Partial epithelial mesenchymal transition (p-EMT) was found to play a potential role in the initial stage of metastasis in human head and neck squamous cell carcinoma (HNSCC). Some long noncoding RNAs (lncRNAs) have been reported to function as promoters or inhibitors of cancer metastasis. This study aimed to identify p-EMT-related lncRNAs in HNSCC.

Recent studies have identified photodynamic therapy (PDT) as a promising approach for cancer treatment. Here, in this study, we have constructed cancer cell membrane (CCM)-coated silica nanoparticles (SIL) as an artificial cell carrier (CCM/SIL) to effectively deliver chlorin e6 (Ce6), a commonly adopted photodynamic reagent (CCM/SIL/Ce6), to achieve enhanced PDT of cancer. In addition, apart from the generally recognized cytotoxicity induced by reactive oxygen species (ROS), our study also revealed that ROS could further potentiate the loss of intercellular junctions and integrity disruption as a result of down-regulation of VE-cadherin and CD31. Consequently, dendritic cells (DCs) were more readily accumulated to the tumor tissue and became maturated, which secreted tumor necrosis factor-α and interleukin-12 (IL-12) to trigger the following immune responses. Our work not only explored the anticancer feasibility of a new system but also demonstrated the underlining mechanisms responsible for PDT-induced anticancer effects, which offers a new perspective to employ and improve the efficacy of PDT and related systems.

The present study was designed to investigate the function of matrix metalloproteinase‑9 (MMP‑9) in human glioma cells and the potential regulatory mechanisms. Reverse transcription‑quantitative polymerase chain reaction was used to analyze the expression of MMP‑9 and microRNA‑34a (miR‑34a) in the plasma of patients with glioma and healthy volunteers. MTT and Transwell assays were used to assess cell growth and migration, respectively. Annexin‑V/propidium iodide staining was used to measure cell apoptosis. In addition, MMP‑9 expression was measured using western blot analysis. In patients with glioma, MMP‑9 expression was increased, while miR‑34a expression was suppressed, compared with the normal group. Overall survival (OS) and disease‑free survival (DFS) of patients with high MMP‑9 expression were decreased compared with those with low MMP‑9 expression. OS and DFS of patients with low miR‑34a expression were decreased compared with those with high miR‑34a expression. Downregulation of miR‑34a promoted cell growth and migration, and inhibited apoptosis in U251‑MG glioma cells. However, overexpression of miR‑34a inhibited cell growth and migration, and induced apoptosis in glioma cells. Furthermore, downregulation of miR‑34a using anti‑miR‑34a induced MMP‑9 protein expression in glioma cells; whereas, overexpression of miR‑34a suppressed MMP‑9 protein expression in glioma cells. SB‑3CT, an inhibitor of MMP‑9, attenuated the effects of miR‑34a mimic on glioma cells. Together, these results indicated that miR‑34a inhibited cell growth and migration in human glioma cells by regulating MMP‑9.

Accumulating studies demonstrate that dihydromyricetin (DMY), a compound extracted from Chinese traditional herb, Ampelopsis grossedentata, attenuates atherosclerotic process by improvement of endothelial dysfunction. However, the underlying mechanism remains poorly understood. Thus, the aim of this study is to investigate the potential mechanism behind the attenuating effects of DMY on tumor necrosis factor alpha- (TNF-α-) induced endothelial dysfunction. In response to TNF-α, microRNA-21 (miR-21) expression was significantly increased in human umbilical vein endothelial cells (HUVECs), in line with impaired endothelial dysfunction as evidenced by decreased tube formation and migration, endothelial nitric oxide synthase (eNOS) (ser1177) phosphorylation, dimethylarginine dimethylaminohydrolases 1 (DDAH1) expression and metabolic activity, and nitric oxide (NO) concentration as well as increased asymmetric dimethylarginine (ADMA) levels. In contrast, DMY or blockade of miR-21 expression ameliorated endothelial dysfunction in HUVECs treated with TNF-α through downregulation of miR-21 expression, whereas these effects were abolished by overexpression of miR-21. In addition, using a nonspecific NOS inhibitor, L-NAME, also abrogated the attenuating effects of DMY on endothelial dysfunction. Taken together, these data demonstrated that miR-21-mediated DDAH1/ADMA/NO signal pathway plays an important role in TNF-α-induced endothelial dysfunction, and DMY attenuated endothelial dysfunction induced by TNF-α in a miR-21-dependent manner.

