Explore the vast range of titles available.

Gastric cancer (GC) is one of the most common malignant neoplasms. Invasion and metastasis are the main causes of GC-related deaths. Recently, kinesins were discovered to be involved in tumor development. The aim of this study was to elucidate the roles of kinesin superfamily protein 26A (KIF26A) in GC and its underlying molecular mechanism in regulating tumor invasion and metastasis. Using real-time quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC), we showed that KIF26A expression was lower in GC tissues without lymph node metastasis (LNM) than in nontumorous gastric mucosa, and even lower in GC tissues with LNM than in GC tissues without LNM. Functional experiments showed that KIF26A inhibited migration and invasion of GC cells. We further identified focal-adhesion kinase (FAK), phosphatidylinositol 3-kinase regulatory subunit alpha (PI3KR1), VAV3, Rac1 and p21-activated kinase 2, and β-PAK (PAK3) as downstream effectors of KIF26A in the focal-adhesion pathway, and we found that KIF26A could regulate FAK mRNA expression through inhibiting c-MYC by MAPK pathway. c-MYC could bind to the promoter of FAK and activate FAK transcription. Moreover, we found that KIF26A-mediated inactivation of the focal-adhesion pathway could reduce the occurrence of the epithelial-to-mesenchymal transition (EMT) by increasing expression of E-cadherin and reducing that of Snail. Luciferase assays and Western blotting revealed that miR-19a and miR-96 negatively regulate KIF26A. Finally, we found that decreased expression of KIF26A has been positively correlated with histological differentiation, Lauren classification, LNM, distal metastasis, and clinical stage, as well as poor survival in patients with GC. These data indicate that KIF26A could inhibit GC migration and invasion by regulating the focal-adhesion pathway and repressing the occurrence of EMT.

Breast cancer (BC) is the most common cancer in women worldwide, and the exploration of aberrantly expressed genes might clarify tumorigenesis and help uncover new therapeutic strategies for BC. Although RGMA was recently recognized as a tumor suppressor gene, its detailed biological function and regulation in BC remain unclear. Herein, we found that RGMA was downregulated in BC tissues compared with non-tumorous breast tissues, particularly in metastatic BC samples, and that patients with low RGMA expression manifested a poorer prognosis. Furthermore, DNMT1 and DNMT3A were found to be recruited to the RGMA promoter and induced aberrant hypermethylation, resulting in downregulation of RGMA expression in BC. In contrast, RGMA overexpression suppressed BC cell proliferation and colony-formation capabilities and increased BC cell apoptosis. Furthermore, RGMA knockdown accelerated BC cell proliferation and suppressed cellular apoptosis in vitro and in vivo. Reversal of RGMA promoter methylation with 5-Aza-CdR restored RGMA expression and blocked tumor growth. Overall, DNMT1- and DNMT3A-mediated RGMA promoter hypermethylation led to downregulation of RGMA expression, and low RGMA expression contributed to BC growth via activation of the FAK/Src/PI3K/AKT-signaling pathway. Our data thus suggested that RGMA might be a promising therapeutic target in BC.

Long noncoding RNAs (lncRNAs) play critical roles in the carcinogenesis and progression of cancers. However, the role and mechanism of the pseudogene lncRNA PIN1P1 in gastric carcinoma remain unclear. The expression and effects of lncRNA PIN1P1 in gastric cancer were investigated. The transcriptional regulation of CREB1 on PIN1P1 was determined by ChIP and luciferase assays. The mechanistic model of PIN1P1 in gastric cancer was further explored by RNA pull‐down, RIP and western blot analysis. PIN1P1 was overexpressed in gastric cancer tissues, and upregulated PIN1P1 predicted poor prognosis in patients. CREB1 was directly combined with the promoter region of PIN1P1 to promote the transcription of PIN1P1. CREB1‐mediated enhanced proliferation, migration and invasion could be partially reversed by downregulation of PIN1P1. Overexpressed PIN1P1 promoted the proliferation, migration and invasion of gastric cancer cells, whereas decreased PIN1P1 showed the opposite effects. PIN1P1 directly interacted with YBX1 and promoted YBX1 protein expression, leading to upregulation of PIN1, in which E2F1 may be involved. Silencing of YBX1 during PIN1P1 overexpression could partially rescue PIN1 upregulation. PIN1, the parental gene of PIN1P1, was elevated in gastric cancer tissues, and its upregulation was correlated with poor patient outcomes. PIN1 facilitated gastric cancer cell proliferation, migration and invasion. To sum up, CREB1‐activated PIN1P1 could promote gastric cancer progression through YBX1 and upregulating PIN1, suggesting that it is a potential target for gastric cancer.

