Activation of Wnt/ß-catenin signaling promotes immune evasion via the ß-catenin/IKZF1/CCL5 axis in hepatocellular carcinoma.

Immune checkpoint therapy (ICT) has been shown to produce durable responses in various cancer patients. However, its efficacy is notably limited in hepatocellular carcinoma (HCC), with only a small percentage of patients responding positively to treatment. The mechanism underlying resistance to ICT in HCC remains poorly understood. Here, we showed that combination treatment of ICG-001, an inhibitor of the Wnt/ß-catenin signaling pathway, with anti-PD-1 antibody effectively suppresses tumor growth and promotes the infiltration of immune cells such as DCs and CD8+ T cells in the tumor microenvironment (TME). By inhibiting the activity of ß-catenin and blocking its binding to the transcription factor IKAROS family zinc finger 1 (IKZF1), ICG-001 upregulated the expression of CCL5. Moreover, IKZF1 regulated the activity of the CCL5 promoter and its endogenous expression. Through inhibition of the WNT/ß-catenin signaling pathway, upregulation of the expression of CCL5 was achieved, which subsequently recruited more DCs into the TME via C-C motif chemokine receptor 5 (CCR5). This, in turn, resulted in an increase in the infiltration of CD8+ T cells in the TME, thereby enhancing the antitumor immune response. Analysis of a tissue microarray derived from HCC patient samples revealed a positive correlation between survival rate and prognosis and the expression levels of CCL5/CD8. In conclusion, our findings suggest that combined application of ICG-001 and anti-PD-1 antibody exhibits significantly enhanced antitumor efficacy. Hence, combining a WNT/ß-catenin signaling pathway inhibitor with anti-PD-1 therapy may be a promising treatment strategy for patients with HCC.

Fibrinogen binding to histones in circulation protects against adverse cellular and clinical outcomes.

BACKGROUND: Circulating histones are released by extensive tissue injury or cell death and play important pathogenic roles in critical illnesses. Their interaction with circulating plasma components and the potential roles in the clinical setting are not fully understood. OBJECTIVES: We aimed to characterize the interaction of histones with fibrinogen and explore its roles in vitro, in vivo, and in patient samples. METHODS: Histone-fibrinogen binding was assessed by electrophoresis and enzyme-linked immunosorbent assay-based affinity assay. Functional significance was explored using washed platelets and endothelial cells in vitro and histone-infusion mouse models in vivo. To determine clinical translatability, a retrospective single-center cohort study was conducted on patients requiring intensive care admission (n = 199) and validated in a cohort of hospitalized patients with COVID-19 (n = 69). RESULTS: Fibrinogen binds histones through its D-domain with high affinity (calf thymus histones, KD = 18.0 ± 5.6 nM; histone 3, KD = 2.7 ± 0.8 nM; and histone 4, KD = 2.0 ± 0.7 nM) and significantly reduces histone-induced endothelial damage and platelet aggregation in vitro and in vivo in a histone-infusion mouse model. Physiologic concentrations of fibrinogen can neutralize low levels of circulating histones and increase the cytotoxicity threshold of histones to 50 µg/mL. In a cohort of patients requiring intensive care, a histone:fibrinogen ratio of ≥6 on admission was associated with moderate-severe thrombocytopenia and independently predicted mortality. This finding was validated in a cohort of hospitalized patients with COVID-19. CONCLUSION: Fibrinogen buffers the cytotoxic properties of circulating histones. Detection and monitoring of circulating histones and histone:fibrinogen ratios will help identify critically ill patients at highest risk of adverse outcomes who might benefit from antihistone therapy.

Targeted Destruction of S100A4 Inhibits Metastasis of Triple Negative Breast Cancer Cells.