Alternative splicing (AS) has emerged as a key event in tumor development and microenvironment formation. However, comprehensive analysis of AS and its clinical significance in head and neck squamous cell carcinoma (HNSC) is urgently required. Methods: Genome-wide profiling of AS events using RNA-Seq data from The Cancer Genome Atlas (TCGA) program was performed in a cohort of 464 patients with HNSC. Cancer-associated AS events (CASEs) were identified between paired HNSC and adjacent normal tissues and evaluated in functional enrichment analysis. Splicing networks and prognostic models were constructed using bioinformatics tools. Unsupervised clustering of the CASEs identified was conducted and associations with clinical, molecular and immune features were analyzed. Results: We detected a total of 32,309 AS events and identified 473 CASEs in HNSC; among these, 91 were validated in an independent cohort (n = 15). Functional protein domains were frequently altered, especially by CASEs affecting cancer drivers, such as PCSK5. CASE parent genes were significantly enriched in pathways related to HNSC and the tumor immune microenvironment, such as the viral carcinogenesis (FDR < 0.001), Human Papillomavirus infection (FDR < 0.001), chemokine (FDR < 0.001) and T cell receptor (FDR < 0.001) signaling pathways. CASEs enriched in immune-related pathways were closely associated with immune cell infiltration and cytolytic activity. AS regulatory networks suggested a significant association between splicing factor (SF) expression and CASEs and might be regulated by SF methylation. Eighteen CASEs were identified as independent prognostic factors for overall and disease-free survival. Unsupervised clustering analysis revealed distinct correlations between AS-based clusters and prognosis, molecular characteristics and immune features. Immunogenic features and immune subgroups cooperatively depict the immune features of AS-based clusters. Conclusion: This comprehensive genome-wide analysis of the AS landscape in HNSC revealed novel AS events related to carcinogenesis and immune microenvironment, with implications for prognosis and therapeutic responses.

Moso bamboo is one of the economically most important plants in China. Moso bamboo is a monocarpic perennial that exhibits poor and slow germination. Thus, the flowering often causes destruction of moso bamboo forestry. However, how control of flowering and seed germination are regulated in moso bamboo is largely unclear. In this study, we identified 5 members (PhFT1-5) of the phosphatidyl ethanolamine-binding proteins (PEBP) family from moso bamboo genome that regulate flowering, flower architecture and germination, and characterized the function of these PEBP family genes further in Arabidopsis. Phylogenetic analysis revealed that 3 (PhFT1, PhFT2 and PhFT3), 1 (PhFT4) and 1 (PhFT5) members belong to the TFL1-like clade, FT-like clade, and MFT-like clade, respectively. These PEBP family genes possess all structure necessary for PEBP gene function. The ectopic overexpression of PhFT4 and PhFT5 promotes flowering time in Arabidopsis, and that of PhFT1, PhFT2 and PhFT3 suppresses it. In addition, the overexpression of PhFT5 promotes seed germination rate. Interestingly, the overexpression of PhFT1 suppressed seed germination rate in Arabidopsis. The expression of PhFT1 and PhFT5 is significantly higher in seed than in tissues including leaf and shoot apical meristem, implying their function in seed germination. Taken together, our results suggested that the PEBP family genes play important roles as regulators of flowering and seed germination in moso bamboo and thereby are necessary for the sustainability of moso bamboo forest.

