Yi Liu

All Publications

• Progranulin protects against Clostridioides difficile infection by enhancing IL-22 production. Gut microbes Huang, J., Liu, B., Liu, Y., You, W., Zhao, P., Liu, Y., Wang, K., Lai, X., Xu, B., Cao, J. 2024; 16 (1): 2409220

  Abstract

  Enhanced mortality, relapse rates, and increased prevalence of Clostridioides difficile infection (CDI) emphasize the need for better therapies and management approaches. Modulating host immune response to ameliorate CDI-associated immunopathology may provide new advantages to currently inadequate antibiotic therapies. Here, we identified progranulin (PGRN) as an important immune target upregulated in response to CDI. PGRN-deficient mice displayed dramatically higher mortality and aggravated epithelial barrier disruption compared with wild type (WT) mice after CDI despite equivalent levels of bacterial burden or toxin in the large intestine. Mechanistically, PGRN protection was mediated by IL-22 production from CD4+ T helper cells, as demonstrated by a decrease in colonic IL-22-producing CD4+ T helper cells in the intestine of PGRN-deficient mice upon CDI and a boost of IL-22-producing CD4+ T helper cells activated by PGRN ex vivo. Clinical evidence suggests that CDI patients had significantly higher serum levels of PGRN compared with healthy controls, which was significantly and positively correlated with IL-22. Our findings thus indicate a critical role for PGRN-promoted CD4+ T cell IL-22 production in shaping gut immunity and reestablishing the intestinal barrier during CDI. As an alternative to pathogen-targeted therapy, this study may provide a new host-directed therapeutic strategy to attenuate severe, refractory CDI.

  View details for DOI 10.1080/19490976.2024.2409220

  View details for PubMedID 39349385

• Bone morphogenetic protein 9 is a candidate prognostic biomarker and host-directed therapy target for sepsis SCIENCE TRANSLATIONAL MEDICINE Bai, H., Liu, Y., Cao, J. 2024; 16

  View details for DOI 10.1126/scitranslmed.adi3275

• Identification and validation of microtubule depolymerizing agent, CYT997, as a potential drug candidate for hepatocellular carcinoma. Liver international : official journal of the International Association for the Study of the Liver Ahmad, F., Ma, L., Wei, W., Liu, Y., Hakim, I., Daugherty, A., Mujahid, S., Radin, A. A., Chua, M., So, S. 2023

  Abstract

  BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is a typically fatal malignancy with limited treatment options and poor survival rates, despite recent FDA approvals of newer treatment options. We aim to address this unmet need by using a proprietary computational drug discovery platform that identifies drug candidates with the potential to advance rapidly and successfully through preclinical studies.METHODS: We generated an in silico model of HCC biology to identify the top 10 small molecules with predicted efficacy. The most promising candidate, CYT997, was tested for its invitro effects on cell viability and cell death, colony formation, cell cycle changes, and cell migration/invasion in HCC cells. We used an HCC patient-derived xenograft (PDX) mouse model to assess its invivo efficacy.RESULTS: CYT997 was significantly more cytotoxic against HCC cells than against primary human hepatocytes, and sensitized HCC cells to sorafenib. It arrested cell cycle at the G2/M phase with associated up-regulations of p21, p-MEK1/2, p-ERK, and down-regulation of cyclin B1. Cell apoptosis and senescence-like morphology were also observed. CYT997 inhibited HCC cell migration and invasion, and down-regulated the expressions of acetylated tubulins, beta-tubulin, glypican-3 (GPC3), beta-catenin, and c-Myc. Invivo, CYT997 (20mg/kg, three times weekly by oral gavage) significantly inhibited PDX growth, while being non-toxic to mice. Immunohistochemistry confirmed the down-regulation of GPC3, c-Myc, and Ki-67, supporting its anti-proliferative effect.CONCLUSION: CYT997 is a potentially efficacious and non-toxic drug candidate for HCC therapy. Its ability to down-regulate GPC3, beta-catenin, and c-Myc highlights a novel mechanism of action.

