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HemoHIM is a standardized medicinal herbal preparation consisting of extracts of Angelica gigas Nakai, Cnidium officinale Makino, and Paeonia lactiflora Pallas that possesses immune regulatory activities. This study aimed to research the potential antioxidant effects of HemoHIM and its capacity for reducing fatigue in aged mice subjected to forced exercise. After administering HemoHIM 125 (500 mg/kg orally) for 4 weeks in 8-month-old female C57BL/6 mice (4 groups of 10 mice), various parameters were evaluated. The analyses revealed that HemoHIM enhanced swimming time and grip strength. In addition, it significantly reduced serum lactate levels and increased liver glutathione peroxidase (GPx) levels after exercise challenge. The expression levels of antioxidant enzymes and factors, including nuclear factor erythroid 2-related factor-2 (Nrf-2), heme oxygenase 1, superoxide dismutase, GPx, and glutathione reductase, were significantly higher in liver and muscle tissues of mice treated with HemoHIM. These results indicate that HemoHIM might function as an anti-fatigue and antioxidant agent by modulating the Nrf-2 signaling pathway.

Ethnopharmacological Relevance: Zanthoxylum piperitum has been used as a traditional Asian medicine to treat hypertension, stroke, bruise and muscle pain. It has been known to induce detoxification; affect anti-bacterial, anti-oxidant, and tyrosinase activity; inhibit osteosarcoma proliferation; anti-osteoarthritis inflammation. In this study, we aim to identify the therapeutic effect of Z. piperitum 90% EtOH extract (ZPE-LR) on rheumatoid arthritis., Material and Methods: We investigated the anti-rheumatoid arthritis and -immunomodulatory activities of the ZPE-LR in collagen-induced arthritic (CIA) mice, a rheumatoid arthritis animal model. In order to assess the analgesic effects of ZPE-LR in vivo, acetic acid injection, formaldehyde injection, hot plate model was used. The mechanism for anti-inflammatory activity of ZPE-LR was identified with LPS-stimulated Raw 264.7 cells., Results: Pharmacologically, oral administration of ZPE-LR into CIA mice resulted in a significant and dose-dependent decrease in clinical arthritis score and paw swelling compared to untreated negative control. Pathologic examination showed that ZPE-LR prevented morphological change in cartilage and destruction of phalanges in CIA mice. This protective effect was associated with reduced pain, inflammatory mediators such as NO, TNF-α, IL-1β, and IL-6, as well as COX-2 and iNOS expression. Furthermore, reduction of phosphor-ERK and BDNF indicates a novel rheumatoid arthritis-regulating mechanism by ZPE-LR treatment., Conclusions: These data suggest that the administration of ZPE-LR remarkably inhibited CIA progression and might be helpful in suppressing inflammation and pain in rheumatoid arthritis., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Although accumulation of amyloid β (Aβ) plaque is a major hallmark of Alzheimer's disease (AD), various pathologies have been suggested therapeutic targets. Therefore, therapies-targeting multiple pathologies would be required for effective managements of AD. Accordingly, natural products, which has multiple active ingredients, have been receiving a lot of attention. In this study, we tested whether standardized ethanol extract of leaves of Perilla frutescens var. acuta (L.) Britt. (Lamiaceae) (ELPF) could modulate various pathologies in AD using 5XFAD mice. ELPF blocked Aβ aggregation and disassembled pre-formed Aβ aggregates. ELPF blocked Aβ aggregates-induced LTP impairment and ELPF-disassembled Aβ aggregates failed to impair hippocampal LTP. Systemic administration of ELPF blocked Aβ aggregates-induced memory impairment in a passive avoidance test. ELPF-disassembled Aβ aggregates failed to impair passive avoidance memory. Prolonged administration of ELPF ameliorated memory impairments in 5XFAD mice. In the hippocampus of 5XFAD mice, ELPF administration significantly reduced Aβ deposits and neuroinflammation. These results demonstrate that ELPF could be a promising therapeutic candidate for AD., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Context: HemoHIM is an herbal preparation containing Angelica gigas Nakai (Apiaceae), Cnidium officinale Makino (Umbelliferae), and Paeonia lactiflora Pallas (Paeoniaceae) developed for immune regulation. To date, studies on the antifatigue effects of HemoHIM have not been conducted., Objective: The antifatigue effects of HemoHIM using models of citrinin and exercise-induced chronic fatigue syndrome were investigated., Materials and Methods: Citrinin-induced L6 skeletal muscle cells were treated with HemoHIM (125, 250, and 500 μg/mL). The antioxidant factors were analysed. ICR mice were divided into four groups (n = 10): control, HemoHIM 250, 500 mg/kg, and creatine 300 mg/kg, respectively. Mice were orally administered HemoHIM or creatine for three weeks; during this time, both rotarod test and forced swimming test (FST) were conducted. The latency time was investigated and antioxidant, antifatigue factors were analysed., Results: HemoHIM significantly restored reduced antioxidant enzymes (SOD, CAT, Txn, GPx, GSr, and GCLC in HemoHIM 500 μg/mL) compared to the citrinin group in L6 cells. In vivo , HemoHIM significantly improved the latency time (FST; 279.88 ± 50.32 sec, rotarod test; 552.35 ± 23.50 sec in HemoHIM 500 mg/kg). Moreover, the FST-induced reduction in glucose and glutathione significantly increased by 3-fold (HemoHIM 500 mg/kg) and increase in LDH and MDA were significantly inhibited by 1.6, 2.1-fold in the HemoHIM 500 mg/kg compared to the control group.

With the increase in human lifespan, population aging is one of the major problems worldwide. Aging is an irreversible progressive process that affects humans via multiple factors including genetic, immunity, cellular oxidation and inflammation. Progressive neuroinflammation contributes to aging, cognitive malfunction, and neurodegenerative diseases. However, precise mechanisms or drugs targeting age-related neuroinflammation and cognitive impairment remain un-elucidated. Traditional herbal plants have been prescribed in many Asian countries for anti-aging and the modulation of aging-related symptoms. In general, herbal plants' efficacy is attributed to their safety and polypharmacological potency via the systemic manipulation of the body system. Radix polygalae (RP) is a herbal plant prescribed for anti-aging and the relief of age-related symptoms; however, its active components and biological functions remained un-elucidated. In this study, an active methanol fraction of RP containing 17 RP saponins (RPS), was identified. RPS attenuates the elevated C3 complement protein in aged mice to a level comparable to the young control mice. The active RPS also restates the aging gut microbiota by enhancing beneficial bacteria and suppressing harmful bacteria. In addition, RPS treatment improve spatial reference memory in aged mice, with the attenuation of multiple molecular markers related to neuroinflammation and aging. Finally, the RPS improves the behavior and extends the lifespan of C. elegans, confirming the herbal plant's anti-aging ability. In conclusion, through the mouse and C. elegas models, we have identified the beneficial RPS that can modulate the aging process, gut microbiota diversity and rectify several aging-related phenotypes., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Cachexia causes high mortality, low quality of life, and rapid weight loss in cancer patients. Sarcopenia, a condition characterized by the loss of muscle, is generally present in cachexia and is associated with inflammation. M2 macrophages, also known as an anti-inflammatory or alternatively activated macrophages, have been shown to play a role in muscle repair. Magnoliae Cortex (M.C) is a widely used medicinal herb in East Asia reported to have a broad range of anti-inflammatory activities; however, the effects of M.C on sarcopenia and on M2 macrophage polarization have to date not been studied. This study was designed to investigate whether the oral administration of M.C could decrease cisplatin-induced sarcopenia by modulating M2 macrophage polarization in mice. C57BL/6 mice were injected intraperitoneally with cisplatin (2.5 mg/kg) to mimic chemotherapy-induced sarcopenia. M.C extract (50, 100, and 200 mg/kg) was administered orally every 3 days (for a total of 12 times). M.C (100 and 200 mg/kg) significantly alleviated the cisplatin-induced loss of body mass, skeletal muscle weight, and grip strength. In addition, M.C increased the expression of M2 macrophage markers, such as MRC1, CD163, TGF-β, and Arg-1, and decreased the expression of M1-specific markers, including NOS2 and TNF-α, in skeletal muscle. Furthermore, the levels of like growth factor-1(IGF-1), as well as the number of M2a and M2c macrophages, significantly increased in skeletal muscle after M.C administration. M.C did not interfere with the anticancer effect of cisplatin in colon cancer. Our results demonstrated that M.C can alleviate cisplatin-induced sarcopenia by increasing the number of M2 macrophages. Therefore, our findings suggest that M.C could be used as an effective therapeutic agent to reverse or prevent cisplatin-induced sarcopenia.

