RESUMO
Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by the accumulation of amyloid-beta plaques and hyperphosphorylated tau proteins, leading to cognitive decline and neuronal death. However, despite extensive research, there are still no effective treatments for this condition. In this study, a series of chloride-substituted Ramalin derivatives is synthesized to optimize their antioxidant, anti-inflammatory, and their potential to target key pathological features of Alzheimer's disease. The effect of the chloride position on these properties is investigated, specifically examining the potential of these derivatives to inhibit tau aggregation and beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1) activity. Our findings demonstrate that several derivatives, particularly RA-3Cl, RA-4Cl, RA-26Cl, RA-34Cl, and RA-35Cl, significantly inhibit tau aggregation with inhibition rates of approximately 50%. For BACE-1 inhibition, Ramalin and RA-4Cl also significantly decrease BACE-1 expression in N2a cells by 40% and 38%, respectively, while RA-23Cl and RA-24Cl showed inhibition rates of 30% and 35% in SH-SY5Y cells. These results suggest that chloride-substituted Ramalin derivatives possess promising multifunctional properties for AD treatment, warranting further investigation and optimization for clinical applications.
Assuntos
Doença de Alzheimer , Secretases da Proteína Precursora do Amiloide , Ácido Aspártico Endopeptidases , Proteínas tau , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Humanos , Proteínas tau/metabolismo , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/metabolismo , Cloretos/química , Antioxidantes/farmacologia , Antioxidantes/síntese química , Antioxidantes/química , Agregados Proteicos/efeitos dos fármacos , Linhagem Celular Tumoral , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/químicaRESUMO
When cells are exposed to freezing temperatures, high concentrations of cryoprotective agents (CPA) prevent ice crystal formation, thus enhancing cell survival. However, high concentrations of CPAs can also cause cell toxicity. Exopolysaccharides (EPSs) from polar marine environments exhibit lower toxicity and display effects similar to traditional CPA. In this study, we sought to address these issues by i) selecting strains that produce EPS with novel cryoprotective activity, and ii) optimizing culture conditions for EPS production. Sixty-six bacteria producing mucous substances were isolated from the Ross Sea (Antarctic Ocean) using solid marine agar plates. Among them, Pseudoalteromonas sp. RosPo-2 was ultimately selected based on the rheological properties of the produced EPS (p-CY02). Cryoprotective activity experiments demonstrated that p-CY02 exhibited significantly cryoprotective activity at a concentration of 0.8% (w/v) on mammalian cells (HaCaT). This activity was further improved when combined with various concentrations of dimethyl sulfoxide (DMSO) compared to using DMSO alone. Moreover, the survival rate of HaCaT cells treated with 5% (v/v) DMSO and 0.8% (w/v) p-CY02 was measured at 87.9 ± 2.8% after freezing treatment. This suggests that p-CY02 may be developed as a more effective, less toxic, and novel non-permeating CPA. To enhance the production of EPS with cryoprotective activity, Response Surface Methodology (RSM) was implemented, resulting in a 1.64-fold increase in production of EPS with cryoprotective activity.
Assuntos
Sobrevivência Celular , Crioprotetores , Meios de Cultura , Polissacarídeos Bacterianos , Pseudoalteromonas , Pseudoalteromonas/metabolismo , Polissacarídeos Bacterianos/farmacologia , Polissacarídeos Bacterianos/biossíntese , Polissacarídeos Bacterianos/metabolismo , Crioprotetores/farmacologia , Crioprotetores/metabolismo , Meios de Cultura/química , Regiões Antárticas , Humanos , Sobrevivência Celular/efeitos dos fármacos , Dimetil Sulfóxido/farmacologia , Dimetil Sulfóxido/metabolismo , Células HaCaT , Linhagem Celular , Água do Mar/microbiologiaRESUMO
Using mass spectrometry (MS)-guided isolation methods, a new thiodiketopiperazine derivative (1) and exserohilone (2) were isolated from an EtOAc-extract of Setosphaeria rostrata culture medium. The chemical structure of the new compound was elucidated by MS and NMR spectroscopy, and the absolute configurations were established by the quantum mechanical calculations of electronic circular dichroism. All isolated compounds were examined for their effects on reactive oxygen species (ROS) production, matrix metalloproteinase 1 (MMP-1) secretion, and procollagen type I α1 secretion in tumor necrosis factor (TNF)-α-induced human dermal fibroblasts. Compound 1 and exserohilone (2) exhibited the inhibition of TNF-α-induced ROS generation and MMP-1 secretion. Additionally, compound 1 and exserohilone (2) increased the procollagen type I α1 secretion. Compound 1 docked computationally into the active site of MMP-1 (-6.0 kcal/mol).
