CD36+ cancer-associated fibroblasts provide immunosuppressive microenvironment for hepatocellular carcinoma via secretion of macrophage migration inhibitory factor.

Hepatocellular carcinoma (HCC) is an immunotherapy-resistant malignancy characterized by high cellular heterogeneity. The diversity of cell types and the interplay between tumor and non-tumor cells remain to be clarified. Single cell RNA sequencing of human and mouse HCC tumors revealed heterogeneity of cancer-associated fibroblast (CAF). Cross-species analysis determined the prominent CD36+ CAFs exhibited high-level lipid metabolism and expression of macrophage migration inhibitory factor (MIF). Lineage-tracing assays showed CD36+CAFs were derived from hepatic stellate cells. Furthermore, CD36 mediated oxidized LDL uptake-dependent MIF expression via lipid peroxidation/p38/CEBPs axis in CD36+ CAFs, which recruited CD33+myeloid-derived suppressor cells (MDSCs) in MIF- and CD74-dependent manner. Co-implantation of CD36+ CAFs with HCC cells promotes HCC progression in vivo. Finally, CD36 inhibitor synergizes with anti-PD-1 immunotherapy by restoring antitumor T-cell responses in HCC. Our work underscores the importance of elucidating the function of specific CAF subset in understanding the interplay between the tumor microenvironment and immune system.

[Expression of inflammation cytokines and network analysis in acute rejection of renal transplantation].

OBJECTIVE: To explore the changes of inflammation cytokines during acute renal transplantation rejection and decipher the functions of their protein-protein interaction network. METHODS: Serum samples were collected from renal transplantation patients with stable renal function or acute rejection (n = 6 each) to measure the expression level of 40 inflammatory factors by APIX protein array. The differentially expressed proteins were selected and their protein-protein interaction networks constructed. And biologic processes were analyzed by the online tools of String and Network Ontology Analysis. RESULTS: There were 8 differentially expressed cytokines in the AR group versus the stable group (M (Q(1)-Q(3)), CCL24: 700 (255 - 1157) vs 330 (100 - 610) ng/L, ICAM-1: 58 737 (8018 - 105 395) vs 22 660 (137 - 68 914) ng/L, IL-10: 120 (20 - 517) vs 298 (81 - 11 609) ng/L, IL-6sR: 11 328 (3357 - 21 251) vs 7665 (370 - 12 455) ng/L, CCL3: 1712(7002 - 32 634) vs 283 (54 - 1915) ng/L, CCL4: 554 (28 - 2355) vs 283(104 - 1915) ng/L, TIMP-1: 15 560 (13 343 - 42 481) vs 11 271 (1207 - 18 228) ng/L, CCL5: 44 547 (38 252 - 78 631) vs 27 765 (12 073 - 46 627) ng/L, all P < 0.05). The analyses of protein-protein association network showed that these proteins were correlated and involved in such biological processes as taxis, chemotaxis, inflammatory reactions, wound responses and leukocytic migration. CONCLUSIONS: Comparing the inter-group differences of inflammatory cytokines and further developing and analyzing the protein-protein interaction network may help us to explore the mechanisms of acute renal transplantation rejection. And the differential cytokines can be used as candidate diagnostic biomarkers and intervention targets.

Metabonomics-based omics study and atherosclerosis.

Atherosclerosis results from dyslipidemia and systemic inflammation, associated with the strong metabolism and interaction between diet and disease. Strategies based on the global profiling of metabolism would be important to define the mechanisms involved in pathological alterations. Metabonomics is the quantitative measurement of the dynamic multiparametric metabolic response of living systems to pathophysiological stimuli or genetic modification. Metabonomics has been used in combination with proteomics and transcriptomics as the part of a systems biology description to understand the genome interaction with the development of atherosclerosis. The present review describes the application of metabonomics to explore the potential role of metabolic disturbances and inflammation in the initiation and development of atherosclerosis. Metabonomics-based omics study offers a new potential for biomarker discovery by disentangling the impacts of diet, environment and lifestyle.

[Preliminary exploration in proteomic-based mechanistic analysis of patients with acute renal allograft rejection].

