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Babaodan inhibits cell growth by inducing autophagy through the PI3K/AKT/mTOR pathway and enhances antitumor effects of cisplatin in NSCLC cells

期刊: AMERICAN JOURNAL OF TRANSLATIONAL RESEARCH, 2019; 11 (8)

Babaodan capsule (BBD), a traditional Chinese (TCM) formula, has been widely used as an alternative remedy for multiple types of malignancies, clinically. However, the underlying mechanisms behind the efficacy of BBD remain poorly understood, particularly in regard to lung cancer. Herein, we demonstrate that BBD induced autophagic death in A549 and A549DDP cells without apoptosis. Treatment with autophagic inhibitor 3-MA, Baf-A1 and PI3K agonist, IGF-1, fully proved our conclusion, as well as uncovered the potential downregulated signaling pathway, PI3K/AKT/mTOR. The study additionally found that BBD could downregulate the expression of MDR1 and increase the chemosensitivity of cisplatin. Collectively, our results, both in vivo and in vitro, demonstrate that BBD leads to autophagic cell death through downregulating the PI3K/AKT/mTOR signaling pathway and improved the antitumor effects of cisplatin in non-small cell lung cancer (NSCLC).

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SPAG9 promotes prostate cancer proliferation and metastasis via MAPK signaling pathway

期刊: AMERICAN JOURNAL OF TRANSLATIONAL RESEARCH, 2019; 11 (8)

Prostate cancer (PCa) is a worldwide malignant tumor which seriously threats the reproductive health of middle-aged and senior male. Sperm-associated antigen 9 (SPAG9), which belongs to the cancer testis (CT) antigen, overexpressed in multiple human malignant tumors and promoted tumor proliferation, invasion and metastasis. However, little attention has been focused on the relationship between SPAG9 and PCa. SPAG9 protein level was measured by immunohistochemical staining in the PCa tissues. SPAG9 mRNA and protein expression were investigated in various PCa cells by qRT-PCR and Western blot. Depletion and overexpression of SPAG9 were proceeded in PCa cells to evaluate their effects by various malignant approaches in vitro and in vivo. SPAG9 was significantly upregulated in the PCa tissues, mainly expressed in the cytoplasm and occasionally in the nucleus of some cells, while SPAG9 was not detected in normal prostate tissue. SPAG9 protein was detected in three PCa cells. Furthermore, these results revealed that upregulation of SPAG9 could promote cell proliferation, migration, motility and cycle of PC-3 cell line, vice versa, downregulation of SPAG9 resulted in the opposite effect. In vivo, knockout of SPAG9 expression induced suppression of tumor growth in athymic nude mice. In summary, the present study indicated that SPAG9 was closely related to the Gleason scores of PCa. SPAG9 could promote cell proliferation, migration, motility and cell cycle via MAPK signaling pathway, suggesting that SPAG9 may be a potential therapeutic target for PCa.

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Long non-coding RNA ZEB2-AS1 promotes proliferation and inhibits apoptosis of colon cancer cells via miR-143/bcl-2 axis

期刊: AMERICAN JOURNAL OF TRANSLATIONAL RESEARCH, 2019; 11 (8)

Colon cancer (CC) is the third most common cancer and the fourth leading cause of cancer-associated death in the world. Long non-coding RNA (lncRNA) ZEB2-AS1 was reported to be dysregulated and play important roles in multiple human cancers. However, the expression level and functions of ZEB2-AS1 in colon cancer is unknown. Here, we firstly observed that ZEB2-AS1 was significantly upregulated in colon cancer and predicted a poor prognosis. Functional assays showed that silencing ZEB2-AS1 expression remarkably inhibited proliferation, suppressed cell cycle transition while induced apoptosis in CC cells. In addition, miR-143 was demonstrated to act as a tumor suppressor and predicted as a downstream target of ZEB2-AS1 in CC. Furthermore, bcl-2 was identified as a direct target of miR-143 and ZEB2-AS1 could regulate the expression of bcl-2 via miR-143 in CC. A rescue assay indicated that downregulation of miR-143 partly abolished the suppressive effect of ZEB2-AS1 silencing on CC cells proliferation. Collectively, our results revealed that ZEB2-AS1 was upregualted and functioned as an oncogene via regulating miR-143/bcl-2 axis in colon cancer. These findings suggest that ZEB2-AS1 may serve a novel biomarker in the diagnosis and a potential therapeutic target in the treatment of colon cancer.

