Structural Revision of the Stemona Alkaloids Tuberostemonine O, Dehydrocroomines A and B, and Dehydrocroomine.

The structural revision of four Stemona alkaloids from Stemona tuberosa is reported. The misassignment of the tuberostemonine O structure (1) was recognized when a new alkaloid, tuberostemonine P, was isolated and unambiguously assigned structure 1 in this work. Reinvestigation of the spectroscopic data and NMR calculations led to the revised structure 1a for tuberostemonine O. The structural misassignment of dehydrocroomine A as 2 was corrected by reinterpreting the X-ray crystal structure, which was consistent with 2a. The structural reassignments of dehydrocroomine B (3 to 3a) and dehydrocroomine (4 to 4a) were confirmed by X-ray crystallography and NMR calculations, respectively.

New dammarane-type glycosides from Gynostemma pentaphyllum and their lipid-lowering activity.

Gynostemma pentaphyllum (Thunb.) Makino has a long history as food and diary supplement in China. At present, there are some products for hyperlipidemia in the market, including G. pentaphyllum tea, healthy wine and healthy food. In order to discover proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, fourteen new triterpenoid saponins named gypenoside LXXXVIII-CI (1-14) along with six known compounds (15-20) were isolated from G. pentaphyllum. Their structures were elucidated by means of various spectroscopic techniques. Eight isolates were evaluated the inhibitory effect on PCSK9 in HepG2 cells. The results showed that three dammarane-type glycosides (2, 3, 15) remarkably reduced PCSK9 expression at 10 µM concentration. These findings suggested that G. pentaphyllum was worthy of further investigation to find small molecule PCSK9 inhibitors and facilitate their utilization as functional food ingredients.

New dammarane-type triterpenoid saponins from Gynostemma pentaphyllum and their Sirt1 agonist activity.

Gynostemma pentaphyllum (Thunb.) Makino (Cucurbitaceae family) is a perennial creeping plant with a common Chinese name of "south ginseng". To date, more than 250 individual saponins with dammarane-type skeleton have been isolated from G. pentaphyllum. The purpose of this study was the isolation and structural characterization of novel, minor gypenosides from G. pentaphyllum and evaluation of their Sirt1 agonist activity. Individual saponins from G. pentaphyllum were isolated and purified by a variety of chromatography techniques, and their structures were elucidated by means of various spectroscopic analysis and comparision with the reported data. Sirt1 enzyme activity detection kit was used to preliminarily evaluate the Sirt1 agonist activity of thirty three individual saponins purified from G. pentaphyllum. Fourteen new triterpenoid saponins named gypenoside CII-CXV (1-14) along with twenty six known compounds (15-40) were isolated from G. pentaphyllum. Thirty three of all the isolates were screened for Sirt1 agonist activity, and the results showed that three dammarane-type saponins (2, 18, 37) and one cucurbitane-type saponin 33 exhibited satisfactory Sirt1 agonist activity. These findings suggested that G. pentaphyllum was worthy of further investigation to find small molecule Sirt1 agonist and facilitate their utilization as "south ginseng".

Cablinosides A and B, Two Glycosidic Phenylacetic Acid Derivatives from the Leaves of Pogostemon cablin.

A pair of new glycosidic epimers, cablinosides A (1a) and B (1b) were isolated from the leaves of Pogostemon cablin. The structures with absolute configurations of 1a and 1b were elucidated by extensive NMR investigation, and quantum chemical CD calculations. The epimer mixture 1 showed moderate α-glucosidase inhibitory activity and no significant cytotoxic activity against HepG2 cells.

α-Glucosidase Inhibitory Prenylated Anthranols from Harungana madagascariensis.

Four new prenylated anthranols, harunganols C-F (1-4), along with kenganthranol A (5), harunganin (6), and ferruginin A (7), were identified from the leaves of Harungana madagascariensis. The structures of compounds 2, 5, and 7 were confirmed by single-crystal X-ray diffraction analysis. Compound 1 is a unique symmetrical anthranol dimer connected via a CH2 group. Compound 4 possesses a unique C-10 hemiketal group. All anthranols were evaluated for their α-glucosidase inhibitory activities. They displayed a higher potency compared to acarbose except for 3 and 4. In particular, harunganol C (1) showed an IC50 value of 1.2 µM.

Chemical constituents from stems and leaves of Micromelum integerrimum.

