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1.
Sci Total Environ ; : 150800, 2021 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-34627907

RESUMO

When there is poor ventilation or an irregular radon exhalation rate in an underground environment, it is necessary to judge whether the radon concentration is abnormal. To protect personal safety and health from radon gas, it is necessary to track the location of an abnormal radon source and measure its release rate to formulate emergency control and eradication measures. However, in an underground environment, it is impossible to fully monitor the radon concentration at every location, and as a result, blind spots are present, making it difficult to obtain timely early warnings in the event of an abnormal radon exhalation rate. Based on the distribution of radon concentration in an underground environment, this research establishes a theoretical mathematical model of an underground ventilation network containing radon. We combined particle swarm optimization with the long short-term memory (PSO-LSTM) method, which uses part of a time series signal of monitored radon concentrations to track the location of an abnormal radon source and determine an abnormal radon exhalation rate. Performing experiments of theoretical examples and actual underground ventilation environment examples, we prove the necessity of optimizing the monitoring position of the angle-connected ventilation network. The results show that the PSO-LSTM model based on radon concentration monitoring can process time series signals. Its accuracy and decision coefficient greater that is than 0.9 indicate the reliability of the model and method.

2.
Front Immunol ; 12: 746447, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34603333

RESUMO

Influenza viruses undergo antigenic changes in the immuno-dominant hemagglutinin (HA) head domain, necessitating annual re-formulation of and re-vaccination with seasonal influenza virus vaccines for continuing protection. We previously synthesized mosaic HA (mHA) proteins of influenza B viruses which redirect the immune response towards the immuno-subdominant conserved epitopes of the HA via sequential immunization. As ~90% of current influenza virus vaccines are manufactured using the inactivated virus platform, we generated and sequentially vaccinated mice with inactivated influenza B viruses displaying either the homologous (same B HA backbones) or the heterologous (different B HA backbones) mosaic HAs. Both approaches induced long-lasting and cross-protective antibody responses showing strong antibody-dependent cellular cytotoxicity (ADCC) activity. We believe the B virus mHA vaccine candidates represent a major step towards a universal influenza B virus vaccine.

3.
Org Lett ; 2021 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-34606288

RESUMO

Metallaphotocatalysis often needs light-absorbing metal-polypyridyl complexes, semiconductors, or organic dyes, which can modify the oxidation state of metal catalysts. Here, we first report that photoexcitation of Hantzsch ester can directly activate chromium reagents through a single-electron transfer process. The synthetic application was demonstrated through a photoredox decarboxylative allylation of aldehydes with feedstock butadiene without exogenous photocatalysts, metallic reductants, or additives.

4.
Artigo em Inglês | MEDLINE | ID: mdl-34595704

RESUMO

Rapeseed (Brassica napus L.) is an ideal crop for remediation in cadmium (Cd)-contaminated soil in farmland. The main objective of this study was focused on the combined effects of four nitrogen forms (urea, ammonium nitrogen, nitrate nitrogen, ammonium nitrate fertilizer), four pH levels (5, 6, 7, 8), and three water levels (low water, middle water, high water) on Cd speciation and characteristics of Cd uptake by rapeseed. A pot experiment was conducted at the Xindu Experimental Park in Sichuan Province, China. Experimental results indicated that the interaction effects of pH and nitrogen forms, three factors on Cd speciation (except organic-bound Cd and exchangeable Cd), were significant and the interaction effects of pH and nitrogen forms on Cd uptake by rapeseed also was significant only under the condition of planting rapeseed. The higher the water level was or the lower the pH value was, the better the repair effect rapeseed to Cd was. High water significantly increased the stem Cd content by 11.89% and 29.55% through significantly increasing the content of exchangeable Cd by 23.40% and 52.63%, respectively, compared with middle water and low water as planting rapeseed, and pH 5 significantly increased the stem Cd content, total Cd enrichment coefficients, bio-availability coefficient, and Cd removal rate by 24.45~40.33%, 49.45~76.62%, 60.00~166.67%, and 16.67~26.00%, respectively, through significantly increasing the content of exchangeable Cd by 37.78~113.79%, compared with pH 7 and pH 8 as the significant decreasing of carbonate-bound Cd, bound to Fe-Mn oxide, and content of organic-bound Cd and residual Cd. Ammonium nitrate also significantly increased total Cd enrichment coefficients, bio-availability coefficient, and Cd removal rate by 45.63~138.10%, 21.05~109.09%, and 40.00~77.50%, respectively, compared with other three nitrogen forms as good growth and Cd resistance of rapeseed. Path analysis structural equation modeling revealed that content of exchangeable Cd and residual Cd had significant and direct path coefficients with variances in stem Cd content of rapeseed. Combined with the safety of edible oil, the best management practices for optimal remediation efficiency of rapeseed to Cd-contaminated soil were ammonium nitrate fertilizer, pH = 5, and high water.

