Synthesis of Polycyclic Imidazolidinones via Cascade [3 + 2]-Annulation of ß-Oxo-acrylamides with Cyclic N-Sulfonyl Imines.

An Et3N-catalyzed cascade [3 + 2]-annulation of ß-oxo-acrylamides with cyclic N-sulfonyl ketimines or sulfamate-derived imines is developed under mild reaction conditions, which provides a concise and efficient route to access valuable sultam- or sulfamidate-fused imidazolidinone derivatives in good to excellent yields (80-95% yields) with excellent diastereoselectivities (>20:1 drs). The current protocol features atom economy, a transition-metal-free process, and broad functional group tolerance. Moreover, the asymmetric variant of the [3 + 2]-cycloaddition reaction was achieved in the presence of diphenylethanediamine or quinine-based bifunctional squaramide organocatalysts C-1 and C-11, giving the corresponding chiral polycyclic imidazolidinones in 68-90% yields with 25-94% ees and >20:1 drs in all cases.

Ferumoxytol-ß-glucan Inhibits Melanoma Growth via Interacting with Dectin-1 to Polarize Macrophages into M1 Phenotype.

Background: Regulating the polarization of macrophages to antitumor M1 macrophages is a promising strategy for overcoming the immunosuppression of the tumor microenvironment for cancer therapy. Ferumoxytol (FMT) can not only serve as a drug deliver agent but also exerts anti-tumor activity. ß-glucan has immuno-modulating properties to prevent tumor growth. Thus, a nanocomposite of FMT surface-coated with ß-glucan (FMT-ß-glucan) was prepared to explore its effect on tumor suppression. Methods: Male B16F10 melanoma mouse model was established to explore the antitumor effect of FMT-ß-glucan. The viability and apoptotic rates of B16F10 cells were detected by cell counting kit-8 and Annexin-V/PI experiments. The levels of M1 markers were quantified by quantitative reverse transcription-polymerase chain reaction and enzyme linked immunosorbent assay. Phagocytic activity and intracellular reactive oxygen species (ROS) in macrophages were evaluated by the neutral red uptake assay and flow cytometry, respectively. Small interfering RNA (siRNA) transfection was applied to knock down the Dectin-1 gene in RAW 264.7 cells. Results: FMT-ß-glucan suppressed tumor growth to a greater extent and induced higher infiltration of M1 macrophages than the combination of FMT and ß-glucan (FMT+ß-glucan) in vivo. In vitro, supernatant from FMT-ß-glucan-treated RAW 264.7 cells led to lower cell viability and induced more apoptosis of B16F10 cells than that from the FMT+ß-glucan group. Moreover, FMT-ß-glucan boosted the expression of M1 type markers, and increased phagocytic activity and ROS in RAW 264.7 cells. Further research indicated that FMT-ß-glucan treatment promoted the level of Dectin-1 on the surface of RAW 264.7 cells and that knockdown of Dectin-1 abrogated the phosphorylation levels of several components in MAPK and NF-κB signaling. Conclusion: The nanocomposite FMT-ß-glucan suppressed melanoma growth by inducing the M1 macrophage-activated tumor microenvironment.

Rs1520220 and Rs2195239 Polymorphisms of IGF-1 Gene Associated with Histopathological Grades in IgA Nephropathy in Northwestern Chinese Han Population.

BACKGROUND/AIMS: Insulin-like growth factor-1 (IGF-1) plays important roles in cellular proliferation, differentiation, and growth. Previous studies showed that single-nucleotide polymorphisms (SNPs) of IGF-1 are associated with various diseases. This case-control study aimed to examine the relationship between IGF-1 polymorphisms and IgA nephropathy (IgAN) risk in a Chinese Han population. METHODS: We recruited 351 IgAN patients and 310 healthy controls from Northwestern China. Sequenom MassARRAY was utilized to examine the genotypes of two common IGF-1 SNPs (rs1520220 and rs2195239). Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated by the Chi square test to evaluate the associations between IGF-1 and IgAN. RESULTS: Our study demonstrated that IGF-1 gene rs1520220 and rs2195239 polymorphisms did not confer susceptibility to IgAN. We found no correlation between gender, blood pressure, proteinuria, eGFR, and IgAN in both SNPs. However, the rs1520220 and rs2195239 variants were correlated with M1 and E1 in patients with IgAN (M0/M1: CC vs. CG+GG: OR = 1.62, P = 0.04; E0/E1: CC vs. CG+GG: OR = 1.95, P = 0.004; GG vs. GC+CC: OR = 1.90, P = 0.004, respectively). CONCLUSION: These results indicate that IGF-1 gene polymorphisms play crucial roles in the histopathological progression of IgAN in the Chinese Han population.