A new benzene derivative microintegerrin C (1) and a new norsesquiterpenoid microintegerrin D (2), along with six known compounds (3-8), were isolated and identified from stems and leaves of Micromelum integerrimum by various chromatographies such as silica gel, Sephadex LH-20, RP-18 column chromatography and HPLC. Their structures were mainly identified based on the spectral data analysis such as 1D-, 2D-NMR and HR-EI-MS. All known compounds were isolated from this plant for the first time.

[Chemical constituents from barks of Nothopanax delavayi].

Eleven compounds were isolated and purified from the barks extract of Nothopanax delavayi and their structures were identified as serratagenic acid-3-O-alpha-L-arabinopyranosyl-28-O-beta-D-glucopyranosyl ester (1), serratagenic acid-3-0-alpha-L-arabi-nopyranosyl-28-O-[alpha-L-rhamnopyranosyl-(1-->4)-beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranosyl] ester (2), serratagenic acid (3), serratagenic acid-3-O-alpha-L-arabinopyranoside (4), serratagenic acid-beta-O-beta-(2', 4'-O-diacetyl) -D-xylopyranosyl-28-O-[alpha-L-rhamnopy-ranosyl-(1-->4)-beta-D-glucopyranosyl-(1-->46)-beta-D-glucopyranosyl] ester (5), serratagenic acid-3-O-alpha-(4'-O-acetyl)-L-arabino pyrano-syl-28-0- [-alpha-L-rhamnopyranosyl-(1-->4)-beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranosyl] ester(6), serratagenic acid-3-O-alpha-(2'-O-acetyl)-L-arabinopyranosyl-28-O-[-alpha-L-rhamnopyranosyl- (1-->4) -beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranosyl] ester(7), serratagenic acid-3-0-beta-D-xylopyranosyl-28-O-[-alpha-L-rhamnopyranosyl-(1-->4)-beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranosyl] ester (8), protocatechuic acid (9), ethyl caffeate (10) and caffeic anhydride (11) by physicochemical properties and spectroscopic data analysis. Among them, compounds 3-4 and 9-11 were firstly isolated from the genus Nothopanax, and compounds 5-8 were isolated from this plant for the first time.

3-O-Methyl-D-Glucose Blunts Cold Ischemia Damage in Kidney via Inhibiting Ferroptosis.

BACKGROUND: The glucose derivative 3-O-methyl-D-glucose (OMG) is used as a cryoprotectant in freezing cells. However, its protective role and the related mechanism in static cold storage (CS) of organs are unknown. The present study aimed to investigate the effect of OMG on cod ischemia damage in cold preservation of donor kidney. METHODS: Pretreatment of OMG on kidney was performed in an isolated renal cold storage model in rats. LDH activity in renal efflux was used to evaluate the cellular damage. Indicators including iron levels, mitochondrial damage, MDA level, and cellular apoptosis were measured. Kidney quality was assessed via a kidney transplantation (KTx) model in rats. The grafted animals were followed up for 7 days. Ischemia reperfusion (I/R) injury and inflammatory response were assessed by biochemical and histological analyses. RESULTS: OMG pretreatment alleviated prolonged CS-induced renal damage as evidenced by reduced LDH activities and tubular apoptosis. Kidney with pCS has significantly increased iron, MDA, and TUNEL+ cells, implying the increased ferroptosis, which has been partly inhibited by OMG. OMG pretreatment has improved the renal function (p <0.05) and prolonged the 7-day survival of the grafting recipients after KTx, as compared to the control group. OMG has significantly decreased inflammation and tubular damage after KTx, as evidenced by CD3-positive cells and TUNEL-positive cells. CONCLUSION: Our study demonstrated that OMG protected kidney against the prolonged cold ischemia-caused injuries through inhibiting ferroptosis. Our results suggested that OMG might have potential clinical application in cold preservation of donor kidney.

New alkaloids from Stemona tuberosa and structural revision of tuberostemonols P and R.

Three Stemona alkaloids named stemotuberines A-C (1-3) with unique C17N frameworks, presumably formed by elimination of the C-11-C-15 lactone ring of the stichoneurine skeleton, were isolated from the roots of Stemona tuberosa. Their structures were elucidated by spectroscopic analysis, X-ray diffraction, and computational methods. Compounds 2 and 3 showed inhibition (IC50 values of 37.1 and 23.2 µM, respectively) against LPS-induced nitric oxide production in RAW 264.7 cells. In addition, concern was expressed about the reported plant origin (S. sessilifolia) of the recently described alkaloids tuberostemonols O-R (4-7), which should be S. tuberosa. NMR calculations indicated structural misassignment of these compounds except for 6. Isolation of tuberostemonol P (5) from our material of S. tuberosa allowed for a close examination of the spectroscopic data leading to the revised structure 5a. Tuberostemonol R (7) was found to have identical 1H and 13C NMR data to the well-known alkaloid croomine, and therefore its structure including relative stereochemistry must be revised as 7a.

