoprotective effects after lethal HSV-2 challenge. The exact causes underlying high-dose, CCL28-induced lesions remain unknown. In an intramuscularly immunized mouse model, we investigated the immune-enhancement mechanisms of low-dose CCL28 as a molecular adjuvant combined with the relatively weak immunogen HSV-2 gB. Compared with the plasmid gB antigen group, we found that a low-dose of plasmid CCL28 (pCCL28) codelivered with pgB induced increased levels of gB-specific serum IgG and vaginal fluid IgA, serum neutralizing antibodies (NAb), Th1-polarized IgG2a, and cytokine IL-2 (>5-fold). Furthermore, low-dose pCCL28 codelivery with pgB enhanced CCL28/CCR10-axis responsive CCR10− plus CCR10+ B-cell (~1.2-fold) and DC pools (~4-fold) in the spleen, CCR10− plus CCR10+ T-cell pools (~2-fold) in mesenteric lymph nodes (MLNs), and the levels of IgA-ASCs in colorectal mucosal tissues, leading to an improved protective effect against a lethal dose of HSV-2 challenge. Findings in this study provide a basis for the development of CCL28-adjuvant vaccines against viral mucosal infections.

A Bright Monomeric Near-Infrared Fluorescent Protein with an Excitation Peak at 633 nm for Labeling Cellular Protein and Reporting Protein-Protein Interaction.

Bright monomeric near-infrared fluorescent proteins (NIR-FPs) are useful as markers for labeling proteins and cells and as sensors for reporting molecular activities in living cells and organisms. However, current monomeric NIR-FPs are dim under excitation with common 633/635/640 nm lasers, limiting their broad use in cellular/subcellular level imaging. Here, we report a bright monomeric NIR-FP with maximum excitation at 633 nm, named mIFP663, engineered from Xanthomonas campestris pv Campestris phytochrome (XccBphP). mIFP663 has high molecular brightness with a large extinction coefficient (86,600 M-1 cm-1) and a decent quantum yield (19.4%), and high cellular brightness that is 3-6 times greater than those of spectrally similar NIR-FPs in HEK293T cells in the presence of exogenous BV. Moreover, we demonstrate that mIFP663 is able to label critical cellular and viral proteins without perturbing subcellular localization and virus replication, respectively. Finally, with mIFP663, we engineer improved bimolecular fluorescence complementation (BiFC) and new bioluminescent resonance energy transfer (BRET) systems to detect protein-protein interactions in living cells.

Effect of dexmedetomidine for prevention of acute kidney injury after cardiac surgery: an updated systematic review and meta-analysis.

BACKGROUND: Acute kidney injury (AKI) is a serious complication related to cardiac surgery. Several studies have been conducted to investigate the effect of dexmedetomidine administration on AKI prevention. OBJECTIVE: To assess if dexmedetomidine is associated with a protective effect of renal function after cardiac surgery. And the aim of conducting this meta-analysis is to summarize the literature and determine the clinical utility of dexmedetomidine administration in patients undergoing cardiac surgery. METHODS: PubMed, Cochrane Library, and EMBASE databases were comprehensively searched for all randomized controlled trials (RCTs) published before 1 December, 2021 that investigated the effect of dexmedetomidine on AKI prevention. RESULTS: Our analysis included 16 studies involving 2148 patients. Compared with the control group, dexmedetomidine administration significantly reduced AKI incidence (OR, 0.47; 95% CI, 0.36-0.61; p < 0.00001; I2 = 26%) and the length of stay in the intensive care unit (ICU) but did not alter mortality rate, length of stay in the hospital, and mechanical ventilation time. Furthermore, the incidence of delirium among patients treated with dexmedetomidine was significantly decreased. CONCLUSION: Dexmedetomidine administration has a positive effect on preventing AKI and postoperative delirium after cardiac surgery and significantly reduces the length of stay in the ICU.

Fusion Proteins CLD and CLDmut Demonstrate Potent and Broad Neutralizing Activity against HIV-1.

HIV-1 envelope glycoprotein (Env) interacts with cellular receptors and mediates virus entry into target cells. Blocking Env-receptor interactions represents an effective interventional strategy for developing HIV-1 entry inhibitors. We previously designed a panel of CD4-linker-DC-SIGN (CLD) constructs by fusing the extracellular CD4 and DC-SIGN domains with various linkers. Such CLDs produced by the prokaryotic system efficiently inhibited HIV-1 infection and dissemination in vitro and ex vivo. In this study, following the construction and identification of the most promising candidate with a linker of 8 Gly4Ser repeats (named CLD), we further designed an improved form (named CLDmut) by back mutating Cys to Ser at amino acid 60 of CD4. Both CLD and CLDmut were produced in mammalian (293F) cells for better protein translation and modification. The anti-HIV-1 activity of CLD and CLDmut was assessed against the infection of a range of HIV-1 isolates, including transmitted and founder (T/F) viruses. While both CLD and CLDmut efficiently neutralized the tested HIV-1 isolates, CLDmut demonstrated much higher neutralizing activity than CLD, with an IC50 up to one log lower. The neutralizing activity of CLDmut was close to or more potent than those of the highly effective HIV-1 broadly neutralizing antibodies (bNAbs) reported to date. Findings in this study indicate that mammalian cell-expressed CLDmut may have the potential to be used as prophylaxis or/and therapeutics against HIV-1 infection.

Molecular Epidemiology of SARS-CoV-2 by Sequencing.

Sequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contains preliminary information on the phylodynamics and phylogeography of this new virus. A maximum clade credibility tree (MCCT) was constructed using available whole genome sequences of SARS-CoV-2 and highly similar whole genome sequences from bat SARS-like coronavirus, which are available in GenBank. In this chapter, we describe the molecular epidemiology of SARS-CoV-2 by sequencing the viral genomes from confirmed COVID-19 patients, utilizing methods such as target fragment amplification, sequencing, alignment, and maximum similarity mapping.

Human Norovirus Induces Aquaporin 1 Production by Activating NF-κB Signaling Pathway.

Human norovirus (HuNoV) is one of the major pathogens of acute nonbacterial gastroenteritis. Due to the lack of a robust and reproducible in vitro culture system and an appropriate animal model, the mechanism underlying HuNoV-caused diarrhea remains unknown. In the current study, we found that HuNoV transfection induced the expression of aquaporin 1 (AQP1), which was further confirmed in the context of virus infection, whereas the enterovirus EV71 (enterovirus 71) did not have such an effect. We further revealed that VP1, the major capsid protein of HuNoV, was crucial in promoting AQP1 expression. Mechanistically, HuNoV induces AQP1 production through the NF-κB signaling pathway via inducing the expression, phosphorylation and nuclear translocation of p65. By using a model of human intestinal epithelial barrier (IEB), we demonstrated that HuNoV and VP1-mediated enhancement of small molecule permeability is associated with the AQP1 channel. Collectively, we revealed that HuNoV induced the production of AQP1 by activating the NF-κB signaling pathway. The findings in this study provide a basis for further understanding the significance of HuNoV-induced AQP1 expression and the potential mechanism underlying HuNoV-caused diarrhea.