A total 42.68 g/L monosaccharide with 0.10 g/L HMF was obtained from 10% (w/v) Kappaphycus alvarezii with thermal acid hydrolysis using 350 mM HNO 3 at 121 °C for 60 min and enzymatic saccharification with a 1:1 mixture of Viscozyme L and Celluclast 1.5 L for 72 h. To enhance the galactose utilization rate, fermentation was performed with overexpression of GAL1 (galactokinase), GAL7 (galactose-1-phosphate uridyltransferase), GAL10 (UDP-glucose-4-epimerase), and PGM2 (phosphoglucomutase 2) in Saccharomyces cerevisiae CEN.PK2 using CCW12 as a strong promoter. Among the strains, the overexpression of PGM2 showed twofold high galactose utilization rate (UR gal ) and produced ethanol 1.4-fold more than that of the control. Transcriptional analysis revealed the increase of PGM2 transcription level leading to enhance glucose-6-phosphate and fructose-6-phosphate and plays a key role in ensuring a higher glycolytic flux in the PGM2 strain. This finding shows particular importance in biofuel production from seaweed because galactose is one of the major monosaccharides in seaweeds such as K. alvarezii.

Inflammatory macrophages stimulated by LPS disrupt homeostasis in the production of inflammatory cytokines and nitric oxide (NO). These are the causes of inflammation-related diseases and various cancers. The present study aimed to evaluate the protective effects of Korean ginseng berry extract (KGB) on lipopolysaccharide (LPS)-induced inflammation in RAW264.7 macrophage cells. NO and prostaglandin E2 (PGE[Formula: see text] production was elevated in response to LPS stimulation and was dose-dependently reduced by pretreatment with KGB. The expression levels of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) mRNA and protein were also reduced by KGB treatment. KGB treatment significantly suppressed the LPS-induced gene expression and production of cytokines, including interleukin (IL)-1[Formula: see text], IL-6, and tumor necrosis factor-[Formula: see text] (TNF-[Formula: see text]. Furthermore, KGB inhibited the translocation of nuclear expression of nuclear factor-kappa B (NF-[Formula: see text]B) by preventing inhibitory factor-kappa B (I[Formula: see text]B[Formula: see text] phosphorylation and suppressing the phosphorylation of extracellular signal-related kinase (ERK1/2), c-Jun N-terminal kinase (JNK), and p38. Additionally, decreased reactive oxygen species (ROS) generation and increased glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and catalase (CAT) activities were observed following KGB treatment. Taken together, these results indicated that KGB possesses anti-inflammatory and anti-oxidant effects, mediated by the inhibition of the mitogen-activated protein kinases (MAPKs) signaling pathway in LPS-induced RAW264.7 macrophages. KGB may represent a potential therapeutic agent for inflammatory and oxidative stress-related diseases.

Ethnopharmacological Relevance: Angelica dahurica (Hoffm.) Benth. & Hook.f. ex Franch. & Sav. (Umbelliferae family) is an herbaceous, perennial plant native to northern and eastern Asia. The root of A. dahurica has traditionally been used under the name "Bai Zhi" as a medicinal plant for colds, dizziness, ulcers, and rheumatism. Moreover, it is also an important ingredient of various prescriptions, such as Gumiganghwal-Tang, for the common cold and influenza., Aim of the Study: Even though various biological activities of the root of A. dahurica have been reported along with its chemical components, the detailed mechanism of how it exerts anti-influenza activity at the compound level has not been studied. Therefore, we investigated the anti-influenza properties of furanocoumarins purified by bioactivity-guided isolation., Materials and Methods: Bioactivity-guided isolation from a 70% EtOH extract of the root of A. dahurica was performed to produce four active furanocoumarins. The inhibition of cytopathic effects (CPEs) was evaluated to ascertain the antiviral activity of these compounds against influenza A (H1N1 and H9N2) viruses. The most potent compound was subjected to detailed mechanistic studies such as the inhibition of viral protein synthesis, CPE inhibition in different phases of the viral replication cycle, neuraminidase (NA) inhibition, antiapoptotic activity using flow cytometry, and immunofluorescence., Results: The bioactivity-guided isolation produced four active furanocoumarins, isoimperatorin (1), oxypeucedanin (2), oxypeucedanin hydrate (3) and imperatorin (4) from the n-BuOH fraction. Among them, compound 2 (followed by compounds 1, 4 and 3) showed a significant CPE inhibition effect, which was stronger than that of the positive control ribavirin, against both H1N1 and H9N2 with an EC 50 (μM) of 5.98 ± 0.71 and 4.52 ± 0.39, respectively. Compound 2 inhibited the synthesis of NA and nucleoprotein (NP) in a dose-dependent manner. In the time course assays, the cytopathic effects of influenza A-infected MDCK cells were reduced by 80-90% when treated with compound 2 for 1 and 2 h after infection and declined drastically 3 h after infection. The level of viral NA and NP production was markedly reduced to less than 20% for both proteins in compound 2 (20 μM)-treated cells compared to untreated cells at 2 h after infection. In the molecular docking analysis, compound 2 showed a stronger binding affinity for the C-terminus of polymerase acidic protein (PAC; -36.28 kcal/mol) than the other two polymerase subunits. Compound 2 also exerted an antiapoptotic effect on virus infected cells and significantly inhibited the mRNA expression of caspase-3 and Bax., Conclusion: Our results suggest that compound 2 might exert anti-influenza A activity via the inhibition of the early phase of the viral replication cycle, not direct neutralization of surface proteins, such as hemagglutinin and NA, and abnormal apoptosis induced by virus infection. Taken together, these findings suggest that furanocoumarins predominant in A. dahurica play a pivotal role in its antiviral activity. These findings can also explain the reasons for the ethnopharmacological uses of this plant as an important ingredient in many antiviral prescriptions in traditional Chinese medicine (TCM)., Competing Interests: Declaration of competing interest All authors declare that they have no conflict of interest regarding this study., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Introduction: Momordica charantia (bitter melon) is widely used for its glucose-lowering effects. This study was conducted to assess the efficacy and safety of M. charantia as an adjuvant treatment in patients with type 2 diabetes., Methods: We performed a randomized, placebo-controlled study. Blood glucose levels, lipid profile, and adverse events were investigated after 12 weeks of treatment. Ninety subjects were included in the final analysis for glucose lowering efficacy of bitter melon., Results: There were no differences in age, sex, or glycated hemoglobin (HbA1c) levels between the bitter melon extract and placebo groups. After treatment with bitter melon extract for 12 weeks, the HbA1c levels of the bitter melon and placebo groups remained unchanged; however, the average fasting glucose level of the bitter melon group decreased (p = 0.014). No serious adverse events were reported during the treatment period., Conclusions: Our data showed that bitter melon has effects of glucose lowering in patients with type 2 diabetes., (Copyright © 2020. Published by Elsevier Ltd.)

New antibacterial treatments against Helicobacter pylori are needed as H. pylori is acquiring antibiotic resistance. β-caryophyllene is a natural bicyclic sesquiterpene, with anti-inflammatory and antimicrobial effects. This study investigates the effects of H-002119-00-001 from β-caryophyllene on the eradication of H. pylori in a mouse model, and its effects on the inflammation of the gastric mucosa. To evaluate the anti- H.pylori efficacy of β-caryophyllene, a total of 160 mice were divided into eight groups ( n = 10 each) and were administered different treatments for 2 and 4 weeks. H. pylori eradication was assessed using a Campylobacter-like organism (CLO) test and H. pylori qPCR of the gastric mucosa. The levels of inflammation of gastric mucosa were assessed using histology and immunostaining. H-002119-00-001 decreased bacterial burden in vitro. When H-002119-00-001 was administered to mice once daily for 2 weeks, cure rates shown by the CLO test were 40.0%, 60.0%, and 70.0% in groups 6, 7, and 8, respectively. H. pylori levels in gastric mucosa decreased dose-dependently after H-002119-00-001 treatment. H-002119-00-001 also reduced levels of inflammation in gastric mucosa. H-002119-00-001 improved inflammation and decreased bacterial burden in H. pylori -infected mouse models. H-002119-00-001 is a promising and effective therapeutic agent for the treatment of H. pylori infection.

