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A new pregnane steroid, jasminanthoside (1), together with three known compounds, telosmoside A7 (2), syringaresinol (3), and methyl 6–deoxy–3–O–methyl–β–D–allopyranosyl–(1→4)–β–D–oleandropyranoside (4) were isolated from the ethyl acetate extract of Jasminanthes tuyetanhiae roots collected in Vietnam. Their chemical structures were elucidated by NMR and MS spectroscopic data analysis along with the comparison of their data with the published ones in the literature. Although 4 was a known compound, its full NMR data were reported for the first time. All isolated compounds, evaluated for their α-glucosidase inhibition, showed activities stronger than the positive control acarbose. Among them, 1 was the best with the IC50 value of 7.41 ± 0.59 µM. [ABSTRACT FROM AUTHOR]

This article presents a comprehensive overview of recent discoveries and advancements in the field of steroid chemistry, highlighting the isolation and characterization of various steroidal compounds from natural sources. This paper discusses a wide range of steroids, including pregnane steroids, steroidal alkaloids, ketosteroids, and novel triterpenoids, derived from marine organisms, fungi, and plants. Significant findings include the isolation of bioactive compounds such as the cytotoxic erectsterates from microorganisms, soft corals, the unusual tetracyclic steroid penicillitone from a fungal culture, and innovative steroidal derivatives with potential anti-inflammatory and anticancer activities. The synthesis of steroids from microorganisms as a tool for pharmaceutical development is also explored, showcasing the role of microbial biotransformation in generating steroidal drugs. Additionally, this paper emphasizes the ecological and medicinal relevance of these compounds, which are often used in traditional medicine and have potential therapeutic applications in treating diseases like cancer and microbial infections. This article serves as a vital resource for researchers interested in the chemical diversity of steroids and their applications in drug discovery and development. [ABSTRACT FROM AUTHOR]

Pregnane neuroactive steroids, notably allopregnanolone and pregnenolone, exhibit efficacy in mitigating inflammatory signals triggered by toll-like receptor (TLR) activation, thus attenuating the production of inflammatory factors. Clinical studies highlight their therapeutic potential, particularly in conditions like postpartum depression (PPD), where the FDA-approved compound brexanolone, an intravenous formulation of allopregnanolone, effectively suppresses TLR-mediated inflammatory pathways, predicting symptom improvement. Additionally, pregnane neurosteroids exhibit trophic and anti-inflammatory properties, stimulating the production of vital trophic proteins and anti-inflammatory factors. Androstane neuroactive steroids, including estrogens and androgens, along with dehydroepiandrosterone (DHEA), display diverse effects on TLR expression and activation. Notably, androstenediol (ADIOL), an androstane neurosteroid, emerges as a potent anti-inflammatory agent, promising for therapeutic interventions. The dysregulation of immune responses via TLR signaling alongside reduced levels of endogenous neurosteroids significantly contributes to symptom severity across various neuropsychiatric disorders. Neuroactive steroids, such as allopregnanolone, demonstrate efficacy in alleviating symptoms of various neuropsychiatric disorders and modulating neuroimmune responses, offering potential intervention avenues. This review emphasizes the significant therapeutic potential of neuroactive steroids in modulating TLR signaling pathways, particularly in addressing inflammatory processes associated with neuropsychiatric disorders. It advances our understanding of the complex interplay between neuroactive steroids and immune responses, paving the way for personalized treatment strategies tailored to individual needs and providing insights for future research aimed at unraveling the intricacies of neuropsychiatric disorders. [ABSTRACT FROM AUTHOR]

Erythroleukemia is a rare form of acute myeloid leukemia (AML). Its molecular pathogenesis remains vague, and this disease has no specific therapeutic treatments. Previously, our group isolated a series of Carbon 21 (C-21) steroidal glycosides with pregnane skeleton from the root of Cynanchum atratum Bunge. Among them, we found that a compound, named BW18, can induce S-phase cell cycle arrest and apoptosis via the mitogen-activated protein kinase (MAPK) pathway in human chronic myeloid leukemia K562 cells. However, its anti-tumor activity against erythroleukemia remains largely unknown. In this study, we aimed to investigate the anti-erythroleukemia activity of BW18 and the underlying molecular mechanisms. Our results demonstrated that BW18 exhibited a good anti-erythroleukemia activity in the human erythroleukemia cell line HEL and an in vivo xenograft mouse model. In addition, BW18 induced cell cycle arrest at the G2/M phase and promoted megakaryocytic and erythroid differentiation in HEL cells. Furthermore, RNA sequencing (RNA-seq) and rescue assay demonstrated that overexpression of platelet-derived growth factor receptor beta (PDGFRB) reversed BW18-induced megakaryocytic differentiation in HEL cells, but not erythroid differentiation. In addition, the network pharmacology analysis, the molecular docking and cellular thermal shift assay (CETSA) revealed that BW18 could inactivate Janus tyrosine kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway, which might mediate BW18-induced erythroid differentiation. Taken together, our findings elucidated a novel role of PDGFRB in regulating erythroleukemia differentiation and highlighted BW18 as an attractive lead compound for erythroleukemia treatment. [ABSTRACT FROM AUTHOR]

The structural identification and efficient synthesis of bioactive 2,6-dideoxyglycosides are daunting challenges. Here, we report the total synthesis and structural revision of a series of 2,6-dideoxyglycosides from folk medicinal plants Ecdysanthera rosea and Chonemorpha megacalyx, which feature pregnane steroidal aglycones bearing an 18,20-lactone and glycans consisting of 2,6-dideoxy-3-O-methyl-β-pyranose residues, including ecdysosides A, B, and F and ecdysantheroside A. All the eight possible 2,6-dideoxy-3-O-methyl-β-pyranoside stereoisomers (of the proposed ecdysantheroside A) have been synthesized that testify the effective gold(I)-catalyzed glycosylation methods for the synthesis of various 2-deoxy-β-pyranosidic linkages and lays a foundation via nuclear magnetic resonance data mapping to identify these sugar units which occur promiscuously in the present and other natural glycosides. Moreover, some synthetic natural compounds and their isomers have shown promising anticancer, immunosuppressive, anti-inflammatory, and anti-Zika virus activities. [ABSTRACT FROM AUTHOR]

