Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death and its prognosis remains poor due to the high risk of tumor recurrence and metastasis. Berberine (BBR) is a natural compound derived from some medicinal plants, and accumulating evidence has shown its potent anti-tumor activity with diverse action on tumor cells, including inducing cancer cell death and blocking cell cycle and migration. Molecular targets of berberine involved in its inhibitory effect on the invasiveness remains not yet clear. In this study, we identified that berberine exhibits a potent inhibition on the invasion and migration of HCC cells. This was accompanied by a dose-dependent down-regulation of expression of Cyclooxygenase-2 (COX-2), nuclear factor kappa B (NF-κB), urokinase-type plasminogen activator (uPA) and matrix metalloproteinase (MMP)-9 in berberine-treated HCC cells. Furthermore, berberine inactivated p38 and Erk1/2 signaling pathway in HCC cells. Primarily, this may be attributed to the up-regulation of plasminogen activator inhibitor-1 (PAI-1), a tumor suppressor that can antagonize uPA receptor and down-regulation of uPA. Blockade of uPA receptor-associated pathways leads to reduced invasiveness and motility of berberine-treated HCC cells. In conclusion, our findings identified for the first time that inactivation of uPA receptor by up-regulation of PAI-1 and down-regulation of uPA is involved in the inhibitory effect of berberine on HCC cell invasion and migration.

Numerous studies have investigated the prognostic role of YKL-40 in breast cancer, but yielded inconsistent results. To derive a more precise evaluation, relevant publications assessing the association between YKL-40 expression and clinical outcome of breast cancer patients were electronically searched and identified. A combined analysis of included studies was performed using fixed- or random-effect model to calculate the pooled hazard ratio (HR) or odds ratio(OR) and 95% confidence interval (95%CI) for the assessment of the association. Ten eligible studies involving 1250 patients were ultimately included in the meta-analysis. Overall, the pooled analysis showed that elevated YKL-40 expression was significantly associated with a poor overall survival(OS: HR=1.48, 95%CI= 1.11-1.97) and disease-free survival(DFS: HR=1.51, 95%CI= 1.10-2.07). The subgroup analysis by detection methods revealed an unfavorable OS in breast cancer patients with elevated YKL-40 expression evaluated by IHC(HR=1.39, 95%CI=1.12-1.71) but not by ELISA/RIA. Also, the stratification analysis by ethnicity showed a significant association between increased YKL-40 expression and shorter OS of breast cancer patients in western population(HR=1.51, 95%CI=1.03-2.21) as well as Asian population (HR=1.40, 95%CI= 1.05-1.86). Similarly, the subgroup analysis by detection methods revealed a significantly inferior DFS in breast cancer patients with increased YKL-40 expression disregarding the use of IHC(HR=2.02, 95%CI=1.47-2.79) or ELISA/RIA(HR=1.06, 95%CI= 1.02 -1.10). Additionally, increased YKL-40 expression was found to significantly correlate with larger tumor size (OR=2.38, 95%CI=1.41-4.05).The present meta-analysis indicate that elevated YKL-40 expression is associated with a poor prognosis in breast cancer patients. YKL-40 may serve as a promising predictive biomarker of prognosis of breast cancer.

Objective. To conduct a comprehensive PRISMA-compliant systematic review and meta-analysis to evaluate the efficacy and safety of Chinese medicines (CMs) as an adjuvant therapy for unresectable HCC during transarterial chemoembolization (TACE). Methods. Main databases were searched up to October 2012 for randomized controlled trials (RCTs) evaluating the effects of CMs plus TACE on unresectable HCC compared with TACE alone. References of relevant reviews and eligible studies were also assessed. Risk ratios with 95% confidence intervals and mean difference were calculated. Heterogeneity and publication bias were examined. Results. Sixty-seven trials (N = 5,211) were included in the meta-analysis. Sensitivity analysis and random-effects model were performed for assessing significant heterogeneity. CMs plus TACE showed beneficial effects on tumor response, survival at 6, 12, 18, 24, and 36 months, quality of life, and TACE toxicity reduction compared with TACE alone. Conclusion. The results show that the use of CMs may increase the efficacy and reduce the toxicity of TACE in treating patients with unresectable HCC. These findings suggest that CMs could be considered as an adjuvant therapy for unresectable HCC patients during TACE. Larger-scale RCTs using standard methods and long-term follow-up are warranted to confirm these findings.