Assuntos
Ascomicetos , Metaloproteinase 1 da Matriz , Fator de Necrose Tumoral alfa , Humanos , Metaloproteinase 1 da Matriz/farmacologia , Espécies Reativas de Oxigênio , FibroblastosRESUMO
Three new fusidane-type nortriterpenoids, simplifusinolide A, 24-epi simplifusinolide A, and simplifusidic acid L (1-3), were isolated from the EtOAc extract of the Arctic marine-derived fungus Simplicillium lamellicola culture medium, together with fusidic acid (4) and 16-O-deacetylfusicid acid (5). The structures of the isolated compounds were elucidated by NMR and MS analyses. The absolute configurations of compounds 1-3 were established by the quantum mechanical calculations of electronic circular dichroism and gauge-including atomic orbital NMR chemical shifts, followed by DP4 + analysis. Benign prostatic hyperplasia (BPH) is a major urological disorder in men worldwide. The anti-BPH potentials of the isolated compounds were evaluated using BPH-1 and WPMY-1 cells. Treatment with simplifusidic acid L (3) and fusidic acid (4) significantly downregulated the mRNA levels of the androgen receptor (AR) and its downstream effectors, inhibiting the proliferation of BPH-1 cells. Specifically, treatment with 24-epi simplifusinolide A (2) significantly suppressed the cell proliferation of both BPH-1 and DHT-stimulated WPMY-1 cells by inhibiting AR signaling. These results suggest the potential of 24-epi simplifusinolide A (2), simplifusidic acid L (3) and fusidic acid (4) as alternative agents for BPH treatment by targeting AR signaling.
Assuntos
Hypocreales , Hiperplasia Prostática , Masculino , Humanos , Hiperplasia Prostática/tratamento farmacológico , Ácido Fusídico/farmacologia , Extratos Vegetais/farmacologia , Proliferação de CélulasRESUMO
Cryopreservation of human red blood cells (RBCs) is vital for regenerative medicine and organ transplantation, but current cryoprotectants (CPAs) like glycerol and hydroxyethyl starch (HES) have limitations. Glycerol requires post-thaw washing due to cell membrane penetration, while HES causes high viscosity. To address these issues, we explored exopolysaccharides (EPS) from Antarctic Pseudoalteromonas sp. strain CY01 as a non-penetrating CPA for RBC cryopreservation. The EPS, p-CY01, consisted mainly of repeating (1-4) glucose and (1-6) galactose linkages with a molecular mass of 1.1 × 107 Da. Through mild acid hydrolysis, we obtained low molecular weight p-CY01 (p-CY01 LM) with a molecular weight of 2.7 × 105 Da, offering reduced viscosity, improved solubility, and cryoprotective properties. Notably, combining low concentrations of penetrating CPAs (>1% glycerol and dimethyl sulfoxide) with 2.5% (w/v) p-CY01 LM demonstrated significant cryoprotective effects. These findings highlight the potential of p-CY01 LM as a highly effective CPA for human RBC cryopreservation, replacing HES and glycerol and enabling the long-term storage of biological materials.
