Colorectal cancer (CRC) is the third most common cancer and the fourth most common cause of cancer-related death. Most cases of CRC are detected in Western countries, with its incidence increasing year by year. The probability of suffering from colorectal cancer is about 4%–5% and the risk for developing CRC is associated with personal features or habits such as age, chronic disease history and lifestyle. In this context, the gut microbiota has a relevant role, and dysbiosis situations can induce colonic carcinogenesis through a chronic inflammation mechanism. Some of the bacteria responsible for this multiphase process include Fusobacterium spp, Bacteroides fragilis and enteropathogenic Escherichia coli. CRC is caused by mutations that target oncogenes, tumour suppressor genes and genes related to DNA repair mechanisms. Depending on the origin of the mutation, colorectal carcinomas can be classified as sporadic (70%); inherited (5%) and familial (25%). The pathogenic mechanisms leading to this situation can be included in three types, namely chromosomal instability (CIN), microsatellite instability (MSI) and CpG island methylator phenotype (CIMP). Within these types of CRC, common mutations, chromosomal changes and translocations have been reported to affect important pathways (WNT, MAPK/PI3K, TGF-β, TP53), and mutations; in particular, genes such as c-MYC, KRAS, BRAF, PIK3CA, PTEN, SMAD2 and SMAD4 can be used as predictive markers for patient outcome. In addition to gene mutations, alterations in ncRNAs, such as lncRNA or miRNA, can also contribute to different steps of the carcinogenesis process and have a predictive value when used as biomarkers. In consequence, different panels of genes and mRNA are being developed to improve prognosis and treatment selection. The choice of first-line treatment in CRC follows a multimodal approach based on tumour-related characteristics and usually comprises surgical resection followed by chemotherapy combined with monoclonal antibodies or proteins against vascular endothelial growth factor (VEGF) and epidermal growth receptor (EGFR). Besides traditional chemotherapy, alternative therapies (such as agarose tumour macrobeads, anti-inflammatory drugs, probiotics, and gold-based drugs) are currently being studied to increase treatment effectiveness and reduce side effects.

/pdf/colorectal-carcinoma-a-general-overview-and-future-2e96vugrtz.pdf

Colorectal Carcinoma: A General Overview and Future Perspectives in Colorectal Cancer

Cancer is one of the main causes of death worldwide. Despite the significant development of methods of cancer healing during the past decades, chemotherapy still remains the main method for cancer treatment. Depending on the mechanism of action, commonly used chemotherapeutic agents can be divided into several classes (antimetabolites, alkylating agents, mitotic spindle inhibitors, topoisomerase inhibitors, and others). Multidrug resistance (MDR) is responsible for over 90% of deaths in cancer patients receiving traditional chemotherapeutics or novel targeted drugs. The mechanisms of MDR include elevated metabolism of xenobiotics, enhanced efflux of drugs, growth factors, increased DNA repair capacity, and genetic factors (gene mutations, amplifications, and epigenetic alterations). Rapidly increasing numbers of biomedical studies are focused on designing chemotherapeutics that are able to evade or reverse MDR. The aim of this review is not only to demonstrate the latest data on the mechanisms of cellular resistance to anticancer agents currently used in clinical treatment but also to present the mechanisms of action of novel potential antitumor drugs which have been designed to overcome these resistance mechanisms. Better understanding of the mechanisms of MDR and targets of novel chemotherapy agents should provide guidance for future research concerning new effective strategies in cancer treatment.

Mechanisms of Multidrug Resistance in Cancer Chemotherapy.