Chemoresistance induced by cisplatin has become the major impediment to lung cancer chemotherapy. This study explored the potential chemoresistant genes and underlying mechanisms of chemoresistance in NSCLC.

Aberrant signal transducer and activator of transcription 3 (STAT3) signaling promotes the initiation and progression of cancer in humans by either inhibiting apoptosis or inducing cell proliferation, angiogenesis, invasion, and metastasis. The role of resveratrol（RES）in inhibiting the STAT3 signaling pathway in vivo, particularly in cervical cancer is still unknown. This study aims to investigate the role of STAT3 and its phosphorylation in RES-mediated suppression of cervical cancer. The effects of RES on cervical cancer were determined by examining tumor tissues, their histological changes, and the volume and weight of tumor tissues grown from HeLa cells injected in female athymic BALB/C nude mice. The structure and target interaction of RES were virtually screened using the molecular docking program Autodock Vina. The status of phosphorylated STAT3, protein levels of epithelial-mesenchymal transition molecular markers and extracellular matrix degradation enzymes were determined through Western blot. We demonstrated that RES could suppress the proliferation and metastatic potential of cervical cancer cells by inactivating phosphorylation of STAT3 at Tyr705 but not Ser727. This effect was intensified by inhibition of the STAT3 signal pathway.

Thrombosis is a major cause of morbidity and mortality worldwide. Platelet activation by exposed collagen through glycoprotein VI (GPVI) and formation of neutrophil extracellular traps (NETs) are critical pathogenic factors for arterial and venous thrombosis. Both events are regulated by spleen tyrosine kinase (Syk)-mediated signalling events. Asebogenin is a dihydrochalcone whose pharmacological effects remain largely unknown. This study aims to investigate the antithrombotic effects of asebogenin and the underlying molecular mechanisms.

Reynoutria multiflora (Thunb.) Moldenke (He Shou Wu) has been used for about 20 centuries as a Chinese medicinal herb for its activities of anticancer, anti-hyperlipidemia, and anti-aging. Previously, we found that He Shou Wu ethanol extract could induce apoptosis in hepatocellular carcinoma cells, and we also screened its active components. In this study, we investigated whether lowering lipid metabolism of emodin, a main active component in He Shou Wu, was associated with inhibitory effects in hepatocellular carcinoma cells. The correlation of apoptosis induction and lipid metabolism was investigated. The intrinsic apoptotic cell death, lipid production, and their signaling pathways were investigated in emodin-treated human hepatocellular carcinoma cells Bel-7402. The data showed that emodin triggered apoptosis in Bel-7402 cells. The mitochondrial membrane potential (ΔΨm) was reduced in emodin-treated Bel-7402 cells. We also found that emodin activated the expression of intrinsic apoptosis signaling pathway-related proteins, cleaved-caspase 9 and 3, Apaf 1, cytochrome c (CYTC), apoptosis-inducing factor, endonuclease G, Bax, and Bcl-2. Furthermore, the level of triglycerides and desaturation of fatty acids was reduced in Bel-7402 cells when exposed to emodin. Furthermore, the expression level of messenger RNA (mRNA) and protein of sterol regulatory element binding protein 1 (SREBP1) as well as its downstream signaling pathway and the synthesis and the desaturation of fatty acid metabolism-associated proteins (adenosine triphosphate citrate lyase, acetyl-CoA carboxylase alpha, fatty acid synthase (FASN), and stearoyl-CoA desaturase D) were also decreased. Notably, knock-out of SREBP1 in Bel-7402 cells was also found to induce less intrinsic apoptosis than did emodin. In conclusion, these results indicated that emodin could induce apoptosis in an SREBP1-dependent and SREBP1-independent manner in hepatocellular carcinoma cells.