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Phosphorylation of TOB1 at T172 and S320 is critical for gastric cancer proliferation and progression

期刊: AMERICAN JOURNAL OF TRANSLATIONAL RESEARCH, 2019; 11 (8)

We previously revealed that increased phosphorylation of TOB1, a tumor suppressor protein, may promote the progression of gastric cancer. However, the phosphorylated sites on TOB1 and their functional implication in gastric cancer remain to be clarified. Here, we addressed these questions using the gastric mucosal epithelial cell line GES-1 and three gastric cancer cell lines (HGC-27, AGS, and MKN-1). Compared with the control GES-1 cells, the gastric cancer cells showed decreased levels of TOB1 protein and increased levels of phosphorylated TOB1 (p-TOB1) by Western blotting. Then, TOB1 protein was enriched and purified by immunoprecipitation. Two novel phosphorylation sites at threonine 172 (T172) and serine 320 (S320) in TOB1 were identified in gastric cancer MKN-1 cells using LC-MS/MS. Furthermore, treatment with the serine/threonine kinase inhibitor staurosporine (STS; 2 nmol/L, 8 h) significantly decreased the levels of p-TOB1. As a result, the proliferation, migration, and invasion of gastric cancer cells were diminished, accompanied by an increased proportion of cells in G1 phase and a decreased proportion of cells in G2 phase. Taken together, these findings indicate for the first time that TOB1 is phosphorylated at T172 and S320 in gastric cancer cells, which are sensitive to STS. Downregulation of p-TOB1 levels by STS treatment can weaken the malignant phenotype of gastric cancer cells and block their progression through the cell cycle. Moreover, STS may exert its antiproliferative activity in gastric cancers by restoring TOB1 protein activity.

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Resveratrol improves cardiac function by promoting M2-like polarization of macrophages in mice with myocardial infarction

期刊: AMERICAN JOURNAL OF TRANSLATIONAL RESEARCH, 2019; 11 (8)

Macrophage polarization determines the transition from the inflammation phase to the inflammation resolution phase after myocardial infarction (MI). The aim of the present study was to investigate whether resveratrol (RSV) could inhibit the inflammatory mediators associated with the regulation of macrophage phenotypes and functions in MI mice. We initially discovered that RSV significantly improved cardiac function and suppressed the expression of fibrosis markers, such as collagen-I, collagen-III, and fibronectin, and pro-inflammatory cytokines, including interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-alpha). RSV inhibited the expression of M1-like macrophage-related biomarkers (e.g., TNF-alpha and MCP-1) when bone marrow-derived macrophages (BMDMs) were stimulated with lipopolysaccharide (LPS) and interferon-gamma (INF-gamma). In contrast, it upregulated M2-like macrophage-related biomarkers (e.g., CD163 and Arg-1) when BMDMs were stimulated with interleukin-4 (IL-4) and interleukin-10 (IL-10). In addition, we found that RSV promoted M2-like macrophage polarization under anoxic conditions, which could be related to JAK2-SATA3 phosphorylation. In summary, RSV might promote anti-inflammatory M2-like polarization of macrophages after MI to improve cardiac function via the regulation of JAK2- SATA3 phosphorylation.

