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1.
ChemSusChem ; : e202401263, 2024 Oct 09.
Artículo en Inglés | MEDLINE | ID: mdl-39384939

RESUMEN

Biomimetic nicotinamide coenzymes, including nicotinamide mononucleotide (NMN+), have been demonstrated as promising low-cost alternatives to nicotinamide adenine dinucleotide (phosphate) (NAD(P)+) in biocatalysis. Herein, to efficiently regenerate NMNH from NMN+ in vitro powered by biomass sugars, a thermophilic NADP+-dependent glucose 6-phosphate dehydrogenase from Thermotoga maritima (TmG6PDH) was engineered to increase the activity toward NMN+. The catalytic efficiency (kcat/Km) of optimal mutant (TmG6PDH-R7) toward NMN+ increased by 71.7-fold than TmG6PDH-WT. As a result, compared to the wild type, the coenzyme specificity ([kcat/Km]NMN+/[kcat/Km]NADP+) of TmG6PDH-R7 increased by ~2.0×105-fold. The structural analysis revealed that the introduced hydrophobic and bulky residues lead to the formation of a smaller binding pocket, which resulting in a higher affinity for NMN+ with small size than NADP+. Then several in vitro synthetic enzymatic biosystems (ivSEBs) comprising this thermophilic TmG6PDH-R7 and a previously engineered thermophilic 6-phosphogluconate dehydrogenase were constructed. These ivSEBs harnessed the complete oxidation of renewable biomass sugars to facilitate the stoichiometric regeneration of 12 molecules of NMNH from 1 molecule of glucose, thereafter producing various products such as levodione, 2,3-butanediol or bioelectricity, over a wide temperature range. This study could pave the way for using stable and low-cost biomimetic coenzymes in ivSEBs for industrial biomanufacturing.

2.
Bioorg Chem ; 153: 107851, 2024 Sep 27.
Artículo en Inglés | MEDLINE | ID: mdl-39368142

RESUMEN

Two new stilbenes, denominated Cajanotone B (CAB) and Cajanotone C (CAC), were isolated from the leaves of Cajanus cajan. In this study, the structures of CAB and CAC were unambiguously elucidated by a combination of various spectral methods. Both compounds significantly inhibited the adipogenesis in 3T3-L1 adipocytes by reducing the lipid accumulation, triglyceride content and FFA secretion. CAB and CAC also substantially inhibit the mRNA expression of HSL, ATGL, C/EBPα and PPARγ as deciphered based by RT-PCR assay. Down-regulation of PPAR is believed to be the primary mechanism underlying which CAB and CAC inhibited adipogenic differentiation because the lipid-promoting activity of PPAR agonists can be counteracted by these compounds. The molecular interaction between CAB/CAC and PPARγ was revealed with the help of molecular docking. Taken together, CAB and CAC could serve as new lead compounds with the potential to speed up the development of novel lipid-lowering and weight-control therapies.

3.
Abdom Radiol (NY) ; 2024 Sep 27.
Artículo en Inglés | MEDLINE | ID: mdl-39333410

RESUMEN

BACKGROUND: The Liver Imaging Reporting and Data System (LI-RADS) does not consider factors extrinsic to the observation of interest, such as concurrent LR-5 observations. PURPOSE: To evaluate whether the presence of a concurrent LR-5 observation is associated with a difference in the probability that LR-3 or LR-4 observations represent hepatocellular carcinoma (HCC) through an individual participant data (IPD) meta-analysis. METHODS: Multiple databases were searched from 1/2014 to 2/2023 for studies evaluating the diagnostic accuracy of CT/MRI for HCC using LI-RADS v2014/2017/2018. The search strategy, study selection, and data collection process can be found at https://osf.io/rpg8x . Using a generalized linear mixed model (GLMM), IPD were pooled across studies and modeled simultaneously with a one-stage meta-analysis approach to estimate positive predictive value (PPV) of LR-3 and LR-4 observations without and with concurrent LR-5 for the diagnosis of HCC. Risk of bias was assessed using a composite reference standard and Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2). RESULTS: Twenty-nine studies comprising 2591 observations in 1456 patients (mean age 59 years, 1083 [74%] male) were included. 587/1960 (29.9%) LR-3 observations in 1009 patients had concurrent LR-5. The PPV for LR-3 observations with concurrent LR-5 was not significantly different from the PPV without LR-5 (45.4% vs 37.1%, p = 0.63). 264/631 (41.8%) LR-4 observations in 447 patients had concurrent LR-5. The PPV for LR-4 observations with concurrent LR-5 was not significantly different from LR-4 observations without concurrent LR-5 (88.6% vs 69.5%, p = 0.08). A sensitivity analysis for low-risk of bias studies (n = 9) did not differ from the primary analysis. CONCLUSION: The presence of concurrent LR-5 was not significantly associated with differences in PPV for HCC in LR-3 or LR-4 observations, supporting the current LI-RADS paradigm, wherein the presence of synchronous LR-5 may not alter the categorization of LR-3 and LR-4 observations.