Aminobenzotriazole (ABT) is commonly used as a non‐selective inhibitor of cytochrome P450 (CYP) enzymes to assign contributions of CYP versus non‐CYP pathways to the metabolism of new chemical entities. Despite widespread use, a systematic review of the drug–drug interaction (DDI) potential for ABT has not been published nor have the implications for using it in plated hepatocyte models for low clearance reaction phenotyping. The goal being to investigate the utility of ABT as a pan‐CYP inhibitor for reaction phenotyping of low clearance compounds by evaluating stability over the incubation period, inhibition potential against UGT and sulfotransferase enzymes, and interaction with nuclear receptors involved in the regulation of drug metabolizing enzymes and transporters. Induction potential for additional inhibitors used to ascribe fraction metabolism (fm), pathway including erythromycin, ketoconazole, azamulin, atipamezole, ZY12201, and quinidine was also investigated. ABT significantly inhibited the clearance of a non‐selective UGT substrate 4‐methylumbelliferone, with several UGTs shown to be inhibited using selective probe substrates in human hepatocytes and rUGTs. The inhibitors screened in the induction assay were shown to induce enzymes regulated through Aryl Hydrocarbon Receptor, Constitutive Androstane Receptor, and Pregnane X Receptor. Lastly, a case study identifying the mechanisms of a clinical DDI between Palbociclib and ARV‐471 is provided as an example of the potential consequences of using ABT to derive fm. This work demonstrates that ABT is not an ideal pan‐CYP inhibitor for reaction phenotyping of low clearance compounds and establishes a workflow that can be used to enable robust characterization of other prospective inhibitors. [ABSTRACT FROM AUTHOR]

Actinomycetes are known to be a source of natural products and drugs. Gordonia terrae, an actinomycete pigment producer, shows potential in producing pigment with antimicrobial activity. This study aims to determine the antimicrobial activity of the active pigment fraction produced by the actinomycete G. terrae, assess the effects of the active pigment fraction on microbial cells, and identify the types of compounds present in the fraction. The pigment extract exhibited antimicrobial activity against Gram-positive bacteria and fungi. Specifically, it showed activity against Bacillus subtilis ATCC 6633, Staphylococcus aureus ATCC 25293, and Candida albicans ATCC 10231. Furthermore, the study evaluated the antimicrobial activities of the active fractions, revealed the active fraction had better antimicrobial activity than the crude extract. Scanning electron microscopy (SEM) confirmed that the active fraction of the pigment causes damage to B. subtilis ATCC 6633 cells, inhibits the formation of filaments in C. albicans ATCC 10231, and alters the normal shape of the cells. LC-MS/ MS results showed that the active fraction contained several compounds known for their antimicrobial activity. Among the dominant compounds identified were cholestyramine, aminopregnane, and sphinganine. Thus, this study demonstrated that the orange pigment extract derived from G. terrae JSN1.9 exhibits promising antimicrobial activity. [ABSTRACT FROM AUTHOR]

Two new compounds geobomlin A (1) and geobomlin B (2) were isolated from the roots of Stachys geobombycis C. Y. Wu. Structural determinations were established principally by two-dimensional NMR and MS data analyses. Geobomlin B showed moderate inhibitory activity against α-glucosidase with IC50 = 248.77 μM. We have also determined the mechanism by which geobomlin B elicit its inhibitory effect on α-glucosidase, for which we have established a competitive inhibition mode. Docking studies confirmed our results on geobomlin B α-glucosidase inhibitory properties. [ABSTRACT FROM AUTHOR]

The central nervous system is susceptible to the modulation of various neurophysiological processes by the cytochrome P450 enzyme (CYP), which plays a crucial role in the metabolism of neurosteroids. The antiepileptic drug phenytoin (PHT) has been observed to induce neuronal side effects in patients, which could be attributed to its induction of CYP expression and testosterone (TES) metabolism in the hippocampus. While pregnane X receptor (PXR) is widely known for its regulatory function of CYPs in the liver, we have discovered that the treatment of mice with pregnenolone 16α-carbonitrile (PCN), a PXR agonist, has differential effects on CYP expression in the liver and hippocampus. Specifically, the PCN treatment resulted in the induction of cytochrome P450, family 3, subfamily a, polypeptide 11 (CYP3A11), and CYP2B10 expression in the liver, while suppressing their expression in the hippocampus. Functionally, the PCN treatment protected mice from PHT-induced hippocampal nerve injury, which was accompanied by the inhibition of TES metabolism in the hippocampus. Mechanistically, we found that the inhibition of hippocampal CYP expression and attenuation of PHT-induced neurotoxicity by PCN were glucocorticoid receptor dependent, rather than PXR independent, as demonstrated by genetic and pharmacological models. In conclusion, our study provides evidence that PCN can negatively regulate hippocampal CYP expression and attenuate PHT-induced hippocampal neurotoxicity independently of PXR. Our findings suggest that glucocorticoids may be a potential therapeutic strategy for managing the neuronal side effects of PHT. [Display omitted] • PCN had differential effects on CYP expression in the liver and hippocampus. • PCN attenuated phenytoin-induced neurotoxicity by inhibiting hippocampal CYPs. • The attenuation of phenytoin-induced neurotoxicity by PCN was PXR independent. • Glucocorticoids may be used to manage the neuronal side effect of phenytoin. [ABSTRACT FROM AUTHOR]

Objectives: Caralluma speciosa (N.E. Br.) N.E. Br. (Asclepiadaceae) and other succulent plants of the genus Caralluma have mainly been known for their appetite suppressing and weight loss properties, due to the presence of pregnane compounds. This study aimed to investigate chemical constituents and evaluate antimicrobial and antioxidant activities of stems of C speciosa. Methods: The chloroform and methanol stems extracts were subjected to silica gel chromatographic separation. The structures of isolated compounds were established by FT-IR, 1D-NMR, and GC-MS instruments, and in comparison with reported data. The antimicrobial and antioxidant activities were performed using agar disc diffusion and DPPH assaying methods. Results: The phytochemical investigation afforded 5 compounds, 3 pregnane derivatives (3-5), and 2 other compounds, heptacos-1-ene (1) and di-(2-ethylhexyl) phthalate (2). The chloroform: methanol (1:1) extract showed a good antifungal activity against Candida albicans up to 25 mg/mL dose (9.00 ± 1.00 mm to 17.17 ± 1.04 mm), equivalent to ketoconazole standard (17.67 ± 2.52 mm at 0.01 mg/disc). Compounds 3 and 5 were found violated 3 of the Lipinski's rule of 5. Compounds 2 and 4 exhibited a carcinogenicity property; while compounds 3, 4, and 5 were found as immunotoxic isolates. Conclusion: All the extracts and isolated compounds 1-5 showed a negligible antibacterial and antioxidant activities compared to the antibiotic chloramphenicol (7.3 ± 0.4 to 21.15 ± 0.5 mm) and antioxidant ascorbic acid (IC50 value of 5.62 µg/mL). Hence, further biological activities study (including the anticancer, anti-inflammatory, and antifungal activities) would be needed on all the extracts and isolated compounds to look for better efficacy and predict the structure–activity relationship of the compounds. [ABSTRACT FROM AUTHOR]

