Exploring and exploiting plant cyclic peptides for drug discovery and development.

Ever since the discovery of insulin, natural peptides have become an important resource for therapeutic development. Decades of research has led to the discovery of a long list of peptide drugs with broad applications in clinics, from antibiotics to hypertension treatment to pain management. Many of these US FDA-approved peptide drugs are derived from microorganisms and animals. By contrast, the great potential of plant cyclic peptides as therapeutics remains largely unexplored. These macrocyclic peptides typically have rigid structures, good bioavailability and membrane permeability, making them appealing candidates for drug development and engineering. In this review, we introduce the three major classes of plant cyclic peptides and summarize their potential medical applications. We discuss how we can leverage the genome information of many different plants to quickly search for new cyclic peptides and how we can take advantage of the insights gained from their biosynthetic pathways to transform the process of production and drug development. These recent developments have provided a new angle for exploring and exploiting plant cyclic peptides, and we believe that many more peptide drugs derived from plants are about to come.

JSI-124 inhibits IgE production in an IgE B cell line.

IgE is a key effector molecule in atopic diseases; however, the regulation mechanisms of IgE production in IgE B cells remain poorly understood. In the present study, we demonstrate that JSI-124 (cucurbitacin I), a selective STAT3 inhibitor, selectively inhibits production of IgE by a human IgE B cell line, CRL-8033 cells, while does not affect the IgG production by IgG B cell lines. In the aspect of molecular mechanism, we found that Igλ, but not Ighe, gene expression was suppressed by JSI-124. The above effects of JSI-124 were not mediated by affecting cellular proliferation or apoptosis. Furthermore, multiple B cell differentiation-related genes expression was not significantly affected by JSI-124. Taken together, we demonstrate a potential strategy of therapeutically suppressing IgE production without affecting IgG production in atopic patients.

Glioma-derived small extracellular vesicles induce pericyte-phenotype transition of glioma stem cells under hypoxic conditions.

BACKGROUND: Glioblastoma (GBM) is the most common and lethal primary brain tumor characterized by extensive vascularization. Anti-angiogenic therapy for this cancer offers the possibility of universal efficacy. However, preclinical and clinical studies suggest that anti-VEGF drugs, such as Bevacizumab, actively promote tumor invasion, which ultimately leads to a therapy-resistant and recurrent phenotype of GBMs. Whether Bevacizumab can improve survival over chemotherapy alone remains debated. Herein, we emphasize the importance of small extracellular vesicles (sEVs) internalization by glioma stem cells (GSCs) in giving rise to the failure of anti-angiogenic therapy in the treatment of GBMs and discover a specific therapeutic target for this damaging disease. METHODS: To experimentally prove that hypoxia conditions promote the release of GBM cells-derived sEVs, which could be taken up by the surrounding GSCs, we used an ultracentrifugation strategy to isolate GBM-derived sEVs under hypoxic or normoxic conditions, performed bioinformatics analysis and multidimensional molecular biology experiments, and established a xenograft mouse model. RESULTS: The internalization of sEVs by GSCs was proven to promote tumor growth and angiogenesis through the pericyte-phenotype transition. Hypoxia-derived sEVs could efficiently deliver TGF-ß1 to GSCs, thus resulting in the activation of the TGF-ß signaling pathway and the consequent pericyte-phenotype transition. Specifically targeting GSC-derived pericytes using Ibrutinib can reverse the effects of GBM-derived sEVs and enhance the tumor-eradicating effects when combined with Bevacizumab. CONCLUSION: This present study provides a new interpretation of the failure of anti-angiogenic therapy in the non-operative treatment of GBMs and discovers a promising therapeutic target for this intractable disease.

Pathologic features and clinical outcome of central neurocytoma: analysis of 15 cases.