Thoracic radiotherapy is a mainstay of the treatment for lung, esophageal, and breast cancers. Radiation-induced pulmonary injury (RIPI) is a common side effect of thoracic radiotherapy, which may limit the radiotherapy dose and compromise the treatment results. However, the current strategies for RIPI are not satisfactory and may induce other side effects. Chinese medicines (CMs) have been used for more than a thousand years to treat a wide range of diseases, including lung disorders. In this review, we screened the literature from 2007 to 2017 in different online databases, including China National Knowledge Infrastructure (CNKI), Chongqing VIP, Wanfang, and PubMed; summarized the effectiveness of CMs in preventing and treating RIPI; explored the most frequently used drugs; and aimed to provide insights into potential CMs for RIPI. Altogether, CMs attenuated the risk of RIPI with an occurrence rate of 11.37% vs. 27.78% (P < 0.001) compared with the control groups. We also found that CMs (alone and combined with Western medical treatment) for treating RIPI exerted a higher efficacy rate than that of the control groups (78.33% vs. 28.09%, P < 0.001). In the screened literature, 38 CMs were used for the prevention and treatment of RIPI. The top five most frequently used CMs were Astragali Radix (with a frequency of 8.47%), Ophiopogonis Radix (with a frequency of 6.78%), Glycyrrhizae Radix et Rhizome (with a frequency of 5.08%), Paeoniae Radix Rubra (with a frequency of 5.08%), and Prunellae Spica (with a frequency of 5.08%). However, further high-quality investigations in CM source, pharmacological effects and underlying mechanisms, toxicological aspects, and ethical issues are warranted. Taken together, CMs might have a potential role in RIPI prevention and treatment and still have a long way to investigate.

Bushen Huayu extract (BSHY), a traditional Chinese medicine, has been demonstrated to treat postmenopausal osteoporosis, however, the underlying mechanism remains to be fully elucidated. The aim of the present study was to investigate the therapeutic effect of BSHY and the mechanisms underlying this effect in an in vivo postmenopausal osteoporosis animal model. A total of 1 g BSHY containing 7.12 μg icariin was prepared. Low-dose BSHY (BSHY-L; 11.1 g/kg), medium-dose BSHY (BSHY-M; 22.2 g/kg) and high-dose BSHY (BSHY-H; 44.4 g/kg) was administered to oophorectomized rats using intragastric infusion. Estradiol (E2), interleukin-6 (IL-6) and serum alkaline phosphatase (ALP) levels, as well as bone density, were determined. It was found that the levels of serum ALP in the BSHY-L, BSHY-M and BSHY-H groups (197.75±41.74, 166.63±44.83 and 165.63±44.90 IU/l, respectively) were significantly decreased compared with the model group (299.13±45.79 IU/l; P<0.05), whilst the levels of E2 (16.89±1.71, 17.95±1.40 and 18.34±1.43 pg/ml, respectively) increased compared with the model group (14.54±1.61; P<0.05). In addition, the levels of IL-6 decreased in the BSHY-L, BSHY-M and BSHY-H groups (91.85±14.81, 82.99±15.65 and 80.54±14.61 pg/ml, respectively) compared with the model group (105.93±16.50 pg/ml; P<0.05). Furthermore, it was demonstrated that BSHY increased the bone density in the BSHY-L, BSHY-M and BSHY-H groups (0.20±0.014, 0.22±0.016 and 0.22±0.017 g/cm2, respectively) compared with the model group (0.19±0.011 g/cm2; P<0.05). BSHY was also found to increase the number of osteoblasts in the BSHY-L, BSHY-M and BSHY-H groups (25.38±2.17, 29.25±2.12 and 30.00±2.39, respectively), compared with in the model group (14.75±2.38; P<0.05), and decrease the number of osteoclasts in the BSHY-L, BSHY-M and BSHY-H groups (4.00±1.85, 4.25±1.39 and 5.75±1.49, respectively) compared with 9.50±1.60 observed in the model group (P<0.05). These results suggest that BSHY is a potential therapeutic drug for the treatment of osteoporosis in vivo. Furthermore, these results suggest that the mechanism by which BSHY decreases the serum levels of IL-6 may be by regulating E2.

