Oncogenic Role of Exosomal Circular and Long Noncoding RNAs in Gastrointestinal Cancers.

Circular RNAs (circRNAs) and long noncoding RNAs (lncRNAs) are differentially expressed in gastrointestinal cancers. These noncoding RNAs (ncRNAs) regulate a variety of cellular activities by physically interacting with microRNAs and proteins and altering their activity. It has also been suggested that exosomes encapsulate circRNAs and lncRNAs in cancer cells. Exosomes are then discharged into the extracellular environment, where they are taken up by other cells. As a result, exosomal ncRNA cargo is critical for cell-cell communication within the cancer microenvironment. Exosomal ncRNAs can regulate a range of events, such as angiogenesis, metastasis, immune evasion, drug resistance, and epithelial-to-mesenchymal transition. To set the groundwork for developing novel therapeutic strategies against gastrointestinal malignancies, a thorough understanding of circRNAs and lncRNAs is required. In this review, we discuss the function and intrinsic features of oncogenic circRNAs and lncRNAs that are enriched within exosomes.

The Role of Noncoding RNAs in the Regulation of Anoikis and Anchorage-Independent Growth in Cancer.

Cancer is a global health concern, and the prognosis of patients with cancer is associated with metastasis. Multistep processes are involved in cancer metastasis. Accumulating evidence has shown that cancer cells acquire the capacity of anoikis resistance and anchorage-independent cell growth, which are critical prerequisite features of metastatic cancer cells. Multiple cellular factors and events, such as apoptosis, survival factors, cell cycle, EMT, stemness, autophagy, and integrins influence the anoikis resistance and anchorage-independent cell growth in cancer. Noncoding RNAs (ncRNAs), such as microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), are dysregulated in cancer. They regulate cellular signaling pathways and events, eventually contributing to cancer aggressiveness. This review presents the role of miRNAs and lncRNAs in modulating anoikis resistance and anchorage-independent cell growth. We also discuss the feasibility of ncRNA-based therapy and the natural features of ncRNAs that need to be contemplated for more beneficial therapeutic strategies against cancer.

The Hypoxia-Long Noncoding RNA Interaction in Solid Cancers.

Hypoxia is one of the representative microenvironment features in cancer and is considered to be associated with the dismal prognosis of patients. Hypoxia-driven cellular pathways are largely regulated by hypoxia-inducible factors (HIFs) and notably exert influence on the hallmarks of cancer, such as stemness, angiogenesis, invasion, metastasis, and the resistance towards apoptotic cell death and therapeutic resistance; therefore, hypoxia has been considered as a potential hurdle for cancer therapy. Growing evidence has demonstrated that long noncoding RNAs (lncRNAs) are dysregulated in cancer and take part in gene regulatory networks owing to their various modes of action through interacting with proteins and microRNAs. In this review, we focus attention on the relationship between hypoxia/HIFs and lncRNAs, in company with the possibility of lncRNAs as candidate molecules for controlling cancer.

Anti-Cancer Activity of Phytochemicals Targeting Hypoxia-Inducible Factor-1 Alpha.

Hypoxia-inducible factor-1 alpha (HIF-1α) is overexpressed in cancer, leading to a poor prognosis in patients. Diverse cellular factors are able to regulate HIF-1α expression in hypoxia and even in non-hypoxic conditions, affecting its progression and malignant characteristics by regulating the expression of the HIF-1α target genes that are involved in cell survival, angiogenesis, metabolism, therapeutic resistance, et cetera. Numerous studies have exhibited the anti-cancer effect of HIF-1α inhibition itself and the augmentation of anti-cancer treatment efficacy by interfering with HIF-1α-mediated signaling. The anti-cancer effect of plant-derived phytochemicals has been evaluated, and they have been found to possess significant therapeutic potentials against numerous cancer types. A better understanding of phytochemicals is indispensable for establishing advanced strategies for cancer therapy. This article reviews the anti-cancer effect of phytochemicals in connection with HIF-1α regulation.

