RESUMO
Nine new sesquiterpenes, hyperhubeins A-I (1-9), and 14 known analogues (10-23) were isolated from the aerial portions of Hypericum hubeiense. Their structures and absolute configurations were determined unambiguously via spectroscopic analysis, single-crystal X-ray diffraction, and electronic circular dichroism calculations. Compounds 1-3 possess an unprecedented sesquiterpene carbon skeleton. Further, a plausible biosynthetic pathway from farnesyl diphosphate (FPP) is proposed. The isolated phytochemicals were evaluated for neuroprotective and anti-neuroinflammatory properties in vitro. Compounds 1, 2, 5-8, 14, and 21 displayed notable neuroprotective activity against hydrogen peroxide (H2O2)-induced lesions in PC-12 cells at 10 µM. Additionally, compounds 1, 2, 12, and 13 exhibited inhibition of lipopolysaccharide (LPS)-induced nitric oxide (NO) production in BV-2 microglial cells, with their IC50 values ranging from 4.92 to 6.81 µM. Possible interactions between these bioactive compounds and inducible nitric oxide synthase (iNOS) were predicted via molecular docking. Moreover, Western blotting indicated that compound 12 exerted anti-neuroinflammatory activity by suppressing LPS-stimulated expression of toll-like receptor-4 (TLR-4) and inhibiting consequent activation of nuclear factor-kappa-B (NF-κB) signaling.
Assuntos
Hypericum , Sesquiterpenos , Anti-Inflamatórios/química , Lipopolissacarídeos/farmacologia , Lipopolissacarídeos/metabolismo , Peróxido de Hidrogênio , Simulação de Acoplamento Molecular , NF-kappa B/metabolismo , Microglia/metabolismo , Dicroísmo Circular , Óxido Nítrico , Óxido Nítrico Sintase Tipo II/metabolismoRESUMO
A phytochemical investigation of the steroidal saponins from the rhizomes of Paris polyohylla var. latifolia led to the discovery and characterization of three new spirostanol saponins, papolatiosides A-C (1-3), and nine known compounds (4-12). Their structures were established via extensive spectroscopic data analysis and chemical methods. Interestingly, compounds 1 and 2 possessed a fructosyl in their oligosaccharide moiety, which is rare in natural product and was firstly reported in family Melanthiaceae. The cytotoxicity of these saponins against several human cancer cell lines was evaluated by a CCK-8 experiment. As a result, compound 1 exhibited a significant cytotoxic effect on LN229, U251, Capan-2, HeLa, and HepG2 cancer cells with IC50 values of 4.18 ± 0.31, 3.85 ± 0.44, 3.26 ± 0.34, 3.30 ± 0.38 and 4.32 ± 0.51 µM, respectively. In addition, the result of flow cytometry analysis indicated that compound 1 could induce apoptosis of glioma cells LN229. The underlying mechanism was explored by network pharmacology and western bolt experiments, which indicated that compound 1 could induce glioma cells LN229 apoptosis by regulating the EGFR/PI3K/Akt/mTOR pathway.
Assuntos
Antineoplásicos , Glioma , Liliaceae , Melanthiaceae , Saponinas , Humanos , Rizoma/química , Fosfatidilinositol 3-Quinases , Liliaceae/química , Antineoplásicos/análise , Saponinas/farmacologia , Saponinas/químicaRESUMO
The investigation of the leaves of Pittosporum elevaticostatum Chang et Yan led to the isolation of fifteen pentacyclic triterpenoids (1-15), including five previously undescribed ones (1-5), and nine others (16-24). The structures of compounds 1-5 were elucidated based on comprehensive spectroscopic techniques, including one dimension (1D) and 2D nuclear magnetic resonance (NMR), high resolution electrospray ionization mass spectroscopy (HR-ESI-MS), and other methods. Compounds 2 and 13 demonstrated significant inhibitory activity against Listeria monocytogenes (L. monocytogenes) with minimum inhibitory concentration (MIC) values of 32 µM. Scanning electron microscopy (SEM) observations revealed insights into the antibacterial mechanism, indicating that compounds 2 and 13 either prevent biofilm formation of dispersed the preformed cell membranes. Additionally, compounds 1, 5, 7, and 12 exhibited anti-inflammatory activity on lipopolysaccharide (LPS)-stimulated BV-2 microglial cells with IC50 values ranging from 11.27 to 17.80 µM.