[Chemical constituents from ethyl acetate extract of Shiaria bambusicola].

Fourteen compounds were isolated and purified from the ethyl acetate of the ethanol extract of Shiaria bambusicola by various chromatographic methods, and their structures were elucidated by spectral techniques and physicochemical properties as hypocrellin A (1), hypocrellin B (2), hypocrellin C (3), hypomycin A (4), ergosterol (5), ergosterol peroxide (6), (22E, 24R)-5alpha, 8alpha-epidioxy-6,9(11),22-trien-3beta-ol (7), ergosta-7, 24(28)-dien-3beta-ol (8), (22E, 24R)-ergost-7, 22-dien-3beta, 5alpha, 6beta-triol (9), (22E,24R)-ergosta-7, 22-diene-3beta, 5alpha, 6beta-triol-3-O-palmitate (10), (22E, 24R)-ergosta-7, 22-diene-3beta, 5alpha, 6beta-triol-6-O-palmitate (11), 1-O-monostearin (12), 1, 3-O-distearin (13), and mannitol (14). Among them, compounds 7-13 were firstly isolated from this genus.

[Alkaloids from bulbs of Lycoris radiata].

Ten Amaryllidaceae alkaloids were isolated from the bulbs of Lycoris radiata. Their structures were identified as oxovittatine (1), apohaemanthamine (2), 9-O-demethylhomolycorine N-oxide (3), incartine (4), ismine (5), 6-O-methylpretazettine (6), tazettine (7), ungeremine (8), homolycorine (9), and O-methyllycorenine (10) by spectroscopic data analyses. Compound 1 was a new natural product. Compounds 2 and 3 were reported form the genus Lycoris for the first time and compounds 4-6 were isolated form the title plant for the first time.

Structurally diverse glycosides with α-glucosidase inhibitory properties from water extract of the leaves of Cyclocarya paliurus.

In this work we investigated the chemical constituents of water extract of the leaves of Cyclocarya paliurus. Two new megastigmane glycosides (3 and 8), three aliphatic alcohol glycosides (9-11), and two aromatic glycosides (12 and 13), along with fourteen known compounds were isolated, and their in vitro inhibitory activity against α-glucosidase was evaluated. Compounds 13 and 15-18 displayed inhibitory activity with IC50 values varying from 27.05 to 96.58 µM, and the structure-activity relationship among isolated compounds was discussed.

A comparative study of the ameliorative effects of hyaluronic acid oligosaccharides and hyaluronic acid on DSS-induced colitis in mice and research on relevant mechanisms.

As a dietary supplement, hyaluronic acid (HA) has exhibited appreciable immunomodulatory activity and an ameliorative effect on rodent colitis. However, its high viscosity is not only refractory to absorb through the gut, but also causes flatulence. In contrast to HA, hyaluronic acid oligosaccharides (o-HAs) can overcome the above-mentioned constraints, but their treatment effect still remains ill-defined contemporarily. Herein, the current study intends to compare the modulatory effects of HA and o-HA on colitis and assess the underlying molecular mechanism. We first showed that o-HA had a better preventive effect than HA in alleviating colitis symptoms, as evidenced by lower body weight loss, lower disease activity index scores, a lower inflammatory response (TNF-α, IL-6, IL-1ß, p-NF-κB), and more intact colon epithelial integrity in vivo. The best efficiency was observed in the o-HA treated group with a dosage of 30 mg kg-1. In an in vitro barrier function assay, o-HA exerted a better protective effect on the transepithelial electrical resistance (TEER), FITC permeability, and wound healing and modulated the expression of tight junction (TJ) proteins (ZO-1, occludin) in lipopolysaccharide (LPS)-stimulated Caco-2 cells. In summary, both HA and o-HA showed the potential to reduce inflammation and ameliorate intestinal damage in DSS-induced colitis and LPS-induced inflammation, but o-HA had improved outcomes. The results also provided a glimpse of the latent mechanism by which HA and o-HA enhanced intestinal barrier function via MLCK/p-MLC signaling pathway suppression.

