RESUMO
BACKGROUND: Wound management is a critical procedure in veterinary practice. A wound is an injury that requires the body's cells' alignment to break down due to external assault, such as trauma, burns, accidents, and diseases. Re-epithelization, extracellular matrix deposition, especially collagen, inflammatory cell infiltration, and development of new blood capillaries are the four features that are used to evaluate the healing process. Using a natural extract for wound management is preferred to avoid the side effects of synthetic drugs. The current study aimed to assess the effect of major pregnane glycoside arabincoside B (AR-B) isolated from Caralluma arabica (C. arabica) for the wound healing process. METHOD: AR-B was loaded on a gel for wound application. Rats were randomly distributed into six groups: normal, positive control (PC), MEBO®, AR-B 0.5%, AR-B 1%, and AR-B 1.5%, to be 6 animals in each group. Wounds were initiated under anesthesia with a 1 cm diameter tissue needle, and treatments were applied daily for 14 days. The collected samples were tested for SOD, NO, and MDA. Gene expression of VEGF and Caspase-3. Histopathological evaluation was performed at two-time intervals (7 and 14 days), and immunohistochemistry was done to evaluate α -SMA, TGF-ß, and TNF-α. RESULT: It was found that AR-B treatment enhanced the wound healing process. AR-B treated groups showed reduced MDA and NO in tissue, and SOD activity was increased. Re-epithelization and extracellular matrix deposition were significantly improved, which was confirmed by the increase in TGF-ß and α -SMA as well as increased collagen deposition. TNF-α was reduced, which indicated the subsiding of inflammation. VEGF and Caspase-3 expression were reduced. CONCLUSION: Our findings confirmed the efficiency of AR-B in enhancing the process of wound healing and its potential use as a topical wound dressing in veterinary practice.
Assuntos
Cicatrização , Animais , Cicatrização/efeitos dos fármacos , Ratos , Masculino , Apocynaceae/química , Bandagens , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Glicosídeos/farmacologia , Glicosídeos/uso terapêutico , Pregnanos/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/genética , Superóxido Dismutase/metabolismo , Caspase 3/metabolismo , Caspase 3/genética , Ratos Sprague-DawleyRESUMO
SARS-CoV-2 caused pandemic represented a major risk for the worldwide human health, animal health and economy, forcing extraordinary efforts to discover drugs for its prevention and cure. Considering the extensive interest in the pregnane glycosides because of their diverse structures and excellent biological activities, we investigated them as antiviral agents against SARS-COV-2. We selected 21â pregnane glycosides previously isolated from the genus Caralluma from Asclepiadaceae family to be tested through virtual screening molecular docking simulations for their potential inhibition of SARS-CoV-2 Mpro. Almost all target compounds showed a more or equally negative docking energy score relative to the co-crystallized inhibitor X77 (S=-12.53â kcal/mol) with docking score range of (-12.55 to -19.76â kcal/mol) and so with a potent predicted binding affinity to the target enzyme. The activity of the most promising candidates was validated by inâ vitro testing. Arabincosideâ C showed the highest activity (IC50=35.42â µg/ml) and the highest selectivity index (SI=9.9) followed by Russeliosideâ B (IC50=50.80â µg/ml), and Arabincosideâ B (IC50=53.31â µg/ml).
Assuntos
Apocynaceae , COVID-19 , Proteases 3C de Coronavírus , Animais , Humanos , Antivirais/farmacologia , Antivirais/química , Apocynaceae/química , Proteases 3C de Coronavírus/antagonistas & inibidores , Glicosídeos/farmacologia , Glicosídeos/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Pregnanos/farmacologia , Pregnanos/química , Inibidores de Proteases/farmacologia , Inibidores de Proteases/química , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/metabolismoRESUMO
A new alkaloids, aplysingoniopora A (1), and new configuration pregnane type steroid compound, 9,17-α-pregn-1,4,20-en-3-one (2), and two known pregnane type steroid compounds (3 and 4) were isolated from hydranth of Goniopora columna corals. The compounds structures and absolute configurations were determined by extensive spectroscopic analysis, MS data, single-crystal X-ray diffraction analysis and quantum chemical calculation. The anticancer effect of the compounds were explored in human non-small-cell lung cancer (NSCLC) A549â cell lines. As the results, the compound 3 and 4 induces toxicity and has proliferation inhibitory effects on A549 cells (IC50=58.99â µM and 58.77â µM, respectively) inâ vitro.