Most patients who die of cancer do so from its metastasis to other organs. The calcium-binding protein S100A4 can induce cell migration/invasion and metastasis in experimental animals and is overexpressed in most human metastatic cancers. Here, we report that a novel inhibitor of S100A4 can specifically block its increase in cell migration in rat (IC50, 46 µM) and human (56 µM) triple negative breast cancer (TNBC) cells without affecting Western-blotted levels of S100A4. The moderately-weak S100A4-inhibitory compound, US-10113 has been chemically attached to thalidomide to stimulate the proteasomal machinery of a cell. This proteolysis targeting chimera (PROTAC) RGC specifically eliminates S100A4 in the rat (IC50, 8 nM) and human TNBC (IC50, 3.2 nM) cell lines with a near 20,000-fold increase in efficiency over US-10113 at inhibiting cell migration (IC50, 1.6 nM and 3.5 nM, respectively). Knockdown of S100A4 in human TNBC cells abolishes this effect. When PROTAC RGC is injected with mouse TNBC cells into syngeneic Balb/c mice, the incidence of experimental lung metastases or local primary tumour invasion and spontaneous lung metastasis is reduced in the 10-100 nM concentration range (Fisher's Exact test, p ≤ 0.024). In conclusion, we have established proof of principle that destructive targeting of S100A4 provides the first realistic chemotherapeutic approach to selectively inhibiting metastasis.

Dual FGFR and VEGFR inhibition synergistically restrain hexokinase 2-dependent lymphangiogenesis and immune escape in intrahepatic cholangiocarcinoma.

BACKGROUND: Therapies for cholangiocarcinoma are largely limited and ineffective. Herein, we examined the role of the FGF and VEGF pathways in regulating lymphangiogenesis and PD-L1 expression in intrahepatic cholangiocarcinoma (iCCA). METHODS: The lymphangiogenic functions of FGF and VEGF were evaluated in lymphatic endothelial cells (LECs) and iCCA xenograft mouse models. The relationship between VEGF and hexokinase 2 (HK2) was validated in LECs by western blot, immunofluorescence, ChIP and luciferase reporter assays. The efficacy of the combination therapy was assessed in LECs and xenograft models. Microarray analysis was used to evaluate the pathological relationships of FGFR1 and VEGFR3 with HK2 in human lymphatic vessels. RESULTS: FGF promoted lymphangiogenesis through c-MYC-dependent modulation of HK2 expression. VEGFC also upregulated HK2 expression. Mechanistically, VEGFC phosphorylated components of the PI3K/Akt/mTOR axis to upregulate HIF-1α expression at the translational level, and HIF-1α then bound to the HK2 promoter region to activate its transcription. More importantly, dual FGFR and VEGFR inhibition with infigratinib and SAR131675 almost completely inhibited lymphangiogenesis, and significantly suppressed iCCA tumor growth and progression by reducing PD-L1 expression in LECs. CONCLUSIONS: Dual FGFR and VEGFR inhibition inhibits lymphangiogenesis through suppression of c-MYC-dependent and HIF-1α-mediated HK2 expression, respectively. HK2 downregulation decreased glycolytic activity and further attenuated PD-L1 expression. Our findings suggest that dual FGFR and VEGFR blockade is an effective novel combination strategy to inhibit lymphangiogenesis and improve immunocompetence in iCCA.

Photosensitive small extracellular vesicles regulate the immune microenvironment of triple negative breast cancer.