OBJECTIVE: To explore the application of proteomics in the mechanistic analysis of acute rejection (AR). METHODS: Quantified proteomics with isobaric tags for relative and absolute quantitation (iTRAQ) labeling was utilized to identify the protein profiling between the transplantation patients with (n = 5) or without AR (n = 8) from 2008 to 2010. RESULTS: Among the 179 identified proteins, 66 proteins in AR patients had at least a 2-fold change as compared with those without AR. The results demonstrated the dominant processes and responses associated with inflammation and complement activation. It was consistent with the underlying immune rejection associated with AR. Moreover, the results also indicated that high-coagulation state existed in AR patients. A number of transcription factors were identified in AR patients, including nuclear factor-κB, signal transducer and activator of transcription 1, signal transducer and activator of transcription 3. The analysis of transcription regulation networks suggested that the cross-talks among these key transcription factors might play an important role in the acute response and activation of coagulation system. CONCLUSION: The application of proteomics provides a new strategy of mechanistic analysis in AR.

Effects of fasudil on early atherosclerotic plaque formation and established lesion progression in apolipoprotein E-knockout mice.

Rho kinases have been shown to be involved in the pathogenesis of atherosclerosis. This study examined the effects of fasudil, a specific Rho kinase inhibitor, on plaque development and progression in atherosclerotic mice. Sixty apolipoprotein E-knockout (apoE-KO) mice were fed a high-fat diet. Mice started to receive fasudil at the same time as fat feeding (early treatment), or after 12 weeks of fat feeding (delayed treatment). In each administrative schedule, mice were divided into three groups: low dose fasudil group (30 mg/kg/day), high dose fasudil group (100mg/kg/day) and control group (tap water) (n=10, respectively). Plaque size was determined by using ultrasound biomicroscopy (UBM) and histological examinations. Brachiocephalic artery UBM analysis showed that in early treatment, both doses of fasudil significantly reduced lesion size compared with the controls (P<0.05). In delayed-fasudil treatment, plaque area was reduced by 54% (P<0.05) after 12 weeks of treatment at a high dose of fasudil (100mg/kg/day). The UBM findings were confirmed by histological studies at the corresponding arterial sites. The beneficial effect was also observed in the left common carotid arteries that delayed-fasudil treatment reduced the plaque size in a dose-dependent manner. The arterial intima-medial thickness (IMT) and maximal flow velocity of both arteries were lower in fasudil-treated group (100mg/kg/day) in comparison with the control mice. Furthermore, fasudil treatment (100mg/kg/day) reduced the macrophage accumulation in atherosclerotic lesions. However, fasudil had no effects on blood pressure and plasma lipid concentrations in both studies. In conclusion, our studies showed that blocking Rho kinase reduced both the early development and later progression of atherosclerotic plaques in apoE-KO mice by using a novel micro-ultrasound approach.

[Effect of shexiang baoxin pill in alleviating myocardial fibrosis in spontaneous hypertensive rats].

OBJECTIVE: To investigate the effects and mechanisms of Shexiang Baoxin Pill (SBP) on myocardial fibrosis in spontaneous hypertensive rats (SHR). METHODS: SHR of 12 weeks old were divided into the SBP group, the control group (treated with benazepril) and the model control group. The effects on such indexes as systolic blood pressure (SBP), left ventricular mass (LVM), left ventricular mass index (LVMI), content of myocardial collagen (MC) in left ventricle, extracellular matrix fibronectin (FN), laminin (LN), cardiac fibroblast (cFb) and transforming growth factor-beta1 (TGF-beta1) were determined after 12 weeks of treatment. RESULTS: SBP had no marked pressure depressive effect, but had the effect similar to that of benazepril in reducing the level of LVM, LVMI and content of MC (P < 0.05), as well as the content of LN, FN in myocardium, cFb count and TGF-beta1 expression (P < 0.05). CONCLUSION: SBP can prevent and treat myocardial fibrosis, whose action is independent of its hypotensive effect. The mechanism may be associated with such factors as the decrease of MC synthesis in left ventricle and the deposition of extracellular matrix.