  View details for DOI 10.1111/liv.15756

  View details for PubMedID 37833852

• Enkurin: A novel marker for myeloproliferative neoplasms from platelet, megakaryocyte, and whole blood specimens. Blood advances Mosale Seetharam, S., Liu, Y., Wu, J., Fechter, L., Murugesan, K., Maecker, H. T., Gotlib, J., Zehnder, J. L., Paulmurugan, R., Krishnan, A. 2023

  Abstract

  Impaired protein homeostasis, though well established in age-related disorders, has been linked in recent research with the pathogenesis of myeloproliferative neoplasms (MPNs). As yet, however, little is known about MPN-specific modulators of proteostasis, thus impeding our ability for increased mechanistic understanding and discovery of additional therapeutic targets. Loss of proteostasis, in itself, is traced to dysregulated mechanisms in protein folding and intracellular calcium signaling at the endoplasmic reticulum (ER). Here, using ex vivo and in vitro systems (including CD34+ cultures from patient bone marrow, and healthy cord/peripheral blood specimens), we extend our prior data from MPN patient platelet RNA sequencing, and discover select proteostasis-associated markers at RNA and/or protein levels in each of platelets, parent megakaryocytes, and whole blood specimens. Importantly, we identify a novel role in MPNs for enkurin (ENKUR), a calcium mediator protein, implicated originally only in spermatogenesis. Our data reveal consistent ENKUR downregulation at both RNA and protein levels across MPN patient specimens and experimental models, with a concomitant upregulation of a cell cycle marker, CDC20. Silencing of ENKUR by shRNA in CD34+ derived megakaryocytes further confirm this association with CDC20 at both RNA and protein levels; and indicate a likely role for the PI3K/Akt pathway. The inverse association of ENKUR and CDC20 expression was further confirmed upon treatment with thapsigargin (an agent that causes protein misfolding in the ER by selective loss of calcium) in both megakaryocyte and platelet fractions at RNA and protein levels. Together, our work sheds light on enkurin as a novel marker of MPN pathogenesis beyond the genetic alterations; and indicates further mechanistic investigation into a role for dysregulated calcium homeostasis, and ER and protein folding stress in MPN transformation.

  View details for DOI 10.1182/bloodadvances.2022008939

  View details for PubMedID 37315179

• Extracellular Vesicles (EVs) in Tumor Diagnosis and Therapy. Technology in cancer research & treatment Tan, M., Ge, Y., Wang, X., Wang, Y., Liu, Y., He, F., Teng, H. 2023; 22: 15330338231171463

  Abstract

  In recent years, extracellular vesicles (EVs) have gained significant attention due to their tremendous potential for clinical applications. EVs play a crucial role in various aspects, including tumorigenesis, drug resistance, immune escape, and reconstruction of the tumor microenvironment. Despite the growing interest in EVs, many questions still need to be addressed before they can be practically applied in clinical settings. This paper aims to review EVs' isolation methods, structure research, the roles of EVs in tumorigenesis and their mechanisms in multiple types of tumors, their potential application in drug delivery, and the expectations for their future in clinical research.

  View details for DOI 10.1177/15330338231171463

  View details for PubMedID 37122245

• Advances in Novel Tumor Therapeutics Based on Nanomaterial Technologies Biomaterials and Biosensors Liu, Y., Li, C. 2023; 2 (1)

  View details for DOI 10.58567/bab02010001

• CXCL14 Protects Against Polymicrobial Sepsis by Enhancing Antibacterial Functions of Macrophages. American journal of respiratory cell and molecular biology Lai, X., Ding, H., Yu, R., Bai, H., Liu, Y., Cao, J. 2022

  Abstract

  Rapid and effective control of bacterial infection is critical for the treatment of bacterial sepsis. CXCL14 is an important chemokine involved in infection and immunity, which can bind to CXCR4. However, the contribution of CXCL14/CXCR4 chemokine axis to bacterial clearance in sepsis remains unknown. Here the impact of CXCL14/CXCR4 blockade or CXCL14 administration on sepsis was assessed using murine and cell models, as well as human samples. CXCL14 protein levels were elevated in mice after cecal ligation and puncture (CLP)-induced sepsis. In vivo, CXCL14 blockade using anti-CXCL14 antibody or CXCL14 knockdown by adeno-associated virus carrying-CXCL14 shRNA significantly increased mortality and bacterial burden, which was paralleled by significantly decreased macrophage influx and M2 macrophage polarization at the site of infection after CLP. Therapeutic administration of CXCL14 improved mortality and bacterial clearance after CLP in a CXCR4-dependent manner, and macrophages, but not neutrophils, were important for the protective effect of CXCL14 in sepsis. In vitro, CXCL14 directly enhanced bacterial phagocytosis and killing of macrophages, and it also increased phagosome formation and reactive oxygen species (ROS) production in macrophages. Furthermore, inhibiting the activation of PI3K/Akt and NF-κB signaling pathways, but not STAT1, abrogated the enhanced antibacterial effects of CXCL14 on macrophages. Finally, circulating CXCL14 levels were significantly up-regulated in the patients with sepsis. CXCL14 could enhance bacterial phagocytosis and killing in human monocyte-derived macrophages, which was dependent on CXCR4. Therefore, our results indicate a previously undescribed role of CXCL14/CXCR4 axis and suggest CXCL14 as a potential adjunct therapy in bacterial sepsis.