5.
J Med Chem ; 64(18): 13918-13932, 2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34516133

RESUMO

Human dihydroorotate dehydrogenase (hDHODH) is an attractive tumor target essential to de novo pyrimidine biosynthesis. Novel potent hDHODH inhibitors with low toxicity are urgently needed. Herein, we demonstrate the isolation of 25 ascochlorin (ASC) derivatives, including 13 new ones, from the coral-derived fungus Acremonium sclerotigenum, and several of them showed pronounced inhibitions against hDHODH and triple-negative breast cancer (TNBC) cell lines, MDA-MB-231/-468. Interestingly, we found that hDHODH is required for proliferation and survival of TNBC cells, and several ASCs significantly inhibited TNBC cell growth and induced their apoptosis via hDHODH inhibition. Furthermore, the novel and potent hDHODH inhibitors (1 and 21) efficiently suppressed tumor growth in patient-derived TNBC xenograft models without obvious body weight loss or overt toxicity in mice. Collectively, our findings offered a novel lead scaffold as the hDHODH inhibitor for further development of potent anticancer agents and a potential therapeutic strategy for TNBC.

6.
Seizure ; 92: 76-81, 2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34474329

RESUMO

PURPOSE: Felt stigma and social anxiety are both common in patients with epilepsy (PWE) and they share an important relationship. Here in the present study, we investigated how social anxiety and different concepts of felt stigma relate to each other in PWE in order to provide some suggestions for the prevention and intervention of social anxiety and felt stigma in PWE. METHODS: A total of 189 patients with epilepsy were enrolled in our study. Social anxiety was evaluated with the Liebowitz social anxiety scale. Felt stigma was evaluated with the Kilifi stigma scale for epilepsy. The data were subjected to network analysis. RESULTS: The findings indicated that eight edges with the strongest regularized partial correlations existed in the network, such as the edge between S3 "Embarrassed" and S4 "Disappointed", and the edge between S14 "Discriminate" and S15 "Outcast". In addition, S10 "Inferior" and S11 "Avoid" had the highest strength and predictability. The flow network of social anxiety indicated that most concepts of felt stigma were directly connected with social anxiety. The strongest edge existed between S8 "Uncomfortable" and social anxiety, while S6 "Society" and S5 "Rewarding life" were also closely connected with social anxiety. CONCLUSION: The current study highlighted the critical central concept S10 "Inferior" and critical concepts associated with social anxiety, including S8 "Uncomfortable", S6 "Society" and S5 "Rewarding life". The findings revealed in this study may offer some help in the clinical prevention and intervention of felt stigma and social anxiety in PWE. However, all of the conclusions above need further confirmatory studies to validate them.

7.
Nat Prod Res ; : 1-8, 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34542359

RESUMO

A new glyoxylate-containing benzene derivative, methyl 2-(4-hydroxy-3-(3'-methyl-2'-butenyl)phenyl)-2-oxoacetate (1), together with ten known compounds (2-11), were isolated from the marine algicolous fungus, Aspergillus sp. SCSIO 41304. Their planar structures and absolute configurations were elucidated by detailed NMR, MS spectroscopic analysis and comparing with literature data. Compound 1 was isolated as a new fungal secondary metabolite, possessing a methyl glyoxylate moiety R-CO-CO-OCH3, which is rare in natural sources. All the isolated compounds (1-11) were tested for their antibacterial and enzyme inhibitory activities against acetylcholinesterase (AChE) and pancreatic lipase (PL). Among these compounds, aspulvinone H (4) showed moderate inhibition against AChE and PL with IC50 values of 25.95 and 47.06 µM, respectively. Further molecular docking simulation exhibited that compound 4 could well bind to the catalytic pockets of the AChE and PL.