Autism spectrum disorder (ASD) is a complex and prevalent neurodevelopmental disorder characterized by deficits in social communication and social interaction as well as repetitive behaviors. Alterations in function connectivity are widely recognized in recent electroencephalogram (EEG) studies. However, most studies have not reached consistent conclusions, which could be due to the developmental nature and the heterogeneity of ASD.

Objective: To observe whether urethral injection of chemokine (c-c motif) ligand 7 (CCL7) and overexpressing CC receptor 1 (CCR1) in mesenchymal stem cells (MSCs) can promote their homing and engraftment to the injured tissue, and improve the recovery of simulated birth injury-induced stress urinary incontinence (SUI) in rats. Methods: Female rats underwent a dual injury consisting of vaginal distension (VD) and pudendal nerve crush (PNC) to induce SUI. Bone marrow-derived MSCs were transduced with lentivirus carrying CCR1 (MSC-CCR1) and green fluorescent protein (GFP). Forty virgin Sprague-Dawley rats were evenly distributed into four groups: sham SUI + MSC-CCR1+CCL7, SUI + MSCs, SUI + MSC-CCR1, and SUI + MSC-CCR1+CCL7 group. The engrafted MSCs in urethra were quantified. Another three groups of rats, including sham SUI + sham MSC-CCR1+CCL7 treatment, SUI + sham MSC-CCR1+CCL7 treatment, and SUI + MSC-CCR1+CCL7 treatment group, were used to evaluate the functional recovery by testing external urethral sphincter electromyography (EUS EMG), pudendal nerve motor branch potentials (PNMBP), and leak point pressure (LPP) 1 week after injury and injection. Urethra and vagina were harvested for histological examination. Results: The SUI + MSC-CCR1+CCL7 group received intravenous injection of CCR1-overexpressing MSCs and local injection of CCL7 after simulated birth injury had the most engraftment of MSCs to the injured tissues and best functional recovery from SUI compared to other groups. Histological examination showed a partial repair in the SUI + MSC-CCR1+CCL7 group. Conclusions: Our study demonstrated combined treatment with CCR1-overexpressing MSCs and CCL7 can increase engraftment of MSCs and promote the functional recovery of simulated birth trauma-induced SUI in rats, which could be a new therapeutic strategy for SUI.

Hepatocellular carcinoma (HCC) remains a challenge in the medical field due to its high malignancy and mortality rates particularly for HCC, which has developed multidrug resistance. Therefore, the identification of efficient chemotherapeutic drugs for multidrug resistant HCC has become an urgent issue. Natural products have always been of significance in drug discovery. In the present study, a cell-based method was used to screen a natural compound library, which consisted of 78 compounds, and the doxorubicin-resistant cancer cell line, HepG2/ADM, as screening tools. The findings of the present study led to the shortlisting of one of the compounds, digitoxin, which displayed an inhibitory effect on HepG2/ADM cells, with 50% inhibitory concentration values of 132.65±3.83, 52.29±6.26, and 9.13±3.67 nM for 24, 48, and 72 h, respectively. Immunofluorescence, western blotting and cell cycle analyses revealed that digitoxin induced G2/M cell cycle arrest via the serine/threonine-protein kinase ATR (ATR)-serine/threonine-protein kinase Chk2 (CHK2)-M-phase inducer phosphatase 3 (CDC25C) signaling pathway in HepG2/ADM cells, which may have resulted from a DNA double-stranded break. Digitoxin also induced mitochondrial apoptosis, which was characterized by changes in the interaction between Bcl-2 and Bax, the release of cytochrome c, as well as the activation of the caspase-3 and -9. To the best of our knowledge, the present study is the first report that digitoxin displays an anti-HCC effect on HepG2/ADM cells through G2/M cell cycle arrest, which was mediated by the ATR-CHK2-CDC25C signaling pathway and mitochondrial apoptosis. Therefore, digitoxin could be a promising chemotherapeutic agent for the treatment of patients with HCC.