Blueberry fruit exhibits strong antioxidant activity owing to the presence of anthocyanin. As blueberry-leaf extract (BLE) contains chlorogenic acid and flavonol glycosides, we hypothesized that phenolic-enriched BLE would improve glucose homeostasis and insulin sensitivity. In this study, we examined whether BLE administration decreases the glucose levels and enhances the pancreatic function in mice with high-fat diet (HFD)-induced obesity and diabetes. C57BL/6J mice were divided into the following four groups: control diet (CD), HFD (60 kcal% fat diet), BLE (HFD with 1% BLE wt/wt diet), and yerba mate extract (YME; HFD with 0.5% YME wt/wt diet). Dietary BLE and YME reduced glucose tolerance, body weight, and plasma glucose, glycated hemoglobin, insulin, homeostasis model assessment of insulin resistance, triglyceride (TG), and non-esterified fatty acid levels. Compared with those of the HFD group, BLE was found to significantly reduce the pancreatic islet size and insulin content. Moreover, it increased the mRNA levels of pancreatic β-cell proliferation-related genes, Ngn3, MafA, Pax4, Ins1, and Ins2, and pancreatic insulin signaling-related genes, IRS-1, IRS-2, PIK3ca, PDK1, PKCε, and GLUT-2, and decreased the transcriptional expression of the β-cell apoptosis-related gene, FoxO1. Both BLE and YME improved insulin sensitivity by inhibiting TG synthesis and enhancing lipid utilization in the liver and white adipose tissue (WAT). In pancreatic MIN6 β-cells, BLE and its main component (chlorogenic acid) increased β-cell proliferation and promoted insulin signaling. Overall, BLE enriched with phenolic compounds has the capacity to prevent HFD-induced glucose tolerance and hyperglycemia by improving the pancreatic β-cell function., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Context: HemoHIM is a medicinal herbal preparation of Angelica gigas Nakai (Apiaceae), Cnidium officinale Makino (Umbelliferae), and Paeonia japonica Miyabe (Paeoniaceae) developed for immune regulation. HemoHIM has been investigated for its ability to enhance tissue self-renewal and stimulate immune systems. To date, studies on the protective effects of HemoHIM against gastritis and gastric ulcers have not been conducted. Objective: The protective effects of HemoHIM using models of indomethacin and ethanol/hydrochloric acid (EtOH/HCl)-induced gastric mucosal injury were investigated. Materials and methods: Rats were divided into five groups ( n  = 10): control, indomethacin, or EtOH/HCl groups, HemoHIM 250, 500 mg kg -1 , and cimetidine 100 mg kg -1 , respectively. Indomethacin (80 mg kg -1 ) and 60% EtOH/150 mM HCl were administered orally 1 h after the administration of samples and rats were anesthetized 3 h after induction. The lesion area (%), inhibition ratio (%), and total acidity were investigated, and tissues were histopathologically analyzed using hematoxylin and-eosin (H&E) staining. Results: HemoHIM significantly reduced gastric injury in indomethacin-induced model (250 and 500 mg kg -1 ; 64.30% and 67.75%, p  < 0.001) compared to indomethacin group. In the EtOH/HCl-induced model, HemoHIM reduced gastric lesion (250 and 500 mg kg -1 ; 61.05% and 73.37%, p  < 0.001) and gastric acidity (250 and 500 mg kg -1 ; 37.80 and 45.20 meq L -1 , p <  0.001) compared to EtOH/HCl group. H&E staining of the gastric mucosa showed decreased erosion and hemorrhage in HemoHIM group compared to EtOH/HCl group. Discussion and conclusions: Based on the results, HemoHIM is potential candidate for the treatment of gastritis and gastric ulcers.

Lespedeza bicolor , a traditional herbal medicine widely used in Australia, North America, and Eastern Asia, has various therapeutic effects on inflammation, nephritis, hyperpigmentation, and diuresis. In this study, to evaluate the effects of L. bicolor on cognitive function, we examined whether L. bicolor improved amyloid beta-induced memory impairment and assessed the possible mechanisms in mice. Catechin, rutin, daidzein, luteolin, naringenin, and genistein were identified in the powdered extract of L. bicolor by HPCL-DAD analyses. In behavioral experiments, L. bicolor (25 and 50 mg/kg, p. o.) significantly improved amyloid beta 25 - 35 (6 nmol, intracerebroventricular)-induced cognitive dysfunction in the Y-maze, novel recognition, and passive avoidance tests. Our molecular studies showed L. bicolor (25 and 50 mg/kg, p. o.) significantly recovered the reduced glutathione content as well as increased thiobarbituric acid reactive substance and acetylcholinesterase activities in the hippocampus. Furthermore, we found that L. bicolor significantly increased the expression of brain-derived neurotrophic factor, and phospho-Akt, extracellular signal-regulated kinase, and cAMP response element binding caused by amyloid beta 25 - 35 in the hippocampus. In conclusion, L. bicolor exerts a potent memory-enhancing effect on cognitive dysfunction induced by amyloid beta 25 - 35 in mice., Competing Interests: The authors declare that they have no conflict of interest., (Georg Thieme Verlag KG Stuttgart · New York.)

Objective: Renal ischemia/reperfusion (I/R) injury is characterized by the acute deterioration of renal function during ischemia and renal inflammation. Cassia tora has various effects, including antioxidant, antidiabetic, and hypolipidemic properties. In the present study, we investigated whether C tora has a renoprotective effect on I/R-induced acute kidney injury in rats., Methods: We fed Sprague-Dawley rats either C tora (100 mg/kg/d) or saline. One week later, ischemia was induced by bilateral renal pedicle occlusion for 30 minutes, followed by reperfusion. Rats were randomized into 3 major groups, which were treated as follows: 1. the sham operation group; 2. the I/R group; and 3. the I/R-C tora group., Results: Compared to the sham group, the I/R group had higher levels of blood urea nitrogen and serum creatinine in serum and lower expression of catalase, superoxide dismutase, glutathione peroxidase, antioxidant, and nitric oxide. Compared to the I/R group, the I/R-C tora group had higher expression of catalase, superoxide dismutase, glutathione peroxidase, antioxidant, and nitric oxide, as well as lower levels of blood urea nitrogen and creatinine in serum., Conclusions: These results suggest that C tora has significant therapeutic effects in ischemic renal injury., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Protective effects of a mixed hot water extracts of Astragalus membranaceus (AWE) and Laminaria japonica (LWE), AWE: LWE 85:15 (g/g; AL mix), were investigated against propylthiouracil (PTU)-induced hypothyroidism in rats. Rats were challenged with PTU, resulting in, increased thyroid gland weight, decreased liver weight and antioxidant activities, reduced serum tri-iodothyronine and thyroxine levels with increased thyroid stimulating hormone levels, and elevated serum aspartate aminotransferase level. However, orally administered AL mix with 100, 200, and 400 mg kg -1  day -1 , significantly inhibited such abnormalities, dose-dependently. Moreover, PTU-induced abnormal histological architecture of the rat thyroid gland and liver were also significantly ameliorated by an AL mix. The results suggested that, therapeutic use of AL mix for treating hypothyroidism can be characterized by its diversified active ingredients particularly iodine and ferulic acid as confirmed by phytochemical analyses. PRACTICAL APPLICATIONS: The AL mix has synergistic effects in modulating thyroid hormone synthesis and preventing liver damages in PTU-induced hypothyroid rats. These effects of AL mix are mainly related to its richness specifically in iodine and ferulic acid. The growing interests of iodine and ferulic acid in AL mix are principally due to their beneficial effects in releasing sufficient thyroid hormones in hypothyroid conditions and promoting liver-protective functions through its antioxidant and anti-inflammatory potentials, respectively. Moreover, the results of AL mix are well-matched with the effects of standard drug levothyroxine in the present study. Therefore, appropriate dosage of AL mix will be promising as new medicinal food for preventing thyroid dysfunctions and its related liver damages., (© 2019 Wiley Periodicals, Inc.)

Pavetta indica L. is used in traditional medicine for the treatment of various diseases including hemorrhoids, headache, urinary conditions, ulcerated nose, and dropsy. However, no study has evaluated the anticancer effect of P. indica L. In this study, we found that a methanol extract of the leaves and branches of P. indica L. (MEPI) caused cellcycle arrest at the sub-G1 phase and induced apoptosis, as indicated by the activation of caspase-8, -3, -7, and c-PARP. Western blotting revealed that MEPI significantly reduced the levels of markers of the epithelial-mesenchymal transition, such as Vimentin, Snail, Slug, and matrix metallopeptidase 9. Notably, the expression of multidrug resistance-associated protein 1 in triple negative breast cancer (TNBC) was significantly decreased by MEPI. Moreover, the co-treatment with MEPI and doxorubicin resulted in a synergistic reduction in cell viability. MEPI also induced radiation sensitization of TNBC cells. Gas chromatography-mass spectrometry analysis revealed that 5,6-dehydrokawain (DK) is the major constituent of MEPI. Interestingly, DK exerted significant anti-invasive and anti-metastatic effects. Our results provide a strong rationale for investigating the molecular mechanisms of action of MEPI in TNBC., Competing Interests: The authors declare no conflict of interest.

Chronic prostatitis typically occurs in aging men, and its symptoms include frequent and painful urination. In recent study, several studies have shown that Korean red ginseng (KRG) can be used in the prevention and treatment of various diseases. The objective of this study is to investigate whether KRG can play a role in repressing the development of chronic nonbacterial prostatitis (CNP) in male Wistar rats. To induce CNP, rats were castrated and beta-estradiol (0.25 mg/kg) was subcutaneously (s.c.) injected daily. 7-week-old male Wistar rats were divided into 5 groups (the normal group, CNP group, positive group, and KRG group (0.25g/kg) and another KRG (0.50g/kg) group. After 4 weeks, all rats were sacrificed and their prostate and serum were analyzed. Compared to the positive group, the KRG groups (0.25g/kg and 0.50g/kg) showed similar protective properties on CNP based on the histopathologic morphology of the prostate and the inflammation cytokines in the prostate tissue. Also, results of the immunohistochemistry staining showed that expression levels of vascular endothelial growth factor A (VEGFA), interleukin 6 (IL6), interleukin 1 beta (IL-1ß), tumor necrosis factor (TNF-alpha), and cytochrome c oxidase subunit II (COX2) were also decreased in KRG group (0.25g/kg) and KRG group (0.50g/kg). These results suggested that KRG inhibited the development of CNP and might a useful herbal treatment or functional food for CNP.

