Mechanism Study on Chinese Medicine in Treatment of Nodular Goiter.

Nodular goiter has become increasingly prevalent in recent years. Clinically, there has been a burgeoning interest in nodular goiter due to the risk of progression to thyroid cancer. This review aims to provide a comprehensive summary of the mechanisms underlying the therapeutic effect of Chinese medicine (CM) in nodular goiter. Articles were systematically retrieved from databases, including PubMed, Web of Science and China National Knowledge Infrastructure. New evidence showed that CM exhibited multi-pathway and multi-target characteristics in the treatment of nodular goiter, involving hypothalamus-pituitary-thyroid axis, oxidative stress, blood rheology, cell proliferation, apoptosis, and autophagy, especially inhibition of cell proliferation and promotion of cell apoptosis, involving multiple signal pathways and a variety of cytokines. This review provides a scientific basis for the therapeutic use of CM against nodular goiter. Nonetheless, future studies are warranted to identify more regulatory genes and pathways to provide new approaches for the treatment of nodular goiter.

Tubeimoside-1: A review of its antitumor effects, pharmacokinetics, toxicity, and targeting preparations.

Tubeimoside-1 (TBMS-1), a natural triterpenoid saponin found in traditional Chinese herbal medicine Bolbostemmatis Rhizoma, is present in numerous Chinese medicine preparations. This review aims to comprehensively describe the pharmacology, pharmacokinetics, toxicity and targeting preparations of TBMS-1, as well the therapeutic potential for cancer treatement. Information concerning TBMS-1 was systematically collected from the authoritative internet database of PubMed, Web of Science, and China National Knowledge Infrastructure applying a combination of keywords involving "tumor," "pharmacokinetics," "toxicology," and targeting preparations. New evidence shows that TBMS-1 possesses a remarkable inhibitory effect on the tumors of the respiratory system, digestive system, nervous system, genital system as well as other systems in vivo and in vitro. Pharmacokinetic studies reveal that TBMS-1 is extensively distributed in various tissues and prone to degradation by the gastrointestinal tract after oral administration, causing a decrease in bioavailability. Meanwhile, several lines of evidence have shown that TBMS-1 may cause adverse and toxic effects at high doses. The development of liver-targeting and lung-targeting preparations can reduce the toxic effect of TBMS-1 and increase its efficacy. In summary, TBMS-1 can effectively control tumor treatment. However, additional research is necessary to investigate in vivo antitumor effects and the pharmacokinetics of TBMS-1. In addition, to reduce the toxicity of TBMS-1, future research should aim to modify its structure, formulate targeting preparations or combinations with other drugs.

Periostin involved in the activated hepatic stellate cells-induced progression of residual hepatocellular carcinoma after sublethal heat treatment: its role and potential for therapeutic inhibition.

BACKGROUND: Incomplete thermal ablation may induce invasiveness of hepatocellular carcinoma (HCC). Here, we investigated whether activated hepatic stellate cells (HSCs) would accelerate the progression of residual HCC after sublethal heat treatment, and thus sought to identify the potential targets. METHODS: Hepatocellular carcinoma cells were exposed to sublethal heat treatment and then cultured with the conditioned medium from activated HSCs (HSC-CM). The cell proliferation, migration, invasion and parameters of epithelial-mesenchymal transition (EMT) were analyzed. In vivo tumor progression of heat-treated residual HCC cells inoculated with activated HSCs was studied in nude mice. RESULTS: HSC-CM significantly enhanced the proliferation, motility, invasion, prominent EMT activation and decreased apoptosis of heat-exposed residual HCC cells. These increased malignant phenotypes were markedly attenuated by neutralizing periostin (POSTN) in HSC-CM. Furthermore, exogenous POSTN administration exerted the similar effects of HSC-CM on heat-treated residual HCC cells. POSTN induced the prominent activation of p52Shc and ERK1/2 via integrin ß1 in heat-exposed residual HCC cells. Vitamin D analog calcipotriol blocked POSTN secretion from activated HSCs. Calcipotriol plus cisplatin significantly suppressed the activated HSCs-enhanced tumor progression of heat-treated residual HCC cells via the inhibited POSTN expression and the increased apoptosis. CONCLUSIONS: Activated HSCs promote the tumor progression of heat-treated residual HCC through the release of POSTN, which could be inhibited by calcipotriol. Calcipotriol plus cisplatin could be used to thwart the accelerated progression of residual HCC after suboptimal heat treatment.