This study is to investigate the effects and the mechanisms of mitochondrial ferritin (FtMt) on the glioma tumorigenesis and angiogenesis.

To study the correlation between single nucleotide polymorphism (SNP) of the 3' untranslated region (UTR) rs9722 locus in S100B and the risk of chronic heart failure (CHF), plasma levels of S100B protein as well as has-miR-340-3p in a Chinese Han population.A total of 215 patients with CHF (124 ischemic cardiomyopathy (ICM) and 91 dilated cardiomyopathy (DCM)) and 215 healthy controls were recruited to analyze the S100B rs9722 genotype by Sanger sequencing. The levels of hsa-miR-340-3p in the plasma were detected by RT-PCR, and S100B levels were detected by ELISA.The risk of CHF in S100B rs9722 locus T allele carriers was 4.24 times higher than that in those with the C allele (95% CI: 2.84-6.33, P < .001). The association of S100B rs9722 locus SNP with ICM and DCM risk was not affected by factors such as age, gender, and body mass index (BMI). The levels of plasma S100B and hsa-miR-340-3p in patients with ICM and DCM were significantly higher than those in the control group (P < .001). There was no significant difference in plasma S100B levels between patients with ICM and DCM (P > .05). Among ICM, DCM, and control subjects, TT genotype carriers had the highest levels of plasma S100B and hsa-miR-340-3p, followed by the CT genotype and TT genotype, and the difference was statistically significant (P < .05). Plasma hsa-miR-340-3p levels were positively correlated with S100B levels in the control subjects and patients with ICM and DCM.The S100B rs9722 locus SNP is associated with CHF risk in a Chinese Han population.

Coronaviruses are specific crown-shaped viruses that were first identified in the 1960s, and three typical examples of the most recent coronavirus disease outbreaks include severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and COVID-19. Particularly, COVID-19 is currently causing a worldwide pandemic, threatening the health of human beings globally. The identification of viral pathogenic mechanisms is important for further developing effective drugs and targeted clinical treatment methods. The delayed revelation of viral infectious mechanisms is currently one of the technical obstacles in the prevention and treatment of infectious diseases. In this study, we proposed a random walk model to identify the potential pathological mechanisms of COVID-19 on a virus-human protein interaction network, and we effectively identified a group of proteins that have already been determined to be potentially important for COVID-19 infection and for similar SARS infections, which help further developing drugs and targeted therapeutic methods against COVID-19. Moreover, we constructed a standard computational workflow for predicting the pathological biomarkers and related pharmacological targets of infectious diseases.

This study investigates mosquito proboscis-inspired (MPI) insertion applied to the clinically used biopsy needle to reduce tissue deformation and organ displacement. Advanced medical imagining has enabled early-stage identification of cancerous lesions that require needle biopsy for minimally invasive tissue sampling and pathological analysis. Accurate cancer diagnosis depends on the accuracy of needle deployment to the targeted cancerous lesion site. However, currently available needle delivery systems deform and move soft tissue and organs, leading to a non-diagnostic biopsy or undersampling of the target. Two features inspired by the mosquito proboscis were adopted for MPI insertion in prostate biopsy: (1) the harpoon-shape notches at the needle tip and (2) reciprocating needle-cannula motions for incremental insertion. The local tissue deformation and global prostate displacement during the MPI vs. traditional direct insertions were quantified by optically tracking the displacement of particle-embedded tissue-mimicking phantoms. Results show that the MPI needle insertion reduced both local tissue deformation and global prostate displacement because of the opposite needle-cannula motions and notches which stabilized and reduced the tissue deformation during insertion. Findings provide proof of concept for MPI insertion in the clinical biopsy procedures as well as insights of needle-tissue interaction for future biopsy technology development.

