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Metastasis is one of the most aberrant behaviors of cancer cells. Patients with cancers, including colorectal cancer (CRC), have a higher risk of tumor recurrence and cancer-related mortality once metastasis is diagnosed. Existing treatment strategies fail to cure cancer mostly due to the onset of metastasis. Therefore, metastasis remains a challenge in cancer treatment. Some complementary and alternative medical therapies using traditional Chinese medicine have been demonstrated to be clinically effective in cancer treatment. Scutellaria barbata D. Don (SB) is a promising medicinal herb. It was previously reported that the ethanol extract of SB (EESB) is able to promote apoptosis, and inhibit cell proliferation and angiogenesis in human colon cancer cells. However, the anticancer effect of SB and the underlying mechanism require further investigation, particularly its role against metastasis. To further elucidate the antimetastatic effect of SB, MTT and Transwell assays were used in the present study to evaluate the effect of EESB on the proliferation, migration and invasion of the CRC cell line HCT-8. In addition, western blot analysis was performed to detect the expression of matrix metalloproteinases (MMPs), cadherins and other metastasis-associated proteins. EESB significantly reduced HCT-8 cell viability and attenuated the migration and invasion ability of HCT-8 cells in a dose-dependent manner. In addition, EESB decreased the expression of MMP-1, MMP-2, MMP-3/10, MMP-9 and MMP-13, and proteins in the phosphoinositide 3-kinase (PI3K)/AKT and transforming growth factor (TGF)-β/Smad pathways, but not the epithelial-mesenchymal transition (EMT)-related factors E-cadherin and N-cadherin. In conclusion, the results suggested that SB inhibits CRC cell metastasis via the suppression of PI3K/AKT and TGF-β/Smad signaling pathways, which may represent a mechanism by which SB exerts an anticancer effect. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are small, short endogenous non-coding RNA that act as oncogenes or tumor suppressors, and serve an important role in various human malignant cancers, including colorectal cancer (CRC). Evidence has indicated that miRNAs regulate the expression of various genes associated with human cancer, in particular the miR-34 family. A well-known traditional Chinese formula, Pien Tze Huang (PZH), has a significant clinical effect on CRC. Previous studies have demonstrated that PZH inhibits CRC growth in vitro and in vivo via multiple mechanisms, including the induction of apoptosis, inhibition of cell proliferation and tumor angiogenesis. To further elucidate the molecular mechanisms underlying the antitumor activity of PZH, in the present study its effects on cell proliferation and miRNA expression in human colon carcinoma (HCT)-8 cell lines was examined. It was observed that treatment with PZH inhibited cell viability and upregulated the expression of miR-34c-5p in HCT-8 cells. In addition, transfection with an miR-34c-5p mimic and treatment with PZH inhibited cell survival and arrested the cell cycle between the G0/G1 and S phase in HCT-8 cells. Furthermore, PZH treatment and transfection with miR-34c-5p downregulated the expression of cyclin-dependent kinase 4 and cMyc (a promoter of cell proliferation), and increased the expression of p53, which is a promoter of apoptosis. These results suggest that PZH may suppress proliferation in CRC cells by upregulating the expression of miR-34c-5p, which provides a novel perspective for understanding the mode of action of PZH. [ABSTRACT FROM AUTHOR]

The well-known traditional Chinese medicine formula Pien Tze Huang (PZH) has long been used to treat various malignancies, including colorectal cancer (CRC). It was recently reported that PZH possesses the ability to overcome multidrug resistance in CRC cells. In the present study, a 5-fluorouracil (5-FU) resistant human CRC cell line (HCT-8/5-FU) was used to further evaluate the effect of PZH on chemotherapy (chemo)-resistance and investigate the mechanisms through which this occurs. The results identified that PZH significantly reduced the viability and cell density of HCT-8/5-FU cells in a dose- and time-dependent manner (P<0.05). PZH inhibited cell survival, reduced the proportion of cells in S-phase, and suppressed the expression of pro-proliferative proteins cyclin D1 and cyclin-dependent kinase 4. In addition, PZH treatment induced nuclear condensation and fragmentation, activated caspase-9 and -3 and increased the pro-apoptotic Bcl-2-associated X protein/B-cell lymphoma 2 protein ratio. Furthermore, PZH treatment upregulated the expression of microRNA-22 (miR-22) and downregulated the expression of c-Myc (a target gene of miR-22). In conclusion, the findings from the present study suggest that PZH can overcome chemo-resistance in cancer cells, likely through increasing miR-22 expression, and by reversing the imbalance between levels of proliferation and apoptosis. [ABSTRACT FROM AUTHOR]