4.
Phys Chem Chem Phys ; 2024 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-39347748

RESUMEN

Enzymatic capture and conversion of carbon dioxide (CO2) into value-added chemicals are of great interest in the field of biocatalysis and have a positive impact on climate change. The quantum chemical methods, recognized as valuable tools for studying reaction mechanisms, have been widely employed in investigating the reaction mechanisms of the enzymes involved in CO2 utilization. In this perspective, we review the mechanistic studies of representative enzymes that are either currently used or have the potential for converting CO2, utilizing the quantum chemical cluster approach and the quantum mechanical/molecular mechanical (QM/MM) method. We begin by summarizing current trends in enzymatic CO2 conversion, followed by a brief description of the computational details of quantum chemical methods. Then, a series of representative examples of the computational modeling of biocatalytic CO2 conversion are presented, including the reduction of CO2 to C1 species (carbon monoxide and formate), and the fixation of CO2 to form aliphatic and aromatic carboxylic acids. The microscopic views of reaction mechanisms obtained from these studies are helpful in guiding the rational design of current enzymes and the discovery of novel enzymes with enhanced performance in converting CO2. Additionally, they provide key information for the de novo design of new-to-nature enzymes. To conclude, we present a perspective on the potential combination of machine learning with quantum description in the study of enzymatic conversion of CO2.

5.
Nat Commun ; 15(1): 8312, 2024 Sep 27.
Artículo en Inglés | MEDLINE | ID: mdl-39333130

RESUMEN

Enzymes are making a significant impact on chemical synthesis. However, the range of chemical products achievable through biocatalysis is still limited compared to the vast array of products possible with organic synthesis. For instance, azoxy products have rarely been synthesized using enzyme catalysts. In this study, we discovered that fungal unspecific peroxygenases are promising catalysts for synthesizing azoxy products from simple aniline starting materials. The catalytic features (up to 48,450 turnovers and a turnover frequency of 6.7 s-1) and substrate transformations (up to 99% conversion with 98% chemoselectivity) highlight the synthetic potential. We propose a mechanism where peroxygenase-derived hydroxylamine and nitroso compounds spontaneously (non-enzymatically) form the desired azoxy products. This work expands the reactivity repertoire of biocatalytic transformations in the underexplored field of azoxy compound formation reactions.


Asunto(s)
Compuestos Azo , Biocatálisis , Oxigenasas de Función Mixta , Oxigenasas de Función Mixta/metabolismo , Compuestos Azo/química , Compuestos Azo/metabolismo , Compuestos de Anilina/química , Compuestos de Anilina/metabolismo , Compuestos Nitrosos/química , Compuestos Nitrosos/metabolismo , Hidroxilamina/química , Hidroxilamina/metabolismo
6.
Plants (Basel) ; 13(18)2024 Sep 20.
Artículo en Inglés | MEDLINE | ID: mdl-39339610

RESUMEN

The family Apiaceae, distributed throughout the Northern Hemisphere, is the largest family of angiosperms. However, little is known about the conservation status, diversity, and distribution of Apiaceae species in Mongolia. This study had two main aims: (1) to assess the national status of Apiaceae species under IUCN Red List Criterion B; (2) to evaluate the species diversity and richness of Apiaceae across Mongolia. We utilized ConR packages to assess the national Red List status of all known Mongolian Apiaceae species by analyzing their most comprehensive occurrence records. The results indicated that 27 species were classified as threatened, including 4 Critically Endangered (CR), 9 Endangered (EN), and 14 Vulnerable (VU) species. Meanwhile, 39 species were assessed as non-threatened, with 2 Near Threatened (NT) species and 37 species of Least Concern (LC). Furthermore, detailed distribution maps for 66 Apiaceae species in Mongolia were presented. We assessed the species diversity and Shannon and Simpson diversity indices of Apiaceae by analyzing all occurrence records using the iNext package. Overall, the Hill diversity estimates indicate that the sampling conducted in Mongolia adequately captured species occurrences. For species pattern analysis, we examined the species richness, weighted endemism, and the corrected weighted endemism index using Biodiverse v.4.1 software. Mongolia was portioned into 715 grid cells based on 0.5° × 0.5° grid sizes (equivalent to approximately 50 × 50 km2). There was a total of 3062 unique occurrences of all Apiaceae species across Mongolia. In the species richness analysis, we identified 10 grids that exhibited high species richness (18-29 species) and 36 grids with 11-17 species. For genus richness, we observed seven grids that exhibited a high genus richness of 16-22 genera. Furthermore, we analyzed species richness with a specific focus on threatened species, encompassing CR, EN, and VU species throughout Mongolia. A total of 92 grids contained at least one threatened species. There were six grids that had two to five threatened species, which were adequately covered by protected areas in western Mongolia. Overall, our results on species richness and conservation status will serve as important foundational research for future conservation and land management efforts in Mongolia.

