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1.
Nat Commun ; 13(1): 4565, 2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35931700

RESUMO

Reactions that lead to destruction of aromatic ring systems often require harsh conditions and, thus, take place with poor selectivities. Selective partial dearomatization of fused arenes is even more challenging but can be a strategic approach to creating versatile, complex polycyclic frameworks. Herein we describe a general organophotoredox approach for the chemo- and regioselective dearomatization of structurally diverse polycyclic aromatics, including quinolines, isoquinolines, quinoxalines, naphthalenes, anthracenes and phenanthrenes. The success of the method for chemoselective oxidative rupture of aromatic moieties relies on precise manipulation of the electronic nature of the fused polycyclic arenes. Mechanistic studies show that the addition of a hydrogen atom transfer (HAT) agent helps favor the dearomatization pathway over the more thermodynamically downhill aromatization pathway. We show that this strategy can be applied to rapid synthesis of biologically valued targets and late-stage skeletal remodeling en route to complex structures.


Assuntos
Fenantrenos , Antracenos , Isoquinolinas , Naftalenos , Oxirredução
2.
Sci Rep ; 12(1): 11462, 2022 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-35794136

RESUMO

Lung cancer is the most malignant form of cancer and has the highest morbidity and mortality worldwide. Due to drug resistance, the current chemotherapy for lung cancer is not effective and has poor therapeutic effects. Tripchlorolide (T4), a natural extract from the plant Tripterygium wilfordii, has powerful immunosuppressive and antitumour effects and may become a potential therapeutic agent for lung cancer. Therefore, this study aimed to investigate the effect of T4 on reducing chemoresistance in lung cancer cells and to explore the mechanism. 1. A549 and A549/DDP cells were separately transfected with AEG-1 overexpression and AEG-1 knockdown plasmids. A549/DDP cells were divided into the A549/DDP empty group, T4 group, and T4 + AEG-1 overexpression group. A CCK-8 assay was used to evaluate the proliferation of cells in each group. RT-qPCR and Western blotting were used to detect the expression of AEG-1 and MDR-1. Expression of AEG-1 in A549 and A549/DDP cells was positively correlated with cisplatin resistance. When the AEG-1 protein was overexpressed in A549 cells, the lethal effect of cisplatin on A549 cells was attenuated (all P < 0.05). After the AEG-1 protein was knocked down in A549/DDP cells, cisplatin was applied. The lethal effect was significantly increased compared to that in the corresponding control cells (all P < 0.05). AEG-1 protein expression gradually decreased with increasing T4 concentration in A549 and A549/DDP cells. Resistance to cisplatin was reduced after the addition of T4 to A549/DDP cells (P < 0.05), and this effect was enhanced after transfection with the AEG-1 knockdown plasmid. T4 plays an important role in increasing the sensitivity of lung cancer cells to cisplatin.


Assuntos
Antineoplásicos , Neoplasias Pulmonares , Proteínas de Membrana , Proteínas de Ligação a RNA , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Cisplatino/farmacologia , Diterpenos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/biossíntese , Proteínas de Membrana/genética , Fenantrenos , Proteínas de Ligação a RNA/antagonistas & inibidores , Proteínas de Ligação a RNA/biossíntese , Proteínas de Ligação a RNA/genética , Fatores de Transcrição/genética
3.
Pharmacol Res Perspect ; 10(4): e00982, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35822549

RESUMO

Non-selective cation channels in urinary bladder smooth muscle (UBSM) are thought to mediate increases in cellular excitability and contractility. For transient receptor potential melastatin type-4 (TRPM4) channels, the evidence primarily relies on the inhibitor 9-phenanthrol, which exhibits pharmacological limitations. Recently, 4-chloro-2-[2-(2-chloro-phenoxy)-acetylamino]-benzoic acid (CBA) has been discovered as a novel TRPM4 channel blocker. We examined how, in comparison to 9-phenanthrol, CBA affects the excitability of freshly isolated guinea pig UBSM cells and the contractility of UBSM strips. Additionally, non-selective TRPM4 channel inhibitor flufenamic acid (FFA) and potentiator BTP2 (also known as YM-58483) were studied in UBSM cells. Unlike robust inhibition for 9-phenanthrol already known, CBA (up to 100 µM) displayed either no or a very weak reduction (<20%) in spontaneous phasic, 20 mM KCl-induced, and electrical field stimulated contractions. For 300 µM CBA, reductions were higher except for an increase in the frequency of KCl-induced contractions. In UBSM cells, examined under amphotericin B-perforated patch-clamp, CBA (30 µM) did not affect the membrane potential (I = 0) or voltage step-induced whole-cell cation currents, sensitive to 9-phenanthrol. The currents were not inhibited by FFA (100 µM), increased by BTP2 (10 µM), nor enhanced under a strongly depolarizing holding voltage of -16 or + 6 mV (vs. -74 mV). None of the three compounds affected the cell capacitance, unlike 9-phenanthrol. In summary, the novel inhibitor CBA and nonselective FFA did not mimic the inhibitory properties of 9-phenanthrol on UBSM function. These results suggest that TRPM4 channels, although expressed in UBSM, play a distinct role rather than direct regulation of excitability and contractility.


