Hypersampsonone H attenuates ulcerative colitis via inhibition of PDE4 and regulation of cAMP/PKA/CREB signaling pathway.

BACKGROUND AND OBJECTIVES: Ulcerative colitis (UC) is a recurrent intestinal inflammatory disease which poses a serious threat to the life of patients. However, there are no specific drugs for UC yet. Hypericum sampsonii Hance (HS) is a Chinese herbal medicine traditionally used to treat enteritis and dysentery. Our previous studies have demonstrated that HS holds potential anti-UC effects, and a novel compound named Hypersampsonone H (HS-1) isolated from HS possesses significant anti-inflammatory activity. However, the beneficial effects of HS-1 on UC remain unclear. This study aimed to investigate the therapeutic effects of HS-1 on UC and its potential mechanisms, both in vitro and in vivo. METHODS: The in vitro model was employed using LPS-induced RAW264.7 cells to investigate the anti-inflammatory effects of HS-1 and its possible mechanisms. Furthermore, the therapeutic efficacy and potential mechanisms of HS-1 against dextran sulfate sodium (DSS)-induced acute colitis were assessed through histopathological examination, biochemical analysis, and molecular docking. RESULTS: In vitro, HS-1 significantly reduced LPS-induced inflammatory responses, as indicated by inhibiting NO production, down-regulating the overexpression of COX-2 and iNOS, as well as regulating the imbalanced levels of IL-6, TNF-α, and IL-10. Moreover, HS-1 also inhibited the expression of PDE4, elevated the intracellular cAMP level, and promoted the phosphorylation of CREB, thereby activating the PKA/CREB pathway in RAW264.7 cells. In vivo, HS-1 demonstrated therapeutic capacity against DSS-induced colitis by alleviating the symptoms of colitis mice, regulating the abnormal expression of inflammatory mediators, protecting the integrity of intestinal epithelial barrier, and reducing tissue fibrosis. Consistently, HS-1 was found to decrease the expression of PDE4 isoforms, subsequently activating the cAMP/PKA/CREB signaling pathway. Furthermore, the molecular docking results indicated that HS-1 exhibited a high affinity for PDE4, particularly PDE4D. Further mechanistic validation in vitro demonstrated that HS-1 possessed a synergistic effect on forskolin and an antagonistic effect on H-89 dihydrochloride, thereby exerting anti-inflammatory effects through the cAMP/PKA/CREB signaling pathway. CONCLUSION: We disclose that HS-1 serves as a promising candidate drug for the treatment of UC by virtue of its ability to reduce DSS-induced colitis via the inhibition of PDE4 and the activation of cAMP/PKA/CREB signaling pathway.

Polycyclic polyprenylated acylphloroglucinols from Hypericum sampsonii Hance and their anti-inflammatory activity.

Phytochemical investigation of Hypericum sampsonii Hance resulted in the isolation of thirty-five polycyclic polyprenylated acylphloroglucinols including six new ones (1, 3, 5, and 15-17). Their structures were elucidated by UV, IR, NMR, HRESIMS, and calculated ECD analysis. Some compounds were evaluated for their anti-inflammatory effects in LPS-induced RAW264.7 cells. Compounds 1 and 26 showed significant inhibitory effects on LPS-induced NO production, and markedly suppressed the protein expression of iNOS and COX-2 in LPS-activated RAW264.7 cells.

Protective effects of 4-geranyloxy-2,6-dihydroxybenzophenonel on DSS-induced ulcerative colitis in mice via regulation of cAMP/PKA/CREB and NF-κB signaling pathways.