Assuntos
Alcaloides , Antozoários , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Animais , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Alcaloides/farmacologia , Alcaloides/química , Esteroides/farmacologia , Esteroides/química , Pregnanos/farmacologia , Estrutura MolecularRESUMO
Four new polyhydroxy pregnane glycosides, named volubilosides G-K (3, 5-7), along with three known secondary metabolites, dregeoside Da1 (1), dregeoside Ka1 (2), and volubiloside E (4) were isolated from the twigs and leaves of Dregea volubilis (DV). The chemical structures of these compounds (1-7) were elucidated using spectroscopic techniques (1D and 2D NMR and HR-ESI-MS analyses) and compared with those in the published literature. Compounds (1-7) were evaluated for cytotoxicity against eight cancer cell lines (MB49, K562, MKN-7, HT29, A549, MCF-7, MDA-MB-231, and HepG2), revealing varying levels of cytotoxic effects with IC50 values ranging from 4.29 to 21.05â µM. The results indicated that compounds 1-7 may serve as potential lead compounds for the discovery and development of novel anti-cancer drugs.
Assuntos
Antineoplásicos Fitogênicos , Antineoplásicos , Saponinas , Saponinas/farmacologia , Saponinas/química , Estrutura Molecular , Glicosídeos/química , Pregnanos/farmacologia , Folhas de Planta , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/químicaRESUMO
Salmonella is a Gram-negative bacterium that causes gastrointestinal diseases in 20 to 40 million people globally. Stemmoside C is a steroidal glycoside isolated from Argel, although its antibacterial and antibiofilm properties have not been studied. The antibacterial activity of Stemmoside C against Salmonella enterica was revealed, where MIC of the compound was 16 µg/mL (0.15 µM). Biofilm-associated Stemmoside C treatment destroyed S. typhi cells and reduced viable S. typhi numbers below detectable levels. When compared to Stemmoside C or Ciprofluxacin-treated mice, infected BALB/c mice had a greater death rate and a larger bacterial blood burden. The protective effects of orally administered Stemmoside C at dose of 25 and 50 mg/kg b.wt. against bacterial infection was associated with reduction in the levels of inflammatory cytokines (IFN-γ, Il-1ß, IL-2, IL-6, MPO, and TNF-α) and elevation of anti-inflammatory cytokine (IL-10 and IL-12) in serum. Where, Stemmoside C at dose of 50 mg/kg b.wt. regulated the levels almost as normal control group and demonstrated apparently normal intestinal sections. It also resulted in a decrease in the number of viable S. typhi retrieved from feces. Stemmoside C is a promising drug for the treatment or prevention of S. typhimurium infection.
Assuntos
Salmonella enterica , Salmonella typhimurium , Animais , Humanos , Camundongos , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Citocinas , Camundongos Endogâmicos BALB C , Sorogrupo , Pregnanos/farmacologia , Pregnanos/uso terapêuticoRESUMO
Eighteen previously unreported pregnane glycosides, namely marsdenosides S1-S18, along with 15 known analogues, have been isolated from the stems of Marsdenia tenacissima. The structures of the undescribed compounds were elucidated by spectroscopic means, and their absolute configurations were established on the basis of time-dependent density functional theory (TD-DFT) based electronic circular dichroism (ECD) calculation, X-ray crystallography and acid hydrolysis. All the isolates were evaluated for their chemo-reversal ability against P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) in MCF-7/ADR cell line, and nine ones displayed moderate MDR reversal activity with reversal folds in the range of 2.45-9.01. The most active 12-O-acetyl-20-O-benzoyl-(14,17,18-orthoacetate)-dihydrosarcostin-3-O-ß-d-thevetopyranosyl-(1 â 4)-O-ß-d-oleandropyranosyl-(1 â 4)-O-ß-d-cymaropyranoside increased the sensitivity of MCF-7/ADR cell to adriamycin comparably to the reference drug verapamil (RF = 8.93).