Participation of MicroRNAs in the Treatment of Cancer with Phytochemicals.

Cancer is a global health concern and one of the main causes of disease-related death. Even with considerable progress in investigations on cancer therapy, effective anti-cancer agents and regimens have thus far been insufficient. There has been compelling evidence that natural phytochemicals and their derivatives have potent anti-cancer activities. Plant-based anti-cancer agents, such as etoposide, irinotecan, paclitaxel, and vincristine, are currently being applied in medical treatments for patients with cancer. Further, the efficacy of plenty of phytochemicals has been evaluated to discover a promising candidate for cancer therapy. For developing more effective cancer therapy, it is required to apprehend the molecular mechanism deployed by natural compounds. MicroRNAs (miRNAs) have been realized to play a pivotal role in regulating cellular signaling pathways, affecting the efficacy of therapeutic agents in cancer. This review presents a feature of phytochemicals with anti-cancer activity, focusing mainly on the relationship between phytochemicals and miRNAs, with insights into the role of miRNAs as the mediators and the regulators of anti-cancer effects of phytochemicals.

Testosterone depletion increases the susceptibility of brain tissue to oxidative damage in a restraint stress mouse model.

Among sex hormones, estrogen is particularly well known to act as neuroprotective agent. Unlike estrogen, testosterone has not been well investigated in regard to its effects on the brain, especially under psychological stress. To investigate the role of testosterone in oxidative brain injuries under psychological stress, we adapted an orchiectomy and restraint stress model. BALB/c mice were subjected to either an orchiectomy or sham operation. After allowing 15 days for recovery, mice were re-divided into four groups according to exposure of restraint stress: sham, sham plus stress, orchiectomy, and orchiectomy plus stress. Serum testosterone was undetectable in orchiectomized groups and restraint-induced stress significantly reduced testosterone levels in sham plus stress group. The serum levels of corticosterone and adrenaline were notably elevated by restraint stress, and these elevated hormones were markedly augmented by orchiectomy. Two oxidative stressors and biomarkers for lipid and protein peroxidation were significantly increased in the cerebral cortex and hippocampus by restraint stress, while the reverse pattern was observed in antioxidant enzymes. These results were supported by histopathological findings, with 4-hydroxynonenal staining for oxidative injury and Fluoro-Jade B staining showing the degenerating neurons. The aforementioned patterns of oxidative injury were accelerated by orchiectomy. These findings strongly suggest the conclusion that testosterone exerts a protective effect against oxidative brain damage, especially under stressed conditions. Unlike estrogen, the effects of testosterone on the brain have not been thoroughly investigated. In order to investigate the role of testosterone in oxidative brain injuries under psychological stress, we adapted an orchiectomy and restraint stress model. Orchiectomy markedly augmented the restraint stress-induced elevation of serum corticosterone and adrenaline levels as well as oxidative alterations in brain tissues, especially in the hippocampus. These findings are the first evidence that testosterone depletion makes the brain prone to oxidative injury.

Etoposide-induced MicroRNA-205-5p Suppresses Proliferation and Migration by Targeting ERBB4 in MCF-7 Cells.

BACKGROUND/AIM: Patients with breast cancer frequently encounter a dismal prognosis due to the lack of effective and curative therapies. MicroRNAs (miRNAs) are aberrantly regulated in many types of cancer and have been recognized to play crucial roles in cancer progression. We performed a preclinical investigation of the anti-cancer effect of etoposide and microRNA-205-5p (miRNA-205-5p) and their relationship in MCF-7 cells. MATERIALS AND METHODS: Two cell culture systems, namely monolayers and spheroids, were employed for evaluating the effect of etoposide and miRNA-205-5p on cell proliferation and migration. Real time quantitative polymerase chain reaction was used for the measurement of mRNA and miRNA levels. Luciferase and western blot assays were utilized for the validation of the target gene of miRNA-205-5p. RESULTS: Treatment with etoposide, suppressed both cell proliferation and migration in MCF-7 monolayers. Also, the growth of MCF-7 spheroids as demonstrated by size measurements was inhibited by etoposide treatment. Furthermore, etoposide was found to upregulate the level of miRNA-205-5p. Over-expression of miRNA-205-5p inhibits cell proliferation and migration by directly targeting Erb-B2 receptor tyrosine kinase 4 (ERBB4). CONCLUSION: miRNA-205-5p may act as an important mediator of the anti-cancer effect of etoposide and miRNA-205-5p-based therapy may expand the therapeutic opportunities for breast cancer.