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Protective effect of pantoprazole against sepsis-induced acute lung and kidney injury in rats

期刊: AMERICAN JOURNAL OF TRANSLATIONAL RESEARCH, 2019; 11 (8)

To investigate the effect of pantoprazole on acute lung and kidney injury with sepsis and its possible mechanism. Rats were randomly divided into six groups, the status and lung wet/dry weight ratio were determined at various time points. Hematoxylin Eosin staining (HE) for pathological changes in the lungs and kidneys of rats with sepsis. Western blot (WB) and immunohistochemistry were used to detect the pulmonary surfactant protein A(SPA) and D(SPD). The levels of markers for kidney damage in serum and urine various time points were measured by ELISA. The apoptosis in lung and kidney tissue of rats were detected using TUNEL assay. Subsequently, the cell apoptosis of LPS-induced BEAS-2B and HK-2 cells after pantoprazole treatment were detected using flow cytometry. The levels of RHOA/ROCK signaling pathway proteins in the lung and kidney tissues and cells were detected using WB. Our results indicated that Pantoprazole could suppress the expression of inflammatory factors in the blood and alleviate pathological damage of lung and kidney tissues in rats with sepsis. Pantoprazole treatment could reduce apoptosis in lung and kidney tissues and inhibit cell apoptosis induced by LPS. In addition, pantoprazole can inhibit RHOA/ROCK signaling pathway proteins and the levels of inflammatory factors in LPS-induced BEAS-2B and HK-2 cells. Pantoprazole can improve the symptoms of acute lung and kidney injury in septic rats, which suggested that pantoprazole might be used to guide the treatment of sepsis.

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Overexpression of B7-H3 as an opportunity for targeted therapy in head and neck cancers

期刊: AMERICAN JOURNAL OF TRANSLATIONAL RESEARCH, 2019; 11 (8)

Head and neck cancers (HNCs) are the sixth most common type of cancer in the world. Despite the development of refined surgical techniques and precise targeted radiation, patients with HNCs have a dismal prognosis. Here, we examine the expression profile of B7-H3 in HNCs and verify whether B7-H3 can serve as a novel therapeutic target for HNCs via anti-B7-H3xCD3 bispecific antibodies (biAbs). We analyzed the expression level of B7-H3 in 274 HNC samples and evaluated the association between B7-H3 expression and clinicopathological parameters. Anti-B7-H3xCD3 biAbs were constructed, and the efficacy of these biAbs in targeting HNCs was assessed in vitro and in vivo. As a result, high expression of B7-H3 was detected in 66.1% of clinical HNC samples and was correlated with poor survival. Specific antitumor effects of anti-B7-H3xCD3 biAbs were confirmed in vitro using HNC cell lines. In xenograft HNC mouse model, anti-B7-H3xCD3 biAbs delayed tumor growth and prolonged survival. In conclusion, B7-H3 is frequently overexpressed in HNCs and could be a promising therapeutic target for biAb therapy.

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lncRNA SNHG20 promotes prostate cancer migration and invasion via targeting the miR-6516-5p/SCGB2A1 axis

期刊: AMERICAN JOURNAL OF TRANSLATIONAL RESEARCH, 2019; 11 (8)

Accumulating evidence has demonstrated the vital roles of long noncoding RNA (lncRNA) in prostate cancer (PCa). However, the function of small nucleolar RNA host gene 20 (SNHG20) in PCa is still unclear. This study aimed to investigate the expression and biological roles of SNHG20 in PCa. SNHG20 expression in PCa tissues and cell lines was measured by quantitative real-time PCR. Gain and loss-of-function experiments were conducted to examine the biological roles of SNHG20. Bioinformatic analysis and dual luciferase activity reporter assay were conducted to establish the SNHG20/secretoglobin family 2A member 1 (SCGB2A1)/microRNA-6516-5p (miR-6516-5p) axis. SHNG20 expression was found markedly elevated in PCa tissues and cell lines. Overexpression of SNHG20 increased PCa cell proliferation and invasion but decreased cell apoptosis. However, the knockdown of SNHG20 will cause the opposite effects on PCa cell behaviors. Mechanical investigation found that SNHG20 could relive the SCGB2A1 protein expression via sponging the miR-6516-5p, acting as miRNA sponge. In conclusion, this finding suggests the SNHG20/miR-6516-5p/SCGB2A1 axis in PCa tumorigenesis, providing the novel insight for the molecular mechanism of PCa.