Hypericum sampsonii Hance has traditionally been used to treat enteritis and diarrhea. As one of the main benzophenones isolated from H. sampsonii, 4-geranyloxy-2,6-dihydroxybenzophenonel (4-GDB) has been shown to possess anti-inflammatory effects. However, the therapeutic effect and potential mechanisms of 4-GDB in ulcerative colitis (UC) remain unclear. This study aimed to evaluate the role of 4-GDB in UC using a dextran sulfate sodium-induced colitis mouse model. Intragastric administration of 4-GDB (20 mg/kg/day) for 8 days significantly attenuated colonic injury, reduced the expression of inflammatory mediators, and improved colonic barrier function in mice with colitis. Furthermore, in vivo and in vitro experiments indicated that 4-GDB could activate cAMP/PKA/CREB and inhibit the NF-κB pathway. Collectively, 4-GDB may be a potential agent for treating UC by regulating the cAMP/PKA/CREB and NF-κB pathways.

Hypericumsampsonii attenuates inflammation in mice with ulcerative colitis via regulation of PDE4/PKA/CREB signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Hypericum sampsonii Hance (Yuanbaocao), a traditional herbal medicine with various pharmacological properties, is traditionally used to treat diarrhea and enteritis in China for hundreds of years. Investigations have uncovered its anti-inflammatory effects and corresponding bioactive constituents in H. sampsonii, however, the mechanisms of action for the treatment of enteritis are still unclear. AIMS OF THE STUDY: This study aims to investigate the therapeutic effects and molecular mechanisms of H. sampsonii in a dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) mice model. MATERIALS AND METHODS: The major ingredients of the ethyl acetate extract (HS) in H. sampsonii were analyzed by UPLC-QTOF-MS. The inflammatory state of UC mice was caused by 3% DSS once daily for seven days. During DSS treatment, the mice in the positive drug group and the other three groups were orally administered 5-ASA (positive control) or HS daily. After treatment with HS or 5-ASA for a week, colonic pathological observation and the molecular biological index were performed for therapeutic evaluation, including visual inspection in the length and weight of colons and spleens, pathological morphology by hematoxylin and eosin (HE) staining, determination of oxidative markers, inflammatory cytokines and tumor necrosis factor-alpha (TNF-α) levels in colonic tissues as well as spleen index. Gene expression levels of inflammatory cytokines, antioxidant enzymes and PDE4 were detected using kits and PCR, while the expression of colonic tight junction proteins and relative signals of PKA/CREB signaling pathway were analyzed by Western blot. RESULTS: The main components in HS were found to be polycyclic polyprenylated acylphloroglucinols (PPAPs). HS distinctly alleviated DSS-stimulated UC-like lesions symptoms as evidenced by a significant recovery from body weight, colon lengths, and histological injuries of colons. HS reduced the accumulation of pro-inflammatory cytokines and improved the mRNA level of IL-10. Simultaneously, the colonic mRNA expression levels of IL-1ß, IL-17, iNOS and COX-2 were all significantly suppressed by HS in a dose-dependent manner. Furthermore, HS restored the protein expression of tight junction-associated protein (ZO-1 and occluding). Besides, HS significantly inhibited the protein level of PDE4 and decreased the expressions of PKA and phosphorylated CREB. CONCLUSION: This is the first work about main composition and anti-UC effect of Hypericum sampsonii Hance. For the first time, this study reveals HS is not toxic in a single dose and exert significantly protective effect in DSS-colitis mice. The underlying mechanisms may involve the improvement to inflammatory status, the protection for intestinal barrier function, the inhibition of PDE4, and the activation of PKA/CREB signaling pathway. This study provided an experimental basis for the traditional application of H. sampsonii Hance in the treatment of diarrhea and dysentery.

Rare cytochalasans isolated from the mangrove endophytic fungus Xylaria arbuscula.

Four new cytochalasans, arbuschalasins A-D (1-4), along with thirteen known analogues (5-17), were isolated from the solid rice medium of endophytic fungus Xylaria arbuscula. Arbuschalasins A-B feature a rare 5/6/6/6 fused ring system while arbuschalasin D was characterized as the first example of natural cytochalasans that possesses a 5/5/11 fused scaffold. The structures of 1-4 were assigned by spectroscopic data, with their absolute structures being determined by electronic circular dichroism (ECD) calculations. All of the isolates were evaluated against the human colorectal adenocarcinoma cell lines (HCT15). Compounds 6 and 7 showed significant inhibitory effects (IC50 values were 13.5 and 13.4 µM, respectively), being more active than those of the positive control, fluorouracil (103.1 µM).