RESUMO
Strategies for reducing inflammation in neurodegenerative diseases have attracted increasing attention. Herein, we discovered and evaluated the neuroprotective potential of fungal metabolites isolated from the Antarctic fungus Pseudogymnoascus sp. (strain SF-7351). The chemical investigation of the EtOAc extract of the fungal strain isolate revealed a novel naturally occurring epi-macrosphelide J (1), a novel secondary metabolite macrosphelide N (2), and three known compounds, namely macrosphelide A (3), macrosphelide B (4), and macrosphelide J (5). Their structures were established unambiguously using spectroscopic methods, such as one-dimensional and two-dimensional nuclear magnetic resonance (1D and 2D-NMR) spectroscopy, high-resolution electrospray ionization mass spectrometry (HR-ESI-MS), and gauge-including atomic orbital (GIAO) NMR chemical shift calculations, with the support of the advanced statistical method DP4+. Among the isolated metabolites, the absolute configuration of epi-macrosphelide J (1) was further confirmed using single-crystal X-ray diffraction analysis. The neuroprotective effects of the isolated metabolites were evaluated in lipopolysaccharide (LPS)-induced BV2 and glutamate-stimulated HT22 cells. Only macrosphelide B (4) displayed substantial protective effects in both BV2 and HT22 cells. Molecular mechanisms underlying this activity were investigated using western blotting and molecular docking studies. Macrosphelide B (4) inhibited the inflammatory response by reducing the nuclear translocation of NF-κB (p65) in LPS-induced BV2 cells and induced the Nrf2/HO-1 signaling pathway in both BV2 and HT22 cells. The neuroprotective effect of macrosphelide B (4) is related to the interaction between Keap1 and p65. These results suggest that macrosphelide B (4), present in the fungus Pseudogymnoascus sp. (strain SF-7351), may serve as a candidate for the treatment of neurodegenerative diseases.
RESUMO
Cold acclimation refers to a phenomenon in which plants become more tolerant to freezing after exposure to non-lethal low temperatures. Aulacomnium turgidum (Wahlenb.) Schwaegr is a moss found in the Arctic that can be used to study the freezing tolerance of bryophytes. To improve our understanding of the cold acclimation effect on the freezing tolerance of A. turgidum, we compared the electrolyte leakage of protonema grown at 25 °C (non-acclimation; NA) and at 4 °C (cold acclimation; CA). Freezing damage was significantly lower in CA plants frozen at -12 °C (CA-12) than in NA plants frozen at -12 °C (NA-12). During recovery at 25 °C, CA-12 demonstrated a more rapid and greater level of the maximum photochemical efficiency of photosystem II than NA-12, indicating a greater recovery capacity for CA-12 compared to NA-12. For the comparative analysis of the transcriptome between NA-12 and CA-12, six cDNA libraries were constructed in triplicate, and RNA-seq reads were assembled into 45,796 unigenes. The differential gene expression analysis showed that a significant number of AP2 transcription factor genes and pentatricopeptide repeat protein-coding genes related to abiotic stress and the sugar metabolism pathway were upregulated in CA-12. Furthermore, starch and maltose concentrations increased in CA-12, suggesting that cold acclimation increases freezing tolerance and protects photosynthetic efficiency through the accumulation of starch and maltose in A. turgidum. A de novo assembled transcriptome can be used to explore genetic sources in non-model organisms.
RESUMO
Alkyl butyrate with fruity flavor is known as an important additive in the food industry. We synthesized various alkyl butyrates from various fatty alcohol and butyric acid using immobilized Rhodococcus cutinase (Rcut). Esterification reaction was performed in a non-aqueous system including heptane, isooctane, hexane, and cyclohexane. As a result of performing the alkyl butyrate synthesis reaction using alcohols of various chain lengths, it was found that the preference for the alcohol substrate had the following order: C6 > C4 > C8 > C10 > C2. Through molecular docking analysis, it was found that the greater the hydrophobicity of alcohol, the higher the accessibility to the active site of the enzyme. However, since the number of torsions increased as the chain length increased, it became difficult for the hydroxyl oxygen of the alcohol to access the γO of serine at the enzyme active site. These molecular docking results were consistent with substrate preference results of the Rcut enzyme. The Rcut maintained the synthesis efficiency at least for 5 days in isooctane solvent. We synthesized as much as 452 mM butyl butyrate by adding 100 mM substrate daily for 5 days and performing the reaction. These results show that Rcut is an efficient enzyme for producing alkyl butyrate used in the food industry.