Assuntos
Contração Muscular , Bexiga Urinária , Animais , Ácido Benzoico/farmacologia , Cátions/farmacologia , Cobaias , Músculo Liso , Fenantrenos
4.
Chem Pharm Bull (Tokyo) ; 70(7): 483-491, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35786567

RESUMO

The first total syntheses of natural phenanthrene alkaloids, namely, uvariopsamine (1), noruvariopsamine (2), 8-hydroxystephenanthrine (3), 8-methoxyuvariopsine (4), thalihazine (5), and secophoebine (6), have been realized. In addition, their in vitro antimalarial activity against the multidrug-resistant K1 strain of Plasmodium falciparum and in vitro cytotoxic activity against the human nasopharynx carcinoma (KB), small cell lung cancer (NCI-H187), and breast cancer (MCF7) human cancer cell lines were investigated. All the phenanthrene alkaloids showed significant antiplasmodial activity (IC50 1.07-7.41 µM), and most compounds displayed low to no toxicity against the three cancer cell lines tested. Particularly, 3 exhibited the best antimalarial activity with an IC50 value of 1.07 µM, no toxicity to NCI-H187 (IC50 > 50 µM), and low toxicity against KB (IC50 24.53 µM) and MCF7 (IC50 42.67 µM) cell lines.


Assuntos
Alcaloides , Antimaláricos , Antineoplásicos , Fenantrenos , Alcaloides/farmacologia , Antimaláricos/farmacologia , Antineoplásicos/farmacologia , Humanos , Plasmodium falciparum
5.
Int J Mol Sci ; 23(13)2022 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-35806121

RESUMO

Magnaporthe oryzae, the causal agent of rice blast disease, produces devastating damage to global rice production. It is urgent to explore novel strategies to overcome the losses caused by this disease. 9-phenanthrol is often used as a transient receptor potential melastatin 4 (TRPM4) channel inhibitor for animals, but we found its fungal toxicity to M. oryzae. Thus, we explored the antimicrobial mechanism through transcriptome and metabolome analyses. Moreover, we found that overexpression of a gene encoding 4-hydroxyphenylpyruvate dioxygenase involved in the tyrosine degradative pathway enhanced the tolerance of 9-phenanthrol in M. oryzae. Thus, our results highlight the potential fungal toxicity mechanism of 9-phenanthrol at metabolic and transcriptomic levels and identify a gene involving 9-phenanthrol alleviation. Importantly, our results demonstrate the novel mechanism of 9-phenanthrol on fungal toxicity that will provide new insights of 9-phenanthrol for application on other organisms.


Assuntos
4-Hidroxifenilpiruvato Dioxigenase , Magnaporthe , Micotoxinas , Oryza , 4-Hidroxifenilpiruvato Dioxigenase/genética , Ascomicetos , Proteínas Fúngicas/metabolismo , Magnaporthe/genética , Magnaporthe/metabolismo , Metaboloma , Micotoxinas/metabolismo , Oryza/metabolismo , Fenantrenos , Doenças das Plantas/genética , Doenças das Plantas/microbiologia , Transcriptoma
6.
Molecules ; 27(14)2022 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-35889227