Chemotherapeutic agents, including 5-fluorouracil (5-FU), frequently cause intestinal mucositis as a side effect, leading to life quality reduction in colorectal cancer (CRC) patients and interruption of CRC treatment. Traditional Chinese medicines (TCMs) have recently received attention due to their relatively few adverse effects. Pien Tze Huang (PZH), a well-known TCM formulation first documented to have been prescribed >450 years ago, has been demonstrated to be clinically effective in treating various types of cancer including CRC. Although previous studies by our group reported that PZH possesses a variety of anti-cancer activities via multiple mechanisms, it has remained elusive whether it is able to reduce intestinal mucositis induced by 5-FU. The present study evaluated the effect of PZH on 5-FU-induced intestinal mucositis in CT-26 tumor-bearing xenograft mice and investigated the possible molecular mechanism. The results indicated that administration of PZH effectively alleviated the severity of 5-FU-induced diarrhea and morphological intestinal damages, but had no significant effect on body weight loss. In addition, a terminal deoxynucleotidyl transferase dUTP nick end labeling assay revealed that PZH treatment significantly inhibited cell apoptosis in the intestinal crypt. Furthermore, immunohistochemical staining showed that PZH treatment reduced the protein expression of pro-apoptotic B-cell lymphoma 2 (Bcl-2)-associated X protein but enhanced that of anti-apoptotic Bcl-2 in the intestinal crypt. Taken together, the results of the present study suggested that PZH effectively attenuates 5-FU-induced intestinal mucositis, which is in part associated with its inhibitory effect on cell apoptosis in the intestinal crypt. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate the expression level of collapsin response mediator protein 4 (CRMP-4) in human colorectal cancer (CRC) tissue and to evauluate its impact on SW480 cell proliferation, in addition to tumor growth in a mouse xenograft model. Clinical CRC tissue samples were collected to detect the CRMP-4 protein expression levels using western blot and immunohistochemistry analyses. A specific small interfering RNA sequence targeting the CRMP-4 gene (DPYSL3) was constructed and transfected into an SW480 cell line using a lentivirus vector to obtain a stable cell line with low expression of CRMP-4. The effectiveness of the interference was evaluated using western blot and reverse transcription-quantitative polymerase chain reaction, and the cell proliferation was determined using MTT and BrdU colorimetric methods. Tumor growth was assessed by subcutaneously inoculating the constructed cells into BALB/c nude mice. The protein expression levels of CRMP-4 were markedly increased in colon tumor tissue of the human samples. The proliferation of SW480 cells and the tumor growth rate in nude mice of the si-CPMR-4 group were evidently depressed compared with the si-scramble group. Thus, the present results suggest that CRMP-4 may be involved in the pathogenesis of CRC. [ABSTRACT FROM AUTHOR]

Previous studies have demonstrated that Hedyotis diffusa Willd (HDW), a traditional Chinese herbal medicine, exhibits potent anticancer activity in models of colorectal cancer (CRC). Aggressive forms of CRC exhibit resistance to widely used chemotherapeutic drugs, including the antimetabolite, 5-fluorouracil (5-FU); however, less is known with regard to the activity of HDW against 5-FU-resistant cancer. In the present study, the mechanism of action and the potency of ethanol extracts of HDW (EEHDW) were investigated on a multidrug-resistant CRC HCT-8/5-FU cell line. Using an MTT cell proliferation assay, EEHDW treatment was shown to significantly reduce the cell viability of HCT-8/5-FU cells in a dose- and time-dependent manner. Furthermore, EEHDW significantly increased the retention of the ATP-binding cassette (ABC) transporter substrate, rhodamine-123, as compared with the untreated controls. To further investigate the molecular mechanisms targeted by EEHDW in the resistant cells, the expression levels of the ABC drug transporter protein, P-glycoprotein (P-gp), and ABC subfamily G member 2 (ABCG2), were analyzed using reverse-transcription polymerase chain reaction and western blot analysis. The mRNA and protein expression levels of P-gp and ABCG2 were reduced in the HCT-8/5-FU cells following EEHDW treatment, indicating that EEHDW inhibits ABCG2-mediated drug resistance by downregulating the expression of ABCG2 and P-gp. Therefore, the potential application of EEHDW as a chemotherapeutic adjuvant represents a promising alternative approach to the treatment of drug-resistant CRC. [ABSTRACT FROM AUTHOR]

