Pharmacological Benefits and Underlying Mechanisms of Salvia miltiorrhiza against Molecular Pathology of Various Liver Diseases: A Review.

Salvia miltiorrhiza Bunge, called Danshen in Chinese, is the dried root and rhizome of S. miltiorrhiza, which is part of the mint family, Lamiaceae; it has chiefly been used to treat blood stasis and improve blood flow in cerebrovascular and cardiovascular diseases for over 2000 years. Recent preclinical studies have indicated that S. miltiorrhiza has a wide range of pharmacological properties making it useful for the treatment of diverse liver diseases. S. miltiorrhiza protects the liver from harmful hepatotoxins, reduces hepatic oxidative stress, ameliorates steatosis, and alleviates hepatic inflammation, fibrosis, and cancer. Moreover, several key mechanisms, including apoptosis, AMP-activated protein kinase, mitogen-activated protein kinase, and nuclear factor kappa B, may be involved in the benefits of S. miltiorrhiza in hepatic disorders. In particular, salvianolic acid B and cryptotanshinone, both compounds derived from S. miltiorrhiza, possess therapeutic activities similar to those of S. miltiorrhiza, and thus may play a crucial role in the therapeutic activity of S. miltiorrhiza in liver diseases. Because reports on the pharmacological effects of this herb are scattered, this review aimed to consolidate the available literature to allow the re-evaluation and identification of gaps to guide future research. This review focuses on the role of S. miltiorrhiza in improving the molecular pathology of liver diseases, as reported in in vitro and in vivo studies.

Beneficial Activities of Alisma orientale Extract in a Western Diet-Induced Murine Non-Alcoholic Steatohepatitis and Related Fibrosis Model via Regulation of the Hepatic Adiponectin and Farnesoid X Receptor Pathways.

The hepatic adiponectin and farnesoid X receptor (FXR) signaling pathways play multiple roles in modulating lipid and glucose metabolism, reducing hepatic inflammation and fibrosis, and altering various metabolic targets for the management of non-alcoholic fatty liver disease (NAFLD). Alisma orientale (AO, Ze xie in Chinese and Taeksa in Korean) is an herbal plant whose tubers are enriched with triterpenoids, which have been reported to exhibit various bioactive properties associated with NAFLD. Here, the present study provides a preclinical evaluation of the biological functions and related signaling pathways of AO extract for the treatment of NAFLD in a Western diet (WD)-induced mouse model. The findings showed that AO extract significantly reversed serum markers (liver function, lipid profile, and glucose) and improved histological features in the liver sections of mice fed WD for 52 weeks. In addition, it also reduced hepatic expression of fibrogenic markers in liver tissue and decreased the extent of collagen-positive areas, as well as inhibited F4/80 macrophage aggregation and inflammatory cytokine secretion. The activation of adiponectin and FXR expression in hepatic tissue may be a major mechanistic signaling cascade supporting the promising role of AO in NAFLD pharmacotherapy. Collectively, our results demonstrated that AO extract improves non-alcoholic steatohepatitis (NASH) resolution, particularly with respect to NASH-related fibrosis, along with the regulation of liver enzymes, postprandial hyperglycemia, hyperlipidemia, and weight loss, probably through the modulation of the hepatic adiponectin and FXR pathways.

Potential Roles and Key Mechanisms of Hawthorn Extract against Various Liver Diseases.

The genus Crataegus (hawthorn), a flowering shrub or tree, is a member of the Rosaceae family and consists of approximately 280 species that have been primarily cultivated in East Asia, North America, and Europe. Consumption of hawthorn preparations has been chiefly associated with pharmacological benefits for cardiovascular diseases, including congestive heart failure and angina pectoris. Treatment with hawthorn extracts can be related to improvements in the complex pathogenesis of various hepatic and cardiovascular disorders. In this regard, the present review described that the presence of hawthorn extracts ameliorated hepatic injury, lipid accumulation, inflammation, fibrosis, and cancer in an abundance of experimental models. Hawthorn extracts might have these promising activities, largely by enhancing the hepatic antioxidant system. In addition, several mechanisms, including AMP-activated protein kinase (AMPK) signaling and apoptosis, are responsible for the role of hawthorn extracts in repairing the dysfunction of injured hepatocytes. Specifically, hawthorn possesses a wide range of biological actions relevant to the treatment of toxic hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease, and hepatocellular carcinoma. Accordingly, hawthorn extracts can be developed as a major source of therapeutic agents for liver diseases.