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Molecular mechanisms involved in TGF-beta 1-induced Muscle-derived stem cells differentiation to smooth muscle cells

期刊: AMERICAN JOURNAL OF TRANSLATIONAL RESEARCH, 2019; 11 (8)

We investigated the molecular mechanisms involved in transforming growth factor beta 1 (TGF-beta 1)-induced myogenic stem cell differentiation to smooth muscle cells. We isolated muscle-derived stem cells (MDSCs) from gastrocnemius muscles following their identification by immunohistochemistry analysis of desmin and flow cytometry analysis of SCA-1, CD34, and CD45. MDSCs at passage 3 (PP3) were cultured in vitro to examine the effects of MDSC induction. Gene ontology and KEGG pathway analyses were performed to analyze these differentially expressed genes. Reduced representation bisulfite sequencing was performed in TGF-beta 1-treated and untreated cells to evaluate differences in the methylation status and analyze the chromosomal distribution of differentially methylated sites (DMSs). Significant morphological changes to cells were observed at PP3, and most PP3 cells were positive for desmin and SCA-1, and were confirmed to be MDSCs. Results of western blot and immunohistochemistry analyses suggested that expressions of a-SMA and CNN1 significantly increased after treatment with TGF-beta 1. Global transcriptome analysis identified 1996 differentially expressed genes (MSC_TGF beta 1/MSC_NC). Results of methylome analysis indicated that there were more hypermethylation sites in the untreated group than in the TGF-beta 1-treated group. Most DMSs were hypermethylated, whereas a small portion was hypomethylated. The chromosomal distribution of DMSs indicated that chromosome 1 had the highest proportion of DMSs, whereas the Y chromosome had the fewest DMSs. Sud2, Pcdh19, and Nat14 are potential core genes involved in cell differentiation. These results may explain the mechanisms of cell differentiation and provide useful information regarding diseases such as pelvic organ prolapse.

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PKI-587 enhances chemosensitivity of oxaliplatin in hepatocellular carcinoma through suppressing DNA damage repair pathway (NHEJ and HR) and PI3K/AKT/mTOR pathway

期刊: AMERICAN JOURNAL OF TRANSLATIONAL RESEARCH, 2019; 11 (8)

Oxaliplatin resistance limits its effectiveness in the treatment of hepatocellular carcinoma (HCC). Abnormal activation of the PI3K/AKT/mTOR pathway has been associated with decreased survival of HCC patients, anti-apoptosis after chemotherapeutic drug-induced DNA damage, and chemoresistance. In this research, we evaluated the effect of the dual PI3K/mTOR inhibitor, PKI-587, on the sensitivity of oxaliplatin in HCC. Two HCC cell lines (HepG2 and SK-Hep1) were used to analyze PKI-587 for DNA damage response, cell proliferation, clonogenic survival, cell cycle and apoptosis after oxaliplatin treatment. A HepG2 tumor-bearing model was used to assess the in vivo effects of the combination of the two compounds. In HCC cells, oxaliplatin stably activated the PI3K/AKT/mTOR pathway, including up-regulation of p-Akt (Ser473), p-mTOR (Ser2448), p-mTOR (Ser2481), p-eIF4EBP1, and p-S6K1, and activated the DNA damage repair pathways (non-homologous end joining (NHEJ) and homologous recombination (HR)), up-regulation of p-DNAPKcs (Ser2056), p-ATM (Ser1981), and p-ATR (Ser428), which were attenuated by PKI-587. Compared with oxaliplatin alone, the combination of PKI-587 and oxaliplatin increased the number of gamma-H2AX/cells, decreased proliferation of cells, and an increased the percentage of G0/G1 phase cells and apoptotic cells. In vivo, the combination of oxaliplatin with PKI-587 inhibited tumor growth. Anti-tumor effects were associated with induction of mitochondrial apoptosis and inhibition of phosphorylation of mTOR, Akt and gamma-H2AX. We conclude that PKI-587 enhances chemosensitivity of oxaliplatin in HCC through suppressing the PI3K/AKT/mTOR signalling pathway and inhibiting the DNA damage repair pathway. The combination of PKI-587 and oxaliplatin appears to be a promising regimen for the treatment of HCC.