One of the most critical cellular signal transduction pathways known to malfunction in colorectal cancer is the interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3) pathway. Scutellaria barbata D. Don (SB) is well-known traditional medicine in China that targets STAT3 signaling, and it has long been used to treat various types of cancer; however, the precise mechanism of its anti-tumor activity remains largely unclear. In order to further elucidate this underlying mechanism, an ethanol extract of SB (EESB) in cancer treatment. The aim of the present study was to evaluate the effects of EESB on the IL-6-inducible STAT3 pathway. We tested the dose-response association between EESB, IL-6-induced proliferation and apoptosis using an MTT assay, colony formation and low cytometry analysis in vitro. In addition, caspase-9 and caspase-3 activation was determined using a colorimetric assay, the activity of IL-6-induced STAT3 pathway was evaluated using western blot analysis, and the expression levels of cyclin D1, cyclin-dependent kinase 4, Bcl2 and Bcl2-associated X were determined using reverse transcription-polymerase chain reaction and western blot analysis. In the present study it was found that EESB could significantly inhibit the IL-6-mediated increase in STAT3 phosphorylation levels and transcriptional activity in HT-29 human colon carcinoma cells, resulting in the suppression of cell proliferation and the induction of apoptosis. In addition, treatment with EESB markedly inhibited the IL-6-induced upregulation of cyclin D1 and B-cell lymphoma-2, two key target genes of the STAT3 pathway. These results suggest that treatment with EESB could effectively inhibit the proliferation and promote the apoptosis of human colon carcinoma cells via modulation of the IL-6/STAT3 signaling pathway and its target genes. [ABSTRACT FROM AUTHOR]

Spasticity is common in various central neurological conditions, including after a stroke. Such spasticity may cause additional problems, and often becomes a primary concern for afflicted individuals. A number of studies have identified nuclear factor (erythroid-derived 2)-like 2 (Nrf2) as a key regulator in the adaptive survival response to oxidative stress. Elevated expression of Nrf2, combined with heme oxygenase 1 (HO-1) resistance, in the central nervous system is known to elicit key internal and external oxidation protection. Gua Lou Gui Zhi decoction (GLGZD) is a popular traditional Chinese formula with a long history of clinical use in China for the treatment of muscular spasticity following a stroke, epilepsy or a spinal cord injury. However, the mechanism underlying the efficacy of the medicine remains unclear. In the present study, the antioxidative effects of GLGZD were evaluated and the underlying molecular mechanisms were investigated, using hydrogen peroxide (H2O2)-induced rat pheochromocytoma cells (PC12 cells) as an in vitro oxidative stress model of neural cells. Upon application of different concentrations of GLGZD, a 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT) assay and ATP measurement were conducted to assess the impact on PC12 cell proliferation. In addition, inverted microscopy observations, and the MTT and ATP assessments, revealed that GLGZD attenuated H2O2-induced oxidative damage and signaling repression in PC12 cells. Furthermore, the mRNA and protein expression levels of Nrf2 and HO-1, which are associated with oxidative stress, were analyzed using reverse transcription quantitative polymerase chain reaction (PCR) and confocal microscopy. Confocal microscopy observations, as well as the quantitative PCR assay, revealed that GLGZD exerted a neuroprotective function against H2O2-induced oxidative damage in PC12 cells. Therefore, the results demonstrated that GLGZD protected PC12 cells injured by H2O2, which may be associated with the upregulation of Nrf2 and HO-1 mRNA and protein expression levels in PC12 cells. [ABSTRACT FROM AUTHOR]

Angiogenesis plays an important role in the progression and development of benign prostatic hyperplasia (BPH), and has become a promising target for BPH treatment. The hypoxia-inducible factor-1a (HIF-1a) signaling pathway promotes the process of angiogenesis, contributing to the growth and progression of a number of hyperplasia diseases, including BPH. Qianliening capsule (QC) is a traditional Chinese formula that has been used clinically in China to treat BPH for a number of years. Recently, QC was demonstrated to inhibit prostatic cell growth and induce apoptosis in vivo and in vitro via regulating the epidermal growth factor/signal transducer and activator of transcription 3 signaling pathway and mitochondrion-dependent apoptosis pathway. However, the mechanisms underlying the anti-BPH effect remain largely unknown. To further elucidate the mechanism of QC activity in BPH treatment, a rat BPH model established by injecting testosterone following castration was established and the effect of QC on prostatic tissue angiogenesis was evaluated, as well as the underlying molecular mechanisms. QC was shown to reduce the prostatic index in BPH rats, but without affecting the body weight, demonstrating that QC is effective in the treatment of BPH and without apparent toxicity. In addition, QC treatment significantly reduced the intraprostatic microvessel density, indicating antiangiogenesis activity in vivo. In addition, treatment with QC inhibited the expression of HIF-1a in BPH rats, as well as the expression of vascular endothelial growth factor and basic fibroblast growth factor. Therefore, for the first time, the present study hypothesized that QC inhibits angiogenesis in prostatic tissue of BPH rats via the inhibition of the HIF-1a signaling pathway, which may be one of the mechanisms in which QC treats BPH. [ABSTRACT FROM AUTHOR]