  View details for DOI 10.1165/rcmb.2022-0249OC

  View details for PubMedID 35926119

• Inhaled Gold Nano-Star Carriers for Targeted Delivery of Triple Suicide Gene Therapy and Therapeutic MicroRNAs to Lung Metastases: Development and Validation in a Small Animal Model ADVANCED THERAPEUTICS Liu, Y., Sukumar, U., Jugniot, N., Seetharam, S., Rengaramachandran, A., Sadeghipour, N., Mukherjee, P., Krishnan, A., Massoud, T. F., Paulmurugan, R. 2022

  View details for DOI 10.1002/adtp.202200018

  View details for Web of Science ID 000815596100001

• Prognostic and pathogenic role of CXC motif ligand 16 in sepsis MICROBES AND INFECTION Gong, Y., Li, J., Huang, L., Liu, Y., Cao, J. 2022; 24 (1): 104882

  Abstract

  Chemokine CXC motif ligand 16 (CXCL16) is an important mediator that has been shown to participate in various human diseases. The role of CXCL16 in the immunopathology of sepsis remains unidentified. In this study, we found that human patients with sepsis had significantly higher soluble levels of serum CXCL16 than healthy volunteers on day of intensive care unit (ICU) admission. Soluble CXCL16 remained significantly up-regulated in the patients with sepsis, which correlated with disease severity. Furthermore, nonsurvivors displayed significantly higher admission levels of soluble CXCL16 compared with survivors of septic patients. Soluble CXCL16 levels revealed significant prognostic value for 28-day mortality, and CXCL16 was shown to be an independent predictor of 28-day mortality in the patients with sepsis. In a murine model of cecal ligation and puncture (CLP)-induced nonsevere sepsis, supplementation of recombinant CXCL16 protein could increase sepsis-induced mortality and tissue injury. Conversely, neutralizing CXCL16 by anti-CXCL16 monoclonal antibody could decrease mortality and tissue injury in CLP-induced severe sepsis. However, CXCL16 did not affect the ability of these mice to clear bacteria in CLP. Taken together, CXCL16 could be related to sepsis not only as a novel biomarker of prognosis, but also as a potential target for therapeutic intervention.

  View details for DOI 10.1016/j.micinf.2021.104882

  View details for Web of Science ID 000779630800009

  View details for PubMedID 34454064

• BRET Sensors for Imaging Membrane Integrity of Microfluidically Generated Extracellular Vesicles. Methods in molecular biology (Clifton, N.J.) Paulmurugan, R., Liu, Y., Sukumar, U. K., Kanada, M., Massoud, T. F. 2022; 2525: 227-238

  Abstract

  Extracellular vesicles (EVs) derived from various cell lines have been extensively used as natural nanodelivery vehicles for drug, protein, and nucleic acid deliveries in therapeutic applications for cancer. Recently, we developed a microfluidic-based reconstruction strategy as a novel method to generate microRNA-loaded membrane vesicles for cancer therapy in vivo. We used EVs and cell membranes isolated from different source of cells for this reconstruction process. The microfluidic system produced reconstructed vesicles of uniform sizes with high microRNA loading efficiency independent of input membrane sources (EVs or cell membranes). To address the functional integrity of the membrane structure and of proteins in the reconstructed EVs, we introduce a membrane-insertable bioluminescence resonance energy transfer (BRET) sensor system. This sensor, with its membrane-insertable palmitoylation signal peptide sequence derived from a growth-associated protein 43 (GAP43), helps in trafficking the fusion protein to the cell membrane upon its expression in cells and allows for imaging reconstructed membrane vesicles using optical imaging. In this chapter, we detail the stepwise methods used for the engineering of cells using this sensor, isolation of EVs from the engineered cells, preparation of reconstructed EVs by microfluidic processing, and BRET imaging of reconstructed EVs for membrane integrity evaluation.