8.
Nat Prod Res ; : 1-9, 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34498972

RESUMO

A new indole diketopiperazine alkaloid, named penilline D (1), together with five known indole alkaloid analogues (2-5, 11), two meroterpenoids (6 and 12), and four butenolide derivatives (7-10), were isolated from the Antarctic fungus Penicillium sp. SCSIO 05705. Extensive spectroscopic analysis and electronic circular dichroism (ECD) calculation were used to elucidate the structure of penilline D (1), including its absolute configuration. All isolated compounds (1-12) were evaluated for their cytotoxic, antibacterial and enzyme inhibitory activities against acetylcholinesterase (AChE) and pancreatic lipase (PL). Among them, compound 5 exhibited moderate in vitro cytotoxic activity against the 143B cell line with IC50 value of 12.64 ± 0.78 µM. Compound 6 showed strong inhibitory activity against AChE with IC50 value of 0.36 nM (IC50 18.7 nM for Tacrine), while compounds 6 and 11 showed weak PL enzyme inhibitory activity. Furthermore, an in silico molecular docking study was also performed between 6 and AChE.

9.
J Hazard Mater ; 416: 126126, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34492920

RESUMO

Biomass-derived heteroatom-doped porous carbon-based materials are emerging as low-cost adsorbents for removing common pollutants, although the adsorption performance is still unsatisfactory and the main adsorption mechanisms are still controversial. Herein, we report a facile and general method for fabricating biomass-derived N/S dual-doped hierarchically porous carbon adsorbent (MZ-NSPC). The MZ-NSPC material exhibits excellent adsorption capacity (295.8 mg/g for bisphenol F (BPF), 308.7 mg/g for bisphenol S (BPS)), short equilibrium time (30 min), and good reusability (the decline efficiency < 6.15% after five times). The remarkable adsorption performance originates from a large BET surface area, hierarchically porous structure, and N/S heteroatoms dual-doping. Combined with comparative experiments and density functional theory (DFT) calculations, we revealed that the doped N, S heteroatoms played a synergistic effect which promoted the adsorption performance and adsorption sites are mainly the oxidized-S and pyridinic-N. Importantly, for BPF, the proportion contribution of different mechanisms followed the order of hydrophobic interaction > π-π interaction > hydrogen bonding interaction. However, adsorption mechanism of BPS was mainly controlled by π-π interaction. This work not only promotes the development of low-cost and sustainable heteroatom-doped carbon-based materials, but also systematically studies adsorption mechanism of heteroatom-doped carbon-based materials for bisphenols.


Assuntos
Carbono , Compostos Benzidrílicos , Biomassa , Fenóis , Porosidade , Sulfonas
10.
PLoS One ; 16(9): e0256628, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34492040

RESUMO

Paratuberculosis a contagious and chronic disease in domestic and wild ruminants, is caused by Mycobacterium avium subspecies paratuberculosis (MAP). Typical clinical signs include intractable diarrhea, progressive emaciation, proliferative enteropathy, and mesenteric lymphadenitis. Paratuberculosis is endemic to many parts of the world and responsible for considerable economic losses. In this study, different types of paratuberculosis and MAP in sheep and goats were investigated in Inner Mongolia, a northern province in China contiguous with two countries and eight other provinces. A total of 4434 serum samples were collected from six cities in the western, central, and eastern regions of Inner Mongolia and analyzed using the ELISA test. In addition, tissue samples were collected from seven animals that were suspected to be infected with MAP. Finally, these tissues samples were analyzed by histopathological examination followed by polymerase chain reaction (PCR), IS1311 PCR-restriction enzyme analysis (PCR-REA), and a sequence analysis of five genes. Among all 4434 ruminant serum samples collected from the six cities in the western, central, and eastern regions of Inner Mongolia, 7.60% (337/4434) measured positive for the MAP antibody. The proportions of positive MAP antibody results for serum samples collected in the western, central, and eastern regions were 5.10% (105/2058), 6.63% (85/1282), and 13.44% (147/1094), respectively. For the seven suspected infected animals selected from the herd with the highest rate of positivity, the gross pathology and histopathology of the necropsied animals were found to be consistent with the pathological features of paratuberculosis. The PCR analysis further confirmed the diagnosis of paratuberculosis. The rest of the results demonstrated that herds of sheep and goats in Inner Mongolia were infected with both MAP type II and type III. To the best of our knowledge, this is the first study of the two subtypes of MAP strains in sheep and goats in Inner Mongolia.

11.
Org Biomol Chem ; 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34476433

RESUMO

A novel one-pot protocol for the convenient and efficient synthesis of (2-phenylimidazo[1,2-a]pyridin-3-yl)alkane-1,2-diones (3) in good yields (32-88%) from 2-phenylimidazo[1,2-a]pyridines (1) and terminal alkynes (2) has been established with a wide range of substrate scope. A tandem reaction sequence containing gold-catalyzed double oxidations of terminal alkynes to generate glyoxals, nucleophilic addition of 2-phenylimidazo[1,2-a]pyridines to glyoxals to yield α-hydroxyl ketones, and oxygenation of the α-hydroxyl ketones to afford the final products 3 under air atmosphere is involved in this method. Simple operation, mild reaction conditions, and widely available substrates make this strategy more affordable.