Two new pregnane glycosides, parasiticoside A (1) and parasiticoside B (2), were isolated from the leaves of Hoya parasitica. Their structures were determined by spectroscopic analysis 1D and 2D NMR, and mass spectrometry (HR-ESI-MS in positive mode) techniques as 3β,20-dihydroxy-pregn-5-ene-3-O-β-Dfucopyranoside-20-O-β-D-glucopyranoside (1), and 3β,20-dihydroxy-pregn-5-ene-3-O-α-L-rhamnopyranosyl- (1→2)-β-D-fucopyranoside-20-O-β-D-glucopyranoside (2). These compounds are believed to be the first example of pregnane glycosides from a plant of the genus Hoya. [ABSTRACT FROM AUTHOR]

Pharmaceuticals and environmental contaminants contribute to hypercholesterolemia. Several chemicals known to cause hypercholesterolemia, activate pregnane X receptor (PXR). PXR is a nuclear receptor, classically identified as a sensor of chemical environment and regulator of detoxification processes. Later, PXR activation has been shown to disrupt metabolic functions such as lipid metabolism and recent findings have shown PXR activation to promote hypercholesterolemia through multiple mechanisms. Hypercholesterolemia is a major causative risk factor for atherosclerosis and greatly promotes global health burden. Metabolic disruption by PXR activating chemicals leading to hypercholesterolemia represents a novel toxicity pathway of concern and requires further attention. Therefore, we constructed an adverse outcome pathway (AOP) by collecting the available knowledge considering the molecular mechanisms for PXR-mediated hypercholesterolemia. AOPs are tools of modern toxicology for systematizing mechanistic knowledge to assist health risk assessment of chemicals. AOPs are formalized and structured linear concepts describing a link between molecular initiating event (MIE) and adverse outcome (AO). MIE and AO are connected via key events (KE) through key event relationships (KER). We present a plausible route of how PXR activation (MIE) leads to hypercholesterolemia (AO) through direct regulation of cholesterol synthesis and via activation of sterol regulatory element binding protein 2-pathway. [ABSTRACT FROM AUTHOR]

Two novel pregnane–cholesterol and cholesterol–cholesterol prodrugs have been synthesized. The synthetic route involved preparation of 2-(cholest-5-en-3-yloxycarbonyl)benzoic acid (2) by the esterification of cholesterol (1) with phthalic anhydride. The pregnane–cholesterol prodrug (4) was synthesized by treating 2-(cholest-5-en-3-yloxycarbonyl)benzoic acid (2) with 3β-hydroxypregna-5,16-dien-20-one (3), and cholesterol–cholesterol prodrug (5) was synthesized by treating acid 2 with cholesterol. The synthesized compounds have been characterized with the help of spectroscopic techniques like 1H and 13C NMR, FT-IR, UV-visible spectroscopy, and mass spectrometry. The prodrugs have shown potential cytotoxic effect in cervical cancer cell line HeLa. Compounds 2 and 4 were found to be effective prodrugs, the latter being the most effective. It showed less than 10% cell viability at 1 µM concentration, which signifies that these prodrugs may help to reduce cancer burden in human populations. Quantum chemical calculations of compounds 2–5 were performed in the ground state using the DFT of B3LYP level with 6-31G(d,p) basis set. The electronic properties such as HOMO and LUMO energies were determined by the time-dependent DFT approach. Intramolecular interactions have been identified by the AIM (Atoms in Molecules) approach. The reactivity and reactive sites within the synthesized prodrugs were examined with reactivity descriptors (global and local). The calculated dipole moments, polarizabilities, and first static hyperpolarizabilities indicated that the synthesized compounds might behave as good nonlinear optical materials. The probable reaction paths of prodrugs were calculated with molecular electrostatic potential (MEP) surface analysis. [ABSTRACT FROM AUTHOR]

In this study, three new compounds, roxburic acid A (1) and two flavone glycosides isorhamnetin-3-O-α-L-rhamnosyl-(1→6)-β-D-glucopyranose-(1→3)-β-D-glucopyranoside (2), and kaempferol-7-O-β-D-glucopyranosyl-(1→3)-β-D-glucopyranoside (3) were isolated from an ethanol extract of the fresh Anoectochilus roxburghii (Wall.) Lindl., together with 10 known compounds (4-13). The structures of these compounds were comprehensively characterized by HR-ESI-MS, 1H NMR, 13C NMR, and 2 D-NMR. The DPPH free radical scavenging activity of the isolated compounds was evaluated, and the results showed that kaempferol-7-O-β-D-glucopyranosyl- (1→3) -β-D-glucopyranoside (3) and rutin (11) has the potential antioxidant activity with IC50 values of 139 μg/mL and 22.5 μg/mL respectively. [ABSTRACT FROM AUTHOR]

Two new phenolic glycosides, 4-(3-hydroxypropyl)-2,6-dimethoxyphenol β-D-apiofuranosyl-(1→6)-β-D-glucopyranoside (1), trans-cinnamyl alcohol 9-O-(6′-O-β-D-apiofuranosyl)-β-D-glucopyranoside (2), together with nine known phenolic glycosides (3-11) were isolated from the roots of Pandanus tonkinensis. Their structures were determined by extensive analysis of HRESIMS and NMR spectral data, as well as by comparison of their spectral data (including CD spectra) with those reported in the literature. Compounds 1-4 and 6-11 inhibited NO production in LPS-activated RAW264.7 cells with IC50 values in the range from 0.80 ± 0.06 µM to 43.38 ± 3.92 µM, whereas compound 5 was inactive. The NO production inhibitory activities of compounds 1, 4, 8, and 10 with IC50 values of 10.16 ± 1.05, 0.80 ± 0.06, 1.10 ± 0.13, and 2.79 ± 0.21 µM, respectively, are as potent as that of the positive control of NG-monomethyl-L-arginine acetate (L-NMMA) with an IC50 value of 9.80 ± 0.78 µM. [ABSTRACT FROM AUTHOR]