  View details for DOI 10.1007/978-1-0716-2473-9_17

  View details for PubMedID 35836072

• Camouflaged Hybrid Cancer Cell-Platelet Fusion Membrane Nanovesicles Deliver Therapeutic MicroRNAs to Presensitize Triple-Negative Breast Cancer to Doxorubicin ADVANCED FUNCTIONAL MATERIALS Liu, Y., Sukumar, U. K., Kanada, M., Krishnan, A., Massoud, T. F., Paulmurugan, R. 2021

  View details for DOI 10.1002/adfm.202103600

  View details for Web of Science ID 000673272900001

• SARS-CoV-2 Vaccine Development: An Overview and Perspectives. ACS pharmacology & translational science Liu, Y., Wang, K., Massoud, T. F., Paulmurugan, R. 2020; 3 (5): 844–58

  Abstract

  Coronavirus disease 2019, abbreviated as COVID-19, is caused by a new strain of coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It started in late December 2019 in Wuhan, China, and by mid-March 2020, the disease had spread globally. As of July 17, 2020, this pandemic virus has infected 13.9 million people and claimed the life of approximately 593 000 people globally, and the numbers continue to climb. An unprecedented effort is underway to develop therapeutic and prophylactic strategies against this disease. Various drugs and vaccines are undergoing rapid development, and some of these are already in phase III clinical trials. Although Russia was the first to release a vaccine by skipping phase III clinical trials, there is no evidence of large-scale clinical trials, and the safety and efficacy of the vaccine are still a concern. Nevertheless, critical lessons can be learned and data garnered for developing promising vaccines against this rapidly emerging virus or other similar pathogens in the future. In this overview, we cover the available information on the various vaccine development initiatives by different companies, the potential strategies adopted for vaccine design, and the challenges and clinical impact expected from these vaccines. We also briefly discuss the possible role of these vaccines and the specific concerns for their use in patients with pre-existing disease conditions such as cardiovascular, lung, kidney, and liver diseases, cancer patients who are receiving immunosuppressive medications, including anticancer chemotherapies, and many other sensitive populations, such as children and the elderly.

  View details for DOI 10.1021/acsptsci.0c00109

  View details for PubMedID 33062951

• Ultrasound-Mediated Long-Circulating Nanopolymer Delivery of Therapeutic siRNA and Antisense MicroRNAs Leads to Enhanced Paclitaxel Sensitivity in Epithelial Ovarian Cancer Chemotherapy ACS BIOMATERIALS SCIENCE & ENGINEERING Liu, Y., Long, T., Zhang, N., Qiao, B., Yang, Q., Luo, Y., Cao, J., Luo, J., Yuan, D., Sun, Y., Li, Y., Yang, Z., Wang, Z. G. 2020; 6 (7): 4036–50

  Abstract

  Epithelial ovarian cancer (EOC) is one of the leading malignant tumors that seriously threaten women's health. The development of new drugs or increasing the sensitivities of current chemotherapy drugs is critically needed. The purpose of this study was to assess the synergistic effects of two silencing RNAs [salt-inducible kinase 2 (SIK2) siRNA and antisense-microRNA21 (anti-miR21)] encapsulated in long-circulating folate-lipid-poly(lactic-co-glycolic acid) (PLGA) hybrid nanopolymers (FaLPHNPs) administered using an ultrasound- and microbubble (US-MB)-mediated approach to sensitize human EOC xenografts to paclitaxel (PTX). In the in vitro assays, this lipid-PLGA hybrid nanopolymer exhibited an extended circulation profile (t1/2: ∼8.5 h); US-MB-mediated complementary delivery of FaLPHNPs resulted in a significant reduction in EOC cell (OVCR3, A2780, and SKOV3) proliferation. In vivo, there was a 2.5-fold increase (p < 0.05) in RNA delivery in EOC xenografts, which resulted in a notable inhibition of tumor growth compared with that in the non-ultrasound-mediated and PTX alone-treated controls. We validated the therapeutic roles of SIK2, the target gene in treating advanced ovarian cancer, and anti-miR21 by evaluating the significant inhibition of tumor growth upon SIK2 silencing and inhibition of endogenous miR21 function. In summary, the results of this study revealed that US-MB-mediated codelivery of SIK2 siRNA, and anti-miR21 encapsulated in a folate-lipid-PLGA hybrid polymer nanoparticle could significantly improve the sensitivity of EOC tumors to PTX and is a highly effective approach for treating EOC in complementary experiments. Further research of this strategy could lead to better treatment results for patients with EOC.