Assuntos
Butiratos , Octanos , Esterificação , Simulação de Acoplamento Molecular , Especificidade por Substrato , Butiratos/química , Ácido Butírico , Álcoois , Enzimas Imobilizadas/metabolismoRESUMO
Atopic dermatitis (AD) is a chronic inflammatory skin disease with a profound negative impact on patients' quality of life. Four known secondary fungal metabolites were found in the chemical study of the Antarctic fungus Pleosporales sp. SF-7343, including 14-methoxyalternate C (1), 5'-methoxy-6-methyl-biphenyl-3,4,3'-triol (2), 3,8,10-trihydroxy-4-methoxy-6-methylbenzocoumarin (3), and alternariol monomethyl ether (4). Additionally, we identified the skin anti-inflammatory composition from the SF-7343 strain. Interleukin-8 and -6 Screening results showed that compound 1 inhibited IL-8 and IL-6 in tumor necrosis factor-α/interferon-γ stimulated HaCaT cells. Compound 1 showed inhibitory effects on MDC and RANTES. It also downregulated the expression of intercellular adhesion molecule-1 (ICAM-1) and upregulated the expression of involucrin. The results of the mechanistic study showed that compound 1 inhibited the nuclear translocation of nuclear factor-kappa B p65 and STAT3. In conclusion, this study demonstrates the potential of the Antarctic fungal strain SF-7343 as a bioactive resource to inhibit skin inflammation, such as AD.
Assuntos
Dermatite Atópica , NF-kappa B , Humanos , NF-kappa B/metabolismo , Qualidade de Vida , Citocinas/metabolismo , Queratinócitos/metabolismo , Anti-Inflamatórios/uso terapêutico , Fator de Necrose Tumoral alfa/metabolismo , Dermatite Atópica/metabolismo , Janus Quinase 2/metabolismo , Fator de Transcrição STAT3/metabolismoRESUMO
Recently, microorganisms and their metabolites in the Antarctic marine environment have attracted attention as useful sources for novel therapeutics, including anticancer drugs. Here, we investigated the effects of citromycin, isolated from the Antarctic marine-derived fungus, Sporothrix sp., on human ovarian cancer cells. Citromycin inhibited the migration and invasion of human ovarian cancer SKOV3 and A2780 cells, but had no cytotoxic activity against them. Additionally, it inhibited the expression of epithelial-mesenchymal transition (EMT) markers and the activation of matrix metalloproteinase (MMP)-2 and MMP9. Moreover, extracellular signal-regulated kinase (ERK)-1/2 signaling was inhibited after citromycin treatment, and the ectopic expression of ERK negated the anti-invasive activity of citromycin. Our findings suggest that citromycin inhibits the migration and invasion of human ovarian cancer cells by downregulating the expression levels of EMT markers and MMP-2/9 via inhibition of the ERK1/2 pathway.