Therapeutic role of d-pinitol on experimental colitis via activating Nrf2/ARE and PPAR-γ/NF-κB signaling pathways.

Ulcerative colitis is a recrudescent intestinal inflammation coupled with diarrhea, weight loss, pus, and blood stool, which seriously impacts the quality of patient life. d-Pinitol, which can be a food supplement isolated from the food plant-like soybeans, Ceratonia siliqua Linn and Bruguiera gymnorrhiza, has been proved to show anti-oxidative and anti-inflammatory effects. However, the potential mechanism of d-pinitol still remains ill-defined contemporarily. In the current study, the therapeutic effect and potential mechanisms of d-pinitol against colitis were investigated. Oxidative stress and inflammation of experimental colitis were caused by 3% DSS treatment once daily for 7 days. During DSS treatment, the mice of the positive drug group and three other groups were orally administered SASP or d-pinitol once daily. Clinical symptoms were analyzed, and macroscopic scores were calculated. The levels of oxidative and inflammatory cytokines were measured using assay kits and RT-PCR. Additionally, the protein expression of the Nrf2/ARE pathway and PPAR-γ was measured by Western blot. Results showed that d-pinitol enormously alleviated DSS-induced bodyweight loss, colon shortening, and histological injuries, achieving a therapeutic efficacy superior to SASP. Moreover, the oxidative stress and colonic inflammatory response were mitigated. d-pinitol not only significantly activated the Nrf2/ARE signaling pathway via facilitating the translocation of Nrf2 from sitoplazma to cytoblast, upregulating the protein expression levels of GCLC, GCLM, HO-1, and NQO1, but also improved the PPAR-γ level by binding to the active site of PPAR-γ, when suppressing NF-κB p65 and IκBα phosphorylation. In conclusion, d-pinitol exhibited a dramatic anti-colitis efficacy by activating the Nrf2/ARE pathway and PPAR-γ. Hence, d-pinitol may be a promising therapeutic drug against UC in the future.

Direct conversion of cellulose to 5-hydroxymethylfurfural (HMF) using an efficient and inexpensive boehmite catalyst.

High efficiency conversion of cellulose to 5-hydroxymethylfurfural (HMF) remains a challenge today. A simple solid acid catalyst Boehmite (γ-AlOOH) with high hydrothermal stability was prepared and used as sole catalyst for the direct conversion of cellulose into HMF in mixed reaction solvents of ionic liquid 1-buthyl-3-methylimidazolium chloride (BmimCl) and dimethyl sulfoxide (DMSO). This was aimed at developing an efficient and inexpensive catalyst for the production of HMF. The effects of factors such as water, solvent, catalyst load, temperature and reaction duration were investigated. An impressive HMF yield of 58.4% with 97.2% cellulose conversion was obtained at 160 °C after 2 h. More importantly, the catalyst γ-AlOOH was reused several times without loss of its catalytic properties. After five reaction runs, an HMF yield of 47.8% with 91.0% conversion was also obtained. In addition, the catalyst γ-AlOOH displayed excellent catalytic effects on the degradation of other carbohydrates. High yields of HMF from other carbohydrates such as glucose (61.2%), starch (62.7%) and inulin (70.5%) were achieved using γ-AlOOH as the catalyst. The proposed catalytic method shows a promising potential for HMF preparation, especially for industrial-scale HMF production from renewable bioresources.

Hypolipidemic Activity of Peony Seed Oil Rich in α-Linolenic, is Mediated Through Inhibition of Lipogenesis and Upregulation of Fatty Acid ß-Oxidation.

