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Obesity treatment efficiency can be increased by targeting both central and peripheral pathways. In a previous study, we identified two natural compounds (hispidulin and

Background Cordyceps species have been used as tonics to enhance energy, stamina, and libido in traditional Asian medicine for more than 1600 years, indicating their potential for improving reproductive hormone disorders and energy metabolic diseases. Among Cordyceps, Cordyceps militaris has been reported to prevent metabolic syndromes including obesity and benefit the reproductive hormone system, suggesting that Cordyceps militaris can also regulate obesity induced by the menopause. We investigated the effectiveness of Cordyceps militaris extraction (CME) on menopausal obesity and its mechanisms. Methods We applied an approach combining in vivo, in vitro, and in silico methods. Ovariectomized rats were administrated CME, and their body weight, area of adipocytes, liver and uterus weight, and lipid levels were measured. Next, after the exposure of MCF-7 human breast cancer cells to CME, cell proliferation and the phosphorylation of estrogen receptor and mitogen-activated protein kinases (MAPK) were measured. Finally, network pharmacological methods were applied to predict the anti-obesity mechanisms of CME. Results CME prevented overweight, fat accumulation, liver hypertrophy, and lowered triglyceride levels, some of which were improved in a dose-dependent manner. In MCF-7 cell lines, CME showed not only estrogen receptor agonistic activity through an increase in cell proliferation and the phosphorylation of estrogen receptors, but also phosphorylation of extracellular-signal-regulated kinase and p38. In the network pharmacological analysis, bioactive compounds of CME such as cordycepin, adenine, and guanosine were predicted to interact with non-overlapping genes. The targeted genes were related to the insulin signaling pathway, insulin resistance, the MARK signaling pathway, the PI3K–Akt signaling pathway, and the estrogen signaling pathway. Conclusions These results suggest that CME has anti-obesity effects in menopause and estrogenic agonistic activity. Compounds in CME have the potential to regulate obesity-related and menopause-related pathways. This study will contribute to developing the understanding of anti-obesity effects and mechanisms of Cordyceps militaris.

Cisplatin is a platinum-based chemotherapeutic agent for treating solid tumors; however, it presents a risk factor for nephropathy. In the present study, we investigated the antioxidant and anti-inflammatory effects of 3-dehydroxyceanothetric acid 2-methyl ester (3DC2ME) isolated from Ziziphus jujuba Mill. in LLC-PK1 cells following cisplatin-induced cytotoxicity. These cells were exposed to 3DC2ME for 2 h, followed by treatment with cisplatin for 24 h. The treated cells were subjected to cell viability analysis using the Ez-Cytox assay. Reactive oxygen species (ROS) were detected via 2′, 7′- dichlorodihydrofluorescein diacetate (DCFH-DA) staining. In addition, western blotting and fluorescent immunostaining were performed to evaluate protein expressions related to oxidative stress and inflammation pathways. Pretreatment with 3DC2ME protected LLC-PK1 cells from cisplatin-induced cytotoxicity and oxidative stress. In addition, pretreatment with 3DC2ME upregulated heme oxygenase 1 (HO-1) via the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in the cisplatin-treated LLC-PK1 cells. Furthermore, the increase in the expressions of IκB kinase α/β (IKKα/β), inhibitor of kappa B alpha (IκBα), nuclear factor kappa B (NF-κB), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) in these cells was inhibited. These results provide basic scientific evidence for understanding the antioxidant and anti-inflammatory effects of 3DC2ME isolated from Z. jujuba against cisplatin-induced kidney epithelial cell death.

Diarrhea is a common adverse effect of antibiotics particularly that acts on anaerobes. Moutan Radicis Cortex (MRC) is an herbal medicine used for its anti-inflammatory and antibacterial actions. The purpose of this study was to analyze the active components of MRC to determine their effect on antibiotic-associated diarrhea (AAD) and anti-inflammatory effects. Of the various components of MRC, seven compounds (gallic acid, oxypaeoniflorin, paeoniflorin, ethyl gallate, benzoic acid, benzoylpaeoniflorin, paeonol) were identified and assessed for anti-inflammation effects. Paeonol was found to effectively reduce nitric oxide production and levels of IL-6 and TNF-α in a concentration-dependent manner. Paeonol also effectively reduced the mRNA expression level of IL-6, IL-1β, and TNF-α. Western blotting analysis confirmed the reduction of COX-2 and NF-κB levels; p-p38 MAPK levels increased in the presence of a low concentration (25 μM) of paeonol but decreased in the presence of a high concentration (50 μM). In the mouse model of lincomycin-induced AAD, all experimental groups treated with paeonol (25, 50, and 100 mg/kg concentrations) showed diminished diarrhea status scores. Finally, the expression levels of TNF-α and IL-4 were reduced compared with those in the control group. Therefore, paeonol may have active compounds of MRC to alleviate the diarrhea symptoms of AAD and reduce inflammatory mediators. Other components of the MRC extract could contribute to its known anti-inflammatory and antibacterial activity and should be tested for their possible activity.

The epithelial–mesenchymal transition (EMT) of cancer cells is a crucial process in cancer cell metastasis. An Aquimarina sp. MC085 extract was found to inhibit A549 human lung cancer cell invasion, and caprolactin C (1), a new natural product, α-amino-ε-caprolactam linked to 3-methyl butanoic acid, was purified through bioactivity-guided isolation of the extract. Furthermore, its enantiomeric compound, ent-caprolactin C (2), was synthesized. Both 1 and 2 inhibited the invasion and γ-irradiation-induced migration of A549 cells. In transforming growth factor-β (TGF-β)-treated A549 cells, 2 inhibited the phosphorylation of Smad2/3 and suppressed the EMT cell marker proteins (N-cadherin, β-catenin, and vimentin), as well as the related messenger ribonucleic acid expression (N-cadherin, matrix metalloproteinase-9, Snail, and vimentin), while compound 1 did not suppress Smad2/3 phosphorylation and the expression of EMT cell markers. Therefore, compound 2 could be a potential candidate for antimetastatic agent development, because it suppresses TGF-β-induced EMT.

Fourteen azaphilone-type polyketides (

The fruits of the mulberry tree (Morus alba L.), known as white mulberry, have been consumed in various forms, including tea, beverages, and desserts, worldwide. As part of an ongoing study to discover bioactive compounds from M. alba fruits, the anti-inflammatory effect of compounds from M. alba were evaluated in lipopolysaccharide (LPS)-stimulated mouse RAW 264.7 macrophages. Phytochemical analysis of the ethanol extract of the M. alba fruits led to the isolation of 22 compounds. Among the isolated compounds, to the best of our knowledge, compounds 1, 3, 5, 7, 11, 12, and 14–22 were identified from M. alba fruits for the first time in this study. Inhibitory effects of 22 compounds on the production of the nitric oxide (NO) known as a proinflammatory mediator in LPS-stimulated RAW 264.7 macrophages were evaluated using NO assays. Western blot analysis was performed to evaluate the anti-inflammatory effects of cyclo(L-Pro-L-Val) (5). We evaluated whether the anti-inflammatory effects of cyclo(L-Pro-L-Val) (5) following LPS stimulation in RAW 264.7 macrophages occurred because of phosphorylation of IκB kinase alpha (IKKα), IκB kinase beta (IKKβ), inhibitor of kappa B alpha (IκBα), nuclear factor kappa B (NF-κB) and activations of inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). Cyclo(L-Pro-L-Val) (5) significantly suppressed phosphorylations of IKKα, IKKβ, IκBα, and NF-κB and activations of iNOS and COX-2 in a concentration-dependent manner. Taken together, these results indicate that cyclo(L-Pro-L-Val) (5) can be considered a potential therapeutic agent for the treatment of inflammation-associated disorders.