Assuntos
Neoplasias Ovarianas , Sporothrix , Regiões Antárticas , Linhagem Celular Tumoral , Movimento Celular , Feminino , Fungos , Humanos , Invasividade Neoplásica/prevenção & controle , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , EstreptotricinasRESUMO
Microglia play a significant role in immune defense and tissue repair in the central nervous system (CNS). Microglial activation and the resulting neuroinflammation play a key role in the pathogenesis of neurodegenerative disorders. Recently, inflammation reduction strategies in neurodegenerative diseases have attracted increasing attention. Herein, we discovered and evaluated the anti-neuroinflammatory potential of compounds from the Antarctic fungi strain Aspergillus sp. SF-7402 in lipopolysaccharide (LPS)-stimulated BV2 cells. Four metabolites were isolated from the fungi through chemical investigations, namely, 5-methoxysterigmatocystin (1), sterigmatocystin (2), aversin (3), and 6,8-O-dimethylversicolorin A (4). Their chemical structures were elucidated by extensive spectroscopic analysis and HR-ESI-MS, as well as by comparison with those reported in literature. Anti-neuroinflammatory effects of the isolated metabolites were evaluated by measuring the production of nitric oxide (NO), tumor necrosis factor (TNF)-α, and interleukin (IL)-6 in LPS-activated microglia at non-cytotoxic concentrations. Sterigmatocystins (1 and 2) displayed significant effects on NO production and mild effects on TNF-α and IL-6 expression inhibition. The molecular mechanisms underlying this activity were investigated using Western blot analysis. Sterigmatocystin treatment inhibited NO production via downregulation of inducible nitric oxide synthase (iNOS) expression in LPS-stimulated BV2 cells. Additionally, sterigmatocystins reduced nuclear translocation of NF-κB. These results suggest that sterigmatocystins present in the fungal strain Aspergillus sp. are promising candidates for the treatment of neuroinflammatory diseases.
Assuntos
Microglia , NF-kappa B , Regiões Antárticas , Anti-Inflamatórios/química , Aspergillus/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/farmacologia , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Transdução de Sinais , Esterigmatocistina/metabolismo , Esterigmatocistina/farmacologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
A lipolytic enzyme (Rcut) was discovered from the Rhodococcusstrain (RosL12) isolated from the Antarctic Ross Sea. The corresponding gene composed of 651 bases encoding 216 amino acids. It was found to be a cutinase gene through BLAST search. Rcut has a signal sequence consisting of 29 amino acids. An active Rcut was produced after the intact gene containing the signal sequence was transformed into Escherichia coli Rosetta-gami™ 2 (DE3) pLysS. Rcut was purified through a nickel-nitrilotriacetic acid purification system and a carboxymethyl Sepharose column chromatography. Its specific activity was 2190 U/mg. Rcut showed the highest activity at 40 °C and had a low activation energy of 3.16 kcal/mol. This means that it is a typical cold-adapted enzyme. Rcut showed high activity towards medium chain fatty acids (C4-C10). Rcut degraded polycaprolactone and polyethylene terephthalate, suggesting that it could be used for decomposition of synthetic plastics causing environmental pollution. Rcut was immobilized on methacrylate-divinyl benzene bead. This immobilized Rcut (immRcut) showed higher thermal stability than the free enzyme. ImmRcut performed transesterification of various esters and ethanol in a non-polar solvent, suggesting that it could be used for the synthesis of industrially useful ester compounds.