Drug resistance is a major problem in the treatment of non-small-cell lung cancer (NSCLC). In this study, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was performed to identify the differentially expressed genes in Adriamycin (ADR)-resistant NSCLC A549/ADR cells compared with parental A549 cells. Among the tested phytochemicals, nobiletin (NBT) is able to overcome the ADR resistance of A549/ADR cells. NBT treatment decreased the expression of a neuroblastoma-derived MYC (MYCN) and multidrug resistance-associated protein 1 (MRP1) as well as downregulating Akt, GSK3β, and β-catenin. Consistent with these results, NBT treatment resulted in the accumulation of intracellular ADR. A combination index (CI) assay confirmed the synergistic effect of combined treatment with NBT and ADR in reducing the viability of A549/ADR cells (CI = 0.152). Combined treatment with NBT and ADR enhanced apoptosis in A549/ADR cells, as evidenced by increased caspase-3 activation, poly (ADP-ribose) polymerase (PARP) cleavage, and sub-G1 population compared to treatment with ADR alone. In vivo experiments using a mouse xenograft model revealed that combination therapy with NBT and ADR significantly reduced tumor volume by 84.15%. These data suggest that NBT can sensitize ADR-induced cytotoxicity against A549/ADR cells by inhibiting MRP1 expression, indicating that NBT could serve as an effective adjuvant agent for ADR-based chemotherapy in lung cancer.

Background: Following radioiodine (RI) therapy, oxidative stress is a putative damage mechanism resulting in salivary gland (SG) dysfunction. Since ginseng is a known anti-oxidative herb, we examined the SG radioprotective effects of Korea red ginseng (KRG) in a mouse model, when administered prior to RI., Methods: Four-week-old mice (n = 60) were divided into four groups: (1) normal control, (2) RI only treated (0.01 mCi/g, orally), (3) KRG administered (0.2 mg/g, intraperitoneal injection) 0.5 and 24 hours before RI, and (4) amifostine-treated group (0.2 mg/g, intraperitoneally) 0.5 hour before RI. The salivary lag times and flow rates were assessed, and sampled tissues were subjected to histologic examinations including hematoxylin and eosin and immunohistochemical staining. Apoptosis was examined by the terminal deoxynucleotidyl transferase biotin-dUDP nick end labeling (TUNEL) assay, and excretion changes in salivary 99m Tc pertechnetate were evaluated by single-photon emission computed tomography., Results: The body weight of the KRG group was similar to the control group. Salivary lag times and flow rates in the RI + KRG group were faster than in the RI only group. There was no significant intergroup difference in the SG weight. The RI + KRG group exhibited more mucin-containing parenchyma and less fibrotic tissues than the RI only group. Salivary epithelial (aquaporin 5) and myoepithelial (smooth muscle actin) cells of the RI + KRG group were protected from radiation damage. Low 8-OhdG (oxidative stress biomarker) and high superoxide dismutase 2 (reactive oxygen species scavenger) immunostaining reactivity was detected in the RI + KRG group when compared with the RI only group. Fewer apoptotic cells were observed in the RI + KRG or amifostine group compared to the RI only group in the TUNEL assay. The 99m Tc pertechnetate excretion level recovered in the KRG group., Conclusion: Pretreatment with KRG before RI therapy is potentially beneficial in protecting against RI-induced salivary dysfunction.

Background: Vigna nakashimae (VN) extract has been shown to have antidiabetic and antiobesity effects in various animal studies; however, to our knowledge, no data on such effects exist in humans., Methods: We performed a randomized placebo-controlled study to investigate the antidiabetic effects of VN extract treatment for 12 weeks in humans. A total of 18 Korean patients with type 2 diabetes were enrolled in this study and were allocated randomly to either the VN extract group (1 g thrice daily) or control group (placebo tablets) for 12 weeks. We investigated blood glucose levels, body weight, lipid profiles, and adverse events after 12 weeks of treatment. Fifteen subjects were included in the final analysis., Results: There was no difference in age, sex, fasting glucose levels, or lipid profiles between the VN extract and control groups at baseline. However, the baseline glycosylated hemoglobin (HbA 1c ) levels of the control group were lower than those of the VN extract group. After treatment with VN extract for 12 weeks, the body weight and lipid profile of the VN extract group remained unchanged; however, the HbA 1C levels decreased by 0.36% ± 0.33% (p = 0.027). In contrast, the HbA 1C levels of the control group did not change after 12 weeks (p = 0.228). During the 12-week treatment with VN extract, no serious adverse events were reported., Conclusion: Our data indicate that VN extract has implications for glucose lowering in type 2 diabetic patients.

Stress can lead to inflammation, accelerated aging, and some chronic diseases condition. Mentha arvensis (MA) is a traditional medicine having antioxidant and anti-inflammatory activities. The present study investigated the anti-stress role of MA and fermented MA (FMA) extract in immobilized rats. We studied the lipopolysaccharide (LPS)-induced inflammation in RAW 264.7 cells and rats were immobilized for 2 h per day for 14 days using a restraining cage. MA (100 mg/kg) and FMA (100 mg/kg) were orally administered to rats 1 h prior to immobilization. Using high-performance liquid chromatography (HPLC) analysis, we determined the rosmarinic acid content of MA and FMA. The generation of malondialdehyde (MDA) and nitric oxide (NO) in RAW 246.7 cells were suppressed by both MA and FMA. In rats, MA and FMA notably improved the body weight, daily food intake, and duodenum histology. MDA and NO level were gradually decreased by MA and FMA treatment. MA and FMA significantly controlled the stress-related hormones by decreasing corticosterone and β-endorphin and increasing serotonin level. Moreover, protein expression levels of mitogen activated protein kinases (MAPK) and cyclooxygenase-2 (COX-2) were markedly downregulated by MA and FMA. Taken together, MA and FMA could ameliorate immobilized-stress by reducing oxidative stress, regulating stress-related hormones, and MAPK/COX-2 signaling pathways in rats. Particularly, FMA has shown greater anti-stress activities than MA., Competing Interests: The authors declare no conflict of interest.

Quercetin and fisetin, known as catechol-containing flavonoids, could positively affect the absorption of catechins due to their strong affinity for catechol-O-methyl transferase (COMT), which can methylate and cause the excretion of catechins. The current study examined the effect of quercetin and fisetin on the absorption of epi-catechins (ECs) by using a Caco-2 cell line and an in vivo model. The intestinal transport of total catechins by Caco-2 cells was enhanced from 1.3- to 1.6-fold and 1.4- to 1.7-fold by adding quercetin and fisetin, respectively, compared to the control. It was even higher in the treatment with a mixture of quercetin and fisetin. While EC had the highest value of intestinal transport (169% of the control) in 10% quercetin treatment, EGC (235%), EGCG (244%), and ECG (242%) were significantly transported in the treatment with a 5% mixture of quercetin and fisetin (p < 0.05). In an in vivo pharmacokinetic study, the values of the area under the plasma concentration-time curve (AUC, ng h mL -1 ) were also higher in rats orally administered EGCG with 10% quercetin (365.5 ± 25.5) or 10% fisetin (825.3 ± 46.7) than in those administered EGCG only (111.3 ± 13.1). Methylated quercetin and methylated fisetin were determined to be m/z 317.24 and m/z 301.25 [M + H] + with their own product ions, respectively. The results indicate that quercetin or fisetin is superior to ECs for methylation by COMT.

Although garlic induces apoptosis in cancer cells, it is unclear whether the effects are similar to those of cisplatin against bladder cancer (BC). Therefore, this study investigated whether garlic extracts and cisplatin show similar activity when used to treat BC. The effect of garlic on T24 BC cell line was examined in a BALB/C-nude mouse xenograft model and compared with that of cisplatin. Tissue microarray analysis and gene network analysis were performed to identify differences in gene expression by control tumors and tumors exposed to garlic extract or cisplatin. Investigation of gene expression based on tissues from 165 BC patients and normal controls was then performed to identify common targets of garlic and cisplatin. Tumor volume and tumor weight in cisplatin (0.05[Formula: see text]mg/kg)- and garlic-treated mice were significantly smaller than those in negative control mice. However, cisplatin-treated mice also showed a significant reduction in body weight. Microarray analysis of tumor tissue identified 515 common anticancer genes in the garlic and cisplatin groups ([Formula: see text]). Gene network analysis of 252 of these genes using the Cytoscape and ClueGo software packages mapped 17 genes and 9 gene ontologies to gene networks. BC (NMIBC and MIBC) patients with low expression of centromere protein M (CENPM) showed significantly better progression-free survival than those with high expression. Garlic extract shows anticancer activity in vivo similar to that of cisplatin, with no evident of side effects. Both appear to act by targeting protein-DNA complex assembly; in particular, expression of CENPM.