Noncoding RNAs Associated with Therapeutic Resistance in Pancreatic Cancer.

Therapeutic resistance is an inevitable impediment towards effective cancer therapies. Evidence accumulated has shown that the signaling pathways and related factors are fundamentally responsible for therapeutic resistance via regulating diverse cellular events, such as epithelial-to-mesenchymal transition (EMT), stemness, cell survival/apoptosis, autophagy, etcetera. Noncoding RNAs (ncRNAs) have been identified as essential cellular components in gene regulation. The expression of ncRNAs is altered in cancer, and dysregulated ncRNAs participate in gene regulatory networks in pathological contexts. An in-depth understanding of molecular mechanisms underlying the modulation of therapeutic resistance is required to refine therapeutic benefits. This review presents an overview of the recent evidence concerning the role of human ncRNAs in therapeutic resistance, together with the feasibility of ncRNAs as therapeutic targets in pancreatic cancer.

Luteolin-regulated MicroRNA-301-3p Targets Caspase-8 and Modulates TRAIL Sensitivity in PANC-1 Cells.

BACKGROUND/AIM: MicroRNAs (miRNAs) play regulatory roles in pancreatic ductal adenocarcinoma (PDAC). However, it is still required to identify the function of miRNA-301-3p in pancreatic cancer cells. MATERIALS AND METHODS: Effects of luteolin on cell growth, TRAIL cytotoxicity, and miR-301-3p levels were evaluated. The role of miRNA-301-3p in regulating cell proliferation, target gene expression, and TRAIL cytotoxicity were studied. RESULTS: The levels of miR-301-3p were down-regulated in PANC-1 cells exposed to luteolin, which inhibits the growth of PANC-1 cells and sensitizes cells to TRAIL. The knockdown of miR-301-3p attenuates cell proliferation and enhances TRAIL cytotoxicity. In addition, caspase-8 was directly targeted by miR-301-3p. CONCLUSION: Our findings unveil a critical biological function of miR-301-3p in regulating cell proliferation and elevating an antiproliferative effect of TRAIL on cancer cells. Our observation of miR-301-3p/caspase-8 relationship can also serve to clarify the role of miR-301-3p in other cancer types and related diseases.

Extracellular Vesicles (EVs) and Pancreatic Cancer: From the Role of EVs to the Interference with EV-Mediated Reciprocal Communication.

Pancreatic cancer is malignant and the seventh leading cause of cancer-related deaths worldwide. However, chemotherapy and radiotherapy are-at most-moderately effective, indicating the need for new and different kinds of therapies to manage this disease. It has been proposed that the biologic properties of pancreatic cancer cells are finely tuned by the dynamic microenvironment, which includes extracellular matrix, cancer-associated cells, and diverse immune cells. Accumulating evidence has demonstrated that extracellular vesicles (EVs) play an essential role in communication between heterogeneous subpopulations of cells by transmitting multiplex biomolecules. EV-mediated cell-cell communication ultimately contributes to several aspects of pancreatic cancer, such as growth, angiogenesis, metastasis and therapeutic resistance. In this review, we discuss the role of extracellular vesicles and their cargo molecules in pancreatic cancer. We also present the feasibility of the inhibition of extracellular biosynthesis and their itinerary (release and uptake) for a new attractive therapeutic strategy against pancreatic cancer.

Isolation and antifungal activity of lignans from Myristica fragrans against various plant pathogenic fungi.

