Zimu Zhang

Adiponectin-derived active peptide ADP355 exerts anti-inflammatory and anti-fibrotic activities in thioacetamide-induced liver injury.

Adiponectin is an adipocyte-derived circulating protein with beneficial effects on injured livers. Adiponectin-deficient (adipo(−/−)) mice develop enhanced liver fibrosis, suggesting that adiponectin could be a therapeutic target for liver injury. In the present study, we investigated the protective role of ADP355, an adiponectin-based active short peptide, in thioacetamide (TAA)-induced acute injury and chronic liver fibrosis in mice. ADP355 remarkably reduced TAA-induced necroinflammation and liver fibrosis. ADP355 treatment increased liver glycogen, decreased serum alanine transaminase and alkaline phosphatase activity, and promoted body weight gain, hyper-proliferation and hypo-apoptosis. In addition, ADP355 administration suppressed the TAA-induced activation of hepatic stellate cells and macrophages in the liver. These were associated with the inactivation of TGF-β1/SMAD2 signaling and the promotion of AMPK and STAT3 signaling. Sensitivity of adipo(−/−) mice to chronic liver injury was decreased with ADP355. In conclusion, ADP355 could mimic adiponectin’s action and may be suitable for the preclinical or clinical therapy of chronic liver injury.

CAR-T cell therapy in gastrointestinal tumors and hepatic carcinoma: From bench to bedside

ABSTRACT The chimeric antigen receptor (CAR) is a genetically engineered receptor that combines a scFv domain, which specifically recognizes the tumor-specific antigen, with T cell activation domains. CAR-T cell therapies have demonstrated tremendous efficacy against hematologic malignancies in many clinical trials. Recent studies have extended these efforts to the treatment of solid tumors. However, the outcomes of CAR-T cell therapy for solid tumors are not as remarkable as the outcomes have been for hematologic malignancies. A series of hurdles has arisen with respect to CAR-T cell-based immunotherapy, which needs to be overcome to target solid tumors. The major challenge for CAR-T cell therapy in solid tumors is the selection of the appropriate specific antigen to demarcate the tumor from normal tissue. In this review, we discuss the application of CAR-T cells to gastrointestinal and hepatic carcinomas in preclinical and clinical research. Furthermore, we analyze the usefulness of several specific markers in the study of gastrointestinal tumors and hepatic carcinoma.

Arctigenin Suppress Th17 Cells and Ameliorates Experimental Autoimmune Encephalomyelitis Through AMPK and PPAR-γ/ROR-γt Signaling

Arctigenin is a herb compound extract from Arctium lappa and is reported to exhibit pharmacological properties, including neuronal protection and antidiabetic, antitumor, and antioxidant properties. However, the effects of arctigenin on autoimmune inflammatory diseases of the CNS, multiple sclerosis (MS), and its animal model experimental autoimmune encephalomyelitis (EAE) are still unclear. In this study, we demonstrated that arctigenin-treated mice are resistant to EAE; the clinical scores of arctigenin-treated mice are significantly reduced. Histochemical assays of spinal cord sections also showed that arctigenin reduces inflammation and demyelination in mice with EAE. Furthermore, the Th1 and Th17 cells in peripheral immune organs are inhibited by arctigenin in vivo. In addition, the Th1 cytokine IFN-γ and transcription factor T-bet, as well as the Th17 cytokines IL-17A, IL-17F, and transcription factor ROR-γt are significantly suppressed upon arctigenin treatment in vitro and in vivo. Interestedly, Th17 cells are obviously inhibited in CNS of mice with EAE, while Th1 cells do not significantly change. Besides, arctigenin significantly restrains the differentiation of Th17 cells. We further demonstrate that arctigenin activates AMPK and inhibits phosphorylated p38, in addition, upregulates PPAR-γ, and finally suppresses ROR-γt. These findings suggest that arctigenin may have anti-inflammatory and immunosuppressive properties via inhibiting Th17 cells, indicating that it could be a potential therapeutic drug for multiple sclerosis or other autoimmune inflammatory diseases.