Promising Anticancer Activities of Alismatis rhizome and Its Triterpenes via p38 and PI3K/Akt/mTOR Signaling Pathways.

The flowering plant genus Alisma, which belongs to the family Alismataceae, comprises 11 species, including Alisma orientale, Alisma canaliculatum, and Alisma plantago-aquatica. Alismatis rhizome (Ze xie in Chinese, Takusha in Japanese, and Taeksa in Korean, AR), the tubers of medicinal plants from Alisma species, have long been used to treat inflammatory diseases, hyperlipidemia, diabetes, bacterial infection, edema, oliguria, diarrhea, and dizziness. Recent evidence has demonstrated that its extract showed pharmacological activities to effectively reverse cancer-related molecular targets. In particular, triterpenes naturally isolated from AR have been found to exhibit antitumor activity. This study aimed to describe the biological activities and plausible signaling cascades of AR and its main compounds in experimental models representing cancer-related physiology and pathology. Available in vitro and in vivo studies revealed that AR extract possesses anticancer activity against various cancer cells, and the efficacy might be attributed to the cytotoxic and antimetastatic effects of its alisol compounds, such as alisol A, alisol B, and alisol B 23-acetate. Several beneficial functions of triterpenoids found in AR might be due to p38 activation and inhibition of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathways. Moreover, AR and its triterpenes inhibit the proliferation of cancer cells that are resistant to chemotherapy. Thus, AR and its triterpenes may play potential roles in tumor attack, as well as a therapeutic remedy alone and in combination with other chemotherapeutic drugs.

Beneficial Actions of Orostachys japonica and Its Compounds against Tumors via MAPK Signaling Pathways.

Tumors are one of the most life-threatening diseases, and a variety of cancer treatment options have been continuously introduced in order to overcome cancer and improve conventional therapy. Orostachys japonica (O. japonica), which is a perennial plant belonging to the genus Orostachys of the Crassulaceae family, has been revealed to exhibit pharmacological properties against various tumors in numerous studies. The present review aimed to discuss the biological actions and underlying molecular mechanisms of O. japonica and its representative compounds-kaempferol and quercetin-against tumors. O. japonica reportedly has antiproliferative, anti-angiogenic, and antimetastatic activities against various types of malignant tumors through the induction of apoptosis and cell cycle arrest, a blockade of downstream vascular endothelial growth factor (VEGF)-VEGFR2 pathways, and the regulation of epithelial-to-mesenchymal transition. In addition, emerging studies have highlighted the antitumor efficacy of kaempferol and quercetin. Interestingly, it was found that alterations of the mitogen-activated protein kinase (MAPK) signaling cascades are involved in the pivotal mechanisms of the antitumor effects of O. japonica and its two compounds against cancer cell overgrowth, angiogenesis, and metastasis. In summary, O. japonica could be considered a preventive and therapeutic medicinal plant which exhibits antitumor actions by reversing altered patterns of MAPK cascades, and kaempferol and quercetin might be potential components that can contribute to the efficacy and underlying mechanism of O. japonica.

Preclinical Evidence of Curcuma longa and Its Noncurcuminoid Constituents against Hepatobiliary Diseases: A Review.