The Endothelial Nitric Oxide Synthase Gene Polymorphism is Associated with the Susceptibility to Immunoglobulin a Nephropathy in Chinese Population.

BACKGROUND/AIMS: Endothelial nitric oxide synthase (eNOS) is one of the most important enzymes for producting nitric oxide (NO), which regulate the function of many organs and cells. The single nucleotide polymorphisms (SNPs) of eNOS were found to be associated with many kidney diseases. However, it is lack of relevant studies to evaluate the associations between eNOS polymorphisms and immunoglobulin A nephropathy (IgAN). This case-control study aimed to evaluate the relationship between eNOS polymorphisms and IgAN. METHODS: We recruited 351 IgAN patients and 310 age- and sex-matched healthy controls from Northwest China. Sequenom MassARRAY was used to detect the genotypes of two common eNOS SNPs (rs1799983 and rs2070744). Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated by the Chi square test to evaluate the associations between eNOS and IgAN. Phase 2.1 was used to conduct haplotype analysis. RESULTS: In the overall analysis, we found that the rs1799983 polymorphism was associated with a decreased risk of IgAN (G/T vs. G/G: OR=0.57, 95%CI=0.34-0.96; G/T+T/T vs. G/G: OR=0.52, 95%CI=0.31-0.86; G/T vs. G/G-T/T: OR=0.60, 95%CI=0.36-0.99; Log-additive model: OR=0.48, 95%CI=0.30-0.78). Haplotype analysis indicated that Trs1799983Crs2070744 is a protective factor against IgAN (OR=0.62, 95%CI=0.42--0.92). However, no significant differences were found between the two SNPs (rs1799983 and rs2070744) and clinical features (age, sex, blood pressure, and Lee's grade) of IgAN. CONCLUSION: The eNOS gene rs1799983 polymorphism and Trs1799983Crs2070744 haplotype may reduce the risk of IgAN in Chinese populations.

Association of Interleukin-10 Polymorphisms (rs1800872, rs1800871, and rs1800896) with Predisposition to IgA Nephropathy in a Chinese Han Population: A Case-Control Study.

BACKGROUND/AIMS: IgA nephropathy (IgAN) is a common form of primary glomerulonephritis worldwide. Previous studies indicated that IL-10 single nucleotide polymorphisms (SNP) play an important role in IgAN pathogenesis, but the results were controversy. This study aimed to investigate the association between IL-10 SNPs (rs1800872, rs1800871, and rs1800896) with IgAN in a Chinese Han population. METHODS: We conducted a case-control study that included 351 patients with IgAN and 310 age-, gender- and ethnicity-matched healthy controls. Three promoter SNPs (rs1800872, rs1800871, and rs1800896) of IL-10 were genotyped by Sequenom MassARRAY. Odds ratios (ORs) with 95% confidence intervals (CI) were used to assess the relationship with IgAN. RESULTS: We found that the rs1800896 did not correlate with IgAN risk, whereas rs1800872 and rs1800871 were significantly associated with increased IgAN risk in all genetic models. The haplotype analysis indicated that the CCA haplotype was associated with increased IgAN risk (OR = 1.36; 95% CI = 1.05-1.75). Moreover, there were no associations between these SNPs and blood pressure or gender, whereas the rs1800896 variant was correlated with higher 24-hour urine protein in patients with IgAN. CONCLUSION: Taken together, these results suggest that IL-10 is a susceptibility gene in patients with IgAN.

Association Between IFN-γ Gene Polymorphisms and IgA Nephropathy in a Chinese Han Population.