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A new megastigmane glycoside, (3S,4R,7E)-megastigma-5,7-diene-9-one-3,4-diol 3-O-β-D-apiofuranosyl-(1→2)-β-D-glucopyranoside (1) and a new cyanogenic glycosyl derivative, (S)-2-(6′-O-R-rosmarinoyl-β-D-glucopyranosyloxy)-phenylacetonitrile (2) were isolated from the methanol extract of the Elsholtzia ciliata together with twelve known compounds, 1-O-β-D-glucopyranosyl-2-hydroxy-4-allylbenzene (3), citrusin C (4), 1,2-di-O-β-D-glucopyranosyl-4-allylbenzene (5), manglieside B (6), 4-allyl-2-hydroxyphenyl 1-O-β-D-apiofuranosyl-(1→6)-β-D-glucopyranoside (7), (-)-isolariciresinol 3α-β-D-glucopyranoside (8), 7R,8R-threo-4,7,9-trihydroxy-3,3′-dimethoxy-8-O-4′-neolignan-9′-O-β-D-glucopyranoside (9), 7R,8R-threo-4,7,9,9′-tetrahydroxy-3-methoxy-8-O-4′-neolignan-9′-O-β-D-glucopyranoside (10), cedrusin-4-O-β-D-glucopyranoside (11), icariside E3 (12), everlastoside L (13) and rosmarinic acid (14). Their chemical structures were elucidated on the basic of extensive 1D and 2D-NMR experiments, as well as their mass spectroscopic data. The absolute configurations of the compounds 1 and 2 were successfully indicated by both theoretical and calculated CD spectra. Compounds 3–7, 9 and 10 potential inhibited NO production in LPS-activated RAW264.7 cells with IC50 values of 6.71, 8.97, 12.38, 14.27, 16.13, 13.54, 16.27 µM, respectively, compared to that of the positive control of NG-monomethyl-L-arginine acetate (L-NMMA), IC50 = 32.51 µM. [ABSTRACT FROM AUTHOR]

'Globemaster' is an ornamental hybrid cultivar whose parent plants are Allium cristophii and A. macleanii. The chemical constituents of 'Globemaster' bulbs have not yet been examined; thus, a systematic phytochemical investigation was undertaken herein. A series of chromatographic separations of the MeOH extract of 'Globemaster' bulbs afforded 27 steroidal glycosides (1–27), which are classified into 23 spirostanol glycosides (1–8 and 11–25), two furostanol glycosides (9 and 26), a pregnane glycoside (10), and a cholestane glycoside (27). The structures of the hitherto undescribed compounds (1–10) were determined from the two-dimensional NMR spectroscopic data and hydrolysis. The cytotoxicity of the isolated compounds (1–27) toward HL-60 human promyelocytic leukemia cells, A549 human adenocarcinoma lung cancer cells, and SBC-3 human small-cell lung cancer cells was evaluated. Compounds 8, 22, 23, 24, and 26 exhibited cytotoxicity toward all cell lines in a dose-dependent manner, with IC50 values in the 1.3–49 µM range. [ABSTRACT FROM AUTHOR]

Mastitis refers to the inflammation in the mammary gland caused by various reasons. Protocatechuic acid (PCA) exerts anti‐inflammatory effect. However, no studies have shown the protective role of PCA on mastitis. We investigated the protective effect of PCA on LPS‐induced mastitis in mice and elucidated its possible mechanism. LPS‐induced mastitis model was established by injection of LPS into the mammary gland. The pathology of mammary gland, MPO activity and inflammatory cytokine production were detected to evaluate the effects of PCA on mastitis. In vivo, PCA significantly attenuated LPS‐induced mammary pathological changes, MPO activity, TNF‐α and IL‐1β production. In vitro, the production of inflammatory cytokines TNF‐α and IL‐1β was significantly reduced by PCA. Furthermore, LPS‐induced NF‐κB activation was also inhibited by PCA. In addition, PCA was found to activate pregnane X receptor (PXR) transactivation and PCA dose‐dependently increased the expression of PXR downstream molecule CYP3A4. In addition, the inhibitory effect of PCA on inflammatory cytokine production was also reversed when PXR was knocked down. In conclusion, the protective effects of PCA on LPS‐induced mastitis in mice through regulating PXR. [ABSTRACT FROM AUTHOR]

Fifteen phenolic constituents were isolated from the 80% ethanol extract of Kalimeris shimadae, including two phenolic glycosides (1, 2), six flavonoids (3–8), five phenylpropanoids (9–13), and two lignans (14, 15). Their structures were identified by spectroscopic analysis and comparison with literature data. Compound 1 was a new glucosyringic acid derivative, whereas compounds 2–14 were first discovered from K. shimadae. [ABSTRACT FROM AUTHOR]

One new hopane-type triterpene, indicuen (1), along with eight known compounds (2–9) were isolated from the n-hexane extract of the lichen Parmotrema indicum Hale. The chemical structures of isolated compounds were identified by interpretation of their spectroscopic data (1D, 2D NMR and HRESIMS) combined with DFT-NMR chemical shift calculations and subsequent assignment of DP4+ probabilities and by comparison with the literature. Indicuen represents for a rare hopane bearing a 1-carboxyethyl substituent at C-21 in lichens. Compounds 1–3 and 5–8 were evaluated for α-glucosidase inhibition and cytotoxicity against K562 and HepG2 cancer cell lines. Compounds 1, 5 and 7 exhibited moderate α-glucosidase inhibition with IC50 values of 201.1, 156.3 and 187.4 µM, respectively. Compound 1 also showed weak cytotoxicity toward K562 cell line while others showed no activity. [ABSTRACT FROM AUTHOR]

One new phenolic glycoside (1) and one new benzofuran derivative (2) were isolated from the leaves of Illicium dunnianum. The structures of these compounds were established by using comprehensive spectroscopic data analysis, including the 1D and 2D NMR, IR, HR-ESI-MS, electronic circular dichroism and comparison with literature data. All isolates were evaluated for the inhibition against the production of NO by LPS-stimulated RAW 264.7 macrophages. [ABSTRACT FROM AUTHOR]

Three new benzophenone glycosides, 2-O-β-D-glucopyranosyl-6,3',4'-trihydroxy-4-methoxybenzophenone (1), 4'-O-β-D-glucopyranosyl-2,4,6,3'-tetramethoxybenzophenone (2) and 2-O-β-D-glucopyranosyl-4'-hydroxy-6-methylbenzophenone (3), and a new flavonoid glycoside 5'-hydroxyombuoside (6), along with three known phenolic glycosides 4-O-β-D-glucopyranosyl-2,6,4'-trihydroxybenzophenone (4), mangiferin (5), and ombuoside (7), were isolated from the 80% ethanol extract of roots of Dobinea delavayi. Their structures were determined by the comprehensive analyses of the physicochemical properties and spectroscopic data (1D NMR, 2D NMR, and HR-ESI-MS). Cytotoxicity and in vitro antimalarial activity of compounds 1, 3, 4, 6, and 7 were evaluated by MTT colorimetric assay and β-hematin formation inhibition assay, respectively. [ABSTRACT FROM AUTHOR]

