Establishment of humanized mice and its application progress in cancer immunotherapy.

The current high prevalence of malignant tumors has attracted considerable attention, and treating advanced malignancies is becoming increasingly difficult. Although immunotherapy is a hopeful alternative, it is effective in only a few people. Thus, development of preclinical animal models is needed. Humanized xenotransplantation mouse models can help with selecting treatment protocols, evaluating curative effects and assessing prognosis. This review discusses the establishment of humanized mouse models and their application prospects in cancer immunotherapy to identify tailored therapies for individual patients.

Immunotherapy is a promising treatment option for patients with advanced malignant tumors; however, it is not effective in all patients. Therefore, it is particularly important to identify effective preclinical models and develop individualized treatment plans for each patient. Humanized animal models can simulate the human immune microenvironment, enabling comprehensive evaluation of the efficacy, safety and feasibility of various immunotherapy strategies. Such models provide a theoretical basis for the individualized treatment of patients with advanced malignant tumors as well as serving as a promising medium for the research and development of preclinical drugs.

Boric acid was orally toxic to different instars of Blattella germanica (L.) (Blattodea: Blattellidae) and caused dysbiosis of the, gut microbiota.

Boric acid, a well-established chemical insecticide, has a good control effect on various types of cockroaches. In this study, we investigated the oral virulence effect of boric acid on German cockroach (Blattella germanica) of various instars and characterized its effect on the gut microbiota by high-throughput sequencing technology. The results of an oral toxicity test showed that the toxicity of boric acid was positively correlated with its concentration and negatively correlated with the instar of cockroach nymphs. The 1-3 instar nymphs showed the strongest sensitivity to boric acid, which exhibited a median lethal time of only 3.16 d, while the 6-7 instar nymphs showed the weakest sensitivity, and exhibited a median lethal time of 10.15 d. There was no significant difference between male and female insects regarding their sensitivity to boric acid. Oral treatment of boric acid resulted in severe dysbiosis in cockroaches, the relative abundances of Bacteroides, which can degrade a variety of complex macromolecules, and Enterococcus, which can inhibit pathogenic microorganisms, were significantly reduced, while the relative abundance of the opportunistic pathogenic bacterium Weissella was significantly increased. It was speculated that dysbiosis of gut microbiota might accelerate the toxicity of boric acid on German cockroaches.

NF-κB-driven miR-34a impairs Treg/Th17 balance via targeting Foxp3.

The subset of regulatory T (Treg) cells, with its specific transcription Foxp3, is a unique cell type for the maintenance of immune homeostasis by controlling effector T (Teff) cell responses. Although it is common that a defect in Treg cells with Treg/Teff disorder causes autoimmune diseases; however, the precise mechanisms are not thoroughly revealed. Here, we report that miR-34a could attenuate human and murine Foxp3 gene expression via targeting their 3' untranslated regions (3' UTR). The human miR-34a, increased in peripheral blood mononuclear cells (PBMCs) and CD4+ T cells from rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) patients, displayed a positive correlation with some serum markers of inflammation including rheumatoid factor (RF), anti-streptolysin antibody (ASO), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) as well as Th17 signature gene RORγt, but inversely correlated with the mRNA expression levels of FOXP3. In addition, murine miR-34a levels were downregulated in TGF-ß-induced Treg cells but upregulated in Th17 cells induced in vitro compared to activated CD4+ T cells. It has also been demonstrated that elevated miR-34a disrupting Treg/Th17 balance in vivo contributed to the progress of pathogenesis of collagen induced arthritis (CIA) mice. Furthermore, IL-6 and TNF-α were responsible for the upregulation of miR-34a and downregulation of Foxp3, which was reverted by the addition of NF-κB/p65 inhibitor BAY11-7082, thus indicating that NF-κB/p65 inhibited Foxp3 expression in an miR-34a-dependent manner. Finally, IL-6 or TNF-α-activated p65 could bind to the miR-34a promotor and enhance its activity, resulting in upregulation of its transcription. Taken together, we show that NF-κB activated by inflammatory cytokines, such as IL-6 and TNF-α, ameliorates Foxp3 levels via regulating miR-34a expression, which provides a new mechanistic and therapeutic insight into the ongoing of autoimmune diseases.

Brain-Derived Neurotrophic Factor Mediated Perfluorooctane Sulfonate Induced-Neurotoxicity via Epigenetics Regulation in SK-N-SH Cells.

Perfluorooctane sulfonate (PFOS), a new kind of persistent organic pollutant, is widely distributed in the environment and exists in various organisms, where it is also a neurotoxic compound. However, the potential mechanism of its neurotoxicity is still unclear. To examine the role of epigenetics in the neurotoxicity induced by PFOS, SK-N-SH cells were treated with different concentrations of PFOS or control medium (0.1% DMSO) for 48 h. The mRNA levels of DNA methyltransferases (DNMTs) and Brain-derived neurotrophic factor (BDNF), microRNA-16, microRNA-22, and microRNA-30a-5p were detected by Quantitative PCR (QPCR). Enzyme Linked Immunosorbent Assay (ELISA) was used to measure the protein levels of BDNF, and a western blot was applied to analyze the protein levels of DNMTs. Bisulfite sequencing PCR (BSP) was used to detect the methylation status of the BDNF promoter I and IV. Results of MTT assays indicated that treatment with PFOS could lead to a significant decrease of cell viability, and the treated cells became shrunk. In addition, PFOS exposure decreased the expression of BDNF at mRNA and protein levels, increased the expression of microRNA-16, microRNA-22, microRNA-30a-5p, and decreased the expression of DNMT1 at mRNA and protein levels, but increased the expression of DNMT3b at mRNA and protein levels. Our results also demonstrate that PFOS exposure changes the methylation status of BDNF promoter I and IV. The findings of the present study suggest that methylation regulation of BDNF gene promoter and increases of BDNF-related-microRNA might underlie the mechanisms of PFOS-induced neurotoxicity.

PFOS Disturbs BDNF-ERK-CREB Signalling in Association with Increased MicroRNA-22 in SH-SY5Y Cells.

Perfluorooctane sulfonate (PFOS), a ubiquitous environmental pollutant, is neurotoxic to mammalian species. However, the underlying mechanism of its neurotoxicity was unclear. We hypothesized that PFOS suppresses BDNF expression to produce its neurotoxic effects by inhibiting the ERK-CREB pathway. SH-SY5Y human neuroblastoma cells were exposed to various concentrations of PFOS to examine the role of the BDNF-ERK-CREB signalling pathway in PFOS-induced apoptosis and cytotoxicity. Furthermore, to ascertain the mechanism by which PFOS reduces BDNF signalling, we examined the expression levels of miR-16 and miR-22, which potentially regulate BDNF mRNA translation at the posttranscriptional level. Results indicated that PFOS significantly decreased cell viability and induced apoptosis in SH-SY5Y cells. In addition, BDNF and pERK protein levels decreased after PFOS treatment; however, pCREB protein levels were significantly elevated in PFOS treated groups. TrkB protein expression increased in the 10 µM and 50 µM PFOS groups and significantly decreased in the 100 µM PFOS group. Our results demonstrated that PFOS exposure decreased miR-16 expression and increased miR-22 expression, which may represent a possible mechanism by which PFOS decreases BDNF protein levels. PFOS may inhibit BDNF-ERK-CREB signalling by increasing miR-22 levels, which may, in part, explain the mechanism of PFOS neurotoxicity.