Androgen receptor (AR) plays an important role in many kinds of cancers. However, the molecular mechanisms of AR in gastric cancer (GC) are poorly characterized. Here, we investigated the role of AR in GC cell migration, invasion and metastatic potential. Our data showed that AR expression was positively correlated with lymph node metastasis and late TNM stages. These findings were accompanied by activation of AKT and upregulation of matrix metalloproteinase 9 (MMP9). AR overexpression induced increases in GC cell migration, invasion and proliferation in vitro and in vivo. These effects were attenuated by inhibition of AKT, AR and MMP9. AR overexpression upregulated MMP9 protein levels, whereas this effect was counteracted by AR siRNA. Inhibition of AKT by siRNA or an inhibitor (MK-2206 2HC) decreased AR protein expression in both stably transfected and parental SGC-7901 cells. Luciferase reporter and chromatin immunoprecipitation assays demonstrated that AR bound to the AR-binding sites of the MMP9 promoter. In summary, AR overexpression induced by AKT phosphorylation upregulated MMP9 by binding to its promoter region to promote gastric carcinogenesis. The AKT/AR/MMP9 pathway plays an important role in GC metastasis and may be a novel therapeutic target for GC treatment.

Elevated MELK expression is featured in multiple tumors and correlated with tumorigenesis and tumor development. This study is aimed to investigate the mechanisms of MELK-mediated development of gastric cancer.

Several studies suggest that mesenchymal stem cells (MSCs) possess antitumor properties; however, the exact mechanisms remain unclear. Recently, microvesicles (MVs) are considered as a novel avenue intercellular communication, which may be a mediator in MSCs-related antitumor effect. In the present study, we evaluated whether MVs derived from human umbilical cord Wharton's jelly mesenchymal stem cells (hWJMSCs) may inhibit bladder tumor T24 cells growth using cell culture and the BALB/c nu/nu mice xenograft model. CCK-8 assay and Ki-67 immunostaining were performed to estimate cell proliferation in vitro and in vivo. Flow cytometry and TUNEL assay were used to assess cell cycle and apoptosis. To study the conceivable mechanism by which hWJMSC-MVs attenuate bladder tumor T24 cells, we estimated the expression of Akt/p-Akt, p-p53, p21 and cleaved Caspase 3 by Western blot technique after exposing T24 cells to hWJMSC-MVs for 24, 48 and 72h. Our data indicated that hWJMSC-MVs can inhibit T24 cells proliferative viability via cell cycle arrest and induce apoptosis in T24 cells in vitro and in vivo. This study showed that hWJMSC-MVs down-regulated phosphorylation of Akt protein kinase and up-regulated cleaved Caspase 3 during the process of anti-proliferation and pro-apoptosis in T24 cells. These results demonstrate that hWJMSC-MVs play a vital role in hWJMSC-induced antitumor effect and may be a novel tool for cancer therapy as a new mechanism of cell-to-cell communication.

In this study, we examined the expression of lncRNA ENST00000413528 in glioma and determined its role in glioma development.

Microvesicles (MVs) derived from human Wharton's jelly mesenchymal stem cells (MSC-MVs) were demonstrated to ameliorate acute lung injury (ALI). We have previously found that MSC-MV-transferred hepatocyte growth factor was partly involved in their therapeutic effects. Since MSC-MVs also contained a substantial quantity of miR-100, which plays an important role in lung cancer and injury, we speculated that miR-100 might similarly account for a part of the therapeutic effects of MSC-MVs.

During acute kidney injury (AKI), tubular cell dedifferentiation initiates cell regeneration; hepatocyte growth factor (HGF) is involved in modulating cell dedifferentiation. Mesenchymal stem cell (MSC)-derived microvesicles (MVs) deliver RNA into injured tubular cells and alter their gene expression, thus regenerating these cells. We boldly speculated that MVs might induce HGF synthesis via RNA transfer, thereby facilitating tubular cell dedifferentiation and regeneration. In a rat model of unilateral AKI, the administration of MVs promoted kidney recovery. One of the mechanisms of action is the acceleration of tubular cell dedifferentiation and growth. Both in vivo and in vitro, rat HGF expression in damaged rat tubular cells was greatly enhanced by MV treatment. In addition, human HGF mRNA present in MVs was delivered into rat tubular cells and translated into the HGF protein as another mechanism of HGF induction. RNase treatment abrogated all MV effects. In the in vitro experimental setting, the conditioned medium of MV-treated injured tubular cells, which contains a higher concentration of HGF, strongly stimulated cell dedifferentiation and growth, as well as Erk1/2 signaling activation. Intriguingly, these effects were completely abrogated by either c-Met inhibitor or MEK inhibitor, suggesting that HGF induction is a crucial contributor to the acceleration of cell dedifferentiation and growth. All these findings indicate that MV-induced HGF synthesis in damaged tubular cells via RNA transfer facilitates cell dedifferentiation and growth, which are important regenerative mechanisms.