Assuntos
Marsdenia , Marsdenia/química , Estrutura Molecular , Glicosídeos/farmacologia , Glicosídeos/química , Pregnanos/farmacologia , Pregnanos/química , Resistência a Múltiplos MedicamentosRESUMO
Twenty compounds comprising four pregnane steroids (2-4 & 20) and 16 pregnane glycosides (1 & 5-19) have been obtained from the ethanol extract of the roots of a Dai ethnological herb, Marsdenia tenacissima. Their structures were characterized on the basis of comprehensive spectroscopic analyses with 17 ones (1-17) being reported for the first time, including the rare cases (2 & 3) of free C21 steroids with 17α-acetyl substitution, compounds 4-7 bearing an unusual 14α-OH, and the first examples with simultaneous 14α-OH/17α-acetyl substitution (7) and glycosylation at C-12 position (10 & 11). An empirical rule for the identification of C-17 configuration, in C21 steroids incorporating the marsdenin constitution structure, was also proposed. All the isolates, along with an array of previously reported analogues in our compound library, were screened for their chemo-reversal ability against P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) in MCF-7/ADR cell line, and six compounds exhibited moderate MDR reversal activity with reversal folds ranging from 1.92 to 4.44.
Assuntos
Marsdenia , Marsdenia/química , Estrutura Molecular , Esteroides/farmacologia , Esteroides/química , Pregnanos/farmacologia , Pregnanos/química , Glicosídeos/farmacologia , Glicosídeos/química , Resistência a Múltiplos MedicamentosRESUMO
Two new pregnane glycosides (1 and 2), together with four known ones (3- 6), were isolated from the roots of Cynanchum auriculatum Royle ex Wight (Asclepiadaceae). On the basis of detailed spectroscopic analysis and chemical method, the structures of new compounds were characterized to be metaplexigenin 3-O-ß-D-cymaropyranosyl- (1â4)-α-L-diginopyranosyl-(1â4)-ß-D-cymaropyranoside (1), metaplexigenin 3-O-α-L-diginopyranosyl-(1â4)-ß-D-cymaropyranoside (2). All the isolated compounds (1-6) were tested for their in vitro inhibitory activity against the growth of human colon cancer cell lines HCT-116. Compounds 5 and 6 showed significant cytoxicities with IC50 values of 43.58 µM and 52.21 µM.
Assuntos
Cynanchum , Humanos , Cynanchum/química , Raízes de Plantas/química , Pregnanos/farmacologia , Pregnanos/química , Glicosídeos/farmacologia , Glicosídeos/química , Estrutura MolecularRESUMO
Phytochemical investigation on the stems of Strophanthus divaricatus led to the isolation of four undescribed cardiac glycosides and one undescribed C21 pregnane, together with eleven known steroids. Their structures were elucidated by a comprehensive analysis of HRESIMS, 1D and 2D NMR spectra. The absolute configuration of 16 was determined by comparison of the experimental and computed ECD spectra. Compounds 1-13 and 15 displayed potent to significant cytotoxicity against human cancer cell lines K562, SGC-7901, A549 and HeLa with IC50 values of 0.02-16.08, 0.04-23.13, 0.06-22.31 and 0.06-15.13 µM, respectively.