OBJECTIVE: To get better recognition of central neurocytoma and diminish misdiagnosis. METHODS: A retrospective review identified 15 cases of central neurocytoma. All cases of central neurocytoma were analyzed for their clinical symptoms, pathologic changes, immunohistochemical staining, prognosis and differential diagnosis. Clinical follow up was performed. RESULTS: There were 8 males and 7 females aged 10-64 years (median 32.93 years). The most common presenting symptoms were those related to increased intracranial pressure (ICP), including headache (100%), papilledema (93%) and vomiting (80%). All tumors were located in the ventricular system. The tumors were composed of uniform cells with round nuclei and a fine chromatin pattern, and in some areas, small cells with perinuclear halo could be seen. In particular, the anuclear areas may have a fine fibrillary matrix (neuropil). Nuclear atypia and vascular proliferation appeared in two cases, respectively. Focal necrosis could be seen in one case. Immunohistochemical findings included expression of synaptophysin (15/15), neuron specific enolase (12/15) and glial fibrillary acidic protein (GFAP) (3/15). MIB-1 proliferation index ranged from 0.8-12.5%, and was more than 2% in 3 of 15 cases assessed. Follow-up information of 11 patients was available. CONCLUSIONS: Central neurocytoma has a favorable prognosis in general, but in some cases, the clinical course could be aggressive. Increase of GFAP positivity, proliferation index and vascular proliferation might suggest a more malignant process.

Whole transcriptome analysis reveals non-coding RNA's competing endogenous gene pairs as novel form of motifs in serous ovarian cancer.

The non-coding RNA (ncRNA) regulation appears to be associated to the diagnosis and targeted therapy of complex diseases. Motifs of non-coding RNAs and genes in the competing endogenous RNA (ceRNA) network would probably contribute to the accurate prediction of serous ovarian carcinoma (SOC). We conducted a microarray study profiling the whole transcriptomes of eight human SOCs and eight controls and constructed a ceRNA network including mRNAs, long ncRNAs, and circular RNAs (circRNAs). Novel form of motifs (mRNA-ncRNA-mRNA) were identified from the ceRNA network and defined as non-coding RNA's competing endogenous gene pairs (ceGPs), using a proposed method denoised individualized pair analysis of gene expression (deiPAGE). 18 cricRNA's ceGPs (cceGPs) were identified from multiple cohorts and were fused as an indicator (SOC index) for SOC discrimination, which carried a high predictive capacity in independent cohorts. SOC index was negatively correlated with the CD8+/CD4+ ratio in tumour-infiltration, reflecting the migration and growth of tumour cells in ovarian cancer progression. Moreover, most of the RNAs in SOC index were experimentally validated involved in ovarian cancer development. Our results elucidate the discriminative capability of SOC index and suggest that the novel competing endogenous motifs play important roles in expression regulation and could be potential target for investigating ovarian cancer mechanism or its therapy.

ADAR1 Prevents R-loop Accumulation-Driven ATR Pathway Activation in Ovarian Cancer.

Adenosine (A)-to-inosine (I) RNA editing is the most prevalent RNA editing mechanism, in which adenosine deaminase acting on RNA 1 (ADAR1) is a major adenosine deaminase. Increasing evidence suggests that editing dysregulation of ADAR1 plays an important role in human tumorigenesis, while the underlying mechanism remains elusive. Here, we demonstrated that ADAR1 was highly expressed in ovarian cancer tissues and negatively correlated with progression free survival of ovarian cancer patients. Importantly, silence of ADAR1 repressed ovarian cancer cell growth and colony formation in vitro and inhibited ovarian cancer cell tumorigenesis in vivo. Further cell cycle and transcriptome profile analysis revealed that silence of ADAR1 in ovarian cancer cells induced cell cycle arrest at G1/G0 stage. Mechanistically, loss of ADAR1 caused R-loop abnormal accumulation, thereby contributing to single stand DNA break and ATR pathway activation. Additionally, ADAR1 interacted with DHX9 to regulate R-loop complex formation, and A-to-I editing of nascent RNA repressed R-loop formation during co-transcriptional process. Together, our results identify a novel ADAR1/R-loop/ATR axis critical for ovarian cancer progression and a potential target for ovarian cancer therapy.