BACKGROUND/AIMS: IFN-γ was reported to be involved in the development and progression of Immunoglobulin A nephropathy (IgAN), however, few studies have investigated the association between IFN-γ polymorphisms and IgAN. Therefore, we performed a case-control study to assess the association between IFN-γ polymorphisms and the risk of IgAN. METHODS: Sequenom MassARRAY was used to genotype two SNPs (rs1861494 and rs2430561) in 351 patients with IgAN and 310 healthy controls. Associations were evaluated as odd ratios (OR) with 95% confidence intervals (CI). RESULTS: No association was found between IFN-γ rs1861494 and IgAN risk or clinical parameters. For rs2430561, the AA genotype was more common in patients with IgAN, compared with controls (AT vs. AA: OR = 0.57, P = 0.035). IFN-γ-rs2430561 T allele may be a protective factor for IgAN susceptibility (T vs. A: OR = 0.59, P = 0.04). Subgroup analysis based on clinical features revealed no significant association between rs2430561 polymorphism and clinical data such as gender, 24-h urine protein, blood pressure, Oxford classifcation and estimated glomerular fltration rate. IgAN patients had a higher IFN-γ serum level than healthy controls and patients with rs1861494 AA genotype had a higher IFN-γ serum level compared with those with AG/GG genotypes. CONCLUSIONS: IFN-γ polymorphisms may be involved in the development and progression of IgAN.

Lack of association between cytotoxic T-lymphocyte antigen-4 gene polymorphisms and lymphoid malignancy risk: evidence from a meta-analysis.

Cytotoxic T-lymphocyte antigen-4 (CTLA-4) polymorphisms have been associated with susceptibility to lymphoid malignancies. However, results from the published single studies are inconsistent. Therefore, the present meta-analysis was conducted to get a more accurate estimation of the relationship between CTLA-4 gene polymorphisms and the lymphoid malignancy risk. We identified nine independent studies accounting for 3090 subjects up to January 30, 2016. Summary odds ratios (OR) and 95 % confidence intervals (CI) were used to evaluate the risk of lymphoid malignancies. Overall, no significant association was found between +49A/G (rs231775), -318C/T (rs5742909), and +6230A/G (rs3087243) CTLA-4 gene polymorphisms and lymphoid malignancies. Furthermore, ethnicity (Asian and Caucasian) and histopathology subgroup analyses (non-Hodgkin's lymphoma) also failed to detect an association between the studied polymorphisms and lymphoid malignancy risk. Our study shows that common CTLA-4 gene polymorphisms may not contribute to lymphoid malignancy susceptibility based on the current evidence.

Polyaniline Induced Trivalent Ni in Laser-Fabricated Nickel Oxides for Efficient Oxygen Evolution Reaction.

Although it is generally acknowledged that transition metals at high oxidation states represent superior oxygen evolution reaction (OER) activity, the preparation and stability of such a high-valence state are still a challenge, which requires relatively harsh reaction conditions and is unstable under ambient conditions. Herein, we report the formation of trivalent nickel (Ni3+) in laser-fabricated nickel oxides induced by polyaniline (PANI) under electrochemical activation via a significant charge transfer between Ni and N, as confirmed by X-ray photoelectron spectroscopy and density functional theory calculations. Thereafter, the presence of Ni3+ and the improved conductivity by PANI effectively increase the electrochemical OER activity of the samples together with excellent long-term stability. This work provides new insights for the rational manufacture of high-valence metal for electrochemical reactions.

DesTrans: A medical image fusion method based on Transformer and improved DenseNet.

Medical image fusion can provide doctors with more detailed data and thus improve the accuracy of disease diagnosis. In recent years, deep learning has been widely used in the field of medical image fusion. The traditional method of medical image fusion is to operate by superimposing and other methods of pixels. The introduction of deep learning methods has improved the effectiveness of medical image fusion. However, these methods still have problems such as edge blurring and information redundancy. In this paper, we propose a deep learning network model based on Transformer and an improved DenseNet network module integration that can be applied to medical images and solve the above problems. At the same time, the method can be moved to natural images. The use of Transformer and dense concatenation enhances the feature extraction capability of the method by limiting the feature loss which reduces the risk of edge blurring. We compared several representative traditional methods and more advanced deep learning methods with this method. The experimental results show that the Transformer and the improved DenseNet network module have a strong capability of feature extraction. The method yields good results both in terms of visual quality and objective image evaluation metrics.

The efficacy of combination therapy using adeno-associated virus-mediated co-expression of apoptin and interleukin-24 on hepatocellular carcinoma.

