Shao-hsuan Kao | Chung Shan Medical University (original) (raw)
Papers by Shao-hsuan Kao
Biology of Reproduction, May 1, 2008
Journal of Investigative Dermatology, Sep 1, 2020
The induction of immunogenic cell death (ICD) in cancer cells triggers specific immune responses ... more The induction of immunogenic cell death (ICD) in cancer cells triggers specific immune responses against the same cancer cells. Imiquimod (IMQ) is a synthetic ligand of toll-like receptor 7 that exerts antitumor activity by stimulating cell-mediated immunity or by directly inducing apoptosis. Whether IMQ causes tumors to undergo ICD and elicits a specific antitumor immune response is unknown. We demonstrated that IMQ-induced ICDassociated features, including the surface exposure of calreticulin and the secretion of adenosine triphosphate and HMGB1, were mediated by ROS and endoplasmic reticulum stress. In a B16F10 melanoma mouse model, vaccinating mice with IMQ-induced ICD cell lysate or directly injecting IMQ in situ reduced tumor growth that was mediated by inducing tumor-specific T-cell proliferation, promoting tumor-specific cytotoxic killing by CD8 þ T cells, and increasing the infiltration of various immune cells into tumor lesions. The ICD-associated features were crucial in the induction of specific antitumor immunity in vivo. The glycolytic inhibitor 2deoxyglucose enhanced IMQ-induced ICD-associated features and strengthened the antitumor immunity mediated by IMQ-induced ICD cell lysate in p53-mutant cancer cells, which were IMQ-resistant in vitro. We conclude that IMQ is an authentic ICD inducer and provide a concept connecting IMQ-induced cancer cell death and antitumor immune responses.
PLOS ONE, Nov 6, 2015
The AMP-activated protein kinase (AMPK) signaling system plays a key role in cellular stress by r... more The AMP-activated protein kinase (AMPK) signaling system plays a key role in cellular stress by repressing the inflammatory responses induced by the nuclear factor-kappa B (NF-κB) system. Previous studies suggest that the anti-inflammatory role of AMPK involves activation by adenine, but the mechanism that allows adenine to produce these effects has not yet been elucidated. In human umbilical vein endothelial cells (HUVECs), adenine was observed to induce the phosphorylation of AMPK in both a time-and dose-dependent manner as well as its downstream target acetyl Co-A carboxylase (ACC). Adenine also attenuated NF-κB targeting of gene expression in a dose-dependent manner and decreased monocyte adhesion to HUVECs following tumor necrosis factor (TNF-α) treatment. The short hairpin RNA (shRNA) against AMPK α1 in HUVECs attenuated the adenine-induced inhibition of NF-κB activation in response to TNF-α, thereby suggesting that the anti-inflammatory role of adenine is mediated by AMPK. Following the knockdown of adenosyl phosphoribosyl transferase (APRT) in HUVECs, adenine supplementation failed to induce the phosphorylation of AMPK and ACC. Similarly, the expression of a shRNA against APRT nullified the anti-inflammatory effects of adenine in HUVECs. These results suggested that the role of adenine as an AMPK activator is related to catabolism by APRT, which increases the cellular AMP levels to activate AMPK.
Background and purpose: Cholecystokinin (CCK) and the gastrin receptors, CCKAR and CCKBR, are ove... more Background and purpose: Cholecystokinin (CCK) and the gastrin receptors, CCKAR and CCKBR, are overexpressed in different malignancies of the human digestive tract; however, limited information is available regarding the correlation of their expression in colon cancer. The present study aimed to investigate whether the levels of expression of CCKAR and CCKBR were associated with the clinicopathological features of patients with colon cancer. Methods: CCKAR and CCKBR expression levels were determined using immunohistochemical analysis. Samples obtained from 49 surgical specimens were used for pathological examinations. Results: Cytoplasmic and nuclear staining of CCKAR was detected in 78% and 49% of samples, respectively, and did not correlate with the patients’ sex, tumor grade, or stage of tumor progression. However, strong nuclear, but not cytoplasmic, staining of CCKAR was significantly associated with relatively poor 1-year survival (P = 0.032). In contrast to CCKAR, weak to mode...
BMC Cancer
Background Adjuvant chemotherapy is recommended as the standard treatment for patients with stage... more Background Adjuvant chemotherapy is recommended as the standard treatment for patients with stage II/III resected gastric cancer. However, it is unclear whether older patients also benefit from an adjuvant chemotherapy strategy. This study aimed to investigate the clinical impact of adjuvant chemotherapy in older patients with stage II/III gastric cancer. Methods This retrospective, real-world study analyzed 404 patients with stage II/III gastric cancer visited at our institute between January 2009 and December 2019. The clinical characteristics and outcomes of patients aged 70 years or older who received adjuvant chemotherapy were compared with those who did not receive this type of treatment. Propensity score analysis was performed to mitigate selection bias. Results Of the 404 patients analyzed, 179 were aged 70 years or older. Fewer older patients received adjuvant chemotherapy than did younger patients (60.9% vs. 94.7%, respectively; P < 0.001). Among patients aged 70 years ...
