BackgroundA vast diversity of microbes colonizes in the human gastrointestinal tract, referred to intestinal microbiota. Microbiota and products thereof are indispensable for shaping the development and function of host innate immune system, thereby exerting multifaceted impacts in gut health.MethodsThis paper reviews the effects on immunity of gut microbe-derived nucleic acids, and gut microbial metabolites, as well as the involvement of commensals in the gut homeostasis. We focus on the recent findings with an intention to illuminate the mechanisms by which the microbiota and products thereof are interacting with host immunity, as well as to scrutinize imbalanced gut microbiota (dysbiosis) which lead to autoimmune disorders including inflammatory bowel disease (IBD), Type 1 diabetes (T1D) and systemic immune syndromes such as rheumatoid arthritis (RA).ResultsIn addition to their well-recognized benefits in the gut such as occupation of ecological niches and competition with pathogens, commensal bacteria have been shown to strengthen the gut barrier and to exert immunomodulatory actions within the gut and beyond. It has been realized that impaired intestinal microbiota not only contribute to gut diseases but also are inextricably linked to metabolic disorders and even brain dysfunction.ConclusionsA better understanding of the mutual interactions of the microbiota and host immune system, would shed light on our endeavors of disease prevention and broaden the path to our discovery of immune intervention targets for disease treatment.

Mutations in KRAS exon 2, BRAF and PIK3CA are commonly present in colorectal cancer (CRC) worldwide, but few data about RAS mutations outside KRAS exon 2 are available for Chinese CRCs. We, therefore, determined the mutation frequencies and prognostic values of KRAS exon 2, 3 and 4, NRAS exon 2 and 3, PIK3CA exon 9 and 20, and BRAF exon 15 by PCR and direct sequencing in 353 CRC patients from two Chinese clinical centers. KRAS exon 2, BRAF, PIK3CA mutations were identified in 42.2%, 4.5%, 12.3% of the cases, respectively. We found “rare mutations” in RAS genes in nearly 14% of CRCs-i.e., in almost a quarter (24.0%) of KRAS exon 2 wild type CRCs, including 2.3% in KRAS exon 3, 8.2% in KRAS exon 4 and 3.4% in NRAS. Stage I-III patients with PIK3CA or NRAS mutations developed more distant metastases (3-year risk in PIK3CA mutated and wild type patients: 23.3% vs 11.5%, P = 0.03; multivariate Hazard ratio (HR) = 3.129, P = 0.003; 3-year risk in NRAS mutated and wild type patients: 40.0% vs 12.2%, P = 0.012; multivariate HR = 5.152, P = 0.003). Our data emphasizes the importance of these novel molecular features in CRCs.

Primary biliary cholangitis (PBC) is an autoimmune liver disease with a strong hereditary component. Here, we report a genome-wide association study that included 1,122 PBC cases and 4,036 controls of Han Chinese descent, with subsequent replication in a separate cohort of 907 PBC cases and 2,127 controls. Our results show genome-wide association of 14 PBC risk loci including previously identified 6p21 (HLA-DRA and DPB1), 17q12 (ORMDL3), 3q13.33 (CD80), 2q32.3 (STAT1/STAT4), 3q25.33 (IL12A), 4q24 (NF-κB) and 22q13.1 (RPL3/SYNGR1). We also identified variants in IL21, IL21R, CD28/CTLA4/ICOS, CD58, ARID3A and IL16 as novel PBC risk loci. These new findings and histochemical studies showing enhanced expression of IL21 and IL21R in PBC livers (particularly in the hepatic portal tracks) support a disease mechanism in which the deregulation of the IL21 signalling pathway, in addition to CD4 T-cell activation and T-cell co-stimulation are critical components in the development of PBC.

Since the expected therapeutic results of ischemic stroke are strictly time dependent, early and accurate diagnosis as well as short intervals between diagnosis and treatment are key factors for the survival of stroke patients. In this study, we fabricated platelet (PLT) membrane-derived biomimetic nanobubbles (PNBs) for timely perfusion intervention and ultrasound imaging of acute ischemic stroke.Methods: The PNBs are fabricated by sonication-assisted reassembly of repeatedly freeze-thawed live platelet-derived PLT membrane vesicles (PMVs). The TEM, SEM, EDS and DLS were used to analyze the morphology and physicochemical properties of PNBs. The HPLC and LC-MS/MS were applied to confirm the lipid and protein compositions of PNBs. The in vitro macrophage uptake and platelet aggregation of PNBs were designed to examine the immune escape and thrombotic response characteristics. Furthermore, based on a photothrombotic ischemic stroke mouse model, the biodistribution, stroke microvascular network change, as well as cerebral blood flow of PNBs were studied by using near-infrared fluorescence imaging, multimodal optical imaging, and full-field laser perfusion imager. Finally, we assessed the brain ultrasound imaging of PNBs with a high-resolution micro-imaging system using both B-mode and contrast mode.Results: The natural lipid and protein components isolated from PLT membrane endow the PNBs with accurate lesion-targeting ability. The preferentially accumulated PNBs exhibit microvascular bio-remodeling ability of the stroke lesion, which is critical for recanalization of the obstructed vessels to protect the neural cells around the ischemic region of the stroke. Furthermore, with the increased accumulation of PNBs clusters in the lesion, PNBs in the lesion can be monitored by real-time contrast-enhanced ultrasound imaging to indicate the severity and dynamic development of the stroke.Conclusions: In summary, platelet membrane-based nanobubbles for targeting acute ischemic lesions were developed as microvascular recanalization nanoformulation for acute ischemic stroke lesion theranostics. This biomimetic PNBs theranostic strategy will be valuable for ischemic stroke patients in the future.

Promoter hypermethylation mediated by DNA methyltransferases (DNMTs) is the main reason for epigenetic inactivation of tumor suppressor genes (TSGs). Previous studies showed that DNMT1 and DNMT3B play an important role in CpG island methylation in tumorigenesis. Little is known about the role of DNMT3A in this process, especially in hepatocellular carcinoma (HCC). In the present study, increased DNMT3A expression in 3 out of 6 HCC cell lines and 16/25 (64%) HCC tissues implied that DNMT3A is involved in hepatocellular carcinogenesis. Depletion of DNMT3A in HCC cell line SMMC-7721 inhibited cell proliferation and decreased the colony formation (about 65%). Microarray data revealed that 153 genes were upregulated in DNMT3A knockdown cells and that almost 71% (109/153) of them contain CpG islands in their 5′ region. 13 of them including PTEN, a crucial tumor suppressor gene in HCC, are genes involved in cell cycle and cell proliferation. Demethylation of PTEN promoter was observed in DNMT3A-depleted cells implying that DNMT3A silenced PTEN via DNA methylation. These results provide insights into the mechanisms of DNMT3A to regulate TSGs by an epigenetic approach in HCC.