Acute kidney injury (AKI) is a common clinical problem that is associated with high mortality due to multiple complex mechanisms. Cisplatin is the most important and highly effective chemotherapeutic agent used for the treatment of various solid tumors; however, it is associated with dose-dependent adverse effects, particularly in the kidney where it can cause severe nephrotoxicity. The pathophysiological basis of cisplatin-induced nephrotoxicity has been investigated over the last few decades, and the key pathological occurrences in cisplatin nephrotoxicity include renal tubular cell injury and death. Necrostatin-1 (Nec-1) has been confirmed to act as a specific and potent small-molecule inhibitor of necroptosis. However, the effects of three structurally distinct necrostatins on cisplatin-induced nephrotoxicity remain ambiguous. The aim of this study was to determine if three types of necrostatins (Nec-1, Nec-3-A, and/or Nec-3-B) can exert protective effects in regard to the AKI induced by cisplatin. Our results indicated that necrostatins can prevent cisplatin induced nephrotoxicity via modulating apoptotic pathways through the suppression of cleaved caspase-3 and also by influencing the function of mitogen-activated protein kinase pathway members, including extracellular signal-regulated kinases, c-Jun N-terminal kinases, and p38, in the renal tubular epithelial cell line LLC-PK1. These findings suggest that necrostatins exert beneficial anti-apoptotic effects in the context of AKI induced by cisplatin.

Estrogen replacement therapy is a treatment to relieve the symptoms of menopause. Many studies suggest that natural bioactive ingredients from plants resemble estrogen in structure and biological functions and can relieve symptoms of menopause. The fruit of V. rotundifolia, called “Man HyungJa” in Korean, is a traditional medicine used to treat headache, migraine, eye pain, neuralgia, and premenstrual syndrome in Korea and China. The aim of the present study was to confirm that V. rotundifolia fruit extract (VFE) exerts biological functions similar to those of estrogen in menopausal syndrome. We investigated its in vitro effects on MCF-7 cells and in vivo estrogen-like effects on weight gain and uterine contraction in ovariectomized rats. Using the polar extract, the active constituents of VFE (artemetin, vitexicarpin, hesperidin, luteolin, vitexin, and vanillic acid) with estrogen-like activity were identified in MCF-7 cells. In animal experiments, the efficacy of VFE in ameliorating body weight gain was similar to that of estrogen, as evidenced from improvements in uterine atrophy. Vitexin and vitexicarpin are suggested as the active constituents of V. rotundifolia fruits.

Menopause, caused by decreases in estrogen production, results in symptoms such as facial flushing, vaginal atrophy, and osteoporosis. Although hormone replacement therapy is utilized to treat menopausal symptoms, it is associated with a risk of breast cancer development. We aimed to evaluate the estrogenic activities of Spartina anglica (SA) and its compounds and identify potential candidates for the treatment of estrogen reduction without the risk of breast cancer. We evaluated the estrogenic and anti-proliferative effects of extracts of SA and its compounds in MCF-7 breast cancer cells. We performed an uterotrophic assay using an immature female rat model. Among extracts of SA, belowground part (SA-bg-E50) had potent estrogenic activity. In the immature female rat model, the administration of SA-bg-E50 increased uterine weight compared with that in the normal group. Among the compounds isolated from SA, 1,3-di-O-trans-feruloyl-(-)-quinic acid (1) had significant estrogenic activity and induced phosphorylation at serine residues of estrogen receptor (ER)α. All extracts and compounds from SA did not increase MCF-7 cell proliferation. Compound 1 is expected to act as an ERα ligand and have estrogenic effects, without side effects, such as breast cancer development.

Oxidative stress leads to protein degeneration or mitochondrial dysfunction, causing neuronal cell death. Glutamate is a neurotransmitter that nerve cells use to send signals. However, the excess accumulation of glutamate can cause excitotoxicity in the central nervous system. In this study, we deciphered the molecular mechanism of catechin-mediated neuroprotective effect on glutamate-induced oxidative stress in mouse hippocampal neuronal HT22 cells. Cellular antioxidant activity was determined using the 1,1-diphenyl-picryl hydrazyl (DPPH) assay and 2′,7′-dichlorodihydrofluorescein diacetate (DCFDA) staining. Furthermore, the levels of intracellular calcium (Ca2+) as well as nuclear condensation and protein expression related to neuronal damage were assessed. All five catechins (epigallocatechin gallate, gallocatechin gallate (GCG), gallocatechin, epicatechin gallate, and epicatechin) showed strong antioxidant effects. Among them, GCG exhibited the highest neuroprotective effect against glutamate excitotoxicity and was used for further mechanistic studies. The glutamate-induced increase in intracellular Ca2+ was reduced after GCG treatment. Moreover, GCG reduced nuclear condensation and the phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinases (JNK) involved in cell death. The neuroprotective effect of GCG against glutamate-induced oxidative stress in HT22 cells was attributed to the reduction in intracellular free radicals and Ca2+ influx and also the inhibition of phosphorylation of ERK and JNK. Furthermore, the antioxidant effect of GCG was found to be likely due to the inhibition of phosphorylation of ERK and JNK that led to the effective suppression of neurocytotoxicity caused by glutamate in HT22 cells.

Phenolic compounds from natural products are considered effective enhancers of insulin secretion to prevent and treat type 2 diabetes (T2DM). The flowers of Prunus persica (L.) Batsch also contain many phenolic compounds. In this study, the extract of flowers of P. persica (PRPE) exhibited an insulin secretion effect in a glucose-stimulated insulin secretion (GSIS) assay, which led us to isolate and identify the bioactive compound(s) responsible for these effects. Compounds isolated from PRPE were screened for their efficacy in INS-1 rat pancreatic β-cells. Among them, caffeic acid (5), methyl caffeate (6), ferulic acid (7), chlorogenic acid (8), naringenin (11), nicotiflorin (12), and astragalin (13) isolated from PRPE increased GSIS without inducing cytotoxicity. Interestingly, the GSIS effect of methyl caffeate (6) as a phenolic compound was similar to gliclazide, an antidiabetic sulfonylurea drug. Western blot assay showed that methyl caffeate (6) enhanced the related signaling proteins of the activated pancreatic and duodenal homeobox-1 (PDX-1) and peroxisome proliferator-activated receptor-γ (PPAR-γ), but also the phosphorylation of the total insulin receptor substrate-2 (IRS-2), phosphatidylinositol 3-kinase (PI3K), and Akt, which influence β-cell function and insulin secretion. This study provides evidence that methyl caffeate (6) isolated from PRPE may aid in the management of T2DM.

Eight new naphtho[1,2-c]furan derivatives (1–8) along with six known analogues (9–14) were isolated from culture medium of the basidiomycete Basidioradulum radula. The structures of these compounds were identified using spectroscopic analysis, and their absolute configurations were resolved using X-ray diffraction, ECD, and VCD. Compounds 7 and 14 inhibited the cell viability of human prostate cancer DU-145 cells with IC50 values of 7.54 ± 0.03 μM and 5.04 ± 0.03 μM, respectively. At 8 μM, compounds 7 and 14 increased the percentage of apoptotic cells and upregulated the protein expression related to the apoptosis caspase pathways in DU-145 cells. Furthermore, the hallmarks of cells undergoing apoptosis, such as chromatin condensation, were also observed at this concentration. However, compound 7 and 14 showed no effect on the proliferation of splenocytes isolated from cyclophosphamide-induce immunosuppressed mice.

The aim of the present study was to examine the protective effect of &gamma, mangostin, a component of the mangosteen shell, against oxidative damage to nerve cells induced by excessive glutamate, a known excitatory neurotransmitter. To investigate the effect of &gamma, mangostin on apoptosis, 5 mM of glutamate was used to induce apoptotic cell death in mouse hippocampal HT22 cells. In this study, &gamma, mangostin was found to exert a stronger protection than N-acetyl cysteine against glutamate-induced cell damage. &gamma, Mangostin showed prevented glutamate-induced apoptosis in HT22 cells by reducing the production of reactive oxygen species and stimulating the expression of heme oxygenase-1 protein. In addition, glutamate significantly induced the accumulation of intracellular calcium ions, whereas treatment with &gamma, mangostin markedly reduced it. Hoechst 33342 staining showed an improvement in glutamate-induced nuclear condensation following &gamma, mangostin treatment. Furthermore, the number of annexin V-positive cells was significantly reduced following treatment with &gamma, mangostin. Western blot analysis showed the inhibition of glutamate-induced mitogen-activated protein kinase phosphorylation by &gamma, mangostin. &gamma, mangostin also inhibited the regulation of the intrinsic mitochondrial apoptotic pathway. Thus, the results of this study suggest that &gamma, mangostin is an active ingredient of mangosteen and exerts neuroprotective activities in HT22 cells.