Kidney Research and Clinical Practice
Background: Mounting evidence indicates that melatonin has possible activity against different tu... more Background: Mounting evidence indicates that melatonin has possible activity against different tumors. Pazopanib is an anticancer drug used to treat renal cell carcinoma (RCC). This study tested the anticancer activity of melatonin combined with pazopanib on RCC cells and explored the underlying mechanistic pathways of its action. Methods: The 786-O and A-498 human RCC cell lines were used as cell models. Cell viability and tumorigenesis were detected with the MTT and colony formation assays, respectively. Apoptosis and autophagy were assessed using TUNEL, annexin V/propidium iodide, and acridine orange staining with flow cytometry. The expression of cellular signaling proteins was investigated with western blotting. The in vivo growth of tumors derived from RCC cells was evaluated using a xenograft mouse model. Results: Together, melatonin and pazopanib reduced cell viability and colony formation and promoted the apoptosis of RCC cells. Furthermore, the combination of melatonin and pazopanib triggered more mitochondrial, caspase-mediated, and LC3-II-mediated autophagic apoptosis than melatonin or pazopanib alone. The combination also induced higher activation of the p38 mitogen-activated protein kinase (p38MAPK) in the promotion of autophagy and apoptosis by RCC cells than melatonin or pazopanib alone. Finally, tumor xenograft experiments confirmed that melatonin and pazopanib cooperatively inhibited RCC growth in vivo and predicted a possible interaction between melatonin/pazopanib and LC3-II. Conclusion: The combination of melatonin and pazopanib inhibits the growth of RCC cells by inducing p38MAPK-mediated mitochondrial and autophagic apoptosis. Therefore, melatonin might be a potential adjuvant that could act synergistically with pazopanib for RCC treatment.
Biomedicines
Acute aortic dissection (AAD) and acute myocardial infarction (AMI) are both severe cardiovascula... more Acute aortic dissection (AAD) and acute myocardial infarction (AMI) are both severe cardiovascular diseases that may cause sudden death. However, whether serum proteins are differentially expressed between AAD and AMI remains unclear. Here, we aimed to explore serum protein profiles between AAD and AMI patients. A total of 75 serum samples were collected, including AAD patients without AMI (n = 25), AMI patients without AAD (n = 25), and normal subjects (n=25). Protein identities and expression levels were assessed by LC-MS/MS analysis and a label-free quantitation method, respectively. After depletion of albumin and IgG, a total of 117 proteins with differential expression (fold change ≥2 or ≤−2.0, p < 0.05) were identified, of which 60 were upregulated and 57 were downregulated in AAD sera as compared to AMI sera. Bioinformatic analysis revealed that the differentially expressed serum proteins were mainly derived from exosomes and the extracellular space, and their molecular fu...
Pharmaceuticals
Cisplatin has been widely used in cancer treatments. Recent evidence indicates that adenine has p... more Cisplatin has been widely used in cancer treatments. Recent evidence indicates that adenine has potential anticancer activities against various types of cancers. However, the effects of the combination of adenine and cisplatin on hepatocellular carcinoma (HCC) cells remain sketchy. Here, our objective was to elucidate the anticancer activity of adenine in combination with cisplatin in HCC cells and its mechanistic pathways. Cell viability and cell cycle progression were assessed by the SRB assay and flow cytometry, respectively. Apoptosis was demonstrated by PI/annexin V staining and flow cytometric analysis. Protein expression, signaling cascade, and mRNA expression were analyzed by Western blotting and quantitative RT-PCR, respectively. Our results showed that adenine jointly potentiated the inhibitory effects of cisplatin on the cell viability of SK-Hep1 and Huh7 cells. Further investigation showed that adenine combined with cisplatin induced higher S phase arrest and apoptosis i...
Frontiers in Physiology, 2019
Adipose-derived stem cells (ADSCs) have shown great promise for the treatment of myocardial infar... more Adipose-derived stem cells (ADSCs) have shown great promise for the treatment of myocardial infarction (MI), although their potential therapeutic mechanism remains poorly understood. Growing evidence has implicated microRNAs (miRNAs or miRs) in the biological processes whereby ADSCs could ameliorate cardiovascular disease. In this study, we explored the contribution of miR-34a-5p down-regulation to the protective actions of ADSCs against MI. We initially identified the interaction between miR-34a-5p and C1q/tumor necrosis factor-related protein-9 (CTRP9) through in silico analysis. We next tested the effects of miR-34a-5p and CTRP9 on the expression of extracellular signal-regulated kinase 1 (ERK1), matrix metalloproteinase-9 (MMP-9), nuclear factor (erythroid-derived 2)-like 2 (NRF2), and antioxidant proteins [manganese superoxide dismutase (MnSOD), and heme oxygenase-1 (HO-1)] through gain-and loss-of-function tests. In other experiments, we assessed the proliferation, migration, and apoptosis of ADSCs using the EdU assay, scratch test, Transwell assay, and flow cytometry. Finally, we studied whether miR-34a-5p/CTRP9 axis could modulate the protective effect of ADSCs against MI during stem cell transplantation in MI mouse models. miR-34a-5p could target and down-regulate CTRP9 in cardiomyocytes. Down-regulated miR-34a-5p increased the expression of ERK1, MMP-9, NRF2, MnSOD, and HO-1, whereas downregulation of miR-34a-5p or up-regulation of CTRP9 in vitro promoted ADSC proliferation and migration and inhibited ADSC apoptosis. Moreover, miR-34a-5p down-regulation or CTRP9 up-regulation promoted the protective role of ADSCs against MI damage in vivo. Thus, inhibition of miR-34a-5p may facilitate ADSC's protective function against MI damage by stimulating the expression of CTRP9.
BioMed Research International, 2014
Adenosine 5′-monophosphate-activated protein kinase (AMPK) is a key regulator of cellular energy ... more Adenosine 5′-monophosphate-activated protein kinase (AMPK) is a key regulator of cellular energy homeostasis via modulating metabolism of glucose, lipid, and protein. In addition to energy modulation, AMPK has been demonstrated to associate with several important cellular events including inflammation. The results showed that ENERGI-F704 identified from bamboo shoot extract was nontoxic in concentrations up to 80 μM and dose-dependently induced phosphorylation of AMPK (Thr-172) in microglia BV2 cells. Our findings also showed that the treatment of BV2 with ENERGI-F704 ameliorated the LPS-induced elevation of IL-6 and TNF-αproduction. In addition, ENERGI-F704 reduced increased production of nitric oxide (NO) and prostaglandin E2 (PGE2) via downregulating the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2), respectively. Moreover, ENERGI-F704 decreased activated nuclear translocation and protein level of NF-κB. Inhibition of AMPK with compound C resto...