BACKGROUND: In a search for plant extracts with potent in vivo antifungal activity against various plant diseases, we found that treatment with a methanol extract of Myristica fragrans Houttyn (nutmeg) seeds reduced the development of various plant diseases. The objectives of the present study were to isolate and determine antifungal substances from My. fragrans and to evaluate their antifungal activities. RESULTS: Three antifungal lignans were isolated from the methanol extract of My. fragrans seeds and identified as erythro-austrobailignan-6 (EA6), meso-dihydroguaiaretic acid (MDA) and nectandrin-B (NB). In vitro antimicrobial activity of the three lignans varied according to compound and target species. Alternaria alternata, Colletotrichum coccodes, C. gloeosporioides, Magnaporthe grisea, Agrobacterium tumefaciens, Acidovorax konjaci and Burkholderia glumae were relatively sensitive to the three lignans. In vivo, all three compounds effectively suppressed the development of rice blast and wheat leaf rust. In addition, EA6 and NB were highly active against the development of barley powdery mildew and tomato late blight, respectively. Both MDA and NB also moderately inhibited the development of rice sheath blight. CONCLUSION: This is the first study to demonstrate the in vitro and in vivo antifungal activities of the three lignans from My. fragrans against plant pathogenic fungi.

Anti-melanoma activity of Cynanchi atrati Radix is mediated by regulation of NF-kappa B activity and pro-apoptotic proteins.

ETHNOPHARMACOLOGICAL RELEVANCE: Cynanchi atrati Radix has been traditionally prescribed for patients with inflammatory fever or chronic tumoral disorders. Melanoma is one of the most devastating cancer types, in which overexpression of nuclear factor kappa B (NF-κB) enables the cancer to survive without apoptosis. To identify a potential anti-melanoma candidate, we evaluated the apoptotic activity of an ethanol extract of Cynanchi atrati Radix (CAE) on melanoma and its underlying mechanisms. MATERIALS AND METHODS: Sixty C57BL/6N mice with melanoma were orally administrated CAE (100 or 200mg/kg) or distilled water for 10 days. Survival, tumor weight and volume were monitored and measured. Intratumoral apoptotic change was measured using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining. To confirm the pro-apoptotic activity of CAE (10, 50 or 100µg/mL) compared to positive drug (10µg/mL of IKK-2 inhibitor IV), cell proliferation, caspase-3/7 activity, flow cytometric analysis, TUNEL and DAPI staining, immunoblotting and gene expression analyses for apoptosis-associated genes were conducted using B16F10 cell line. RESULTS: CAE administration remarkably improved survivability with a significant reduction in tumor weight (p<0.01) and volume (p<0.01), as well as increased apoptotic bodies in melanoma tissue. The CAE treatment significantly inhibited proliferation of B16F10 cells (p<0.001), but increased caspase-3/7 activity (p<0.01 or 0.001) and apoptotic population. The CAE partially blocked nuclear translocation of NF-κB but activated the p53-associated apoptotic pathway. CONCLUSION: These results indicate that the CAE has anti-melanoma potential, and the underlying mechanisms involve inhibition of the activities of NF-κB and its target proteins as well as promoting the activities of pro-apoptotic proteins.

Ethanol extract of Astragali Radix and Salviae Miltiorrhizae Radix, Myelophil, exerts anti-amnesic effect in a mouse model of scopolamine-induced memory deficits.