Oxidative stress is one of the main causes of brain cell death in neurological disorders. The use of natural antioxidants to maintain redox homeostasis contributes to alleviating neurodegeneration. Glutamate is an excitatory neurotransmitter that plays a critical role in many brain functions. However, excessive glutamate release induces excitotoxicity and oxidative stress, leading to programmed cell death. Our study aimed to evaluate the effect of osmundacetone (OAC), isolated from Elsholtzia ciliata (Thunb.) Hylander, against glutamate-induced oxidative toxicity in HT22 hippocampal cells. The effect of OAC treatment on excess reactive oxygen species (ROS), intracellular calcium levels, chromatin condensation, apoptosis, and the expression level of oxidative stress-related proteins was evaluated. OAC showed a neuroprotective effect against glutamate toxicity at a concentration of 2 μM. By diminishing the accumulation of ROS, as well as stimulating the expression of heat shock protein 70 (HSP70) and heme oxygenase-1 (HO-1), OAC triggered the self-defense mechanism in neuronal cells. The anti-apoptotic effect of OAC was demonstrated through its inhibition of chromatin condensation, calcium accumulation, and reduction of apoptotic cells. OAC significantly suppressed the phosphorylation of mitogen-activated protein kinases (MAPKs), including c-Jun NH2-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and p38 kinases. Thus, OAC could be a potential agent for supportive treatment of neurodegenerative diseases.

Catalpa pod has been used in traditional medicine for the treatment of diabetes mellitus in South America. Studies on the constituents of Catalpa species have shown that it is rich in iridoids. In the present study, three previously undescribed compounds (2–4), including two secoiridoid derivatives along with twelve known compounds, were isolated from the fruits of Catalpa bignonioides Walt. In addition, fully assigned 13C-NMR of 5,6-dihydroxy-7,4’-dimethoxyflavone-6-O-sophoroside (1) is reported for the first time in the present study. The structures of compounds were determined on the basis of extensive spectroscopic methods, including UV, IR, 1D, and 2D NMR, mass spectroscopy, and CD spectroscopic data. All the isolated compounds were evaluated for α-glucosidase inhibitory activity. Among the tested compounds, compounds 2, 3, and 9 exhibited significant inhibitory activity against α-glucosidase enzyme assay. Meanwhile, the effect of compounds 2, 3, and 9 on glucose-stimulated insulin secretion (GSIS) was measured using pancreatic β-cells. Compounds 2, 3, and 9 exhibited non-cytotoxicity-stimulated insulin secretion in INS-1 cells. The expression levels of proteins associated with β-cell function and insulin secretion such as phosphorylation of total insulin receptor substrate-2 (IRS-2), phosphatidylinositol 3-kinase (PI3K), Akt, activated pancreatic duodenal homeobox-1 (PDX-1), and peroxisome proliferator-activated receptor-γ (PPAR-γ) were increased in INS-1 cells after treatment with compounds 2, 3, and 9. The findings of the present study could provide a scientific warrant for their application as a potential antidiabetic agent.

Noni (Morinda citrifolia L.) fruit juice has been used in Polynesia as a traditional folk medicine and is very popular worldwide as a functional food supplement. In this study, compounds present in Hawaiian Noni fruit juice, with anti-inflammatory activity in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells were identified. Five compounds were isolated using a bioassay-driven technique and phytochemical analysis of noni fruit juice: asperulosidic acid (1), rutin (2), nonioside A (3), (2E,4E,7Z)-deca-2,4,7-trienoate-2-O-β-d-glucopyranosyl-β-d-glucopyranoside (4), and tricetin (5). The structures of these five compounds were determined via NMR spectroscopy and LC/MS. In an anti-inflammatory assay, compounds 1–5 inhibited the production of nitric oxide (NO), which is a proinflammatory mediator, in LPS-stimulated macrophages. Moreover, the mechanisms underlying the anti-inflammatory effects of compounds 1–5 were investigated. Parallel to the inhibition of NO production, treatment with compounds 1–5 downregulated the expression of IKKα/β, I-κBα, and NF-κB p65 in LPS-stimulated macrophages. Furthermore, treatment with compounds 1–5 downregulated the expression of nitric oxide synthase and cyclooxygenase-2. Thus, these data demonstrated that compounds 1–5 present in noni fruit juice, exhibited potential anti-inflammatory activity; these active compounds may contribute preventively and therapeutically against inflammatory diseases.

A new phenolic glucoside, (7

Roots of Glehnia littoralis have been used to heal stroke as a traditional medicine. Even though many studies on this plant have been conducted, the secondary metabolites produced by its endophytes and their bioactivities have not been investigated thus far. Therefore, a new meroditerpenoid named sartorypyrone E (1) and eight known compounds (2-9) were isolated from extracts of cultured Neosartorya fischeri JS0553, an endophyte of G. littoralis. The isolated metabolites were identified using spectroscopic methods and chemical reaction, based on a comparison to literature data. Relative and absolute stereochemistries of compound 1 were also elucidated. To identify the protective effects of isolated compounds (1-9) in HT22 cells against glutamate-induced cytotoxicity, we assessed inhibition of cell death, intracellular reactive oxygen species (ROS) accumulation, and calcium ion (Ca2+) influx. Among the isolates, compound 8, identified as fischerin, showed significant neuroprotective activity on glutamate-mediated HT22 cell death through inhibition of ROS, Ca2+ influx, and phosphorylation of mitogen-activated protein kinase, including c-Jun N-terminal kinase, extracellular signal-regulated kinase, and p38. The results suggested that the metabolites produced by the endophyte N. fischeri JS0553 might be related to the neuroprotective activity of its host plant, G. littoralis.

Two new isochromanone derivatives, (3S,4S)-3,8-dihydroxy-6-methoxy-3,4,5-trimethylisochroman-1-one (1) and methyl (S)-8-hydroxy-6-methoxy-5-methyl-4a-(3-oxobutan-2-yl)benzoate (2), together with six known compounds (3‒8) were isolated from the cultures of an endophytic fungus Phoma sp. PF2 obtained from Artemisia princeps. The chemical structures of the isolated compounds were elucidated by interpretation of spectroscopic data (1D, 2D NMR, HRESIMS, and CD) and calculation of ECD. All the isolated compounds (1‒8) showed moderate inhibitory activities on nitric oxide levels in lipopolysaccharide-induced RAW264.7 machrophage cells.

Background The transplantation of isolated pancreatic islets is a promising treatment for diabetes. Curcumin has been used for its pharmacologic effects, such as antidiabetic and anti-inflammatory activities. Tetrahydrocurcumin (THC), one of the major metabolites of curcumin, has been reported to have antioxidant and anti-inflammatory activities. This study examines the hypothesis that preoperative THC treatment can attenuate ischemic damage and apoptosis before islet transplantation. Methods Islets isolated from Balb/c mice were randomly divided into 2 groups and cultured in medium supplemented with or without THC. In vitro islet viability and function were assessed. After treatment with a cytokine cocktail consisting of tumor necrosis factor-α, interferon-β, and interleukin-1β, islet cell viability, function, and apoptotic status were determined. Proteins related to apoptosis were analyzed using INS-1 cell after streptozocin treatment. Results There was no difference in cell viability between the 2 groups. Islets cultured in the medium supplemented with THC showed 1.3-fold higher glucose-induced insulin secretion than the islets cultured in the medium without THC. After treatment with a cytokine cocktail, glucose-induced insulin release, and NO of the islets were significantly improved in THC-treated islets compared with islets not treated with THC. Apoptosis was significantly decreased, and B-cell lymphoma-2 was elevated in the THC-treated group. The streptozocin-treated INS-1 cell produced significantly higher levels of and B-cell lymphoma-2-associated X protein, caspase-3, and caspase-9 than INS-1 treated with THC. Conclusions These results suggest that preoperative THC administration enhances islet function before transplantation and attenuates the cytokine-induced damage associated with apoptosis.