Metabolic reprogramming is a feature of cancer cells and crucial for tumor growth and metastasis. Interferon-γ (IFNγ) is a cytokine that plays a pivotal role in host antitumor immunity. However, little is known about the roles of metabolic reprogramming in immune responses. Here, we show that colon cancer cells reprogram metabolism to coordinate proper cellular responses to IFNγ by downregulating mitochondrial pyruvate carrier (MPC)1 and 2 via STAT3 signaling. Forced overexpression of MPC promote the production of reactive oxygen species and enhance the apoptosis induced by IFNγ in colon cancer cells. Moreover, inhibiting STAT3 sensitize the antitumor efficacy of IFN-γ against colon cancer cells. Our findings present a previously unrecognized mechanism that colon cancer manipulate to resist IFNγ mediated antitumor immunity that have implications for targeting a unique aspect of this disease.

Isocitrate dehydrogenase (IDH) is one key rate-limiting enzyme in the tricarboxylic acid cycle, which is related to various cancers. Tomatillo (Physalis ixocarpa), a special tomato, is widely consumed as nutritious vegetable in Mexico, USA, etc. As a rich source for withanolides, the fruits of P. ixocarpa were investigated, leading to the isolation of 11 type-A withanolides including 4 new ones (1 is an artificial withanolide). All these withanolides were evaluated for their inhibition on mutant IDH1 enzyme activity. Among them, physalin F (11) exhibited potent enzyme inhibitory activity and binding affinity with mutant IDH1. It inhibits the proliferation of HT1080 cells by selectively inhibiting the activity of mutant IDH1. Since Ixocarpalactone A, another major type-B withanolide in this plant, could act on another energy metabolism target PHGDH, the presence of different types of withanolides in tomatillo and their synergistic effect could make it a potential antitumor functional food or drug.

Trans-resveratrol (RES) exhibits a wide range of biological activities. Various methodological approaches have been established to improve the pharmacokinetic properties of RES. Moreover, additional in vivo studies are required to support clinical application. In this study, RES/HP-β-CD (RHSD) inclusion complex was prepared and characterized by FTIR, PXRD, DSC and NMR data. The effect and potential mechanism of RHSD against cervical cancer were investigated in a mouse xenograft tumor model by qPCR assay, Western blot assay, and immunohistochemical assay. Results showed that RHSD significantly decreased tumor growth compared with free RES, while the effect of preventing tumor growth was more prominent in vivo. Notably, RHSD could inhibit tumor development by suppressing the expression of HPV E6 and E7 oncogenes and upregulating P53 and Rb1 protein in cervical cancer. These findings demonstrated that RHSD was safe and potential for development of a new oral administration drug to treat cervical cancer.