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HtrA1 upregulates the expression of ADAMTS-5 in HNPCs via the ERK/NF-kappa B/JNK signaling pathway

期刊: AMERICAN JOURNAL OF TRANSLATIONAL RESEARCH, 2019; 11 (8)

Intervertebral disc degeneration (IDD) is a form of chronic inflammation and is one of the most common disorders reported to be involved in low back pain (LBP). The pathophysiology of degeneration is not completely understood, but the consensus is that the degradation of extracellular matrix (ECM) proteins in the disc is the leading factor contributing to IDD. High temperature requirement A1 (HtrA1) is serine protease that has been shown to be increased in degenerated intervertebral discs as a result of an increase in the expression of matrix metall-oproteinases (MMPs), but no study has focused on the effect of HtrA1 on a disintegrin-like and metalloproteinase with thrombospondin motifs (ADAMTSs). In the present study, we successfully isolated human nucleus pulposus cells (HNPCs) from IDD patients who were our research subjects to elaborate on the potential role of HtrA1 in the pathogenesis of IDD. We confirmed that HtrA1 has the potential to induce the expression of ADAMTS-5 in a dose-dependent manner. Consistently, this was mediated by the ERK, NF-kappa B and JNK pathways. By using inhibitors of these pathways, the increase in ADAMTS-5 could be reduced. Our findings indicated that HtrA1 can induce the expression of ADAMTS-5 in HNPCs via the ERK/NF-kappa B/JNK signaling pathway, and our study also elucidated the involved induction mechanisms in HNPCs, which may provide new insights for the treatment of IDD.

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Glycyrrhizin suppresses inflammation and cell apoptosis by inhibition of HMGB1 via p38/p-JUK signaling pathway in attenuating intervertebral disc degeneration

期刊: AMERICAN JOURNAL OF TRANSLATIONAL RESEARCH, 2019; 11 (8)

Intervertebral disc degeneration (IDD) is associated with the nucleus pulposus (NP) cells inflammation and apoptosis. Previous studies have shown that glycyrrhizin (GL) is a valid inhibitor of the high-mobility group box-1 gene (HMGB1) which expressed much higher in an inflammatory condition. However, it is not known whether GL protects against IDD by the inhibition of HMGB1. To study the effect and mechanism of glycyrrhizin on intervertebral disc degeneration. We analyzed the expression of HMGB1 in different degree of degenerate disc tissues. Interleukin 1 beta (IL-1 beta) was used in stimulating the NP cells to degeneration. We used recombined human HMGB1 to resist the function of GL to explore whether GL acted via the target of HMGB1. Our study showed that the expression of HMGB1 markedly increased in severely degenerated disc tissues. IL-1 beta promoted the progress of IDD, and the stimulation of GL could reverse the effects of IL-1 beta. Moreover, p38 and p-JNK were significantly suppressed by GL stimuli. These results suggested that GL prevented NP degradation via restraining inflammation and cell apoptosis by inhibition of HMGB1 via p38/p-JNK signaling pathway. GL may become a novel cytokine for the therapy of IDD in the future.

