Recently, increasing evidence has suggested the association between gut dysbiosis and Alzheimer's disease (AD) progression, yet the role of gut microbiota in AD pathogenesis remains obscure. Herein, we provide a potential mechanistic link between gut microbiota dysbiosis and neuroinflammation in AD progression. Using AD mouse models, we discovered that, during AD progression, the alteration of gut microbiota composition leads to the peripheral accumulation of phenylalanine and isoleucine, which stimulates the differentiation and proliferation of pro-inflammatory T helper 1 (Th1) cells. The brain-infiltrated peripheral Th1 immune cells are associated with the M1 microglia activation, contributing to AD-associated neuroinflammation. Importantly, the elevation of phenylalanine and isoleucine concentrations and the increase of Th1 cell frequency in the blood were also observed in two small independent cohorts of patients with mild cognitive impairment (MCI) due to AD. Furthermore, GV-971, a sodium oligomannate that has demonstrated solid and consistent cognition improvement in a phase 3 clinical trial in China, suppresses gut dysbiosis and the associated phenylalanine/isoleucine accumulation, harnesses neuroinflammation and reverses the cognition impairment. Together, our findings highlight the role of gut dysbiosis-promoted neuroinflammation in AD progression and suggest a novel strategy for AD therapy by remodelling the gut microbiota.

BackgroundThe identification of human disease-related microRNAs (disease miRNAs) is important for further investigating their involvement in the pathogenesis of diseases. More experimentally validated miRNA-disease associations have been accumulated recently. On the basis of these associations, it is essential to predict disease miRNAs for various human diseases. It is useful in providing reliable disease miRNA candidates for subsequent experimental studies.Methodology/Principal FindingsIt is known that miRNAs with similar functions are often associated with similar diseases and vice versa. Therefore, the functional similarity of two miRNAs has been successfully estimated by measuring the semantic similarity of their associated diseases. To effectively predict disease miRNAs, we calculated the functional similarity by incorporating the information content of disease terms and phenotype similarity between diseases. Furthermore, the members of miRNA family or cluster are assigned higher weight since they are more probably associated with similar diseases. A new prediction method, HDMP, based on weighted k most similar neighbors is presented for predicting disease miRNAs. Experiments validated that HDMP achieved significantly higher prediction performance than existing methods. In addition, the case studies examining prostatic neoplasms, breast neoplasms, and lung neoplasms, showed that HDMP can uncover potential disease miRNA candidates.ConclusionsThe superior performance of HDMP can be attributed to the accurate measurement of miRNA functional similarity, the weight assignment based on miRNA family or cluster, and the effective prediction based on weighted k most similar neighbors. The online prediction and analysis tool is freely available at http://nclab.hit.edu.cn/hdmpred.

A web service for the prediction and analysis of disease miRNAs is available at http://bioinfolab.stx.hk/midp/.

Demanded as an essential trace element that supports cell growth and basic functions, iron can be harmful and cancerogenic though. By exchanging between its different oxidized forms, iron overload induces free radical formation, lipid peroxidation, DNA, and protein damages, leading to carcinogenesis or ferroptosis. Iron also plays profound roles in modulating tumor microenvironment and metastasis, maintaining genomic stability and controlling epigenetics. in order to meet the high requirement of iron, neoplastic cells have remodeled iron metabolism pathways, including acquisition, storage, and efflux, which makes manipulating iron homeostasis a considerable approach for cancer therapy. Several iron chelators and iron oxide nanoparticles (IONPs) has recently been developed for cancer intervention and presented considerable effects. This review summarizes some latest findings about iron metabolism function and regulation mechanism in cancer and the application of iron chelators and IONPs in cancer diagnosis and therapy.