Assuntos
Rhodococcus , Aminoácidos , Regiões Antárticas , Hidrolases de Éster Carboxílico , Estabilidade Enzimática , Ésteres , Concentração de Íons de Hidrogênio , Sinais Direcionadores de Proteínas , Rhodococcus/genética , Especificidade por Substrato , TemperaturaRESUMO
The pathogenesis of Alzheimer's disease (AD) is still unclear, and presently there is no cure for the disease that can be used for its treatment or to stop its progression. Here, we investigated the therapeutic potential of ramalin (isolated from the Antarctic lichen, Ramalina terebrata), which exhibits various physiological activities, in AD. Specifically, derivatives were synthesized based on the structure of ramalin, which has a strong antioxidant effect, BACE-1 inhibition activity, and anti-inflammatory effects. Therefore, ramalin and its derivatives exhibit activity against multiple targets associated with AD and can serve as potential therapeutic agents for the disease.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Glutamatos/uso terapêutico , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Antioxidantes/síntese química , Antioxidantes/química , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/metabolismo , Compostos de Bifenilo/antagonistas & inibidores , Glutamatos/síntese química , Glutamatos/química , Humanos , Estrutura Molecular , Picratos/antagonistas & inibidoresRESUMO
Chemical investigation of the Antarctic lichen-derived fungal strain Acremonium sp. SF-7394 yielded a new amphilectane-type diterpene, acrepseudoterin (1), and a new acorane-type sesquiterpene glycoside, isocordycepoloside A (2). In addition, three known fungal metabolites, (-)-ternatin (3), [D-Leu]-ternatin (4), and pseurotin A (5), were isolated from the EtOAc extract of the fungal strain. Their structures were mainly elucidated by analyzing their NMR and MS data. The absolute configuration of 1 was proposed by electronic circular dichroism calculations, and the absolute configuration of the sugar unit in 2 was determined by a chemical method. The inhibitory effects of the isolated compounds on protein tyrosine phosphatase 1B (PTP1B) were evaluated by enzymatic assays; results indicated that acrepseudoterin (1) and [D-Leu]-ternatin (4) dose-dependently inhibited the enzyme activity with IC50 values of 22.8 ± 1.1 µM and 14.8 ± 0.3 µM, respectively. Moreover, compound 1 was identified as a competitive inhibitor of PTP1B.
Assuntos
Acremonium , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Inibidores EnzimáticosRESUMO
Chemical investigation of the Antarctic fungi Pleosporales sp. SF-7343 revealed four known secondary fungal metabolites: alternate C (1), altenusin (2), alternariol (3), and altenuene (4). The compound structures were identified primarily by NMR and MS analyses. Atopic dermatitis, an inflammatory disease, is driven by the abnormal activation of T helper (Th) 2 cells and barrier dysfunction. We attempted to identify the anti-inflammatory components of SF-7343. Initial screening showed that compounds 1 and 3 inhibited the secretion of interleukin-8 and -6 in tumor necrosis factor-α/interferon-γ-treated HaCaT cells, and these compounds also showed inhibitory effects on CCL5 and CCL22. Compounds 1 and 3 also downregulated the protein expression levels of intercellular adhesion molecule-1 and upregulated the expression of filaggrin and involcurin. The mechanism study results showed that compounds 1 and 3 inhibited nuclear translocation of nuclear factor-kappa B p65 and the phosphorylation of STAT1 and STAT3. Compound 1, but not compound 3, significantly promoted the expression of heme oxygenase (HO)-1. The effects of compound 1 were partly reversed by co-treatment with a HO-1 inhibitor, tin protoporphyrin IX. Taken together, this study demonstrates the potential value of Antarctic fungal strain SF-7343 isolates as a bioresource for bioactive compounds to prevent skin inflammation.
Assuntos
Anti-Inflamatórios/farmacologia , Ascomicetos/química , Produtos Biológicos/farmacologia , Queratinócitos/efeitos dos fármacos , Regiões Antárticas , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Proteínas Filagrinas , Expressão Gênica , Heme Oxigenase-1/metabolismo , Humanos , Molécula 1 de Adesão Intercelular , Interferon gama/metabolismo , Queratinócitos/metabolismo , Estrutura Molecular , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
A new α-pyrone analog, arthrifuranone A (1) was isolated from an EtOAc-extract of Arthrinium pseudosinense culture medium. The isolation workflow was guided by a Molecular Networking-based dereplication strategy. The chemical structure of the new compound was elucidated using MS and NMR spectroscopic techniques, and the absolute configuration was established by the Mosher's method and gauge-including atomic orbital NMR chemical shift calculations, followed by DP4 + analysis. The isolated compound was evaluated for its estrogenic activity using the MCF-7 estrogen responsive human breast cancer cells. Compound 1 showed estrogenic activity by increasing the proliferation of MCF-7 cells at the concentration of 3.125 µM via phosphorylation of estrogen receptor-α.