13. T. Satoh, S. Nakai, T. Sato, M. Kimura, J. Neurosci. 23,9913 (2003).14. H. Nakahara, H. Itoh, R. Kawagoe, Y. Takikawa, O.Hikosaka, Neuron 41, 269 (2004).15. P. Redgrave, T. J. Prescott, K. Gurney, Trends Neurosci.22, 146 (1999).16. M. Steriade, E. G. Jones, C. D. McCormick, in Thalamus,M. Steriade et al., Eds. (Elsevier Science, Oxford, 1997),vol. 1, pp. 55–73.17. H. J. Groenewegen, H. W. Berendse, Trends Neurosci.17, 52 (1994).18. N. Hatanaka et al., J. Comp. Neurol. 462, 121 (2003).19. Y. Smith, D. V. Raju, J. F. Pare, M. Sidibe, TrendsNeurosci. 27, 520 (2004).20. N. Matsumoto, T. Minamimoto, A. M. Graybiel, M.Kimura, J. Neurophysiol. 85, 960 (2001).21. T. Minamimoto, M. Kimura, J. Neurophysiol. 87,3090 (2002).22. A. M. Graybiel, T. Aosaki, A. W. Flaherty, M. Kimura,Science 265, 1826 (1994).23. M. Kimura, T. Minamimoto, N. Matsumoto, Y. Hori,Neurosci. Res. 48, 355 (2004).24. Materials and methods are available as supportingmaterial on Science Online.25. M. Botvinick, L. E. Nystrom, K. Fissell, C. S. Carter, J. D.Cohen, Nature 402, 179 (1999).26. We thank B. J. Richmond, H. Yamada, and K. Samejimafor their helpful comments and R. Sakane for hertechnical assistance. This study was supported by agrant in aid from the Ministry of Education, Culture,Sports, Science, and Technology of Japan (MEXT).Supporting Online Materialwww.sciencemag.org/cgi/content/full/308/5729/1798/DC1Materials and MethodsSOM TextFigs. S1 to S3Table S1References27 December 2004; accepted 6 April 200510.1126/science.1109154

A Mutation in the TRPC6 Cation Channel Causes Familial Focal

Over the past decade, the amount of research and the number of publications on associations between circulating small and long non-coding RNAs (ncRNAs) and cancer have grown exponentially. Particular focus has been placed on the development of diagnostic and prognostic biomarkers to enable efficient patient management — from early detection of cancer to monitoring for disease recurrence or progression after treatment. Owing to their high abundance and stability, circulating ncRNAs have potential utility as non-invasive, blood-based biomarkers that can provide information on tumour biology and the effects of treatments, such as targeted therapies and immunotherapies. Increasing evidence highlights the roles of ncRNAs in cell-to-cell communication, with a number of ncRNAs having the capacity to regulate gene expression outside of the cell of origin through extracellular vesicle-mediated transfer to recipient cells, with implications for cancer progression and therapy resistance. Moreover, ‘foreign’ microRNAs (miRNAs) encoded by non-human genomes (so-called xeno-miRNAs), such as viral miRNAs, have been shown to be present in human body fluids and can be used as biomarkers. Herein, we review the latest developments in the use of circulating ncRNAs as diagnostic and prognostic biomarkers and discuss their roles in cell-to-cell communication in the context of cancer. We provide a compendium of miRNAs and long ncRNAs that have been reported in the literature to be present in human body fluids and that have the potential to be used as diagnostic and prognostic cancer biomarkers. Evidence of the functional roles of non-coding RNAs in cancer is expanding, and the potential of these RNAs as diagnostic and prognostic biomarkers is increasingly recognized. Herein, the authors review the recent developments in these areas and provide compendiums of circulating microRNAs and long non-coding RNAs that have promise as diagnostic and prognostic cancer biomarkers.

Clinical utility of circulating non-coding RNAs — an update

Decoctions prepared from the roots of Astragali Radix are known as "Huangqi" and are widely used in traditional Chinese medicine for treatment of viral and bacterial infections, inflammation, as well as cancer. Astragaloside IV (AS-IV), one of the major compounds from the aqueous extract of Astragalus membranaceus, is a cycloartane-type triterpene glycoside chemical. To date, many studies in cellular and animal models have demonstrated that AS-IV possesses potent protective effects in cardiovascular, lung, kidney and brain. Based on studies over the past several decades, this review systematically summarizes the pharmacological effects, pharmacokinetics and the toxicity of AS-IV. We analyze in detail the pharmacological effects of AS-IV on neuroprotection, liver protection, anti-cancer and anti-diabetes, attributable to its antioxidant, anti-inflammatory, anti-apoptotic properties, and the roles in enhancement of immunity, attenuation of the migration and invasion of cancer cells and improvement of chemosensitivity of chemotherapy drugs. In addition, the latest developments in the combination of AS-IV and other active ingredients of traditional Chinese medicine or chemical drugs are detailed. These pharmacological effects are associated with multiple signaling pathways, including the Raf-MEK-ERK pathway, EGFR-Nrf2 signaling pathway, Akt/PDE3B signaling pathway, AMPK signaling pathway, NF-κB signaling pathway, Nrf2 antioxidant signaling pathways, PI3K/Akt/mTOR signaling pathway, PKC-α-ERK1/2-NF-κB pathway, IL-11/STAT3 signaling pathway, Akt/GSK-3β/β-catenin pathway, JNK/c-Jun/AP-1 signaling pathway, PI3K/Akt/NF-κB pathway, miRNA-34a/LDHA pathway, Nox4/Smad2 pathway, JNK pathway and NF-kB/PPARγ pathway. This review will provide an overall understanding of the pharmacological functions of astragaloside IV on neuroprotection, liver protection, anti-cancer and anti-diabetes. In light of this, AS-IV will be a potent alternative therapeutic agent for treatment of the above mentioned diseases.