One of the most common causes of chronic liver disease, nonalcoholic fatty liver disease (NAFLD), is strongly associated with obesity and dysregulated insulin action in the liver. However, there are no pharmacological agents currently established for the treatment of NAFLD. A flowering plant in the Asteraceae family, Cirsium japonicum (CJ), exhibits a variety of pharmacological and antioxidative properties that promote hepatoprotection. In the present study, CJ ethanol extract was shown to reduce hepatic triglyceride (TG) and cholesterol accumulation. CJ significantly increased AMP-activated protein kinase (AMPK) phosphorylation in HepG2 hepatocytes and downregulated the level of the target genes, acetyl-CoA carboxylase and fatty acid synthase. In addition, CJ upregulated the expression of carnitine palmitoyltransferase-1, which is involved in fatty acid oxidation. The results of the present study indicated that the positive effects of CJ extract on high-fat diet-induced hepatic TG accumulation were mediated via the AMPK signaling pathway, indicating a potential target for the preventative treatment of NAFLD. [ABSTRACT FROM AUTHOR]

Hypoxia-induced activation of the hypoxia-inducible factor 1 (HIF-1) signaling pathway is frequently observed in solid tumors and is strongly associated with numerous pathophysiological processes, including the induction of epithelial-mesenchymal transition (EMT), which result in cancer progression and metastasis. Thus, inhibiting EMT through the suppression of the HIF-1 pathway may be a promising strategy for anticancer chemotherapy. Pien Tze Huang (PZH), a well-established traditional Chinese medicine has been prescribed for >450 years and has been used for centuries to clinically treat various types of human cancer. We previously reported that PZH suppresses multiple intracellular signaling pathways and thereby promotes the apoptosis of cancer cells and the inhibition of cell proliferation and tumor angiogenesis. In the present study, to further explore the mechanisms underlying the antitumor action of PZH, HCT-8 human colon carcinoma cells were cultured under hypoxic conditions and the effect of PZH on hypoxia-induced EMT was assessed. Hypoxia was found to induce EMT-associated morphological changes in HCT-8 cells, including loss of cell adhesion and the development of spindle-shaped fibroblastoid-like morphology. In addition, hypoxia was observed to reduce the expression of the epithelial marker E-cadherin, but increase that of the mesenchymal marker N-cadherin. In addition, hypoxia significantly enhanced HCT-8 cell migration and invasion and induced the activation of the HIF-1 pathway. However, treatment of the HCT-8 cells with PZH significantly inhibited the hypoxia-mediated EMT and HIF-1 signaling. These findings suggest that PZH inhibits hypoxia-induced cancer EMT through the suppression of the HIF-1 pathway, which may be one of the molecular mechanisms by which PZH exerts its antitumor activity. [ABSTRACT FROM AUTHOR]

Intervertebral disk degeneration (IDD) is a severe health problem that results in lower back pain and disability. Previous evidence has indicated that excessive apoptosis of nucleus pulposus (NP) cell is involved in the occurrence and development of IDD. However, the underlying mechanisms regulating NP cell apoptosis are unclear. The present study aimed to investigate the function of a novel long non-coding RNA RP11-81H3.2 in modulating NP cell apoptosis and the potential underlying mechanisms. The results demonstrated that the RP11-81H3.2 expression levels were significantly decreased in NP tissues from patients with IDD compared with those from healthy controls, and that lower expression levels were associated with higher-grade disk degeneration. Functionally, RP11-81H3.2 silencing promoted apoptosis and decreased the viability of NP cells derived from tissue samples of patients with IDD, whereas RP11-81H3.2 overexpression induced opposite effects. Bioinformatics analysis, luciferase assays and reverse transcription-quantitative PCR revealed that microRNA (miR)-1539 was a direct target of RP11-81H3.2. A mechanistic analysis demonstrated that RP11-81H3.2 functioned as an RNA sink to downregulate miR-1539, which led to the upregulation of collagen type 2 α 1 chain (COL2A1), a target of miR-1539. Collectively, the present results suggested that lower RP11-81H3.2 expression levels were associated with higher-grade IDD, and that RP11-81H3.2 inhibited NP cell apoptosis by decreasing the levels of miR-1539 to increase COL2A1 expression levels. The present study identified a beneficial role of RP11-81H3.2 against NP cell apoptosis. [ABSTRACT FROM AUTHOR]