ETHNOPHARMACOLOGICAL RELEVANCE: Myelophil, a combination of extracts taken from Astragali Radix and Salviae Miltiorrhizae Radix, is a traditional Chinese medicine used for the treatment of chronic fatigue-associated disorders. Here we examined the ability of Myelophil to alleviate memory impairment in a mouse model. We aimed to investigate whether Myelophil has the pharmacological effects on memory deficits associated with brain dysfunctions using an animal model. MATERIALS AND METHODS: Ten week-old male C57BL/6N mice were pretreated with Myelophil (50, 100, or 200 mg/kg), or tacrine (10 mg/kg) for 7 days, and then intraperitoneally injected with scopolamine (1 mg/kg). Memory-related behaviors were evaluated using the Morris water maze for 5 days. Levels of biomarkers of oxidative stress, antioxidant activity, acetylcholinesterase (AChE) activity, and extracellular signal-regulated kinase (ERK) were measured in brain tissues. RESULTS: Scopolamine treatment increased the escape latency time and shortened time spent in the target quadrant; these effects were ameliorated by pretreatment with Myelophil. Scopolamine-induced changes in reactive oxygen species (ROS), malondialehyde (MDA), and AChE activity were significantly attenuated in mice pretreated with Myelophil. Recovery of antioxidant capacities, including total glutathione (GSH) content, and the activities of GSH-reductase, GSH-S-transferase, and catalase was also evident in Myelophil-treated mice. The strongest effects were seen for ERK and muscarinic acetylcholine receptor 1 (mAChR1) at both the protein and gene expression levels, with significant amelioration of expression levels in the Myelophil pretreatment group. CONCLUSIONS: These results suggest that Myelophil confers anti-amnesic properties in a mouse model of memory impairment, driven in part by the modulation of cholinergic activity.

Artemisia capillaris extract protects against bile duct ligation-induced liver fibrosis in rats.

Artemisia capillaris has been widely used as a traditional herbal medicine in the treatment of liver diseases. However, no previous study has investigated whether A. capillaries alone is effective in treating pathological conditions associated with cholestatic liver injury. In the present study, we evaluated the anti-hepatofibrotic effects of A. capillaris (aqueous extract, WAC) in a bile duct ligation (BDL)-induced cholestatic fibrosis model. After BDL, rats were given WAC (25 or 50 mg/kg) or urosodeoxycholic acid (UDCA, 25 mg/kg) orally for 2 weeks (once per day). The serum cholestatic markers, malondialdehyde, and liver hydroxyproline levels were drastically increased in the BDL group, while administering WAC significantly reduced these alterations. Administering WAC also restored the BDL-induced depletion of glutathione content and glutathione peroxidase activity. Cholestatic liver injury and collagen deposition were markedly attenuated by WAC treatment, and these changes were paralleled by the significantly suppressed expression of fibrogenic factors, including hepatic alpha-smooth muscle actin (α-SMA), platelet-derived growth factor (PDGF), and transforming growth factor beta (TGF-ß). The beneficial effects of WAC administration are associated with antifibrotic properties via both upregulation of antioxidant activities and downregulation of ECM protein production in the rat BDL model.

CGX, a multiple herbal drug, improves cholestatic liver fibrosis in a bile duct ligation-induced rat model.

ETHNOPHARMACOLOGIC RELEVANCE: CGX is a modification of a traditional herbal medicine that has been used for various liver disorders as a meaning of "cleaning the liver". The cholestatic liver disorders become prevalent. BACK GROUND AND AIM: This study aimed to investigate the anti-hepatic fibrosis effects of CGX and its underlying mechanisms in a rat model of bile duct ligation (BDL). MATERIALS AND METHODS: BDL was conducted in SD rats except shame operation group. The rats were orally administrated with distilled water, CGX (25 or 50 mg/kg) or ursodeoxycholic acid (UDCA, 25 mg/kg) for two weeks. The pharmaceutical effects and mechanisms were analyzed in histopathology, biochemistry, oxidative stress/antioxidant biomarkers and hepatic fibrogenic cytokines levels. RESULTS: BDL markedly elevated white blood cell (WBC) counts as well as changed subset proportions such as increased neutrophils and decreased lymphocytes in peripheral blood. BDL drastically elevated the serum levels of aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), total bilirubin, and hepatic tissue levels of hydroxyproline and malondialdehyde (MDA), while it reduced the total glutathione (GSH) content and the activities of GSH-redox system enzymes such as GSH-peroxidase, GSH-reductase and GSH-S-transferase. These alterations were significantly attenuated by CGX treatment (mainly 50 mg/kg). CGX treatment normalized both the accumulation of collagen in hepatic tissue and the increased levels of profibrogenic cytokine including transforming growth factor-ß1 (TGF-ß1) and platelet-derived growth factor-BB (PDGF-BB). Moreover, CGX treatment enhanced interferon-gamma (IFN-γ) expression compare to the BDL group at the protein and gene level. CONCLUSION: These results suggest that CGX exerts anti-hepatofibrotic effect in rat BDL model, and the responsible mechanisms involve the inhibition of hepatic fibrogenic cytokines and oxidative stress.

