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Hypoxic preconditioning has been shown to improve hypoxic tolerance in mice, accompanied by the downregulation of DNA methyltransferases (DNMTs) in the brain. However, the roles played by DNMTs in the multiple neuroprotective mechanisms associated with hypoxic preconditioning remain poorly understood. This study aimed to establish an in vitro model of hypoxic preconditioning, using a cultured mouse hippocampal neuronal cell line (HT22 cells), to examine the effects of DNMTs on the endogenous neuroprotective mechanisms that occur during hypoxic preconditioning. HT22 cells were divided into a control group, which received no exposure to hypoxia, a hypoxia group, which was exposed to hypoxia once, and a hypoxic preconditioning group, which was exposed to four cycles of hypoxia. To test the ability of hypoxic preadaptation to induce hypoxic tolerance, cell viability was measured using the 3-(4,5-dimethylthiazol-2-yl)-5(3-carboxymethonyphenol)-2-(4-sulfophenyl)-2H-tetrazolium assay. Cell viability improved in the hypoxic preconditioning group compared with that in the hypoxia group. The effects of hypoxic preconditioning on the cell cycle and apoptosis in HT22 cells were examined by western blot assay and flow cytometry. Compared with the hypoxia group, the expression levels of caspase-3 and spectrin, which are markers of early apoptosis and S-phase arrest, respectively, noticeably reduced in the hypoxic preconditioning group. Finally, enzyme-linked immunosorbent assay, real-time polymerase chain reaction, and western blot assay were used to investigate the changes in DNMT expression and activity during hypoxic preconditioning. The results showed that compared with the control group, hypoxic preconditioning downregulated the expression levels of DNMT3A and DNMT3B mRNA and protein in HT22 cells and decreased the activities of total DNMTs and DNMT3B. In conclusion, hypoxic preconditioning may exert anti-hypoxic neuroprotective effects, maintaining HT22 cell viability and inhibiting cell apoptosis. These neuroprotective mechanisms may be associated with the inhibition of DNMT3A and DNMT3B.

To evaluate the wound-healing effect of Antheraea pernyi epidermal growth factor (ApEGF), we performed the sequence analysis, cloning, and prokaryotic expression of cDNA from the ApEGF gene, examined the transcriptional changes, and investigated the wound-healing effect of this protein in cells and rat epidermis. Primers were designed based on available sequence information related to the ApEGF gene in a public database, and part of the ApEGF sequence was obtained. The full-length cDNA sequence of ApEGF was obtained using inverse PCR. The gene sequence fragment of ApEGF was 666 bp in length, encoding 221 amino acids, with a predicted protein mass of 24.19 kD, an isoelectric point of 5.15, and no signal peptide sequence. Sequence homology analysis revealed 86.1% sequence homology with Bombyx mori, 92.7% with Manducal sexta, 92.6% with Trichoplusia ni, and 91.8% with Helicoverpa armigera. ApEGF was truncated and then subjected to prokaryotic expression, isolation, and purification. Truncated ApEGF was used for wound-healing experiments in vitro and in vivo. The results showed that after 48 h, transforming growth factor (TGF)-β1 had 187.32% cell growth effects, and the ApEGF group had 211.15% cell growth compared to the control group in vitro. In rat epidermis, truncated ApEGF showed a significantly better healing effect than the control. This result indicated that ApEGF, which exerted a direct wound-healing effect, could be used in wound-healing therapy.