The main purpose of this study is to examine the lifetime tobacco consumption and the degree of nicotine dependence related gray matter (GM) and white matter (WM) volume alterations in young adult-male smokers. Fifty-three long-term male smokers and 53 well-matched male healthy non-smokers participated in the study, and the smokers were respectively categorized into light and heavy tobacco consumption subgroups by pack-years and into moderate and severe nicotine dependence subgroups using the Fagerström Test for Nicotine Dependence (FTND). Voxel-based morphometry analysis was then performed, and ANCOVA analysis combined with subsequent test were used to explore the between-group brain volume abnormalities related to the smoking amount and nicotine dependence. Light and heavy smokers displayed smaller GM and WM volumes than non-smokers, while heavy smokers were found with more significant brain atrophy than light smokers in GM areas of precuneus, inferior and middle frontal gyrus, superior temporal gyrus, cerebellum anterior lobe and insula, and in WM areas of cerebellum anterior lobe. However, the contrary trend was observed regarding alterations associated with severity of nicotine dependence. Severe nicotine dependence smokers rather demonstrated less atrophy levels compared to moderate nicotine dependence smokers, especially in GM areas of precuneus, superior and middle temporal gyrus, middle occipital gyrus, posterior cingulate and insula, and in WM areas of precuneus, posterior cingulate, cerebellum anterior lobe and midbrain. The results reveal that the nicotine dependence displays a dissimilar effect on the brain volume in comparison to the cigarette consumption. Our study could provide new evidences to understand the adverse effects of smoking on the brain structure, which is helpful for further treatment of smokers.

It is widely accepted that β-amyloid oligomers (Aβos) play a key role in the progression of Alzheimer’s disease (AD) by inducing neuron damage and cognitive impairment, but Aβos are highly heterogeneous in their size, structure and cytotoxicity, making the corresponding studies tough to carry out. Nevertheless, a number of studies have recently made remarkable progress in the describing the characteristics and pathogenicity of Aβos. We here review the mechanisms by which Aβos exert their neuropathogenesis for AD progression, including receptor binding, cell membrane destruction, mitochondrial damage, Ca2+ homeostasis dysregulation and tau pathological induction. We also summarize the characteristics and pathogenicity such as the size, morphology and cytotoxicity of dimers, trimers, Aβ*56 and spherical oligomers, and suggest that Aβos may play a different role at different phases of AD pathogenesis, resulting in differential consequences on neuronal synaptotoxicity and survival. It is warranted to investigate the temporal sequence of Aβos in AD human brain and examine the relationship between different Aβos and cognitive impairment.

Background Tau pathology is a hallmark of Alzheimer’s disease (AD) and other tauopathies. During disease progression, abnormally phosphorylated forms of tau aggregate and accumulate into neurofibrillary tangles, leading to synapse loss, neuroinflammation, and neurodegeneration. Thus, targeting of tau pathology is expected to be a promising strategy for AD treatment. Methods The effect of rutin on tau aggregation was detected by thioflavin T fluorescence and transmission electron microscope imaging. The effect of rutin on tau oligomer-induced cytotoxicity was assessed by MTT assay. The effect of rutin on tau oligomer-mediated the production of IL-1β and TNF-α in vitro was measured by ELISA. The uptake of extracellular tau by microglia was determined by immunocytochemistry. Six-month-old male Tau-P301S mice were treated with rutin or vehicle by oral administration daily for 30 days. The cognitive performance was determined using the Morris water maze test, Y-maze test, and novel object recognition test. The levels of pathological tau, gliosis, NF-kB activation, proinflammatory cytokines such as IL-1β and TNF-α, and synaptic proteins including synaptophysin and PSD95 in the brains of the mice were evaluated by immunolabeling, immunoblotting, or ELISA. Results We showed that rutin, a natural flavonoid glycoside, inhibited tau aggregation and tau oligomer-induced cytotoxicity, lowered the production of proinflammatory cytokines, protected neuronal morphology from toxic tau oligomers, and promoted microglial uptake of extracellular tau oligomers in vitro. When applied to Tau-P301S mouse model of tauopathy, rutin reduced pathological tau levels, regulated tau hyperphosphorylation by increasing PP2A level, suppressed gliosis and neuroinflammation by downregulating NF-kB pathway, prevented microglial synapse engulfment, and rescued synapse loss in mouse brains, resulting in a significant improvement of cognition. Conclusion In combination with the previously reported therapeutic effects of rutin on Aβ pathology, rutin is a promising drug candidate for AD treatment based its combinatorial targeting of tau and Aβ.