Objectives This study demonstrates the biological and chemical analysis of the mushroom Armillariella tabescens (Scop.) Sing. (Tricholomataceae). Methods Chemical structures of the isolates were determined by 1D and 2D NMR, and ESI-MS, as well as comparison with previously reported data. All isolates were tested for anti-inflammatory effects based on their ability to inhibit LPS-stimulated nitric oxide (NO) production in RAW264.7 cells. Key findings We found that the MeOH extract of the fruiting bodies of A. tabescens showed antigastritis activity against ethanol-induced gastric damage in rats and notably reduced the gastric damage index compared to control in a concentration-dependent manner. Chemical investigation of the MeOH extract led to the isolation of four steroids (1–4), three alkaloids (5–7), two nucleic acids (8–9) and four fatty acids (10–13). This is the first study to report the identification of all isolates, except for compound 7, from A. tabescens. Compounds 1, 2, 3, 4 and 10 showed inhibition on LPS-stimulated NO production. Treatment with compound 10 inhibited expression of iNOS, COX-2, phospho-IKKα, IKKα, phospho-IκBα, IκBα and NF-kappa B in LPS-stimulated RAW264.7 cells. Conclusions Compound 10 likely contributes to the health benefits of A. tabescens as an antigastritis agent through its anti-inflammatory effects.

Background Blocking the formation and invasive growth of pannus and its secretion of inflammatory cytokines and MMPs is important for treating rheumatoid arthritis. Hypothesis/Purpose Anti-arthritic activity of Aralia continentalis Kitag., an oriental herbal medicine, and the underlying mechanisms involved were investigated. Study Design Anti-inflammatory and anti-nocicpetive activities of the ethanolic extract (50% v/v) of Aralia continentalis Kitag. harvested from Imsil, Korea (ACI) were investigated in IL-1β-stimulated human fibroblast-like synoviocyte (FLS) cells and rodent models of collagen-induced polyarthritis and carrageenan-induced acute paw pain. Methods In IL-1β-stimulated FLS cells derived from rheumatoid arthritis patients, the anti-inflammatory activity of ACI was examined by analyzing the expression levels of inflammatory mediators such as TNF-α, IL-6, IL-8, MMP-1, MMP-3, MMP-13, PGE2, and COX-2 using ELISA and RT-PCR analysis. The anti-arthritic activity of ACI was investigated by measuring body weight, squeaking score, paw volume, and arthritis index in collagen-induced polyarthritis mice. The anti-nociceptive activity of ACI was examined in the paw-pressure test and Tail-flick latency test in rats. Results The ethanolic extract (50% v/v) of ACI reduced the levels of TNF-α, IL-6, IL-8, MMP-1, and MMP-13 secreted by IL-1β-stimulated FLS cells, whereas MMP-3, COX-2, and PGE2 were not significantly affected. ACI inhibited the migration of NF-κB into the nucleus through the inhibition of ERK- and JNK-dependent MAP kinase pathways in IL-1β-stimulated FLS cells. In collagen-induced polyarthritis mice, oral administration of ACI extract (200 mg/kg) significantly alleviated arthritic behaviors. Histological observations of arthritic mouse knees were consistent with their behaviors. The anti-arthritic and anti-inflammatory activities of 200 mg/kg ACI extract were comparable to those of 10 mg/kg prednisolone when administered to mice. However, ACI administration did not significantly affect carrageenan-induced hyperalgesia or thermal nociception in rats. Conclusion These results suggest that the ethanolic extract of ACI have significant anti-inflammatory and anti-arthritic effects in a rodent arthritis model and in IL-1β-stimulated FLS cells. Thus, ACI may be a useful candidate for developing pharmaceuticals or dietary supplements for the treatment of inflammatory arthritis.

Hispidulin is abundant in Arrabidaea chica, Crossostephium chinense, and Grindelia argentina, among others. p-Synephrine is the main phytochemical constituent of Citrus aurantium. It has been used in combination with various other phytochemicals to determine synergistic effects in studies involving human participants. However, there have been no reports comparing the anti-adipogenic effects of the combination of hispidulin and p-synephrine. The current study explores the anti-adipogenic effects of hispidulin alone and in combination with p-synephrine in a murine preadipocyte cell line, 3T3-L1. Co-treatment resulted in a greater inhibition of the formation of red-labeled lipid droplets than the hispidulin or p-synephrine-alone treatments. Co-treatment with hispidulin and p-synephrine also significantly inhibited adipogenic marker proteins, including Akt, mitogen-activated protein kinases, peroxisome proliferator-activated receptor gamma, CCAAT/enhancer-binding protein alpha, glucocorticoid receptor, and CCAAT/enhancer-binding protein β. Although further studies are required to assess the effects of each drug on pharmacokinetic parameters, a combination treatment with hispidulin and p-synephrine may be a potential alternative strategy for developing novel anti-obesity drugs.

Flowers of Prunus persica (L.) Batsch (Rosaceae), known as peach blossoms, have been reported to exert anti-obesity effects by improving hepatic lipid metabolism in obese mice. However, little is known regarding the anti-adipogenic effects of the phenolic compounds isolated from P. persica flowers. This study investigated the inhibitory effects of compounds extracted from P. persica flowers (PPF) on adipogenesis in 3T3-L1 murine preadipocytes using adipogenic differentiation assays. Additionally, we compared the anti-adipogenic effects of the phenolic compounds isolated from PPF, such as prunasin amide (1), amygdalin amide (2), prunasin acid (3), mandelamide (4), methyl caffeate (5), ferulic acid (6), chlorogenic acid (7), benzyl α– l -xylpyranosyl-(1 → 6)-β- d -glucopyranoside (8), prunin (9), naringenin (10), nicotiflorin (11), astragalin (12), afzelin (13), and uridine (14), on adipogenesis in 3T3-L1 murine preadipocytes. PPF and compounds 4–7 and 10 significantly inhibited adipogenesis. Among them, mandelamide (4) exhibited the maximum inhibitory activity with an IC50 of 36.04 ± 1.82 μM. Additionally, mandelamide downregulated the expression of key adipogenic markers, such as extracellular signal-regulated kinase, c-Jun-N-terminal kinase, P38, CCAAT/enhancer-binding protein α, CCAAT/enhancer-binding protein β, peroxisome proliferator activated receptor γ, and glucocorticoid receptor. These results indicate that mandelamide is an active ingredient of PPF possessing anti-obesity properties.

Glutamate is the major excitatory neurotransmitter in the central nervous system and is involved in oxidative stress during neurodegeneration. In the present study, casuarinin prevented glutamate-induced HT22 murine hippocampal neuronal cell death by inhibiting intracellular reactive oxygen species (ROS) production. Moreover, casuarinin reduced chromatin condensation and annexin-V-positive cell production induced by glutamate. We also confirmed the underlying protective mechanism of casuarinin against glutamate-induced neurotoxicity. Glutamate markedly increased the phosphorylation of extracellular signal regulated kinase (ERK)-1/2 and p38, which are crucial in oxidative stress-mediated neuronal cell death. Conversely, treatment with casuarinin diminished the phosphorylation of ERK1/2 and P38. In conclusion, the results of this study suggest that casuarinin, obtained from natural products, acts as potent neuroprotective agent by suppressing glutamate-mediated apoptosis through the inhibition of ROS production and activation of the mitogen activated protein kinase (MAPK) pathway. Thus, casuarinin can be a potential therapeutic agent in the treatment of neurodegenerative diseases.