Assuntos
Antibacterianos , Anti-Inflamatórios , Listeria monocytogenes , Testes de Sensibilidade Microbiana , Triterpenos Pentacíclicos , Folhas de Planta , Folhas de Planta/química , Antibacterianos/farmacologia , Antibacterianos/isolamento & purificação , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/isolamento & purificação , Estrutura Molecular , Camundongos , Animais , Listeria monocytogenes/efeitos dos fármacos , Triterpenos Pentacíclicos/farmacologia , Triterpenos Pentacíclicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/isolamento & purificação , Microglia/efeitos dos fármacos , Linhagem Celular , ChinaRESUMO
The phytochemical investigation on the rhizomes of Paris yunnanensis Franch. resulted in the discovery and characterisation of six compounds, including two new saponins named parisyunnanosides M-N (1-2), and four known ones (3-6). The structures of isolated compounds were determined by spectroscopic data analysis and chemical methods. Compound 2 is a pregnane-type saponin with a special α,ß-unsaturated carboxylic acid moiety at C-17, which is first discovered in genus Paris. The anti-inflammatory activity of the isolated compounds was assessed in vitro. The results demonstrated that compounds 3 and 4 could significantly inhibit the production of NO which was induced by LPS in RAW 264.7 cells with IC50 values of 0.67 ± 0.17 µM and 0.85 ± 0.12 µM, respectively.
RESUMO
Four new triterpenoid saponins named clematangosides A-D (1-4) along with six known saponins (5-10) were isolated from the whole plants of Clematis tangutica. Their structures were determined by extensive spectral analysis and chemical evidences. All saponins were evaluated for their protective effects in hypoxia-induced myocardial injury model. Compounds 2-4, 6, and 10 exhibited anti-myocardial ischemia activities with ED50 values in the range of 75.77-127.22 µM.
Assuntos
Clematis/química , Isquemia Miocárdica/tratamento farmacológico , Saponinas/uso terapêutico , Triterpenos/uso terapêutico , Configuração de Carboidratos , Espectroscopia de Ressonância Magnética , Saponinas/química , Saponinas/isolamento & purificação , Espectrometria de Massas por Ionização por Electrospray , Triterpenos/química , Triterpenos/isolamento & purificaçãoRESUMO
Paris polyphylla var. yunnanensis (Franch.) Hand.-Mazz. (Melanthiaceae), an important specie of the genus Paris, has long been in a traditional Chinese medicine (TCM) for a long time. This study aimed to isolate and identify the structures of bioactive saponins from the rhizomes of P. polyphylla var. yunnanensis and evaluate their cytotoxicity against BxPC-3, HepG2, U373 and SGC-7901 carcinoma cell lines. Seven previously undescribed and seven known saponins were identified, and Paris saponins VII (PSVII) showed significant cytotoxicity against the BxPC-3 cell line with IC50 values of 3.59 µM. Furthermore, flow cytometry, transmission electron microscopy and western-bolt analysis revealed that PSVII inhibited the proliferation of BxPC-3 cells and might be involved in inducing apoptosis and pyroptosis by activating caspase-3, -7 and caspase-1, respectively.