A minor review of microRNA-338 exploring the insights of its function in tumorigenesis.

MicroRNAs(miRNAs) are small non-coding RNAs which have a critical role in various biological processes via direct binding and post-transcriptionally regulating targeted genes expression. More than one-half of human genes were regulated by miRNAs and their aberrant expression was detected in various human diseases, including cancers. miRNA-338 is a new identified miRNA and increasing evidence show that miRNA-338 participates in the progression of lots of cancers, such as lung cancer, hepatocellular cancer, breast cancer, glioma, and so on. Although a range of targets and signaling pathways such as MACC1 and Wnt/ß-catenin signaling pathway were illustrated to be regulated by miRNA-338, which functions in tumor progression are still ambiguous and the underlying molecular mechanisms are also unclear. Herein, we reviewed the latest studies in miRNA-338 and summarized its roles in different type of human tumors, which might provide us new idea for further investigations and potential targeted therapy.

Prenatal diagnosis of a rare ß-thalassemia gene －90 (C>T) (HBB: c.-140 C>T) mutation associated with deletional Hb H disease (--SEA /-α4.2 ).

BACKGROUND: Hemoglobin H (Hb H) disease can be caused by compound heterozygosity for two different mutations or from homozygotes for mutations, and conventional genetic methods may lead to misdiagnosis when Hb H disease is combined with a rare ß-thalassemia. METHODS: Hematology parameters and hemoglobin electrophoresis analysis, gap-polymerase chain reaction (gap-PCR) and reverse dot-blot hybridization (RDB-PCR) were employed to identify common α-thalassemia and Hb H disease. Rare ß-thalassemia mutations were detected by DNA sequencing. RESULTS: Hematological analysis and hemoglobin electrophoresis revealed a mild anemia α0 -thalassemia trait (Hb 90 g/L, MCV 71 fL, and MCH 22.7 pg) compound with ß+ -thalassemia trait (MCV 71 fL, MCH 22.7 pg, and HbA2 5.51%) for the pregnant woman. DNA sequencing for the ß-globin gene revealed rare a －90 (C>T) (HBB: c.-140 C>T) mutation for the woman. DNA analysis identified that the fetus inherited the α0 -thalassemia mutation [--SEA (Southeast Asian)] and a rare ß+ -thalassemia mutation －90 (C>T) (HBB: c.-140 C>T) from the mother, and the α+ -thalassemia mutation [-α4.2 (leftward)] from the father. CONCLUSION: We reported a rare －90 (C>T) (HBB: c.-140 C>T) mutation combined with the --SEA /-α4.2 in a family. This finding enriched the mutation spectrum of thalassemia molecular characteristics in China and emphasized the significance in DNA sequencing in mutation screening for the families with thalassemia.

The LXR-623-induced long non-coding RNA LINC01125 suppresses the proliferation of breast cancer cells via PTEN/AKT/p53 signaling pathway.