Astragaloside IV derived from Astragalus membranaceus: A research review on the pharmacological effects

Objectives
microRNAs (miRNAs), are non-coding RNAs that regulate gene expression, and are involved in tumour development. The aim of this study was to investigate microRNA-497 (miR-497) expression and its role in development of colorectal cancer (CRC).

Materials and methods
RT-PCR was performed to detect expression of miR-497 in CRC cell lines (HCT8, LOVO, Ls-174, HCT116 and HT29) and in clinical cancer specimens. To further understand its role, we restored expression of miR-497 in the HCT116 cell line by transfection with miR-497 mimics or inhibitors. Effects of miR-497 on cell proliferation, migration and invasion of targets were also determined both in vitro and in vivo.

Results
miR-497 expression decreased in 34 CRC tissues compared to non-tumour tissues and in tumour cell lines. Overexpression of miR-497 did not inhibit cancer cell growth but suppressed metastasis and invasion both in vitro and in vivo. Vascular endothelial growth factor-A (VEGF-A) was confirmed to be a target of miR-497. Furthermore, we found overexpression of miR-497 altered expression of key molecules of the VEGF-A/ERK/MMP-9 signalling pathway.

Conclusions
Thus our results provide evidence that miR-497 might function as a metastasis suppressor in CRC. Targeting miR-497 may provide a strategy for blocking its metastasis.

/pdf/microrna-497-inhibits-invasion-and-metastasis-of-colorectal-309t25kgzx.pdf

microRNA-497 inhibits invasion and metastasis of colorectal cancer cells by targeting vascular endothelial growth factor-A.

Background. Uremic pruritus (UP) is a common symptom in patients undergoing maintenance hemodialysis for end-stage renal disease (ESRD). Objective. To determine the clinical efficacy of auricular acupressure therapy on pruritus in hemodialysis patients and to explore possible underlying mechanisms. Methods. Patients receiving maintenance hemodialysis at a referral medical center were recruited and assigned to intervention (n = 32) and control (n = 30) groups. The intervention group underwent auricular acupressure treatment three times a week for six weeks. Auricular acupressure was not applied to patients in the control group. However, tape without Vaccaria seeds was applied to the same six auricular acupoints as the intervention group. Pruritus scores were assessed using VAS scores, and enzyme-linked immunosorbent assays (ELISA) were used to measure levels of other possible contributory biochemical factors. Results. There was a significant difference in mean VAS scores between the postintervention and control groups during follow-up (3.844 ± 1.687 versus 5.567 ± 2.285, F = 22.32, P < 0.0001). Compared to the control group, serum histamine levels in the postintervention group at the six-week follow-up had decreased significantly (F = 5.01, P = 0.0290). Conclusion. Our findings suggest that auricular acupressure may be a useful treatment in the multidisciplinary management of UP in ESRD patients.

/pdf/effect-of-auricular-acupressure-on-uremic-pruritus-in-2b44yv9a3b.pdf

Effect of Auricular Acupressure on Uremic Pruritus in Patients Receiving Hemodialysis Treatment: A Randomized Controlled Trial

Diabetic nephropathy (DN) is one of the most important causes of end‑stage renal disease. Astragaloside IV (AS-IV) is a saponin isolated from Astragalus membranaceus, which possesses various pharmacological activities. AS‑IV prevents podocyte apoptosis and ameliorates renal injury in DN; however, few studies have focused on its effects on ion channels. The transient receptor potential channel 6 (TRPC6) is an important Ca2+‑permeable ion channel in podocytes, which is involved in high glucose (HG)-induced podocyte apoptosis. The aim of the present study was to investigate whether AS‑IV prevented HG‑induced podocyte apoptosis via TRPC6. Cultured podocytes were pre‑treated with 10, 20 or 40 µM AS‑IV for 1 h prior to HG exposure for 24 h. Apoptosis, cell viability, expression of TRPC6, nuclear factor of activated T cells (NFAT2) and B‑cell lymphoma 2‑associated X protein (Bax), as well as the intracellular Ca2+ concentration were subsequently analyzed. The results indicated that HG induced podocyte apoptosis and upregulation of TRPC6, and increased intracellular Ca2+. Furthermore, enhanced NFAT2 and Bax expression was detected. Conversely, AS‑IV protected HG‑induced podocyte apoptosis, downregulated TRPC6 expression and suppressed intracellular Ca2+ in HG-stimulated podocytes. AS‑IV also suppressed NFAT2 and Bax expression. These results suggest that AS‑IV may prevent HG-induced podocyte apoptosis via downregulation of TRPC6, which is possibly mediated via the calcineurin/NFAT signaling pathway.