Myelophil attenuates brain oxidative damage by modulating the hypothalamus-pituitary-adrenal (HPA) axis in a chronic cold-stress mouse model.

ETHNOPHARMACOLOGICAL RELEVANCE: Myelophil is composed of Astragali Radix and Salviae Miltiorrhizae Radix, according to the long traditional pharmacological practices, and it has been used for patients with chronic fatigue-associated symptoms including concentration problem or memory loss. AIM OF THE STUDY: This study aimed to evaluate the clinical relevance of Myelophil on brain oxidative damage using a chronic cold stress mice model. MATERIAL AND METHODS: Balb/c mice were subjected to cold stress (4°C for 4h) six times per week for 2 weeks with or without oral administration of Myelophil (50, 100, or 200mg/kg), or ascorbic acid (50mg/kg). RESULTS: Chronic cold stress induced histopathological hippocampal apoptosis with drastically increased serum levels of total reactive oxygen species and nitric oxide, as well as brain lipid peroxidation levels, protein carbonyl, and caspase-3/7 activity. These alterations were significantly ameliorated by Myelophil treatment. Myelophil administration significantly recovered the depleted glutathione and its enzymes, superoxide dismutase activity, and catalase protein and gene expression levels. Serum levels of corticosterone, dopamine, and adrenaline were notably altered by chronic cold stress but were significantly ameliorated by Myelophil treatment. Myelophil also normalized alterations in tumor necrosis factor-α, interleukin (IL)-1ß, and IL-10 gene expression and protein levels. Chronic cold stress up-regulated gene expression levels of phenylethanolamine N-methyltransferase and monoamine oxidase-B, and glucocorticoid receptors in the hypothalamus and hippocampus, respectively, whereas Myelophil treatment completely normalized these levels. CONCLUSIONS: These results suggest that Myelophil has potent pharmaceutical effects against chronic cold-stress-induced brain damage by relieving oxidative stress and inflammation and regulating stress hormones in mice.

Aqueous extract of Artemisia capillaris exerts hepatoprotective action in alcohol-pyrazole-fed rat model.

ETHNOPHARMACOLOGICAL RELEVANCE: Artemisia capillaris, also called "InJin" in Korean, has been widely used to treat various hepatic disorders in traditional Oriental medicine. AIMS: The purpose of this study is to evaluate the hepatoprotective effect of Artemisia capillaris (aqueous extract, WAC) on alcoholic liver injury. MATERIALS AND METHODS: Liver injury was induced by oral administration of 30% alcohol (10 mL/kg, twice per day) plus pyrazole (PRZ, 30 mg/kg) with/without WAC (50, 100mg/kg, orally once per day) or silymarin (50mg/kg) for 10 days. The hepatoprotective effects were assessed by observing histopathological changes, hepatic transaminase enzymes, hepatic oxidation and antioxidant parameters, inflammatory cytokines, and alcohol metabolic enzymes in serum and hepatic gene expression level, respectively. RESULTS: Alcohol-PRZ treatment drastically increased the serum levels of aspartate transaminase (AST), alanine transaminase (ALT), and malondialdehyde (MDA) levels in serum and liver tissues while these changes were significantly ameliorated by WAC administration (p<0.05 or 0.01). The prominent microvesicular steatosis and mild necrosis in hepatic histopathology were induced by alcohol-PRZ treatment, but notably attenuated by WAC administration. Moreover, the alcohol-PRZ treatment-induced depletions of the antioxidant components including glutathione content, total antioxidant capacity (TAC), activities of glutathione peroxidase (GSH-Px), reductase (GSH-Rd), catalase, and superoxide dismutase (SOD) were significantly ameliorated by WAC administration (p<0.05, except GSH-Rd). These results were in accordance with the modulation of NF-E2-related factor (Nrf2) and heme oxygenase-1 (HO-1) gene expression. Alcohol-PRZ treatment increased the levels of tumor necrosis factor-alpha (TNF-α) and transforming growth factor-beta (TGF-ß) in hepatic tissues. However they were significantly normalized by WAC administration (p<0.05 or 0.01). In addition, WAC administration significantly attenuated the alterations of aldehyde dehydrogenase (ALDH) level in serum and hepatic gene expressions of ALDH and alcohol dehydrogenase (ADH). CONCLUSIONS: These results support the relevance in clinical use of Artemisia capillaris for alcohol-associated hepatic disorders. The underlying mechanisms may involve both enhancement of antioxidant activities and modulation of proinflammatory cytokines.