Extracellular matrix collagen I promotes the tumor progression of residual hepatocellular carcinoma after heat treatment.

BACKGROUND: Accelerated malignant behaviors induced by insufficient thermal ablation have been increasingly reported, however, the exact mechanisms are still unclear. Here, we investigated the importance of the extracellular matrix (ECM) in modulating the progression of residual hepatocellular carcinoma (HCC) after heat treatment. METHODS: Heat-exposed residual HCC cells were cultured in different ECM gels. We used basement membrane gel (Matrigel) to simulate the normal microenvironment and collagen I to model the pathological stromal ECM. The alterations of morphology and parameters of proliferation, epithelial-mesenchymal transition (EMT) and stemness were analyzed in vitro and in vivo. RESULTS: Increased collagen I deposition was observed at the periablational zone after incomplete RFA of HCC in a xenograft model. The markers of cell proliferation, EMT, motility and progenitor-like traits of heat-exposed residual HCC cells were significantly induced by collagen I as compared to Matrigel (p values all < 0.05). Importantly, collagen I induced the activation of ERK phosphorylation in heat-exposed residual HCC cells. ERK1/2 inhibitor reversed the collagen I-promoted ERK phosphorylation, cell proliferative, protrusive and spindle-like appearance of heat-treated residual HCC cells in vitro. Moreover, collagen I promoted the in vivo tumor progression of heat-exposed residual HCC cells, and sorafenib markedly reversed the collagen I-mediated protumor effects. CONCLUSIONS: Our findings demonstrate that collagen I could enhance the aggressive progression of residual HCC cells after suboptimal heat treatment and sorafenib may be a treatment approach to thwart this process.

Interferon-α Combined With Herbal Compound "Songyou Yin" Effectively Inhibits the Increased Invasiveness and Metastasis by Insufficient Radiofrequency Ablation of Hepatocellular Carcinoma in an Animal Model.

OBJECTIVE: We had previously proved that insufficient radiofrequency ablation (RFA) could enhance invasiveness and metastasis of hepatocellular carcinoma (HCC) through epithelial-mesenchymal transition (EMT), which is mediated by activating ß-catenin signaling. Thus, the aim of the present study was to demonstrate whether the combined treatment of interferon-α (IFN-α) and "Songyou Yin" (SYY) minimizes the pro-metastatic effects of insufficient RFA, as well as to explore its underlying mechanism. METHODS: Insufficient RFA was performed in an orthotopic nude mice model of HCCLM3 with high metastatic potential. The effects of IFN-α, SYY, and combined IFN-α and SYY were observed in the animal model. Tumor sizes, lung metastasis, and survival time were assessed. Immunochemistry staining, real-time polymerase chain reaction, and Western blot were used to examine gene expression related to metastasis and angiogenesis in residual cancer after insufficient RFA. RESULTS: For up to 8 weeks of treatment, the combined therapy significantly decreased the residual cancer sizes, minimized the lung metastasis rate, and prolonged the survival time of nude mice, which might be due to suppression of the EMT via ß-catenin signal blockade, in addition to attenuating angiogenesis in residual cancer after insufficient RFA. CONCLUSION: IFN-α combined with SYY significantly weakened the enhanced metastatic potential of residual cancer after insufficient RFA by attenuating EMT, which is mediated through inhibiting activation of ß-catenin. In addition, decreasing angiogenesis of residual cancer might also play a certain role.

Increased matrix stiffness promotes tumor progression of residual hepatocellular carcinoma after insufficient heat treatment.