Assuntos
Antineoplásicos , Strophanthus , Humanos , Glicosídeos/química , Pregnanos/farmacologia , Pregnanos/química , Linhagem Celular Tumoral , Estrutura MolecularRESUMO
Cynanchum viminale subsp. australe, more commonly known as caustic vine, is a leafless succulent that grows in the northern arid zone of Australia. Toxicity toward livestock has been reported for this species, along with use in traditional medicine and its potential anticancer activity. Disclosed herein are novel seco-pregnane aglycones cynavimigenin A (5) and cynaviminoside A (6), together with new pregnane glycosides cynaviminoside B (7) and cynavimigenin B (8). Cynavimigenin B (8) contains an unprecedented 7-oxobicyclo[2.2.1]heptane moiety in the seco-pregnane series, likely arising from a pinacol-type rearrangement. Interestingly, these isolates displayed only limited cytotoxicity in cancer and normal human cell lines, in addition to low activity against acetylcholinesterase and Sarcoptes scabiei bioassays, suggesting that 5-8 are not associated with the reported toxicity of this plant species.
Assuntos
Cáusticos , Cynanchum , Humanos , Acetilcolinesterase , Austrália , Glicosídeos/farmacologia , Pregnanos/farmacologia , Raízes de PlantasRESUMO
Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a potential target for inflammatory-breast cancer treatment as it participates in its pathogenesis, such as tumor initiation, progression, survival, metastasis, and recurrence. In this study, we aimed to discover a novel anti-cancer treatment from natural products by targeting NF-κB activity. Using the 4T1-NFκB-luciferase reporter cell line, we tested three pregnane glycosides extracted from the herb Caralluma tuberculata and discovered that Russelioside A markedly suppressed NF-κB activity in breast cancer. Russelioside A inhibited NF-κB (p65) transcriptional activity and its phosphorylation. Following NF-κB inhibition, Russelioside A exerted anti-proliferative and anti-metastatic effects in breast cancer cells in vitro. Moreover, it inhibited the NF-κB constitutive expression of downstream pathways, such as VEGF-b, MMP-9, and IL-6 in 4T1 cells. In addition, it reduced the metastatic capacity in a 4T1 breast cancer model in vivo. Collectively, our conclusions reveal that Russelioside A is an attractive natural compound for treating triple-negative breast cancer growth and metastasis through regulating NF-κB activation.
Assuntos
Apocynaceae , Produtos Biológicos , Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Apocynaceae/metabolismo , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Feminino , Glicosídeos/farmacologia , Glicosídeos/uso terapêutico , Humanos , Interleucina-6/metabolismo , Metaloproteinase 9 da Matriz , NF-kappa B/metabolismo , Pregnanos/farmacologia , Pregnanos/uso terapêutico , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Fator B de Crescimento do Endotélio VascularRESUMO
Metastasis is an important cause of cancer-related death. Previous studies in our laboratory found that pregnane alkaloids from Pachysandra terminalis had antimetastatic activity against breast cancer cells. In the current study, we demonstrated that treatment with one of the alkaloid derivatives, (Z)-3ß-ethylamino-pregn-17(20)-en (1), led to the downregulation of the HIF-1α/VEGF/VEGFR2 pathway, suppressed the phosphorylation of downstream molecules Akt, mTOR, FAK, and inhibited breast cancer metastasis and angiogenesis both in vitro and in vivo. Furthermore, the antimetastasis and antiangiogenesis effects of 1 treatment (40 mg/kg) were more effective than that of Sorafenib (50 mg/kg). Surface plasmon resonance (SPR) analysis was performed and the result suggested that HSP90α was a direct target of 1. Taken together, our results suggested that compound 1 might represent a candidate antitumor agent for metastatic breast cancer.