Chrysin suppresses human CD14 + monocyte-derived dendritic cells and ameliorates experimental autoimmune encephalomyelitis

Chrysin, a naturally flavonoid of plant, has various biological activities. However, the effects of chrysin on dendritic cells (DCs) and multiple sclerosis (MS) remain unknown. In this study, we demonstrate that chrysin inhibited human DC differentiation, maturation, function and the expression of the Th1 cells polarizing cytokines IFN-γ and IL-12p35 form DCs. In addition, chrysin ameliorated experimental autoimmune encephalomyelitis (EAE), an animal model of MS, by reducing CNS inflammation and demyelination. Furthermore, chrysin suppressed DCs and Th1 cells in the EAE mice. Taken together, chrysin exerts anti-inflammatory and immune suppressive effects, and suggests a possible therapeutic application of chrysin in MS.

Adiponectin suppresses T helper 17 cell differentiation and limits autoimmune CNS inflammation via the SIRT1/PPARγ/RORγt pathway

T helper 17 (Th17) cells are vital components of the adaptive immune system involved in the pathogenesis of most autoimmune and inflammatory syndromes, and adiponectin(ADN) is correlated with inflammatory diseases such as multiple sclerosis (MS) and type II diabetes. However, the regulatory effects of adiponectin on pathogenic Th17 cell and Th17-mediated autoimmune central nervous system (CNS) inflammation are not fully understood. In this study, we demonstrated that ADN could inhibit Th1 and Th17 but not Th2 cells differentiation in vitro. In the in vivo study, we demonstrated that ADN deficiency promoted CNS inflammation and demyelination and exacerbated experimental autoimmune encephalomyelitis (EAE), an animal model of human MS. Furthermore, ADN deficiency increased the Th1 and Th17 cell cytokines of both the peripheral immune system and CNS in mice suffering from EAE. It is worth mentioning that ADN deficiency predominantly promoted the antigen-specific Th17 cells response in autoimmune encephalomyelitis. In addition, in vitro and in vivo, ADN upregulated sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor γ (PPARγ) and inhibited retinoid-related orphan receptor-γt (RORγt); the key transcription factor during Th17 cell differentiation. These results systematically uncovered the role and mechanism of adiponectin on pathogenic Th17 cells and suggested that adiponectin could inhibit Th17 cell-mediated autoimmune CNS inflammation.

Adiponectin modulates oxidative stress-induced mitophagy and protects C2C12 myoblasts against apoptosis

Adiponectin (APN), also known as apM1, Acrp30, GBP28 and adipoQ, is a circulating hormone that is predominantly produced by adipose tissue. Many pharmacological studies have demonstrated that this protein possesses potent anti-diabetic, anti-atherogenic and anti-inflammatory properties. Although several studies have demonstrated the antioxidative activity of this protein, the regulatory mechanisms have not yet been defined in skeletal muscles. The aim of the present study was to examine the cytoprotective effects of APN against damage induced by oxidative stress in mouse-derived C2C12 myoblasts. APN attenuated H2O2-induced growth inhibition and exhibited scavenging activity against intracellular reactive oxygen species that were induced by H2O2. Furthermore, treating C2C12 cells with APN significantly induced heme oxygenase-1 (HO-1) and nuclear factor-erythroid 2 related factor 2 (Nrf2). APN also suppressed H2O2-induced mitophagy and partially inhibited the colocalization of mitochondria with autophagosomes/lysosomes, correlating with the expression of Pink1 and Parkin and mtDNA. Moreover, APN protected C2C12 myoblasts against oxidative stress-induced apoptosis. Furthermore, APN significantly reduced the mRNA and protein expression levels of Bax. These data suggest that APN has a moderate regulatory role in oxidative stress-induced mitophagy and suppresses apoptosis. These findings demonstrate the antioxidant potential of APN in oxidative stress-associated skeletal muscle diseases.