7.
World J Hepatol ; 16(8): 1167-1176, 2024 Aug 27.
Artículo en Inglés | MEDLINE | ID: mdl-39221094

RESUMEN

BACKGROUND: Neoadjuvant chemotherapy can cause hepatic sinusoidal obstruction syndrome (SOS) in patients with colorectal cancer liver metastases and increases postoperative morbidity and mortality. AIM: To evaluate T1 mapping based on gadoxetic acid-enhanced magnetic resonance imaging (MRI) for diagnosis of hepatic SOS induced by monocrotaline. METHODS: Twenty-four mice were divided into control (n = 10) and experimental (n = 14) groups. The experimental groups were injected with monocrotaline 2 or 6 days before MRI. MRI parameters were: T1 relaxation time before enhancement; T1 relaxation time 20 minutes after enhancement (T1post); a reduction in T1 relaxation time (△T1%); and first enhancement slope percentage of the liver parenchyma (ESP). Albumin and bilirubin score was determined. Histological results served as a reference. Liver parenchyma samples from the control and experimental groups were analyzed by western blotting, and organic anion transporter polypeptide 1 (OATP1) was measured. RESULTS: T1post, △T1%, and ESP of the liver parenchyma were significantly different between two groups (all P < 0.001) and significantly correlated with the total histological score of hepatic SOS (r = -0.70, 0.68 and 0.79; P < 0.001). △T1% and ESP were positively correlated with OATP1 levels (r = 0.82, 0.85; P < 0.001), whereas T1post had a negative correlation with OATP1 levels (r = -0.83; P < 0.001). CONCLUSION: T1 mapping based on gadoxetic acid-enhanced MRI may be useful for diagnosis of hepatic SOS, and MRI parameters were associated with OATP1 levels.

8.
J Integr Med ; 22(5): 588-599, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39181774

RESUMEN

OBJECTIVE: Studies have shown that electroacupuncture (EA) can alleviate cognitive impairments from Alzheimer's disease (AD) by regulating the expression of adenosine monophosphate-activated protein kinase (AMPK), but the specific mechanism involved remains to be elucidated. Therefore, this study explores the potential mechanism by which EA improves cognitive function from the perspective of mitochondrial dynamics. METHODS: The four-month-old transgenic mice with amyloid precursor protein (APP)/presenilin 1 (PS1) and AMPKα1-subunit conditional knockout (AMPKα1-cKO) were used for experiments. To evaluate the effects of EA treatment on cognitive function, the T-maze and Morris water maze were used. In addition, chemical exchange saturation transfer, thioflavin staining, transmission electron microscopy, mitochondrial membrane potential, and Western blotting were used to examine the potential mechanisms underlying the effects of EA on APP/PS1 mice. RESULTS: Both APP/PS1 mice and AMPKα1-cKO mice exhibited dysfunction in mitochondrial dynamics accompanied by learning and memory impairment. Inactivation of the AMPK/peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) pathway increased pathological amyloid-ß (Aß) deposition and aggravated the dysfunction in mitochondrial dynamics. In addition, EA rescued learning and memory deficits in APP/PS1 mice by activating the AMPK/PGC-1α pathway, specifically by reducing pathological Aß deposition, normalizing energy metabolism, protecting the structure and function of mitochondria, increasing the levels of mitochondrial fusion proteins, and downregulating the expression of fission proteins. However, the therapeutic effect of EA on cognition in APP/PS1 mice was hindered by AMPKα1 knockout. CONCLUSION: The regulation of hippocampal mitochondrial dynamics and reduction in Aß deposition via the AMPK/PGC-1α pathway are critical for the ability of EA to ameliorate cognitive impairment in APP/PS1 mice. Please cite this article as: Jia WW, Lin HW, Yang MG, Dai YL, Ding YY, Xu WS, Wang SN, Cao YJ, Liang SX, Wang ZF, Chen C, Liu WL. Electroacupuncture activates AMPKα1 to improve learning and memory in the APP/PS1 mouse model of early Alzheimer's disease by regulating hippocampal mitochondrial dynamics. J Integr Med. 2024; 22(5): 588-599.