Multigene-based combination therapy is an effective practice in cancer gene therapy. Apoptin is a chicken anemia virus-derived, p53-independent, Bcl-2-insensitive apoptotic protein with the ability to specifically induce apoptosis in various human tumor cells. Interleukin-24 (IL-24) displays ubiquitous antitumor property and tumor-specific killing activity. Adeno-associated virus (AAV) is a promising gene delivery vehicle due to its advantage of low pathogenicity and long-term gene expression. In this study, we assessed the efficacy of combination therapy using AAV-mediated co-expression of apoptin and interleukin-24 on hepatocellular carcinoma in vitro and in vivo. Our results showed that AAV-mediated co-expression of IL-24 and apoptin significantly suppressed the growth and induced the apoptosis of HepG2 cells in vitro. Furthermore, AAV-mediated combined treatment of IL-24 and apoptin significantly suppressed tumor growth and induced apoptosis of tumor cells in xenograft nude mice. These data suggest that AAV vectors that co-express apoptin and IL-24 have great potential in cancer gene therapy.

Apoptin selectively induces the apoptosis of tumor cells by suppressing the transcription of HSP70.

Apoptin is a nonstructural viral protein encoded by VP3 gene of chicken anemia virus, which could specially induce apoptosis of tumor cells. However, the mechanism of apoptin-induced apoptosis in tumor cells without any side effects in normal cells has not yet been well characterized. This study aimed to investigate the molecular mechanism underlying the selective antitumor effects of apoptin. HepG2 cells were treated with apoptin or transfected with apoptin expression vector. Heat shock protein 70 (HSP70) expression was examined by Western blot. The binding of apoptin to HSP70 promoter was detected by electrophoretic mobility shift assay, chromatin immunoprecipitation, and luciferase assay. The results showed that apoptin inhibited HSP70 expression in HepG2 cells and apoptin-induced apoptosis of HepG2 cells was dependent on the expression level of HSP70. Furthermore, apoptin promoted HSF1 trimer depolymerization and inhibited HSF1-mediated HSP70 transcription. In addition, apoptin competed with HSF1 to bind heat shock element in HSP70 promoter, leading to reduced HSP70 transcription. Both these mechanisms contribute to the suppression of HSP70 transcription and expression. Our findings provide the first evidence that apoptin induces tumor cell apoptosis by specifically downregulating the expression of HSP70, which helps explain the specific antitumor effects of apoptin.

Inflammation and cancer: paradoxical roles in tumorigenesis and implications in immunotherapies.

Chronic inflammation caused by persistent infections and metabolic disorders is thought to contribute to the increased cancer risk and the accelerated cancer progression. Oppositely, acute inflammation induced by bacteria-based vaccines or that is occurring after cancer selectively inhibits cancer progression and metastasis. However, the interaction between inflammation and cancer may be more complex than the current explanations for the relationship between chronic and acute inflammation and cancer. In this review, we described the impact of inflammation on cancer on the basis of three perspectives, including inflammation with different durations (chronic and acute inflammation), different scopes (systemic and local inflammation) and different occurrence sequences (inflammation occurring after and before cancer). In addition, we also introduced bacteria/virus-based cancer immunotherapies. We perceive that inflammation may be a double-edged sword with cancer-promoting and cancer-suppressing functions in certain cases. We expect to further improve the understanding of the relationship between inflammation and cancer and provide a theoretical basis for further research on their complex interaction.

Electronic Structure Modulation of Fe-N4-C for Oxygen Evolution Reaction via Transition Metal Dopants and Axial Ligands.

The popular single-atom catalyst (SAC) Fe-N4 is generally believed to be an excellent oxygen reduction reaction (ORR) electrocatalyst, which is less active in the oxygen evolution reaction (OER). Herein, FeM-N6 configuration catalysts (M = Fe, Co, Ni, Cu, Ag, and Au) were constructed for the oxygen evolution reaction by embedding M dopants on Fe-N4 systems based on the density functional theory. The electronic structure analysis reveals that the Fe-M metal interactions play dominant roles in regulating the d orbital distributions of Fe sites, which in turn alter the catalytic OER performance. Subsequent thermodynamic results indicate that the potential-determining step (PDS) for all catalysts is the formation of OOH*, which exhibits a tendency of decreased overpotentials with enhanced metal interactions. Apart from these, the effects of axial ligands on the OER activity of the catalysts in practical conditions were considered. Generally, most of the axial ligands are found to be thermodynamically favorable for the OER process. Interestingly, a competitive relationship of the electrons from the d orbital of Fe sites was found between the axial ligand and the adsorbed intermediate species during the reaction, which raises the energy barrier for OH* to O* conversion and can even alter the PDS in certain cases. The present work sheds new light on the design of future high-performance OER catalysts.