12.
Hortic Res ; 8(1): 205, 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34480029

RESUMO

Zanthoxylum bungeanum is an important spice and medicinal plant that is unique for its accumulation of abundant secondary metabolites, which create a characteristic aroma and tingling sensation in the mouth. Owing to the high proportion of repetitive sequences, high heterozygosity, and increased chromosome number of Z. bungeanum, the assembly of its chromosomal pseudomolecules is extremely challenging. Here, we present a genome sequence for Z. bungeanum, with a dramatically expanded size of 4.23 Gb, assembled into 68 chromosomes. This genome is approximately tenfold larger than that of its close relative Citrus sinensis. After the divergence of Zanthoxylum and Citrus, the lineage-specific whole-genome duplication event η-WGD approximately 26.8 million years ago (MYA) and the recent transposable element (TE) burst ~6.41 MYA account for the substantial genome expansion in Z. bungeanum. The independent Zanthoxylum-specific WGD event was followed by numerous fusion/fission events that shaped the genomic architecture. Integrative genomic and transcriptomic analyses suggested that prominent species-specific gene family expansions and changes in gene expression have shaped the biosynthesis of sanshools, terpenoids, and anthocyanins, which contribute to the special flavor and appearance of Z. bungeanum. In summary, the reference genome provides a valuable model for studying the impact of WGDs with recent TE activity on gene gain and loss and genome reconstruction and provides resources to accelerate Zanthoxylum improvement.

13.
J Chromatogr Sci ; 2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34491317

RESUMO

A simple high performance liquid chromatography (HPLC) method was developed and validated for the determination of coumarin-3-carboxylic acid analogues (C3AA) in rat plasma and a preliminary study on pharmacokinetics. Ferulic acid (FA) was used as the internal standard substance, and coumarin-3-carboxylic acid (C3A) was used as a substitute for quantitative C3AA. After protein precipitation with methanol, the satisfactory separation was achieved on an ODS2 column when the temperature was maintained at 30 ± 2°C. The correlation coefficient r in the C3A linear equation is equal to 0.9990. Pharmacokinetic parameters for t1/2, Tmax, Cmax, area under the curve (AUC)0-t, average residence time (MRT), apparent volume of distribution (V z/F) and clearance (Cl/F) were 1.89 ± 0.03 h, 0.39 ± 0.14 h, 1.81 ± 0.10 g· mL-1 ·h, 7.88 ± 0.24 g·mL-1·h, 3.23 ± 0.14 h, 0.43 ± 0.03 (mg·kg-1)·(g·mL-1)-1·h-1, respectively. The high performance liquid chromatography-photo diode array detector (HPLC-PDA) method established in this study can be used to separate and determine the content of C3AA in plasma of rats after 60% ethanol extraction by gavage. The plasma concentration-time curve and pharmacokinetic parameters reflect the absorption of C3AA in rat blood after oral administration to some extent.

14.
Extremophiles ; 2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34402982

RESUMO

The haloalkalitolerant bacterium Egicoccus halophilus EGI 80432T exhibits high adaptability to saline-alkaline environment. The salinity adaptation mechanism of E. halophilus EGI 80432T was fully understood based on transcriptome analyses and physiological responses; however, the alkaline response mechanism has not yet been investigated. Here, we investigated the alkaline response mechanism of E. halophilus EGI 80432T by a transcriptomic comparison. In this study, the genes involved in the glycolysis, TCA cycle, starch, and trehalose metabolism for energy production and storage, were up-regulated under highly alkaline condition. Furthermore, genes responsible for the production of acidic and neutral metabolites, i.e., acetate, pyruvate, formate, glutamate, threonine, and ectoine, showed increased expression under highly alkaline condition, compared with the control pH condition. In contrast, the opposite results were observed in proton capture or retention gene expression profiles, i.e., cation/proton antiporters and ATP synthases. The above results revealed that E. halophilus EGI 80432T likely tended to adopt an "acidic metabolites production" strategy in response to a highly alkaline condition. These findings would pave the way for further studies in the saline-alkaline adaptation mechanisms of E. halophilus EGI 80432T, and hopefully provide a new insight into the foundational theory and application in ecological restoration with saline-alkaline strains.