Currently, the treatment of triple-negative breast cancer (TNBC) is limited by the special pathological characteristics of this disease. In recent years, photodynamic therapy (PDT) has created new hope for the treatment of TNBC. Moreover, PDT can induce immunogenic cell death (ICD) and improve tumor immunogenicity. However, even though PDT can improve the immunogenicity of TNBC, the inhibitory immune microenvironment of TNBC still weakens the antitumor immune response. Therefore, we used the neutral sphingomyelinase inhibitor GW4869 to inhibit the secretion of small extracellular vesicles (sEVs) by TNBC cells to improve the tumor immune microenvironment and enhance antitumor immunity. In addition, bone mesenchymal stem cell (BMSC)-derived sEVs have good biological safety and a strong drug loading capacity, which can effectively improve the efficiency of drug delivery. In this study, we first obtained primary BMSCs and sEVs, and then the photosensitizers Ce6 and GW4869 were loaded into the sEVs by electroporation to produce immunomodulatory photosensitive nanovesicles (Ce6-GW4869/sEVs). When administered to TNBC cells or orthotopic TNBC models, these photosensitive sEVs could specifically target TNBC and improve the tumor immune microenvironment. Moreover, PDT combined with GW4869-based therapy showed a potent synergistic antitumor effect mediated by direct killing of TNBC and activation of antitumor immunity. Here, we designed photosensitive sEVs that could target TNBC and regulate the tumor immune microenvironment, providing a potential approach for improving the effectiveness of TNBC treatment. STATEMENT OF SIGNIFICANCE: We designed an immunomodulatory photosensitive nanovesicle (Ce6-GW4869/sEVs) with the photosensitizer Ce6 to achieve photodynamic therapy and the neutral sphingomyelinase inhibitor GW4869 to inhibit the secretion of small extracellular vesicles (sEVs) by triple-negative breast cancer (TNBC) cells to improve the tumor immune microenvironment and enhance antitumor immunity. In this study, the immunomodulatory photosensitive nanovesicle could target TNBC cells and regulate the tumor immune microenvironment, thus providing a potential approach for improving the treatment effect in TNBC. We found that the reduction in tumor sEVs secretion induced by GW4869 improved the tumor-suppressive immune microenvironment. Moreover, similar therapeutic strategies can also be applied in other kinds of tumors, especially immunosuppressive tumors, which is of great value for the clinical translation of tumor immunotherapy.

LncRNA HClnc1 facilitates hepatocellular carcinoma progression by regulating PKM2 signaling and indicates poor survival outcome after hepatectomy.

AIM: Long noncoding RNAs (lncRNAs) are key mediators with a wide range of pathophysiological functions, but their role in human hepatocellular carcinoma (HCC) is still unclear. METHODS: An unbiased microarray study evaluated a novel lncRNA, HClnc1, that is linked to the development of HCC. In vitro cell proliferation assays and an in vivo xenotransplanted HCC tumor model were performed to determine its functions, followed by antisense oligo-coupled mass spectrometry to identify HClnc1-interacting proteins. To study relevant signaling pathways, in vitro experiments were performed, including chromatin isolation by RNA purification, RNA immunoprecipitation, luciferase, and RNA pull-down assay. RESULTS: HClnc1 levels were considerably greater in patients with advanced tumor-node-metastatic stages, and it was found to be inversely connected to survival rates. Moreover, the proliferative and invasive potential of the HCC cells was attenuated by HClnc1 RNA knockdown in vitro, while HCC tumor growth and metastasis were found to be reduced in vivo. HClnc1 interacted with pyruvate kinase M2 (PKM2) to prevent its degradation and thus facilitated aerobic glycolysis and PKM2-STAT3 signaling. CONCLUSIONS: HClnc1 is involved in a novel epigenetic mechanism of HCC tumorigenesis and PKM2 regulation. HClnc1 is not only a more accurate prognostic indicator of HCC but also a potential therapeutic target for HCC treatment.

The Importance of Pore-Forming Toxins in Multiple Organ Injury and Dysfunction.