Aggravated behaviors of hepatocellular carcinoma (HCC) will occur after inadequate thermal ablation. However, its underlying mechanisms are not fully understood. Here, we assessed whether the increased matrix stiffness after thermal ablation could promote the progression of residual HCC. Heat-treated residual HCC cells were cultured on tailorable 3D gel with different matrix stiffness, simulating the changed physical environment after thermal ablation, and then the mechanical alterations of matrix stiffness on cell phenotypes were explored. Increased stiffness was found to significantly promote the proliferation of the heat-treated residual HCC cells when the cells were cultured on stiffer versus soft supports, which was associated with stiffness-dependent regulation of ERK phosphorylation. Heat-exposed HCC cells cultured on stiffer supports showed enhanced motility. More importantly, vitamin K1 reduced stiffness-dependent residual HCC cell proliferation by inhibiting ERK phosphorylation and suppressed the in vivo tumor growth, which was further enhanced by combining with sorafenib. Increased matrix stiffness promotes the progression of heat-treated residual HCC cells, proposing a new mechanism of an altered biomechanical environment after thermal ablation accelerates HCC development. Vitamin K1 plus sorafenib can reverse this protumor effect.

Astragaloside IV inhibits metastasis in hepatoma cells through the suppression of epithelial-mesenchymal transition via the Akt/GSK-3ß/ß-catenin pathway.

Our previous studies demonstrated that traditional Chinese herbal medicine 'Songyou Yin' inhibited the growth and invasion of hepatocellular carcinoma (HCC) cells, and altered epithelial­mesenchymal transition (EMT) markers in oxaliplatin­treated HCC tissues and cell lines. In the present study, we aimed to explore whether astragaloside IV (AS-IV), a component of 'Songyou Yin', can affect the growth and invasion of HCC cells and the underlying mechanism involved. Human HCC cell lines Huh7 and MHCC97-H, with low and high metastatic potential, respectively, were treated with increasing doses of AS-IV. The Cell Counting Kit-8 (CCK-8), plate clone formation, Transwell, wound healing and immunofluorescence assays were used to investigate the effects of AS-IV on HCC cell proliferation, migration and invasion. The protein expression levels were analyzed by western blotting and immunofluorescence assay. The CCK-8 and plate clone formation assays showed that AS-IV had little effect on the proliferation of HCC cells in vitro. However, the Transwell and wound healing assays demonstrated that AS-IV inhibited the migration and invasion of HCC cells in a dose-dependent manner and the morphology of HCC cells was altered from spindle into oval shaped in the AS-IV pretreated groups. The upregulation of E-cadherin and downregulation of N-cadherin, vimentin, α-SMA and Slug were also observed in the AS-IV pretreated groups. Additionally, AS-IV treatment resulted in a profound decrease in the phosphorylated forms of Akt and GSK-3ß, which in turn inhibited the expression of ß-catenin. Thus, we conclude that AS-IV attenuates the invasive and migratory abilities of HCC cells through the inhibition of EMT by targeting the Akt/GSK-3ß/ß-catenin pathway.

Antiangiogenic therapy promoted metastasis of hepatocellular carcinoma by suppressing host-derived interleukin-12b in mouse models.

Antiangiogenic therapy, specially sorafenib, has become the standard of care for patients with advanced hepatocellular carcinoma (HCC), however, the improvement in survival time is not satisfactory. Previous studies have found that, in some circumstances, antiangiogenic therapy promoted tumor metastasis and the mechanistic studies were mainly focus on cancer-cell-autonomous manners. In two experimental metastasis models with tail-vein injection with hepatoma cells and an orthotopic HCC mouse model, we found that pretreatment with two vascular endothelial growth factor receptor (VEGFR) inhibitors, sunitinib and sorafenib, facilitated tumor cell survival in blood stream and promoted lung metastasis from tumors that were subsequently incubated after drug discontinuation, indicating that host response joined into the pro-metastatic effects. An antibody microarray identified that interleukin (IL)-12b was decreased in the peripheral blood of the mice treated with the two VEGFR inhibitors. IL-12b suppression in macrophages and dendritic cells from host organs was found to play a crucial role in treatment-induced metastasis. Supplement with recombinant mouse IL-12b or restoration of IL-12b expression in the host by zoledronic acid, which was previously reported to enhance IL-12 expression in vitro and in vivo, alleviated the metastasis-promoting effects of sunitinib and sorafenib. These studies suggest that host response to VEGFR inhibitors facilitates HCC metastasis and restoration of IL-12b expression could translate into clinical benefits.