Assuntos
Antineoplásicos , Liliaceae , Melanthiaceae , Saponinas , Rizoma/química , Saponinas/farmacologia , Liliaceae/química , Melanthiaceae/químicaRESUMO
The chemical constituent investigation on the starfish Culcita novaeguineae resulted in the isolation of two new polyhydroxylated steroidal glycosides and two known ones. The new compounds were identified as (25S)-3-O-(2-O-methyl-ß-D-xylopyranosyl)-26-O-(ß-D-xylopyranosyl)-cholest-4-ene-3ß,6ß,7α,8,15α,16ß,26-heptaol (1) and (25S)-3-O-(2-O-methyl-ß-D-xylopyranosyl)-26-O-(ß-D-xylopyranosyl)-cholest-4,24(28)-diene-3ß,6ß,7α,8,15α,16ß,26-heptaol (2) and the known compounds were determined as linckosides I and H (3-4). The structures of the isolated compounds were elucidated on the basis of extensive spectroscopic studies and chemical evidence. In addition, the cytotoxicity of the two new compounds against human glioblastoma cell lines U87, U251 and SHG44 was evaluated by MTT method.
Assuntos
Estrelas-do-Mar , Esteroides , Animais , Linhagem Celular , Glicosídeos/química , Humanos , Estrelas-do-Mar/química , Esteroides/químicaRESUMO
Four new sesquiterpenoid glycoside esters, Pitqinlingoside N-Q (1-4), together with eleven known metabolites (5-15), were isolated from 95% EtOH extract of the twigs, fruits and leaves of P. qinlingense. The structures of new compounds were elucidated on the basis of extensive spectroscopic analyses, including IR, UV, HRMS, NMR and electronic circular dichroism spectra. Unusal glycoside esters are characterized by the presence of polyacylated ß-D-fucopyranosyl and ß-d-glucopyranosyl units. Pitqinlingoside N (1), O (2), P (3), boscialin (5) and arvoside C (6) showed significant nitric oxide production inhibition in lipopolysaccharide (LPS)-induced BV-2 microglial cells with IC50 values ranging from 1.58 to 28.74 µM. Structure-activity relationships of the isolated compounds are discussed.
Assuntos
Rosales , Sesquiterpenos , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Glicosídeos/farmacologia , Lipopolissacarídeos/farmacologia , Estrutura Molecular , Óxido Nítrico/metabolismo , Extratos Vegetais/química , Rosales/metabolismo , Sesquiterpenos/química , Sesquiterpenos/farmacologiaRESUMO
ABSTRACT: Aging and average life expectancy have been increasing at a rapid rate, while there is an exponential risk to suffer from brain-related frailties and neurodegenerative diseases as the population ages. Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide with a projected expectation to blossom into the major challenge in elders and the cases are forecasted to increase about 3-fold in the next 40 years. Considering the etiological factors of AD are too complex to be completely understood, there is almost no effective cure to date, suggesting deeper pathomechanism insights are urgently needed. Metabolites are able to reflect the dynamic processes that are in progress or have happened, and metabolomic may therefore provide a more cost-effective and productive route to disease intervention, especially in the arena for pathomechanism exploration and new biomarker identification. In this review, we primarily focused on how redox signaling was involved in AD-related pathologies and the association between redox signaling and altered metabolic pathways. Moreover, we also expatiated the main redox signaling-associated mechanisms and their cross-talk that may be amenable to mechanism-based therapies. Five natural products with promising efficacy on AD inhibition and the benefit of AD intervention on its complications were highlighted as well.