5-epi-ent-Kaurane diterpenoids from the aerial parts of Isodon eriocalyx and their anti-atherosclerotic potential.

The phytochemical investigation of the EtOAc extract from the aerial parts of Isodon eriocalyx afforded seventeen diterpenoids, including eight undescribed compounds. Eriocalyxins H-L have unique structural characteristics featuring a 5-epi-ent-kaurane diterpenoid scaffold with eriocalyxins H-K also possess an unusual 6,11-epoxyspiro-lactone ring while eriocalyxin L, a 1,7:3,20-diepoxy-ent kaurene, features an 1,7-oxygen linkage. The structures of these compounds were elucidated by spectroscopic data interpretation, and the absolute configurations of eriocalyxins H, I, L, and M were confirmed by single-crystal X-ray diffraction. The isolates were screened for their inhibitory activities against VCAM-1 and ICAM-1 at 5 µM. While eriocalyxin O, coetsoidin A and laxiflorin P were found to significantly inhibit both VCAM-1 and ICAM-1, 8 (17),13-ent-labdadien-15 â†’ 16-lactone-19-oic acid displayed evidently inhibitory effect against ICAM-1.

Two new triterpenoids from the leaves of Cyclocarya paliurus (Batalin) Iljinskaja.

Two previously undescribed triterpenoids (1-2), along with thirteen known compounds (3-15) were isolated from a CHCl3-soluble extract of the leaves of Cyclocarya paliurus. Their structures were established on the basis of chemical and spectroscopic approaches. These compounds were assessed for their therapeutic effects on diabetic nephropathy (DN)-evoked fibrosis through High-Glucose and transforming growth factor-ß1 (TGF-ß1) challenged HK-2 cells. Among them, compounds 3, 5 and 8 could remarkedly decrease the level of fibronectin to relieve DN with 27.66 ± 2.77%, 6.09 ± 0.57% and 17.74 ± 5.83% inhibition rate at 10 µM, 10 µM and 1 µM, respectively.

Dammarane-type saponins with proprotein convertase subtilisin/kexin type 9 inhibitory activity from Gynostemma pentaphyllum.

Seven undescribed dammarane-type saponins, gypenosides LXXXI-LXXXVII, together with four known compounds, were isolated from the whole herb of Gynostemma pentaphyllum. The chemical structures of these undescribed compounds were elucidated on the basis of physical and spectroscopic analysis and comparison with literature data. All the isolates were evaluated for their proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitory activities in HepG2 cells. Among them, gypenosides LXXXII-LXXXVII, gynosaponin II, IV and VI suppressed the expression of PCSK9 in LPDS-induced HepG2 cells at 20 µM; gypenosides LXXXII, LXXXV and LXXXVII showed inhibitory activities against PCSK9 at 10 µM; notably, gypenoside LXXXII still exhibited inhibitory activity against PCSK9 at 5 µM.

Aloin A prevents ulcerative colitis in mice by enhancing the intestinal barrier function via suppressing the Notch signaling pathway.

BACKGROUND: Previous studies reported that Aloe vera ameliorated DSS-induced colitis and promoted mucus secretion. However, the effect of Aloin A (AA), a major compound of Aloe vera, on colitis and its exact mechanism remains uncovered. METHODS: C57BL/6 mice were successively subjected to 3% DSS solution for 5 days and distilled water for 2 days. Concurrently, AA (25, 50 mg/kg) and 5-aminosalicylic (500 mg/kg) were administrated intragastrically from day 1 to day 7. Colitis was evaluated by disease active index (DAI), colon length, inflammation response, and intestinal barrier function. In vitro LS174T cells challenged with 50 ng/ml of lipopolysaccharides (LPS) were used to validate the modulatory action of AA on the Notch signaling pathway. RESULTS: Our results showed that oral administration with AA prominently prevented DSS-induced colitis symptoms in terms of decreased DAI, prevention of colon shortening, and reduced pathological damage. AA mitigated the inflammatory response evidenced by the decreased proinflammatory cytokines (TNF-α, IL-1ß, IL-6) and increased anti-inflammatory cytokine (IL-10). Besides, AA inhibited apoptosis and facilitated proliferation in colons. Moreover, AA treatment up-regulated the expression of tight junction (TJ) proteins (ZO-1, Occludin) and promoted the secretion of MUC2 to decrease colon permeability. Mechanistically, AA inhibited the Notch pathway to promote the secretion of MUC2, which was consistent with LPS-challenged LS174 cells. CONCLUSION: These results suggested that AA could prevent colitis by enhancing the intestinal barrier function via suppressing the Notch signaling pathway. Thus, AA might be a prospective remedy for ulcerative colitis.