It has been suggested that there is a critical window for estrogen replacement therapy (ERT) in postmenopausal women with Alzheimer's disease (AD); however, supporting evidence is lacking. To address this issue, we investigated the effective period for estradiol (E2) treatment using a mouse model of AD. Four-month-old female APPswe/PSEN1dE9 (APP/PS1) mice were ovariectomized (OVX) and treated with E2 for 2 months starting at the age of 4 months (early period), 6 months (mid-period), or 8 months (late period). We then evaluated hippocampal neurogenesis, β-amyloid (Aβ) accumulation, telomerase activity, and hippocampal-dependent behavior. Compared to age-matched wild type mice, APP/PS1 mice with intact ovaries showed increased proliferation of hippocampal neural stem cells (NSCs) at 8 months of age and decreased proliferation of NSCs at 10 months of age; meanwhile, Aβ accumulation progressively increased with age, paralleling the reduced survival of immature neurons. OVX-induced depletion of E2 in APP/PS1 mice resulted in elevated Aβ levels accompanied by elevated p75 neurotrophin receptor (p75NTR) expression and increased NSC proliferation at 6 months of age, which subsequently declined; accelerated reduction of immature neurons starting from 6 months of age, and reduced telomerase activity and worsened memory performance at 10 months of age. Treatment with E2 in the early period post-OVX, rather than in the mid or late period, abrogated these effects, and p75NTR inhibition reduced the overproliferation of NSCs in 6-month-old OVX-APP/PS1 mice. Thus, E2 deficiency in young APP/PS1 mice exacerbates cognitive deficits and depletes the hippocampal NSC pool in later life; this can be alleviated by E2 treatment in the early period following OVX, which prevents Aβ/p75NTR-induced NSC overproliferation and preserves telomerase activity.

Dihydromyricetin, the most abundant natural flavonoid isolated from Ampelopsis grossedentata, exhibits broad anti-tumor effects. However, the effects of dihydromyricetin on cholangiocarcinoma remain unclear. This study examined the anti-tumor effects of dihydromyricetin in two human cholangiocarcinoma cell lines HCCC9810 and TFK-1, and the underlying mechanism was also investigated. Our study was the first to show that dihydromyricetin significantly inhibited cell proliferation, migration, invasion and promoted apoptosis in cholangiocarcinoma cells. By analyzing the TCGA dataset, we found that expression of miR-21, an oncogene and a potential target of anticancer drugs for cholangiocarcinoma, was upregulated in cholangiocarcinoma tissues compared to paired control tissues. Moreover, dihydromyricetin significantly reduced the expression of miR-21 in a dose-dependent manner. Overexpression of miR-21 remarkably abolished the inhibitory effects of dihydromyricetin on cell proliferation, migration, invasion and abrogated its effect of promoting cell apoptosis in both HCCC9810 and TFK-1 cells. Dihydromyricetin remarkably increased the expression of PTEN and decreased the expression of phosphorylated Akt, while overexpression of miR-21 abrogated the modulation of PTEN/ Akt pathway by dihydromyricetin. Taken together, our study demonstrates that dihydromyricetin inhibits cell proliferation, migration, invasion and promotes apoptosis in cholangiocarcinoma cells via regulating miR-21.

Heterotypic interactions between tumor cells and macrophages can enable tumor progression and hold potential for the development of therapeutic interventions. However, the communication between tumors and macrophages and its mechanism are poorly understood. Here, we find that tumor-associated macrophages (TAM) from tumor-bearing mice have high amounts of lipid as compared to macrophages from tumor-free mice. TAM also present high lipid content in clinical human gastric cancer patients. Functionally, TAM with high lipid levels are characterized by polarized M2-like profiling, and exhibit decreased phagocytic potency and upregulated programmed death ligand 1 (PD-L1) expression, blocking anti-tumor T cell responses to support their immunosuppressive function. Mechanistically, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis identifies the specific PI3K pathway enriched within lipid-laid TAM. Lipid accumulation in TAM is mainly caused by increased uptake of extracellular lipids from tumor cells, which leads to the upregulated expression of gamma isoform of phosphoinositide 3-kinase (PI3K-γ) polarizing TAM to M2-like profiling. Correspondingly, a preclinical gastric cancer model is used to show pharmacological targeting of PI3K-γ in high-lipid TAM with a selective inhibitor, IPI549. IPI549 restores the functional activity of macrophages and substantially enhances the phagocytosis activity and promotes cytotoxic-T-cell-mediated tumor regression. Collectively, this symbiotic tumor-macrophage interplay provides a potential therapeutic target for gastric cancer patients through targeting PI3K-γ in lipid-laden TAM.

