Two Undescribed Germacrane-Type Sesquiterpenoids from Salvia cavaleriei var. simplicifolia Stib. and Their Anti-Alzheimer's Disease Activity.

Two undescribed germacrane-type sesquiterpenoids, salcasins A (1) and B (2), together with three known compounds (3-5) were isolated and identified from the whole plant of Salvia cavaleriei var. simplicifolia Stib. The structures of the undescribed compounds were elucidated on the basis of spectroscopic methods, such as HR-ESI-MS, 1D and 2D NMR data. The relative configurations of 1 and 2 were established by analyzing their NOESY spectra as well as by 13C NMR calculations with DP4+ probability analyses. The absolute configurations of 1 and 2 were determined by comparing experimental and calculated ECD spectra. Furthermore, the in vivo anti-Alzheimer's disease activities of 1-5 were evaluated using Caenorhabditis elegans AD pathological model. Among all isolated compounds, salcasin A (1) significantly delayed AD-like symptoms of worm paralysis, which may be a potential anti-AD candidate agent.

Antimicrobial diterpenoids from the leaves and twigs of Croton kongensis Gagnepain.

Croton kongensis Gagnepain. belongs to the genus Croton, the Euphorbiaceae family, mainly distributed in Hainan and southern Yunnan, China. The aim of present study was to acquire secondary metabolites of the ethanol extract obtained from the leaves and twigs of C. kongensis. Three new abietane-type diterpenoids, crokongenolides A-C (1-3), together with seven known diterpenoids (4-10), were isolated from the leaves and twigs of C. kongensis. The structures of the new compounds were determined by extensive spectroscopic methods (1D and 2D NMR, IR, and HRESIMS), and their absolute configurations were confirmed by single-crystal X-ray diffraction analysis or electronic circular dichroism (ECD) calculations. The absolute configuration of 4 was determined for the first time by single-crystal X-ray diffraction analysis with Cu-Kα irradiation. Some compounds were evaluated for their antimicrobial properties by assessing their inhibitory effects on Staphylococcus aureus, Candida albicans, and Escherichia coli. Compound 10 showed significant antimicrobial activity against S. aureus with MIC value of 1.56 µg/ml.

An Enhanced Lemaitre Model and Fracture Map for Cr5 Alloy Steel during High-Temperature Forming Process.

To effectively control and predict crack defects in the high-temperature forming process of Cr5 alloy steel, based on the traditional Lemaitre damage model, a new high-temperature damage model of Cr5 alloy steel was proposed which considered the change of material elastic modulus with temperature, the influence of material hydrostatic pressure as well as temperature and strain rate on material damage. Because Cr5 alloy steels are usually forged at high temperatures, tensile testing is an important method to study the damage behaviour of materials. Through the high-temperature tensile test and elastic modulus measurement test of the Cr5 alloy steel, the stress-strain curves and the relationship curves of the elastic modulus value with the temperature of Cr5 alloy steel under different temperatures and strain rates were obtained. A new high-temperature damage model of Cr5 alloy steel was built by introducing the Zener-Hollomon coefficient considering the influence of temperature and strain rate. The established high-temperature damage model was embedded in Forge® finite element software through the program's secondary development method to numerically simulate the experimental process of Cr5 alloy steel. Comparing the difference between the displacement-load curves of the numerical simulation and the actual test of the tensile process of the experimental samples, the correlation coefficient R2 is 0.987 and the difference between the experimental value and the simulated value of the tensile sample elongation at break is 1.28%. The accuracy of the high-temperature damage model of Cr5 alloy steel established in this paper was verified. Finally, the high-temperature damage map of Cr5 alloy steel was constructed to analyse the variation law of various damage parameters with the temperature and strain rate of the high-temperature damage model of Cr5 alloy steel.

GLT25D2 Is Critical for Inflammatory Immune Response to Promote Acetaminophen-Induced Hepatotoxicity by Autophagy Pathway.