Hepatobiliary disease currently serves as an important public health issue due to the fact that it is one of the major causes of death among economically active individuals and can easily progress to chronic diseases. Despite the development of vaccines and numerous drugs, a definite treatment remains lacking owing to different stages of the disease itself, its intricate pathogenesis, an effect uncertainty for long-term use, resistance, and side effects. Curcuma longa (C. longa), which belongs to the family Zingiberaceae and the genus Curcuma, has long been used not only as spice for curry or dye but also as a constituent of herbal formula for the treatment of different diseases due to its bioactive activities. Recently, many studies on the experimental results of C. longa have been published relative to hepatobiliary diseases such as fatty liver, hepatitis, cirrhosis, and tumors. Therefore, in this review, we aimed to summarize the pharmacological effects and underlying molecular mechanisms of C. longa and its four compounds, ß-elemene, germacrone, ar-turmerone, and bisacurone, against hepatobiliary diseases. C. longa exhibited antioxidant, hepatoprotective, antisteatotic, anti-inflammatory, antifibrotic, antitumor, and cholagogic effects by regulating apoptosis, CYP2E1, Nrf, lipid metabolism-related factors, TGF-ß, NF-κB, CYP7A1, and so on. In particular, ß-elemene could be an attractive compound owing to its remarkable hepatoprotective, anti-inflammatory, antifibrotic, and antitumor activities. Altogether, the present review provides a preclinical basis for the efficacy of C. longa as an effective therapeutic agent for the prevention and treatment of hepatobiliary diseases, despite the need for further studies to establish the extraction conditions and separation of active constituents with high bioavailability, and warrants further evaluation in clinical trials.

Pharmacological Activities of Alisma orientale against Nonalcoholic Fatty Liver Disease and Metabolic Syndrome: Literature Review.

Nonalcoholic fatty liver disease (NAFLD) is a rapidly emerging hepatic manifestation of metabolic syndrome. However, its unrevealed mechanism and complicated comorbidities have led to no specific medication, except for weight loss and lifestyle modification. Alisma orientale (Sam.) Juzep (A. orientale, Alismataceae) has been increasingly reported on therapeutic effects of A. orientale against NAFLD and metabolic syndrome such as insulin resistance, hyperlipidemia, and obesity. Therefore, this study aimed to review the preclinical efficacy of A. orientale and its chemical constituents including Alisol A 24-acetate, Alisol B 23-acetate, Alisol F, and Alismol against NAFLD and metabolic syndrome. A. orientale prevented hepatic triglyceride accumulation through suppressing de novo lipogenesis and increasing lipid export. In addition, it controlled oxidative stress markers, lipoapoptosis, liver injury panels, and inflammatory and fibrotic mediators, eventually influencing steatohepatitis and liver fibrosis. Moreover, it exhibited pharmacological activities against hyperlipidemia, obesity, and hyperglycemia as well as appetite. These biological actions of A. orientale might contribute to adiponectin activation or a role as a farnesoid X receptor agonist. In particular, Alisol A 24-acetate and Alisol B 23-acetate could be expected as main compounds. Taken together, A. orientale might be an effective candidate agent for the treatment of NAFLD and its comorbidities, although further assessment of its standardization, safety test, and clinical trials is consistently required.

Preclinical Evaluation of In Vitro and In Vivo Antiviral Activities of KCT-01, a New Herbal Formula against Hepatitis B Virus.

Hepatitis B virus (HBV) infectious diseases currently remain incurable due to limitations of conventional antivirals such as incapability of eradicating HBV DNA, prolonged use, drug resistance, and virological relapse. KCT-01, a 30% ethanol extract consisting of Artemisia capillaris, Sanguisorba officinalis, and Curcuma longa, was newly developed. The objective of this study was to investigate pharmacological activities of KCT-01 against HBV using HepG2.2.15 cells and a hydrodynamic injection model. KCT-01 significantly lowered antigen secretion, virion production, and pgRNA synthesis in HepG2.2.15 cells without affecting cell viability. KCT-01 administration also resulted in significant decrease of serum virion production, liver covalently closed circular (ccc) DNA levels, and mRNA synthesis of cytokines in the liver of mice injected with HBV DNA hydrodynamically. Interestingly, coadministration of KCT-01 with entecavir enhanced its in vitro and in vivo antiviral activities. Moreover, safety of KCT-01 was assured up to 5000 mg/kg in rats in both single and repeated-dose preclinical studies. Taken together, our findings demonstrate that KCT-01 is capable of suppressing HBV replication and inflammatory cytokine production in in vitro and in vivo models without showing toxicity, suggesting the potential of using KCT-01 alone or in combination with entecavir as antiviral agent.

Phytotherapeutic Activities of Sanguisorba officinalis and its Chemical Constituents: A Review.

