MANF brakes TLR4 signaling by competitively binding S100A8 with S100A9 to regulate macrophage phenotypes in hepatic fibrosis

The mesencephalic astrocyte-derived neurotrophic factor (MANF) has been recently identified as a neurotrophic factor, but its role in hepatic fibrosis is unknown. Here, we found that MANF was upregulated in the fibrotic liver tissues of the patients with chronic liver diseases and of mice treated with CCl4. MANF deficiency in either hepatocytes or hepatic mono-macrophages, particularly in hepatic mono-macrophages, clearly exacerbated hepatic fibrosis. Myeloid-specific MANF knockout increased the population of hepatic Ly6Chigh macrophages and promoted HSCs activation. Furthermore, MANF-sufficient macrophages (from WT mice) transfusion ameliorated CCl4-induced hepatic fibrosis in myeloid cells-specific MANF knockout (MKO) mice. Mechanistically, MANF interacted with S100A8 to competitively block S100A8/A9 heterodimer formation and inhibited S100A8/A9-mediated TLR4-NF-κB signal activation. Pharmacologically, systemic administration of recombinant human MANF significantly alleviated CCl4-induced hepatic fibrosis in both WT and hepatocytes-specific MANF knockout (HKO) mice. This study reveals a mechanism by which MANF targets S100A8/A9-TLR4 as a "brake" on the upstream of NF-κB pathway, which exerts an impact on macrophage differentiation and shed light on hepatic fibrosis treatment.

Allosteric inhibition reveals SHP2-mediated tumor immunosuppression in colon cancer by single-cell transcriptomics

Colorectal cancer (CRC), a malignant tumor worldwide consists of microsatellite instability (MSI) and stable (MSS) phenotypes. Although SHP2 is a hopeful target for cancer therapy, its relationship with innate immunosuppression remains elusive. To address that, single-cell RNA sequencing was performed to explore the role of SHP2 in all cell types of tumor microenvironment (TME) from murine MC38 xenografts. Intratumoral cells were found to be functionally heterogeneous and responded significantly to SHP099, a SHP2 allosteric inhibitor. The malignant evolution of tumor cells was remarkably arrested by SHP099. Mechanistically, STING-TBK1-IRF3-mediated type I interferon signaling was highly activated by SHP099 in infiltrated myeloid cells. Notably, CRC patients with MSS phenotype exhibited greater macrophage infiltration and more potent SHP2 phosphorylation in CD68+ macrophages than MSI-high phenotypes, suggesting the potential role of macrophagic SHP2 in TME. Collectively, our data reveals a mechanism of innate immunosuppression mediated by SHP2, suggesting that SHP2 is a promising target for colon cancer immunotherapy.

SHP2 inhibition triggers anti-tumor immunity and synergizes with PD-1 blockade

Tyrosine phosphatase SHP2 is a promising drug target in cancer immunotherapy due to its bidirectional role in both tumor growth promotion and T-cell inactivation. Its allosteric inhibitor SHP099 is known to inhibit cancer cell growth both and . However, whether SHP099-mediated SHP2 inhibition retards tumor growth anti-tumor immunity remains elusive. To address this, a CT-26 colon cancer xenograft model was established in mice since this cell line is insensitive to SHP099. Consequently, SHP099 minimally affected CT-26 tumor growth in immuno-deficient nude mice, but significantly decreased the tumor burden in CT-26 tumor-bearing mice with intact immune system. SHP099 augmented anti-tumor immunity, as shown by the elevated proportion of CD8IFN- T cells and the upregulation of cytotoxic T-cell related genes including , which decreased the tumor load. In addition, tumor growth in mice with SHP2-deficient T-cells was markedly slowed down because of enhanced anti-tumor responses. Finally, the combination of SHP099 and anti-PD-1 antibody showed a higher therapeutic efficacy than either monotherapy in controlling tumor growth in two colon cancer xenograft models, indicating that these agents complement each other. Our study suggests that SHP2 inhibitor SHP099 is a promising candidate drug for cancer immunotherapy.