Ethnopharmacological relevance Resin known as Resina Pini is listed in the Korean and Japanese pharmacopoeias and has been used for treating skin wounds and inflammation. Resin is composed of more than 50% abietic acid and 10% neutral substances. Objective In the present study, the wound-healing effects of abietic acid and the possible underlying mechanism of action were investigated in various in vitro and in vivo models. Materials and methods The effects of abietic acid on tube formation and migration were measured in human umbilical vein vascular endothelial cells (HUVECs). Protein expression of mitogen-activated protein kinase (MAPK) activation was evaluated via Western blotting analysis. The wound-healing effects of abietic acid were assessed using a mouse model of cutaneous wounds. Results The results showed that abietic acid enhanced cell migration and tube formation in HUVECs. Abietic acid induced significant angiogenic potential, which is associated with upregulation of extracellular signal-regulated kinase (ERK) and p38 expression. Additionally, 0.8 μM abietic acid-treated groups showed accelerated wound closure compared to the controls in a mouse model of cutaneous wounds. Conclusion The current data indicate that abietic acid treatment elevated cell migration and tube formation in HUVECs by the activation of ERK and p38 MAPKs. We suggest that abietic acid can be developed as a wound-healing agent.

Pleurotus cornucopiae (Pleurotaceae) is an edible and medicinal mushroom widely distributed in Korea, China, and Japan. The MeOH extract of the fruiting bodies of P. cornucopiae showed renoprotective effects against cisplatin-induced kidney cell damage. Chemical investigation of the MeOH extract led to the isolation and identification of 12 compounds including noransine (1), uridine (2), uracil (3), (3β, 5α, 6β, 22E, 24S) -ergosta-7, 22-diene-3, 5, 6, 9-tetrol (4), (22E,24S)-ergosta-7,22-diene-3β,5α,6β-triol (5), (22E,24R)-ergosta-8(14),22-diene-3β,5α,6β,7α-tetrol (6), cerebroside B (7), (2R) -N- [(1S, 2R, 3E, 7E) -1- [(β-d-glucopyranosyloxy) methyl] -2-hydroxy-8-methyl-3, 7-heptadecadien-1-yl] -2-hydroxy-heptadecanamide (8), cerebroside D (9), nicotinamide (10), 1,2-bis(hydroxymethyl)-4,5-dimethoxybenzene (11), and benzoic acid (12). Among them, compounds 1 and 11 were isolated as naturally occurring products for the first time, though they were reported as synthetic products in previous papers. All of the compounds (except 8 and 11) abrogated cisplatin-induced LLC-PK1 cell damage in a dose-dependent manner. Of special note, compounds 2, 5, 6, and 12 ameliorated cisplatin-induced nephrotoxicity to 80% of the control value at 10μM. The protective effects of compounds 2, 5, 6, and 12 were mediated via the deactivation of JNK-caspase 3 apoptotic cascade. This study is the first to demonstrate that the chemical constituents of P. cornucopiae display renoprotective effects against anticancer drug-induced damage in kidney cells.

Iodixanol is a non-ionic iso-osmolar contrast agent, but it is a risk factor for kidney damage and increases morbidity and mortality. In this study, we investigated the effect of 9 sesquiterpenes isolated from mugwort (Artemisia argyi) in contrast agent-induced cytotoxicity in LLC-PK1 cells. Cells were exposed to nine sesquiterpene compounds for 2 h, followed by incubation with iodixanol for 3 h. Cell viability was assessed using the Ez-Cytox assay. The level of reactive oxygen species was measured using 2′,7′-dichlorodihydrofluorescein diacetate staining. Apoptotic cell death was detected using annexin V/PI staining. In addition, immunofluorescence staining and western blotting were performed using antibodies against proteins related to apoptosis, oxidative stress, and MAPK pathways. The most effective 3-epi-iso-seco-tanapartholide (compound 8) among the 9 sesquiterpene compounds protected LLC-PK1 cells from iodixanol-induced cytotoxicity, oxidative stress, and apoptotic cell death. Pretreatment with compound 8 reversed iodixanol-induced increases in the expression of JNK, ERK, p38, Bax, caspase-3, and caspase-9. It also reversed the iodixanol-induced decrease in Bcl-2 expression. Furthermore, pretreatment with compound 8 caused nuclear translocation of Nrf2 and upregulated HO-1 via the Nrf2 pathway in iodixanol-treated LLC-PK1 cells. Thus, we demonstrated here that compound 8 isolated from A. argyi has the potential to effectively prevent iodixanol-induced kidney epithelial cell death via the caspase-3/MAPK pathways and HO-1 via the Nrf2 pathway.

Chronic exposure to cisplatin is associated with irreversible kidney impairment. In this present study, we explored the protective effects of 3-dehydroxyceanothetric acid 2-methyl ester (3DC2ME) isolated from roots of jujube (Ziziphus jujuba, Rhamnaceae) against cisplatin-induced damage in vitro. In kidney epithelial LLC-PK1 cells, western blotting and staining with specific autophagy epifluorescent dye CytoID were used to determine the molecular pathways involving autophagy. Treatment with 3DC2ME reduced the increased Cyto-ID-stained autophagic vesicles and reversed the protein expressions of 5&rsquo, AMP-activated protein kinase subunit &beta, 1 (AMPK)/mammalian target of rapamycin (mTOR)-dependent signaling pathway in cisplatin-induced cell death. Additionally, treatment with autophagy inhibitor 3-methyladenine (3-MA) and with or without 3DC2ME attenuated the cisplatin-induced apoptosis. Although further research is necessary to substantiate the effects, we evaluated the potential mechanism of action of 3DC2ME as an adjuvant for cancer patients.

Immune response is a necessary self-defense mechanism that protects the host from infectious organisms. Many medicinal plants are popularly used in Asian folk medicine to increase body resistance. An herbal formulation named KM1608 was prepared from three medicinal plants: Saussurea lappa, Terminalia chebula, and Zingiber officinale. In this study, we evaluated the immune stimulatory effect of KM1608 on RAW 264.7 murine macrophages. Network pharmacological analyses were used to predict potential immune response pathways of major compounds from KM1608. The cytotoxicity and immuno-stimulating effect of KM1608 were determined using cell viability and nitric oxide assays. The underlying mechanism of immunomodulatory activity was evaluated by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) of pro-inflammatory cytokines. The results of network pharmacological analysis suggested that major compounds from KM1608 possess anticancer potential via immune signaling pathways. After treatment with KM1608 at 25&ndash, 100 &micro, g/mL for 24 h, the level of nitric oxide was increased in the dose-dependent manner. The results of quantitative real-time PCR showed that KM1608 stimulates the expression of immune cytokines (interferon (IFN)-&alpha, -&beta, IL-1&beta, -6, IL-10, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2)) in macrophages. KM1608 extract is a potential agent for immune response enhancement.

In the central nervous system, glutamate is a major excitable neurotransmitter responsible for many cellular functions. However, excessive levels of glutamate induce neuronal cell death via oxidative stress during acute brain injuries as well as chronic neurodegenerative diseases. The present study was conducted to examine the effect of tetrahydrocurcumin (THC), a major secondary metabolite of curcumin, and its possible mechanism against glutamate-induced cell death. We prepared THC using curcumin isolated from Curcuma longa (turmeric) and demonstrated the protective effect of THC against glutamate-induced oxidative stress in HT22 cells. THC abrogated glutamate-induced HT22 cell death and showed a strong antioxidant effect. THC also significantly reduced intracellular calcium ion increased by glutamate. Additionally, THC significantly reduced the accumulation of intracellular oxidative stress induced by glutamate. Furthermore, THC significantly diminished apoptotic cell death indicated by annexin V-positive in HT22 cells. Western blot analysis indicated that the phosphorylation of mitogen-activated protein kinases including c-Jun N-terminal kinase, extracellular signal-related kinases 1/2, and p38 by glutamate was significantly diminished by treatment with THC. In conclusion, THC is a potent neuroprotectant against glutamate-induced neuronal cell death by inhibiting the accumulation of oxidative stress and phosphorylation of mitogen-activated protein kinases.