Background: Hepatocellular carcinoma (HCC) is a lethal malignancy lacking effective treatment. The Cyclin-dependent kinases 4/6 (CDK4/6) and PI3K/AKT signal pathways play pivotal roles in carcinogenesis and are promising therapeutic targets for HCC. Here we identified a new CDK4/6 and PI3K/AKT multi-kinase inhibitor for the treatment of HCC.Methods: Using a repurposing and ensemble docking methodology, we screened a library of worldwide approved drugs to identify candidate CDK4/6 inhibitors. By MTT, apoptosis, and flow cytometry analysis, we investigated the effects of candidate drug in reducing cell-viability,inducing apoptosis, and causing cell-cycle arrest. The drug combination and thermal proteomic profiling (TPP) method were used to investigate whether the candidate drug produced antagonistic effect. The in vivo anti-cancer effect was performed in BALB/C nude mice subcutaneously xenografted with Huh7 cells.Results: We demonstrated for the first time that the anti-plasmodium drug aminoquinol is a new CDK4/6 and PI3K/AKT inhibitor. Aminoquinol significantly decreased cell viability, induced apoptosis, increased the percentage of cells in G1 phase. Drug combination screening indicated that aminoquinol could produce antagonistic effect with the PI3K inhibitor LY294002. TPP analysis confirmed that aminoquinol significantly stabilized CDK4, CDK6, PI3K and AKT proteins. Finally, in vivo study in Huh7 cells xenografted nude mice demonstrated that aminoquinol exhibited strong anti-tumor activity, comparable to that of the leading cancer drug 5-fluorouracil with the combination treatment showed the highest therapeutic effect.Conclusion: The present study indicates for the first time the discovery of a new CDK4/6 and PI3K/AKT multi-kinase inhibitor aminoquinol. It could be used alone or as a combination therapeutic strategy for the treatment of HCC.

Hydrogen sulfide (H2S), a gaseous signaling molecule, is associated with the development of various malignancies via modulating various cellular signaling cascades. Published research has established the fact that inhibition of endogenous H2S production or exposure of H2S donors is an effective approach against cancer progression. However, the effect of pharmacological inhibition of endogenous H2S-producing enzymes (cystathionine-γ-lyase (CSE), cystathionine-β-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (3-MPST)) on the growth of breast cancer (BC) remains unknown. In the present study, DL-propargylglycine (PAG, inhibitor of CSE), aminooxyacetic acid (AOAA, inhibitor of CBS), and L-aspartic acid (L-Asp, inhibitor of 3-MPST) were used to determine the role of endogenous H2S in the growth of BC by in vitro and in vivo experiments. An in silico study was also performed to confirm the results. Corresponding to each enzyme in separate groups, we treated BC cells (MCF-7 and MDA-MB-231) with 10 mM of PAG, AOAA, and L-Asp for 24 h. Findings reveal that the combined dose (PAG + AOAA + L-Asp) group showed exclusive inhibitory effects on BC cells’ viability, proliferation, migration, and invasion compared to the control group. Further, treated cells exhibited increased apoptosis and a reduced level of phospho (p)-extracellular signal-regulated protein kinases such as p-AKT, p-PI3K, and p-mTOR. Moreover, the combined group exhibited potent inhibitory effects on the growth of BC xenograft tumors in nude mice, without obvious toxicity. The molecular docking results were consistent with the wet lab experiments and enhanced the reliability of the drugs. In conclusion, our results demonstrate that the inhibition of endogenous H2S production can significantly inhibit the growth of human breast cancer cells via the AKT/PI3K/mTOR pathway and suggest that endogenous H2S may act as a promising therapeutic target in human BC cells. Our study also empowers the rationale to design novel H2S-based anti-tumor drugs to cure BC.

Abstract Background Socially disadvantaged groups, such as drug users, sex workers and homeless individuals, are labelled as “hard-to-reach” (HTR) in public health and medical research. HIV disproportionately impacts these populations, but data on how the HTR status could affect antiretroviral therapy (ART) adherence among HIV-positive people are limited and have not been previously synthesized in a systematic manner. We performed a meta-analysis to explore the association between HTR status and optimal antiretroviral therapy adherence in the HIV-infected population to provide evidence and recommendations regarding ART adherence improvement and HIV infection control and prevention among HTR people. Methods The PubMed, EMBASE, and Cochrance Library databases and the bibliographies of relevant studies were systematically searched up to December 2018. Full-text studies published in English were included, and no geographic or race restrictions were applied. Studies that quantitatively assessed the association between HTR status and optimal ART adherence among HIV-infected populations with a status of homelessness, sex work, or drug use were eligible for inclusion. We estimated the pooled odds ratios (ORs) of HTR characteristics related to ART adherence from each eligible study using a random effects model. The sensitivity, heterogeneity and publication bias were assessed. Results Our search identified 593 articles, of which 29 studies were eligible and included in this meta-analysis. The studies were carried out between 1993 and 2017 and reported between 1999 and 2018. The results showed that HTR status resulted in a 45% reduction in the odds of achieving optimal ART adherence compared to odds in the general population (OR = 0.55, 95% confidential intervals (CIs) 0.49–0.62), and this significant inverse association was consistently found regardless of study design, exposure measurement, adherence cut-off points, etc. Subgroup analyses revealed that the HTRs tend to be suboptimal adhering during a longer observational period. Conclusions HIV treatment adherence is extremely negatively affected by HTR status. It is crucial to develop appropriate interventions to improve ART adherence and health outcomes among HTR people who are HIV-infected.