Sanguisorba officinalis Linne (S. officinalis, Rosaceae) has been used as a medicinal plant for the treatment of burns, hematemesis, melena, intestinal infections, and dermatitis for a long time in China, Korea, and Japan. The therapeutic efficacy of this herb is intimately associated with its anti-oxidant, anti-inflammatory, antiviral, antifungal, hemostatic, and anticancer activities. Its root contains triterpenoid saponins (zigyuglycoside I: C[Formula: see text]H[Formula: see text]O[Formula: see text] and ziyuglycoside II: C[Formula: see text]H[Formula: see text]O8) and tannins (sanguiin H-6: C[Formula: see text]H[Formula: see text]O[Formula: see text]). It has been recently revealed that these active constituents of S. officinalis possess antiwrinkle properties without cytotoxicity. They also have anticancer effects by inducing apoptosis and cell cycle arrest. Moreover, they can inhibit proliferative tumorigenesis. The underlying mechanism involved in the pharmacological actions of these active constituents is mainly related to p38 MAPK signaling. Although various studies have reported its therapeutic activities and major chemical components, review articles that extensively organize various properties of S. officinalis and its major constituents are still scarce. Taken together, the objective of this paper is to provide overall pharmacological and phytochemical profiles of S. officinalis and its constituents (including ziyuglycoside I, ziyuglycoside II, and sanguiin H-6), and their potential roles in clinical applications for the treatment of inflammatory diseases, bleeding disorders, and cancer.

Rhus verniciflua Stokes extract induces inhibition of cell growth and apoptosis in human chronic myelogenous leukemia K562 cells.

Rhus verniciflua Stokes has been widely used as a traditional medicinal plant with a variety of pharmacological activities. We investigated the mechanisms involved in mediating the effects of Rhus verniciflua Strokes (R. verniciflua) extract in human chronic myelogenous leukemia K562 cells, including caspase-dependent apoptotic pathways related to cell-cycle arrest, as well as the inhibition of nuclear factor NF-κB activation and upregulation of the mitogen-activated protein kinase (MAPK) signaling pathway. R. verniciflua extract suppressed the abnormal cellular proliferation of K562 cells in a dose- and time­dependent manner and increased the quantitative proportions of cells involved in the early and late process of apoptosis. Furthermore, R. verniciflua extract significantly mediated the mRNA levels of pro-apoptotic and anti-apoptotic regulators, such as Bcl-2, Bax, Mcl-1 and survivin in apoptotic cells. Particularly, the treatment of K562 cells with R. verniciflua extract augmented the caspase­3 activity and increased the expression of caspase­3 protein, while co-treatment with R. verniciflua extract and the permeant pan­caspase inhibitor Z-VAD-FMK and caspase­3 inhibitor Z-DEVD-FMK inversely enhanced the proliferation of K562 cells. The extract of R. verniciflua inhibited the activation of NF-κB and the phosphorylation of ERK. Collectively, these results indicated that the extract of R. verniciflua inhibited the proliferation of human chronic myelogenous leukemia K562 cells by activating the apoptotic process via caspase­3 overexpression and the regulation of the NF-κB and MAPK signaling.

The therapeutic effects of Yongdamsagan-tang on autoimmune hepatitis models.

Autoimmune hepatitis (AIH) is an immunity disorder that is the result of antibodies in the liver tissue of the patient that are attacked by activated immune cells due to an unknown cause. In this study, we aimed to investigate the anti-inflammatory effect of Yongdamsagan-tang (YST) extracts and confirm effects on autoimmune hepatitis models as the therapeutic agent using the YST extracted by various solvents. YST, a mixture of 11 herbal extracts, is known in traditional Korean medicine as a widely used treatment for inflammatory diseases. We proposed the AIH-condition in vitro model by the addition of recombinant IL-17A and then observed several markers linked to AIH symptoms, including an increase of IL-6 expression, lipid accumulation, and fibrosis. In AIH-condition hepatic cell model, YST reduced IL-6 expression and lipid accumulation caused by treatment of IL-17 combination in hepatocyte cells. Also, YST blocked several activated fibrosis factors including transforming growth factor-ß (TGF- ß1), collagen type 1 (Col-α1(I)), and α-smooth muscle actin (α-SMA) in liver stellate cells. Furthermore, pretreatment with YST protected hepatic damage and reduces histological injury by suppressing apoptosis mediator and inflammatory cytokines expression in concanavalin A (Con A)-induced autoimmune hepatitis mice model. The findings here improve our understanding of YST extracted by 80% ethanol, suggesting that YST can be used as a therapeutic treatment for AIH.