Cervical cancer is the second most common cancer in women. Despite advances in cervical cancer therapy, tumor recurrence and metastasis remain the leading causes of mortality. High expression of BMI1 is significantly associated with poor tumor differentiation, high clinical grade, and poor prognosis of cervical cancer, and is an independent prognostic factor in cervical carcinoma. Alantolactone (AL), a sesquiterpene lactone, exhibits potent anti-inflammatory and anticancer activities. In this paper, we investigated the mechanism of AL in reducing the proliferation, migration, and invasion of HeLa and SiHa cervical cancer cells as well as its promotion of mitochondrial damage and autophagy. BMI1 silencing decreased epithelial-mesenchymal transformation-associated proteins and increased autophagy-associated proteins in HeLa cells. These effects were reversed by overexpression of BMI1 in HeLa cells. Thus, BMI1 expression is positively correlated with invasion and negatively correlated with autophagy in HeLa cells. Importantly, AL decreased the weight, volume, and BMI1 expression in HeLa xenograft tumors. Furthermore, the structure of BMI1 and target interaction of AL were virtually screened using the molecular docking program Autodock Vina; AL decreased the expression of N-cadherin, vimentin, and P62 and increased the expression of LC3B and Beclin-1 in xenograft tumors. Finally, expression of BMI1 increased the phosphorylation of STAT3, which is important for cell proliferation, survival, migration, and invasion. Therefore, we suggest that AL plays a pivotal role in inhibiting BMI1 in the tumorigenesis of cervical cancer and is a potential therapeutic agent for cervical cancer.

Although the vast majority of patients with papillary thyroid cancer (PTC) have a favorable prognosis when conventional treatments are implemented, local recurrence and distant metastasis of advanced PTCs still hamper the survival and clinical management in certain patients. As immune checkpoint blockade (ICB) therapy achieves a great success in some advanced cancers, we aimed to investigate the immune landscape in PTC and its potential implications for prognosis and immunotherapy. In this study, different algorithms were conducted to estimate immune infiltration in PTC samples. A series of bioinformatic and machine learning approaches were performed to identify PTC-specific immune-related genes (IRGs) and distinct immune clusters. Differences in intrinsic tumor immunogenicity and potential immunotherapy response were observed between distinct immune clusters. A prognostic immune-related signature (IRS) was established to predict progression-free survival (PFS). IRS exhibited more powerful prognostic capacity and accurate survival prediction compared to conventional clinicopathological features. Furthermore, an integrated survival decision tree and a scoring nomogram were constructed to improve prognostic stratification and predictive accuracy for individual patients. In addition, altered pathways, mutational patterns, and potential applicable drugs were analyzed in different immune-related risk groups. Our study gained some insight into the immune landscape of PTC, and provided some useful clues for introducing immune-based molecular classification into risk stratification and guiding ICB decision-making.

Abstract: Currently, decision-making regarding biochemical recurrence (BCR) following prostatectomy relies solely on clinical parameters. We therefore attempted to develop an integrated prediction model based on a molecular signature and clinicopathological features, in order to forecast the risk for BCR and guide clinical decision-making for postoperative therapy. Using high-throughput screening and least absolute shrinkage and selection operator (LASSO) in the training set, a novel gene signature for biochemical recurrence-free survival (BCRFS) was established. Validation of the prognostic value was performed in five other independent datasets, including our patient cohort. Multivariate Cox regression analysis was performed to evaluate the importance of risk for BCR. Time-dependent receiver operating characteristic (tROC) was used to evaluate the predictive power. In combination with relevant clinicopathological features, a decision tree was built to improve the risk stratification. The gene signature exhibited a strong capacity for identifying high-risk BCR patients, and multivariate Cox regression analysis demonstrated that the gene signature consistently acted as a risk factor for BCR. The decision tree was successfully able to identify the high-risk subgroup. Overall, the gene signature established in the present study is a powerful predictor and risk factor for BCR after radical prostatectomy.