Acetaminophen (APAP) overdose induces hepatocyte necrosis and causes liver hepatotoxicity. Currently, the role of galactosyltransferase in APAP-induced liver injury is still unclear. This study assessed the contribution of the GLT25D2 gene, a kind of collagen galactosyltransferase, to the development of APAP-induced liver injury. This study found that the expression of GLT25D2 markedly increased first and then decreased in the liver of mice treated with APAP, however, it downregulated in the liver of APAP overdose-patients compared with normal controls. Knockout of GLT25D2 significantly ameliorated the liver injury, meanwhile, it downregulated the proinflammatory cytokines (IL-6, TNF-α) and chemokines (CXCL-10, MIG and CXCL-1) levels, however, and upregulated the anti-inflammatory cytokines (IL-22, IL-10) levels. Mechanistic explorations showed that (1) GLT25D2 knockout promoted autophagy pathway; and (2) the GLT25D2 knockout-induced autophagy selected to clear damaged mitochondria in APAP-induced liver injury by mitophagy; and (3) the autophagy intervention by Atg 7 siRNA cancelled liver protection by knockout of GLT25D2 through regulating liver inflammation. In conclusion, our study proves that the upregulated expression of GLT25D2 decreased autophagy contributing to APAP-induced hepatotoxicity by mediating the inflammatory immune regulatory mechanism.

Biosorption of sterols from tobacco waste extract using living and dead of newly isolated fungus Aspergillus fumigatus strain LSD-1.

Sterols are verified to be able to produce polycyclic aromatic hydrocarbons during its pyrolysis. In this study, a kind of Aspergillus fumigatus (LSD-1) was isolated from cigar leaves, and the biosorption effects on the stigmasterol, ß-sitosterol, campesterol, cholesterol, and ergosterol by using living and dead biomass of LSD-1 were investigated. The results showed that both living and dead biomass could efficiently remove these sterols in aqueous solution and tobacco waste extract (TWE). Interestingly, compared with the living biomass of LSD-1, the dead biomass of LSD-1 not only kept a high adsorption efficiency but also did not produce ergosterol. Overall, dead biomass of LSD-1 was a more suitable biosorbent to sterols in TWE. Furthermore, Brunner-Emmet-Teller (BET), Fourier transformed infrared spectrometer (FTIR) and scanning electron microscope (SEM) analysis were used to explore the biosorption process of living and dead biomass and their differences, suggesting that the biosorption of sterols was a physical process.

[Regulation of autophagy by GLT25D2 gene in acetaminophen-induced hepatotoxicity injury].

OBJECTIVE: To investigate whether GLT25D2 gene regulates autophagy in acetaminophen (APAP)-induced hepatotoxicity injury. METHODS: GLT25D2+/+ wild-type C57BL/6J mice and GLT25D2-/- C57BL/6J mice were selected as subjects. (1) In vivo experiment: 20 for wild-type mice and 20 for GLT25D2-/- mice were respectively divided into phosphate buffer (PBS) control group and APAP intervention group according to random number table, with 10 mice in each group. The hepatotoxicity injury model of mice was reproduced by intraperitoneal injection of 25 g/L APAP solution 500 mg/kg. The PBS control group was intraperitoneally injected with the same amount of PBS. The mice were sacrificed immediately after model reproduction, and the liver tissues were harvested. Western Blot was used to detect the expressions of autophagy-related proteins ATG5, ATG7, microtubule-associated protein 1 light chain 3 (LC3) and P62. The ultrastructural changes in liver tissue were observed under electron microscope to observe the level of autophagy. (2) In vitro experiment: primary hepatocytes extracted by two-step collagen perfusion from one GLT25D2+/+ wild-type mouse and one GLT25D2-/- mouse were divided into two parts respectively. One part was treated with 5 mmol/L APAP solution. The cells were harvested at 0, 8, and 12 hours, and the expressions of autophagy-related proteins ATG5, ATG7, LC3, and P62 were determined by Western Blot. The other part was transfected with the green fluorescent protein-LC3 plasmid (GFP-LC3) for 24 hours. The cells were cultured with PBS (PBS control group) or 5 mmol/L APAP (APAP intervention group) for 12 hours, and the positive expression of GFP-LC3 was observed under the fluorescence microscope, thereby reflecting the expression of autophagosomes. RESULTS: (1) In vivo experiment: compared with the corresponding PBS control group, the expressions of the positive-associated proteins ATG5, ATG7 and LC3-II in liver tissue of the APAP intervention group were down-regulated in the wild-type and GLT25D2-/- mice, while the expression of the negative correlation protein P62 was up-regulated, indicating that the overall level of autophagy decreased after treatment with APAP. Compared with wild-type mice, the expressions of autophagy positive correlation proteins ATG5 and ATG7 were up-regulated in GLT25D2-/- mice (ATG5/ß-actin: 1.21±0.29 vs. 0.84±0.19, ATG7/ß-actin: 1.29±0.14 vs. 1.54±0.40, both P > 0.05), LC3-II expression was slightly down-regulated (LC3-II/ß-actin: 0.52±0.06 vs. 0.58±0.06, P > 0.05), while negative correlation protein P62 was down-regulated (P62/ß-actin: 1.13±0.94 vs. 1.54±0.40, P > 0.05), indicating that the expression of autophagy in GLT25D2-/- mice was higher than that in wild-type mice. Ultrastructural observation under electron microscope showed that the number of autophagosomes in the liver tissue of wild-type mice did not change significantly after APAP intervention as compared with that in PBS control group, but the number of autophagosomes in GLT25D2-/- mice was increased. (2) In vitro experiment: with the prolongation of APAP intervention, the expressions of ATG5 and ATG7 in the primary hepatocytes of wild-type and GLT25D2-/- mice were up-regulated, LC3 was slightly fluctuated, and the expression of negative-related protein P62 was gradually down-regulated. The peak value or the trough value reached at 12 hours. It was indicated that the expression of autophagy in APAP-stimulated cells was enhanced with a time-dependent manner. Compared with wild-type mice, the expressions of autophagy correlation proteins ATG5, ATG7, LC3-II and P62 were up-regulated in GLT25D2-/- mice at 12 hours (ATG5/ß-actin: 0.93±0.09 vs. 0.74±0.06, ATG7/ß-actin: 0.80±0.09 vs. 0.65±0.10, LC3-II/ß-actin: 1.35±0.30 vs. 1.15±0.20, P62/ß-actin: 0.36±0.02 vs. 0.31±0.03, all P > 0.05), indicating that the expression of autophagy was enhanced after gene knockout. Fluorescence microscopy showed that GFP-LC3 positive cells in both wild-type and GLT25D2-/- mice hepatocytes were significantly increased after APAP intervention as compared with those of PBS control group, and the proportion of GFP-LC3 positive cells in GLT25D2-/- mice was significantly higher than that in wild-type mice (0.64±0.08 vs. 0.36±0.05, P > 0.05). CONCLUSIONS: GLT25D2 is a negative regulator of autophagy. Knockout of GLT25D2 gene can enhance the autophagy level of APAP-induced hepatotoxicity injury in mice.