Asunto(s)
Proteínas Quinasas Activadas por AMP , Enfermedad de Alzheimer , Modelos Animales de Enfermedad , Electroacupuntura , Hipocampo , Dinámicas Mitocondriales , Animales , Masculino , Ratones , Enfermedad de Alzheimer/terapia , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/psicología , Enfermedad de Alzheimer/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Proteínas Quinasas Activadas por AMP/genética , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Hipocampo/metabolismo , Aprendizaje , Aprendizaje por Laberinto , Memoria , Ratones Transgénicos , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Presenilina-1/genética
9.
Cell Biochem Biophys ; 82(3): 2673-2685, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38954352

RESUMEN

Hepatocellular carcinoma (HCC), a widely prevalent malignancy strongly linked to inflammation, remains a significant public health concern. Triggering receptor expressed on myeloid cells 1 (TREM1), a modulator of inflammatory responses identified in recent years, has emerged as a crucial facilitator in cancer progression. Despite its significance, the precise regulatory mechanism of TREM1 in HCC metastasis remains unanswered. In the present investigation, we observed aberrant upregulation of TREM1 in HCC tissues, which was significantly linked to poorer overall survival. Inhibition of TREM1 expression resulted in a significant reduction in HCC Huh-7 and MHCC-97H cell proliferation, invasion, and epithelial-mesenchymal transition (EMT) process. Furthermore, inhibiting TREM1 decreased protein expressions of toll-like receptor 2/4 (TLR2/4) and major myeloid differentiation response gene 88 (MyD88), leading to the inactivation of phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) in HCC cells. Notably, these effects were reversed by treatment with TLR2-specific agonist (CU-T12-9), indicating a potential crosstalk between TREM1 and TLR2/4. Mechanistic studies revealed a direct interaction between TREM1 and both TLR2 and TLR4. In vivo studies demonstrated that inhibition of TREM1 suppressed the growth of HCC cells in the orthotopic implant model and its metastatic potential in the experimental lung metastasis model. Overall, our findings underscore the role of TREM1 inhibition in regulating EMT and metastasis of HCC cells by inactivating the TLR/PI3K/AKT signaling pathway, thereby providing deeper mechanistic insights into how TREM1 regulates metastasis during HCC progression.


Asunto(s)
Carcinoma Hepatocelular , Transición Epitelial-Mesenquimal , Neoplasias Hepáticas , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Receptor Activador Expresado en Células Mieloides 1 , Receptor Activador Expresado en Células Mieloides 1/metabolismo , Receptor Activador Expresado en Células Mieloides 1/genética , Receptor Activador Expresado en Células Mieloides 1/antagonistas & inhibidores , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Línea Celular Tumoral , Animales , Transición Epitelial-Mesenquimal/efectos de los fármacos , Ratones , Fosfatidilinositol 3-Quinasas/metabolismo , Proliferación Celular/efectos de los fármacos , Receptor Toll-Like 4/metabolismo , Receptor Toll-Like 4/genética , Factor 88 de Diferenciación Mieloide/metabolismo , Factor 88 de Diferenciación Mieloide/genética , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 2/genética , Masculino , Ratones Desnudos , Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/genética , Ratones Endogámicos BALB C
11.
Molecules ; 29(10)2024 May 16.
Artículo en Inglés | MEDLINE | ID: mdl-38792214