Evidence-Based Complementary and Alternative Medicine, 2012
Ocimum gratissimum(OG) is known as a food spice and traditional herb, which has been recommended ... more Ocimum gratissimum(OG) is known as a food spice and traditional herb, which has been recommended for the treatment of various diseases. To investigate the hepatoprotective effect of OG aqueous extract (OGAE), male Wistar rats challenged by carbon tetrachloride (CCl4) were used as the animal model of chronic hepatic injury. Significantly increased serum catalase and DPPH levels were detected in CCl4-administrated rats that were treated with OGAE or silymarin as compared to those rats that were treated with saline or CCl4. In contrast, significantly decreased stress proteins including HSP70 and iNOS were observed in livers of CCl4-administrated rats that were treated with OGAE or sylimarin as compared to those rats that were treated with saline or CCl4. Moreover, significant decreases of MMP-9/MMP-2 ratio, uPA, phosphorylated ERK (p-ERK) and NF-κB (p-P65) were detected in livers of CCl4-administrated rats that were treated with OGAE or sylimarin as compared to those rats that were tre...
Pharmaceuticals
Rosmarinic acid (RA) is a phenolic compound that has several bioactivities, such as anti-inflamma... more Rosmarinic acid (RA) is a phenolic compound that has several bioactivities, such as anti-inflammatory and antioxidant activities. Here, we further investigate the anti-inflammatory effect of RA on rat A7r5 aortic smooth muscle cells with exposure to lipopolysaccharide (LPS). Our findings showed that low-dose RA (10–25 μM) did not influence the cell viability and morphology of A7r5 cells and significantly inhibited LPS-induced mRNA expression of the pro-inflammatory mediators TNFα, IL-8, and inducible NO synthase (iNOS). Consistently, RA reduced the production of TNFα, IL-8, and NO by A7r5 cells with exposure to LPS. Signaling cascade analysis showed that LPS induced activation of Erk, JNK, p38 mitogen-activated protein kinase (MAPK), and NF-κB, and RA treatments attenuated the activation of the three MAPKs and NF-κB. Moreover, cotreatment with RA and Erk, JNK, p38 MAPK, or NF-κB inhibitors further downregulated the mRNA expression of TNFα, IL-8, and iNOS, and decreased the productio...
Journal of Food and Drug Analysis
Camphorataimide B suppresses the metastasis of human Camphorataimide B suppresses the metastasis ... more Camphorataimide B suppresses the metastasis of human Camphorataimide B suppresses the metastasis of human colorectal cancer cell by inhibiting Smad/FAK/Akt axis and colorectal cancer cell by inhibiting Smad/FAK/Akt axis and promoting degradation of Snail/BMP4 complex promoting degradation of Snail/BMP4 complex
Tumor metastasis is a major cause of death of patients with colorectal cancer (CRC). Our previous... more Tumor metastasis is a major cause of death of patients with colorectal cancer (CRC). Our previous findings show that adenine has antiproliferation activity against tumor cells. However, whether adenine reduces the invasiveness of DLD-1 and SW480 CRC cells has not been thoroughly explored. In this study, we aimed to explore the effects of adenine on the invasion potential of DLD-1 cells. Our findings showed that adenine at concentrations of ≤200 μM did not influence the cell viability of DLD-1 and SW480 CRC cells. By contrast, adenine reduced the migratory potential of the CRC cells. Moreover, it decreased the invasion capacity of the CRC cells in a dose-dependent manner. We further observed that adenine downregulated the protein levels of tissue plasminogen activator, matrix metalloproteinase-9, Snail, TWIST, and vimentin, but upregulated the tissue inhibitor of metalloproteinase-1 expression in DLD-1 cells. Adenine decreased the integrin αV level and reduced the activation of integ...
International Journal of Medical Sciences
Background: Adenine exhibits potential anticancer activity against several types of malignancies.... more Background: Adenine exhibits potential anticancer activity against several types of malignancies. However, whether adenine has anticancer effects on hepatocellular carcinoma (HCC) cells is incompletely explored. Methods: Human HCC cell lines HepG2 and SK-Hep-1 (p53-wild type) and Hep3B (p53-deficient) were used as cell model. Cell growth and cell cycle distribution were determined using MTT assay and flow cytometric analysis, respectively. Protein expression and phosphorylation were assessed by Western blot. Involvement of AMP-activated protein kinase (AMPK) was evaluated using specific inhibitor and small inhibitory RNA (siRNA). Results: Adenine treatments (0.5-2 mM) clearly decreased the cell growth of Hep G2 and SK-Hep-1 cells to 72.5 ± 3.4% and 71.3 ± 4.6% of control, respectively. In parallel, adenine also induced sub-G1 and S phase accumulation in both HCC cells. However, adenine did not affect the cell growth and cell cycle distribution of Hep3B cell. Western blot analysis showed that adenine reduced expression of cyclin A/D1 and cyclin-dependent kinase (CDK)2 and upregulated p53, p21, Bax, PUMA, and NOXA in HepG2 cell. Moreover, adenine induced AMPK activation that was involved in the p53-associated apoptotic cascade in HepG2 cells. Inhibition of AMPK activation or knockdown of AMPK restored the decreased cell growth of HepG2 and SK-Hep-1 cells in response to adenine. Conclusions: These findings reveal that adenine reduces the cell growth of HepG2 and SK-Hep-1 but not Hep3B cells, attributing to the AMPK/p53-mediated S phase arrest and apoptosis. It suggests that adenine has anticancer potential against p53-wild type HCC cells and may be beneficial as an adjuvant for HCC treatment.