Assuntos
Alcaloides , Antineoplásicos , Neoplasias de Mama Triplo Negativas , Humanos , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Sorafenibe/uso terapêutico , Linhagem Celular Tumoral , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Antineoplásicos/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Alcaloides/farmacologia , Alcaloides/uso terapêutico , Pregnanos/farmacologia , Subunidade alfa do Fator 1 Induzível por HipóxiaRESUMO
Mandevilla Lindl. is an important genus of the Apocynaceae family, not only as ornamental plants but also for its medicinal uses. In Brazil, Mandevilla species are indicated to treat asthma and skin infections, their anti-inflammatory potential and wound healing properties are also reported in the literature. Concerning their chemical composition, this group of plants is a conspicuous producer of pregnane glycosides. Mandevilla dardanoi is an endemic species from the Brazilian semiarid region not studied by any phytochemical methods. In view of the medicinal potential of Mandevilla species, this study aimed to isolate new pregnane glycosides from M. dardanoi. To achieve this main goal, modern chromatography techniques were employed. Five new pregnane glycosides, dardanols A-E, were isolated from the roots of M. dardanoi by HPLC. Their structures were determined using extensive 1D and 2D-NMR and mass spectrometry (MSn and HRESIMS) data. The cytotoxicity and the anti-inflammatory potential of these compounds were evaluated. The first was evaluated by measuring proinflammatory cytokines and nitric oxide production by stimulated macrophages. Dardanols were able to inhibit the production of nitric oxide and reduce IL-1ß and TNF-α. The current work demonstrates the chemodiversity of Brazilian semiarid species and contributes to amplifying knowledge about the biological potential of the Mandevilla genus.
Assuntos
Apocynaceae , Óxido Nítrico , Anti-Inflamatórios/farmacologia , Apocynaceae/química , Glicosídeos/química , Glicosídeos/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Plantas , Pregnanos/química , Pregnanos/farmacologia , Fator de Necrose Tumoral alfaRESUMO
For our interest in the potential biologically active and structurally unique steroidal glycosides, continued phytochemical investigation of Cynanchum taihangense was carried out; twelve new seco-pregnane glycosides, cynataihosides I-L (1-4), M-T (7-14), and two known glycosides, glaucoside A (5) and atratcynoside F (6), were isolated from the 95% ethanol extract of Cynanchum taihangense. Two new aglycones were found among compounds 10, 11, 13, and 14. The structures of the glycosides were elucidated based on 1D and 2D NMR spectroscopic data, HR-ESI-MS analysis, and chemical evidence. The cytotoxicity of compounds against three human tumor cell lines (HL-60, THP-1, and PC-3) were evaluated by MTT assay. Compound 11 displayed significant cytotoxicity against THP-1 and PC-3 cell line with IC50 values of 5.08 and 22.75 µm, respectively. Compounds 3 and 14 exhibited moderate and selective cytotoxicity on HL-60 and THP-1 with IC50 values of 17.78 and 16.02 µm, respectively.
Assuntos
Cynanchum , Cynanchum/química , Glicosídeos/química , Humanos , Estrutura Molecular , Raízes de Plantas/química , Pregnanos/química , Pregnanos/farmacologiaRESUMO
The ability of endogenous neurosteroids (NSs) with pregnane skeleton modified at positions C-3 and C-5 to modulate the functional activity of inhibitory glycine receptors (GlyR) and ionotropic É£-aminobutyric acid receptors (GABAA R) was estimated. The glycine and GABA-induced chloride current (IGly and IGABA ) were measured in isolated pyramidal neurons of the rat hippocampus and in isolated rat cerebellar Purkinje cells, respectively. Our experiments demonstrated that pregnane NSs affected IGABA and IGly in a different manner. At low concentrations (up to 5 µM), tested pregnane NSs increased or did not change the peak amplitude of the IGABA , but reduced the IGly by decreasing the peak amplitude and/or accelerating desensitization. Namely, allopregnanolone (ALLO), epipregnanolone (EPI), pregnanolone (PA), pregnanolone sulfate (PAS) and 5ß-dihydroprogesterone (5ß-DHP) enhanced the IGABA in Purkinje cells. Dose-response curves plotted in the concentration range from 1 nM to 100 µM were smooth for EPI and 5ß-DHP, but bell-shaped for ALLO, PA and PAS. The peak amplitude of the IGly was reduced by PA, PAS, and 5α- and 5ß-DHP. In contrast, ALLO, ISO and EPI did not modulate it. Dose-response curves for the inhibition of the IGly peak amplitude were smooth for all active compounds. All NSs accelerated desensitization of the IGly . The dose-response relationship for this effect was smooth for ALLO, PA, PAS and 5ß-DHP, but it was U-shaped for EPI, 5α-DHP and ISO. These results, together with our previous results on NSs with androstane skeleton, offer comprehensive overview for understanding the mechanisms of effects of NSs on IGly and IGABA .