RESUMEN

BACKGROUND: Staphylococcus aureus is a common pathogenic microorganism in humans and animals. Type II NADH oxidoreductase (NDH-2) is the only NADH:quinone oxidoreductase present in this organism and represents a promising target for the development of anti-staphylococcal drugs. Recently, myricetin, a natural flavonoid from vegetables and fruits, was found to be a potential inhibitor of NDH-2 of S. aureus. The objective of this study was to evaluate the inhibitory properties of myricetin against NDH-2 and its impact on the growth and expression of virulence factors in S. aureus. RESULTS: A screening method was established to identify effective inhibitors of NDH-2, based on heterologously expressed S. aureus NDH-2. Myricetin was found to be an effective inhibitor of NDH-2 with a half maximal inhibitory concentration (IC50) of 2 µM. In silico predictions and enzyme inhibition kinetics further characterized myricetin as a competitive inhibitor of NDH-2 with respect to the substrate menadione (MK). The minimum inhibitory concentrations (MICs) of myricetin against S. aureus strains ranged from 64 to 128 µg/mL. Time-kill assays showed that myricetin was a bactericidal agent against S. aureus. In line with being a competitive inhibitor of the NDH-2 substrate MK, the anti-staphylococcal activity of myricetin was antagonized by MK-4. In addition, myricetin was found to inhibit the gene expression of enterotoxin SeA and reduce the hemolytic activity induced by S. aureus culture on rabbit erythrocytes in a dose-dependent manner. CONCLUSIONS: Myricetin was newly discovered to be a competitive inhibitor of S. aureus NDH-2 in relation to the substrate MK. This discovery offers a fresh perspective on the anti-staphylococcal activity of myricetin.


Asunto(s)
Flavonoides , Pruebas de Sensibilidad Microbiana , Staphylococcus aureus , Flavonoides/farmacología , Flavonoides/química , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/enzimología , Antibacterianos/farmacología , Antibacterianos/química , NADH Deshidrogenasa/antagonistas & inhibidores , NADH Deshidrogenasa/metabolismo , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Animales , Proteínas Bacterianas/antagonistas & inhibidores , Proteínas Bacterianas/metabolismo , Humanos , Factores de Virulencia/antagonistas & inhibidores , Factores de Virulencia/metabolismo
12.
J Steroid Biochem Mol Biol ; 242: 106544, 2024 09.
Artículo en Inglés | MEDLINE | ID: mdl-38754521

RESUMEN

Sex steroid hormones such as estrogen estradiol (E2) and androgen dihydrotestosterone (DHT) are involved in the development of hormone-dependent cancers. Blockade of 17ß-hydroxysteroid dehydrogenase type 7 (17ß-HSD7), a member of the short chain dehydrogenase/reductase superfamily, is thought to decrease E2 levels while increasing those of DHT. Therefore, its unique double action makes this enzyme as an interesting drug target for treatment of breast cancer. The chemical synthesis, molecular characterization, and preliminary biological evaluation as 17ß-HSD7 inhibitors of novel carbamate derivatives 3 and 4 are described. Like previous 17ß-HSD7 inhibitors 1 and 2, compounds 3 and 4 bear a hydrophobic nonyl side chain at the C-17ß position of a 4-aza-5α-androstane nucleus, but compound 3 has an oxygen atom replacing the CH2 in the steroid A-ring C-2 position, while compound 4 has a C17-spiranic E-ring containing a carbamate function. They both inhibited the in vitro transformation of estrone (E1) into E2 by 17ß-HSD7, but the introduction of a (17 R)-spirocarbamate is preferable to replacing C-2 methylene with an oxygen atom since compound 4 (IC50 = 63 nM) is an inhibitor 14 times more powerful than compound 3 (IC50 = 900 nM). Furthermore, when compared to the reference inhibitor 1 (IC50 = 111 nM), the use of a C17-spiranic E-ring made it possible to introduce differently the hydrophobic nonyl side chain, without reducing the inhibitory activity.


Asunto(s)
17-Hidroxiesteroide Deshidrogenasas , Inhibidores Enzimáticos , 17-Hidroxiesteroide Deshidrogenasas/antagonistas & inhibidores , 17-Hidroxiesteroide Deshidrogenasas/metabolismo , Humanos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Estradiol/química , Estradiol/metabolismo , Estradiol/farmacología , Carbamatos/química , Carbamatos/farmacología , Carbamatos/síntesis química , Estrona/química , Estrona/farmacología , Estrona/síntesis química
13.
World J Gastroenterol ; 30(17): 2321-2331, 2024 May 07.
Artículo en Inglés | MEDLINE | ID: mdl-38813052