Myelophil ameliorates brain oxidative stress in mice subjected to restraint stress.

We evaluated the pharmacological effects of Myelophil, a 30% ethanol extract of a mix of Astragali Radix and Salviae Radix, on oxidative stress-induced brain damage in mice caused by restraint stress. C57BL/6 male mice (eight weeks old) underwent daily oral administration of distilled water, Myelophil (25, 50, or 100mg/kg), or ascorbic acid (100mg/kg) 1h before induction of restraint stress, which involved 3h of immobilization per day for 21days. Nitric oxide levels, lipid peroxidation, activities of antioxidant enzymes (superoxide dismutase, catalase, and glutathione redox system enzymes), and concentrations of adrenaline, corticosterone, and interferon-γ, were measured in brain tissues and/or sera. Restraint stress-induced increases in nitric oxide levels (serum and brain tissues) and lipid peroxidation (brain tissues) were significantly attenuated by Myelophil treatment. Restraint stress moderately lowered total antioxidant capacity, catalase activity, glutathione content, and the activities of glutathione reductase, glutathione peroxidase, and glutathione S-transferase; all these responses were reversed by Myelophil. Myelophil significantly attenuated the elevated serum concentrations of adrenaline and corticosterone and restored serum and brain interferon-γ levels. Moreover, Myelophil normalized expression of the genes encoding monoamine oxidase A, catechol-O-methyltransferase, and phenylethanolamine N-methyltransferase, which was up-regulated by restraint stress in brain tissues. These results suggest that Myelophil has pharmacological properties protects brain tissues against stress-associated oxidative stress damage, perhaps in part through regulation of stress hormones.

Aqueous extract of Artemisia iwayomogi Kitamura attenuates cholestatic liver fibrosis in a rat model of bile duct ligation.

Cholestatic liver fibrosis, characterized by excessive accumulation of extracellular matrix (ECM) proteins, is associated with bile acid-induced oxidative stress and lipid peroxidation. We evaluated the therapeutic or protective effect of an aqueous extract of Artemisia iwayomogi Kitamura (WAI) in a rat bile duct ligation (BDL)-induced hepatic fibrogenesis model. After BDL, rats were treated once daily with 25 or 50 mg/kg of WAI for 2weeks. The serum bilirubin, aspartate transaminase, alanine transaminase, malondialdehyde, and liver hydroxyproline levels were drastically increased in the BDL group. WAI administration significantly reduced these markers and restored BDL-induced depletion of glutathione content and glutathione peroxidase activity. Cholestatic liver injury and collagen deposition were markedly attenuated by WAI treatment, and these changes were paralleled by significantly suppressed gene and protein expression of fibrogenic factors, including hepatic alphasmooth muscle actin, platelet-derived growth factor, and transforming growth factor ß. Our data suggest that WAI may have antifibrotic properties via both improvement of antioxidant activities and inhibition of ECM protein production in the rat model of BDL.