RESUMO

Salvia miltiorrhiza is a medicinal plant that synthesises biologically-active tanshinones with numerous therapeutic properties. An important rate-limiting enzyme in the biosynthesis of their precursors is 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR). This study presents the organ-specific expression profile of the S. miltiorrhiza HMGR4 gene and its sensitivity to potential regulators, viz. gibberellic acid (GA3), indole-3-acetic acid (IAA) and salicylic acid (SA). In addition, it demonstrates the importance of the HMGR4 gene, the hormone used, the plant organ, and the culture environment for the biosynthesis of tanshinones. HMGR4 overexpression was found to significantly boost the accumulation of dihydrotanshinone I (DHTI), cryptotanshinone (CT), tanshinone I (TI) and tanshinone IIA (TIIA) in roots by 0.44 to 5.39 mg/g dry weight (DW), as well as TIIA in stems and leaves. S. miltiorrhiza roots cultivated in soil demonstrated higher concentrations of the examined metabolites than those grown in vitro. GA3 caused a considerable increase in the quantity of CT (by 794.2 µg/g DW) and TIIA (by 88.1 µg/g DW) in roots. In turn, IAA significantly inhibited the biosynthesis of the studied tanshinones in root material.


Assuntos
Salvia miltiorrhiza , Salvia , Abietanos , Acil Coenzima A , Coenzima A , Furanos , Oxirredutases/metabolismo , Fenantrenos , Raízes de Plantas/genética , Raízes de Plantas/metabolismo , Quinonas , Salvia miltiorrhiza/metabolismo
7.
Environ Pollut ; 308: 119730, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-35809715

RESUMO

PAHs have been widely detected to accumulate in saline and hypersaline environments. Moderately halophilic microbes are considered the most suitable player for the elimination of PAHs in such environments. In this study, consortium 5H was enriched under 5% salinity and completely degraded phenanthrene in 5 days. By high-throughput sequencing, consortium 5H was identified as being mainly composed of Methylophaga, Marinobacter and Thalassospira. Combined with the investigation of intermediates and enzymatic activities, the degradation pathway of consortium 5H on phenanthrene was proposed. Consortium 5H was identified as having the ability to tolerate a wide range of salinities (1%-10%) and initial PAH concentrations (50 mg/L to 400 mg/L). It was also able to function under neutral to weak alkaline conditions (pH from 6 to 9) and the phytotoxicity of the produced intermediates showed no significant difference with distilled water. Furthermore, the metagenome of consortium 5H was measured and analyzed, which showed a great abundance of catabolic genes contained in consortium 5H. This study expanded the knowledge of PAH-degradation under hypersaline environments and consortium 5H was proposed to have good potential for the elimination of PAH pollution in saline/hypersaline environments.


Assuntos
Marinobacter , Fenantrenos , Hidrocarbonetos Policíclicos Aromáticos , Biodegradação Ambiental , Marinobacter/genética , Marinobacter/metabolismo , Fenantrenos/metabolismo , Hidrocarbonetos Policíclicos Aromáticos/metabolismo , Salinidade
8.
Int J Oncol ; 61(3)2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35894141

RESUMO

Pyruvate dehydrogenase kinase 4 (PDK4) is an important regulator of energy metabolism. Previously, knockdown of PDK4 by specific small interfering RNAs (siRNAs) have been shown to suppress the expression of Κirsten rat sarcoma viral oncogene homolog (KRAS) and the growth of lung and colorectal cancer cells, indicating that PDK4 is an attractive target of cancer therapy by altering energy metabolism. The authors previously reported that a novel small molecule, cryptotanshinone (CPT), which inhibits PDK4 activity, suppresses the in vitro three­dimensional (3D)­spheroid formation and in vivo tumorigenesis of KRAS­activated human pancreatic and colorectal cancer cells. The present study investigated the molecular mechanism of CPT­induced tumor suppression via alteration of glutamine and lipid metabolism in human pancreatic and colon cancer cell lines with mutant and wild­type KRAS. The antitumor effect of CPT was more pronounced in the cancer cells containing mutant KRAS compared with those containing wild­type KRAS. CPT treatment decreased glutamine and lipid metabolism, affected redox regulation and increased reactive oxygen species (ROS) production in the pancreatic cancer cell line MIAPaCa­2 containing mutant KRAS. Suppression of activated KRAS by specific siRNAs decreased 3D­spheroid formation, the expression of acetyl­CoA carboxylase 1 and fatty acid synthase (FASN) and lipid synthesis. The suppression also reduced glutathione­SH/glutathione disulfide and increased the production of ROS. Knockdown of FASN suppressed lipid synthesis in MIAPaCa­2 cells, partially promoted ROS production and mildly suppressed 3D­spheroid formation. These results indicated that CPT reduced tumorigenesis by inhibiting lipid metabolism and promoting ROS production in a mutant KRAS­dependent manner. This PDK4 inhibitor could serve as a novel therapeutic drug for KRAS­driven intractable cancers via alteration of cell metabolism.