LXR-623 (WAY-252623), a liver X receptor agonist, reduces atherosclerotic plaque progression and remarkably inhibits the proliferation of glioblastoma cells, owing to its brain-penetrant ability. However, the role of LXR-623 against the proliferation of other cancer cells and the underlying mechanism remain unknown. Long non-coding RNAs (lncRNAs) serve as novel and crucial regulators that participate in cancer tumorigenesis and diverse biological processes. Here, we report a previously uncharacterized mechanism underlying lncRNA-mediated exocytosis of LXR-623 via the phosphatase and tensin homolog (PTEN)/protein kinase B (AKT)/p53 axis to suppress the proliferation of cancer cells in vitro. We found that LXR-623 significantly inhibited the proliferation and induced apoptosis and cell cycle arrest at S phase in breast cancer cells in a concentration- and time-dependent manner. Experiments using a xenograft mouse model revealed the inhibitory effects of LXR-623 on tumor growth. We used lncRNA microarray to investigate the potential genes regulated by LXR-623. As a result, LINC01125 was found to be significantly upregulated in the cells treated with LXR-623. Gain- and loss-of-function assays were conducted to investigate the anti-proliferation role of LINC01125. LINC01125 knockdown resulted in the inhibition of the cytotoxic effect of LXR-623; in contrast, LINC01125 overexpression significantly enhanced the effect of LXR-623. LXR-623 and LINC01125-mediated anti-growth regulation is, at least in part, associated with the participation of the PTEN/AKT/mouse double minute 2 homolog (MDM2)/p53 pathway. In addition, SF1670, a specific PTEN inhibitor with prolonged intracellular retention, may strongly block the anti-proliferation effect induced by LXR-623 and LINC01125 overexpression. Chromatin immunoprecipitation (ChIP) assay results suggest that p53 binds to the promoter of LINC01125 to strengthen the expression of the PTEN/AKT pathway. Taken together, our findings suggest that LXR-623 possesses significant antitumor activity in breast cancer cells that is partly mediated through the upregulation in LINC01125 expression and enhancement in apoptosis via the PTEN/AKT/MDM2/p53 pathway.

Erythropoietin Gene Polymorphism rs551238 is Associated with a Reduced Susceptibility to Brain Injury in Preterm Infants.

BACKGROUND: Single Nucleotide Polymorphisms (SNPs) in the Erythropoietin (EPO) promoter region have been shown to influence EPO protein expression, and high blood levels of EPO are associated with an increased risk of brain injury in very preterm infants. Here, we investigated the genotype distributions and association of three EPO gene polymorphisms (rs1617640, rs551238, and rs507392) with the risk of brain injury in preterm infants. METHODS: 304 preterm infants with a gestational age of 28 to 34 weeks were enrolled in this study. Brain injury was evaluated by brain ultrasound and MRI examination. EPO gene Single- Nucleotide Polymorphisms (SNPs) were genotyped by the Agena MassARRAY system, and their association with brain injury susceptibility in preterm infants was analyzed. RESULTS: EPO polymorphism rs551238 showed a significant difference in the genotypic distributions between the brain injury group and the control group, and was significantly correlated with reduced susceptibility to brain injury in preterm infants according to the results obtained from both the additive model (OR = 0.520, 95% CI: 0.339-0.799, P = 0.003) and the dominant model (OR = 0.523, 95% CI: 0.332-0.853, P = 0.009). EPO polymorphisms rs1617640 and rs507392 did not meet the Hardy-Weinberg equilibrium in the study population (P < 0.05) and were, thus, not subjected to further analysis for their impacts on brain injuries. CONCLUSION: The "C" allele of rs551238 was correlated with a reduced risk of brain injury in preterm infants which may serve as a potential marker for brain injury prediction in preterm infants.

Resveratrol provides neuroprotection by regulating the JAK2/STAT3/PI3K/AKT/mTOR pathway after stroke in rats.

Ischemic stroke is a common disease with high mortality and morbidity worldwide. One of the important pathophysiological effects of ischemic stroke is apoptosis. A neuroprotective effect is defined as the inhibition of neuronal apoptosis to rescue or delay the infarction in the surviving ischemic penumbra. Resveratrol is a natural polyphenol that reportedly prevents cerebral ischemia injury by regulating the expression of PI3K/AKT/mTOR. Therefore, this study aimed to elucidate the neuroprotective effect of resveratrol on cerebral ischemia/reperfusion injury and to investigate the signaling pathways and mechanisms through which resveratrol regulates apoptosis in the ischemic penumbra. Rats were subjected to middle cerebral artery occlusion for 2 h followed by 24 h reperfusion. Cerebral infarct volume was measured using 2% TTC staining. TUNEL staining was conducted to evaluate neuronal apoptosis. Western blotting and immunohistochemistry were used to detect the proteins involved in the JAK2/STAT3/PI3K/AKT/mTOR pathway. The results suggested that resveratrol significantly improved neurological function, reduced cerebral infarct volume, decreased neuronal damage, and markedly attenuated neuronal apoptosis; these effects were attenuated by the inhibition of PI3K/AKT with LY294002 and JAK2/STAT3 with AG490. We also found that resveratrol significantly upregulated the expression of p-JAK2, p-STAT3, p-AKT, p-mTOR, and BCL-2 and downregulated expression of cleaved caspase-3 and BAX, which was partially reversed by LY294002 and AG490. These results suggested that resveratrol provides a neuroprotective effect against cerebral ischemia/reperfusion injury, which is partially mediated by the activation of JAK2/STAT3 and PI3K/AKT/mTOR. Resveratrol may indirectly upregulate the PI3K/AKT/mTOR pathway by activating JAK2/STAT3.