Light is essential for plant organogenesis and development. Light-regulated shoot morphogenesis has been extensively studied; however, the mechanisms by which plant roots perceive and respond to aboveground light are largely unknown, particularly because the roots of most terrestrial plants are usually located underground in darkness. To mimic natural root growth conditions, we developed a root-covered system (RCS) in which the shoots were illuminated and the plant roots could be either exposed to light or cultivated in darkness. Using the RCS, we observed that root growth of wild-type plants was significantly promoted when the roots were in darkness, whereas it was inhibited by direct light exposure. This growth change seems to be regulated by ELONGATED HYPOCOTYL 5 (HY5), a master regulator of photomorphogenesis. Light was found to regulate HY5 expression in the roots, while a HY5 deficiency partially abolished the inhibition of growth in roots directly exposed to light, suggesting that HY5 expression is induced by direct light exposure and inhibits root growth. However, no differences in HY5 expression were observed between illuminated and dark-grown cop1 roots, indicating that HY5 may be regulated by COP1-mediated proteasome degradation. We confirmed the crucial role of HY5 in regulating root development in response to light under soil-grown conditions. A transcriptomic analysis revealed that light controls the expression of numerous genes involved in phytohormone signaling, stress adaptation, and metabolic processes in a HY5-dependent manner. In combination with the results of the flavonol quantification and exogenous quercetin application, these findings suggested that HY5 regulates the root response to light through a complex network that integrates flavonol biosynthesis and reactive oxygen species signaling. Collectively, our results indicate that HY5 is a master regulator of root photomorphogenesis.

The study determined the chemical constituents and anti-inflammatory effects of leaf oil from Cinnamomum subavenium (CS-LO) that has been used in folk medicine to treat various symptoms including inflammation. The anti-inflammatory effects of the oil were evaluated by LPS-stimulated RAW264.7 cells and the Carr-induced hind mouse paw edema model, respectively. In vitro, nitric oxide (NO), prostaglandin E2 (PGE2), TNF-α, IL-6, and IL-1β were significantly decreased by CS-LO, and the expression of nuclear factor-κB (NF-κB) protein was blocked as well. In in vivo, the malondialdehyde (MDA) and paw edema levels were decreased by CS-LO, and the same result came up on the NO and tumor necrosis factor (TNF-a) of serum at the 5th h after Carr injection. In addition, iNOS and COX-2 immunoreactive cells of the paw tissue were decreased significantly by CS-LO (200 mg/kg) in histological examination. The present findings indicated that CS-LO have anti-inflammatory properties, and the effects might be caused through inhibiting iNOS, COX-2, TNF-α, IL-1β, and IL-6 expression via affecting NF-κB pathway, which will provide a power scientific basis for CS-LO to be used as the treatment of inflammatory diseases.

Resveratrol is a representative polyphenol of diet‑derived putative cancer chemopreventive agents, which have attracted increasing interest in the cancer chemoprevention community. The inhibition of the action of human papillomavirus (HPV) E6 and E7 has been considered a key approach for cervical cancer therapy. Resveratrol has been shown to induce the apoptosis, and reduce both the viability and mitotic index of a number of cancer cell lines, including human cervical cancer cells. In the present study, it was confirmed that resveratrol inhibited the HPV E6 mRNA, HPV E6 protein and phosphorylated retinoblastoma protein (p‑pRb1) levels, and increased the p53 protein levels in HeLa and Ca Ski cells, as well as in subcutaneous tumor tissue grown from HeLa cells. High‑risk HPV uses a bicistronic RNA to control E6 and E7 genes simultaneously. On the whole, the present study demonstrates that resveratrol inhibits cervical cancer development by suppressing the transcription and translation of E6 and E7, and also by promoting the apoptosis and G1/S phase transition arrest. These findings may provide the basis for the development of resveratrol as a candidate for cervical cancer therapy.

Interferon-α (IFN-α) plays a pivotal role in host antitumor immunity, and the evasion of IFN-α signaling pathway can lead to IFN-α resistance during the treatment of cancer. Although the interplay between IFN-α and tumor cells has been extensively investigated in differentiated tumor cells, much less attention has been directed to tumor-repopulating cells (TRCs).

The present study was to evaluate the prognostic value of protein expression of Pofut1 and Notch1 signaling in breast cancer.