Assuntos
Neoplasias Colorretais , Neoplasias Pancreáticas , Carcinogênese/genética , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Transformação Celular Neoplásica/metabolismo , Neoplasias Colorretais/patologia , Glutamina/metabolismo , Humanos , Lipídeos , Lipogênese , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Fenantrenos , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
9.
Drug Des Devel Ther ; 16: 1621-1645, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35669282

RESUMO

Background: Huo Luo Xiao Ling Dan (HLXLD), a famous Traditional Chinese Medicine (TCM) classical formula, possesses anti-atherosclerosis (AS) activity. However, the underlying molecular mechanisms remain obscure. Aim: The network pharmacology approach, molecular docking strategy, and in vitro validation experiment were performed to explore the potential active compounds, key targets, main signaling pathways, and underlying molecular mechanisms of HLXLD in treating AS. Methods: Several public databases were used to search for active components and targets of HLXLD, as well as AS-related targets. Crucial bioactive ingredients, potential targets, and signaling pathways were acquired through bioinformatics analysis. Subsequently, the molecular docking strategy and molecular dynamics simulation were carried out to predict the affinity and stability of active compounds and key targets. In vitro cell experiment was performed to verify the findings from bioinformatics analysis. Results: A total of 108 candidate compounds and 321 predicted target genes were screened. Bioinformatics analysis suggested that quercetin, dihydrotanshinone I, pelargonidin, luteolin, guggulsterone, and ß-sitosterol may be the main ingredients. STAT3, HSP90AA1, TP53, and AKT1 could be the key targets. MAPK signaling pathway might play an important role in HLXLD against AS. Molecular docking and molecular dynamics simulation results suggested that the active compounds bound well and stably to their targets. Cell experiments showed that the intracellular accumulation of lipid and increased secretory of TNF-α, IL-1ß, and MCP-1 in ox-LDL treated RAW264.7 cells, which can be significantly suppressed by pretreating with dihydrotanshinone I. The up-regulation of STAT3, ERK, JNK, and p38 phosphorylation induced by ox-LDL can be inhibited by pretreating with dihydrotanshinone I. Conclusion: Our findings comprehensively demonstrated the active compounds, key targets, main signaling pathways, and underlying molecular mechanisms of HLXLD in treating AS. These findings would provide a scientific basis for the study of the complex mechanisms underlying disease and drug action.


Assuntos
Aterosclerose , Medicamentos de Ervas Chinesas , Aterosclerose/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Furanos , Humanos , Medicina Tradicional Chinesa , Simulação de Acoplamento Molecular , Farmacologia em Rede , Fenantrenos , Quinonas
10.
Mol Med Rep ; 26(1)2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35656892

RESUMO

Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies and primarily presents with hyperandrogenism. Although environmental factors and genetic factors are thought to be the major reason, there still exists a lot of questions need to be answered. High expression of C­terminal­binding protein 1 antisense (CTBP1­AS) was identified as an independent risk factor for PCOS; however, the molecular mechanism of CTBP1­AS in PCOS regulation is unknown. In the present study, the expression level of CTBP1­AS was found to be significantly upregulated in patients with PCOS compared with healthy control patients. CTBP1­AS knockdown was demonstrated to reduce the proliferation and promote the apoptosis of granulosa tumor cells in vitro. It was also identified that the two core catalytic subunits of Polycomb repressive complex 2 (enhancer of zeste homolog 2 and embryonic and ectoderm development protein) interacted with CTBP1­AS in primary granulosa cells and KGN cells. In addition, cryptotanshinone treatment was demonstrated to effectively downregulate CTBP1­AS expression level. Data from the present study suggested a pathophysiological role of CTBP1­AS in PCOS and may provide a new potential target for PCOS treatment.