Polyacetylenic compounds isolated from Panax species are comprised of non-polar C17 compounds, exhibiting anti-inflammatory, antitumor, and antifungal activities. Panaxynol represents the major component of the essential oils of ginseng. We investigated whether panaxynol isolated from Panax vietnamensis (Vietnamese ginseng, VG) could prevent cisplatin-induced renal damage induced in vitro and in vivo. Cisplatin-induced apoptotic cell death was observed by staining with annexin V conjugated with Alexa Fluor 488, and western blotting evaluated the molecular mechanism. Panaxynol at concentrations above 0.25 μM prevented cisplatin-induced LLC-PK1 porcine renal proximal tubular cell death. LLC-PK1 cells treated with cisplatin demonstrated an increase in apoptotic cell death, whereas pretreatment with 2 and 4 μM panaxynol decreased this effect. Cisplatin demonstrated a marked increase in the phosphorylation of c-Jun N-terminal kinase (JNK), P38, and cleaved caspase-3. However, pretreatment with 2 and 4 μM panaxynol reversed the upregulated phosphorylation of JNK, P38, and the expression of cleaved caspase-3. We confirmed that the protective effect of panaxynol isolated from P. vietnamensis in LLC-PK1 cells was at least partially mediated by reducing the cisplatin-induced apoptotic damage. In the animal study, panaxynol treatment ameliorated body weight loss and blood renal function markers and downregulated the mRNA expression of inflammatory mediators.

This study was conducted to evaluate the biological activities of Pueraria lobata (PL) on menopause-related metabolic diseases and to explore the underlying mechanism of PL by network pharmacological analyses. We used ovariectomized (OVX) rats as a postmenopausal model and administered PL at different doses (50, 100, and 200 mg/kg). In OVX rats, decreased uterine weights and PPAR-&gamma, (peroxisome proliferator-activated receptor-gamma) mRNA expression in the thigh muscle were significantly recovered after PL administration. PL also significantly alleviated OVX-induced increases in total cholesterol, triglyceride, alanine aminotransferase (ALT/GPT), and aspartate aminotransferase (AST/GOT) levels. To identify the systems-level mechanism of PL, we performed network pharmacological analyses by predicting the targets of the potential bioactive compounds and their associated pathways. We identified 61 targets from four potential active compounds of PL: formononetin, beta-sitosterol, 3&rsquo, methoxydaidzein, and daidzein-4,7-diglucoside. Pathway enrichment analysis revealed that among female sex hormone-related pathways, the estrogen signaling pathways, progesterone-mediated oocyte maturation, oxytocin signaling pathways, and prolactin signaling pathways were associated with multiple targets of PL. In conclusion, we found that PL improved various indicators associated with lipid metabolism in the postmenopausal animal model, and we also identified that its therapeutic effects are exerted via multiple female sex hormone-related pathways.

In type 2 diabetes (T2D), insufficient secretion of insulin from the pancreatic β-cells contributes to high blood glucose levels, associated with metabolic dysregulation. Interest in natural products to complement or replace existing antidiabetic medications has increased. In this study, we examined the effect of Astragalus membranaceus extract (ASME) and its compounds 1–9 on glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells. ASME and compounds 1–9 isolated from A. membranaceus stimulated insulin secretion in INS-1 cells without inducing cytotoxicity. A further experiment showed that compounds 2, 3, and 5 enhanced the phosphorylation of total insulin receptor substrate-2 (IRS-2), phosphatidylinositol 3-kinase (PI3K), and Akt, and activated pancreatic and duodenal homeobox-1 (PDX-1) and peroxisome proliferator-activated receptor-γ (PPAR-γ), which are associated with β-cell function and insulin secretion. The data suggest that two isoflavonoids (2 and 3) and a nucleoside (compound 5), isolated from the roots of A. membranaceus, have the potential to improve insulin secretion in β-cells, representing the first step towards the development of potent antidiabetic drugs.

Five hybrid polyketides (1a, 1b, and 2−4) containing tetramic acid core including a new hybrid polyketide, cladosin L (1), were isolated from the marine fungus Cladosporium sphaerospermum SW67, which was isolated from the marine hydroid polyp of Hydractinia echinata. The hybrid polyketides were isolated as a pair of interconverting geometric isomers. The structure of 1 was determined based on 1D and 2D NMR spectroscopic and HR-ESIMS analyses. Its absolute configuration was established by quantum chemical electronic circular dichroism (ECD) calculations and modified Mosher’s method. Tetramic acid-containing compounds are reported to be derived from a hybrid PKS-NRPS, which was also proved by analyzing our 13C-labeling data. We investigated whether compounds 1−4 could prevent cell damage induced by cisplatin, a platinum-based anticancer drug, in LLC-PK1 cells. Co-treatment with 2 and 3 ameliorated the damage of LLC-PK1 cells induced by 25 μM of cisplatin. In particular, the effect of compound 2 at 100 μM (cell viability, 90.68 ± 0.81%) was similar to the recovered cell viability of 88.23 ± 0.25% with 500 μM N-acetylcysteine (NAC), a positive control.

Insulin plays a key role in glucose homeostasis and is hence used to treat hyperglycemia, the main characteristic of diabetes mellitus. Annulohypoxylon annulatum is an inedible ball-shaped wood-rotting fungus, and hypoxylon F is one of the major compounds of A. annulatum. The aim of this study is to evaluate the effects of hypoxylonol F isolated from A. annulatum on insulin secretion in INS-1 pancreatic β-cells and demonstrate the molecular mechanisms involved. Glucose-stimulated insulin secretion (GSIS) values were evaluated using a rat insulin ELISA kit. Moreover, the expression of proteins related to pancreatic β-cell metabolism and insulin secretion was evaluated using Western blotting. Hypoxylonol F isolated from A. annulatum was found to significantly enhance glucose-stimulated insulin secretion without inducing cytotoxicity. Additionally, hypoxylonol F enhanced insulin receptor substrate-2 (IRS-2) levels and activated the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway. Interestingly, it also modulated the expression of peroxisome proliferator-activated receptor γ (PPARγ) and pancreatic and duodenal homeobox 1 (PDX-1). Our findings showed that A. annulatum and its bioactive compounds are capable of improving insulin secretion by pancreatic β-cells. This suggests that A. annulatum can be used as a therapeutic agent to treat diabetes.

Genistein (4,5,7-trihydroxyisoflavone) is abundant in various dietary vegetables, especially soybeans, and is known to have not only an estrogenic effect but also an antiadipogenic effect. Atorvastatin (dihydroxy monocarboxylic acid) is a statin used to prevent heart disease. Although genistein and atorvastatin have been reported to possess antiadipogenic effects, their combined effects are still unclear. The aim of the current study was to explore whether the combination of genistein and atorvastatin at low concentrations significantly suppresses adipogenesis in a murine preadipocyte cell line (3T3-L1) compared to treatment with genistein or atorvastatin alone. Our results showed that cotreatment with 50 µM genistein and 50 nM atorvastatin significantly suppressed preadipocyte differentiation, whereas when each compound was used alone, there was no inhibitory effect. Additionally, cotreatment with genistein and atorvastatin significantly downregulated adipogenic marker proteins, including mitogen-activated protein kinases (MAPKs), peroxisome proliferator-activated receptor γ (PPARγ), CCAAT/enhancer-binding protein alpha (C/EBPα), glucocorticoid receptor (GR), and CCAAT/enhancer-binding protein β (C/EBPβ). This is the first evidence of the combined antiadipogenic effects of genistein and atorvastatin. Although additional experiments are required, combinational treatment with genistein and atorvastatin may be an alternative treatment for menopause-associated lipid metabolic disorders and obesity.