HSV-2 is the major cause of genital herpes, and its infection increases the risk of HIV-1 acquisition and transmission. After initial infection, HSV-2 can establish latency within the nervous system and thus maintains lifelong infection in humans. It has been suggested that HSV-2 can inhibit type I IFN signaling, but the underlying mechanism has yet to be determined. In this study, we demonstrate that productive HSV-2 infection suppresses Sendai virus (SeV) or polyinosinic-polycytidylic acid-induced IFN-β production. We further reveal that US1, an immediate-early protein of HSV-2, contributes to such suppression, showing that US1 inhibits IFN-β promoter activity and IFN-β production at both mRNA and protein levels, whereas US1 knockout significantly impairs such capability in the context of HSV-2 infection. US1 directly interacts with DNA binding domain of IRF-3, and such interaction suppresses the association of nuclear IRF-3 with the IRF-3 responsive domain of IFN-β promoter, resulting in the suppression of IFN-β promoter activation. Additional studies demonstrate that the 217-414 aa domain of US1 is critical for the suppression of IFN-β production. Our results indicate that HSV-2 US1 downmodulates IFN-β production by suppressing the association of IRF-3 with the IRF-3 responsive domain of IFN-β promoter. Our findings highlight the significance of HSV-2 US1 in inhibiting IFN-β production and provide insights into the molecular mechanism by which HSV-2 evades the host innate immunity, representing an unconventional strategy exploited by a dsDNA virus to interrupt type I IFN signaling pathway.

The miR-17-92 cluster and its 6 different mature microRNAs, including miR-17, miR-18a, miR-19a, miR-20a, miR-19b-1, and miR-92a, play important roles in embryo development, immune system, kidney and heart development, adipose differentiation, aging, and tumorigenicity. Currently, increasing evidence indicates that some members of miR-17-92 cluster may be critical players in spermatogenesis, including miR-17, miR-18a, and miR-20a. However, the roles and underlying mechanisms of miR-17-92 in spermatogenesis remain largely unknown. Our results showed that the targeted disruption of miR-17-92 in the testes of adult mice resulted in severe testicular atrophy, empty seminiferous tubules, and depressed sperm production. This phenotype is partly because of the reduced number of spermatogonia and spermatogonial stem cells, and the significantly increased germ cell apoptosis in the testes of miR-17-92-deficient mice. In addition, overactivation of the mammalian target of rapamycin signaling pathway and upregulation of the pro-apoptotic protein Bim, Stat3, c-Kit, and Socs3 were also observed in miR-17-92-deficient mouse testes, which might be, at least partially if not all, responsible for the aforementioned phenotypic changes in mutant testes. Taken together, these findings suggest that miR-17-92 is essential for normal spermatogenesis in mice.

This study was designed to determine the effect of human umbilical cord multipotent mesenchymal stromal cells (hUC-MSC) on acute ischemia/reperfusion (I/R) injury of spermatogenic cells.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of coronavirus disease 2019, it binds to angiotensin-converting enzyme 2 (ACE2) to enter into human cells. The expression level of ACE2 potentially determine the susceptibility and severity of COVID-19, it is thus of importance to understand the regulatory mechanism of ACE2 expression. Tripartite motif containing 28 (TRIM28) is known to be involved in multiple processes including antiviral restriction, endogenous retrovirus latency and immune response, it is recently reported to be co-expressed with SARS-CoV-2 receptor in type II pneumocytes; however, the roles of TRIM28 in ACE2 expression and SARS-CoV-2 cell entry remain unclear. This study showed that knockdown of TRIM28 induces ACE2 expression and increases pseudotyped SARS-CoV-2 cell entry of A549 cells and primary pulmonary alveolar epithelial cells (PAEpiCs). In a co-culture model of NK cells and lung epithelial cells, our results demonstrated that NK cells inhibit TRIM28 and promote ACE2 expression in lung epithelial cells, which was partially reversed by depletion of interleukin-2 and blocking of granzyme B in the co-culture medium. Furthermore, TRIM28 knockdown enhanced interferon-γ (IFN-γ)- induced ACE2 expression through a mechanism involving upregulating IFN-γ receptor 2 (IFNGR2) in both A549 and PAEpiCs. The upregulated ACE2 induced by TRIM28 knockdown and co-culture of NK cells was partially reversed by dexamethasone in A549 cells. Our study identified TRIM28 as a novel regulator of ACE2 expression and SARS-CoV-2 cell entry.