Assuntos
Síndrome do Ovário Policístico , RNA Antissenso , Oxirredutases do Álcool , Proteínas de Ligação a DNA , Feminino , Humanos , Fenantrenos , Complexo Repressor Polycomb 2 , Síndrome do Ovário Policístico/tratamento farmacológico , Síndrome do Ovário Policístico/genética , RNA Antissenso/genética , Ativação Transcricional , Regulação para Cima
11.
Molecules ; 27(11)2022 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-35684456

RESUMO

Lung cancer continues to be the world's leading cause of cancer death and the treatment of non-small cell lung cancer (NSCLC) has attracted much attention. The tubers of Bletilla striata are regarded as "an excellent medicine for lung diseases" and as the first choice to treat several lung diseases. In this study, seventeen phenanthrene derivatives, including two new compounds (1 and 2), were isolated from the tubers of B. striata. Most compounds showed cytotoxicity against A549 cells. An EdU proliferation assay, a cell cycle assay, a wound healing assay, a transwell migration assay, a flow cytometry assay, and a western blot assay were performed to further investigate the effect of compound 1 on A549 cells. The results showed that compound 1 inhibited cell proliferation and migration and promoted cell apoptosis in A549 cells. The mechanisms might correlate with the regulation of the Akt, MEK/ERK, and Bcl-2/Bax signaling pathways. These results suggested that the phenanthrenes of B. striata might be important and effective substances in the treatment of NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Orchidaceae , Fenantrenos , Células A549 , Apoptose , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proliferação de Células , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Fenantrenos/farmacologia
12.
Oxid Med Cell Longev ; 2022: 3192607, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35757509

RESUMO

Triptolide exhibits promising efficacy in various cancers and immune diseases while its clinical application has been strongly restricted by its severe side effects, especially cardiotoxicity. However, the underlying mechanism of triptolide-induced cardiotoxicity (TIC) remains unclear. The RNA-seq analysis of triptolide-injured AC16 human cardiomyocyte cell line hinted that ferroptosis is involved in TIC. Further experimental validations proved that triptolide triggered ferroptosis, as evidenced by significant accumulation of lipid peroxidation (4-HNE and MDA levels) and ferrous iron, as well as depletion of intracellular GSH. Furthermore, triptolide-induced iron overload involved the upregulation of TF/TRFC/DMT1 signal axis and the degradation of ferritin, which contribute to ROS generation via Fenton reaction. In addition, inhibition of the antioxidant Nrf2/HO-1 pathway was observed in TIC, which may also lead to the overproduction of lethal lipid peroxides. Mechanistically, using streptavidin-biotin affinity pull-down assay and computational molecular docking, we unveiled that triptolide directly binds to SLC7A11 to inactivate SLC7A11/GPX4 signal axis. More importantly, employment of a ferroptosis inhibitor Ferrostatin-1 alleviated TIC by partially reversing the inhibitory effects of triptolide on SLC7A11/GPX4 signal. Altogether, our study demonstrated that SLC7A11/GPX4 inactivation-mediated ferroptosis contributed to the pathogenesis of TIC. Combating ferroptosis may be a promising therapeutic avenue to prevent TIC.


Assuntos
Cardiotoxicidade , Ferroptose , Fenantrenos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Sistema y+ de Transporte de Aminoácidos/metabolismo , Cardiotoxicidade/metabolismo , Diterpenos/farmacologia , Compostos de Epóxi/farmacologia , Ferroptose/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Fenantrenos/farmacologia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo
13.
Immun Inflamm Dis ; 10(7): e667, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35759241

RESUMO

BACKGROUND: Herpes simplex virus-type 1 (HSV-1) can cause diseases, especially amongst neonates and immunocompromised hosts. Hence, developing a novel anti-HSV-1 drug with low-level toxicity is vital. Triptolide (TP), a diterpenoid triepoxide is a natural product with range of bioactivity qualities. METHODS: In this study, viral infection was assessed in different phases of the HSV-1 replication cycle on A549 cells, using various assays, such as adsorption inhibition assay, penetration inhibition assay, time-of-addition assay, and quantitative polymerase chain reaction (qPCR). RESULTS: The results indicate that TP can effectively inhibit HSV-1 infection in the lowest range of concentration. TP exhibited significant inhibitory effect on HSV-1 plaque formation, with 50% effective concentration (EC50) of 0.05 µM. Furthermore, the time-of-addition assay suggests that TP has viral inhibitory effects when it was added less than 8 h postinfection (h.p.i.). This result is further confirmed by decline in the expression viral immediate-early genes (ICP4, ICP22, and ICP27) in 6 h.p.i in the TP-treated group compared to the control group, evaluated by real-time qPCR. The Western blotting result was also consistent with the previous findings, which confirms that TP can positively affect ICP4 during HSV-1 infection. CONCLUSIONS: The TP also showed antiviral activity against HSV-1. This dose-dependent activity is an indication of a particular cellular component, rather than cytotoxicity that has mediated its function. Finally, the result suggest a new approach for an effective treatment option of the HSV-1 infections.