A nationwide study of the incidence rate of herb-induced liver injury in Korea.

Discrepant incidence has been reported regarding the incidence of herb-induced liver injury (HILI). To address the growing worldwide concern of HILI, we evaluated the risk of HILI in a nationwide prospective study. Between April 2013 and January 2016, 1001 inpatients (360 males and 641 females) from 10 tertiary hospitals throughout South Korea were treated with herbal drugs and had their liver enzymes periodically measured. A total of six patients met the criteria for HILI with RUCAM scores ranging from 4 to 7. All these participants were women and developed the hepatocellular type of HILI. One HILI participant met the criteria for Hy's law; however, none of six cases presented clinical symptoms related to liver injury. This is the first nationwide prospective study that estimated the extent of the incidence of HILI [total: 0.60%, 95% confidence interval (CI) 0.12-1.08; women: 0.95%, 95% CI 0.19-1.68] and described its features in hospitalized participants.

Kyungheechunggan-Tang-01, a New Herbal Medication, Suppresses LPS-Induced Inflammatory Responses through JAK/STAT Signaling Pathway in RAW 264.7 Macrophages.

Medicinal plants have been used as alternative therapeutic tools to alleviate inflammatory diseases. The objective of this study was to evaluate anti-inflammatory properties of Kyungheechunggan-tang- (KCT-) 01, KCT-02, and Injinchunggan-tang (IJCGT) as newly developed decoctions containing 3-11 herbs in LPS-induced macrophages. KCT-01 showed the most potent inhibitory effects on LPS-induced NO, PGE2, TNF-α, and IL-6 production among those three herbal formulas. In addition, KCT-01 significantly inhibited LPS-induced iNOS and COX-2 at protein levels and expression of iNOS, COX-2, TNF-α, and IL-6 at mRNA levels. Molecular data revealed that KCT-01 attenuated the activation of JAK/STAT signaling cascade without affecting NF-κB or AP-1 activation. In ear inflammation induced by croton oil, KCT-01 significantly reduced edema, MPO activity, expression levels of iNOS and COX-2, and STAT3 phosphorylation in ear tissues. Taken together, our findings suggest that KCT-01 can downregulate the expression of proinflammatory genes by inhibiting JAK/STAT signaling pathway under inflammatory conditions. This study provides useful data for further exploration and application of KCT-01 as a potential anti-inflammatory medicine.

Evaluation of antitumor activity of Artemisia capillaris extract against hepatocellular carcinoma through the inhibition of IL-6/STAT3 signaling axis.

Interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) signaling pathway plays critical roles in the development and progression of hepatocellular carcinoma (HCC). Artemisia capillaris (AC) has been widely used to treat various liver diseases including HCC as a herbal medicine. The effects of AC on IL-6/STAT3 signaling axis in HCC cells and subsequent anticancer activity of AC against HCC were analyzed using HCC cell lines and HBV W4P-LHB-expressing NIH3T3 cell line, which has been shown to gain tumorigenicity by activating IL-6/STAT3 signaling in our previous study. AC extract significantly suppressed the growth and colony formation of HCC cells. In addition, it inhibited the activation of STAT3 by IL-6 and subsequent synthesis of downstream molecules in HCC and W4P-NIH3T3 cells. Consequently, migration of cells was significantly suppressed by the AC extract. Collectively, the findings suggest that AC extract is capable of conferring various antitumor effects against HCC through the modulation of the IL-6/STAT3 pathway. The results provide a basis for the therapeutic use of AC in the treatment of HCC. Identification of the compound responsible for the effect may lead to the development of a novel anticancer agent against HCC.

Anti-lipoapoptotic effects of Alisma orientalis extract on non-esterified fatty acid-induced HepG2 cells.