  View details for DOI 10.1021/acsbiomaterials.0c00330

  View details for Web of Science ID 000551355300030

  View details for PubMedID 33463352

• Oncostatin M Is a Prognostic Biomarker and Inflammatory Mediator for Sepsis JOURNAL OF INFECTIOUS DISEASES Gong, Y., Yan, X., Sun, X., Chen, T., Liu, Y., Cao, J. 2020; 221 (12): 1989–98

  Abstract

  Oncostatin M (OSM) is a pleiotropic cytokine of the interleukin-6 family. The role of OSM in sepsis remains unknown.Serum OSM level was determined and analyzed in septic patients on the day of intensive care unit (ICU) admission. Furthermore, the effects of OSM on polymicrobial sepsis induced by cecal ligation and puncture (CLP) were assessed.On the day of ICU admission, septic patients had significantly higher serum OSM levels when compared with ICU patient controls and healthy volunteers, which were related to the severity of sepsis, including parameters such as the sequential (sepsis-related) organ failure assessment score, procalcitonin level, and white blood cell number. A high serum OSM level on ICU admission was associated with 28-day mortality in septic patients. In CLP-induced polymicrobial sepsis, anti-OSM antibody decreased tissue inflammation and injury, and thus improved survival, while local and systemic bacterial dissemination was almost constant. Complementarily, supplementation with recombinant OSM protein in septic mice increased tissue injury, amplified inflammation, and worsened mortality after CLP, while it did not affect bacterial dissemination in septic mice.Sepsis results in an increased production of OSM, which might be a potential prognostic biomarker and therapeutic target for sepsis.

  View details for DOI 10.1093/infdis/jiaa009

  View details for Web of Science ID 000544189300011

  View details for PubMedID 31930328

• Interleukin-17D Aggravates Sepsis by Inhibiting Macrophage Phagocytosis CRITICAL CARE MEDICINE Yan, X., Tu, H., Liu, Y., Chen, T., Cao, J. 2020; 48 (1): E58–E65

  Abstract

  Interleukin-17D has been shown to participate in the control of viral infections and cancer. Here we hypothesized that interleukin-17D may play a potential role in sepsis.Prospective randomized animal investigation and in vitro human blood studies.Research laboratory from a university hospital.Female C57BL/6J mice, sepsis patients by Sepsis-3 definitions, ICU patient controls, and healthy individuals.Serum concentrations of interleukin-17D were measured and analyzed in human sepsis patients, patient controls, and healthy individuals. The contribution of interleukin-17D to sepsis-related survival, bacterial burden, and organ injury was assessed in a murine model of cecal ligation and puncture-induced polymicrobial sepsis by the use of anti-interleukin-17D antibody and recombinant interleukin-17D protein. The effects of interleukin-17D on bacterial phagocytosis by macrophages were also investigated using in vitro cell models.On the day of ICU admission (day 0), septic patients had significantly higher serum concentrations of interleukin-17D than patient controls and healthy individuals. Serum interleukin-17D levels remained significantly elevated in septic patients from ICU admission to day 3 and correlated with Sequential (Sepsis-related) Organ Failure Assessment scores and documented bacteremia on day 0. Furthermore, nonsurvivors of septic patients displayed significantly higher interleukin-17D levels compared with survivors of septic patients on days 0 and 1 of ICU admission. In animal models of sepsis, treatment with anti-interleukin-17D antibody protected mice from cecal ligation and puncture-induced severe sepsis, which was associated with improved bacterial clearance and organ injury. Conversely, administration of recombinant interleukin-17D protein aggravated cecal ligation and puncture-induced nonsevere sepsis. Furthermore, we found that interleukin-17D impaired bacterial phagocytosis by macrophages. Phagocytosis inhibition by interleukin-17D involved its ability to down-regulate the activation of nuclear factor-κB signaling pathway in macrophages upon bacterial infection.This study indicates a previously undescribed role of interleukin-17D in sepsis and identifies a new target for antisepsis treatment.

  View details for DOI 10.1097/CCM.0000000000004070

  View details for Web of Science ID 000502770900016

  View details for PubMedID 31634237

• Assessment of Apoptosis Inhibitor of Macrophage/CD5L as a Biomarker to Predict Mortality in the Critically Ill With Sepsis CHEST Gao, X., Liu, Y., Xu, F., Lin, S., Song, Z., Duan, J., Yin, Y., Cao, J. 2019; 156 (4): 696–705