This study compared the efficacy of DA-9601 (Dong-A ST Co., Seoul, Korea) and its new formulation, DA-5204 (Dong-A ST Co.), for treating erosive gastritis. This phase III, randomized, multicenter, double-blind, non-inferiority trial randomly assigned 434 patients with endoscopically proven gastric mucosal erosions into two groups: DA-9601 3 times daily or DA-5,204 twice daily for 2 weeks. The final analysis included 421 patients (DA-5204, 209; DA-9601, 212). The primary endpoint (rate of effective gastric erosion healing) and secondary endpoints (cure rate of endoscopic erosion and gastrointestinal [GI] symptom relief) were assessed using endoscopy after the treatment. Drug-related adverse events (AEs), including GI symptoms, were also compared. At week 2, gastric healing rates with DA-5204 and DA-9601 were 42.1% (88/209) and 42.5% (90/212), respectively. The difference between the groups was -0.4% (95% confidence interval, -9.8% to 9.1%), which was above the non-inferiority margin of -14%. The cure rate of gastric erosion in both groups was 37.3%. The improvement rates of GI symptoms with DA-5204 and DA-9601 were 40.4% and 40.8%, respectively. There were no statistically significant differences between the two groups in both secondary endpoints. AEs were reported in 18 (8.4%) patients in the DA-5204 group and 19 (8.8%) in the DA-9601 group. Rates of AE were not different between the two groups. No serious AE or adverse drug reaction (ADR) occurred. These results demonstrate the non-inferiority of DA-5204 compared to DA-9601. DA-5204 is as effective as DA-9601 in the treatment of erosive gastritis. Registered randomized clinical trial at ClinicalTrials.gov (NCT02282670)., Competing Interests: Min-hee Oh is a biostatistician of Dong-A ST Co., but she made no influence on this work in relation with the company or its products. Other authors declare that they have no potential conflicts of interest., (© 2017 The Korean Academy of Medical Sciences.)

There is a growing interest in the use of naturally occurring agents in cancer prevention. This study investigated the garlic extract affects in bladder cancer (BC) prevention. The effect of garlic extract in cancer prevention was evaluated using the T24 BC BALB/C-nude mouse xenograft model. Microarray analysis of tissues was performed to identify differences in gene expression between garlic extract intake and control diet, and gene network analysis was performed to assess candidate mechanisms of action. Furthermore, we investigated the expression value of selected genes in the data of 165 BC patients. Compared to the control group, significant differences in tumor volume and tumor weight were observed in the groups fed 20 mg/kg (p<0.05), 200 mg/kg, and 1000 mg/kg of garlic extract (p<0.01). Genes (645) were identified as cancer prevention-related genes (fold change >2 and p<0.05) by tissue microarray analysis. A gene network analysis of 279 of these genes (p<0.01) was performed using Cytoscape/ClueGo software: 36 genes and 37 gene ontologies were mapped to gene networks. Protein kinase A (PKA) signaling pathway including AKAP12, RDX, and RAB13 genes were identified as potential mechanisms for the activity of garlic extract in cancer prevention. In BC patients, AKAP12 and RDX were decreased but, RAB13 was increased. Oral garlic extract has strong cancer prevention activity in vivo and an acceptable safety profile. PKA signaling process, especially increasing AKAP12 and RDX and decreasing RAB13, are candidate pathways that may mediate this prevention effect.

Diabetes is one of the most popular worldwide diseases, regulated by the defects in insulin secretion, insulin action, or both. The overexpression of protein tyrosine phosphatase 1B (PTP1B) was found to down-regulate the insulin-receptor activation. PTP1B has been known as a strategy for the treatment of diabetes via the regulation of insulin signal transduction pathway. Herein, we investigated the PTP1B inhibitors isolated from natural sources. The chemical investigation of Selaginella tamariscina (Beauv.) Spring revealed seven unsaturated alkynyl phenols 1-7, four new selaginellins T-W 1-4 together with three known compounds 5-7 isolated from the aerial parts. The structures of the isolates were determined by spectroscopic techniques (1D/2D-NMR, MS, and CD). The inhibitory effects of these isolates on the PTP1B enzyme activity were investigated. Among them, compounds 2-7 significantly exhibited the inhibitory effects with the IC 50 values ranging from 4.8 to 15.9μM. Compound 1 moderately displayed the inhibitory activity with an IC 50 of 57.9μM. Furthermore, active compounds were discovered from their kinetic and molecular docking analysis. The results revealed that compounds 2 and 4-7 were mixed-competitive inhibitors, whereas compound 3 was a non-competitive inhibitor. This data confirm that these compounds exhibited potential inhibitory effect on the PTP1B enzyme activity., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Korean red ginseng (Panax ginseng Meyer) is known to rejuvenate testicular effectiveness and the sperm maturation process by regulating redox proteins in aged rats. This study was performed to investigate the effect of Korean red ginseng water extract (KRG-WE) on the expression level of spermatogenesis-related key biomolecules and sex hormone receptors as well as enzymes regulating oxidation, histone deacetylation, and growth-related activities in aged rat testis. KRG-WE (200mg/kg) mixed with a regular pellet diet was administered to 12-month-old rats for 6months (KRG-AC), whereas the young (YC, 2months) and aged (AC, 12months) controls received the vehicle only. The results showed that the expression levels of spermatogenesis-related key biomolecules (inhibin-α, nectin-2, and cyclic adenosine monophosphate [cAMP] responsive element binding protein [CREB]-1), sex hormone receptors (androgen, luteinizing- and follicle-stimulating hormone receptors [AR, LHR, and FSHR, respectively]), and antioxidant enzymes (glutathione S-transferase mu [GSTm]-5, glutathione peroxidase [GPx]-4, peroxiredoxin [PRx]-3), as well as histone deactylation (silent mating type information regulation 2 homolog 1, SIRT1) and growth-related (mammalian target of rapamycin complex 1, mTORC1) molecules were significantly altered in the AC group rat testes compared with those of the YC group. However, KRG-WE treatment of the AC group significantly (p<0.05) attenuated these molecular changes. From these results, it can be concluded that long-term administration of KRG-WE significantly delayed the aging-induced testicular dysfunction., (Copyright © 2017. Published by Elsevier Inc.)

The first record of ginseng use dates back over two millennia, and ginseng is now popular in more than 35 countries. Ginsenosides are the pharmacological constituents responsible for the beneficial effects of ginseng. There is increasing evidence that ginseng and its bioactive ingredients are involved in the regulation of nuclear receptors, molecules that act in response to the specific binding of hormones, which link to a diverse array of signaling pathways, such as the ERK and PI3K/Akt pathways. Knowledge of the mechanism of how ginseng mediates these complexes is essential for the development of multi-target phytomedicine as possible therapy for different diseases. Here, we discuss the literature on the effects of ginseng and its constituents on estrogen, glucocorticoid, peroxisome proliferator-activated, and androgen nuclear hormone receptors, as well as how ginseng and its constituents exert their biological function in the treatment of cancer, obesity, and cardiovascular and neurological disorders. The accumulated results definitely show that the nuclear receptors are cellular targets of ginsenosides, but more rigorous data are required to establish and provide a scientific basis to confirm the suggested efficacy of ginseng or products with ginsenosides.