BACKGROUND: Multiple organ injury and dysfunction often occurs in acute critical illness and adversely affects survival. However, in patients who survive, organ function usually recovers without permanent damage. It is, therefore, likely that there are reversible mechanisms, but this is poorly understood in the pathogenesis of multiple organ dysfunction syndrome (MODS). AIMS: Based on our knowledge of extracellular histones and pneumolysin, as endogenous and exogenous pore-forming toxins, respectively, here we clarify if the extent of cell membrane disruption and recovery is important in MODS. METHODS: This is a combination of retrospective clinical studies of a cohort of 98 patients from an intensive care unit (ICU) in a tertiary hospital, with interventional animal models and laboratory investigation. RESULTS: In patients without septic shock and/or disseminate intravascular coagulation (DIC), circulating histones also strongly correlated with sequential organ failure assessment (SOFA) scores, suggesting their pore-forming property might play an important role. In vivo, histones or pneumolysin infusion similarly caused significant elevation of cell damage markers and multiple organ injury. In trauma and sepsis models, circulating histones strongly correlated with these markers, and anti-histone reagents significantly reduced their release. Comparison of pneumolysin deletion and its parental strain-induced sepsis mouse model showed that pneumolysin was not essential for sepsis development, but enhanced multiple organ damage and reduced survival time. In vitro, histones and pneumolysin treatment disrupt cell membrane integrity, resulting in changes in whole-cell currents and elevated intracellular Ca2+ to lead to Ca2+ overload. Cell-specific damage markers, lactate dehydrogenase (LDH), alanine aminotransferase (ALT), and cardiac troponin I (cTnI), were released from damaged cells. Once toxins were removed, cell membrane damage could be rapidly repaired and cellular function recovered. CONCLUSION: This work has confirmed the importance of pore-forming toxins in the development of MODS and proposed a potential mechanism to explain the reversibility of MODS. This may form the foundation for the development of effective therapies.

Does Brand Truth-Telling Yield Customer Participation? The Interaction Effects of CSR Strategy and Transparency Signaling.

Customer participation in brand environmental responsibility is necessary for enterprises and consumers to co-create value. However, it is not yet clear why some corporate social responsibility (CSR) communications are more effective in attracting higher customer participation in a digitally transparent environment. Based on signal theory and social identity theory, this study examines the impact of the interactive effect of CSR strategy (proactive vs. reactive) and transparency signals (high vs. low) on customer trust (perceived integrity and perceived competence), customer-brand identification, and participation intention in brand environmental responsibility. We conduct a 2 × 2 study with 140 respondents. The findings reveal a significant interaction effect of CSR strategy and transparency signals on perceived integrity, perceived competence, and participation intention in brand environmental responsibility. Mediation analysis reveals that the impact of CSR strategy on participation intention is serially mediated via perceived trust and customer-brand identification and varies across different transparency levels.

Consumer Response to Food Corporate Social Irresponsibility: Food Performance and Company Ethics Irresponsibility.

Corporate social irresponsibility (CSI) seriously damages the rights and interests of stakeholders, particularly consumers. This study analyzes the consumer response to food performance irresponsibility and food corporate ethics irresponsibility by moral emotions. A situational simulation experiment was conducted with the following results: (1) Food performance irresponsibility has the greatest impact on consumer boycotts, while corporate ethics irresponsibility more often leads to consumers' negative word of mouth (NWOM). (2) Moral emotions play a strong mediating role between CSI and consumers' NWOM and boycott behavior. (3) Gender significantly moderates the propagation path from moral emotions to NWOM, and female consumers react more strongly to food performance irresponsibility. In conclusion, the paper offers empirical evidence of the effect food corporate social irresponsibility has on consumers' different responses. Furthermore, it can help food enterprises to identify different CSI types and develop corresponding governance strategies.

Activation function 1 of progesterone receptor is required for progesterone antagonism of oestrogen action in the uterus.

BACKGROUND: Progesterone receptor (PGR) is a master regulator of uterine function through antagonistic and synergistic interplays with oestrogen receptors. PGR action is primarily mediated by activation functions AF1 and AF2, but their physiological significance is unknown. RESULTS: We report the first study of AF1 function in mice. The AF1 mutant mice are infertile with impaired implantation and decidualization. This is associated with a delay in the cessation of epithelial proliferation and in the initiation of stromal proliferation at preimplantation. Despite tissue selective effect on PGR target genes, AF1 mutations caused global loss of the antioestrogenic activity of progesterone in both pregnant and ovariectomized models. Importantly, the study provides evidence that PGR can exert an antioestrogenic effect by genomic inhibition of Esr1 and Greb1 expression. ChIP-Seq data mining reveals intermingled PGR and ESR1 binding on Esr1 and Greb1 gene enhancers. Chromatin conformation analysis shows reduced interactions in these genes' loci in the mutant, coinciding with their upregulations. CONCLUSION: AF1 mediates genomic inhibition of ESR1 action globally whilst it also has tissue-selective effect on PGR target genes.