MicroRNA-181c promotes Th17 cell differentiation and mediates experimental autoimmune encephalomyelitis

Among T helper (Th) cell subsets differentiated from naive CD4+ T cells, IL-17-producing Th17 cells are closely associated with the pathogenesis of autoimmune diseases, including multiple sclerosis (MS) and the MS animal model, experimental autoimmune encephalomyelitis (EAE). The modulation of Th17 differentiation offers a potential avenue for treatment. Although a series of microRNAs (miRNAs) that modulate autoimmune disease development have been reported, further studies on miRNA roles in Th17 differentiation and MS pathogenesis are still warranted. Here, we demonstrated that mice with miR-181c knockdown presented with delayed EAE and slowed disease progression, along with a decreased Th17 cell population. We also found that miR-181c was a Th17 cell-associated miRNA and that Smad7, a negative regulator of TGF-β signaling, was a potential target of miR-181c. miR-181c knockdown rendered T cells less sensitive to TGF-β-induced Smad2/3, enhancing the expression of IL-2 which has been reported to inhibit Th17 cell differentiation. Moreover, through the analysis of published miRNA expression profiles from the Gene Expression Omnibus database, increased miR-181c levels were found in peripheral blood from MS patients. Our results identified a novel miRNA that promotes Th17 cell differentiation and autoimmunity, thus miR-181c may serve as a potential treatment target in patients with MS.

Impact of Immune Response on the Use of iPSCs in Disease Modeling

It has been demonstrated that mouse and human somatic cells can be reprogrammed into an embryonic stem cell-like state by introducing combinations of the transcription factors. The generation of such induced pluripotent stem cells (iPSCs) has enabled the derivation of disease-specific pluripotent cells which opens up new avenues of disease modeling and provides valuable experimental platforms. Moreover, technologies for creating humanized animal models by human iPSCs will be available as well, which will increase the utility of humanized mice for research. Emerging evidences suggest, however, that immunogenicity of iPSCs seems to be a vital and controversial issue surrounding potential of iPSCs. Recent studies on induced multipotent progenitor cells (iMPCs) extend the applications of iPSC technology and provide promising candidates for disease modeling. In this review, we introduce a wide range of applications of iPSCs in disease modeling and discuss the immune response on the use of iPSCs as well as a promising alternative for future directions of disease modeling.

Noncoding RNA-Targeted Therapeutics in Autoimmune Diseases: From Bench to Bedside

Abstract Noncoding RNAs (ncRNAs) act as epigenetic modifiers to strongly regulate gene expression. Increasing evidence support the hypothesis that aberrant expression of ncRNAs, mainly microRNAs (miRNAs) and long noncoding RNAs, may modify gene expression and trigger complicated immune disorders. Abnormal ncRNA expression has been shown to be associated with several autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis. The function of ncRNAs could be efficiently and specifically modified by inhibition or replacement strategies, thus revealing their potential as novel targets for disease therapeutics. The remarkable progress in chemical modifications and delivery strategies has led to a series of ncRNA-targeted therapeutics being used in clinical trials. The biological function and clinical significance of ncRNAs should be further elaborated to facilitate therapeutic development.

lincRNA-Cox2 regulates NLRP3 inflammasome and autophagy mediated neuroinflammation

Inflammasome activation plays key roles in host defense, but also contributes to the pathogenesis of auto-inflammatory, and neurodegenerative diseases. As autophagy is connected with both the innate and adaptive immune systems, autophagic dysfunction is also closely related to inflammation, infection, and neurodegeneration. Here we identify that lincRNA-Cox2, previously known as a mediator of both the activation and repression of immune genes expression in innate immune cells, could bind NF-κB p65 and promote its nuclear translocation and transcription, modulating the expression of inflammasome sensor NLRP3 and adaptor ASC. Knockdown of lincRNA-Cox2 inhibited the inflammasome activation and prevented the lincRNA-Cox2-triggered caspase-1 activation, leading to decreased IL-1β secretion and weakened TIR-domain-containing adapter-inducing interferon-β (TRIF) cleavage, thereby enhancing TRIF-mediated autophagy. Elucidation of the link between lincRNA-Cox2 and the inflammasome-autophagy crosstalk in macrophage and microglia reveals a role for lncRNAs in activation of NLRP3 inflammasome and autophagy, and provides new opportunities for therapeutic intervention in neuroinflammation-dependent diseases.