Polyphyllin G exhibits antimicrobial activity and exerts anticancer effects on human oral cancer OECM-1 cells by triggering G2/M cell cycle arrest by inactivating cdc25C-cdc2.

Plant natural products have long been considered to be important sources of bioactive molecules. A large number of antimicrobial and anticancer agents have been isolated form plants. In the present study we evaluated the antimicrobial and anticancer activity of a plant derived secondery metabolite, Polyphyllin G. The results of antibacterial assays showed that Polyphyllin G prevented the growth of both Gram-positive and Gram-negative bacteria with minimum inhibitory concentrations (MICs) ranging from 13.1 to 78 µg/ml. Antifungal activity measured as inhibition of mycelium growth ranged between 38.32 and 56.50%. Further Polyphyllin G was also evaluated against a panel of cancer cell lines. The IC50 of Polyphyllin G ranged from 10 to 65 µM. However the IC50 of Polyphyllin G was found to be comparatively high (120 µM) against the normal FR2 cancer cell line. The lowest IC50 of 10 µM was found against the oral cancer cell line OECM-1. Therefore further studies were carried out on this cell line only. Our results indicated that Polyphyllin G induced cell arrest in oral cancer OECM-1 cells by inactivation of cdc25C-cdc22 via ATM-Chk 1/2 stimulation. Therefore, we propose that Polyphyllin G might prove a lead molecule in the management of oral cancers and at the same time may prevent the growth of opportunistic microbes.

Risk factors for dislocation after revision total hip arthroplasty: A systematic review and meta-analysis.