RESUMEN

BACKGROUND: The advent of cutting-edge systemic therapies has driven advances in the treatment of hepatocellular carcinoma (HCC), and therapeutic strategies with multiple modes of delivery have been shown to be more efficacious than monotherapy. However, the mechanisms underlying this innovative treatment modality have not been elucidated. AIM: To evaluate the clinical efficacy of targeted therapy plus immunotherapy combined with hepatic arterial infusion chemotherapy (HAIC) of FOLFOX in patients with unresectable HCC. METHODS: We enrolled 53 patients with unresectable HCC who received a combination of targeted therapy, immunotherapy, and HAIC of FOLFOX between December 2020 and June 2021 and assessed the efficacy and safety of the treatment regimen. RESULTS: The objective response rate was 60.4% (32/53), complete response was 24.5% (13/53), partial response was 35.9% (19/53), and stable disease was 39.6% (21/53). The median duration of response and median progression-free survival were 9.1 and 13.9 months, respectively. The surgical conversion rate was 34.0% (18/53), and 1-year overall survival was 83.0% without critical complicating diseases or adverse events (AEs). CONCLUSION: The regimen of HAIC of FOLFOX, targeted therapy, and immunotherapy was curative for patients with unresectable HCC, with no serious AEs and a high rate of surgical conversion.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Hepatocelular , Fluorouracilo , Arteria Hepática , Infusiones Intraarteriales , Leucovorina , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/tratamiento farmacológico , Masculino , Femenino , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Persona de Mediana Edad , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Fluorouracilo/uso terapéutico , Leucovorina/administración & dosificación , Leucovorina/efectos adversos , Leucovorina/uso terapéutico , Anciano , Adulto , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/efectos adversos , Compuestos Organoplatinos/uso terapéutico , Resultado del Tratamiento , Terapia Molecular Dirigida/métodos , Supervivencia sin Progresión , Estudios Retrospectivos , Inmunoterapia/métodos , Inmunoterapia/efectos adversos , Terapia Combinada/métodos
14.
Phys Chem Chem Phys ; 26(23): 16521-16528, 2024 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-38809594

RESUMEN

Indole monooxygenases (IMOs) are enzymes from the family of Group E monooxygenases, requiring flavin adenine dinucleotide (FAD) for their activities. IMOs play important roles in both sulfoxidation and epoxidation reactions. The broad substrate range and high selectivity of IMOs make them promising biocatalytic tools for synthesizing chiral compounds. In the present study, quantum chemical calculations using the cluster approach were performed to investigate the reaction mechanism and the enantioselectivity of the IMO from Variovorax paradoxus EPS (VpIndA1). The sulfoxidation of methyl phenyl sulfide (MPS) and the epoxidation of indene were chosen as the representative reactions. The calculations confirmed that the FADOOH intermediate is the catalytic species in the VpIndA1 reactions. The oxidation of MPS adopts a one-step mechanism involving the direct oxygen-transfer from FADOOH to the substrate and the proton transfer from the -OH group back to FAD, while the oxidation of indene follows a stepwise mechanism involving a carbocation intermediate. It was computationally predicted that VpIndA1 prefers the formation of (S)-product for the MPS sulfoxidation and (1S,2R)-product for the indene epoxidation, consistent with the experimental observations. Importantly, the factors controlling the stereo-preference of the two reactions are identified. The findings in the present study provide valuable insights into the VpIndA1-catalyzed reactions, which are essential for the rational design of this enzyme and other IMOs for industrial applications. It is also worth emphasizing that the quantum chemical cluster approach is again demonstrated to be powerful in studying the enantioselectivity of enzymatic reactions.


Asunto(s)
Oxigenasas de Función Mixta , Oxidación-Reducción , Estereoisomerismo , Oxigenasas de Función Mixta/metabolismo , Oxigenasas de Función Mixta/química , Teoría Cuántica , Sulfuros/química , Sulfuros/metabolismo , Indoles/química , Indoles/metabolismo , Modelos Químicos , Compuestos Epoxi/química , Compuestos Epoxi/metabolismo , Flavina-Adenina Dinucleótido/química , Flavina-Adenina Dinucleótido/metabolismo , Modelos Moleculares
15.
Nat Prod Res ; : 1-10, 2024 Apr 18.
Artículo en Inglés | MEDLINE | ID: mdl-38635344

RESUMEN

Bioassay-guided purification of the xanthine oxidase (XOD) inhibitory extract of the roots of Ampelopsis japonica resulted in the isolation of two new triterpenoids (1-2), designated Ampejaponoside A and B, along with sixteen known compounds (3-18). The structures of Ampejaposide A and B were elucidated by comprehensive analysis of spectroscopic data with the structures of the known compounds 3-18 confirmed by comparison the spectral data with corresponding values reported in literatures. All the isolates were evaluated for their XOD inhibitory activity in vitro. As a result, compounds 2, 8, and 14-16 displayed significant XOD inhibitory effect, particularly 16 being the most potent with an IC50 value of 0.21 µM, superior to positive substance allopurinol (IC50 1.95 µM). Molecular docking uncovered a unique interaction mode of 16 with the active site of XOD. The current study showed that the triterpenoids and polyphenols from A. japonica could serve as new lead compounds with the potential to speed up the development of novel XOD inhibitors with clinical potential to treat hyperuricaemia and gout.