Inhibitors of reactive oxygen species accumulation delay and/or reduce the lethality of several antistaphylococcal agents.

Perturbation of hydroxyl radical accumulation by subinhibitory concentrations of 2,2'-bipyridyl plus thiourea protects Escherichia coli from being killed by 3 lethal antimicrobial classes. Here, we show that 2,2'-bipyridyl plus thiourea delays and/or reduces antimicrobial killing of Staphylococcus aureus by daptomycin, moxifloxacin, and oxacillin. While the protective effect of 2,2'-bipyridyl plus thiourea varied among strains and compounds, the data support the hypothesis that hydroxyl radical enhances antimicrobial lethality.

Local and systemic inflammation triggers different outcomes of tumor growth related to infiltration of anti-tumor or pro-tumor macrophages.

BACKGROUND: Previous evidence suggests inflammation may be a double-edged sword with cancer-promoting and cancer suppressing function. In this study, we explore the impact of local and systemic inflammation on cancer growth. METHODS: Female BALB/C mice were subcutaneously implanted with foreign body (plastic plates) to build up a local inflammation and intraperitoneally injected with PolyIC or lipopolysaccharides (LPS) to build up a systemic inflammation, followed by subcutaneous injection of 5  × 10 5 colon cancer cells. Immunohistochemistry and enzyme linked immunosorbent assay were utilized to detect the Ki67 and interleukin (IL) 6, IL-1ß, and monocyte chemoattractant protein-1 expression in the tumor tissues and serum, respectively. The distributions of immune cells and expression of toll-like receptors (TLRs) were evaluated by flow cytometry (FCM) and quantitative real time-polymerase chain reaction. RESULTS: The results showed that local inflammation induced by foreign body implantation suppressed tumor growth with decreased tumor weight ( P   =  0.001), volume ( P   =  0.004) and Ki67 index ( P   <  0.001). Compared with the control group, myeloid-derived suppressive cells sharply decreased ( P   =  0.040), while CD4 + T cells slightly increased in the tumor tissues of the group of foreign body-induced local inflammation ( P   =  0.035). Moreover, the number of M1 macrophages ( P   =  0.040) and expression of TLRs, especially TLR3 ( P  < 0.001) and TLR4 ( P  < 0.001), were significantly up-regulated in the foreign body group. Contrarily, tumor growth was significantly promoted in LPS or PolyIC-induced systemic inflammation ( P   =  0.009 and 0.006). FCM results showed M1 type macrophages ( P   =  0.017 and 0.006) and CD8 + T cells ( P   =  0.031 and 0.023) were decreased, while M2 type macrophages ( P  = 0.002 and 0.007) were significantly increased in tumor microenvironment of LPS or PolyIC-induced systemic inflammation group. In addition, the decreased expression of TLRs was detected in LPS or PolyIC group. CONCLUSIONS: The foreign body-induced local inflammation inhibited tumor growth, while LPS or PolyIC- induced systemic inflammation promoted tumor growth. The results suggested that the different outcomes of tumor growth might be attributed to the infiltration of anti-tumor or pro-tumor immune cells, especially M1 or M2 type macrophages into tumor microenvironment.

LS-007 inhibits melanoma growth via inducing apoptosis and cell cycle arrest and regulating macrophage polarization.