Value acquisition, value co-creation: The impact of perceived organic grocerant value on customer engagement behavior through brand trust.

Affected by COVID-19, there is a growing trend toward healthy lifestyles and organic food consumption. The literature on organic foods focuses on the factors that influence buying behavior. A thriving organic business requires both sustained consumption and consumer contributions beyond the purchase-customer engagement behavior. The purpose of this study is to examine the factors that may drive member customers to engage with organic grocerants. This study surveyed 280 Chinese member customers of an organic grocerant to explore how to drive customer engagement behavior. Based on value co-creation theory and the customer engagement literature, this study proposed a "value acquisition-value co-creation" framework to explore the relationship between perceived value, brand trust, and customer engagement behavior. The results show that emotional and social value can directly and effectively motivate customer engagement behavior in organic grocerants. However, consumers' perceived quality value and price value will not directly affect customer engagement behavior but instead indirectly affect it through brand trust. Furthermore, improving the perceived value of emotion, quality and price can strengthen brand trust in organic grocerants. The study confirms that brand trust is critical to organic grocerant and customer engagement. Our findings provide a new perspective for understanding the relationship between the value customers receive from organic food consumption and value co-creation through customer engagement behavior.

Immunotherapy-based novel nanoparticles in the treatment of gastrointestinal cancer: Trends and challenges.

Gastrointestinal cancer (GIC) is the most common cancer with a poor prognosis. Currently, surgery is the main treatment for GIC. However, the high rate of postoperative recurrence leads to a low five-year survival rate. In recent years, immunotherapy has received much attention. As the only immunotherapy drugs approved by the Food and Drug Administration (FDA), immune checkpoint blockade (ICB) drugs have great potential in cancer therapy. Nevertheless, the efficacy of ICB treatment is greatly limited by the low immunogenicity and immunosuppressive microenvironment of GIC. Therefore, the targets of immunotherapy have expanded from ICB to increasing tumor immunogenicity, increasing the recruitment and maturation of immune cells and reducing the proportion of inhibitory immune cells, such as M2-like macrophages, regulatory T cells and myeloid-derived suppressor cells. Moreover, with the development of nanotechnology, a variety of nanoparticles have been approved by the FDA for clinical therapy, so novel nanodrug delivery systems have become a research focus for anticancer therapy. In this review, we summarize recent advances in the application of immunotherapy-based nanoparticles in GICs, such as gastric cancer, hepatocellular carcinoma, colorectal cancer and pancreatic cancer, and described the existing challenges and future trends.

Development of a risk prediction nomogram for sarcopenia in hemodialysis patients.

BACKGROUND: Sarcopenia is associated with various adverse outcomes in hemodialysis patients. However, current tools for assessing and diagnosing sarcopenia have limited applicability. In this study, we aimed to develop a simple and reliable nomogram to predict the risk of sarcopenia in hemodialysis patients that could assist physicians identify high-risk patients early. METHODS: A total of 615 patients undergoing hemodialysis at the First Affiliated Hospital College of Medicine Zhejiang University between March to June 2021 were included. They were randomly divided into either the development cohort (n = 369) or the validation cohort (n = 246). Multivariable logistic regression analysis was used to screen statistically significant variables for constructing the risk prediction nomogram for Sarcopenia. The line plots were drawn to evaluate the effectiveness of the nomogram in three aspects, namely differentiation, calibration, and clinical net benefit, and were further validated by the Bootstrap method. RESULTS: The study finally included five clinical factors to construct the nomogram, including age, C-reactive protein, serum phosphorus, body mass index, and mid-upper arm muscle circumference, and constructed a nomogram. The area under the ROC curve of the line chart model was 0.869, with a sensitivity and specificity of 77% sensitivity and 83%, the Youden index was 0.60, and the internal verification C-statistic was 0.783. CONCLUSIONS: This study developed and validated a nomogram model to predict the risk of sarcopenia in hemodialysis patients, which can be used for early identification and timely intervention in high-risk groups.