BACKGROUND: No formal systematic review or meta-analysis was performed up to now to summarize the risk factors of dislocation after revision total hip arthroplasty(THA). AIMS: The present study aimed to quantitatively and comprehensively conclude the risk factors of dislocation after revision total hip arthroplasty. METHODS: A search was applied to CNKI, Embase, Medline, and Cochrane central database (all up to October 2016). All studies assessing the risk factors of dislocation after revision THA without language restriction were reviewed, and qualities of included studies were assessed using the Newcastle-Ottawa Scale. Data were pooled and a meta-analysis completed. RESULTS: A total of 8 studies were selected, which altogether included 4656 revision THAs. 421 of them were cases of dislocation occurred after surgery, suggesting the accumulated incidence of 9.04%. Results of meta-analyses showed that age at surgery (standardized mean difference -0.222; 95% CI -0.413-0.031), small-diameter femoral heads (≤28 mm) (OR 1.451; 95%CI 1.056-1.994), history of instability (OR 2.739; 95%CI 1.888-3.974), number of prior revisions ≥ 3 (OR, 2.226; 95% CI, 1.569-3.16) and number of prior revisions ≥ 2 (OR 1.949; 95% CI 1.349-2.817), acetabular components with elevated rim liner were less likely to develop dislocation after revision THA (OR 0.611; 95% CI 0.415-0.898). CONCLUSIONS: Related prophylaxis strategies should be implemented in patients involved with above-mentioned risk factors to prevent dislocation after revision THA.

Decrease of Functional Activated T and B Cells and Treatment of Glomerulonephitis in Lupus-Prone Mice Using a Natural Flavonoid Astilbin.

Treatment of systemic lupus erythematosus (SLE), a chronic inflammatory disease, involves the long-term use of immunosuppressive agents with significant side effects. New therapeutic approaches are being explored to find better treatment possibilities. In this study, age-matched female MRL/lpr mice were treated orally with a natural flavonoid astilbin. Astilbin administration started either at week 8 or week 12 of age though week 20. In the early treatment regimen, the treatment with astilbin reduced splenomegaly/lymphomegaly, autoantibody production and ameliorated lupus nephritis. Several serum cytokines were significantly decreased upon treatment including IFN-g, IL-17A, IL-1b, TNF-a and IL-6. Both spleen CD44 hi CD62L lo activated T cells and CD138+B220- plasma cells greatly declined. Furthermore, astilbin treatment resulted in decreased mitochondrial membrane potential in activated T cells and downregulated expression of the co-stimulatory molecules CD80 and CD86 on LPS stimulated B cells. Similar but less profound effectiveness was observed in the mice with established disease in the late treatment regimen. These results indicate that the natural product astilbin can mitigate disease development in lupus-prone mice by decreasing functional activated T and B cells.

Sesamin inhibits lipopolysaccharide-induced proliferation and invasion through the p38-MAPK and NF-κB signaling pathways in prostate cancer cells.

Sesamin, a lipid-soluble lignan, is one of the major constituents of sesame. Previous studies have reported that sesamin induces growth inhibition in human cancer cells, particularly prostate cancer cells. In the present study, we mainly explored the mechanism underlying the protective effect of sesamin on prostate cancer cell proliferation and invasion induced by lipopolysaccharide (LPS). We found that the proliferation of PC3 cells, as determined using the MTT assay, and the expression of cyclin D1, COX-2, Bcl-2 and survivin proteins elevated by LPS were distinctly inhibited by sesamin in a dose-dependent manner. Meanwhile, the ability of PC3 cell invasion, as determined using the Transwell assay and the expression of matrix metalloproteinase 9 (MMP-9), intercellular adhesion molecule-1 (ICAM-1) and vascular endothelial growth factor (VEGF) proteins increased by LPS were obviously reduced by sesamin in a dose-dependent manner. In addition, the accumulation of TGF-α and interleukin-6 (IL-6) production induced by LPS in the culture supernatant was found to be decreased dose-dependently with sesamin pretreatment in PC3 cells using the enzyme-linked immunosorbent assay (ELISA) kit. Furthermore, phosphorylation of the p38 protein and nuclear factor (NF)-κB activity in the PC3 cells were enhanced by LPS and further inhibited with sesamin, SB203580 pretreatment or p38-siRNA transfection, respectively. Sesamin or SB203580 pretreatment obviously inhibited PC3 cells-derived tumor growth induced by LPS in vivo. Taken together, these results suggest that the potential ability of sesamin to downregulate the secretion of cytokines and the expression of cell proliferative- and invasive-related gene products induced by LPS was shown to be via the p38 mitogen-activated protein kinase (p38-MAPK) and NF-κB signaling pathways, which may be one of the mechanisms of the anticancer activity of this sesamin agent in prostate cancer cells.

EGFR inhibitor-driven endoplasmic reticulum stress-mediated injury on intestinal epithelial cells.