The pr incipal subtype of lung cancer, non-small cell lung cancer (NSCLC) is a life-threatening m... more The pr incipal subtype of lung cancer, non-small cell lung cancer (NSCLC) is a life-threatening malignancy that causes high mortality rates. Bergapten (5-methoxypsoralen) has been identified to possess anticancer activity against a number of carcinomas. In the present study, the effects of bergapten on NSCLC cells were investigated. The cell viability was determined by MTT assay. Cell cycle distribution was analyzed using flow cytometry. Protein expression and kinase cascade were demonstrated using western blot analysis. The results demonstrated that treatment with bergapten (50 μM for 48 h) inhibited the viability of A549 and NCI-H460 NSCLC cells to 79.1±2.8% and 74.5±3.1%, respectively, compared with the controls. It was identified that bergapten induced G1 phase accumulation in A549 and NCI-H460 cells between ~58 and 75% (P<0.01). In addition, bergapten significantly increased the sub‐G1 phase ratio to ~9% (P<0.05) in the two cell types. Further investigation demonstrated t...
Evidence-based Complementary and Alternative Medicine : eCAM, 2021
Excessive alcohol intake is a major cause of chronic liver damage and is highly associated with t... more Excessive alcohol intake is a major cause of chronic liver damage and is highly associated with the development of a spectrum of hepatic disorders, including steatohepatitis, liver cirrhosis, and liver cancer. Thus, we aimed to explore the hepatoprotective effects of an aqueous mulberry leaf extract (AME) on alcoholic fatty liver disorder (AFLD) by using a mouse model fed with excessive ethanol. Compared with the normal diet, the ethanol diet significantly increased the body weight of the mice, while the AME supplement reduced the weight gain caused by the ethanol diet. The ethanol diet also attenuated the activity of alcohol dehydrogenase and antioxidant enzymes but increased lipid peroxidation in the liver, which were reversed by AME supplementation. Additionally, AME supplementation diminished the ethanol diet-induced hepatic leukocyte infiltration and expressions of IL-6 and TNFα. Moreover, AME supplementation also reduced the ethanol-diet-induced lipid accumulation and expressi...
Metastasis-associated protein 2 (MTA2) is a transcription factor that is highly associated with m... more Metastasis-associated protein 2 (MTA2) is a transcription factor that is highly associated with matrix metalloproteinase 12 (MMP12). Thus, we hypothesized that MTA2 may regulate MMP12 expression and is involved in cervical cancer metastasis. Results showed that MTA2 and MMP12 were highly expressed in cervical cancer cells, and MTA2 knockdown reduced MMP12 expression and inhibited the metastasis of cervical cancer cells in xenograft mice. MMP12 knockdown did not influence the viability of cervical cancer cells but clearly inhibited cell migration and invasion both in vitro and in vivo. MMP12 was highly expressed in cervical tumor tissues and correlated with the poor survival rate of patients with cervical cancer. Further investigations revealed that p38 mitogen-activated protein kinase (p38), mitogen-activated protein kinase kinase 3 (MEK3), and apoptosis signal-regulating kinase 1 (ASK1) were involved in MMP12 downregulation in response to MTA2 knockdown. Results also demonstrated t...
The American Journal of Chinese Medicine
Metastasis is the most prevalent cause of cancer-associated deaths amongst patients with cervical... more Metastasis is the most prevalent cause of cancer-associated deaths amongst patients with cervical cancer. Epithelial–mesenchymal transition (EMT) is essential for carcinogenesis, and it confers metastatic properties to cancer cells. Gossypol is a natural polyphenolic compound with anti-inflammation, anti-oxidant, and anticancer activities. In this study, we investigated the antimetastatic and antitumour effects of gossypol on human cervical cancer cells (HeLa and SiHa cells). Gossypol exerted a strong inhibition effect on the migration and invasion of human cervical cancer cells. It reduced the focal adhesion kinase (FAK) pathway-mediated expression of matrix metalloproteinase-2 and urokinase-type plasminogen activator, subsequently inhibiting the invasion of SiHa cells. In addition, gossypol reversed EMT induced by transforming growth factor beta 1 (TGF-[Formula: see text]1) and up-regulated epithelial markers, such as E-cadherin but significantly suppressed Ras homolog family memb...
Cells
Corosolic acid (CA), a bioactive compound obtained from Actinidia chinensis, has potential anti-c... more Corosolic acid (CA), a bioactive compound obtained from Actinidia chinensis, has potential anti-cancer activities. Glioblastoma (GBM) is a malignant brain tumor and whether CA exerts anti-cancer activity on GBM remains unclear. This study was aimed to explore the anticancer activity and its underlying mechanism of CA in GBM cells. Our findings showed that CA ≤ 20 μM did not affect cell viability and cell proliferative rate of normal astrocyte and four GBM cells. Notably, 10 or 20 μM CA significantly inhibited cell migration and invasion of three GBM cells, decreased the protein level of F-actin and disrupted F-actin polymerization in these GBM cells. Further investigation revealed that CA decreased AXL level by promoting ubiquitin-mediated proteasome degradation and upregulating the carboxyl terminus of Hsc70-interacting protein (CHIP), an inducer of AXL polyubiquitination. CHIP knock-down restored the CA-reduced AXL and invasiveness of GBM cells. Additionally, we observed that CA-r...