  Abstract

  To determine the utility of apoptosis inhibitor of macrophage (AIM)/CD5L as a potentially novel biomarker of morbidity and mortality in patients with sepsis who are critically ill.There were 150 adult patients with sepsis studied. Serum AIM levels on day of ICU admission were determined and compared with survival status and organ dysfunction. For validation, 60 adult patients with sepsis from another medical center were studied. Furthermore, the role of AIM as an outcome predictor in 51 pediatric patients with sepsis was investigated.In the derivation cohort of adult patients, patients with sepsis had markedly increased admission levels of serum AIM compared with ICU control subjects and healthy control subjects. Higher serum AIM levels at admission were significantly associated with higher Sequential (sepsis-related) Organ Failure Assessment (SOFA) scores. On day of ICU admission, the area under the receiver operating characteristic curve (AUC) for AIM level association with 28-day mortality was 0.86, higher than the AUC for SOFA (0.77), procalcitonin (0.73), lactate (0.67), IL-27 (0.65), and C-reactive protein (0.55). Patients with sepsis with higher admission levels of AIM (> 543.66 ng/mL) had significantly increased 28-day mortality compared with those with lower AIM levels (≤ 543.66 ng/mL). The association between admission levels of AIM and 28-day mortality was confirmed in the validation cohort of adult patients. In another cohort of pediatric patients with sepsis, the AUC for AIM level association with 28-day mortality was 0.82.Circulating AIM levels at admission were markedly increased in patients with sepsis, which can serve as a novel prognostic biomarker for predicting mortality.

  View details for DOI 10.1016/j.chest.2019.04.134

  View details for Web of Science ID 000489035200015

  View details for PubMedID 31154043

• Interleukin-26 is overexpressed in human sepsis and contributes to inflammation, organ injury, and mortality in murine sepsis CRITICAL CARE Tu, H., Lai, X., Li, J., Huang, L., Liu, Y., Cao, J. 2019; 23 (1): 290

  Abstract

  Sepsis is a serious syndrome that is caused by an unbalanced host inflammatory response to an infection. The cytokine network plays a pivotal role in the orchestration of inflammatory response during sepsis. IL-26 is an emerging proinflammatory member of the IL-10 cytokine family with multifaceted actions in inflammatory disorders. However, its role in the pathogenesis of sepsis remains unknown.Serum IL-26 level was measured and analyzed in 52 septic patients sampled on the day of intensive care unit (ICU) admission, 18 non-septic ICU patient controls, and 30 healthy volunteers. In addition, the effects of recombinant human IL-26 on host inflammatory response in cecal ligation and puncture (CLP)-induced polymicrobial sepsis were determined.On the day of ICU admission, the patients with sepsis showed a significant increase in serum IL-26 levels compared with ICU patient controls and healthy volunteers, and the serum IL-26 levels were related to the severity of sepsis. Nonsurvivors of septic patients displayed significantly higher serum IL-26 levels compared with survivors. A high serum IL-26 level on ICU admission was associated with 28-day mortality, and IL-26 was found to be an independent predictor of 28-day mortality in septic patients by logistic regression analysis. Furthermore, administration of recombinant human IL-26 increased lethality in CLP-induced polymicrobial sepsis. Despite a lower bacterial load, septic mice treated with recombinant IL-26 had higher concentrations of IL-1β, IL-4, IL-6, IL-10, IL-17A, TNF-α, CXCL1, and CCL2 in peritoneal lavage fluid and blood and demonstrated more severe multiple organ injury (including lung, liver and kidney) as indicated by clinical chemistry and histopathology. Furthermore, septic mice treated with recombinant human IL-26 showed an increased neutrophil recruitment to the peritoneal cavity.Septic patients had elevated serum IL-26 levels, which may correlate with disease severity and mortality. In experimental sepsis, we demonstrated a previously unrecognized role of IL-26 in increasing lethality despite promoting antibacterial host responses.

  View details for DOI 10.1186/s13054-019-2574-7

  View details for Web of Science ID 000483515900001

  View details for PubMedID 31464651

  View details for PubMedCentralID PMC6716900

• Interleukin 28 is a potential therapeutic target for sepsis CLINICAL IMMUNOLOGY Luo, Q., Liu, Y., Liu, S., Yin, Y., Xu, B., Cao, J. 2019; 205: 29–34

  Abstract

  Identification of new therapeutic targets for the treatment of sepsis is imperative. We report here that cytokine IL-28 (IFN-λ) levels were elevated in clinical and experimental sepsis. Neutralization of IL-28 protected mice from lethal sepsis induced by cecal ligation and puncture (CLP), which was associated with improved bacterial clearance and enhanced neutrophil infiltration. Conversely, administration of recombinant IL-28 aggravated mortality, facilitated bacterial dissimilation and limited neutrophil recruitment, in the model of sepsis induced by CLP. This study defines IL-28 as a detrimental mediator during sepsis and identifies a potential therapeutic target for the immune therapy in sepsis.