RESUMO
BACKGROUND: Increasing evidence suggests a link between the gut microbiome and various diseases including hypertension and chronic kidney disease (CKD). However, studies examining the efficacy of controlling blood pressure and inhibiting the renin-angiotensin system (RAS) in preventing CKD progression are limited. METHODS: In the present study, we used 5/6 nephrectomised (NX) and unilateral ureteral obstructed (UUO) rat models and cultured renal tubular epithelial cells and fibroblasts to test whether alisol B 23-acetate (ABA) can attenuate renal fibrogenesis by regulating blood pressure and inhibiting RAS. RESULTS: ABA treatment re-established dysbiosis of the gut microbiome, lowered blood pressure, reduced serum creatinine and proteinuria, suppressed expression of RAS constituents and inhibited the epithelial-to-mesenchymal transition in NX rats. Similarly, ABA treatment inhibited expression of collagen I, fibronectin, vimentin, α-smooth muscle actin and fibroblast-specific protein 1 at both mRNA and protein levels in UUO rats. ABA was also effective in suppressing activation of the transforming growth factor-ß (TGF-ß)/Smad3 and preserving Smad7 expression in both NX and UUO rats. In vitro experiments demonstrated that ABA treatment inhibited the Wnt/ß-catenin and mitochondrial-associated caspase pathways. CONCLUSION: These data suggest that ABA attenuated renal fibrosis through a mechanism associated with re-establishing dysbiosis of the gut microbiome and regulating blood pressure, and Smad7-mediated inhibition of Smad3 phosphorylation. Thus, we demonstrate ABA as a promising candidate for treatment of CKD by improving the gut microbiome and regulating blood pressure.
RESUMO
A new high nitrogen compound hydrazine 3-nitro-1,2,4-triazol-5-one complex (HNTO) was prepared by the reaction of 3-nitro-1,2,4-triazol-5-one with hydrazine hydrate, and its structure was characterized by means of organic elemental analyzer, FT-IR, XRD, (13)C NMR and (15)N NMR. The non-isothermal reaction kinetics of the main exothermic decomposition reaction of HNTO was investigated by means of DSC. The thermodynamic properties of HNTO were calculated. The results showed that the formation of HNTO is achieved by proton transfer of N(4) atom, and it makes a higher nitrogen content and lower acidity. The reaction mechanism of HNTO is classified as nucleation and growth, and the mechanism function is Avramo-Erofeev equation with n=2/5. The kinetic parameters of the reaction are E(a)=195.29 kJ mol(-1), lg(A (s(-1)))=19.37, respectively. The kinetic equation can be expressed as: d(alpha)/d(t) = 10(18.97)(1 - alpha)[-ln(1 - alpha)](3/5) e(-2.35 x 10(4)/T). The safety performances of HNTO were carried out. The critical temperature of thermal explosion are 464.26 and 474.37 K, the adiabatic time-to-explosion is 262s, the impact sensitivity H(50)=45.7 cm, the friction sensitivity P=20% and the electrostatic spark sensitivity E(50)>5.4J (no ignition). It shows that HNTO has an insensitive nature as RDX and NTO, etc.
Assuntos
Substâncias Explosivas/química , Hidrazinas/química , Nitrocompostos/química , Triazóis/química , Varredura Diferencial de Calorimetria , Explosões , Cinética , Espectroscopia de Ressonância Magnética , Temperatura , Termodinâmica , Difração de Raios XRESUMO
BACKGROUND: Tubulo-interstitial fibrosis (TIF) is the common pathway in the chronic kidney disease (CKD). Epithelial-to-mesenchymal transition (EMT) is a major contributor to the TIF by the increased myofibroblasts. Renin-angiotensin system (RAS) is critical mediator on EMT in progressive CKD. Angiotensin II (ANG) mediates EMT and causes TIF by stimulating transforming growth factor-ß1 (TGF-ß1). RAS activation could further activate TGF-ß1. Inhibition of the RAS is one of the most powerful therapies for progressive CKD. 25-O-methylalisol F (MAF) is a new tetracyclic triterpenoid compound isolated from the Alismatis rhizoma, which is extensively used for anti-hypertensive, diuretic and