Biology of Reproduction, May 1, 2008
Journal of Investigative Dermatology, Sep 1, 2020
The induction of immunogenic cell death (ICD) in cancer cells triggers specific immune responses ... more The induction of immunogenic cell death (ICD) in cancer cells triggers specific immune responses against the same cancer cells. Imiquimod (IMQ) is a synthetic ligand of toll-like receptor 7 that exerts antitumor activity by stimulating cell-mediated immunity or by directly inducing apoptosis. Whether IMQ causes tumors to undergo ICD and elicits a specific antitumor immune response is unknown. We demonstrated that IMQ-induced ICDassociated features, including the surface exposure of calreticulin and the secretion of adenosine triphosphate and HMGB1, were mediated by ROS and endoplasmic reticulum stress. In a B16F10 melanoma mouse model, vaccinating mice with IMQ-induced ICD cell lysate or directly injecting IMQ in situ reduced tumor growth that was mediated by inducing tumor-specific T-cell proliferation, promoting tumor-specific cytotoxic killing by CD8 þ T cells, and increasing the infiltration of various immune cells into tumor lesions. The ICD-associated features were crucial in the induction of specific antitumor immunity in vivo. The glycolytic inhibitor 2deoxyglucose enhanced IMQ-induced ICD-associated features and strengthened the antitumor immunity mediated by IMQ-induced ICD cell lysate in p53-mutant cancer cells, which were IMQ-resistant in vitro. We conclude that IMQ is an authentic ICD inducer and provide a concept connecting IMQ-induced cancer cell death and antitumor immune responses.
PLOS ONE, Nov 6, 2015
The AMP-activated protein kinase (AMPK) signaling system plays a key role in cellular stress by r... more The AMP-activated protein kinase (AMPK) signaling system plays a key role in cellular stress by repressing the inflammatory responses induced by the nuclear factor-kappa B (NF-κB) system. Previous studies suggest that the anti-inflammatory role of AMPK involves activation by adenine, but the mechanism that allows adenine to produce these effects has not yet been elucidated. In human umbilical vein endothelial cells (HUVECs), adenine was observed to induce the phosphorylation of AMPK in both a time-and dose-dependent manner as well as its downstream target acetyl Co-A carboxylase (ACC). Adenine also attenuated NF-κB targeting of gene expression in a dose-dependent manner and decreased monocyte adhesion to HUVECs following tumor necrosis factor (TNF-α) treatment. The short hairpin RNA (shRNA) against AMPK α1 in HUVECs attenuated the adenine-induced inhibition of NF-κB activation in response to TNF-α, thereby suggesting that the anti-inflammatory role of adenine is mediated by AMPK. Following the knockdown of adenosyl phosphoribosyl transferase (APRT) in HUVECs, adenine supplementation failed to induce the phosphorylation of AMPK and ACC. Similarly, the expression of a shRNA against APRT nullified the anti-inflammatory effects of adenine in HUVECs. These results suggested that the role of adenine as an AMPK activator is related to catabolism by APRT, which increases the cellular AMP levels to activate AMPK.
Background and purpose: Cholecystokinin (CCK) and the gastrin receptors, CCKAR and CCKBR, are ove... more Background and purpose: Cholecystokinin (CCK) and the gastrin receptors, CCKAR and CCKBR, are overexpressed in different malignancies of the human digestive tract; however, limited information is available regarding the correlation of their expression in colon cancer. The present study aimed to investigate whether the levels of expression of CCKAR and CCKBR were associated with the clinicopathological features of patients with colon cancer. Methods: CCKAR and CCKBR expression levels were determined using immunohistochemical analysis. Samples obtained from 49 surgical specimens were used for pathological examinations. Results: Cytoplasmic and nuclear staining of CCKAR was detected in 78% and 49% of samples, respectively, and did not correlate with the patients’ sex, tumor grade, or stage of tumor progression. However, strong nuclear, but not cytoplasmic, staining of CCKAR was significantly associated with relatively poor 1-year survival (P = 0.032). In contrast to CCKAR, weak to mode...
BMC Cancer
Background Adjuvant chemotherapy is recommended as the standard treatment for patients with stage... more Background Adjuvant chemotherapy is recommended as the standard treatment for patients with stage II/III resected gastric cancer. However, it is unclear whether older patients also benefit from an adjuvant chemotherapy strategy. This study aimed to investigate the clinical impact of adjuvant chemotherapy in older patients with stage II/III gastric cancer. Methods This retrospective, real-world study analyzed 404 patients with stage II/III gastric cancer visited at our institute between January 2009 and December 2019. The clinical characteristics and outcomes of patients aged 70 years or older who received adjuvant chemotherapy were compared with those who did not receive this type of treatment. Propensity score analysis was performed to mitigate selection bias. Results Of the 404 patients analyzed, 179 were aged 70 years or older. Fewer older patients received adjuvant chemotherapy than did younger patients (60.9% vs. 94.7%, respectively; P < 0.001). Among patients aged 70 years ...