Ethnopharmacological Relevance: The plant species Taraxacum coreanum (TC), Youngia sonchifolia (YS), and Ixeris dentata (ID) belong to the family Compositae and are used for medicinal purposes in traditional medicine. However, the anticancer effects of TC, YS, and ID extracts and the underlying molecular mechanisms in melanoma cells have not been elucidated., Aim of the Study: To investigate the potential anticancer effects of TC, YS, and ID extracts on human melanoma cells and explore the potential pharmacological mechanisms in vitro and in vivo., Materials and Methods: In this comparative study, we investigated the effects of TC, YS, and ID extracts on cell proliferation in human melanoma A375P and A375SM cells using MTT[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assays. Apoptotic cells were detected by 4',6-diamidino-2-phenylinodole (DAPI) staining. We also investigated whether the growth-inhibitory effects were associated with the induction of apoptosis and whether the mechanisms of cell death were the result of signaling molecules such as p53, Bax, Bcl-2, caspase-9, Poly-ADP ribose polymerase (PARP), and Erk (Extracellular signal-regulated protein kinase) 1/2. The in vivo antitumor effects were evaluated by measuring the tumor volume and weight and performing Terminal deoxynucleotidyl transferase (TdT) dUTP Nick End Labeling (TUNEL) assay and immunohistochemistry (IHC) in tumor xenograft models., Results: TC, YS, and ID extracts effectively inhibited the growth of A375P and A375SM cells. In addition, several apoptotic events were observed following treatment, including DNA fragmentation and chromatin condensation by DAPI staining. The extracts increased p53, Bax, cleaved-caspase-9 and cleaved-PARP expression, whereas the expression of Bcl-2 was decreased in both cell lines. Furthermore, ID extract significantly inhibited the activation of Erk1/2 in both cell lines. Among the three extracts, ID had the strongest apoptotic effects. The administration of ID extract to mice inhibited tumor growth without any toxicity following 4 weeks of treatment. This extract increased the expression of apoptotic cells and p53 protein and decreased phospho-Erk1/2 protein., Conclusion: TC, YS, and ID extracts suppress the growth of human melanoma cells through apoptosis. Among these extracts, ID has the strongest anticancer and apoptotic effects. It induces apoptosis through the inhibition of Erk1/2 in A375P and A375SM human melanoma cells and in tumor xenograft models and may be a potential chemotherapeutic agent against melanoma., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objective: In order to protect against Mycobacterium tuberculosis (MTB) infection, novel drugs and new targets should be screened from the vast source of plants. We investigated the potentiality of the herbal plant of Artemisia capillaris extract (AC) against Mycobacterium tuberculosis., Design: In this study, we isolated ursolic acid and hydroquinone by bio-activity guided fractionation from the methanol extracts of AC, and tested the inhibitory effects against several strains of MTB. Anti-mycobacterial evaluation of these compounds was carried out using the MGIT™ 960 and resazurin assay. Mycobacterial morphological changes due to the treatment of these compounds were further evaluated by Transmission electron microscopy (TEM)., Results: Ursolic acid (UA) and hydroquinone (HQ) inhibited the growth of both susceptible and resistant strains of M. tuberculosis. The MIC (minimum inhibitory concentration) values of both UA and HQ were 12.5 μg/ml against the susceptible strains of M. tuberculosis. Also both UA and HQ showed 12.5-25 μg/ml of MIC values against MDR/XDR MTB strains. However, against clinical strains of MTB, UA was found sensitive against those strains that are sensitive against both INH and RFP but resistant against those strains that are resistant to INH. On the other hand HQ was sensitive against all clinical strains. TEM image-analysis of the strain H37Ra after treatment with UA revealed cell wall lysis, whereas HQ-treated cells showed deformed cytoplasmic morphology., Conclusion: All these results indicate that AC extracts containing UA and HQ possess promising chemotherapeutic potency against MTB for future use., (Copyright © 2015 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Soshiho-tang, known as Xio-hai-Hu-Tang in Chinese and Sho-Saiko-to in Japanese, has been widely used as a therapeutic agent. Its pharmacological effects include anti-inflammatory, antioxidant, antihepatic fibrosis, antitumor and immunomodulating activities. However, little is known regarding its effects on allergic asthma. Therefore, the aim of the present study was to investigate whether the Soshiho-tang water extract (SSTW) has antiasthmatic effects on airway inflammation in an ovalbumin (OVA)-induced mouse model., Methods: BALB/c mice were used as a model of asthma after induction by sensitization and challenge with OVA. We measured change in eosinophils, other inflammatory cells, and T helper 2 (Th2)-type cytokines, such as interleukin (IL)-4, IL-5, IL-13, IL-17, IL-33, and chemokine (eotaxin) in bronchoalveolar lavage fluid (BALF), presence of total and OVA-specific immunoglobulin (Ig)E in plasma, and expression of mucus production and heme oxygenase (HO)-1 protein in lung tissue., Results: Our results show that SSTW had a suppressive effect on eosinophil influx into BALF and decreased the levels of Th2-type cytokines. Moreover, SSTW exhibited a marked decrease in mucus hypersecretion, total and OVA-specific IgE levels, and significantly induced HO-1 protein expression., Conclusions: These results suggest that SSTW may be used as a valuable therapeutic agent for treating various inflammatory diseases including allergic asthma.

Distortion of intracellular oxidant and antioxidant balances appears to be a common feature that underlies in age-related male sexual impairment. Therefore regulating oxidative defense mechanisms might be an ideal approach in improving male sexual dysfunctions. In the present study, the effect of Korean red ginseng aqueous extract (KRG) on age-induced testicular dysfunction in rats was investigated. KRG (200mg/kg) mixed with regular pellet diet was administered orally for six months and the morphological, spermatogenic and antioxidant enzyme status in testis of aged rats (18months) were evaluated. Data indicated a significant change in morphology and decrease in spermatogenesis-related parameters in aged rats (AC) compared with young rats (YC). Sperm number, germ cell count, Sertoli cell count and Sertoli cell index were significantly (p<0.05) restored in KRG-treated aged rat groups (G-AC). Further the increased lipid peroxidation as measured by malondialdehyde (p<0.05), and altered enzymatic (superoxide dismutase, glutathione peroxidase, glutathione S-transferase, glutathione reductase and catalase) and non-enzymatic (reduced glutathione, ascorbic acid and α-tocopherol) antioxidants (p<0.05) were attenuated by KRG treatment in aged rats to near normal levels as in YC groups. Furthermore, proteomic analysis demonstrated differential expression of selected proteins such as phosphatidylinositol transfer protein, fatty acid binding protein-9, triosephosphate isomerase-1 and aldehyde (aldose) reductase-1in aged rats was significantly (p<0.05) protected by KRG treatment. In conclusion, long-term administration of KRG restored aging-induced testicular ineffectiveness in rats by modulating redox proteins and oxidative defense mechanisms., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The objective of this study was to optimize the slurry contents and salt concentrations for ethanol production from hydrolysates of the seaweed Eucheuma spinosum. A monosaccharide concentration of 44.2 g/l as 49.6% conversion of total carbohydrate of 89.1 g/l was obtained from 120 g dw/l seaweed slurry. Monosaccharides from E. spinosum slurry were obtained by thermal acid hydrolysis and enzymatic hydrolysis. Addition of activated carbon at 2.5% (w/v) and the adsorption time of 2 min were used in subsequent adsorption treatments to prevent the inhibitory effect of HMF. The adsorption surface area of the activated carbon powder was 1,400-1,600 m(2)/g and showed selectivity to 5-hydroxymethyl furfural (HMF) from monosaccharides. Candida tropicalis KCTC 7212 was cultured in yeast extract, peptone, glucose, and high-salt medium, and exposed to 80, 90, 100, and 110 practical salinity unit (psu) salt concentrations in the lysates. The 100 psu salt concentration showed maximum cell growth and ethanol production. The ethanol fermentations with activated carbon treatment and use of C. tropicalis acclimated to a high salt concentration of 100 psu produced 17.9 g/l of ethanol with a yield (YEtOH) of 0.40 from E. spinosum seaweed.

Background: HOX-7 is a newly developed dietary formula composed of traditional oriental herbal medicines. The formula was developed with the aim of improving weight control. We investigated the anti-obesity effect of HOX-7 on high-fat-diet (HFD)-induced obesity in C57BL/6 mice., Methods: The mice were divided into four groups and were fed a normal diet (ND), HFD, or HFD with oral administration of HOX-7 at 100 or 200 mg/kg/day for 12 weeks. Body and fat weight, histological changes of fat tissue, and the expression of key adipogenic transcription factors were investigated., Results: The body weight of mice fed the HFD with HOX-7 was significantly decreased compared to the HFD group. There were no obvious differences in weekly food intake among the 4 groups. The weight of the epididymal and total fat pads was reduced in mice fed the HFD with HOX-7. Treatment with HOX-7 also substantially attenuated the expression of key adipogenic transcription factors, including peroxisome proliferator-activated receptor γ, CCAAT/enhancer binding protein α, sterol regulatory element binding protein 1c, adipocyte P2, liver X receptor, and lipoprotein lipase in the epididymal adipose tissue., Conclusion: Overall, this study highlighted the anti-obesity effects of HOX-7, a finding that could contribute to the development of natural anti-obesity herbal medicines.

Metabolite profiling of red and white pitayas (Hylocereus polyrhizus and Hylocereus undatus) was performed using gas chromatography-time-of-flight-mass spectrometry and ultraperformance liquid chromatography-quadrupole-time-of-flight-mass spectrometry with multivariate analysis. Different species and parts of pitayas (red peel, RP; white peel, WP; red flesh, RF; and white flesh, WF) were clearly separated by partial least-squares discriminate analysis. Furthermore, betalain-related metabolites, such as betacyanins and betaxanthins, or their precursors were described on the basis of their metabolites. The results of antioxidant activity tests [1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS), and ferric reducing ability of plasma (FRAP)], total phenolic contents (TPC), total flavonoid contents (TFC), and total betacyanin contents (TBC) showed the following: RP ≥ WP > RF > WF. TPC, TFC, TBC, and betalain-related metabolites were higher in the peel than in the flesh and suggested to be the main contributors to antioxidant activity in pitayas. Therefore, peels as well as pulp of pitaya could beneficially help in the food industry.