anti-hyperlipidemic effects. METHODS: Inhibitory effect of MAF on EMT is investigated in both TGF-ß1- and ANG-induced tubular epithelial cells (NRK-52E) and fibroblasts (NRK-49F). Western blot analysis, qRT-PCR, siRNA, immunofluorescence staining and co-immunoprecipitation techniques were used to evaluate the inhibition of MAF on EMT and further revealed the intervention effects on RAS, TGF-ß/Smad and Wnt/ß-catenin pathways. RESULTS: MAF treatment significantly inhibited TGF-ß1 and ANG-induced expressions of collagen I, fibronectin, α-SMA, vimentin and E-cadherin at both mRNA and protein levels in the NRK-52E and NRK-49F cells. The action mechanism revealed that MAF significantly ameliorated upregulation of angiotensinogen, renin, ACE and AT1R expressions. Further, MAF attenuated upregulation of Smad3 phosphorylation and downregulation of Smad7, but did not affect the phosphorylation of Smad2, PI3K, ERK1/2 and p38 expressions and Smad4 expression in NRK-52E cells. Co-immunoprecipitation analysis indicated that MAF selectively blocked the combination of Smad3 with TGFßRI and Smad3 with SARA without interfering with the Smad2, TGFßRI and SARA interaction. Additionally, MAF suppressed the expressions of Wnt1 and ß-catenin as well as its downstream target Snail1, Twist, MMP-7, PAI-1 and FSP1 expressions in NRK-52E cells. CONCLUSIONS: MAF simultaneously targeted multiple RAS components and it was a novel RAS inhibitor. MAF inhibited EMT by Smad3-specific signaling in the TGF-ß/Smad-dependent pathway and Wnt/ß-catenin pathway. MAF has an important effect on crosstalk between the TGF-ß/Smad and Wnt/ß-catenin pathway in EMT process by activation of RAS.
Assuntos
Transição Epitelial-Mesenquimal/efeitos dos fármacos , Nefropatias/tratamento farmacológico , Rim/patologia , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Triterpenos/farmacologia , Alisma/química , Angiotensina II/metabolismo , Angiotensina II/farmacologia , Animais , Linhagem Celular , Fibrose/tratamento farmacológico , Rim/efeitos dos fármacos , Rim/metabolismo , Nefropatias/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Ratos , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , Proteínas ras/antagonistas & inibidoresRESUMO
BACKGROUND: The pathogenesis of tubulo-interstitial fibrosis and glomerulosclerosisis was characterized by cellular hypertrophy, extracellular matrix accumulation and podocyte detachment. Poricoic acid ZA (PZA) is a tetracyclic triterpenoid compound extracted from the surface layer of Poria cocos (LPC), which have been used extensively for diuretic and renoprotective effects. METHODS: The anti-fibrotic effect of PZA is investigated in HK-2 cells and podocytes induced by TGF-ß1 and angiotensin II (ANGII). qRT-PCR, siRNA, immunofluorescence staining, co-immunoprecipitation and Western blot analyses are used to evaluate the expression of RAS signaling, TGF-ß/Smad pathway, epithelial-to-mesenchymal transition (EMT) and podocyte markers. RESULTS: PZA restores the mRNA and protein expression of EMT in HK-2 cells. Specific TGF-ß1-siRNA efficiently blocks ANGII-induced protein expression of TGF-ß1 and further inhibits activated Smad signaling. PZA significantly attenuates up-regulation of angiotensinogen, renin, ACE and AT1. Further, PZA reverses up-regulation of TGFßRII and suppresses Smad proteins. Simultaneously, PZA inhibits the protein interaction of TGF-ß receptor and Smads and PZA also inhibits activated RAS and TGF-ß/Smad signaling cascade and up-regulates protein expression of podocyte markers and mitigates podocyte injury. CONCLUSIONS: This study demonstrated the beneficial role of PZA in renal fibrosis and podocyte injury. Our study highlighted that PZA inhibits RAS and further suppresses TGF-ß/Smad pathway through inhibiting Smad2/3 phosphorylation via blocking Smad2/3-TGFßRI protein interaction. PZA is implicated in activation of RAS/TGF-ß/Smad axis in HK-2 cells and podocytes. PZA could be considered as a novel RAS inhibitor for treating CKD.