15.
Molecules ; 26(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34443439

RESUMO

Ten polyketide derivatives (1-10), including a new natural product named (E)-2,4-dihydroxy-3-methyl-6-(2-oxopent-3-en-1-yl) benzaldehyde (1), and five known diketopiperazines (11-15), were isolated from the mangrove-sediment-derived fungus Aspergillus sp. SCSIO41407. The structures of 1-15 were determined via NMR and MS spectroscopic analysis. In a variety of bioactivity screening, 3 showed weak cytotoxicity against the A549 cell line, and 2 exhibited weak antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). Compounds 3, 5, and 6 showed inhibition against acetylcholinesterase (AChE) with IC50 values of 23.9, 39.9, and 18.6 µM. Compounds 11, 12, and 14 exhibited obvious inhibitory activities of lipopolysaccharide (LPS)-induced nuclear factor-κB (NF-κB) with IC50 values of 19.2, 20.9, and 8.7 µM, and they also suppressed RANKL-induced osteoclast differentiation in bone marrow macrophages cells (BMMCs), with the concentration of 5 µM. In silico molecular docking with AChE and NF-κB p65 protein were also performed to understand the inhibitory activities, and 1, 11-14 showed obvious protein/ligand-binding effects to the NF-κB p65 protein.


Assuntos
Aspergillus/efeitos dos fármacos , Dicetopiperazinas/farmacologia , Sedimentos Geológicos/microbiologia , Policetídeos/farmacologia , Rhizophoraceae/química , Células A549 , Acetilcolinesterase/metabolismo , Morte Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Dicetopiperazinas/química , Humanos , Lipopolissacarídeos/farmacologia , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , NF-kappa B/metabolismo , Osteoclastos/citologia , Osteoclastos/efeitos dos fármacos , Policetídeos/química , Espectroscopia de Prótons por Ressonância Magnética , Ligante RANK/farmacologia
16.
Microorganisms ; 9(7)2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34361884

RESUMO

Endophytes associated with halophytes may contribute to the host's adaptation to adverse environmental conditions through improving their stress tolerance and protecting them from various soil-borne pathogens. In this study, the diversity and antifungal activity of endophytic bacteria associated with halophytic samples growing on the shore of the western Aral Sea in Uzbekistan were investigated. The endophytic bacteria were isolated from the nine halophytic samples by using the culture-dependent method and identified according to their 16S rRNA gene sequences. The screening of endophytic bacterial isolates with the ability to inhibit pathogenic fungi was completed by the plate confrontation method. A total of 289 endophytic bacterial isolates were isolated from the nine halophytes, and they belong to Firmicutes, Actinobacteria, and Proteobacteria. The predominant genera of the isolated endophytic bacteria were Bacillus, Staphylococcus, and Streptomyces, accounting for 38.5%, 24.7%, and 12.5% of the total number of isolates, respectively. The comparative analysis indicated that the isolation effect was better for the sample S8, with the highest diversity and richness indices. The diversity index of the sample S7 was the lowest, while the richness index of samples S5 and S6 was the lowest. By comparing the isolation effect of 12 different media, it was found that the M7 medium had the best performance for isolating endophytic bacteria associated with halophytes in the western Aral Sea Basin. In addition, the results showed that only a few isolates have the ability to produce ex-enzymes, and eight and four endophytic bacterial isolates exhibited significant inhibition to the growth of Valsa mali and Verticillium dahlia, respectively. The results of this study indicated that halophytes are an important source for the selection of microbes that may protect plant from soil-borne pathogens.

17.
Mar Drugs ; 19(8)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34436267

RESUMO

The mangrove-sediment-derived actinomycete strain Streptomyces psammoticus SCSIO NS126 was found to have productive piericidin metabolites featuring anti-renal cell carcinoma activities. In this study, in order to explore more diverse piericidin derivatives, and therefore to discover superior anti-tumor lead compounds, the NS126 strain was further fermented at a 300-L scale under optimized fermentation conditions. As a result, eight new minor piericidin derivatives (piericidins L-R (1-7) and 11-demethyl-glucopiericidin A (8)) were obtained, along with glucopiericidin B (9). The new structures including absolute configurations were determined by spectroscopic methods coupled with experimental and calculated electronic circular dichroism. We also proposed plausible biosynthetic pathways for these unusual post-modified piericidins. Compounds 1 and 6 showed selective cytotoxic activities against OS-RC-2 cells, and 2-5 exhibited potent cytotoxicity against HL-60 cells, with IC50 values lower than 0.1 µM. The new piericidin glycoside 8 was cytotoxic against ACHN, HL-60 and K562, with IC50 values of 2.3, 1.3 and 5.5 µM, respectively. The ability to arrest the cell cycle and cell apoptosis effects induced by 1 and 6 in OS-RC-2 cells, 2 in HL-60 cells, and 8 in ACHN cells were then further investigated. This study enriched the structural diversity of piericidin derivatives and confirmed that piericidins deserve further investigations as promising anti-tumor agents.