Assuntos
Diterpenos , Herpes Simples , Herpesvirus Humano 1 , Animais , Antivirais/farmacologia , Chlorocebus aethiops , Diterpenos/metabolismo , Diterpenos/farmacologia , Compostos de Epóxi , Herpes Simples/tratamento farmacológico , Humanos , Recém-Nascido , Fenantrenos , Células Vero
14.
Oxid Med Cell Longev ; 2022: 1492239, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35770044

RESUMO

Triptolide (TP) has limited usage in clinical practice due to its side effects and toxicity, especially liver injury. Hepatic macrophages, key player of liver innate immunity, were found to be recruited and activated by TP in our previous study. The nuclear factor-erythroid-2-related factor 2 (Nrf2) pathway exerts a protective role in TP-induced liver damage, but its effect on the functions of hepatic macrophage has not been elucidated. Here, we determined whether TP can regulate the recruitment and polarization of hepatic macrophages by inhibiting Nrf2 signaling cascade. Our results demonstrated that TP inhibited the Nrf2 signaling pathway in hepatic macrophages. The changes in hepatic macrophages were responsible for the increased susceptibility toward inflammatory stimuli, and hence, TP pretreatment could induce severe liver damage upon the stimulation of a nontoxic dose of lipopolysaccharides. In addition, the Nrf2 agonist protected macrophages from TP-induced toxicity and Nrf2 deficiency significantly aggravated liver injury by enhancing the recruitment and M1 polarization of hepatic macrophages. This study suggests that Nrf2 pathway-mediated hepatic macrophage polarization plays an essential role in TP-induced liver damage, which can serve as a potential therapeutic target for preventing hepatotoxicity induced by TP.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Fator 2 Relacionado a NF-E2 , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Diterpenos , Compostos de Epóxi , Fator de Transcrição de Proteínas de Ligação GA/metabolismo , Humanos , Fígado/metabolismo , Macrófagos/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fenantrenos , Transdução de Sinais
15.
Molecules ; 27(12)2022 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-35744811

RESUMO

Triptolide (TP) is a potential drug candidate for the treatment of cancer, but its use was hampered by its systemic toxicity and poor water solubility. Hence, a TP-CSO prodrug was synthesized by conjugating TP to chitosan oligosaccharide (CSO), and characterized by 1H NMR, FTIR, DSC and XRD analyses. The TP-CSO containing about 4 wt% of TP exhibited excellent water solubility (15 mg/mL) compared to TP (0.017 mg/mL). Compared with TP, the pharmacokinetics of the conjugate after oral administration showed a three-fold increase in the half-life in the blood circulation and a 3.2-fold increase in AUC (0-∞). The orally administered TP-CSO could more effectively inhibit tumor progression but with much lower systemic toxicity compared with TP, indicating significant potential for further clinical trials. In conclusion, CSO-based conjugate systems may be useful as a platform for the oral delivery of other sparingly soluble drugs.


Assuntos
Quitosana , Diterpenos , Neoplasias Pancreáticas , Fenantrenos , Pró-Fármacos , Quitosana/química , Diterpenos/química , Compostos de Epóxi/química , Compostos de Epóxi/uso terapêutico , Humanos , Fenantrenos/química , Fenantrenos/uso terapêutico , Pró-Fármacos/uso terapêutico , Água
16.
Molecules ; 27(12)2022 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-35744840