/pdf/astragaloside-iv-prevents-high-glucose-induced-podocyte-550wxl7aip.pdf

Astragaloside IV prevents high glucose-induced podocyte apoptosis via downregulation of TRPC6

// Ze-Ting Yuan 1, * , Xiao-Jing Shi 1, * , Yu-Xia Yuan 1, * , Yan-Yan Qiu 1 , Yu Zou 1 , Cheng Liu 1 , Hui Yu 1 , Xue He 1 , Ke Xu 1 and Pei-Hao Yin 1, 2 1 Interventional Cancer Institute of Chinese Integrative Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China 2 Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China * These authors have contributed equally to this work Correspondence to: Pei-Hao Yin, email: yinpeihao1975@hotmail.com Ke Xu, email: cola519@163.com Keywords: bufalin, colorectal cancer, multidrug resistance, ABC transporters, ABCB1 Received: October 25, 2016     Accepted: April 29, 2017     Published: May 26, 2017 ABSTRACT Multidrug resistance (MDR), mainly mediated by ABCB1 transporter, is a major cause for chemotherapy failure. Bufalin (BU), an active component of the traditional Chinese medicine chan’su, has been reported to have antitumor effects on various types of cancer cells. The purpose of this present study was to investigate the reversal effect of BU on ABCB1-mediated multidrug resistance in colorectal cancer. BU at safe concentration (5, 10, 20 nM) could reverse chemosensitivity of ABCB1-overexpression HCT8/ADR, LoVo/ADR and HCT8/ABCB1 nearly back to their parental cells level. In addition, results from the drug accumulation studies revealed that BU was able to enhance intracellular accumulation of doxorubicin (DOX) and Rhodamine 123 (Rho-123) in a dose-dependent manner. Furthermore, Western blot assays showed that BU significantly inhibited the expression level of ABCB1 protein. Meanwhile, BU stimulated the ATPase activity of ABCB1, which suggested that BU might be a substrate of ABCB1. More interestingly, docking analysis predicted that BU could be docked into the large hydrophobic drug-binding cavity of human ABCB1. Importantly, BU remarkable increased the effect of DOX against the ABCB1 resistant HCT8/ADR colorectal cell xenografts in nude mice, without inducing any obvious toxicity. Overall, we concluded that BU efficiently reversed ABCB1-mediated MDR through not only inhibited the efflux function of ABCB1, but also down-regulate its protein expression, which might represent a potential and superior ABCB1 modulator in colorectal cancer.

Bufalin reverses ABCB1-mediated drug resistance in colorectal cancer.

Despite the status of cisplatin (DDP) as a classical chemotherapeutic agent in the treatment of cancer, the development of multidrug resistance often leads to a failure of DDP therapy Here we found that phosphorylated cofilin-1 (p-cofilin-1) was overexpressed in the DDP-resistant human gastric cancer cell lines SGC7901/DDP and BGC823/DDP, relative to the respective parent cell lines (SGC7901 and BGC823), and that DDP induced the dephosphorylation of p-cofilin-1 in both parent lines but not in the DDP-resistant lines However, we noted that the traditional Chinese medicine formula Zuo Jin Wan (ZJW) could induce the dephosphorylation of p-cofilin-1 and promote cofilin-1 translocation from the cytoplasm into the mitochondria in both SGC7901/DDP and BGC823/DDP cells This mitochondrial translocation of cofilin-1 was found to induce the conversion of filamentous actin to globular-actin, activate mitochondrial damage and calcium overloading, and induce the mitochondrial apoptosis pathway We further observed that these effects of ZJW on DDP-resistant human gastric cancer cell lines could be reversed via transfection with cofilin-1-specific siRNA, or treatment with a PP1 and PP2A inhibitor These results suggest that ZJW is an effective drug therapy for patients with DDP-resistant gastric cancer

/pdf/the-zuo-jin-wan-formula-induces-mitochondrial-apoptosis-of-3wv7nipyhk.pdf

The Zuo Jin Wan Formula Induces Mitochondrial Apoptosis of Cisplatin-Resistant Gastric Cancer Cells via Cofilin-1.

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