AIMS: The aim of this study is to understand the underlying mechanisms regulating the adverse effect of diarrhea caused by epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). MAIN METHODS: We comparatively examined the effects of two EGFR-TKIs, gefitinib and icotinib, on intestinal epithelial cells (IEC-6). Cell proliferation was measured using MTT analysis. Expression of multiple cytokines was assayed by real-time PCR. Cell cycle and apoptosis of IEC were evaluated using flow cytometry. Protein levels were determined by Western blot. KEY FINDINGS: These two EGFR-TKIs exerted cytotoxicity to inhibit proliferation and induce apoptosis in IEC-6 cells. These effects are due to the ability of these EGFR-TKIs to cause cell cycle arrest at G0/G1 by regulating the expression of cyclin D1 and p27. In addition, gefitinib and icotinib significantly suppressed the levels of cell adhesion molecules while increasing the expression of the proinflammatory cytokines interleukin (IL)-6 and IL-25. Finally, these EGFR-TKIs triggered an endoplasmic reticulum (ER) stress response, characterized by the activation of the RNA dependent protein kinase-like ER kinase (PERK) pathway and the transcriptional induction of XBP-1 signaling, resulting in ER-mediated cell death. Moreover, gefitinib exerted more cytotoxicity than icotinib on IEC-6 cells. SIGNIFICANCE: Because diarrhea is a common adverse event occurring in patients receiving small-molecular EGFR-TKI chemotherapy, the results of this study are clinically significant. The finding that icotinib exerts less cytotoxic activity than gefitinib on IEC-6 cells indicates its usefulness as a less toxic treatment option for non-small-cell lung cancer.

Small molecule-driven mitophagy-mediated NLRP3 inflammasome inhibition is responsible for the prevention of colitis-associated cancer.

Nonresolving inflammation in the intestine predisposes individuals to the development of colitis-associated cancer (CAC). Inflammasomes are thought to mediate intestinal homeostasis, and their dysregulation contributes to inflammatory bowel diseases and CAC. However, few agents have been reported to reduce CAC by targeting inflammasomes. Here we show that the small molecule andrographolide (Andro) protects mice against azoxymethane/dextran sulfate sodium-induced colon carcinogenesis through inhibiting the NLRP3 inflammasome. Administration of Andro significantly attenuated colitis progression and tumor burden. Andro also inhibited NLRP3 inflammasome activation in macrophages both in vivo and in vitro, as indicated by reduced expression of cleaved CASP1, disruption of NLRP3-PYCARD-CASP1 complex assembly, and lower IL1B secretion. Importantly, Andro was found to trigger mitophagy in macrophages, leading to a reversed mitochondrial membrane potential collapse, which in turn inactivated the NLRP3 inflammasome. Moreover, downregulation of the PIK3CA-AKT1-MTOR-RPS6KB1 pathway accounted for Andro-induced autophagy. Finally, Andro-driven inhibition of the NLRP3 inflammasome and amelioration of murine models for colitis and CAC were significantly blocked by BECN1 knockdown, or by various autophagy inhibitors. Taken together, our findings demonstrate that mitophagy-mediated NLRP3 inflammasome inhibition by Andro is responsible for the prevention of CAC. Our data may help guide decisions regarding the use of Andro in patients with inflammatory bowel diseases, which ultimately reduces the risk of CAC.

Andrographolide sulfonate ameliorates experimental colitis in mice by inhibiting Th1/Th17 response.

Inflammatory bowel disease (IBD) is a chronic, relapsing and remitting condition of inflammation involves overproduction of pro-inflammatory cytokines and excessive functions of inflammatory cells. However, current treatments for IBD may have potential adverse effects including steroid dependence, infections and lymphoma. Therefore new therapies for the treatment of IBD are desperately needed. In the present study, we aimed to examine the effect of andrographolide sulfonate, a water-soluble form of andrographolide (trade name: Xi-Yan-Ping Injection), on murine experimental colitis induced by 2, 4, 6-trinitrobenzene sulfonic acid (TNBS). Andrographolide sulfonate was administrated through intraperitoneal injection to mice with TNBS-induced colitis. TNBS-induced body weight loss, myeloperoxidase activity, shortening of the colon and colonic inflammation were significantly ameliorated by andrographolide sulfonate. Both the mRNA and protein levels of pro-inflammatory cytokines were reduced by andrographolide sulfonate administration. Moreover, andrographolide sulfonate markedly suppressed the activation of p38 mitogen-activated protein kinase as well as p65 subunit of nuclear factor-κB (NF-κB). Furthermore, CD4(+) T cell infiltration as well as the differentiation of Th1 (CD4(+)IFN-γ(+)) and Th17 (CD4(+)IL17A(+)) subset were inhibited by andrographolide sulfonate. In summary, these results suggest that andrographolide sulfonate ameliorated TNBS-induced colitis in mice through inhibiting Th1/Th17 response. Our study shows that water-soluble andrographolide sulfonate may represent a new therapeutic approach for treating gastrointestinal inflammatory disorders.