DcR3 promotes hepatoma cell migration by downregulating E-cadherin expression.

Decoy receptor 3 (DcR3), a decoy molecule belonging to the tumor necrosis factor receptor superfamily (TNFRSF), is a soluble receptor that can neutralize the biological effects of three other TNFSF members, namely, Fas ligand (FasL/TNFSF6/CD95L), LIGHT (TNFSF14) and TNF-like molecule 1A (TL1A/TNFSF15). DcR3 expression is increased in tumor cells. As such, DcR3 has been considered a potential biomarker to predict cancer invasion and progression of inflammation. However, the molecular mechanisms of DcR3 in tumor progression and metastasis remain poorly described. In the present study, DcR3 induced cytoskeleton remodeling, inhibited E-cadherin expression, and promoted cancer cell migration. Immunofluorescence and flow cytometry demonstrated that DcR3 expression was increased in hepatoma cells, whereas E-cadherin expression was significantly downregulated. Immunohistochemistry revealed that DcR3 and E-cadherin exhibited an opposite expression pattern between normal and cancerous liver tissues. Moreover, DcR3 treatment promoted IκBα degradation and p65 nuclear translocation. Therefore, the present study uncovered the mechanism underlying the function of DcR3 in cancer cell migration and provides evidence that DcR3 may be a potential target for cancer therapy.

[Grape seed proanthocyanidins inhibits the invasion and migration of A549 lung cancer cells].

OBJECTIVE: To explore the effect of grape seed proanthocyanidins (GSPs) on the invasion and migration of A549 lung cancer cells and the underlying mechanism. METHODS: Trypan blue dye exclusion assay was used to determine the cytotoxic effect of varying doses of GSPs on the BEAS-2B normal human pulmonary epithelial cells. After treated with 0, 10, 20, 40, 80 µg/mL GSP, the proliferation of A549 cells was detected by MTT assay; the invasion and migration of A549 cells were determined by Transwell(TM) assay and scratch wound assay, respectively. The levels of epithelial growth factor receptor (EGFR), E-cadherin, N-cadherin in A549 cells treated with GSPs were detected by Western blotting. RESULTS: (0-40) µg/mL GSPs had no significant toxic effect on BEAS-2B cells, while 80 µg/mL GSPs had significant cytotoxicity to BEAS-2B cells. The proliferation of A549 cells was significantly inhibited within limited dosage in a dose-dependent manner, and the abilities of invasion and migration of A549 cells were also inhibited. Western blotting showed that the expression of EGFR and N-cadherin decreased, while E-cadherin increased after GSPs treatment. CONCLUSION: GSPs could inhibit the abilities of proliferation, invasion and migration of A549 cells, which might be related to the dow-regulation of EGFR and N-cadherin and the up-regulation of E-cadherin.

Resveratrol provides neuroprotection by inhibiting phosphodiesterases and regulating the cAMP/AMPK/SIRT1 pathway after stroke in rats.