Assuntos
Neuroesteroides , Pregnanolona , 5-alfa-Di-Hidroprogesterona/farmacologia , Animais , Cloretos/farmacologia , Glicina/farmacologia , Neurônios/fisiologia , Pregnanos/farmacologia , Pregnanolona/farmacologia , Ratos , Ratos Wistar , Receptores de GABA-A/fisiologia , Ácido gama-AminobutíricoRESUMO
Three new compounds named cynansteroid A (1), cynansteroid B (2) and cynansteroid C (3), together with nine known C21 -steroidal pregnane sapogenins (4-12) were isolated from the hydrolytic extract of the roots of Cynanchum auriculatum. The structures of cynansteroid A-C (1-3) were ascertained via the detailed analysis of the HR-ESI-MS, 1D and 2D NMR, and the calculated and experimental ECD data of cynansteroid B (2). Compound 11 displayed moderate inhibitory activity toward Verticillium dahliae Kleb (IC50 =37.15â µM), furthermore, compounds 11 and 12 showed significant inhibitory activity against Phomopsis sp. (IC50 =16.49â µM and 17.62â µM, respectively).
Assuntos
Cynanchum , Sapogeninas , Cynanchum/química , Glicosídeos/química , Raízes de Plantas/química , Pregnanos/química , Pregnanos/farmacologiaRESUMO
Six unidentified C21 steroidal glycosides, cynwallosides A-F, as well as twenty-two known compounds, were isolated from the roots of Cynanchum wallichii Wight. The structures of cynwallosides A-F were determined by spectroscopic analysis and acidic hydrolysis. Most of these twenty-eight compounds were found to significantly reverse drug resistance in both the MCF-7/ADR and HepG2/ADM cell lines by suppressing P-gp protein expression. Further investigation revealed that three compounds suppressed P-gp expression by significantly inactivating the JNK and NF-κB pathways.
Assuntos
Cynanchum , Cynanchum/química , Resistência a Múltiplos Medicamentos , Glicosídeos/química , Imidazóis , Estrutura Molecular , Raízes de Plantas/química , Pregnanos/química , Pregnanos/farmacologia , Sulfonamidas , TiofenosRESUMO
BACKGROUND AND PURPOSE: N-methyl-D-aspartate receptors (NMDARs) play a critical role in synaptic plasticity, and mutations in human genes encoding NMDAR subunits have been described in individuals with various neuropsychiatric disorders. Compounds with a positive allosteric effect are thought to compensate for reduced receptor function. EXPERIMENTAL APPROACH: We have used whole-cell patch-clamp electrophysiology on recombinant rat NMDARs and human variants found in individuals with neuropsychiatric disorders, in combination with in silico modelling, to explore the site of action of novel epipregnanolone-based NMDAR modulators. KEY RESULTS: Analysis of the action of 4-(20-oxo-5ß-pregnan-3ß-yl) butanoic acid (EPA-But) at the NMDAR indicates that the effect of this steroid with a "bent" structure is different from that of cholesterol and oxysterols and shares a disuse-dependent mechanism of NMDAR potentiation with the "planar" steroid 20-oxo-pregn-5-en-3ß-yl sulfate (PE-S). The potentiating effects of EPA-But and PE-S are additive. Alanine scan mutagenesis identified residues that reduce the potentiating effect of EPA-But. No correlation was found between the effects of EPA-But and PE-S at mutated receptors that were less sensitive to either steroid. The relative degree of potentiation induced by the two steroids also differed in human NMDARs carrying rare variants of hGluN1 or hGluN2B subunits found in individuals with neuropsychiatric disorders, including intellectual disability, epilepsy, developmental delay, and autism spectrum disorder. CONCLUSION AND IMPLICATIONS: Our results show novel sites of action for pregnanolones at the NMDAR and provide an opportunity for the development of new therapeutic neurosteroid-based ligands to treat diseases associated with glutamatergic system hypofunction.