Kidney Research and Clinical Practice
Background: Mounting evidence indicates that melatonin has possible activity against different tu... more Background: Mounting evidence indicates that melatonin has possible activity against different tumors. Pazopanib is an anticancer drug used to treat renal cell carcinoma (RCC). This study tested the anticancer activity of melatonin combined with pazopanib on RCC cells and explored the underlying mechanistic pathways of its action. Methods: The 786-O and A-498 human RCC cell lines were used as cell models. Cell viability and tumorigenesis were detected with the MTT and colony formation assays, respectively. Apoptosis and autophagy were assessed using TUNEL, annexin V/propidium iodide, and acridine orange staining with flow cytometry. The expression of cellular signaling proteins was investigated with western blotting. The in vivo growth of tumors derived from RCC cells was evaluated using a xenograft mouse model. Results: Together, melatonin and pazopanib reduced cell viability and colony formation and promoted the apoptosis of RCC cells. Furthermore, the combination of melatonin and pazopanib triggered more mitochondrial, caspase-mediated, and LC3-II-mediated autophagic apoptosis than melatonin or pazopanib alone. The combination also induced higher activation of the p38 mitogen-activated protein kinase (p38MAPK) in the promotion of autophagy and apoptosis by RCC cells than melatonin or pazopanib alone. Finally, tumor xenograft experiments confirmed that melatonin and pazopanib cooperatively inhibited RCC growth in vivo and predicted a possible interaction between melatonin/pazopanib and LC3-II. Conclusion: The combination of melatonin and pazopanib inhibits the growth of RCC cells by inducing p38MAPK-mediated mitochondrial and autophagic apoptosis. Therefore, melatonin might be a potential adjuvant that could act synergistically with pazopanib for RCC treatment.
Biomedicines
Acute aortic dissection (AAD) and acute myocardial infarction (AMI) are both severe cardiovascula... more Acute aortic dissection (AAD) and acute myocardial infarction (AMI) are both severe cardiovascular diseases that may cause sudden death. However, whether serum proteins are differentially expressed between AAD and AMI remains unclear. Here, we aimed to explore serum protein profiles between AAD and AMI patients. A total of 75 serum samples were collected, including AAD patients without AMI (n = 25), AMI patients without AAD (n = 25), and normal subjects (n=25). Protein identities and expression levels were assessed by LC-MS/MS analysis and a label-free quantitation method, respectively. After depletion of albumin and IgG, a total of 117 proteins with differential expression (fold change ≥2 or ≤−2.0, p < 0.05) were identified, of which 60 were upregulated and 57 were downregulated in AAD sera as compared to AMI sera. Bioinformatic analysis revealed that the differentially expressed serum proteins were mainly derived from exosomes and the extracellular space, and their molecular fu...
Pharmaceuticals
Cisplatin has been widely used in cancer treatments. Recent evidence indicates that adenine has p... more Cisplatin has been widely used in cancer treatments. Recent evidence indicates that adenine has potential anticancer activities against various types of cancers. However, the effects of the combination of adenine and cisplatin on hepatocellular carcinoma (HCC) cells remain sketchy. Here, our objective was to elucidate the anticancer activity of adenine in combination with cisplatin in HCC cells and its mechanistic pathways. Cell viability and cell cycle progression were assessed by the SRB assay and flow cytometry, respectively. Apoptosis was demonstrated by PI/annexin V staining and flow cytometric analysis. Protein expression, signaling cascade, and mRNA expression were analyzed by Western blotting and quantitative RT-PCR, respectively. Our results showed that adenine jointly potentiated the inhibitory effects of cisplatin on the cell viability of SK-Hep1 and Huh7 cells. Further investigation showed that adenine combined with cisplatin induced higher S phase arrest and apoptosis i...
Frontiers in Physiology, 2019
Adipose-derived stem cells (ADSCs) have shown great promise for the treatment of myocardial infar... more Adipose-derived stem cells (ADSCs) have shown great promise for the treatment of myocardial infarction (MI), although their potential therapeutic mechanism remains poorly understood. Growing evidence has implicated microRNAs (miRNAs or miRs) in the biological processes whereby ADSCs could ameliorate cardiovascular disease. In this study, we explored the contribution of miR-34a-5p down-regulation to the protective actions of ADSCs against MI. We initially identified the interaction between miR-34a-5p and C1q/tumor necrosis factor-related protein-9 (CTRP9) through in silico analysis. We next tested the effects of miR-34a-5p and CTRP9 on the expression of extracellular signal-regulated kinase 1 (ERK1), matrix metalloproteinase-9 (MMP-9), nuclear factor (erythroid-derived 2)-like 2 (NRF2), and antioxidant proteins [manganese superoxide dismutase (MnSOD), and heme oxygenase-1 (HO-1)] through gain-and loss-of-function tests. In other experiments, we assessed the proliferation, migration, and apoptosis of ADSCs using the EdU assay, scratch test, Transwell assay, and flow cytometry. Finally, we studied whether miR-34a-5p/CTRP9 axis could modulate the protective effect of ADSCs against MI during stem cell transplantation in MI mouse models. miR-34a-5p could target and down-regulate CTRP9 in cardiomyocytes. Down-regulated miR-34a-5p increased the expression of ERK1, MMP-9, NRF2, MnSOD, and HO-1, whereas downregulation of miR-34a-5p or up-regulation of CTRP9 in vitro promoted ADSC proliferation and migration and inhibited ADSC apoptosis. Moreover, miR-34a-5p down-regulation or CTRP9 up-regulation promoted the protective role of ADSCs against MI damage in vivo. Thus, inhibition of miR-34a-5p may facilitate ADSC's protective function against MI damage by stimulating the expression of CTRP9.
BioMed Research International, 2014
Adenosine 5′-monophosphate-activated protein kinase (AMPK) is a key regulator of cellular energy ... more Adenosine 5′-monophosphate-activated protein kinase (AMPK) is a key regulator of cellular energy homeostasis via modulating metabolism of glucose, lipid, and protein. In addition to energy modulation, AMPK has been demonstrated to associate with several important cellular events including inflammation. The results showed that ENERGI-F704 identified from bamboo shoot extract was nontoxic in concentrations up to 80 μM and dose-dependently induced phosphorylation of AMPK (Thr-172) in microglia BV2 cells. Our findings also showed that the treatment of BV2 with ENERGI-F704 ameliorated the LPS-induced elevation of IL-6 and TNF-αproduction. In addition, ENERGI-F704 reduced increased production of nitric oxide (NO) and prostaglandin E2 (PGE2) via downregulating the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2), respectively. Moreover, ENERGI-F704 decreased activated nuclear translocation and protein level of NF-κB. Inhibition of AMPK with compound C resto...