  View details for DOI 10.1016/j.clim.2019.05.012

  View details for Web of Science ID 000482172600006

  View details for PubMedID 31121287

• Photothermal therapy mediated by phase-transformation nanoparticles facilitates delivery of anti-PD1 antibody and synergizes with antitumor immunotherapy for melanoma JOURNAL OF CONTROLLED RELEASE Zhang, N., Song, J., Liu, Y., Liu, M., Zhang, L., Sheng, D., Deng, L., Yi, H., Wu, M., Zheng, Y., Wang, Z., Yang, Z. 2019; 306: 15–28

  Abstract

  Melanoma remains one of the most challenging malignant tumor related deaths worldwide and alternative approaches to efficiently treat melanoma are eagerly needed. Anti-PD1 antibody (aPD1) immunotherapy is the most significant and impactful therapy for melanoma by immune checkpoint inhibition and T cell stimulation to mediate tumor killing. But the clinical remission rate of aPD1 immunotherapy is limited in melanoma. Here we show a potent combination of aPD1 and photothermal therapy (PTT) by effective delivery of a multifunctional phase-transformation nanocarrier to melanoma tumor. We successfully synthesized multifunctional nanoparticles (NPs) encapsulated with aPD1, iron oxide and perfluoropentane (PFP) in lactic-co-glycolic acid (PLGA) shell modified with poly ethylene glycol (PEG) and Gly-Arg-Gly-Asp-Ser (GRGDS) peptides (GOP@aPD1). In vitro, GOP@aPD1 NPs were characterized for particle size and drug-loading efficiency. The NPs were also tested for photothermal property, optical droplet vaporization (ODV) capacity and the ability of aPD1 release profile. In vivo, GOP@aPD1 NPs were systemically administered to melanoma-bearing mice demonstrated no toxicity and accumulation at tumor site. When mediated with PTT, this synergistic treatment achieved enhanced antitumor efficacy, due to combination of the effective aPD1 release and increased CD8+ T cell infiltration in tumor site. In conclusion, GOP@aPD1 NPs combined with PTT could potentiate the efficacy of aPD1 not only by tumor-targeted delivery of aPD1 but also by activating the immune system in the tumor microenvironment, which is a highly effective approach to treat melanoma.

  View details for DOI 10.1016/j.jconrel.2019.05.036

  View details for Web of Science ID 000474822700002

  View details for PubMedID 31132380

• Flagellin attenuates experimental sepsis in a macrophage-dependent manner CRITICAL CARE Yang, X., Yin, Y., Yan, X., Yu, Z., Liu, Y., Cao, J. 2019; 23: 106

  Abstract

  Sepsis is the leading cause of death among critically ill patients, and no specific therapeutic agent is currently approved for the treatment of sepsis.We assessed the effects of flagellin administration on survival, bacterial burden, and tissue injury after sepsis. In addition, we examined the effects on phagocytosis and bacterial killing in monocytes/macrophages.Therapeutic administration of flagellin increased bacterial clearance, decreased organ inflammation and injury, and reduced immune cell apoptosis after experimental sepsis, in a Toll-like receptor 5 (TLR5)-dependent manner. Macrophages, but not neutrophils, mediated the beneficial effects of flagellin on experimental sepsis, and flagellin induced macrophage polarization into M1 in septic mice. Flagellin treatment could directly enhance phagocytosis and bacterial killing of macrophages, but not neutrophils. Subsequent studies demonstrated that flagellin could promote phagosome formation and increase reactive oxygen species (ROS) levels in macrophages. Finally, we found that the expression of TLR5 was significantly elevated on the surface of circulating monocytes, but not neutrophils, from patients with sepsis. Higher expression levels of TLR5 on monocytes were associated with increased mortality, documented bacteremia, and higher Sequential Organ Failure Assessment scores of the septic patients. Moreover, flagellin treatment rescued the impaired phagocytosis and bacterial killing ability of monocytes/macrophages from patients who died of sepsis.These novel findings not only established the potential value of application of flagellin as an immunoadjuvant in treating sepsis, but also provided new insights into targeted therapeutic strategy on the basis of monocyte TLR5 expression in septic patients.