Drug Anatomical Therapeutic Chemical (ATC) classification system is a widely used and accepted drug classification system. It is recommended and maintained by World Health Organization (WHO). Each drug in this system is assigned one or more ATC codes, indicating which classes it belongs to in each of five levels. Given a chemical/drug, correct identification of its ATC codes in such system can be helpful to understand its therapeutic effects. Several computational methods have been proposed to identify the first level ATC classes for any drug. Most of them built multi-label classifiers in this regard. One previous study proposed a quite different scheme, which contained two network methods, based on shortest path (SP) and random walk with restart (RWR) algorithms, respectively, to infer novel chemicals/drugs for each first level class. However, due to the limitations of SP and RWR algorithms, there still exist lots of hidden chemicals/drugs that above two methods cannot discover. This study employed another classic network algorithm, Laplacian heat diffusion (LHD) algorithm, to construct a new computational method for recognizing novel latent chemicals/drugs of each first level ATC class. This algorithm was applied on a chemical network, which containing lots of chemical interaction information, to evaluate the associations of candidate chemicals/drugs and each ATC class. Three screening tests, which measured the specificity and association to one ATC class, followed to yield more reliable potential members for each class. Some hidden chemicals/drugs were recognized, which cannot be found out by previous methods, and they were extensively analyzed to confirm that they can be novel members in the corresponding ATC class.

Waardenburg syndrome is an uncommon genetic condition characterized by at least some degree of congenital hearing loss and pigmentation deficiencies. However, the genetic pathway affecting the development of stria vascularis is not fully illustrated.

Propofol is the most common intravenous anesthetic agent for induction and maintenance of anesthesia, and has been used clinically for more than 30 years. However, the mechanism by which propofol induces loss of consciousness (LOC) remains largely unknown. The adenosine A2A receptor (A2A R) has been extensively proven to have an effect on physiological sleep. It is, therefore, important to investigate the role of A2A R in the induction of LOC using propofol. In the present study, the administration of the highly selective A2A R agonist (CGS21680) and antagonist (SCH58261) was utilized to investigate the function of A2A R under general anesthesia induced by propofol by means of animal behavior studies, resting-state magnetic resonance imaging and c-Fos immunofluorescence staining approaches. Our results show that CGS21680 significantly prolonged the duration of LOC induced by propofol, increased the c-Fos expression in nucleus accumbens (NAc) and suppressed the functional connectivity of NAc-dorsal raphe nucleus (DR) and NAc-cingulate cortex (CG). However, SCH58261 significantly shortened the duration of LOC induced by propofol, decreased the c-Fos expression in NAc, increased the c-Fos expression in DR, and elevated the functional connectivity of NAc-DR and NAc-CG. Collectively, our findings demonstrate the important roles played by A2A R in the LOC induced by propofol and suggest that the neural circuit between NAc-DR maybe controlled by A2A R in the mechanism of anesthesia induced by propofol.

An increasing number of studies have investigated the value of optical coherence tomography in patients with neuromyelitis optica (NMO) spectrum disorders; however, no systematic review has been performed to date. We aimed to systematically review and investigate the possibility of differentiating NMO and multiple sclerosis (MS) via an optical coherence tomography measurement.