The ethnobotanical plant Marsdenia tenacissima has been used for hundreds of years for Dai people in Yunnan Province, China. Previously, chemical investigations on this plant have revealed that pregnane glycosides were the main biological constituents. Nine new pregnane glycosides, marsdeosides A–I (1–9), were isolated from cultivated dried stems of the medicinal plant Marsdenia tenacissima in this study. The structures were analyzed by extensive spectroscopic analysis, including 1D, 2D NMR, HRESIMS, and IR spectroscopic analysis. The absolute configurations of the sugar moieties were identified by comparing the Rf values and specific optical rotations with those of the commercially available standard samples and the data reported in the literature. Marsdeosides A (1) featured an unusual 8,14-seco-pregnane skeleton. Compounds 1, 8, and 9 showed activity against nitric oxide production in lipopolysaccharide-activated macrophage RAW264.7, with IC50 values of 37.5, 38.8, and 42.8 μM (L-NMMA was used as a positive control, IC50 39.3 μM), respectively. This study puts the knowledge of the chemical profile of the botanical plant M. tenacissima one step forward and, thereby, promotes the sustainable utilization of the resources of traditional folk medicinal plants. [ABSTRACT FROM AUTHOR]

Two new compounds, a pregnane glycoside and a triterpene saponin, were isolated from pericarp of Digitalis ciliata. The structures of the obtained compounds were established using one- and two-dimensional NMR (1H, 13C, HSQC, HMBC, COSY) and mass spectroscopy (ESI-MS). [ABSTRACT FROM AUTHOR]

Bixasteroid (1), one new steroid together with five known compounds (2–6), were isolated from the ethyl acetate fraction of ethanol extract of Bixa orellana fruits. All of these known compounds were isolated from the plant for the first time. Their structures were elucidated on the basis of spectroscopic analysis, and the absolute configuration of compound 1 was determined by X-ray crystallographic data analysis as well as by the quantum chemical ECD calculations. All the isolated compounds were tested for their anti-inflammatory activities. Compounds 1 and 2 showed inhibiting NO release activities in LPS-induced RAW 264.7 macrophages with the IC50 values of 4.72 ± 0.28 and 5.48 ± 1.48 μM, respectively. [ABSTRACT FROM AUTHOR]

Two new polyisoprenylated benzophenones, planchoniones A (1) and B (2), together with two known benzophenones (3, 4) and six known xanthones (5-10), were isolated from an ethyl acetate extract of the pericarp of Garcinia planchonii Pierre. Their structures were established using spectroscopic methods, mainly 1D and 2D NMR. The four benzophenones were evaluated for their cytotoxicity against MCF-7 human breast cancer cells, and showed almost no activity. Meanwhile, compounds 5-10 were investigated for their inhibitory effects towards α-glucosidase, and γ-mangostin (5) exhibited the most remarkable effect with IC50 value of 15.3 ± 0.9 µM (compared with acarbose, IC50 = 224.9 ± 3.6 µM). [ABSTRACT FROM AUTHOR]

Veratrazine A (1), a steroidal alkaloid with a unique 6/5/5 triheterocyclic scaffold as the side chain, was isolated from Veratrum stenophyllum, and its structure was established via spectroscopic analyses and X-ray diffraction. A plausible biosynthetic pathway for 1 is proposed. Bioassy exhibits moderate anti-inflammatory activities in vitro and in vivo. [ABSTRACT FROM AUTHOR]

The use of local intra-articular injection therapy for the treatment of osteoarthritis has experienced an increase in recent decades. With this treatment, frequent injections are necessary to obtain an adequate anti-inflammatory effect, which implies greater inconveniences for the patients. An alternative could be use injectable controlled release systems that allow to reduce the frequency of application. The aim of this research is to develop a system based on dexamethasone-loaded polycaprolactone particles dispersed in a thermosensitive chitosan/Pluronic® F-127 hydrogel. The microparticles were obtained by the double emulsion / solvent evaporation technique. The hydrogel is prepared from a physical mixture of chitosan and Pluronic® F127. The microparticle / hydrogel system was prepared by dispersing 50 mg of particles in 2 mL of the liquid hydrogel. The samples were characterized by Fourier transform infrared spectroscopy and scanning electron microscopy. The cytocompatibility of the samples was evaluated using the C-28 cell line of human chondrocytes by the 3- (4,5-dimethylthiazol-2-yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfophenyl) -2H-tetrazolium (MTS) assay and a study of dexamethasone release in phosphate buffered saline solution (PBS) was carried out for 7 days. The particles have a defined spherical shape and a size between 4-14 µm. The characterization by Fourier transform infrared spectroscopy showed that there are no chemical interactions between chitosan and Pluronic® F127 in the hydrogel. All the analyzed samples were cytocompatible with the C-28 cell line. The release study showed that the system has greater control over dexamethasone release. The system proves to be a promising option as an intra-articular administration system in the pharmacological treatment of osteoarthritis. [ABSTRACT FROM AUTHOR]

In order to study the chemical constituents from the branches and leaves of Heynea trijuga, silica gel, MCI, C18, Sephadex LH-20 and preparative HPLC were applied for the isolation and purification of the constituents. The structures were identified by physicochemical properties and spectrum data. The results were as follows:(1)Six compounds were obtained from methanol extracts of H. trijuga, their structures were identified as heynealigan A(1), 3β,21-dihydroxy-24-methylenecycloartane(2), 3-oxo-threo-23,24,25-trihydroxytirucall-7-ene(3), 16-dehydeoxy-23β-hydroxyliasenin F(4), ergost-5, 24(28)-diene-3β, 23S-diol(5), 7α-hydrositosteol(6).(2)Compound 1 was a new lignan, compounds 2-4 were triterpenoids, compounds 5 and 6 were steroids, and compounds 2-5 were isolated from this plant for the first time. This study provides scientific basis for the rational development and utilization of T. connaroides. [ABSTRACT FROM AUTHOR]