Assuntos
Transtorno do Espectro Autista , Receptores de N-Metil-D-Aspartato , Animais , Mutação , Pregnanos/farmacologia , Ratos , Receptores de N-Metil-D-Aspartato/genética , EsteroidesRESUMO
The rapid spread of drug resistant malaria parasites has necessitated the search for novel antimalarials and chemosensitizers capable of reversing drug resistance in the parasites. A number of studies have revealed the resistance reversal activities of pregnane glycosides and the antimalarial activity of a pregnane glycoside obtained from Gongronema species. However, the pregnane (2) and pregnane glycosides (1, 3-4) isolated from Gongronema latifolium leaf have not been evaluated for these activities. This study was therefore carried out to evaluate the antiplasmodial and chloroquine resistance reversal activities of a pregnane and three pregnane glycosides isolated from G. latifolium leaf in vitro. The compounds were evaluated for their inhibitory activities against P. falciparum 3D7 (a chloroquine-sensitive strain) and P. falciparum W2 (a chloroquine-resistant clone) in vitro. The activities of chloroquine in separate combination with each of the compounds against P. falciparum W2 were also evaluated. Moreover, the interaction of the active compounds (1 and 4) with selected P. falciparum proteins (PfProteins) were evaluated in silico. The results revealed that only 1 and 4 were active against P. falciparum 3D7 and P. falciparum W2. Also, 2 and 3 did not exhibit chloroquine resistance reversal activity. Activity of chloroquine against P. falciparum W2 was potentiated by 1 by 3200% at concentrations higher than 0.625 µg/mL. Also, 1 and 4 demonstrated similar binding patterns and higher binding tendencies to the selected PfProteins compared to chloroquine. Thus, 1 (iloneoside) is an antimalarial pregnane glycoside which can potentiate the activity of chloroquine against multidrug resistant P. falciparum.
Assuntos
Antimaláricos , Apocynaceae , Antagonistas do Ácido Fólico , Malária Falciparum , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Cloroquina/farmacologia , Resistência a Medicamentos , Antagonistas do Ácido Fólico/farmacologia , Glicosídeos/análise , Glicosídeos/farmacologia , Malária Falciparum/tratamento farmacológico , Folhas de Planta/química , Plasmodium falciparum , Pregnanos/análise , Pregnanos/farmacologiaRESUMO
INTRODUCTION: The present study deals with the synthesis of pregnane-oximino-amino-alkyl-ethers and their evaluation for antidiabetic and anti-dyslipidemic activities in validated animal and cell culture models. METHODS: The effect on glucose tolerance was measured in sucrose-loaded rats; antidiabetic activity was evaluated in streptozotocin (STZ)-induced diabetic rats and genetically diabetic db/db mice; the anti-dyslipidemic effect was characterized in high-fructose, high-fat diet (HFD)-fed dyslipidemic hamsters. The effect on glucose production and glucose utilization was analyzed in HepG2 liver and L6 skeletal muscle cells, respectively. RESULTS: From the synthesized molecules, pregnane-oximino-amino-alkyl-ether (compound 14b) improved glucose clearance in sucrose-loaded rats and exerted antihyperglycemic activity on STZ-induced diabetic rats. Further evaluation in genetically diabetic db/db mice showed temporal decrease in blood glucose, and improvement in glucose tolerance and lipid parameters, associated with mild improvement in the serum insulin level. Moreover, compound 14b treatment displayed an anti-dyslipidemic effect characterized by significant improvement in altered lipid parameters of the high-fructose, HFD-fed dyslipidemic hamster model. In vitro analysis in the cellular system suggested that compound 14b decreased glucose production in liver cells and stimulated glucose utilization in skeletal muscle cells. These beneficial effects of compound 14b were associated with the activation of the G-protein-coupled bile acid receptor TGR5. CONCLUSION: Compound 14b exhibits antidiabetic and anti-dyslipidemic activities through activating the TGR5 receptor system and can be developed as a lead for the management of type II diabetes and related metabolic complications.