LS-007, an inhibitor of cyclin-dependent kinase 9 (CDK9), exhibits potential antitumor activity against chronic lymphocytic leukemia and ovarian cancer, but its effect on melanoma and tumor microenvironment (TME) has not been reported yet. This study aimed to investigate the role of LS-007 in B16F10 melanoma and relevant mechanisms. LS-007 significantly inhibited viability and induced apoptosis of B16F10 cells in a dose-dependent manner, which were accompanied with the increased ratio of Bax to Bcl-2 and decreased Mcl-1 mRNA level. Western blot analysis showed that LS-007 increased the expression of cleaved caspase-3 and poly ADP-ribose polymerase (PARP). Furthermore, flow cytometry analysis and qRT-PCR results showed that LS-007 treatment resulted in cell cycle arrest by changing cell cycle-related gene expression. Notably, in vivo evaluation showed that LS-007 significantly decreased the weight and volume of tumor and the expression of Ki67, promoted the expression of iNOS and inhibited the expression of CD206, suggesting that LS-007 might inhibit tumor growth by suppressing polarization of macrophages into tumor-associated macrophages (TAMs) in the TME. The increase in M1/M2 treated with LS-007 detected by flow cytometry hinted that macrophages were polarized towards an antitumor phenotype. In addition, LS-007 induced higher apoptotic rate of B16F10 cells when co-cultured B16F10 with BMDMs. LS-007 has inhibitory effects on B16F10 cells in vivo and in vitro via inducing apoptosis, cell cycle arrest, and changing macrophage function in the TME.

Cancer-associated fibroblasts promote tumor progression by lncRNA-mediated RUNX2/GDF10 signaling in oral squamous cell carcinoma.

Cancer-associated fibroblasts (CAF) are the most abundant stromal cells in tumor and exert a pro-tumoral effect in cancer progression. Numerous evidence shows long non-coding RNA (lncRNA) abnormally regulates gene expression in various cancers. However, little is known about the role of lncRNA in the interaction between CAF and cancer cells. Here, we first identify an uncharacterized lncRNA, LOC100506114, which is significantly upregulated in CAF and is involved in the functional transformation of normal fibroblasts (NF) and CAF. Expression of LOC100506114 enhances the expression of fibroblast activation protein alpha and α-smooth muscle actin in NF and promotes malignant characteristics of NF and CAF in vivo and in vitro. The profile of gene co-expression analysis shows that growth differentiation factor 10 (GDF10) is positively correlated with the expression of LOC100506114. CAF promote stromal fibroblast activation and the proliferation and migration of tumor cells by secreting GDF10. Our data demonstrate that lncRNA plays a critical role in the interplay of stromal fibroblasts and tumor cells in oral squamous cell carcinoma.

Chitosan-Poly(Acrylic Acid) Nanoparticles Loaded with R848 and MnCl2 Inhibit Melanoma via Regulating Macrophage Polarization and Dendritic Cell Maturation.

PURPOSE: Since immune cells in the tumor microenvironment (TME) can affect the development and progression of tumors, strategies modulating immune cells are considered to have an important therapeutic effect. As a TLR7/8 agonist, R848 effectively activates the innate immune cells to exert an anti-tumor effect. Mn2+ has been reported to strongly promote the maturation of antigen-presenting cells (APCs), thereby enhancing the cytotoxicity of CD8+ T cells. Thus, we tried to investigate whether chitosan-poly(acrylic acid) nanoparticles (CS-PAA NPs) loaded with R848 and MnCl2 (R-M@CS-PAA NPs) could exert an anti-tumor effect by regulating the function of immune cells. METHODS: R-M@CS-PAA NPs were prepared, and their basic characteristics, anti-tumor effect, and potential mechanisms were explored both in vitro and in vivo. RESULTS: R-M@CS-PAA NPs easily released MnCl2 and R848 at low pH. In B16F10 mouse melanoma model, R-M@CS-PAA NPs exerted the most significant anti-melanoma effect compared with the control group and CS-PAA NPs loaded with R848 or MnCl2 alone. FITC-labeled R-M@CS-PAA NPs were displayed to be accumulated at the tumor site. R-M@CS-PAA NPs significantly increased the infiltration of M1 macrophages and CD8+ T cells but reduced the number of suppressive immune cells in the TME. Moreover, in vitro experiments showed that R-M@CS-PAA NPs polarized macrophages into the M1 phenotype to inhibit the proliferation of B16F10 cells. R-M@CS-PAA NPs also enhanced the killing function of CD8+ T cells to B16F10 cells. Of note, R-M@CS-PAA NPs not only promoted the maturation of APCs such as dendritic cells and macrophages by STING and NF-кB pathways, but also enhanced the ability of dendritic cells to present ovalbumin to OT-I CD8+ T cells to enhance the cytotoxicity of OT-I CD8+ T cells to ovalbumin-expressing B16F10 cells. CONCLUSION: These data indicate that the administration of R-M@CS-PAA NPs is an effective therapeutic strategy against melanoma.