The present study has tentatively elucidated the structure of two acylated polyoxypregnane glycosides from Caralluma quadrangula (Forssk.) N.E.Br. (CQ). The analyses were performed using an electrospray-ionization quadrupole time-of-flight (ESI-Q-TOF) mass spectrometer in positive ionization modes to explore fragmentation pathways. The used ionization mode provided consistent and/or complementary information for most of the pregnane glycosides, their fragmentation sequences, and their aglycones. Presumably, this is due to higher efficiency, sensitivity, and better selectivity of the mass spectrometry-based method. The present experimental and theoretical report deals with the characteristic fragmentation behaviors of two acylated polyoxypregnane glycosides CQ1 and CQ2 from the aerial parts of C. quadrangular. A DFT Study was performed to elucidate the position of ikemoyl, and benzoyl residues in compounds CQ1 and CQ2, respectively. [ABSTRACT FROM AUTHOR]

Two new tetrahydrofuran lignans 1-2, along with 2,3-seco-lup-20(29)-en-2,3-dioic acid (3), (–)-larreatricin (4), and 15 additional compounds were isolated from Combretum mellifluum (Combretaceae). Their structures were determined by 1D- and 2D- NMR spectroscopic data and HRESIMS. Another 15 compounds were identified after HPLC-DAD-MS/MS analysis. Tested against HT-29 (colon) neoplastic cells, lignan 1 showed marked cytotoxicity (GI50 = 3.9 µM) and high selectivity (SI > 227), compared with non-neoplastic NIH/3T3 cells, while 2 proved less cytotoxic, despite exhibiting SI > 75. Seco-triterpene 3 was strongly cytotoxic to 786-0 (kidney) and HT-29 cells (GI50 = 0.5 and 2.9 µM, respectively), proving roughly 107 and 18 times more selective for these cell lines, respectively, than for NIH/3T3 cells. After 48 h of incubation, 1-3 exhibited potent cytostatic activity against HT-29 cells at all concentrations tested, while 3 had a cytocidal effect on 786-0 cells at 25 µg.mL−1. [ABSTRACT FROM AUTHOR]

The leguminosae of Sophora moorcroftiana (Benth.) Benth.ex Baker is a drought-resistant endemic Sophora shrub species from the Qinghai-Tibet Plateau, and its seeds have hepatoprotective effects. To study the effect of S. moorcroftiana seeds on liver injury and the molecular mechanism underlying the beneficial effects, liquid chromatography-mass spectrometry was used to detect the main active components in the ethanol extract of S. moorcroftiana seeds (SM). Male mice were divided into six groups (n = 8): normal control (NC), CCl4, SM (50, 100, 200 mg/kg), and dimethyl diphenyl bicarboxylate (150 mg/kg) groups. Mice were treated as indicated (once/day, orally) for 14 days, and CCl4 (2 mL/kg) was administered intraperitoneally. The serum and liver of mice were used for biochemical assays. To explore the underlying mechanism, HepG2 cells were treated with SM, stimulated with tert-butyl hydroperoxide (t-BHP, 50 μM), and analyzed by Western blotting. The major active compounds of SM were alkaloids including 22 compounds. Serum alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP) decreased in the SM (200 mg/kg) group. SM can activate the expression of pregnane X receptor (PXR) and downstream molecules cytochrome P4503A11 enzyme (CYP3A11), UDP glucuronosyltransferase 1 family polypeptide A 1 (UGT1A1), and inhibit the multidrug resistance protein 2 (MRP2). In addition, SM improved cell viability in t-BHP-induced HepG2 cells (64% to 83%) and decreased the activation of the mitogen-activated protein kinase (MAPK) pathway. The main compounds in SM were alkaloids. SM showed hepatoprotective effects possibly mediated by the suppression of oxidative stress through the MAPK pathway. [ABSTRACT FROM AUTHOR]

Steroidal alkaloids are derived from the steroid skeleton with one or two nitrogen atoms. They are widely distributed in tropical and subtropical regions and possess a range of biological activities. The structures of steroidal alkaloids are comparable to those of anabolic steroids, steroidal hormones, and corticosteroids, making them a valuable source for drug discovery. Taxonomically, steroidal alkaloids are limited in distribution to certain plant families, predominantly the Apocynaceae, Buxaceae, Solanaceae, and Liliaceae. This review highlights the steroidal alkaloids from the Apocynaceae family and their biological activities. The articles published from 1919 to 2021 were included in this review. A total of 163 steroidal alkaloids and 12 biological activities were reported from plant species belonging to the Apocynaceae family in this period. Of the 410 genera in the Apocynaceae, only 10 contain steroidal alkaloids. Although some alkaloids from the Apocynaceae family were also reported in the Buxaceae family, especially tetracyclic triterpenes with a pregnane side chain, most steroidal alkaloids can only be found in several genera of the Apocynaceae family. [ABSTRACT FROM AUTHOR]

Two dammarane glycosides (1-2) were isolated from the leaves of Cyclocarya paliurus. The structures of new compounds were established by application of spectroscopic methods, including one-dimensional and two-dimensional NMR, HRESIMS, and chemical hydrolysis. When evaluated against seven human cancer cell lines, the two compounds exhibited selective cytotoxicity to MCF-7 cells. [ABSTRACT FROM AUTHOR]

Two new C21 steroids, named 12‐O‐acetyl‐(20S)‐O‐(N‐methyl)anthraniloyl sarcostin‐5α,6β‐hexahydroxypregnane (1) and 12‐O‐acetyl‐(20S)‐O‐(N‐methyl)anthraniloyl sarcostin 3‐O‐β‐D‐cymaropyranoside (2), together with eight known compounds (3–10) were isolated from the dried whole plants of Gymnema tingens. The structures of the new compounds were established by extensive 1D and 2D nuclear magnetic resonance (NMR) spectra with mass spectroscopy data. Compounds 1–9 were tested for glucose uptake in L6 cells, and compounds 3 and 4 showed the most potent glucose uptake activity with the enhancement by 2.98‐ and 3.36‐fold. [ABSTRACT FROM AUTHOR]

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-1β 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. [ABSTRACT FROM AUTHOR]

Two new pregnane glycosides (1 and 2) were isolated from Stapelia gigantea. The structures were determined by 1D and 2D NMR spectral analysis. The absolute configurations of compounds 1 and 2 were determined by NOESY and coupling constants analyses. [ABSTRACT FROM AUTHOR]