[An epidemiological survey on relativity between life events and anger in the worker colony: a cross-sectional study].

OBJECTIVE: To study the relevant correlation of anger-out (expression of anger toward other persons or objects in the environment) or anger-in (holding in or suppression of angry feelings) with life events, so as to gain a better understanding of present-day social influences and assess which life events trigger anger. This study proposes the new hypothesis that "life events constitute originating factors of anger-triggered emotional action". METHODS: A cross-sectional study using epidemiological methods enrolled 1 107 workers. According to the common features of anger and existing data, workers in the cities Jinan and Qingdao of Shandong Province were enrolled as target population. Investigators were specially trained and used designed survey instruments to investigate. Subjects were asked to complete the General Scale of study population, State-trait Anger Expression Inventory-2 (STAXI-2) and Life Events Scale. Logistic regression was used to analyze the correlation between anger-out or anger-in and life events. RESULTS: Those workers displaying anger-out showed positive correlations between the anger-out emotion and life events "not satisfied with sexual life or single" (OR:2.877), and "dissatisfaction with career status" (OR: 3.308). Further statistical analysis showed that anger-out emotion in the worker population was triggered by life events, which constituted risk factors for them. This suggested that the workers would generate anger-out emotion if they improperly dealt with these trigger life events. In the workers with anger-in, positive correlations were found between the anger-in emotion and life events "own (lover) abortion" (OR:2.209), "dissatisfaction with career status" (OR: 2.054), and "strained relations with superiors" (OR:2.714). Further statistical analysis showed that the anger-in emotion in the worker population was triggered by life events, which constituted risk factors for them. This suggested that the workers would generate anger-in emotion if they improperly handled these life events. However, negative correlations were found between anger-in and the life events "marriage", which suggested that the workers would not generate anger-in emotion but potentially generate other emotions if they faced this stimulus event. CONCLUSION: Research results support the hypothesis, life events serve as a stimulus, which can cause anger, both anger-out and anger-in. The research results will expand understanding of the etiology of emotional injuries in traditional Chinese medicine; from the perspective of etiology it will provide a related theoretical basis and support data.

[Phosphorus rhizosphere depletion effect of four aquatic plants].

Four aquatic plants (Alternanthera philoxeroides, Typha latifolia, Sagittaria sagittifolia, Phragmites communis ) were cultured on P-enriched soil in a pot experiment to assess the phosphorus rhizosphere depletion effect and analysis the ratio of root to shoot, root morphology, phosphorus uptake efficiency and phosphorus use efficiency. An obvious variation in P concentration of the soil in the rhizophere and non- rhizophere was observed. Compared with the non-rhizosphere (available P: 167.53 microg x g(-1)), the available P in the rhizosphere soil of Alternanthera philoxeroides, Typha latifolia, Sagittaria sagittifolia and Phragmites communis was reduced to 80.17, 124.37, 155.38 and 161.75 microg x g(-1) respectively, with 81%, 42%, 18% and 16% reduction ratio of water-soluble phosphorus. More effective phosphorus depletion was achieved in Alternanthera philoxeroides by higher phosphorus uptake efficiency (1.32 mg x m(-1)), while rooting system was small and phosphorus use efficiency was low (0.34 g x mg(-1)). Phosphorus uptake efficiency of Typha latjfolia is much lower (0.52 mg x m(-1)) than that of Alternanthera philoxeroides, however, its strong rooting system enhanced soil exploration, with higher phosphorus use efficiency (0.64 g x mg(-1)) and the ratio of root to shoot (0.35). Alternantshera philoxeroides and Typha latfolia were more effective in phosphorus depletion of the rhizosphere soil than that in Sagittaria sagittifolia and Phragmites communis.