Evidence-Based Complementary and Alternative Medicine, 2012
Ocimum gratissimum(OG) is known as a food spice and traditional herb, which has been recommended ... more Ocimum gratissimum(OG) is known as a food spice and traditional herb, which has been recommended for the treatment of various diseases. To investigate the hepatoprotective effect of OG aqueous extract (OGAE), male Wistar rats challenged by carbon tetrachloride (CCl4) were used as the animal model of chronic hepatic injury. Significantly increased serum catalase and DPPH levels were detected in CCl4-administrated rats that were treated with OGAE or silymarin as compared to those rats that were treated with saline or CCl4. In contrast, significantly decreased stress proteins including HSP70 and iNOS were observed in livers of CCl4-administrated rats that were treated with OGAE or sylimarin as compared to those rats that were treated with saline or CCl4. Moreover, significant decreases of MMP-9/MMP-2 ratio, uPA, phosphorylated ERK (p-ERK) and NF-κB (p-P65) were detected in livers of CCl4-administrated rats that were treated with OGAE or sylimarin as compared to those rats that were tre...
Pharmaceuticals
Rosmarinic acid (RA) is a phenolic compound that has several bioactivities, such as anti-inflamma... more Rosmarinic acid (RA) is a phenolic compound that has several bioactivities, such as anti-inflammatory and antioxidant activities. Here, we further investigate the anti-inflammatory effect of RA on rat A7r5 aortic smooth muscle cells with exposure to lipopolysaccharide (LPS). Our findings showed that low-dose RA (10–25 μM) did not influence the cell viability and morphology of A7r5 cells and significantly inhibited LPS-induced mRNA expression of the pro-inflammatory mediators TNFα, IL-8, and inducible NO synthase (iNOS). Consistently, RA reduced the production of TNFα, IL-8, and NO by A7r5 cells with exposure to LPS. Signaling cascade analysis showed that LPS induced activation of Erk, JNK, p38 mitogen-activated protein kinase (MAPK), and NF-κB, and RA treatments attenuated the activation of the three MAPKs and NF-κB. Moreover, cotreatment with RA and Erk, JNK, p38 MAPK, or NF-κB inhibitors further downregulated the mRNA expression of TNFα, IL-8, and iNOS, and decreased the productio...
Journal of Food and Drug Analysis
Camphorataimide B suppresses the metastasis of human Camphorataimide B suppresses the metastasis ... more Camphorataimide B suppresses the metastasis of human Camphorataimide B suppresses the metastasis of human colorectal cancer cell by inhibiting Smad/FAK/Akt axis and colorectal cancer cell by inhibiting Smad/FAK/Akt axis and promoting degradation of Snail/BMP4 complex promoting degradation of Snail/BMP4 complex
Tumor metastasis is a major cause of death of patients with colorectal cancer (CRC). Our previous... more Tumor metastasis is a major cause of death of patients with colorectal cancer (CRC). Our previous findings show that adenine has antiproliferation activity against tumor cells. However, whether adenine reduces the invasiveness of DLD-1 and SW480 CRC cells has not been thoroughly explored. In this study, we aimed to explore the effects of adenine on the invasion potential of DLD-1 cells. Our findings showed that adenine at concentrations of ≤200 μM did not influence the cell viability of DLD-1 and SW480 CRC cells. By contrast, adenine reduced the migratory potential of the CRC cells. Moreover, it decreased the invasion capacity of the CRC cells in a dose-dependent manner. We further observed that adenine downregulated the protein levels of tissue plasminogen activator, matrix metalloproteinase-9, Snail, TWIST, and vimentin, but upregulated the tissue inhibitor of metalloproteinase-1 expression in DLD-1 cells. Adenine decreased the integrin αV level and reduced the activation of integ...
International Journal of Medical Sciences
Background: Adenine exhibits potential anticancer activity against several types of malignancies.... more Background: Adenine exhibits potential anticancer activity against several types of malignancies. However, whether adenine has anticancer effects on hepatocellular carcinoma (HCC) cells is incompletely explored. Methods: Human HCC cell lines HepG2 and SK-Hep-1 (p53-wild type) and Hep3B (p53-deficient) were used as cell model. Cell growth and cell cycle distribution were determined using MTT assay and flow cytometric analysis, respectively. Protein expression and phosphorylation were assessed by Western blot. Involvement of AMP-activated protein kinase (AMPK) was evaluated using specific inhibitor and small inhibitory RNA (siRNA). Results: Adenine treatments (0.5-2 mM) clearly decreased the cell growth of Hep G2 and SK-Hep-1 cells to 72.5 ± 3.4% and 71.3 ± 4.6% of control, respectively. In parallel, adenine also induced sub-G1 and S phase accumulation in both HCC cells. However, adenine did not affect the cell growth and cell cycle distribution of Hep3B cell. Western blot analysis showed that adenine reduced expression of cyclin A/D1 and cyclin-dependent kinase (CDK)2 and upregulated p53, p21, Bax, PUMA, and NOXA in HepG2 cell. Moreover, adenine induced AMPK activation that was involved in the p53-associated apoptotic cascade in HepG2 cells. Inhibition of AMPK activation or knockdown of AMPK restored the decreased cell growth of HepG2 and SK-Hep-1 cells in response to adenine. Conclusions: These findings reveal that adenine reduces the cell growth of HepG2 and SK-Hep-1 but not Hep3B cells, attributing to the AMPK/p53-mediated S phase arrest and apoptosis. It suggests that adenine has anticancer potential against p53-wild type HCC cells and may be beneficial as an adjuvant for HCC treatment.