Pregnane X receptor (PXR, NR1I2), a prototypical member of the nuclear receptor superfamily, has been implicated in various processes including metabolism, immune response, and inflammation. The immune system is made up of many interdependent parts, including lymphoid organs, cells, and cytokines, which play important roles in identifying, repelling, and eliminating pathogens and other foreign chemicals. An impaired immune system could contribute to various physical dysfunction, including severe infections, allergic diseases, autoimmune disorders, and other inflammatory diseases. Recent studies revealed the involvement of PXR in the pathogenesis of immune disorders and inflammatory responses. Thus, the aim of this work is to review and discuss the advances in research associated with PXR on immunity and inflammatory diseases and to provide insights into the development of therapeutic interventions of immune disorders and inflammatory diseases by targeting PXR. [ABSTRACT FROM AUTHOR]

(-)-Epicatechin (EC) is part of a large family of biomolecules called flavonoids and is widely distributed in the plant kingdom. Several studies have shown the beneficial effects of EC consumption. Many of these reported effects are exerted by activating the signaling pathways associated with the activation of two specific receptors: the G protein-coupled estrogen receptor (GPER), a transmembrane receptor, and the pregnane X receptor (PXR), which is a nuclear receptor. However, the effects of EC are so diverse that these two receptors cannot describe the complete phenomenon. The apelin receptor or APLNR is classified within the G protein-coupled receptor (GPCR) family, and is capable of activating the G protein canonical pathways and the β-arrestin transducer, which participates in the phenomenon of receptor desensitization and internalization. β-arrestin gained interest in selective pharmacology and mediators of the so-called "biased agonism". With molecular dynamics (MD) and in vitro assays, we demonstrate how EC can recruit the β-arrestin in the active conformation of the APLN receptor acting as a biased agonist. [ABSTRACT FROM AUTHOR]

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‐5β‐pregnan‐3β‐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‐3β‐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. [ABSTRACT FROM AUTHOR]

This paper aimed to evaluate the role of oxidative stress in the regulation of ABC transporters in human lung cancer (A549) cells facing substrate (doxorubicin, DOX) and nonsubstrate (ethanol, ETH and hydrogen peroxide, HP) chemicals. After 24‐h treatment, all the chemicals caused significant cytotoxicity as reflected by the reduction in cell viability and the increase in reactive oxygen species (ROS) levels. Depending on the rescuing effects of ROS scavenger including glutathione (GSH) and Vitamin C, the toxicity dependence on oxidative stress were found to be HP > ETH > DOX. The addition of transporter inhibitors significantly enhanced the ROS levels and death‐inducing effects of chemicals, indicating the universal detoxification function of ABC transporters. At moderate ROS levels (about 3–4‐folds of control levels, caused by 10 μM DOX, 400 mM ETH, and 400 μM HP), all the three chemicals induced the gene expressions and activities of ABC transporters, but these values decreased at too high ROS levels (8.36‐folds of control levels) caused by HP at LC50 (800 μM). Such induction could be attenuated by GSH and KCZ, and was completely abolished by 50 μM KCZ, indicating an important role of oxidative stress and pregnane X receptor (PXR) in the induction of ABC transporters. Finally, this paper revealed the critical role of oxidative stress in the modulation of ABC transporters by either substrate or nonsubstrate chemicals during 24‐h treatment. Such information should be beneficial for overcoming ABC transporter‐mediated multidrug resistance. [ABSTRACT FROM AUTHOR]

We recently discovered that (3α,5α)3-hydroxypregnan-20-one (allopregnanolone) inhibits pro-inflammatory toll-like receptor (TLR) activation and cytokine/chemokine production in mouse macrophage RAW264.7 cells. The present studies evaluate neurosteroid actions upon TLR activation in human macrophages from male and female healthy donors. Buffy coat leukocytes were obtained from donors at the New York Blood Center (http://nybloodcenter.org/), and peripheral blood mononuclear cells were isolated and cultured to achieve macrophage differentiation. TLR4 and TLR7 were activated by lipopolysaccharide (LPS) or imiquimod in the presence/absence of allopregnanolone or related neurosteroids and pro-inflammatory markers were detected by ELISA or western blotting. Cultured human monocyte-derived-macrophages exhibited typical morphology, a mixed immune profile of both inflammatory and anti-inflammatory markers, with no sex difference at baseline. Allopregnanolone inhibited TLR4 activation in male and female donors, preventing LPS-induced elevations of TNF-α, MCP-1, pCREB and pSTAT1. In contrast, 3α,5α-THDOC and SGE-516 inhibited the TLR4 pathway activation in female, but not male donors. Allopregnanolone completely inhibited TLR7 activation by imiquimod, blocking IL-1-β, IL-6, pSTAT1 and pIRF7 elevations in females only. 3α,5α-THDOC and SGE-516 partially inhibited TLR7 activation, only in female donors. The results indicate that allopregnanolone inhibits TLR4 and TLR7 activation in cultured human macrophages resulting in diminished cytokine/chemokine production. Allopregnanolone inhibition of TLR4 activation was found in males and females, but inhibition of TLR7 signals exhibited specificity for female donors. 3α,5α-THDOC and SGE-516 inhibited TLR4 and TLR7 pathways only in females. These studies demonstrate anti-inflammatory effects of allopregnanolone in human macrophages for the first time and suggest that inhibition of pro-inflammatory cytokines/chemokines may contribute to its therapeutic actions. [ABSTRACT FROM AUTHOR]

The pregnane X receptor (PXR) is a master xenobiotic-sensing receptor in response to toxic byproducts, as well as a key regulator in intermediary lipid metabolism. Therefore, the present study was conducted to investigate the potential role of PXR in mediating the lipid dysregulation and xenobiotic responses under Cu-induced stress in largemouth bass (Micropterus salmoides). Four groups of largemouth bass (52.66 ± 0.03 g) were treated with control, Cu waterborne (9.44 mmol/L), Cu+RIF (Rifampicin, 100 mg/kg, PXR activator), and Cu+KET (Ketoconazole, 20 mg/kg, PXR inhibitor) for 48 h. Results showed that Cu exposure significantly elevated the plasma stress indicators and triggered antioxidant systems to counteract Cu-induced oxidative stress. Acute Cu exposure caused liver steatosis, as indicated by the significantly higher levels of plasma triglycerides (TG), lipid droplets, and mRNA levels of lipogenesis genes in the liver. Liver injuries were detected, as shown by hepatocyte vacuolization and severe apoptotic signals after Cu exposure. Importantly, Cu exposure significantly stimulated mRNA levels of PXR, suggesting the response of this regulator in the xenobiotic response. The pharmacological intervention of PXR by the agonist and antagonist significantly altered hepatic mRNA levels of PXR, implying that RIF and KET were effective agents of PXR in largemouth bass. Administration of RIF significantly exacerbated liver steatosis, and such alterations were dependent on the regulations on pparg and cd36 rather than srebp1 signaling, which suggested that PXR-PPARγ might be another pathway for Cu-induced lipid deposition in fish. Whereas, KET administration showed reverse effects on lipid metabolism as indicated by the lower hepatic TG levels, suppressed mRNA levels of pparg and cd36. Activation of PXR stimulated autophagy and inhibited apoptosis, leading to lower hepatic vacuolization; while inhibition of PXR showed higher apoptotic signals, inhibition of autophagic genes and stimulation of apoptotic genes. Taken together, PXR played a cytoprotective role in Cu-induced hepatotoxicity through regulations on autophagy and apoptosis. Overall, our data has demonstrated for the first time on the dual roles of PXR as a co-regulator in mediating xenobiotic responses and lipid metabolism in fish, which implying the potential of PXR as a therapy target for xenobiotics-induced lipid dysregulation and hepatotoxicity. [ABSTRACT FROM AUTHOR]