Peony seed oil (PSO) is a new resource food rich in α-Linolenic Acid(ALA) (38.66%). The objective of this study was to assess the modulatory effect of PSO on lipid metabolism. Lard oil, safflower oil (SFO), and PSO were fed to wistar rats with 1% cholesterol in the diet for 60 d. Serum and liver lipids showed significant decrease in total cholesterol (TC), triglyceride (TG), and low density lipoprotein-cholesterol (LDL-C) levels in PSO fed rats compared to lard oil and SFO fed rats. ALA, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), contents were significantly increased, whereas linoleic acid (LA), arachidonic acid (AA) levels decreased in serum and liver of PSO fed rats. Feeding PSO increased ALA level and decreased n-6 to n-3 polyunsaturated fatty acid (PUFA) ratio. The hypolipidemic result of PSO indicated that PSO participated in the regulation of plasma lipid concentration and cholesterol metabolism in liver. The decreased expression of sterol regulatory element-binding proteins 1C (SREBP-1c), acetyl-CoA carboxylase (ACC), and fatty acid synthase (FAS)-reduced lipid synthesis; Activation of peroxisome proliferator-activator receptor (PPARα) accompanied by increase of uncoupling protein2 (UP2) and acyl-CoA oxidase (AOX) stimulated lipid metabolism and exerted an antiobesity effect via increasing energy expenditure for prevention of obesity.

Hypocholesterolaemic mechanism of bitter melon aqueous extracts via inhibition of pancreatic cholesterol esterase and reduction of cholesterol micellar solubility.

This study investigated the hypocholesterolaemic effects of bitter melon aqueous extracts (BMAE) in vitro, the inhibitory effects of BMAE on pancreatic cholesterol esterase (CEase) and incorporation of cholesterol into micelles were investigated. BMAE decreased the in vitro micellar solubility of cholesterol in a dose-dependent manner. The conformation of CEase was investigated by means of circular dichroism (CD) and fluorescence. The result revealed the decrease of α-helix contents, increase of ß-sheet and exposure of aromatic amino acid residuals. The incorporation of cholesterol into micelles was inhibited by BMAE. A complex was observed by transmission electron microscopy (TEM), which indicated interaction between cholesterol and BMAE. The result revealed that BMAE can play a role in decreased intestinal cholesterol absorption via inhibition of CEase, and of micelle formation.

Anti-diabetic activity of peony seed oil, a new resource food in STZ-induced diabetic mice.

This study was conducted to investigate the components of a new resource food in China, peony seed oil (PSO) by GC-MS (gas chromatography-mass spectrometry), its inhibitory effects on carbohydrate hydrolyzing enzymes in vitro and its anti-diabetic effects on mice induced by streptozotocin (STZ). The results showed that peony seed oil showed weak anti-α-amylase activity; however, strong anti-α-glucosidase activity was noted. The GC-MS analysis of the oil showed 9 constituents of which α-linolenic acid was found to be the major component (38.66%), followed by linoleic acid (26.34%) and oleic acid (23.65%). The anti-diabetic potential of peony seed oil was tested in STZ induced diabetic mice. Administration of peony seed oil and glibenclamide reduced the blood glucose level and the area under curve (AUC) in STZ induced diabetic mice. There were significant increases in body weight, liver glycogen content, serum insulin level, high-density lipoprotein cholesterol (HDL-C) and decreases in glycosylated hemoglobin (HbA1C), total serum cholesterol (TC), and triglyceride (TG) in test groups as compared to the untreated diabetic groups. In vivo antioxidant studies on STZ induced diabetic mice revealed the reduction of malondialdehyde (MDA) and increase of glutathione peroxides (GSH-px), superoxide dismutase (SOD), and glutathione (GSH). The results provided a sound rationale for future clinical trials of oral administration of peony seed oil to alleviate postprandial hyperglycemia in streptozotocin-induced diabetic mice.