SPION-MSCs enhance therapeutic efficacy in sepsis by regulating MSC-expressed TRAF1-dependent macrophage polarization.

BACKGROUND: Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. The liver has a crucial role in sepsis and is also a target for sepsis-related injury. Macrophage polarization between the M1 and M2 types is involved in the progression and resolution of both inflammation and liver injury. Iron oxide-based synthetic nanoparticles (SPIONs) can be used as antibacterial agents to regulate the inflammatory response. Mesenchymal stromal/stem cells (MSCs) have been widely used in the treatment of autoimmune diseases, sepsis, and other diseases. However, to date, both the effects of SPIONs on MSCs and the fate of SPION-labelled MSCs in sepsis and other diseases are still unclear. METHODS: Mice were subjected to caecal ligation and puncture (CLP) or lipopolysaccharide (LPS) induction to develop sepsis models. The CLP or LPS models were treated with MSCs or SPION-labelled/pretreated MSCs (SPION-MSCs). Bone marrow (BM)-derived macrophages and RAW 264.7 cells were cocultured with MSCs or SPION-MSCs under different conditions. Flow cytometry, transmission electron microscopy, western blotting, quantitative real-time PCR, and immunohistochemical analysis were performed. RESULTS: We found that SPIONs did not affect the basic characteristics of MSCs. SPIONs promoted the survival of MSCs by upregulating HO-1 expression under inflammatory conditions. SPION-MSCs enhanced the therapeutic efficacy of liver injury in both the CLP- and LPS-induced mouse models of sepsis. Moreover, the protective effect of SPION-MSCs against sepsis-induced liver injury was related to macrophages. Systemic depletion of macrophages reduced the efficacy of SPION-MSC therapy. Furthermore, SPION-MSCs promoted macrophages to polarize towards the M2 phenotype under sepsis-induced liver injury in mice. The enhanced polarization towards M2 macrophages was attributed to their phagocytosis of SPION-MSCs. SPION-MSC-expressed TRAF1 was critical for promotion of macrophage polarization and alleviation of sepsis in mice. CONCLUSION: MSCs labelled/pretreated with SPIONs may be a novel therapeutic strategy to prevent or treat sepsis and sepsis-induced liver injury. HIGHLIGHTS: 1. SPIONs enhance the viability of MSCs by promoting HO-1 expression. 2. SPION-labelled/pretreated MSCs effectively improve sepsis by regulating macrophage polarization to M2 macrophages. 3. SPION-labelled/pretreated MSCs regulate macrophage polarization in a manner dependent on MSC-expressed TRAF1 protein.

mTOR inhibitor INK128 promotes wound healing by regulating MDSCs.

BACKGROUND: Skin wounds in diabetic patients hardly recover. Accumulating evidence has shown that mammalian target of rapamycin (mTOR) pathway and myeloid-derived suppressor cells (MDSCs) are involved in inflammatory-related response. INK128 is a novel mTOR kinase inhibitor in clinical development. However, the exact roles of MDSCs and INK128 in healing wound of diabetic patients are unclear. METHODS: Mice models of normal, diabetic, and diabetic+INK128 were constructed. Bone marrow (BM)-derived macrophages and RAW264.7 cell line co-cultured with MDSCs, which were induced at different conditions. Flow cytometry, western blot, quantitative real-time PCR, and immunohistochemical analysis were performed. RESULTS: Diabetic mice (DM) had a slower recovery rate, thinner epidermis and dermis, and less blood vessels than those of normal mice. MDSCs were abnormally accumulated in DM, mTOR was activated in MDSCs of DM, and the cells were treated with high glucose. Moreover, mTOR signaling inhibitor INK128 could promote wound healing through reducing the MDSCs. MDSC function was disordered in DM and high-glucose environments, while INK128 could help retrieve their function. Furthermore, high glucose and other factors in DM could promote M-MDSC differentiation to M1 pro-inflammatory macrophage cells, thus inhibiting wound healing. The differentiation, which was dependent on mTOR signaling, could be reversed by INK128. CONCLUSION: INK128 is potential to be developed as a clinical strategy to promote wound healing of diabetic patients.