BACKGROUND: Liver steatosis was caused by lipid accumulation in the liver. Alisma orientale (AO) is recognized as a promising candidate with therapeutic efficacy for the treatment of nonalcoholic fatty liver disease (NAFLD). HepG2 hepatocyte cell line is commonly used for liver disease cell model. METHOD: The HepG2 cells were cultured with the NEFAs mixture (oleic and palmitic acids, 2:1 ratio) for 24 h to induce hepatic steatosis. Then different doses of Alisma orientale extract (AOE) was treated to HepG2 for 24 h. Incubated cells were used for further experiments. RESULTS: The AOE showed inhibitory effects on lipid accumulation in the Oil Red O staining and Nile red staining tests with no cytotoxicity at a concentration of 300 µg/mL. Fatty acid synthase (FASN) and acetyl-CoA carboxylase 1 (ACC1) mRNA and protein expression level were down-regulated after AOE treatment. Bcl-2 associated X protein (Bax) and c-Jun N-terminal kinase (JNK) mRNA expression level were decreased as well as p-JNK (activated form of JNK), Bax, cleaved caspase-9, caspase-3 protein expression level. Anti-apopototic B-cell lymphoma 2 (Bcl-2) protein level increased after AOE treatment. In addition, inflammatory protein expression including p-p65, p65, COX-2 and iNOS were inhibited by AOE treatment. CONCLUSION: The results suggest that AOE has anti-steatosis effects that involve lipogenesis, anti-lipoapoptosis, and anti-inflammation in the NEFA-induced NAFLD pathological cell model.

Drug-induced liver injury: A 2-year retrospective study of 1169 hospitalized patients in a single medical center.

BACKGROUND: Although herbal medicines (HMs) are widely used in Asian and Western countries, medicinal information concerning their hepatic toxicity or interaction with conventional medicines (CMs) is sparse. PURPOSE: The aim of our study was to estimate the prevalence of drug-induced liver injury (DILI) among total inpatients prescribed HMs or CMs. Furthermore, we noted all medications suspected to be associated with hepatotoxicity in the liver injury group during the period of hospitalization. STUDY DESIGN: We retrospectively observed medical records of 1169 inpatients in a single medical center from January 2012 to July 2014. METHODS: Based on a database of the 1169 inpatients at a single medical center, we researched the occurrence rate and type of liver injury according to the criteria of the Council for International Organization of Medical Science (CIOMS). We also utilized a simplified Roussel Uclaf Causality Assessment Method (RUCAM) score for probable causality assessment between drugs and liver injury. RESULTS: Among a total of 1169 inpatients, 13 cases whose baseline LFTs had been in the normal range at admission had abnormal liver parameters at the time of follow-up, and 11 of them (0.94%) were attributed to drugs: 0.43% (5 of 1169) to HMs, 0.43% (5 of 1169) to CMs, and 0.09% (1 of 1169) to combined drug classes. Two of them were found to have liver injury because of pneumonia and sepsis. As for liver injury type, 8 cases were hepatocellular, 2 were cholestatic, and 1 was of mixed pattern. The common causative HMs for hepatotoxicity were Ephedrae Herba and Scutellariae Radix, while CMs included antidepressants, antihistamines, and antibacterials. CONCLUSIONS: We investigated approximate incidence rates and analyzed suspicious drugs associated with liver damage, which revealed a low frequency of liver injury induced by HMs. However, further study, based on a well-designed, long-term, multicenter prospective study, will be required to determine the safety of HMs.

A Survey of Therapeutic Effects of Artemisia capillaris in Liver Diseases.

Artemisia capillaris has been recognized as an herb with therapeutic efficacy in liver diseases and widely used as an alternative therapy in Asia. Numerous studies have reported the antisteatotic, antioxidant, anti-inflammatory, choleretic, antiviral, antifibrotic, and antitumor activities of A. capillaris. These reports support its therapeutic potential in various liver diseases such as chronic hepatitis B virus (HBV) infection, cirrhosis, and hepatocellular carcinoma. In addition, several properties of its various constituents, which provide clues to the underlying mechanisms of its therapeutic effects, have been studied. This review describes the scientific evidence supporting the therapeutic potential of A. capillaris and its constituents in various liver diseases.

Activation of Caspase-9/3 and Inhibition of Epithelial Mesenchymal Transition are Critically Involved in Antitumor Effect of Phytol in Hepatocellular Carcinoma Cells.