  View details for DOI 10.1186/s13054-019-2408-7

  View details for Web of Science ID 000463795500003

  View details for PubMedID 30944018

  View details for PubMedCentralID PMC6446324

• IR780-loaded folate-targeted nanoparticles for near-infrared fluorescence image-guided surgery and photothermal therapy in ovarian cancer INTERNATIONAL JOURNAL OF NANOMEDICINE Song, J., Zhang, N., Zhang, L., Yi, H., Liu, Y., Li, Y., Li, X., Wu, M., Hao, L., Yang, Z., Wang, Z. 2019; 14: 2757–72

  Abstract

  Background and purpose: Surgery is regarded as the gold standard for patients with advanced ovarian cancer. However, complete surgical removal of tumors remains extremely challenging; fewer than 40% of patients are cured. Here, we developed a new modality of theranostics for ovarian cancer based on a near-infrared light-triggered nanoparticle. Methods: Nanoparticles loading IR780 iodide on base of folate modified liposomes were prepared and used for theranostics of ovarian cancer. Tumor targeting of FA-IR780-NP was evaluated in vitro and in an ovarian xenograft tumor model. A fluorescence stereomicroscope was applied to evaluate the tumor recognition of FA-IR780-NP during surgery. FA-IR780-NP mediated photothermal therapy effect was compared with other treatments in vivo. Results: FA-IR780-NP was demonstrated to specifically accumulate in tumors. IR780 iodide selectively accumulated in tumors; the enhanced permeability and retention effect of the nanoparticles and the active targeting of folate contributed to the excellent tumor targeting of FA-IR780-NP. With the aid of tumor targeting, FA-IR780-NP could be used as an indicator for the real-time delineation of tumor margins during surgery. Furthermore, photothermal therapy mediated by FA-IR780-NP effectively eradicated ovarian cancer tumors compared with other groups. Conclusion: In this study, we present a potential, effective approach for ovarian cancer treatment through near-infrared fluorescence image-guided resection and photothermal therapy to eliminate malignant tissue.

  View details for DOI 10.2147/IJN.S203108

  View details for Web of Science ID 000465567400003

  View details for PubMedID 31118609

  View details for PubMedCentralID PMC6503636

• Diagnosis and prognosis of neutrophil gelatinase-associated lipocalin for acute kidney injury with sepsis: a systematic review and meta-analysis. Critical care (London, England) Zhang, A., Cai, Y., Wang, P. F., Qu, J. N., Luo, Z. C., Chen, X. D., Huang, B., Liu, Y., Huang, W. Q., Wu, J., Yin, Y. H. 2016; 20: 41

  Abstract

  Neutrophil gelatinase-associated lipocalin (NGAL) has been identified as an early biomarker for prediction of acute kidney injury (AKI). However, the utility of NGAL to predict the occurrence of AKI in septic patients remains controversial. We performed a systematic review and meta-analysis to evaluate the evidence on diagnosis of sepsis AKI and the prediction of other clinical outcomes.The MEDLINE, EMBASE, Cochrane Library, Wanfang, and CNKI databases were systematically searched up to August 19, 2015. Quality assessment was applied by using the Quality Assessment for Studies of Diagnostic Accuracy (QUADAS-2) tool. The diagnostic performance of NGAL for the prediction of AKI in sepsis was evaluated using pooled estimates of sensitivity, specificity, likelihood ratio, and diagnostic odds ratio (DOR), as well as summary receiver operating characteristic curves (SROC).Fifteen studies with a total of 1,478 patients were included in the meta-analysis. For plasma NGAL, the pooled sensitivity and specificity with corresponding 95% confidence intervals (CI) were 0.83 (95% CI: 0.77 - 0.88) and 0.57 (95% CI: 0.54 - 0.61), respectively. The pooled positive likelihood ratio (PLR) was 3.10 (95% CI: 1.57 - 6.11) and the pooled negative likelihood ratio (NLR) was 0.24 (95% CI: 0.13 - 0.43). The pooled DOR was 14.72 (95% CI: 6.55 - 33.10) using a random effects model. The area under the curve (AUC) for SROC to summarize diagnostic accuracy was 0.86. For urine NGAL, the pooled sensitivity, specificity, PLR, NLR, DOR, and AUC values were 0.80 (95% CI: 0.77 - 0.83), 0.80 (95% CI: 0.77 - 0.83), 4.42 (95% CI: 2.84 - 6.89), 0.21 (95% CI: 0.13 - 0.35), 24.20 (95% CI: 9.92 - 59.05) and 0.90, respectively. Significant heterogeneity was explored as a potential source. There was no notable publication bias observed across the eligible studies. NGAL for prediction of renal replacement therapy (RRT) and mortality associated with AKI in septic patients were also evaluated.To a certain extent, NGAL is not only an effective predictive factor for AKI in the process of sepsis, but also shows potential predictive value for RRT and mortality. However, future trials are needed to clarify this controversial issue.

  View details for DOI 10.1186/s13054-016-1212-x

  View details for PubMedID 26880194

  View details for PubMedCentralID PMC4754917