The RNA-binding protein PNO1 is critical for ribosome biogenesis, but its potential role in cancer remains unknown. In this study, online data mining, cDNA, and tissue microarrays indicated that PNO1 expression was higher in colorectal cancer tissue than in noncancerous tissue, and its overexpression was associated with worse patient survival. Gain-offunction and loss-of-function studies demonstrated that PNO1 knockdown suppressed growth of colorectal cancer cells in vitro and in vivo, while PNO1 overexpression promoted colorectal cancer cell proliferation in vitro. In colorectal cancer cells expressing wild-type p53, PNO1 knockdown enhanced expression of p53 and its downstream gene p21, and reduced cell viability; these effects were prevented by p53 knockout and attenuated by the p53 inhibitor PFT-a. Moreover, PNO1 knockdown in HCT116 cells decreased levels of 18S rRNA, of 40S and 60S ribosomal subunits, and of the 80S ribosome. It also reduced global protein synthesis, increasing nuclear stress and inhibiting MDM2-mediated ubiquitination and p53 degradation. Overexpressing EBF1 suppressed PNO1 promoter activity and decreased PNO1 mRNA and protein, inhibiting cell proliferation and inducing cell apoptosis through the p53/p21 pathway. In colorectal cancer tissues, the expression of EBF1 correlated inversely with PNO1. Data mining of online breast and lung cancer databases showed increased PNO1 expression and association with poor patient survival; PNO1 knockdown reduced cell viability of cultured breast and lung cancer cells. Taken together, these findings indicate that PNO1 is overexpressed in colorectal cancer and correlates with poor patient survival, and that PNO1 exerts oncogenic effects, at least, in part, by altering ribosome biogenesis.Significance: This study identifies the ribosome assembly factor PNO1 as a potential oncogene involved in tumor growth and progression of colorectal cancer.

Inflammatory response has been shown to play a critical role in brain damage after cerebral ischemia-reperfusion (I/R) injury, which is tightly regulated by the Toll-like receptor (TLR)4/nuclear factor (NF)-κB pathway; therefore, suppression of TLR4/NF-κB signaling has become a promising target for the anti-inflammatory treatment in ischemic stroke. Acupuncture has been used as a complementary and alternative therapy practice that supplements conventional medicine. Numerous studies have demonstrated the clinical efficacy of acupuncture in stroke rehabilitation. However, the precise mechanism of its neuroprotective effect remains poorly understood. Using a focal cerebral I/R injured rat model, in the present study we evaluated the neuroprotective and anti-inflammatory activities of electroacupuncture at Quchi and Zusanli, and investigated the underlying molecular mechanisms. We found that electroacupuncture at Quchi (LI11) and Zusanli (ST36) acupoints significantly improved the ischemia-associated scores of neurological deficits, reduced cerebral infarction and alleviated inflammatory responses. Moreover, the crucial signaling molecules in the TLR4/NF-κB signaling pathway were regulated by acupuncture, which coincided with suppressed secretion levels of inflammatory cytokines such as TNF-α, IL-1β and IL-6. Our data suggest that electroacupuncture exerts a neuroprotective function in ischemic stroke through inhibition of TLR4/NF-κB-mediated inflammation.

The review shows a large number of works which demonstrated that TCM is useful in the treatment of various types of cancers through different mechanisms of action. The results indicate that TCM exerts its anticancer effects through apoptosis induction, proliferation inhibition, metastasis suppression, multidrug resistance reversal and immune function regulation. Moreover, TCM can improve patients' quality of life. The advantage of TCM suggests that TCM may represent a promising therapeutic approach for patients with diverse cancers.