The occurrence of osteoarthritis (OA) is highly correlated with the reduction of joint lubrication performance, in which persistent excessive inflammation and irreversible destruction of cartilage dominate the mechanism. The inadequate response to monotherapy methods, suboptimal efficacy caused by undesirable bioavailability, short retention, and lack of stimulus-responsiveness, are few unresolved issues. Herein, we report a pH-responsive metal-organic framework (MOF), namely, MIL-101-NH 2 , for the co-delivery of anti-inflammatory drug curcumin (CCM) and small interfering RNA (siRNA) for hypoxia inducible factor (HIF-2α). CCM and siRNA were loaded via encapsulation and surface coordination ability of MIL-101-NH 2 . Our vitro tests showed that MIL-101-NH 2 protected siRNA from nuclease degradation by lysosomal escape. The pH-responsive MIL-101-NH 2 gradually collapsed in an acidic OA microenvironment to release the CCM payloads to down-regulate the level of pro-inflammatory cytokines, and to release the siRNA payloads to cleave the target HIF-2α mRNA for gene-silencing therapy, ultimately exhibiting the synergetic therapeutic efficacy by silencing HIF-2α genes accompanied by inhibiting the inflammation response and cartilage degeneration of OA. The hybrid material reported herein exhibited promising potential performance for OA therapy as supported by both in vitro and in vivo studies and may offer an efficacious therapeutic strategy for OA utilizing MOFs as host materials.

The pretreatment of wheat straw has been recognized to be an essential step prior to anaerobic digestion, owing to the high abundance of lignocellulosic materials. In order to choose economical and effective techniques for the disposal of wheat straw, effects of five pretreatment methods including acid, alkali, co-pretreatment of acid and alkali, CaO 2 , and liquid digestate of municipal sewage sludge on anaerobic digestion of wheat straw were investigated by analyzing biogas production and organic matter degradation in the study. The results showed that among these pretreatment methods, the methane yield was highest in the liquid digestate pretreated-wheat straw with 112.6 mL g TS −1 , followed by the acid, alkali, and CaO 2 pretreatments, and the lowest was observed in the co-pretreatment of acid and alkali. Illumina MiSeq sequencing of the microbial communities in the anaerobic digesters revealed that the genera Ruminiclostridium including Ruminiclostridium and Ruminiclostridium 1, Hydrogenispora , and Capriciproducens were the main hydrolytic bacteria, acidogenic bacteria, and acetogenic bacteria, respectively, in the anaerobic digesters. Capriciproducens and Hydrogenispora dominated in the first and the later stages, respectively, in the anaerobic digesters, which could work as indicators of the anaerobic co-digestion stage of sludge and wheat straw. The total solid and SO 4 2− -S contents of the solid digestate and the NH 4 + -N concentration of the liquid digestate had a significant influence on the microbial community in the digesters. These findings indicated that liquid digestate pretreatment was a potential option to improve the anaerobic digestion of wheat straw, due to the low cost without additional chemical agents.

Cancer therapeutic nanovaccines are ideal tools to inhibit tumor growth and provide the body with continuous protecting immune surveillance. However, the conventional subcutaneous (SC) vaccination normally induces limited anti-tumor immune responses with low therapeutic efficacy. Herein, we devised clay-based nanovaccines and directly delivered them to the spleen via intravenous (IV) injection to induce the stronger anti-tumor immunity with higher efficacy for tumor prevention and treatment. The clay, i.e., layered double hydroxide (LDH) was prepared as nanoadjuvant with the average size from 77 to 285 nm and co-loaded with the model antigen ovalbumin (OVA) and bioadjuvant CpG to form CpG/OVA-LDH (CO-LDH) nanovaccines. We found that CO-LDH-215 (the size of LDH was 215 nm) promoted dendritic cells to present the most antigen, and moreover showed the highest spleen enrichment (~ 1.67% of CO-LDH-215 enriched in the spleen at 24 h post IV injection). The in vivo immunologic data showed that CO-LDH-215 induced the most potent anti-tumor immune responses and completely prevented the growth of E.G7-OVA tumor in the mouse model. Furthermore, IV injected CO-LDH-215 nanovaccine more effectively delayed tumor growth than that SC injected, largely due to the direct and quick delivery of more nanovaccines to the spleen. This study demonstrates that the therapeutic efficacy of nanovaccines can be greatly enhanced by targeted delivery of nanovaccines to the spleen via the proper vaccination route.

As an outcome of chronic liver disease, liver fibrosis involves the activation of hepatic stellate cells (HSCs) caused by a variety of chronic liver injuries. It is important to explore approaches to inhibit the activation and proliferation of HSCs for the treatment of liver fibrosis. PLK1 is overexpressed in many human tumour cells and has become a popular drug target in tumour therapy. Therefore, further study of the function of PLK1 in the cell cycle is valid. In the present study, we found that PLK1 expression was elevated in primary HSCs isolated from CCl4‐induced liver fibrosis mice and LX‐2 cells stimulated with TGF‐β1. Knockdown of PLK1 inhibited α‐SMA and Col1α1 expression and reduced the activation of HSCs in CCl4‐induced liver fibrosis mice and LX‐2 cells stimulated with TGF‐β1. We further showed that inhibiting the expression of PLK1 reduced the proliferation of HSCs and promoted HSCs apoptosis in vivo and in vitro. Furthermore, we found that the Wnt/β‐catenin signalling pathway may be essential for PLK1‐mediated HSCs activation. Together, blocking PLK1 effectively suppressed liver fibrosis by inhibiting HSC activation, which may provide a new treatment strategy for liver fibrosis.