Analysis of domestic cardiopulmonary bypass status: eight-year development trends / 中华胸心血管外科杂志

Objective To investigate the development trends of domestic cardiopulmonary bypass(CPB) in the past eight years.Methods Domestic hospitals that carry out cardiovascular sugeries were inquired with questionnaires annually up-on the number of on-pump and off-pump cardiac operations,oxygenators of different types and extracorporeal membrane oxygenations.Classify all the hospitals according to the cardiac surgery amount.Analyze the market share of each grade and the composition of oxygenators.Results The sum amount of cardiac operations and CPB were 170 547 and 136 753 respectively in 2010.In 2010,the composition of imported membrane oxygenator climbed up to 59.75％ from 43.22％ in 2003,while bubble oxygenator composition decreased from 43.78％ to 14.59％.44 hospitals carried out ECMO in 2010 and the sum number of ECMO was 206.The market share of hospitals( 32),with cardiac surgery number over 1000 per year,was 43％.Conclusion CPB in China has went through a rapid development in the past eight years.Medical resources of CPB should be concentrated and normal and systematic train regulations should be established in the future.

Functional magnetic resonance imaging study of working memory changes in healthy male volunteers after 36 hours sleep deprivation / 中华神经科杂志

Objective To observe changes in the working memory and brain functional imaging on functional magnetic resonance imaging(fMRI) after 36 hours sleep deprivation (SD) in healthy volunteers and to explore the possible mechanism of the changes.Methods FMRI scannings were performed in ten male healthy young volunteers before and after 36 hours SD and results were analyzed using SPM2 software.Subjects were also tested LTR and PLUS task to measure the persistence and operation of working memory before and after 36 hours SD.Results The reaction time of LTR task after 36 hours SD ( (866 ± 102) ms)was significantly longer than that before SD ( (754 ± 91 ) ms, t = 2.59, P < 0.01 ).The reaction time of PLUS task after SD ( (848 ± 94) ms) was significantly longer ( t = 2.37, P < 0.05 ) than that before SD ( (756 ± 79) ms).The error rate of LTR task after SD (95.3% ± 3.56% ) was significantly higher (t=3.52,P < 0.01 ) than that before SD (84.8% ± 8.71% ).The error rate of PLUS task after SD (95.7% ±4.72% ) was significantly higher (t =3.38 ,P <0.01 ) than that before SD (84.2% ±9.66% ).There were no significant differences between the two tasks.The frontal and parietal lobes, anterior cingulate gyrus and thalamus were activated during memory tasks testing before SD.Brain activation was broader and stronger in PLUS task than in LTR task.After SD, activation in parietal lobe was decreased and activation in prefrontal and thalamus was increased significantly.Conclusions The working memory performance decreased after SD.Both LTR and PLUS tasks of working memory activate frontal and parietal lobes, anterior cingulate gyrus and thalamus.The activation of parietal lobe decreased and the activation of prefrontal lobe and thalamus increased after 36 hours SD.This is the possible mechanism of SD to causes the cognition decline.

Effect of Grp75 on the alteration of apoptosis related gene Bax and NF-κB induced by glucose deprivation / 解剖学报

Objective To study the effect of glucose regulated protein 75(Grp75) on the alteration of Bax and NF-κB induced by glucose deprivation through the stably transfected PC12 cells with Grp75. Methods The cells of Grp75-overexpressing group and control group incubated in glucose-free DMEM medium for indicated time (6, 12, 24 and 48hours). The expression level of Grp75, Bax and the activity of NF-κB were determined by Western blotting, and the expression level of Bax was determined by semi-quantitative RT-PCR and Western blotting. Immunocytochemistry was performed using a conformation specific anti-Bax (6A7) antibody to detect the activation of Bax. Results The activation of Bax and the decline of NF-κB activity played important roles in the apoptosis of PC12 cells induced by glucose deprivation. Grp75 inhibited the apoptosis induced by glucose deprivation through inhibition of the activation of Bax and the decline of NF-κB activity. There was no change in Bax expression level under glucose deprivation in two groups. Conclusion The activation of Bax and the decline of NF-κB activity were associated with apoptosis of PC12 cells induced by glucose deprivation, and Grp75 provided protection to PC12 cells through inhibition of activation of Bax and maintaining activation of NF-κB.