RESUMO

In the screening of novel natural products against cancer using an in vitro cancer cell model, we recently found that tanshinones from a traditional Chinese medicine, the rhizome of Salvia miltiorrhiza Bunge (Danshen), had potent effects on cell proliferation and migration. Especially for human osteosarcoma U-2 OS cells, tanshinones significantly enhanced the cell adherence, implying a possible role in cell adhesion and cell migration inhibition. In this work, therefore, we aimed to provide a new insight into the possible molecule mechanisms of dihydrotanshinone I, which had the strongest effects on cell adhesion among several candidate tanshinones. RNA-sequencing-based transcriptome analysis and several biochemical experiments indicated that there were comprehensive signals involved in dihydrotanshinone I-treated U-2 OS cells, such as cell cycle, DNA replication, thermogenesis, tight junction, oxidative phosphorylation, adherens junction, and focal adhesion. First, dihydrotanshinone I could potently inhibit cell proliferation and induce cell cycle arrest in the G0/G1 phase by downregulating the expression of CDK4, CDK2, cyclin D1, and cyclin E1 and upregulating the expression of p21. Second, it could significantly enhance cell adhesion on cell plates and inhibit cell migration, involving the hyaluronan CD44-mediated CXCL8-PI3K/AKT-FOXO1, IL6-STAT3-P53, and EMT signaling pathways. Thus, the increased expression of CD44 and lengthened protrusions around the cell yielded a significant increase in cell adhesion. In summary, these results suggest that dihydrotanshinone I might be an interesting molecular therapy for enhancing human osteosarcoma U-2 OS cell adhesion and inhibiting cell migration and proliferation.


Assuntos
Neoplasias Ósseas , Osteossarcoma , Salvia miltiorrhiza , Adesão Celular , Movimento Celular , Quimiocinas , Furanos , Humanos , Receptores de Hialuronatos , Osteossarcoma/tratamento farmacológico , Osteossarcoma/metabolismo , Fenantrenos , Fosfatidilinositol 3-Quinases/metabolismo , Quinonas , Salvia miltiorrhiza/química
17.
Bioresour Technol ; 358: 127408, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35667530

RESUMO

Crude oil bioremediation requires a correct selection of potential biodegraders to address the hazard. The present study investigates biodegradation kinetics of single aliphatic (Hexadecane, HEX), aromatic (Phenanthrene, PHE), and binary mixture (HEX + PHE) as co-contaminants by axenic cultures of A. fabrum SLAJ 731, B. subtilis RSL2 and P. aeruginosa P7815 and their consortium. A proposed integrated kinetic model combining first-order exponential decay and the Monod equation is well-fitted to degradation data. Maximum degradations of both the substrates were observed for microcosm, indicating synergistic effects of selected strains. The degradation rate indicated parallel utilization of HEX while serial utilization of PHE by selected strains. Maximum HEX and PHE degradations of 92.4 and 88.7 % were achieved by microconsortium, which increased to 97.2 and 91.9 % for the binary mixture. The biodegradation efficiencies of HEX and PHE were linearly correlated with Alkane hydroxylase and Catechol-2,3-dioxygenase activities, respectively.


Assuntos
Fenantrenos , Alcanos/metabolismo , Bactérias/metabolismo , Biodegradação Ambiental , Cinética , Fenantrenos/metabolismo
18.
Sci Total Environ ; 838(Pt 3): 156487, 2022 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-35667431

RESUMO

The microbial communities are of high importance to the restoration of ecological function and plant health, while little information about the influence of exogenous pollutants on the resilience and temporal dynamics of root microbial communities is available. In this study, a greenhouse experiment was conducted to investigate the effects of exogenous phenanthrene in terms of time and pollution disturbance on the wheat root-associated microbial communities. It was found that a high phenanthrene degradation rate of 86 % was achieved in the rhizosphere of wheat after the first-week planting. Compared to phenanthrene pollution, temporal changes had more significant impacts on the wheat root microbial communities. Obvious change of microbes influenced by PHE had been revealed at the initial three-week planting even most of PHE has been degraded, and the enriched microbes in the rhizosphere were affiliated to Altererythrobacter, Massilia, Mycobacterium, Ramlibacter, Sphingobium, Novosphingobium and Romboutsia. However, at the later stage after four-week incubation, the wheat root-associated microbial communities gradually recovered to the state without pollution. The results of this study were helpful to deepen the understanding of the response of root-associated microbial resilience to the exogenous phenanthrene pollution, and would benefit the stability and balance of agricultural ecology facing exogenous organic pollutants.