In this study, we investigated the anti-allergic action of mulberry fruit extract (MFE) or MFE in combination with naringinase (MFEN) in IgE-activated RBL-2H3 cells, and investigated the mechanisms responsible for the anti-allergic effects of MFEN. β-hexosaminidase release assay was used to measure the amount of β-hexosaminidase released from the cells, and ELISA was used to measure the levels of tumor necrosis factor-α (TNF-α). We found that MFE significantly reduced the release of β-hexosaminidase (IC(50), 10.59 mg/ml) and TNF-α (IC(50), 4.87 mg/ml). Moreover, MFEN enhanced the inhibitory effects on the release of β-hexosaminidase (IC(50), 123.10 µg/ml) and TNF-α (IC(50), 65.01 µg/ml). Furthermore, MFEN had no cytotoxicity at the concentration range used to exert the anti-allergic effects. In addition, we evaluated the effects of MFEN on the formation of pro-inflammatory lipid mediators, such as prostaglandin D(2) (PGD(2)), leukotriene C(4) (LTC(4)) and leukotriene B(4) (LTB(4)) using enzyme immunoassay (EIA) kits. MFEN markedly reduced the formation of PGD(2) (IC(50), 6.47 µg/ml) and LTC(4) (IC(50), 0.31 µg/ml), but not LTB(4) (IC(50), 25.75 µg/ml). In mechanistic analyses, we measured the phosphorylation of Syk, Lyn and Fyn by immunoblot analysis. MFEN significantly inhibited the phosphorylation of Syk, but not that of Lyn or Fyn. MFEN also suppressed the phosphorylation of phospholipase C (PLC)γ1/2, protein kinase C (PKC)δ, linker for activation of T cells (LAT), extracellular signal-regulated protein kinase (ERK)1/2, JNK, GRB2-associated binding protein 2 (Gab2), phosphoinositide-3-kinase (PI3K), Akt, cytosolic phospholipase A2 and 5-lipoxygenase, as well as the expression of cyclooxygenase-2. In conclusion, these results suggest that MFEN exerts potent inhibitory effects on allergic response through the suppression of the activation of the FcεRI signaling cascade. Our data demonstrating the anti-allergic effects of MFEN may provide further insight into the therapeutic application of MFEN or its use as a functional food.

A Vigna nakashimae (VN) extract has been shown to have antidiabetic and anti-obesity effects. However, the mechanism underlying the effect of a VN extract on hepatic inflammation and endoplasmic reticulum (ER) stress remains unclear. In the present study, we investigated how a VN extract protects against the development of non-alcoholic fatty liver disease (NAFLD). A VN extract for 12 weeks reduced the body weight, serum metabolic parameters, cytokines, and hepatic steatosis in high-fat diet (HFD)-fed mice. A VN extract decreased HFD-induced hepatic acetyl CoA carboxylase and glucose transporter 4 expressions. In addition to the levels of high-mobility group box 1 and receptor for advanced glycation, the hepatic expression of ATF4 and caspase-3 was also reduced by a VN extract. Thus, these data indicate that a chronic VN extract prevented NAFLD through multiple mechanisms, including inflammation, ER stress, and apoptosis in the liver.

Background: Previous studies have reported the protective effects on skin elasticity of the edible marine seaweed Ecklonia cava, which acts through regulation of both antioxidative and anti-inflammatory responses., Aim: We evaluated the effect of E. cava and one of its components, dioxinodehydroeckol, on hair-shaft growth in cultured human hair follicles and on hair growth in mice., Methods: The MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was used to check cell viability of human dermal papilla cells (DPCs) and outer root sheath (ORS) cells after treatment with E. cava and its metabolite, dioxinodehydroeckol. Hair-shaft growth was measured using the in vitro hair-follicle organ-culture system, in the presence or absence of E. cava and dioxinodehydroeckol. Anagen induction activity was examined by topical application of E. cava to the dorsal skin of C57BL/6 mice. Insulin-like growth factor (IGF)-1 expression was measured by reverse transcriptase PCR and ELISA., Results: The proliferation activity was found to be highest for the ethyl acetate-soluble fraction of E. cava (EAFE) in DPCs and in ORS cells. Treatment with EAFE resulted in elongation of the hair shaft in cultured human hair follicles, and promoted transition of the hair cycle from the telogen to the anagen phase in the dorsal skin of C57BL/6 mice. In addition, EAFE induced an increase in IGF-1 expression in DPCs. Dioxinodehydroeckol, a component of E. cava, induced elongation of the hair shaft, an increase in proliferation of DPCs and ORS cells, and an increase in expression of IGF-1 in DPCs., Conclusions: These results suggest that E. cava containing dioxinodehydroeckol promotes hair growth through stimulation of DPCs and ORS cells., (© 2013 British Association of Dermatologists.)

Five new constituents, 5,4'-dihydroxy-7,3'-dimethoxyflavone-4'-O-β-D-xylopyranosyl-(2a→1b)-2a-O-β-D-xylopyranosyl-(2b→1c)-2b-O-β-D-xylopyranosyl-2c-octadecanoate (1), 5,4'-dihydroxy-7,3'-dimethoxyflavone-4'-O-α-D-xylopyranosyl-(2a→1b)-2a-O-α-D-xylopyranosyl-(2b→1c)-2b-O-α-D-xylopyranosyl-(2c→1d)-2c-O-α-D-xylopyranosyl-2d-octadecanoate (2), kaempferol-3-O-α-D-xylopyranosyl-(2a→1b)-2a-O-α-D-xylopyranosyl-(2b→1c)-2b-O-α-D-xylopyranosyl-(2c→1d)-2c-O-α-D-xylopyranosyl-2d-hexadecanoate (3), methyl salicylate-2-O-α-D-xylopyranosyl-(2a→1b)-2a-O-α-D-xylopyranosyl-(2b→1c)-2b-O-α-D-xylopyranosyl-(2c→1d)-2c-O-α-D-xylopyranosyl-(2d→1e)-2d-O-α-D-xylopyranosyl-(2e→1f)-2e-O-α-D-xylopyranosyl-(2f→1g)-2f-O-α-D-xylopyranosyl-(2g→1h)-2g-O-α-D-xylopyranosyl-2h-geranilan-8',10'-dioic acid-1'-oate (4), and oleioyl-β-D-arabinoside (5), along with eight known compounds, were isolated from a methanol extract of Oryza sativa straw. The structures of the new compounds were elucidated using one- and two-dimensional NMR spectroscopies in combination with IR, ESI/MS, and HR-ESI/FTMS. In bioassays with blue-green algae, the efficacies of the algicidal activities of the five new compounds (1-5) were evaluated at concentrations of 1, 10, and 100 mg/L. Compound 5 had the highest growth inhibition (92.6 ± 0.3%) for Microcystis aeruginosa UTEX 2388 at a concentration of 100 ppm (mg/L). Compound 5 has high potential for the ecofriendly control of weeds and algae harmful to water-logged rice.

Ethnopharmacological Relevance: The Leonuri Herba has been traditionally used for women's disease in Asian countries., Aim of the Study: The objective of the present study was to evaluate the subchronic toxicity of Leonuri Herba aqueous extract in male and female F344 rats., Material and Methods: Leonuri Herba aqueous extract was administered orally once daily at dose levels of 0, 125, 250, 500, 1000 and 2000 mg/kg/day for 13 weeks. Toxicological assessment was performed including mortality, clinical signs, body and organ weights, food consumption, ophthalmology, urinalysis, hematology, serum chemistry, gross findings and histopathologic examination., Results: There were no treatment related differences in clinical signs, urinalysis, hematology and serum chemistry, except for a histopathologic examination. The squamous cell hyperplasia in the forestomach was observed in both sexes of rats given 2000 mg/kg/day of Leonuri Herba aqueous extract., Conclusion: In conclusion, the NOAEL (No Observed Adverse Effect Level) for Leonuri Herba aqueous extract was determined as 1000 mg/kg/day in both sexes of rats under the present experimental conditions. And the acceptable daily intake value for Leonuri Herba aqueous extract was calculated to be 10mg/kg body weight per day using a safety factor of 100 to the NOAEL., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Nutritional antioxidants interact with cells in an active mode, including retrieving and sparing one another, to diminish oxidative stress. However, the intracellular balance of prooxidants and antioxidants becomes unbalanced, favoring prooxidants during the aging process. One hypothesis is that an aging-associated increase in oxidative stress is the primary cause of aging. Hence, the research hypothesis for this study is that Korean red ginseng reduces oxidative stress in vivo. Therefore, we investigated the efficacy of Korean red ginseng water extract (GWE) in reducing aging-associated oxidative stress by measuring lipid peroxidation and antioxidant levels in older rats compared with young rats. We observed a significant increase in the markers for oxidative damage (eg, lipid peroxidation) and markers for vital organ damage (eg, aspartate aminotransferase, alanine aminotransferase, urea, and creatinine levels) in aged rats. The oxidative damage was accompanied by a significant decrease in enzymatic antioxidants such as superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glutathione-S-transferase, and nonenzymatic antioxidants such as reduced glutathione, vitamin E, and vitamin C. Aged rats fed a diet supplemented with Korean red ginseng water extract had significantly less oxidative damage, possibly by enhancing the enzymatic and nonenzymatic antioxidants status. Our data suggest that consumption of Korean red ginseng reduces lipid peroxidation and restores antioxidant capacity by suppressing oxidative stress in rats., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The underlying mechanisms of the anticancer activity of the ethanolic extract of mango peel (EEMP) and its constituents were investigated. EEMP induced death of human cervical carcinoma HeLa cells through apoptosis, as evidenced by the increased cell population in the sub-G1 phase and the appearance of fragmented nuclei. Treatment of the cells with EEMP also downregulated anti-apoptotic Bcl-2 expression, resulting in the proteolytic activation of caspase-3, 7, 8, and 9 and the degradation of poly (ADP-ribose) polymerase (PARP) protein. The major components of mango peel were identified by liquid chromatography-electrospray ionisation tandem mass spectrometry and gas chromatography-mass spectrometry. Our data suggest that EEMP is an excellent source of quercetin 3-O-galactoside, mangiferin gallate, isomangiferin gallate, quercetin-3-O-arabinopyranoside, and mangiferin along with unsaturated fatty acids oleic acid, linoleic acid, and ethyl linoleate, which may help to prevent cervical cancer and may be a useful agent for the treatment of some other malignancies., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Paulownia coreana has traditionally been used as the medicine and health food in the treatment of cancer and infectious diseases. In the present study, a new antiproliferation agent, isoatriplicolide tiglate (PCAC) was isolated from the chloroform soluble fraction of the leaves of Paulownia coreana. The antiproliferation activities of PCAC plant extract was examined in breast and cervical cancer cell lines in a time-and dose-dependent manners. Our in vitro experiments showed that PCAC suppresses the cell growth and proliferation of cancer cells at a relatively low concentration (< 10 µg/mL) and induces apoptosis at a high concentration (> 50 µg/mL). Western blot analysis showed that concentration higher than 50 µg/mL induces a time-dependent increase in the percentage of apoptotic cells. In this case, PCAC uses both extrinsic and intrinsic pathways for the apoptosis. PCAC treatment decreased the expression of pro-caspase 8, 9, and 3, the main regulators of apoptotic cell death, in MDA-MB-231 cells, accompanied by the activation of caspase 8, 9, and 3. More importantly, PCAC inhibited the in vitro proliferation of six other human breast and cervical cancer cell lines. In conclusion, our data strongly suggest that PCAC acts as an antiproliferation agents particularly against breast and cervical cancers by inducing cell cycle arrest in the S/G2 phase and caspase dependent apoptosis at relatively low (< 10 μg/mL) and high (> 50 µg/mL) concentrations, respectively.