Bisperoxo (1,10-phenanthroline) oxovanadate (BpV) can reportedly block the cell cycle. The present study examined whether BpV alters gene expression by affecting DNA methyltransferases (DNMTs), which would impact the cell cycle. Immortalized mouse hippocampal neuronal precursor cells (HT22) were treated with 0.3 or 3 μM BpV. Proliferation, morphology, and viability of HT22 cells were detected with an IncuCyte real-time video imaging system or inverted microscope and 3-(4,5-dimethylthiazol-2-yl)-5(3-carboxymethonyphenol)-2-(4-sulfophenyl)-2H-tetrazolium, respectively. mRNA and protein expression of DNMTs and p21 in HT22 cells was detected by real-time polymerase chain reaction and immunoblotting, respectively. In addition, DNMT activity was measured with an enzyme-linked immunosorbent assay. Effects of BpV on the cell cycle were analyzed using flow cytometry. Results demonstrated that treatment with 0.3 μM BpV did not affect cell proliferation, morphology, or viability; however, treatment with 3 μM BpV decreased cell viability, increased expression of both DNMT3B mRNA and protein, and inhibited the proliferation of HT22 cells; and 3 μM BpV also blocked the cell cycle and increased expression of the regulatory factor p21 by increasing DNMT expression in mouse hippocampal neurons.

Hydrogen sulfide (H2S) is an endogenous biologically active gas produced in mammalian tissues. It plays a very critical role in many pathophysiological processes in the body. It can be endogenously produced through many enzymes analogous to the cysteine family, while the exogenous source may involve inorganic sulfide salts. H2S has recently been well investigated with regard to the onset of various carcinogenic diseases such as lung, breast, ovaries, colon cancer, and neurodegenerative disorders. H2S is considered an oncogenic gas, and a potential therapeutic target for treating and diagnosing cancers, due to its role in mediating the development of tumorigenesis. Here in this review, an in-detail up-to-date explanation of the potential role of H2S in different malignancies has been reported. The study summarizes the synthesis of H2S, its roles, signaling routes, expressions, and H2S release in various malignancies. Considering the critical importance of this active biological molecule, we believe this review in this esteemed journal will highlight the oncogenic role of H2S in the scientific community.

Three-dimensional (3D) bioprinting is one of the most promising additive manufacturing technologies for fabricating various biomimetic architectures of tissues and organs. In this context, the bioink, a critical element for biofabrication, is a mixture of biomaterials and living cells used in 3D printing to create cell-laden structures. Recently, decellularized extracellular matrix (dECM)-based bioinks derived from natural tissues have garnered enormous attention from researchers due to their unique and complex biochemical properties. This review initially presents the details of the natural ECM and its role in cell growth and metabolism. Further, we briefly emphasize the commonly used decellularization treatment procedures and subsequent evaluations for the quality control of the dECM. In addition, we summarize some of the common bioink preparation strategies, the 3D bioprinting approaches, and the applicability of 3D-printed dECM bioinks to tissue engineering. Finally, we present some of the challenges in this field and the prospects for future development.

The relationship between antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and lung cancer remains unclear. A 66-year-old man presented with pulmonary nodules. Histological examination of a specimen from computed tomography-guided percutaneous transthoracic biopsy revealed adenocarcinoma. The patient was treated using cryoablation and systemic chemotherapy. Sixteen months later, the patient presented with fever, nasal inflammation, recurrent lung lesions, elevated serum creatinine levels, and high levels of ANCA. Histological examination of a specimen from ultrasound-guided percutaneous renal biopsy revealed pauci-immune necrotizing crescentic glomerulonephritis. The patient responded to treatment, but granulomatosis with polyangiitis recurred and he later died. This case highlights the possibility of sequential AAV with lung cancer. Although this is relatively rare, further research is needed to better understand the association or pathophysiological link between lung cancer and AAV.