The pr incipal subtype of lung cancer, non-small cell lung cancer (NSCLC) is a life-threatening m... more The pr incipal subtype of lung cancer, non-small cell lung cancer (NSCLC) is a life-threatening malignancy that causes high mortality rates. Bergapten (5-methoxypsoralen) has been identified to possess anticancer activity against a number of carcinomas. In the present study, the effects of bergapten on NSCLC cells were investigated. The cell viability was determined by MTT assay. Cell cycle distribution was analyzed using flow cytometry. Protein expression and kinase cascade were demonstrated using western blot analysis. The results demonstrated that treatment with bergapten (50 μM for 48 h) inhibited the viability of A549 and NCI-H460 NSCLC cells to 79.1±2.8% and 74.5±3.1%, respectively, compared with the controls. It was identified that bergapten induced G1 phase accumulation in A549 and NCI-H460 cells between ~58 and 75% (P<0.01). In addition, bergapten significantly increased the sub‐G1 phase ratio to ~9% (P<0.05) in the two cell types. Further investigation demonstrated t...
Evidence-based Complementary and Alternative Medicine : eCAM, 2021
Excessive alcohol intake is a major cause of chronic liver damage and is highly associated with t... more Excessive alcohol intake is a major cause of chronic liver damage and is highly associated with the development of a spectrum of hepatic disorders, including steatohepatitis, liver cirrhosis, and liver cancer. Thus, we aimed to explore the hepatoprotective effects of an aqueous mulberry leaf extract (AME) on alcoholic fatty liver disorder (AFLD) by using a mouse model fed with excessive ethanol. Compared with the normal diet, the ethanol diet significantly increased the body weight of the mice, while the AME supplement reduced the weight gain caused by the ethanol diet. The ethanol diet also attenuated the activity of alcohol dehydrogenase and antioxidant enzymes but increased lipid peroxidation in the liver, which were reversed by AME supplementation. Additionally, AME supplementation diminished the ethanol diet-induced hepatic leukocyte infiltration and expressions of IL-6 and TNFα. Moreover, AME supplementation also reduced the ethanol-diet-induced lipid accumulation and expressi...
Metastasis-associated protein 2 (MTA2) is a transcription factor that is highly associated with m... more Metastasis-associated protein 2 (MTA2) is a transcription factor that is highly associated with matrix metalloproteinase 12 (MMP12). Thus, we hypothesized that MTA2 may regulate MMP12 expression and is involved in cervical cancer metastasis. Results showed that MTA2 and MMP12 were highly expressed in cervical cancer cells, and MTA2 knockdown reduced MMP12 expression and inhibited the metastasis of cervical cancer cells in xenograft mice. MMP12 knockdown did not influence the viability of cervical cancer cells but clearly inhibited cell migration and invasion both in vitro and in vivo. MMP12 was highly expressed in cervical tumor tissues and correlated with the poor survival rate of patients with cervical cancer. Further investigations revealed that p38 mitogen-activated protein kinase (p38), mitogen-activated protein kinase kinase 3 (MEK3), and apoptosis signal-regulating kinase 1 (ASK1) were involved in MMP12 downregulation in response to MTA2 knockdown. Results also demonstrated t...
The American Journal of Chinese Medicine
Metastasis is the most prevalent cause of cancer-associated deaths amongst patients with cervical... more Metastasis is the most prevalent cause of cancer-associated deaths amongst patients with cervical cancer. Epithelial–mesenchymal transition (EMT) is essential for carcinogenesis, and it confers metastatic properties to cancer cells. Gossypol is a natural polyphenolic compound with anti-inflammation, anti-oxidant, and anticancer activities. In this study, we investigated the antimetastatic and antitumour effects of gossypol on human cervical cancer cells (HeLa and SiHa cells). Gossypol exerted a strong inhibition effect on the migration and invasion of human cervical cancer cells. It reduced the focal adhesion kinase (FAK) pathway-mediated expression of matrix metalloproteinase-2 and urokinase-type plasminogen activator, subsequently inhibiting the invasion of SiHa cells. In addition, gossypol reversed EMT induced by transforming growth factor beta 1 (TGF-[Formula: see text]1) and up-regulated epithelial markers, such as E-cadherin but significantly suppressed Ras homolog family memb...
Cells
Corosolic acid (CA), a bioactive compound obtained from Actinidia chinensis, has potential anti-c... more Corosolic acid (CA), a bioactive compound obtained from Actinidia chinensis, has potential anti-cancer activities. Glioblastoma (GBM) is a malignant brain tumor and whether CA exerts anti-cancer activity on GBM remains unclear. This study was aimed to explore the anticancer activity and its underlying mechanism of CA in GBM cells. Our findings showed that CA ≤ 20 μM did not affect cell viability and cell proliferative rate of normal astrocyte and four GBM cells. Notably, 10 or 20 μM CA significantly inhibited cell migration and invasion of three GBM cells, decreased the protein level of F-actin and disrupted F-actin polymerization in these GBM cells. Further investigation revealed that CA decreased AXL level by promoting ubiquitin-mediated proteasome degradation and upregulating the carboxyl terminus of Hsc70-interacting protein (CHIP), an inducer of AXL polyubiquitination. CHIP knock-down restored the CA-reduced AXL and invasiveness of GBM cells. Additionally, we observed that CA-r...