Assuntos
Ascomicetos/metabolismo , Receptor alfa de Estrogênio/efeitos dos fármacos , Estrogênios/farmacologia , Pironas/farmacologia , Neoplasias da Mama/metabolismo , Proliferação de Células/efeitos dos fármacos , Receptor alfa de Estrogênio/metabolismo , Estrogênios/química , Estrogênios/isolamento & purificação , Feminino , Humanos , Células MCF-7 , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Pironas/química , Pironas/isolamento & purificaçãoRESUMO
Inflammation is a vital process that maintains tissue homeostasis. However, it is widely known that uncontrolled inflammation can contribute to the development of various diseases. This study aimed to discover anti-inflammatory metabolites from Penicillium bialowiezense. Seven spiroditerpenoids, including two new compounds, breviones P and Q (1 and 2), were isolated and characterized by various spectroscopic and spectrometric methods. All isolated compounds were initially tested for their inhibitory effects against lipopolysaccharide-induced nitric oxide (NO) production in RAW 264.7 macrophages. Of these, brevione A (3) exhibited this activity with a half-maximal inhibitory concentration value of 9.5 µM. Further mechanistic studies demonstrated that 3 could suppress the expression of pro-inflammatory cytokines and mediators, such as NO, prostaglandin E2, interleukin (IL)-1ß, tumor necrosis factor-α, IL-6, and IL-12 by inhibiting the activation of nuclear factor-kappa B and c-Jun N-terminal kinase.
Assuntos
Anti-Inflamatórios/química , Diterpenos/química , Penicillium/química , Animais , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Diterpenos/isolamento & purificação , Diterpenos/farmacologia , Expressão Gênica/efeitos dos fármacos , Interleucina-1beta/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Conformação Molecular , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Penicillium/metabolismo , Células RAW 264.7 , Compostos de Espiro/química , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Eight new naphtho[1,2-c]furan derivatives (1-8) along with six known analogues (9-14) were isolated from culture medium of the basidiomycete Basidioradulum radula. The structures of these compounds were identified using spectroscopic analysis, and their absolute configurations were resolved using X-ray diffraction, ECD, and VCD. Compounds 7 and 14 inhibited the cell viability of human prostate cancer DU-145 cells with IC50 values of 7.54 ± 0.03 µM and 5.04 ± 0.03 µM, respectively. At 8 µM, compounds 7 and 14 increased the percentage of apoptotic cells and upregulated the protein expression related to the apoptosis caspase pathways in DU-145 cells. Furthermore, the hallmarks of cells undergoing apoptosis, such as chromatin condensation, were also observed at this concentration. However, compound 7 and 14 showed no effect on the proliferation of splenocytes isolated from cyclophosphamide-induce immunosuppressed mice.
Assuntos
Antineoplásicos/farmacologia , Basidiomycota/química , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ciclofosfamida , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Baço/efeitos dos fármacos , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
iTRAQ proteomic profiling was conducted to examine the proteomic responses of the Antarctic copepod Tigriopus kingsejongensis under ultraviolet B (UVB) exposure. Of the 5507 proteins identified, 3479 proteins were annotated and classified into 25 groups using clusters of orthologous genes analysis. After exposing the T. kingsejongensis to 12â¯kJ/m2 UVB radiation, 77 biological processes were modulated over different time periods (0, 6, 12, 24, and 48â¯h) compared with the control. A Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis showed that UVB exposure in T. kingsejongensis downregulated ribosome and glyoxylate and dicarboxylate metabolism at all time points. Furthermore, antioxidant and chaperone proteins were highly downregulated in response to UVB exposure, causing protein damage and activating apoptotic processes in the 48â¯h UVB exposure group. These proteomic changes show the mechanisms that underlie the detrimental effects of UVB on the cellular defense systems of the Antarctic copepod T. kingsejongensis.