Dysfunction of energy metabolism can be a significant and fundamental pathophysiological basis for strokes. In studies of both humans and rodents, resveratrol, a natural polyphenol, has been reported to provide protection from cerebral ischemic injury by regulating expression of silent mating type information regulation 2 homolog 1 (SIRT1). However, direct evidence demonstrating that resveratrol exerts neuroprotection from cerebral ischemia injury by decreasing energy consumption is still lacking. Therefore, the aim of this study was to elucidate the mechanisms and signaling pathways through which resveratrol regulates energy metabolism in the ischemic brain, and to identify potential targets of resveratrol. ATP levels in brain tissues were detected by high performance liquid chromatography. SIRT1 and the phosphorylation of adenosine-monophosphate-activated protein kinase (P-AMPK) expressiones were evaluated by western blot. Levels of phosphodiesterase (PDEs) and cAMP were quantitated by real-time PCR and ELISA, respectively. Results showed that resveratrol significantly reduced the harmful effects of cerebral ischemic injury in vivo. Moreover, levels of ATP, p-AMPK, SIRT1, and cAMP were increased by resveratrol and PDE inhibitors. In conclusion, our findings indicate that resveratrol provides neuroprotection by inhibiting PDEs and regulating the cAMP/AMPK/SIRT1 pathway, which reduces ATP energy consumption during ischemia.

[Changes in glucocorticoid receptor and heat shock protein 70 in liver tissue after trauma with hemorrhagic shock in rats].

OBJECTIVE: To investigate changes and functions of glucocorticoid (GR) and heat shock protein 70 (HSP70) at the level of cellular receptor in liver in hemorrhagic shock after trauma. METHODS: Adult Wistar rats were used and a rat model of shock was reproduced by hemorrhaging accompanied by bilateral femur fracture. Changes in hepatic tissue GR, HSP70, pathology of liver, hepatic function markers in serum were dynamically observed. The expression of GR and HSP70 in hepatic tissue was assayed by Western blot and then analyzed with computer imaging system. RESULTS: Protein content of GR gradually decreased in hepatic tissue after trauma, reduced to the nadir at 6 hours after trauma, and it was decreased even more when trauma was added to bleeding. Protein content of HSP70 was gradually increased in hepatic tissue after severe trauma, peaking at 6 hours after trauma, and it maintained at a rather high level at 8 hours after trauma. It was even more increased in when hemorrhagic shock was followed by trauma. Alterations in hepatic function markers and pathology were not obvious after simple trauma. But after trauma was added to hemorrhagic shock, significant increase in alanine aminotransferase (ALT) and total bilirubin (TB) in serum was noted at 4 and 2 hours after trauma respectively (all P<0.01), and albumin content was obviously decreased (P<0.01). There were more inflammatory cell infiltrations in hepatic sinusoids at 6 hours after trauma. CONCLUSION: GR may play an important role in anti-injury mechanism of hepatic tissue cell after trauma with hemorrhagic shock. HSP70 may participate in initiating anti-injury mechanism of hepatic cells.

Lgr5 is a potential prognostic marker in patients with cervical carcinoma.

OBJECTIVE: To investigate the Lgr5 (Leucine-rich repeat-containing G protein-coupled receptor 5) expression in cervical carcinoma and to estimate its clinical significance. METHODS: The expression of Lgr5 mRNA was evaluated by Real-time PCR in 8 pairs of surgically removed cervical cancer and adjacent normal cervical tissues. Lgr5 protein expression was evaluated by immunohistochemistry in 94 paraffin-embedded cervical carcinoma specimens. The correlation between Lgr5 expression and clinicopathological features were statistically analyzed. RESULTS: Lgr5 expression was significantly higher in cervical cancer tissues compared with that in adjacent normal cervix. High Lgr5 expression was positively correlated with tumor size (P = 0.025) and parametrial infiltration (P = 0.027). Moreover, high levels of Lgr5 was associated with lower overall survival (P = 0.021) and recurrent-free survival (P = 0.008), especially in stage II patients (P = 0.035). Multivariate analysis showed that the expression of Lgr5 was an independent factor of recurrent-free survival for the patients with cervical carcinoma (P = 0.135). CONCLUSION: Lgr5 may play an important role in the development and progression of cervical carcinoma, and may be a potential therapeutic target for the treatment of cervical carcinoma.