16.
J Ethnopharmacol ; 330: 118199, 2024 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-38631486

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Nocardiosis is an uncommon infectious disease that bears certain similarities to tuberculosis, with a continuous increase in its incidence and a poor prognosis. In traditional Chinese medicine, the leaves of Cajanus cajan (L.) Millsp. are employed to treat wounds, malaria, coughs, and abdominal pain. AIM OF THE STUDY: In this study, we investigated the effects and mechanisms of longistylin A (LGA), a natural stilbene isolated from C. cajan, as a potential antibiotic against nocardiosis. MATERIALS AND METHODS: LGA was isolated from the leaves of C. cajan and assessed using a minimum bactericidal concentration (MBC) determination against Nocardia seriolae. Multi-omics analysis encompassing genes, proteins, and metabolites was conducted to investigate the impact of LGA treatment on N. seriolae. Additionally, quantitative analysis of 40 cytokinins in N. seriolae mycelium was performed to assess the specific effects of LGA treatment on cytokinin levels. Cryo-scanning electron microscopy was utilized to examine morphological changes induced by LGA treatment, particularly in the presence of exogenous trans-zeatin-O-glucoside (tZOG). The therapeutic effect of LGA was investigated by feeding N. seriolae-infected largemouth bass. RESULTS: LGA exhibited significant efficacy against N. seriolae, with MBC value of 2.56 µg/mL. Multi-omics analysis revealed that LGA disrupted glycerophospholipid metabolism and hormone biosynthesis by notably reducing the expression of glycerol-3-phosphate dehydrogenase and calmodulin-like protein. Treatment with LGA markedly disrupted 12 distinct cytokinins in N. seriolae mycelium. Additionally, the addition of exogenous tZOG counteracted the inhibitory effects of LGA on filamentous growth, resulting in mycelial elongation and branching. Furthermore, LGA treatment improved the survival rate of largemouth bass infected with N. seriolae. CONCLUSIONS: We found for the first time that LGA from C. cajan exhibited significant efficacy against N. seriolae by interfering with glycerophospholipid metabolism and cytokinin biosynthesis.


Asunto(s)
Antibacterianos , Cajanus , Citocininas , Glicerofosfolípidos , Nocardia , Nocardia/metabolismo , Nocardia/efectos de los fármacos , Citocininas/farmacología , Citocininas/biosíntesis , Citocininas/metabolismo , Glicerofosfolípidos/metabolismo , Glicerofosfolípidos/biosíntesis , Antibacterianos/farmacología , Pruebas de Sensibilidad Microbiana , Hojas de la Planta
17.
RSC Adv ; 14(11): 7763-7769, 2024 Feb 29.
Artículo en Inglés | MEDLINE | ID: mdl-38444970

RESUMEN

Four novel new isocoumarins, cajanolactone B, C, D1 and D2 (1-4), were isolated from ethanolic extracts of the leaves of Cajanus cajan. The structural elucidation has been completed mainly depending on extensive spectroscopic analysis including UV, IR, NMR (1D and 2D), HRESIMS and chiral analysis. Notably, all these new isocoumarins were found to exist in racemic forms, among which compounds 3 and 4 share the same planar structure. This finding suggests that at least the biosynthesis of isocoumarin in C. cajan is chiral tolerant. A plausible biogenetic pathway of compounds 1-4 is proposed.