The antioxidant activity of saponins isolated from Platycodon grandiflorum (PG; Balloon flower) was determined using the total oxidant-scavenging capacity (TOSC) assay. Platycodigenin, polygalacic acid, platycodin D, platycoside E and deapioplatycoside E were isolated and their structures were characterised based on their physical and spectral properties and by comparison of these results with similar data in the literature. Platycodin D showed the greatest TOSC value against peroxyl radicals, followed (in decreasing order) by polygalacic acid, platycodigenin, deapioplatycosides E and platycoside E. Although the TOSC value of the saponins against peroxyl radicals was less than that of glutathione (GSH) and Trolox used as positive controls. However, TOSC value of platycodigenin, deapioplatycoside E, platycodin D or platycoside E against peroxynitrite was 2.35-, 1.27-, 1.02- or 0.75-fold of GSH, respectively, while polygalacic acid exhibited no scavenging capacity of peroxynitrites. These results suggest importance of the presence of hydroxyl group at carbon 24 in platycodigenin in peroxynitrite scavenging. As the number of attached sugar residues in the saponin glycosides is increased, the scavenging capacity of peroxyl radical, but not peroxynitrite was significantly decreased. These results showed that PG saponins have potent antioxidant activities, which is different according to the structure of aglycones and the number of attached sugar residues., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The intracellular levels of oxidant and antioxidant balances are gradually distorted during the aging process. An age associated elevation of oxidative stress occurring throughout the lifetime is hypothesized to be the major cause of aging. The present study was undertaken to evaluate the putative antioxidant activity of the fermented Panax ginseng extract (GINST) on lipid peroxidation and antioxidant status of major organs of aged rats compared to young rats. Increased levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea and creatinine were observed in the serum of aged rats. Increased levels of malondialdehyde (MDA) and significantly lowered activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione-S-transferase (GST) were observed in the liver, kidneys, heart and lungs of aged rats, when compared with those in young rats. Quantitative analysis of the non-enzymatic antioxidants such as reduced glutathione (GSH), ascorbic acid and α-tocopherol levels showed significantly lower values in the liver, kidneys, heart and lungs of aged rats. On the other hand, administration of the fermented Panax ginseng extract (GINST) to aged rats resulted in increased activities of SOD, CAT, GPx, GR and GST as well as elevation in GSH, ascorbic acid and α-tocopherol levels. Besides, the level of MDA, AST, ALT, urea and creatinine were reduced on administration of GINST to aged rats. These results suggested that treatment of GINST can improve the antioxidant status during aging, thereby minimizing the oxidative stress and occurrence of age-related disorders associated with free radicals., (Copyright © 2011. Published by Elsevier Inc.)

Apigenin (5,7,4'-trihydroxyflavone) is a principal ingredient of Cirsium japonicum. These experiments were performed to determine whether apigenin has neuroprotective effects against kainic acid (KA)-induced excitotoxicity in vitro and in vivo. Intraperitoneal (i.p.) administration of apigenin (25, 50 mg/kg) decreased the seizure scores induced by KA injection (40 mg/kg, i.p.) in mice. In addition, the convulsion onset time was significantly delayed by apigenin administration. Moreover, we found that apigenin blocked KA-induced seizure-form electroencephalogram (EEG) discharge activity in the brain cortex. In hippocampal cells, apigenin inhibited KA-induced excitotoxicity in a dose-dependent manner as measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. To study the possible mechanisms underlying the in vitro neuroprotective effects of apigenin against KA-induced cytotoxicity, we also examined the effect of apigenin on intracellular reactive oxygen species (ROS) elevations in cultured hippocampal neurons and found that apigenin treatment dose-dependently inhibited intracellular ROS elevation. The remarkable reduction of glutathione (GSH) levels induced by KA in hippocampal tissues was reversed by apigenin in a dose-dependent manner. In addition, similar results were obtained after pretreatment with free radical scavengers such as trolox and dimethylthiourea (DMTU). Finally, after confirming the protective effect of apigenin in hippocampal CA3 region, we found apigenin is an active compound in KA-induced neuroprotection. These results collectively indicate that apigenin alleviates KA-induced excitotoxicity by quenching ROS as well as inhibiting GSH depletion in hippocampal neurons.

Ethnopharmacological Relevance: Dioscorea japonica Thunb. has been traditionally used to treat polyuria and diabetes in Korea., Aim of the Study: We previously report the effects of Dioscorea japonica Thunb. extract on glucose control, NGF induction, and neuroprotection in a rodent diabetic model. Since the most potent fraction, DA-9801, was identified from a mixture of Dioscorea japonica Thunb. (DJ) and Dioscorea nipponica Makino (DN) following bioactivity-guided fractionation, here, we investigated the potential mechanism of the extract activity against diabetic peripheral neuropathy (DPN)., Materials and Methods: A 1:3 mixture of DJ and DN was extracted with ethanol (DA-9801) and further fractionated into an ethylacetate-soluble fraction (DA-9801E). Effects of these extracts on neurite outgrowth were measured in PC-12 cells and DRG neurons. Effects on cell viability and TrkA phosphorylation were evaluated in PC-12 cells. NGF induction effect was determined in primary Schwann cells as well as IMS32 cells (immortalized Schwann cells)., Results: No cytotoxicity was observed in PC-12 cells at the concentration below 500 μg/ml of either DA-9801 or DA-9801E. DA-9801 and DA-9801E at 100 μg/ml and 10 μg/ml, respectively, showed a significant effect on neurite outgrowth in PC-12 cells and DRG neurons in the presence of or absence a low concentration of NGF (2 ng/ml). The Trk-A phosphorylation effect of DA9801 was confirmed in PC-12 cells. An NGF induction effect of these extracts was not detected in either IMS-32 cells, or primary Schwann cells., Conclusions: The NGF agonistic activity of DA-9801 and DA-9801E was demonstrated, which may contribute to their neuroprotective effect against DPN. Studies of the detailed mechanism of these extracts as well as identification of the active components are warranted for the development of an anti-DPN drug from DJ and DN., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Ethnopharmacological Relevance: Atractylodes macrocephala Koidzumi (AMK) is an herbal medicine traditionally used for treatment of abdominal pain, gastrointestinal disease, obesity, and related complications., Aim of the Study: We investigated the effects and molecular mechanism of AMK rhizome water extract on 3T3-L1 adipogenesis and an animal model of obesity., Materials and Methods: To study the effect of AMK on adipogenesis in vitro, differentiating 3T3-L1 cells were treated every two days with AMK at various concentrations (1-25μg/ml) for eight days. Oil Red O staining was performed to determine the lipid accumulation in 3T3-L1 cells. To elucidate the inhibitory mechanism of AMK on adipogenesis, phosphorylation levels of Akt and expression of perilipin, were analyzed by Western blotting. AMK was administered orally to high fat diet (HFD)-induced obese rats to confirm its effect in vivo., Results: AMK inhibited 3T3-L1 adipocyte differentiation in a dose-dependent manner without cellular toxicity. Phospho-Akt expression was highly decreased by AMK treatment, whereas there was no significant change in perilipin expression. AMK administration significantly reduced the body weight of rats fed a HFD. Plasma triglyceride levels were significantly lower in the AMK-treated HFD group than those in the HFD control group or normal diet (ND) group, although serum total, HDL- and LDL-cholesterol levels did not differ between the groups., Conclusion: These results demonstrate an inhibitory effect of AMK on adipogenesis through reduction of an adipogenic factor, phospho-Akt. AMK had a beneficial effect, reducing body weight gain in a HFD-induced animal model of obesity., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)