Tacrolimus (FK506), a calcineurin inhibitor, is an effective immunosuppressive agent mainly used to lower the risk of organ rejection after allogeneic organ transplant. However, FK506-associated adverse effects, such as nephrotoxicity, may limit its therapeutic use. In this study, we confirmed that epigallocatechin-3-gallate (EGCG), sanguiin H-6, and gallic acid increased cell survival following FK506-induced cytotoxicity in renal epithelial LLC-PK1. Among these compounds, gallic acid exerted the strongest protective effect, further confirmed in the FK506-induced nephrotoxicity rat model. Additionally, we identified supporting evidence for the nephroprotective function of gallic acid using molecular docking and bioavailability investigations.

Ethnopharmacological relevance Jawoongo is a traditional drug ointment (with a traditional botanic formula) used for the treatment of burns and wounds in Korea. One of the components of Jawoongo is Lithospermi Radix (LR, the dried root of Lithospermum erythrorhizon Siebold & Zucc., also known as Zicao or Gromwell), which contains deoxyshikonin and its derivatives. Objective The aim of the present study was to investigate the effects of deoxyshikonin on wound healing. Materials and methods The effects of LR extract and deoxyshikonin on tube formation and migration were measured in human umbilical vein vascular endothelial cells (HUVEC) and HaCaT cells, respectively. We evaluated protein expression of mitogen-activated protein kinase (MAPK) activation by Western blotting. The wound healing effects of deoxyshikonin was assessed in a mouse model of cutaneous wounds. Results The results showed that deoxyshikonin enhanced tube formation in HUVEC and migration in HaCaT cells. From the western blot analysis, we found that deoxyshikonin stimulated the phosphorylation of p38 and extracellular signal-regulated kinase (ERK) in HaCaT cells. Moreover, 20 µm deoxyshikonin-treated groups showed accelerated wound closure compared with the controls in a mouse model of cutaneous wounds. Conclusion In conclusion, the current data indicate that deoxyshikonin treatment elevated tube formation in HUVECs, and that deoxyshikonin-induced proliferation and migration in HaCaT cells were mediated by the activation of ERK and p38 MAPKs, respectively. Collectively, these data suggest that deoxyshikonin in Jawoongo must be an active compound for may be wound healing.

Cisplatin, one of the most common antitumor agents, is widely applied to treat various cancerous diseases and is included in the World Health Organization Model List of Essential Medicines. Cisplatin therapy is used to treat 10&ndash, 20% of all cancerous cases, and its cure rate is especially high in testicular cancer (over 90%). However, a major side effect of this anticancer drug is nephrotoxicity, limiting treatment effect and reducing the quality of life in cancer patients. Muscone, an odoriferous constituent of musk, was confirmed to inhibit cisplatin-induced LLC-PK1 kidney proximal tubule cell death in a dose-dependent manner. In term of renal protective mechanism, muscone inhibited cisplatin oxidative toxicity by decreasing reactive oxygen species (ROS) level and stimulating HO-1 expression. Muscone also exerted anti-inflammation effect through inhibition of p38 phosphorylation. Furthermore, muscone mitigated cisplatin-induced apoptosis in LLC-PK1 cells via both intrinsic and extrinsic pathways by inhibiting pro-apoptotic protein Bax expression, and cleaved caspase-3, 7, and 8, and increase of anti-apoptotic protein Bcl-2 level. In addition, the anti-apoptotic effect of muscone also was enhanced by preventing p53 expression and its phosphorylation. Our study showed that muscone may be a potential protective agent against cisplatin-induced nephrotoxicity.

Background Post-traumatic stress disorder (PTSD) is a disease associated with that the experience of traumatic stress. The traumatic experience results in the development of a prolonged stress response that causes impaired memory function and increased inflammation in the hippocampus. Currently, antidepressants are the only approved therapy for PTSD. However, the efficacy of antidepressants in the treatment of PTSD is marginal. The ethanol extract of Aralia continentalis (AC) is traditionally used in oriental medicine, and has been showed to possess pharmacological properties, including anti-inflammatory, anti-cancer, anti-atherosclerotic, and anti-diabetic effects. Nevertheless, the effects of AC on cognitive memory and its mechanism of action in PTSD remain unclear. Given the necessity of further treatment options for PTSD, we investigated the effect of AC on the spatial cognitive impairment caused by single prolonged stress (SPS) in a rat model of PTSD. Methods Male rats were treated with various intraperitoneal (i.p.) doses of AC for 21 consecutive days after inducing chronic stress with the SPS procedure. Results Cognitive impairment caused by SPS were inhibited after treatment with 100 mg/kg AC, as measured by the Morris water maze test and an object recognition test. Additionally, AC treatment significantly alleviated memory-related decreases in brain-derived neurotrophic factor (BDNF) mRNA and protein levels in the hippocampus. Our results suggest that AC significantly inhibited the cognitive deficits caused by SPS via increased expression of pro-inflammatory cytokines, including tumor necrosis factor-α and interleukin-6, in the rat brain. Conclusions AC reversed the behavioral impairments and inflammation triggered by SPS-derived traumatic stress and should be further evaluated as a potential therapeutic drug for PTSD.

We investigated whether 14 phenolic compounds isolated from Artemisia argyi could prevent the apoptotic damage caused by iodixanol, an iodinated contrast agent, on LLC-PK1 cells. Iodixanol was used to induce cytotoxicity in LLC-PK1 cells. Apoptotic cell death was observed as the fluorescence intensity emitted by annexin V and Hoechst 33342 stains. Western blotting was used to detect specific proteins. Seven phenolic compounds protected against iodixanol-induced LLC-PK1 cell death in a concentration-dependent manner. Among them, methyl caffeate exerted the strongest protective effect, and co-treatment with 50 and 100 μM methyl caffeate decreased intracellular reactive oxygen species elevated by 25 mg/mL iodixanol. In addition, the treatment of LLC-PK1 cells with iodixanol resulted in an increase in apoptotic cell death, which decreased by co-treatment with methyl caffeate. Iodixanol caused a cytotoxicity-related increase in the phosphorylation of extracellular-signal-regulated kinase, c-Jun N-terminal kinase, and P38; and a similar increase in the expression levels of kidney injury molecule-1 and cleaved caspase-3. However, the up-regulation of these proteins was reversed by co-treatment with methyl caffeate. These findings suggest that phenolic compounds isolated from A. argyi play an important role in protecting kidney epithelium cells against apoptotic damage caused by iodixanol.

In recent years, investigations into the biochemistry of insect-associated bacteria have increased. When combined with analytical dereplication processes, these studies provide a powerful strategy to identify structurally and/or biologically novel compounds. Non-ribosomally synthesized cyclic peptides have a broad bioactivity spectrum with high medicinal potential. Here, we report the discovery of three new cyclic tripeptides: natalenamides A&ndash, C (compounds 1&ndash, 3). These compounds were identified from the culture broth of the fungus-growing termite-associated Actinomadura sp. RB99 using a liquid chromatography (LC)/ultraviolet (UV)/mass spectrometry (MS)-based dereplication method. Chemical structures of the new compounds (1&ndash, 3) were established by analysis of comprehensive spectroscopic methods, including one-dimensional (1H and 13C) and two-dimensional (1H-1H-COSY, HSQC, HMBC) nuclear magnetic resonance spectroscopy (NMR), together with high-resolution electrospray ionization mass spectrometry (HR-ESIMS) data. The absolute configurations of the new compounds were elucidated using Marfey&rsquo, s analysis. Through several bioactivity tests for the tripeptides, we found that compound 3 exhibited significant inhibitory effects on 3-isobutyl-1-methylxanthine (IBMX)-induced melanin production. The effect of compound 3 was similar to that of kojic acid, a compound extensively used as a cosmetic material with a skin-whitening effect.