18.
J Antibiot (Tokyo) ; 2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34408287

RESUMO

One new benzophenone derivative, named penibenzophenone C (1), and a new benzophenone natural product, neamed penibenzophenone D (2), together with two known compounds (3, 4) were isolated from the EtOAc extract of the endophytic fungus Penicillium sp. isolated from the mangrove Acanthus ilicifolius L. collected in the South China Sea. The structures of 1-4 were elucidated by extensive NMR spectral interpretation and MS data. The new compounds 1 and 2 showed moderate antibacterial activities against methicillin-resistant Staphylococcus aureus with the MIC values of 3.12 and 6.25 µg ml-1, respectively.

19.
J Med Chem ; 64(14): 9943-9959, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34251816

RESUMO

Reported as two antirenal cell carcinoma (RCC) drug candidates, marine-derived compounds piericidin A (PA) and glucopiericidin A (GPA) exhibit hepatotoxicity in renal carcinoma xenograft mice. Proteomics and transcriptomics reveal the hepatotoxicity related with cholesterol disposition since RCC is characterized by cholesterol accumulation. PA/GPA aggravate hepatotoxicity in high-cholesterol diet (HCD)-fed mice while exhibiting no toxicity in chow diet-fed mice. High cholesterol accumulation in liver is liver X receptor (LXR)-mediated cytochrome P450 family 7 subfamily a member 1 (CYP7A1) depression and low-density lipoprotein receptor (LDLR) activation. The farnesoid X nuclear receptor (FXR) is also depressed with a downregulated target gene OSTα. Different from PA directly combined with LXRα as an inhibitor, GPA exists as a prodrug in the liver and exerts toxic effects due to transformation into PA. Surface plasmon resonance (SPR) and docking results of 17 piericidins illustrate that glycosides exert no LXRα binding activity. A longer survival time of GPA-treated mice indicates that further exploration in anti-RCC drug research should focus on reducing glycosides transformed into PA and concentrating in the kidney tumor rather than the liver for lowering the risk of hepatotoxicity.


Assuntos
Colesterol na Dieta/efeitos adversos , Colesterol/metabolismo , Dieta Hiperlipídica/efeitos adversos , Receptores X do Fígado/metabolismo , Pericardite/metabolismo , Animais , Relação Dose-Resposta a Droga , Células Hep G2 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Pericardite/induzido quimicamente , Pericardite/patologia , Relação Estrutura-Atividade , Células Tumorais Cultivadas
20.
J Nat Prod ; 84(7): 2004-2011, 2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34225450

RESUMO

Malaymycin (1), a new cyclopentenone-containing tetrahydroquinoline alkaloid, and mccrearamycin E (2), a geldanamycin analogue bearing a rare ring-contracted cyclopentenone moiety, and a C2-symmetric macrodiolide (7) were isolated from Streptomyces malaysiensis SCSIO41397. Their structures including absolute configurations were determined by detailed analyses of NMR and HRMS data and ECD calculations. The occurrence of mccrearamycin E (2) bearing a ring-contracted cyclopentenone is rare in the geldanamycin class. All isolated compounds were evaluated for their cytotoxicities against five cancer cell lines. As a result, compounds 1, 4, 5, and 7 showed cytotoxicity against some or all of the five cancer cell lines with IC50 values ranging from 0.067 to 7.2 µM. In particular, compound 1 inhibited the growth of C42B and H446 cell lines with IC50 values of 67 and 70 nM, respectively. Malaymycin (1) significantly induced cell cycle arrest at the G0/G1 phase in C42B cell lines and caused cell shrinkage and inhibited the expression of the androgen receptor (AR) at both the mRNA and protein levels in a dose-dependent manner. Further examination by qRT-PCR analysis showed that 1 strongly suppressed the expression of AR target genes KLK2 and KLK3 in the C42B and 22RV1 cell lines, which suggested that 1 might be a promising potential lead compound for the development of a treatment for the castration-resistant prostate cancer (CRPC).

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