Prostate cancer (PCa) is the second most common malignant tumor among males. Traditional treatments for PCa, which include surgery and endocrine therapy, have shown limited success, and more effective therapies are needed. Cisplatin (DDP) is an approved chemotherapeutic drug that causes DNA damage in cancer, whereas AZD7762, an inhibitor of CHK1, can significantly inhibit DNA repair. The effective therapeutic combination of cisplatin and the DNA damage response inhibitor AZD7762 has been considered to be a potential solution to the resistance to cisplatin and the adverse reactions that occur in many cancers. However, the co-transmission of cisplatin and AZD7762 and the unsatisfactory tumor-targeting efficacy of this therapy remain problems to be solved. Here, we confirmed the combined therapeutic efficacy of cisplatin and AZD7762 in PCa. Furthermore, we show that the glutathione-targeted Cys8E nanoparticles we synthesized, which have high drug-loading capacity, remarkable stability, and satisfactory release efficiency, enhanced the therapeutic efficacy of this treatment and reduced the required dosages of these drugs both in vitro and in vivo. Overall, we propose combination therapy of cisplatin and AZD7762 for PCa and facilitate it using Cys8E nanoparticles, which allow for better drug loading release, higher release efficiency, and more accurate tumor-targeting efficacy.

Colorectal adenocarcinoma (CRC) ranks one of the five most lethal malignant tumors both in China and worldwide. Early diagnosis and treatment of CRC could substantially increase the survival rate. Emerging evidence has revealed the importance of gut microbiome on CRC, thus fecal microbial community could be termed as a potential screen for non-invasive diagnosis. Importantly, few numbers of bacteria genus as non-invasive biomarkers with high sensitivity and specificity causing less cost would be benefitted more in clinical compared with the whole microbial community analysis. Here we analyzed the gut microbiome between CRC patients and healthy people using 16s rRNA sequencing showing the divergence of microbial composition between case and control. Furthermore, ExtraTrees classifier was performed for the classification of CRC gut microbiome and heathy control, and 13 bacteria were screened as biomarkers for CRC. In addition, 13 biomarkers including 12 bacteria genera and FOBT showed an outstanding sensitivity and specificity for discrimination of CRC patients from healthy controls. This method could be used as a non-invasive method for CRC early diagnosis.

A multitude of animal studies substantiates the beneficial effects of Ang-(1-7), a peptide hormone in the protective axis of the renin angiotensin system, in diabetes and its associated complications including diabetic retinopathy (DR). However, the clinical application of Ang-(1-7) is limited due to unfavorable pharmacological properties. As emerging evidence implicates gut dysbiosis in pathogenesis of diabetes and supports beneficial effects of probiotics, we sought to develop probiotics-based expression and delivery system to enhance Ang-(1-7) and evaluate the efficacy of engineered probiotics expressing Ang-(1-7) in attenuation of DR in animal models.

In our previous study, microvesicles (MVs) released from human Wharton's jelly mesenchymal stem cells (hWJ-MSCs) retard the growth of bladder cancer cells. We would like to know if MVs have a similar effect on human renal cell carcinoma (RCC). By use of cell culture and the BALB/c nu/nu mice xeno-graft model, the influence of MVs upon the growth and aggressiveness of RCC (786-0) was assessed. Cell counting kit-8 (CCK-8) assay, incidence of tumor, tumor size, Ki-67 or TUNEL staining was used to evaluate tumor cell growth in vitro or in vivo. Flow cytometry assay (in vitro) or examination of cyclin D1 expression (in vivo) was carried out to determine the alteration of cell cycle. The aggressiveness was analyzed by Wound Healing Assay (in vitro) or MMP-2 and MMP-9 expression (in vivo). AKT/p-AKT, ERK1/2/p-ERK1/2 or HGF/c-MET expression was detected by real-time PCR or western blot. Our data demonstrated that MVs promote the growth and aggressiveness of RCC both in vitro and in vivo. In addition, MVs facilitated the progression of cell cycle from G0/1 to S. HGF expression in RCC was greatly induced by MVs, associated with activation of AKT and ERK1/2 signaling pathways. RNase pre-treatment abrogated all effects of MVs. In summary, induction of HGF synthesis via RNA transferred by MVs activating AKT and ERK1/2 signaling is one of crucial contributors to the pro-tumor effect.

The C-type lectin receptors (CLRs) expressed on dendritic cells (DCs), in particular DC-SIGN and DCIR, likely play an important role in HIV-1 early infection. Here, we systematically compared the capture and transfer capability of DC-SIGN and DCIR using a wide range of HIV-1 isolates. Our results indicated that DC-SIGN plays a stronger role than DCIR in DC-mediated HIV-1 capture and transfer. This was further strengthened by the data from transient and stable transfectants, showing that DC-SIGN had better capability, compared with DCIR in HIV-1 capture and transfer. Following constructing and analyzing a series of soluble DC-SIGN and DCIR truncates and chimeras, we demonstrated that the neck domain, but not the CRD, renders DC-SIGN higher binding affinity to gp120 likely via the formation of tetramerization. Our findings provide insights into CLR-mediated HIV-1 capture and transfer, highlighting potential targets for intervention strategies against gp120-CLR interactions.