Asiatic acid from Cyclocarya paliurus regulates the autophagy-lysosome system via directly inhibiting TGF-ß type I receptor and ameliorates diabetic nephropathy fibrosis.

Diabetic nephropathy (DN) fibrosis is a major cause of end-stage renal disease with unsatisfactory therapy drugs and a low 5-year survival rate. There is a lack of specific and effective treatment drugs. In the present study, we report that asiatic acid (AA), a triterpenic acid found in Cyclocarya paliurus, has good anti-fibrosis activity both in vitro and in vivo. The STZ-induced diabetic model of rats was used to investigate the effects of AA on DN fibrosis. A 15-week AA treatment (10 mg kg-1 or 30 mg kg-1) markedly decreased urine albumin and blood urea nitrogen levels, and ameliorated increased mesangial matrix and glomerular fibrosis. HG + TGF-ß1-induced HK-2 cells were applied to evaluate the anti-fibrosis effect of AA. The results revealed AA selectively blocked the interaction of TGF-ß type I receptor (TGF-ßRI) with Smad3 by binding to TGF-ßRI, suppressed the subsequent phosphorylation and nuclear translocation of Smad3, and downregulated the major fibrotic protein expression of collagen I, fibronectin and a-smooth muscle actin (α-SMA), thereby switching the progress of epithelial-mesenchymal transition (EMT). Furthermore, the protein levels of LC3 and LAMP1 were significantly altered by AA administration, implying that the autophagy-lysosome system might be involved in DN fibrosis. However, the anti-fibrosis capacity of AA was partly counteracted by an autophagy-lysosome inhibitor (chloroquine). These findings indicate AA could decrease TGF-ß1 secretion and suppress tubulointerstitial fibrosis by directly inhibiting TGF-ßR1 and activating the autophagy-lysosome system. Altogether, AA may be a potential candidate drug for preventing DN fibrosis.

Lycojapomines A-E: Lycopodium Alkaloids with Anti-Renal Fibrosis Potential from Lycopodium japonicum.

Five Lycopodium alkaloids featuring novel C17N2 (1 and 2), C29N3 (3 and 4), and C15N2 (5) skeletons were isolated from Lycopodium japonicum. Compound 1 is the first natural product containing a 3-aza[3.3.3]propellane motif. The structures of these compounds were elucidated by spectroscopic analysis, X-ray crystallography, and computational methods. Compounds 1 and 3-5 significantly inhibited TGF-ß1-induced fibronectin deposition in HK-2 cells at a nontoxic concentration of 20 µM.

Arjunolic acid from Cyclocarya paliurus ameliorates diabetic retinopathy through AMPK/mTOR/HO-1 regulated autophagy pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Cyclocarya paliurus (CP) is a traditional Chinese herb and possesses a variety of biological activities including anti-hyperglycemia, anti-hyperlipidemia, antioxidant and anti-inflammation. Arjunolic acid (AA) is an abundant and bioactive ingredient in CP that shows significant protection against many metabolic diseases such as diabetic complication. Diabetic retinopathy (DR) is a serious complication of diabetes and may lead to vision loss. However, the protective effects and underlying mechanisms of AA against DR is not still understood. AIM OF THE STUDY: We aimed to investigate whether AA activates AMPK/mTOR/HO-1 regulated autophagy pathway to alleviate DR. MATERIALS AND METHODS: In the study, the STZ-induced diabetic model of rats was established, and AA with 10 and 30 mg/kg dosages was given orally for ten weeks to investigate their effect on retinal injury of DR. H2O2-induced ARPE-19 cells were applied to evaluate anti-apoptosis and anti-oxidant effect of AA. RESULTS: The results revealed that AA could prevent STZ-induced weight loss and increase the retinal thickness and nuclei counts. The level of HO-1 protein was upregulated both in vivo and in vitro. In addition, AA prevented retinal damage and cell apoptosis through the AMPK-mTOR-regulated autophagy pathway. Furthermore, anti-apoptosis capacity, as well as the expression of HO-1 and LC3 protein, were effectively locked by AMPK inhibitor dorsomorphin dihydrochloride (compound C). CONCLUSIONS: This finding implies that AA may be a promising candidate drug by protecting retinal cells from STZ-induced oxidative stress and inflammation through the AMPK/mTOR/HO-1 regulated autophagy pathway.