Background: Long noncoding RNAs (lncRNAs) are non-protein coding transcripts longer than 200 nucleotides in length. They drive many important cancer phenotypes through their interactions with other cellular macromolecules including DNA, RNA and protein. Recent studies have identified numerous lncRNAs active in colorectal cancer (CRC). The lncRNA small nucleolar RNA host gene 6 (SNHG6) has been reported to have an oncogenic role in multiple cancers. However, the biological role and mechanism of SNHG6 in the tumorigenesis of CRC has not been reported in-deep.Methods: The Cancer Genome Atlas (TCGA) database and GEO database were used to identify SNHG6 expression in different human cancers and explore the relationship between SNHG6 expression and patient prognosis using Kaplan-Meier method analysis. SNHG6 expression in 77 pairs of clinical CRC tissues and different CRC cell lines were analyzed by quantitative real-time PCR (qRT-PCR). A CCK-8 assay was used to assess cell proliferation, transwell assay to detect the cell metastasis, and tumor growth was investigated with a nude mice model in vivo. Whether UPF1 and ZEB1 are downstream targets of SNHG6 was verified by bioinformatics target gene prediction, qRT-PCR and western blot.Results: TCGA data showed that SNHG6 was significantly upregulated in colorectal cancer samples in comparison with healthy data samples (P < 0.01). CRC patients with high levels of SNHG6 had a significantly shorter overall survival than those with low levels of SNHG6 (P = 0.0162). qRT-PCR confirmed that the expression of SNHG6 was significantly upregulated in CRC tissues and cell lines. Upregulation of SNHG6 expression induced RKO and HCT116 cell proliferation as well as RKO cell metastasis, while downregulation of SNHG6 expression supressed the proliferation and metastasis of RKO cells and tumor growth in vivo. UPF1 was upregulated and ZEB1 was decreased when SNHG6 knockdown, regulating the TGF-β/Smad pathway and inducing EMT respectively.Conclusions: SNHG6 may play an oncogenic role in CRC cells by activating TGF-β/Smad signaling pathway via targeting of UPF1 and inducing EMT via regulating ZEB1. This could be a prognostic biomarker and therapeutic target for CRC.

Defensins are antimicrobial peptides important to innate host defense. In addition to their direct antimicrobial effect, defensins modulate immune responses. Increasing evidence indicates that defensins exhibit complex functions by positively or negatively modulating infections of both enveloped and non-enveloped viruses. The effects of defensins on viral infections appear to be specific to the defensin, virus and target cell. Regulation of viral infection by defensins is achieved by multiple mechanisms. This review focuses on the interplay between defensins and viral infections, the mechanisms of action of defensins and the in vivo studies of the role of defensins in viral infections.

AIDS (acquired immune deficient syndrome) is a deadly human viral infectious disease caused by HIV (human immune-deficient virus) infection. Almost every AIDS patient losses his/her life before mid 1990s. AIDS was once the 1st disease killer in US (1993). After one decade hard work, antiviral drug cocktails-high active anti-retroviral therapy (HAART) have been invented for almost all HIV infection treatments. Due to the invention of HAART, 80-90% HIV/AIDS patients still effectively response to HAART for deadly AIDS episode controls and life saving. Yet, this type of HIV therapeutics is incurable. HIV/AIDS patients need to take HAART medications regularly and even life-long. To counteract this therapeutic drawback, more revolutionary efforts (different angles of therapeutic modes/attempts) are urgently needed. In this article, the major progresses and drawbacks of HIV/AIDS chemotherapy (HAART) to HIV/AIDS patients have been discussed. Future trends (updating pathogenesis study, next generations of drug developments, new drug target discovery, different scientific disciplinary and so on) are highlighted.

T cells expressing CD19-targeting chimeric antigen receptors (CARs) reveal high efficacy in the treatment of B cell malignancies. Here, we report that T cell receptor fusion constructs (TRuCs) comprising an antibody-based binding domain fused to T cell receptor (TCR) subunits can effectively reprogram an intact TCR complex to recognize tumor surface antigens. Unlike CARs, TRuCs become a functional component of the TCR complex. TRuC-T cells kill tumor cells as potently as second-generation CAR-T cells, but at significant lower cytokine release and despite the absence of an extra co-stimulatory domain. TRuC-T cells demonstrate potent anti-tumor activity in both liquid and solid tumor xenograft models. In several models, TRuC-T cells are more efficacious than respective CAR-T cells. TRuC-T cells are shown to engage the signaling capacity of the entire TCR complex in an HLA-independent manner.