This study was designed to investigate the antitumor mechanism of Phytol in hepatocellular carcinomas including Huh7 and HepG2 cells in association with caspase dependent apoptosis and epithelial mesenchymal transition (EMT) signaling. Phytol significantly suppressed the viability of Huh7 and HepG2 cells. Also, Phytol significantly increased the sub G1 population and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling (TUNEL) positive cells in a concentration dependent manner in Huh7 and HepG2 cells. Consistently, Phytol cleaved poly (adenosine diphosphate-ribose) polymerase (PARP), activated caspase-9/3, and Bax attenuated the expression of survival genes such as Bcl-2, Mcl-1, and c-Myc in Huh7 and HepG2 cells. Of note, Phytol also suppressed typical morphology change of EMT such as loss of cell adhesion and formation of fibroblast like mesenchymal cells in HepG2 cells. Furthermore, Phytol also reversed the loss of E-cadherin and overexpression of p-smad2/3, alpha-smooth muscle actin, and Snail induced by EMT promoter transforming growth factor beta1 in HepG2 cells. Overall, our findings suggest that Phytol exerts antitumor activity via apoptosis induction through activation of caspas-9/3 and inhibition of EMT in hepatocellular carcinoma cells as a potent anticancer candidate for liver cancer treatment.

Mechanical properties and polymerization shrinkage of composite resins light-cured using two different lasers.

OBJECTIVE: The purpose of the present study was to investigate the usefulness of 457 and 473 nm lasers for the curing of composite resins during the restoration of damaged tooth cavity. BACKGROUND DATA: Monochromaticity and coherence are attractive features of laser compared with most other light sources. Better polymerization of composite resins can be expected. MATERIALS AND METHODS: Eight composite resins were light cured using these two lasers and a light-emitting diode (LED) light-curing unit (LCU). To evaluate the degrees of polymerization achieved, polymerization shrinkage and flexural and compressive properties were measured and compared. RESULTS: Polymerization shrinkage values by 457 and 473 nm laser, and LED ranged from 10.9 to 26.8, from 13.2 to 26.1, and from 11.5 to 26.3 µm, respectively. The values by 457 nm laser was significantly different from those by 473 and LED LCU (p<0.05). However, there was no statistical difference between values by 473 and LED LCU. Before immersion in distilled water, flexural strength (FS) and compressive modulus (CM) of the specimens were inconsistently influenced by LCUs. On the other hand, flexural modulus (FM) and compressive strength (CS) were not significantly different for the three LCUs (p>0.05). For the tested LCUs, no specific LCU could consistently achieve highest strength and modulus from the specimens tested. CONCLUSIONS: Two lasers (457 and 473 nm) can polymerize composite resins to the level that LED LCU can achieve despite inconsistent trends of polymerization shrinkage and flexural and compressive properties of the tested specimens.

Orostachys japonicus inhibits the expression of MMP-2 and MMP-9 mRNA and modulates the expression of iNOS and COX-2 genes in human PMA-differentiated THP-1 cells via inhibition of NF-κB and MAPK activation.

Orostachys japonicus has been used in traditional medicine as an anticancer agent. The present study aimed to investigate the mechanism by which O. japonicus extract affects the expression of matrix metalloproteinase (MMP)-2 and MMP-9, its association with the expression of the inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) genes in phorbol myristate acetate-differentiated THP-1 human monocytic leukemia cells and how it mediates the nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) pathways. Cell proliferation was analyzed by MTT assay, mRNA expression was detected by quantitative polymerase chain reaction and protein expression was measured by western blot analysis. It was demonstrated that O. japonicus suppressed the mRNA expression of MMP-2 and MMP-9. In addition, O. japonicus was found to downregulate iNOS and COX-2 transcription and translocation. Furthermore, O. japonicus inhibited NF-κB p65 activity as well as the phosphorylation of p38 MAPK, MAPK kinase (MEK) and extracellular signal regulated kinase (ERK). The present results suggested that O. japonicus inhibited not only MMP-2 and MMP-9 mRNA expression, but also iNOS and COX-2 gene expression, suppressed NF-κB activation and reduced phosphorylation of p38 MAPK, MEK and ERK. The present results therefore indicated that O. japonicus was able to inhibit the expression of MMP-2 and MMP-9 and suppress the transcription and translocation of iNOS and COX-2 by directly inhibiting the activation of NF-κB and the phosphorylation of the MAPK pathway in THP-1 cells.