Supramolecular nanoparticles for photothermal therapy (PTT) have shown promising therapeutic efficacy in the primary tumor and great potential for turning the whole-body immune microenvironment from “cold” to “hot,” which allows for the simultaneous treatment of the primary tumor and the metastatic site. In this work, we develop a liposome-based PTT nanoparticle through the self-assembly of FDA-approved intravenous injectable lipids and a photothermal agent, indocyanine green (ICG). The obtained ICG-liposome shows long-term storage stability, high ICG encapsulation efficiency (>95%), and enhanced near-infrared (NIR) light-triggered photothermal reaction both in vitro and in vivo. The ICG-liposome efficiently eradicated the primary tumor upon laser irradiation in two colon cancer animal models (CT26 and MC38) and promoted the infiltration of CD8 T cells to distant tumors. However, PTT from ICG-liposome shows only a minimal effect on the inhibition of distant tumor growth in long-term monitoring, predicting other immunosuppressive mechanisms that exist in the distant tumor. By immune-profiling of the tumor microenvironment, we find that the distant tumor growth after PTT highly correlates to compensatory upregulation of immune checkpoint biomarkers, including program death-1 (PD-1), T-cell immunoglobulin, and mucin domain-containing protein 3 (TIM-3), in tumor-infiltrating CD8 T cells. Based on this mechanism, we combine dual PD-1 and TIM-3 blockade with PTT in an MC38 tumor model. This combo successfully clears the primary tumor, generates a systemic immune response, and inhibits the growth of the distant tumor. The ICG-liposome-combined PD-1/TIM-3 blockade strategy sheds light on the future clinical use of supramolecular PTT for cancer immunotherapy.

Among the models that describe the dynamic behaviors of financial market, the discrete time microstructure model stands out because of its efficiency in considering the relationship between the price, excess demand, and liquidity of a market. However, the estimation problem of such a microstructure model is challenging, because the model is essentially a nonlinear state space model. A decent solution is to define a self-organizing state-space model by combining the unknown parameters and the state vector of the original model into a new state vector. Then, the sequential Monte Carlo method can be used to simultaneously estimate the parameters and states. To handle the difficulty in setting the initial distributions of parameters for the self-organizing state space model, we propose to use the results obtained by the Kalman filter on the original microstructure model. Finally, a dynamic asset allocation strategy is designed based on estimated excess demand using the self-organizing state space model. The proposed methodology is evaluated by the China SZSE (ShenZhen Stock Exchange) Composite Index time series, and the results show its effectiveness.

A total of 153 patients with acute ischemic stroke were divided into diabetes group and non-diabetes group. Baseline characteristics and prognosis were observed and compared between patients of the 2 groups. The correlation between diabetes and outcome after intravenous thrombolysis was analyzed by multivariate stepwise Logistic regression analysis. The results showed that the patients in diabetes group accounted for less favorable outcome than that in non-diabetes group (26.83% vs 41.96%; χ2 = 11.692, P = 0.001) at 90 d after thrombolytic treatment. Logistic regression analysis indicated that diabetes was relevant to unfavorable outcome of ischemic stroke (OR = 1.224, 95% CI: 1.034-1.449; P = 0.019). The results illustrate that diabetes is highly relevant to unfavorable outcome of thrombolytic patients with acute ischemic stroke. doi: 10.3969/j.issn.1672-6731.2014.11.018

Mycotoxin contamination in food products may cause serious health hazards and economic losses. The effective control and accurate detection of mycotoxins have become a global concern. Even though a variety of methods have been developed for mycotoxin detection, most conventional methods suffer from complicated operation procedures, low sensitivity, high cost, and long assay time. Therefore, the development of simple and sensitive methods for mycotoxin assay is highly needed. The introduction of nucleic acid signal amplification technology (NASAT) into aptasensors significantly improves the sensitivity and facilitates the detection of mycotoxins. Herein, we give a comprehensive review of the recent advances in NASAT-based aptasensors for assaying mycotoxins and summarize the principles, features, and applications of NASAT-based aptasensors. Moreover, we highlight the challenges and prospects in the field, including the simultaneous detection of multiple mycotoxins and the development of portable devices for field detection. [ABSTRACT FROM AUTHOR]