Genetically encoded red fluorescent copper(I) sensors for cellular copper(I) imaging.

Copper ranks among the most important metal ions in living organism, owing to its key catalytic effect in a range of biochemical processes. Dysregulation of in vivo copper(I) metabolism is extremely toxic and would cause serious diseases in human, such as Wilson's and Menkes. Thus, it would be highly valuable to have a proper approach to monitor the dynamics of copper(I) in vivo, as it is directly related to the onset of human copper(I)-related diseases. Under these circumstance, developing fluorescent protein based copper(I) sensors is highly demanded. However, these established sensors are mostly based on green or yellow FPs. Fluorescent copper(I) sensors with a spectra in the red range are more desirable due to lower phototoxicity, less auto-fluorescent noise and better penetration of red light. In the present work, we grafted a special red FP into three different location of a copper(I) binding protein, and generate a series of red fluorescent copper(I) sensors. Despite their limited in vivo sensitivity toward copper(I), these sensors are viable for cellular copper(I) imaging. Furthermore, these red fluorescent copper(I) sensors are a good starting point to develop superior copper(I) biosensors capable of imaging copper(I) fluctuations within a truly biologically relevant concentration, and further effort to realize this endeavor is under way.

LKB1 suppresses proliferation and invasion of prostate cancer through hedgehog signaling pathway.

Activation of the hedgehog (Hh) signaling pathway has been implicated in the development of many human malignancies. Hh signaling target genes, such as patched (PTCH), smoothened (SMO) and sonic hedgehog (SHH), are markers of Hh signaling activation in most Hh-associated tumors. The protein kinase LKB1 has been shown to slow proliferation and induce cell-cycle arrest in many cell lines. However, the function of LKB1 in prostate cancer development remains largely unclear. In this study, the expression of LKB1 in human prostate cancer tissue samples and prostate cancer cell lines was detected, and the effects of LKB1 on prostate cancer cell proliferation and invasion were evaluated. Moreover, the influence of LKB1 on target genes of the Hh signaling pathway was analyzed. The results indicated that knockdown of LKB1 expression by RNA interference promoted cell proliferation, colony formation and invasion. Meanwhile, we observed that LKB1 siRNA increased the expression of factors related to Hh signaling reporter activity in prostate cancer cells, including PTCH, SMO and SHH. These findings suggest that LKB1 is a putative tumor suppressor gene in prostate cancer, and that LKB1 is negatively correlated with the expression of Hh signaling related transcription factors. Our results suggest that LKB1 may inhibit tumorigenesis by regulating the Hh signaling pathway in certain cancers.

Loss of SHP-2 activity in CD4+ T cells promotes melanoma progression and metastasis.

The Src homology 2 domain-containing tyrosine phosphatase 2 (SHP-2) has been reported to have both tumor-promoting and tumor-suppressing roles in tumorigenesis. However, the role of SHP-2 in tumor immunity remains unclear. Here we observed progressively lower levels of phosphorylated SHP-2 in tumor-associated CD4(+) T cells during melanoma development in a murine model. Similarly, the levels of phosphorylated SHP-2 in the CD4(+) T cells of human melanoma specimens revealed a decrease paralleling cancer development. The CD4(+) T cell-specific deletion of SHP-2 promoted melanoma metastasis in mice. Furthermore, SHP-2 deficiency in CD4(+) T cells resulted in the increased release of inflammatory cytokines, especially IL-6, and the enhanced accumulation of tumor-promoting myeloid-derived suppressor cells (MDSCs) in tumor-bearing mice. An IL-6-neutralizing antibody reduced MDSC accumulation and inhibited tumor growth in CD4(+) T-cell-specific SHP-2-knockout mice. Our results suggest that SHP-2 in CD4(+) T cells plays an important role in preventing melanoma progression and metastasis.