18.
Commun Chem ; 7(1): 64, 2024 Mar 27.
Artículo en Inglés | MEDLINE | ID: mdl-38538750

RESUMEN

Norcoclaurine synthase from Thalictrum flavum (TfNCS) demonstrated high stereospecificity and yield in catalyzing the Pictet-Spengler reaction of dopamine with chiral aldehydes, achieving kinetic resolution of aldehydes. However, the mechanism and the factors contributing to the stereoselectivity remain unclear. Herein, by using quantum chemical calculations, the mechanisms of TfNCS-catalyzed reactions of dopamine with both enantiomers of α-methyl-phenylacetaldehyde are studied. The calculations reveal a mechanism mirroring the reaction of natural substrates, for which the deprotonation of the C5-H of the cyclized intermediate is rate-limiting. The calculated overall barriers are 20.1 kcal mol-1 and 21.6 kcal mol-1 for the reactions of (R)- and (S)-α-methyl-phenylacetaldehyde, respectively. The M97 and L72 residues are proposed to be the key residues contributing to the stereospecificity. The obtained detailed information is helpful for designing new variants of TfNCS with extended substrate scope, and also advancing our understanding of TfNCS reactions for potential applications.

19.
Appl Environ Microbiol ; 90(3): e0181823, 2024 03 20.
Artículo en Inglés | MEDLINE | ID: mdl-38332488

RESUMEN

Zearalenone (ZEN) and its derivatives are estrogenic mycotoxins known to pose significant health threats to humans and animals. Especially, the derivative α-zearalanol (α-ZAL) is over 10 times more toxic than ZEN. Simultaneous degradation of ZEN and its derivatives, especially α-ZAL, using ZEN lactone hydrolases (ZHDs) is a promising solution to eliminate their potential hazards to food safety. However, most available ZHDs exhibit limited activity toward the more toxic α-ZAL compared to ZEN. Here, we identified a broad-substrate spectrum ZHD, named ZHDAY3, from Exophiala aquamarina CBS 119918, which could not only efficiently degrade ZEN but also exhibited 73% relative activity toward α-ZAL. Through rational design, we obtained the ZHDAY3(N153H) mutant, which exhibited the highest specific activity (253.3 ± 4.3 U/mg) reported so far for degrading α-ZAL. Molecular docking, structural comparative analysis, and kinetic analysis collectively suggested that the shorter distance between the side chain of the catalytic residue His242 and the lactone bond of α-ZAL and the increased binding affinity to the substrate were mainly responsible for the improved catalytic activity of ZHDAY3(N153H) mutant. This mechanism was further validated through additional molecular docking of 18 mutants and experimental verification of six mutants.IMPORTANCEThe mycotoxins zearalenone (ZEN) and its derivatives pose a significant threat to food safety. Here, we present a highly promising ZEN lactone hydrolase (ZHD), ZHDAY3, which is capable of efficiently degrading both ZEN and the more toxic derivative α-ZAL. Next, the ZHDAY3(N153H) mutant obtained by single-point mutation exhibited the highest specific activity for degrading α-ZAL reported thus far. We further elucidated the molecular mechanisms underlying the enhanced hydrolytic activity of ZHDAY3(N153H) toward α-ZAL. These findings represent the first investigation on the molecular mechanism of ZHDs against α-ZAL and are expected to provide a significant reference for further rational engineering of ZHDs, which will ultimately contribute to addressing the health risks and food safety issues posed by ZEN-like mycotoxins.


Asunto(s)
Micotoxinas , Zearalenona , Zeranol , Humanos , Animales , Zearalenona/química , Zearalenona/metabolismo , Zeranol/química , Zeranol/metabolismo , Lactonas , Mutación Puntual , Hidrolasas/metabolismo , Simulación del Acoplamiento Molecular , Cinética , Micotoxinas/metabolismo
20.
Nat Commun ; 15(1): 1235, 2024 Feb 09.
Artículo en Inglés | MEDLINE | ID: mdl-38336996

RESUMEN

Hemiacetal compounds are valuable building blocks in synthetic chemistry, but their enzymatic synthesis is limited and often hindered by the instability of hemiacetals in aqueous environments. Here, we show that this challenge can be addressed through reaction engineering by using immobilized peroxygenase from Agrocybe aegerita (AaeUPO) under neat reaction conditions, which allows for the selective C-H bond oxyfunctionalization of environmentally significant cyclic ethers to cyclic hemiacetals. A wide range of chiral cyclic hemiacetal products are prepared in >99% enantiomeric excess and 95170 turnover numbers of AaeUPO. Furthermore, by changing the reaction medium from pure organic solvent to alkaline aqueous conditions, cyclic hemiacetals are in situ transformed into lactones. Lactams are obtained under the applied conditions, albeit with low enzyme activity. These findings showcase the synthetic potential of AaeUPO and offer a practical enzymatic approach to produce chiral cyclic hemiacetals through C-H oxyfunctionalization under mild conditions.

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