Glycosylation plays important roles in gp120 structure and HIV-1 immune evasion. In the current study, we introduced deglycosylations into the 24 N-linked glycosylation sites of a R5 env MWS2 cloned from semen and systematically analyzed the impact on infectivity, antigenicity, immunogenicity and sensitivity to entry inhibitors. We found that mutants N156-T158A, N197-S199A, N262-S264A and N410-T412A conferred decreased infectivity and enhanced sensitivity to a series of antibodies and entry inhibitors. When mice were immunized with the DNA of wild-type or mutated gp160, gp140 or gp120; N156-T158A, N262-S264A and N410-T412A were more effective in inducing neutralizing activity against wild-type MWS2 as well as heterologous IIIB and CH811 Envs. In general, gp160 and gp140 induced higher neutralizing activity compared with gp120. Our study demonstrates for the first time that removal of individual glycan N156, N262 or N410 proximal to CD4-binding region impairs viral infectivity and results in enhanced capability to induce neutralizing activity.

Based on some well-documented reports, we attempted to clarify the antifibrotic mechanisms of human Wharton's-jelly-derived mesenchymal stromal cells (WJ-MSCs) from the perspective of induction of hepatocyte growth factor (HGF) expression in tubular epithelial cells (TECs).

Tumor resistance to radiotherapy is one of the main obstacles to the clinical treatment of nasopharyngeal carcinoma (NPC). Improving the radiosensitivity of tumor cells has an important clinical significance in treatment of clinical NPC. This study aimed to identify that miR-138-1-3p as a novel therapeutic target in radioresistant NPC cells and found its targets, CRIPTO and the JAK2/STAT3 pathway.

The guided filter is a novel explicit image filtering method, which implements a smoothing filter on "flat patch" regions and ensures edge preserving on "high variance" regions. Recently, the guided filter has been successfully incorporated into the process of fuzzy c-means (FCM) to boost the clustering results of noisy images. However, the adaptability of the existing guided filter-based FCM methods to different images is deteriorated, as the factor ε of the guided filter is fixed to a scalar. To solve this issue, this paper proposes a new guided filter-based FCM method (IFCM_GF), in which the guidance image of the guided filter is adjusted by a newly defined influence factor ρ. By dynamically changing the impact factor ρ, the IFCM_GF acquires excellent segmentation results on various noisy images. Furthermore, to promote the segmentation accuracy of images with heavy noise and simplify the selection of the influence factor ρ, we further propose a morphological reconstruction-based improved FCM clustering algorithm with guided filter (MRIFCM_GF). In this approach, the original noisy image is reconstructed by the morphological reconstruction (MR) before clustering, and the IFCM_GF is performed on the reconstructed image by utilizing the adjusted guidance image. Due to the efficiency of the MR to remove noise, the MRIFCM_GF achieves better segmentation results than the IFCM_GF on images with heavy noise and the selection of the influence factor for the MRIFCM_GF is simple. Experiments demonstrate the effectiveness of the presented methods.

HIV-1 envelope glycoprotein (Env) interacts with cellular receptors and mediates virus entry into target cells. Blocking Env-receptor interactions represents an effective interventional strategy for developing HIV-1 entry inhibitors. We previously designed a panel of CD4-linker-DC-SIGN (CLD) constructs by fusing the extracellular CD4 and DC-SIGN domains with various linkers. Such CLDs produced by the prokaryotic system efficiently inhibited HIV-1 infection and dissemination in vitro and ex vivo. In this study, following the construction and identification of the most promising candidate with a linker of 8 Gly4Ser repeats (named CLD), we further designed an improved form (named CLDmut) by back mutating Cys to Ser at amino acid 60 of CD4. Both CLD and CLDmut were produced in mammalian (293F) cells for better protein translation and modification. The anti-HIV-1 activity of CLD and CLDmut was assessed against the infection of a range of HIV-1 isolates, including transmitted and founder (T/F) viruses. While both CLD and CLDmut efficiently neutralized the tested HIV-1 isolates, CLDmut demonstrated much higher neutralizing activity than CLD, with an IC50 up to one log lower. The neutralizing activity of CLDmut was close to or more potent than those of the highly effective HIV-1 broadly neutralizing antibodies (bNAbs) reported to date. Findings in this study indicate that mammalian cell-expressed CLDmut may have the potential to be used as prophylaxis or/and therapeutics against HIV-1 infection.