Excessive glutamate level induces neuronal death in acute brain injuries and chronic neurodegenerative diseases. Natural compounds from medicinal and food plants have been attracting interest as a treatment for neurological disorders. Sanguiin H-11 (SH-11), a hydrolysable ellagitannin, inhibits neutrophil movement and nitric oxide -production. However, its neuroprotective effect has not been studied. Therefore, the present study examined the protective effect of SH-11 from Sanguisorbae radix and its mechanism against glutamate-induced death in HT22 cells. Our results showed that SH-11 possessed a strong antioxidant activity and prevented glutamate-induced death in HT22 cells. As a strong antioxidant, SH-11 significantly reduced glutamate-induced increases in intracellular reactive oxygen species accumulation and calcium ion influx. Western blotting analysis showed that glutamate-induced phosphorylation of mitogen-activated protein kinases (MAPKs), including extracellular signal-related kinases 1/2, c-Jun N-terminal kinase, and p38, was significantly decreased by SH-11. Furthermore, SH-11 significantly decreased the number of annexin V-positive HT22 cells, which is indicating apoptotic cell death. In conclusion, our results suggested that SH-11 exerted a potent neuroprotective activity against glutamate-mediated apoptotic cell death by inhibiting oxidative stress-mediated MAPK activation.

Aucklandia lappa DC., Terminalia chebula Retz and Zingiber officinale Roscoe have been traditionally used in east Asia to treat chronic diarrhea and abdominal pain. This study aimed to evaluated the anti-inflammatory activity of KM1608, which is composed of three natural herbs in a mouse model of dextran sodium sulfate (DSS)-induced ulcerative colitis. The anti-inflammatory activity and underlying mechanism were assessed in vitro using LPS-treated RAW264.7 cells. The in vivo effect of KM1608 on DSS-induced colitis was examined after oral administration in mice. KM1608 significantly inhibited the inflammatory mediators such as nitric oxide, interleukin (IL)-6, monocyte chemotactic protein 1 (MCP-1) and tumor necrosis factor (TNF)-&alpha, in LPS-treated RAW264.7 cells. The inhibitory effect of KM1608 was attributed to the reduction of Akt phosphorylation in the LPS-treated cells. In the mouse model, oral administration of KM1608 significantly improved DSS-induced colitis symptoms, such as disease activity index (DAI), colon length, and colon weight, as well as suppressed the expression of IL-6, TNF-&alpha, and myeloperoxidase (MPO) in the DSS-induced colitis tissues. Taken together, KM1608 improved colitis through the regulation of inflammatory responses, suggesting that KM1608 has potential therapeutic use in the treatment of inflammatory diseases.

Colletotrichum sp. JS-0367 was isolated from Morus alba (mulberry), identified, and cultured on a large scale for chemical investigation. One new anthraquinone (1) and three known anthraquinones (2-4) were isolated and identified using spectroscopic methods including 1D/2D-NMR and HRESIMS. Although the neuroprotective effects of some anthraquinones have been reported, the biological activities of the four anthraquinones isolated in this study have not been reported. Therefore, the neuroprotective effects of these compounds were determined against murine hippocampal HT22 cell death induced by glutamate. Compound 4, evariquinone, showed strong protective effects against HT22 cell death induced by glutamate by the inhibition of intracellular ROS accumulation and Ca2+ influx triggered by glutamate. Immunoblot analysis revealed that compound 4 reduced the phosphorylation of MAPKs (JNK, ERK1/2, and p38) induced by glutamate. Furthermore, compound 4 strongly attenuated glutamate-mediated apoptotic cell death.

Alpha (α)-mangostin, a yellow crystalline powder with a xanthone core structure, is isolated from mangosteen (Garcinia mangostana), which is a tropical fruit of great nutritional value. The aim of the present study was to investigate the anti-diabetic effects of α-mangostin and to elucidate the molecular mechanisms underlying its effect on pancreatic beta (β)-cell dysfunction. To assess the effects of α-mangostin on insulin production, rat pancreatic INS-1 cells were treated with non-toxic doses of α-mangostin (1–10 μM) and its impact on insulin signaling was examined by Western blotting. In addition, the protective effect of α-mangostin against pancreatic β-cell apoptosis was verified by using the β-cell toxin streptozotocin (STZ). Our results showed that α-mangostin stimulated insulin secretion in INS-1 cells by activating insulin receptor (IR) and pancreatic and duodenal homeobox 1 (Pdx1) followed by phosphorylation of phospho-phosphatidylinositol-3 kinase (PI3K), Akt, and extracellular signal regulated kinase (ERK) signaling cascades, whereas it inhibited the phosphorylation of insulin receptor substrate (IRS-1) (Ser1101). Moreover, α-mangostin was found to restore the STZ-induced decrease in INS-1 cell viability in a dose-dependent manner. In addition, treatment of INS-1 cells with 50 μM STZ resulted in an increase in intracellular reactive oxygen species (ROS) levels, which was represented by the fluorescence intensity of 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA). This oxidative stress was decreased by co-treatment with 5 μM α-mangostin. Similarly, marked increases in the phosphorylation of P38, c-Jun N-terminal kinase (JNK), and cleavage of caspase-3 by STZ were decreased significantly by co-treatment with 5 μM α-mangostin. These results suggest that α-mangostin is capable of improving insulin secretion in pancreatic β-cells and protecting cells from apoptotic damage.

Panax ginseng Meyer has been used for the treatment of immune diseases and for strengthening the immune function. In this study, we evaluated the innate immune-stimulating functions and action mechanisms of white ginseng (WG) and heat-processed ginseng (HPG) in RAW264.7 cells. According to LC-MS analysis results, WG contained typical ginsenosides, such as Rb1, Rc, Rb2, Rd, and Rg1, whereas HPG contained Rg3, Rk1, and Rg5 as well as typical ginsenosides. HPG, not WG, enhanced NF-κB transcriptional activity, cytokine production (IL-6 and TNF-α), and MHC class I and II expression in RAW264.7 cells. In addition, HPG phosphorylated MAPKs and NF-kB pathways. In experiments with inhibitors, the ERK inhibitor completely suppressed the effect of HPG on IL-6 and TNF-α production. HPG-induced c-Jun activation was suppressed by an ERK inhibitor and partially suppressed by JNK, p38, and IκBα inhibitors. Collectively, these results suggested that HPG containing Rg3, Rg5, and Rk1 increased macrophage activation which was regulated by the ERK/c-Jun pathway in RAW264.7 cells.

In women, menopause refers to a series of physiological and mental symptoms of distress that result from a decrease in 17β-estradiol. In addition to the loss of fertility, the symptoms include facial flushing, depression, osteoporosis, sexual dysfunction, and genitourinary atrophy. Cirsium japonicum var. maackii is a perennial herbaceous species found in the mountains and fields of Korea, China, and Japan. The medicinal uses of C. japonicum include antioxidant, antidiabetic, antitumor, antifungal, and anti-inflammatory activities. We investigated the effect of C. japonicum extract in a rat model of menopause that exhibited rapid estrogen decline induced by ovariectomy (OVX rats). The rats were treated with C. japonicum extract for 10 weeks and the following parameters were measured: food intake, feed efficiency, body weight, total cholesterol, triglyceride, LDL-cholesterol, HDL-cholesterol, liver weight, 17β-estradiol, uterus weight, AST, ALT, bone mineral density (BMD), bone alkaline phosphatase, calcitonin, and osteocalcin. In OVX rats, the administration of 50 and 100 mg kg-1C. japonicum extract significantly decreased body weight, total cholesterol, triglyceride, HDL-cholesterol, and LDL-cholesterol and significantly increased 17β-estradiol and BMD. During the light/dark box test, the C. japonicum treatment group (100 mg kg-1) spent more time in the light chamber than in the dark area, which was reflective of their diurnal nature. Using a molecular docking simulation, we predicted the plausible binding mode of the active compounds of C. japonicum with the ligand binding domain of estrogen receptor (ER)-α and ER-β. These results showed that C. japonicum extract can treat the symptoms before and after the menopause.