Increase consumers' willingness to pay a premium for organic food in restaurants: Explore the role of comparative advertising.

Offering organic food is a new trend in the hospitality industry seeking sustainable competitiveness. Premiums and information barriers impede continued growth in organic consumption. This study aims to explore the role of comparative advertising (CA) in organic food communication. Three empirical studies were used to verify the effect of CA vs. non-comparative advertising (NCA) on consumers' willingness to pay a premium (WTPP) for organic food, examining how benefit appeals (health vs. environmental) and consumers' organic skepticism affects CA. The results indicate that matching CA and health appeals increase consumers' WTPP, while environmental appeals have no significant differences between the CA and NCA groups (Study 1). Information persuasiveness mediates the interaction between CA and benefit appeal on WTPP (Study 2). CA increases WTPP among consumers with high organic skepticism, while the interaction between CA and health appeal is only effective for low skepticism consumers (Study 3). The findings unravel and explain the mechanics of how CA works in organic products, which can help restaurants, retailers and tourist destinations advertise organic food to increase consumers' WTPP.

The APP intracellular domain promotes LRRK2 expression to enable feed-forward neurodegenerative mechanisms in Parkinson's disease.

Gain-of-function mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are common in familial forms of Parkinson's disease (PD), which is characterized by progressive neurodegeneration that impairs motor and cognitive function. We previously demonstrated that LRRK2-mediated phosphorylation of ß-amyloid precursor protein (APP) triggers the production and nuclear translocation of the APP intracellular domain (AICD). Here, we connected LRRK2 to AICD in a feed-forward cycle that enhanced LRRK2-mediated neurotoxicity. In cooperation with the transcription factor FOXO3a, AICD promoted LRRK2 expression, thus increasing the abundance of LRRK2 that promotes AICD activation. APP deficiency in LRRK2G2019S mice suppressed LRRK2 expression, LRRK2-mediated mitochondrial dysfunction, α-synuclein accumulation, and tyrosine hydroxylase (TH) loss in the brain, phenotypes associated with toxicity and loss of dopaminergic neurons in PD. Conversely, AICD overexpression increased LRRK2 expression and LRRK2-mediated neurotoxicity in LRRK2G2019S mice. In LRRK2G2019S mice or cultured dopaminergic neurons from LRRK2G2019S patients, treatment with itanapraced reduced LRRK2 expression and was neuroprotective. Itanapraced showed similar effects in a neurotoxin-induced PD mouse model, suggesting that inhibiting the AICD may also have therapeutic benefits in idiopathic PD. Our findings reveal a therapeutically targetable, feed-forward mechanism through which AICD promotes LRRK2-mediated neurotoxicity in PD.

What Forms, Maintains, and Changes the Boldness of Swimming Crabs (Portunus trituberculatus)?

Boldness of personality is an important theme in animal behavior and has significant ecological and evolutionary consequences. Studies on boldness in crustaceans typically focus on their behavior, while relatively few studies have focused on the formation and maintenance of and change in boldness, such as energy metabolism and neurotransmission. In this study, we measured the boldness of swimming crabs (Portunus trituberculatus) and analyzed the relationship between boldness and oxygen consumption rate, energy concentration, and the relative expression of energy-metabolism-related and 5-HT genes in mRNA. The results showed that boldness remained stable across repeated tests but changed under dangerous conditions. Swimming crabs could be divided into bold and shy individuals. Bold individuals consumed oxygen at a significantly higher rate than shy individuals. Lactate and glucose concentrations in hemolymph were significantly lower in bold individuals than in shy individuals, and mRNA relative expression of Na+/K+-ATPase and 5-HT genes was significantly higher in bold than in shy individuals. Preliminary results indicate that energy metabolism and neurotransmitters may underlie the formation and maintenance of personality characteristics of swimming crabs. Swimming crabs also exhibit behavioral flexibility in order to cope with risks. This may be an adaptation to their complex environments.