Assuntos
Poluentes Ambientais , Microbiota , Fenantrenos , Poluentes do Solo , Poluentes Ambientais/metabolismo , Fenantrenos/metabolismo , Raízes de Plantas/metabolismo , Microbiologia do Solo , Poluentes do Solo/metabolismo , Triticum/metabolismo
19.
Environ Pollut ; 307: 119591, 2022 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-35688390

RESUMO

The adsorption of hydrophobic organic compounds (HOCs) by microplastics (MPs) has attracted great attention in recent years. However, the ultimate environmental fate of the HOCs sorbed on MPs (HOCs-MPs) is poorly understood. In this work, we investigated the potential influence of the biotransformation process on the environmental fate of phenanthrene (PHE, a model HOC) sorbed on MPs (PHE-MPs) under the existence of humic acid (HA, the main ingredient of dissolved organic matter (DOM)) in the aquatic environment. The results indicated that the adsorption behavior of PHE on MPs decreased its bioavailability and thus inhibited its biotransformation efficiency. However, HA significantly promoted the biodegradation rate and percentage of PHE-MPs. This was probably because HA improved the desorption of PHE from MPs, which promoted the acquisition of PHE by bacteria from the aqueous phase. Further, HA dramatically increased the bacterial community diversity and richness and altered the community composition. The richness of some PHE-degrading bacteria, such as Methylobacillus and Sphingomonas, significantly increased, which may also be an important factor for promoting PHE biodegradation. Molecular ecological network analysis implied that HA enhanced the modularity and complexity of bacterial interaction networks, which was beneficial to maintaining the functional stability of the consortium QY1. Besides, HA decreased the cytotoxicity of functional microbes induced by HOCs-MPs. This work broadens our knowledge of the environmental fate of HOCs-MPs and interactions of MPs, HOCs, DOMs and functional microbial consortiums in aqueous environments.


Assuntos
Substâncias Húmicas , Fenantrenos , Adsorção , Bactérias , Disponibilidade Biológica , Substâncias Húmicas/análise , Microplásticos/toxicidade , Compostos Orgânicos , Fenantrenos/química , Fenantrenos/toxicidade , Plásticos , Água
20.
Int Immunopharmacol ; 108: 108894, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35729830

RESUMO

Ulcerative colitis (UC) is a chronically relapsing inflammatory disease in the intestinal tract. Current unsatisfactory treatments prompt people to seek for alternative therapies and drug candidates. Cryptotanshinone (CTS), a diterpene quinoneextractedfromthe roots ofSalviamiltiorrhiza, has recently been shown to inhibit acute colitis by reducing pro-inflammatory mediators. However, whether CTS can protect against chronic UC and its effect on T lymphocytes remain unknown. In this study, CTS (20, 60 mg/kg) showed potent inhibitory activity against dextran sulfate sodium (DSS)-induced acute UC, as determined by weight loss, disease activity, colon length and histology. Similarly, in a model of DSS-induced chronic colitis, the administration of CTS prevented the disease progression with longer colon length, lower histological scores, and less expression of fibrosis-related collagen and α-smooth muscle actin in the colon. CTS also reduced the proportion of CD4+IL-17A+ Th17 cells in spleen and mesenteric lymph nodes of mice with acute or chronic colitis. However, CTS at 20 mg/kg had no effect on regulatory T cells (Tregs). In addition, CTS reduced the phosphorylation of signal transduction and transcription activator 3 (STAT3) in DSS-treated colon tissue. Further study showed that CTS concentration-dependently suppressed the differentiation of naïve CD4+ T cells into Th17 cells. CTS could not inhibit the activation and proliferation of T lymphocytes or attenuate the secretion of cytokines including IL-10, IL-2, IL-6 and IFN-γ, but could inhibit the production of IL-17A and TNF-α in Con A-stimulated splenocytes. CTS suppressed IL-6-induced phosphorylation and nuclear translocation of STAT3. In conclusion, our study demonstrated that CTS alleviated acute and chronic UC by suppressing STAT3 activation and Th17 cell differentiation, suggesting that it may be a promising candidate drug for the treatment of UC.


Assuntos
Colite Ulcerativa , Colite , Animais , Diferenciação Celular , Colite/induzido quimicamente , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/patologia , Colo/patologia , Sulfato de Dextrana/farmacologia , Modelos Animais de Doenças , Humanos , Interleucina-17/metabolismo , Interleucina-6/metabolismo , Camundongos , Fenantrenos , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Células Th17
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