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 ɣ‐aminobutyric acid receptors (GABAAR) 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 5β‐dihydroprogesterone (5β‐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 5β‐DHP, but bell‐shaped for ALLO, PA and PAS. The peak amplitude of the IGly was reduced by PA, PAS, and 5α‐ and 5β‐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 5β‐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. [ABSTRACT FROM AUTHOR]

Mitotane is the only drug approved to treat adrenocortical carcinoma (ACC), and a relationship of pharmacokinetic/pharmacodynamic has been characterized. However, limited evidence concerning affecting factors in large interindividual variability of the pharmacokinetics of mitotane is available. To address this question, a retrospective analysis was performed on ACC Chinese patients treated with mitotane for more than 3 months. Mitotane plasma trough concentrations were detected at the steady state, and CYP2B6, CYP3A4, and pregnane X receptor (PXR) polymorphisms were genotyped. After examining homogeneous pharmacologic data, we restricted the analyses to 36 patients that received mitotane for a median (interquartile range, IQR) of 9 months (5.00–22.50) with a median dose of 2 g/day (2.00–2.50). As a result, drug exposure was significantly influenced by the cumulative dose of mitotane, and CYP2B6 516GG and CYP2B6 26570CC were at high risk to be below the therapeutic range of mitotane. No association was found between mitotane concentrations with CYP3A4 or PXR polymorphism. Our data firstly indicated that the cumulative dose of mitotane and polymorphisms of CYP2B6 516 and CYP2B6 26570 might significantly affect mitotane plasma trough concentrations in Chinese ACC patients. [ABSTRACT FROM AUTHOR]

Budesonide, a glucocorticosteroid, is used as anti-asthmatic drug that became generic in 2019. Existing preparation methods of budesonide require utilization of corrosive acids and involve expensive purification process. Thus, a new cost-effective continuous flow process for the synthesis of budesonide which belongs to the class of 16,17 acetals of pregnane core, is discussed in the present research findings. Flow reactor parameters such as flow rate, temperature, residence time, solution volumes, anti-solvents and reactor frequency are subjected to investigation on the preparation of molar ratio of budesonide epimers. Further, the suitable parameters entail for obtaining the desired molar ratio of epimers. In another aspect, particle size optimization studies are also performed to get the desired budesonide solid product. A continuous flow process for preparation of budesonide is identified from the present research investigation which can be readily transferred to industrial scale up. [ABSTRACT FROM AUTHOR]

From the aerial parts of Euphorbiagossypina var. coccinea Pax., eight new pregnane glycosides (euphogossypins A–H, 1–8) of the cynanforidine and deacetylmetaplexigenin aglycons, two new lignans (gossypilignans A and B, 9 and 10), and four known compounds, namely, the pregnane 12-O-benzoyldeaxcylmetaplexigenin (11), the lignan 9α-hydroxypinoresinol (12), and the flavonoids naringenin (13) and quercitrin (14) were isolated. The structure elucidation of the new compounds was carried out by a spectroscopic analysis, including HRMS, 1D (1H, 13C JMOD), and 2D NMR (HSQC, 1H–1H COSY, HMBC, and NOESY) experiments. The obtained pregnane glycosides were substituted with acetyl and benzoyl ester moieties, and sugar chains containing thevetose, cymarose, digitoxose, and glucose monosaccharides. All of the compounds are described for the first time from E. gossypina var. coccinea. The isolated pregnanes and lignans were tested for their antiproliferative activity on HeLa cells using the MTT assay; the compounds exerted no significant effect against the tumor cells. [ABSTRACT FROM AUTHOR]

The Turpan-Hami Basin has been considered as the most typical coal-derived-oil basin in China for a long time. However, with the deepening exploration, this theory has caused increasing controversy and some scholars doubt that Permian or Jurassic dark mudstone may be the main source rocks. The origin uncertainty even restricts deciding the exploration direction. Taking the reservoirs of the northern piedmont belt as an example, this paper analyzed oil sources by the geochemical characteristic comparison of inclusions, crude oil, and source rocks. Combined with the previous studies, the hydrocarbon accumulation model is established. The results show that the geochemical characteristics of the inclusions and oil in most areas are obviously different. Most reservoirs are mixed-source reservoirs. The oil sources varied in different regions. In the area near Bogeda, C19+20TT and C28 sterane content in oil are high, indicating that coal and Permian lacustrine mudstone are main contributors. Far away from Bogeda, bounded by the thick coal seam of Xishanyao Formation, oil sources are quite different. Above it, C19+20TT is high and gammacerane and pregnane are low, C29>>C28>C27sterane, indicating that coal and carbonaceous mudstone are main sources. Under that, C21TT and C23TT content in the inclusions are high, C29≥C27>C28sterane, while C19+20TT and pregnane content in the oil are also high, indicating that it is a mixed oil system mainly derived from Jurassic lacustrine mudstone and coal. Lacustrine mudstone has higher contribution. This phenomenon is mainly related to different fault styles in different zones. Near Bogeda, strong stress caused vertical large faults developed, which connected Jurassic reservoirs and Permian source rocks. Far from Bogeda, the faults sliped along the thick coal seam, It is difficult for deep hydrocarbon to enter the shallow layer. In the future, it should be considered to look for the traps with relatively high-quality reservoir-cap combinations for exploration in the hydrocarbon supply window of effected hydrocarbon kitchens. [ABSTRACT FROM AUTHOR]