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Vitisin B as a novel fatty acid synthase inhibitor induces human breast cancer cells apoptosis

期刊: AMERICAN JOURNAL OF TRANSLATIONAL RESEARCH, 2019; 11 (8)

Breast cancer is one of the most common cancers and the second leading cause of cancer mortality in women worldwide. Novel therapies and chemo-therapeutic drugs are still in urgent need to be developed for the treatment of breast cancer. One of the most important metabolic hallmarks of breast cancer cells is enhanced lipogenesis. Increasing evidences suggest that fatty acid synthase (FAS) plays an important role in the development of human breast cancer, for the expression of FAS is significantly higher in breast cancer cells than in normal cells. In addition, FAS inhibitors, such as curcumin, ursolic acid, and resveratrol, have shown anti-cancer potential. In the present study, we discovered that vitisin B, a natural stilbene isolated from the seeds of Iris lactea Pall. var. chinensis (Fisch.), was a novel FAS inhibitor. We found that vitisin B could down-regulate FAS expression and inhibit intracellular FAS activity in MDA-MB-231 cells. Also, we reported for the first time that vitisin B exhibited apoptotic effect on human breast cancer cells. Given all of this, we proposed a hypothesis that vitisin B has an application potential in the chemoprevention and treatment of breast cancer.

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Changes in macular ultrastructural morphology in unilateral anisometropic amblyopia

期刊: AMERICAN JOURNAL OF TRANSLATIONAL RESEARCH, 2019; 11 (8)

It is controversial that retina and photoreceptors are involved in amblyopic development. Lack of imaging devices for quantitative assessment of photoreceptors in vivo impedes further investigation. In this study we investigated the differences of macular thickness, outer nuclear layer (ONL) thickness and cone density among eyes with unilateral anisometropic amblyopia, amblyopic fellow eyes, and normal control eyes using high definition spectral-domain optical coherence tomography and adaptive optics imaging system. Thicker fovea and parafovea with characteristic quantitative retinal changes in unilateral amblyopic patients indicated that the amblyopic process might involve the retina. Cones tended to be homogeneously distributed at 1.5 degrees from the foveal center in all participants. However, we did not detect any significant differences in cone density and ONL thickness at 1.5 degrees from the foveal center in patients with unilateral amblyopia when compared with the fellow eyes and the normal control eyes. This is the first study to explore whether photoreceptors are involved in amblyopic development in vivo that would help for understanding the underlying mechanisms of amblyopia. Whether macular changes relate to cone photoreceptors migration of the amblyopic eyes remains to be determined.

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Endophilin A2 attenuates cardiac hypertrophy induced by isoproterenol through the activation of autophagy

期刊: AMERICAN JOURNAL OF TRANSLATIONAL RESEARCH, 2019; 11 (8)

Decreased autophagy has been reported to contribute to the progression of cardiac hypertrophy. Our previous research has demonstrated that endophilin A2 (EndoA2) attenuates H2O2-induced cardiomyocyte apoptosis by strengthening autophagy. However, the role of EndoA2 in the regulation of autophagy in cardiac hypertrophy is unknown. In this study, we tested the hypothesis that EndoA2 suppresses cardiac hypertrophy induced by isoproterenol (ISO) by activating autophagy. In vivo, we established a cardiac hypertrophy model by subcutaneous injection of ISO and used intramyocardial delivery of adenovirus vector harboring EndoA2 cDNA (Ad-EndoA2) to overexpress EndoA2. The cardiac hypertrophic response and autophagy level were measured. EndoA2 overexpression suppressed pathological cardiac hypertrophy and enhanced autophagy in rat hearts. In addition, the effects of EndoA2 on cardiac hypertrophy and autophagy were observed in cultured neonatal rat cardiomyocytes (NRCMs) with gain - and loss-of-function approaches to regulate EndoA2 expression. The results were consistent with those of the in vivo study. Furthermore, the involvement of EndoA2-mediated autophagy in the attenuation of ISO-induced cardiac hypertrophy was explored by pharmaceutical inhibition of autophagy. Pretreatment with 3-methyladenine (3-MA) clearly diminished the anti-hypertrophic effects of EndoA2 in ISO-treated NRCMs. The results presented here provide the first evidence that EndoA2 is involved in ISO-induced cardiac hypertrophy. The anti-hypertrophic effects of EndoA2 can be partially attributed to its regulation of autophagy.

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