Abstract. Transforming growth factor-β1 (TGF-β1) is a multifunctional cytokine that regulates cell growth, differentiation, apoptosis and autophagy in various cell types. It has been shown that TGF-β1-driven autophagy represents a novel mechanism of tubular decomposition, leading to renal interstitial fibrosis. However, the exact mechanism by which TGF-β1 regulates autophagy is still poorly understood. In the present study, we investigated the effects of exogenous TGF-β1 on cultured human renal proximal tubular epithelial cells (HRPTEpiCs). Presence of TGF-β1 in the medium induced accumulation of autophagosomes in a time-and dose-dependent manner as seen by monitoring the marker LC3 by confocal fluorescence microscopy and immunoblotting. In addition, TGF-β1 induced upregulation of autophagy-related genes, Atg5, Atg7 and Beclin1. Importantly, increased generation of reactive oxygen species (ROS) and enhanced expression of NADPH oxidases were found to be associated with the TGF-β1-induced autophagy. Conversely, treatment with inhibitors of NADPH oxidase markedly reversed the autophagic effects of TGF-β1. Apoptotic effects were evaluated by the TUNEL assay, measuring mitochondrial membrane potential and monitoring expression of the pro-and anti-apoptotic genes, Bim and Bcl-2, respectively. Transcriptional silencing of the above three autophagy-related genes in HRPTEpiCs caused attenuation of TGF-β1-mediated apoptosis. Similarly, when autophagy was prevented at an early stage by application of 3-methyladenine, the pro-apoptotic effects of TGF-β1 were attenuated. These observations suggest that in HRPTEpiCs TGF-β1 promotes autophagy through the generation of ROS, which contributes to its proapoptotic effect. IntroductionAutophagy and apoptosis are two processes, through which injured/aged cells or organelles are eliminated (1,2). Autophagy, or the 'self-eating' function, is characterized by the presence of abundant double-membraned vacuoles called autophagosomes that sequester cytoplasm and cytosolic organelles, such as mitochondria and endoplasmic reticulum. Subsequently, the autophagosome fuses to a lysosome and its contents and inner membrane are degraded and recycled (3). Autophagy is usually regarded as a protective mechanism for cell survival under various conditions including nutrient deprivation and hypoxia (4). However, increasing evidence suggests that in response to excessive stress autophagy may be detrimental and can lead to cell death (5). Excessive autophagic activity may lead to cellular dysfunctions and induce death by destroying a large proportion of the cytosol and organelles, especially the mitochondria and the endoplasmic reticulum (ER) (6,7). The contribution of autophagy to cell death depends on the threshold of the stimuli. It either constitutes a stress adaptation aimed at suppressing apoptosis or conversely provides an alternative pathway to cell death (2,8).Tubular injury is the major contributor to reduction of renal function. Nephron loss can initiate from the tubular decomposition, follo...

Abstract. Signal transducer and activator of transcription 3 (STAT3) is persistently activated in cancer cells and contributes to malignant progression in various types of cancer. The Janus-activated kinase (JAK) family phosphorylates STAT3 in response to stimulation by cytokines or growth factors. The JAK1-STAT3 signaling pathway plays an important role in cell proliferation and apoptosis. Nitidine chloride (NC) is a benzophenanthridine alkaloid that has been reported as an antitumor agent due to its its inhibitory effects on topoisomerase I. Using a mouse xenograft model of hepatocellular carcinoma (HCC), this study aimed to evaluate the effects of NC on tumor growth in vivo and to elucidate the underlying mechanisms. The analysis of the effects of NC on apoptosis in HCC tumor xenografts in mice was carried out by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay; the expression of Bcl-2, Bax, cyclin-dependent kinase (CDK)4, cyclin D1, p21 and proliferating cell nuclear antigen (PCNA) was analyzed by immunohistochemistry; and the protein expression of JAK1 and STAT3 was examined by western blot analysis. Our results revealed that treatment with NC decreased the tumor volume and tumor weight, suggesting that NC inhibits HCC cell growth in vivo. In addition, NC blocked the activation of JAK1-STAT3 in the tumor tissues, which in turn resulted in the induction of cancer cell apoptosis and the inhibition of proliferation. Consequently, treatment with NC downregulated the expression of cyclin D1, CDK4 and Bcl-2 and increased the level of p21 and Bax. Our data provide a molecular basis for the antitumor activity of NC. IntroductionHepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide (1,2) and it has been reported that more than 600,000 individuals succumb to the disease each year (1). It is the second most common cause of cancer-related mortality in China, and 75% of known new cases and deaths in the Asia-Pacific region (3-5). Currently, the main treatment methods for liver cancer include surgical resection, radiotherapy and chemotherapy (4,6). Although surgical resection (which involves removing the tumor completely) offers the best prognosis for long-term survival, only 10-15% of patients are suitable for surgical resection, as the tumor may be too large, or may have grown into major blood vessels or other vital organs (7-9). Related data demonstrate that the percentage of HCC cells is already high at diagnosis with a high expression of the multidrug resistance gene and conventional chemotherapy of HCC fails to provide satisfactory remission and may cause serious side-effects (6,10). Thus, it is necessary to develop a novel effective drug for the treatment of HCC. Natural products have attracted much attention in the search for novel anticancer therapeutic agents as they have relatively few side-effects and have long been used as alternative therapies for various diseases, including cancer (11,12). Therefore, determining naturally occurrin...