Application of lipid nanovesicle drug delivery system in cancer immunotherapy.

Immunotherapy has gradually emerged as the most promising anticancer therapy. In addition to conventional anti-PD-1/PD-L1 therapy, anti-CTLA-4 therapy, CAR-T therapy, etc., immunotherapy can also be induced by stimulating the maturation of immune cells or inhibiting negative immune cells, regulating the tumor immune microenvironment and cancer vaccines. Lipid nanovesicle drug delivery system includes liposomes, cell membrane vesicles, bacterial outer membrane vesicles, extracellular vesicles and hybrid vesicles. Lipid nanovesicles can be used as functional vesicles for cancer immunotherapy, and can also be used as drug carriers to deliver immunotherapy drugs to the tumor site for cancer immunotherapy. Here, we review recent advances in five kinds of lipid nanovesicles in cancer immunotherapy and assess the clinical application prospects of various lipid nanovesicles, hoping to provide valuable information for clinical translation in the future.

Mesenchymal Stem Cell-Secreted TGF-ß1 Restores Treg/Th17 Skewing Induced by Lipopolysaccharide and Hypoxia Challenge via miR-155 Suppression.

Background: Regulatory T cell (Treg)/T helper (Th) 17 skewing is important in the development of acute respiratory distress syndrome (ARDS). Immunomodulatory effects of mesenchymal stem cell- (MSC-) secreted transforming growth factor- (TGF-) ß1 on CD4+ T cells are environment-sensitive and lack discussion in hypoxic and inflammatory conditions. Methods: Mouse splenic CD4+ T cells were precoated with anti-CD3 (5 µg/ml) and anti-CD28 (2 µg/ml) overnight. RAW264.7 cells were added as antigen-presenting cells (APCs). T cells with and without RAW264.7 cells were treated with various LPS concentrations of 0, 10, 100, and 1000 ng/ml or/and at hypoxia condition of 5% O2. Based on LPS (100 ng/ml) and hypoxia conditions (5% O2) as stimuli, MSCs were set as direct coculture or indirect coculture by transwell system. Anti-TGF-ß1 neutralization antibody was added to explore the role of TGF-ß1 among the soluble factors secreted by MSCs; miR-155 overexpression of CD4+ T cells was performed by transfection, and then, cells were added to the MSC-CD4+ T cell coculture system in hypoxic- and LPS-stimulated condition. After 48 hours, cells or supernatants were collected for detection of frequency of Treg and Th17 subsets, CD4+ T cell apoptosis and proliferation capacity assay by flow cytometry, secretion of INF-γ, IL-17A, IL-21, TGF-ß1, and IL-10 by ELISA, and levels of miR-155, Rorc, Foxp3, and Ptpn2 mRNA expression of CD4+ T cells by RT-PCR. Results: MSCs could restore skewed Treg/Th17 induced by LPS and hypoxia compared to groups without MSCs with increased secretion of TGF-ß1, IL-10, and IL-17A (P < 0.05) and attenuate the increased expression of miR-155 in CD4+ T cells via cell-to-cell contact mechanism while TGF-ß1 neutralization significantly inhibited the effects of MSCs restoring skewed Treg/Th17 and abolished its effect on miR-155 expression in CD4+ T cells. Conclusions: These findings suggested miR-155 suppression of CD4+ T cells mediated MSC-secreted TGF-ß1 modulating skewed Treg/Th17 induced by LPS-hypoxia challenge, providing evidence when proposing future T lymphocyte-targeted cell therapy in a specific condition.