Up-regulation of ROR2 is associated with unfavorable prognosis and tumor progression in cervical cancer.

AIMS: To investigate the clinical significance of receptor tyrosine kinase-like orphan receptor 2 (ROR2) in cervical cancer. METHODS: We examined ROR2 levels in 8 pairs of surgically resected cervical cancer and adjacent normal cervical tissues by real-time PCR. Moreover, we performed immunohistochemistry to examine ROR2 expression in 94 paraffin-embedded cervical cancer samples and analyzed the association between ROR2 expression, clinicopathologic factors and prognosis. RESULTS: ROR2 expression was up-regulated in cervical cancer tissues compared with adjacent normal cervix. In paraffin-embedded cervical cancer samples, high expression of ROR2 was shown in 40 (42.6%) of 94 cases, also, it was significantly associated with tumor stage (P = 0.018) and lymph nodes metastasis (P = 0.013). Moreover, survival analysis showed that ROR2 expression was an independent prognostic factor of poor overall and recurrent free survival (P = 0.045 and 0.001, respectively). CONCLUSION: These results indicate that ROR2 is significantly correlated with cancer progression and poor prognosis in cervical cancer.

Effects of emodin extracted from Chinese herbs on proliferation of non-small cell lung cancer and underlying mechanisms.

To aim of this was to observe emodin-mediated cytotoxicity and its influence on Rad51 and ERCC1 expressionin non-small cell lung cancer (NSCLC). NSCLC cells were cultured in vitro with emodin at various concentrations (0, 25, 50, 75 and 100 µmol/L) for 48 h and the proliferation inhibition rate was determined by the MTT method. Then, NSCLC were treated with emodin (SK-MES-1 40 µmol/L, A549 70 µmol/L) or 20 µmol/L U0126 (an ERK inhibitor) for 48 h, or with various concentrations of emodin for 48 h and the protein and mRNA expressions of ERCC1 and Rad51 were determined by RT-PCR and Western blot assay, respectively. Emodin exerted a suppressive effect on the proliferation of NSCLC in a concentration dependent manner. Protein and mRNA expression of ERCC1 and Rad51 was also significantly decreased with the dose. Vacuolar degeneration was observed in A549 and SK-MES-1 cell lines after emodin treatment by transmission electron microscopy. Emodin may thus inhibited cell proliferation in NSCLC cells by downregulation ERCC1 and Rad51.

Rhein inhibits liver fibrosis induced by carbon tetrachloride in rats.

AIM: To investigate the effect of rhein on liver fibrosis induced by the exposure of carbon tetrachloride (CCl4)/ethanol in rats. METHODS: Male Wistar rats were divided into four study groups (n=10 each group): healthy controls, CCl4/ethanol-injured rats left untreated, and CCl4/ethanol-injured rats treated with rhein of low-dose (25 mg/kg) and high-dose (100 mg/kg). Rhein was given once a day since rat received CCl4/ethanol injury. After administration of rhein for 6 weeks rats were killed. The following parameters were determined: the activity of alanine aminotransferase (ALT), hyalauronic acid (HA) and procollagen type III (PC-III) concentrations in serum, liver malondialdehyde (MDA) level, the degree of liver fibrosis, and the expression of alpha-smooth muscle actin (alpha-SMA) and transforming growth factor-beta1 (TGF-beta1) in liver tissue. RESULTS: The treatment of rhein markedly reduced the ALT activity, HA and PC-III concentrations, and liver MDA level in CCl4/ethanol-injured rats (P<0.01). It also improved significantly histological changes of fibrosis and decreased the expression of alpha-SMA and TGF-beta1 in liver of these rats (P<0.05 or P<0.01). CONCLUSION: Rhein has protective effect on liver injury and can inhibit liver fibrosis induced by CCl4/ethanol in rats. The mechanisms possibly contribute to its action of antioxidant and anti-inflammatory activity, also associated with its effect of inhibiting TGF-beta1 and suppressing the activation of hepatic stellate cells.