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1.
Sci Adv ; 9(51): eadk4950, 2023 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-38117889

RESUMO

The development of a reliable method for asymmetric synthesis of unnatural peptides is highly desirable and particularly challenging. In this study, we present a versatile and efficient approach that uses cobalt-catalyzed diastereoselective umpolung hydrogenation to access noncanonical aryl alanine peptides. This protocol demonstrates good tolerance toward various functional groups, amino acid sequences, and peptide lengths. Moreover, the versatility of this reaction is illustrated by its successful application in the late-stage functionalization and formal synthesis of various representative chiral natural products and pharmaceutical scaffolds. This strategy eliminates the need for synthesizing chiral noncanonical aryl alanines before peptide formation, and the hydrogenation reaction does not result in racemization or epimerization. The underlying mechanism was extensively explored through deuterium labeling, control experiments, HRMS identification, and UV-Vis spectroscopy, which supported a reasonable CoI/CoIII catalytic cycle. Notably, acetic acid and methanol serve as safe and cost-effective hydrogen sources, while indium powder acts as the terminal electron source.


Assuntos
Cobalto , Peptídeos , Hidrogenação , Peptídeos/química , Hidrogênio/química , Alanina , Catálise
2.
Angew Chem Int Ed Engl ; 62(20): e202301091, 2023 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-36929860

RESUMO

A cobalt-catalyzed deuteration of amidoacrylates using deuterated methanol afforded α,ß-dideuterio-α-amino esters in excellent enantiomeric ratios (mostly >95 : 5) and almost complete deuteration (99 %). The new protocol was used to prepare dideuterio-α-amino acid fragments in some drugs. Furthermore, the stereoselective deuteration was applied in a concise synthesis of dideuterio l-DOPA.

3.
J Environ Manage ; 331: 117296, 2023 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-36642043

RESUMO

Vegetation restoration on purple soil (Eutric Leptic Regosols) slopes aiming at reducing soil erosion in the Rainy Zone of Western China has significantly altered soil organic carbon (SOC) storage and distribution. A better understanding of the effects of different vegetation restoration types on SOC dynamics and fractions is critical in devising better policy to protect or enhance SOC stocks to improve soil quality and ecosystem function. In the present study, total, labile, and non-labile organic carbon (TOC, LC, and NLC), and carbon management index (CMI) of Cryptomeria fortunei (CF), mixed C. fortunei and Betula luminifera (MF), Neosinocalamus affinis (NA), and Camellia sinensis (CS) were compared with those of Zea mays field (ZM) on purple soil slopes in the Rainy Zone of Western China in order to develop more effective ways to implement vegetation restoration in the future. Different vegetation restoration types (CF, MF, NA and CS) increased TOC stock by 47.79%-118.31% and NLC stock by 56.61%-129.52% in the 0-50 cm soil layer compared with that of ZM. The direction and magnitude of changes in LC stock and CMI, however, depended strongly on the vegetation restoration type. Compared with ZM, CF had the largest increase of LC stock and CMI, whereas NA had the largest decrease of LC stock and CMI in the 0-50 cm soil layer. The LC:TOC ratio in four reforested species all declined significantly compared with that of ZM (p < 0.01), indicating decreased SOC activity after afforestation. The vegetation type and soil depth together explained more than 90% of the changes of TOC and its fractions in the plantations on purple soil slopes. Our study demonstrates that transforming the ZM into the CS is optimal to achieve the sustainable development goal, whereas transforming the ZM into the NA reduces the SOC activity and availability.


Assuntos
Ecossistema , Solo , Carbono/análise , Sequestro de Carbono , China
4.
Front Pharmacol ; 13: 911982, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35620286

RESUMO

Phenolic acids are cardiovascular constituents (originating from the Chinese medicinal herb Salvia miltiorrhiza root/Danshen) of DanHong and many other Danshen-containing injections. Our earlier pharmacokinetic investigation of DanHong suggested that hepatic and/or renal uptake of the Danshen compounds was the crucial steps in their systemic elimination. This investigation was designed to survey the molecular basis underlying hepatobiliary and renal excretion of the Danshen compounds, i.e., protocatechuic acid, tanshinol, rosmarinic acid, salvianolic acid D, salvianolic acid A, lithospermic acid, and salvianolic acid B. A large battery of human hepatic and renal transporters were screened for transporting the Danshen compounds and then characterized for the uptake kinetics and also compared with associated rat transporters. The samples were analyzed by liquid chromatography/mass spectrometry. Because the Danshen phenolic acids are of poor or fairly good membrane permeability, their elimination via the liver or kidneys necessitates transporter-mediated hepatic or renal uptake from blood. Several human transporters were found to mediate hepatic and/or renal uptake of the Danshen compounds in a compound-molecular-mass-related manner. Lithospermic acid and salvianolic acid B (both >500 Da) underwent systemic elimination, initiated by organic anion-transporting polypeptide (OATP)1B1/OATP1B3-mediated hepatic uptake. Rosmarinic acid and salvianolic acids D (350-450 Da) underwent systemic elimination, initiated by OATP1B1/OATP1B3/organic anion transporter (OAT)2-mediated hepatic uptake and by OAT1/OAT2-mediated renal uptake. Protocatechuic acid and tanshinol (both <200 Da) underwent systemic elimination, initiated by OAT1/OAT2-mediated renal uptake and OAT2-mediated hepatic uptake. A similar scenario was observed with the rat orthologs. The investigation findings advance our understanding of the disposition of the Danshen phenolic acids and could facilitate pharmacokinetic research on other Danshen-containing injections.

5.
Artigo em Inglês | MEDLINE | ID: mdl-35595017

RESUMO

The extracellular matrix (ECM) regulates cell behavior through signal transduction and provides a suitable place for cell survival. As one of the major components of the extracellular matrix, type I collagen is involved in regulating cell migration, proliferation and differentiation. We present a system in which 3T3-L1 preadipocyte cells are induced for adipogenic differentiation on type I collagen coated dishes. Our previous study has found that type I collagen inhibits adipogenic differentiation via YAP activation. Here we further reveal that type I collagen inactivates autophagy by up-regulating mTOR activity via the YAP pathway. Under collagen-coating conditions, co-localization of lysosomes with mTOR was increased and the level of downstream protein p-S6K was elevated, accompanied by a decrease in the level of autophagy. Autophagy is negatively correlated with adipogenesis under type I collagen coating. Through the YAP-autophagy axis, type I collagen improves glycolipid metabolism accompanied by increased mitochondrial content, enhanced glucose uptake, reduced release of free fatty acids (FFAs) and decreased intracellular lipid accumulation. Our findings provide insight into the strategy for dealing with obesity: Type I collagen or the drugs with inhibitory effects on autophagy or YAP, have a potential to accelerate the energy metabolism of adipose tissue, so as to better maintain the homeostasis of glucose and lipids in the body, which can be used for achieving weight loss.


Assuntos
Adipócitos , Adipogenia , Colágeno Tipo I , Metabolismo dos Lipídeos , Serina-Treonina Quinases TOR , Proteínas de Sinalização YAP , Células 3T3-L1 , Adipócitos/metabolismo , Adipogenia/genética , Adipogenia/fisiologia , Animais , Autofagia/genética , Autofagia/fisiologia , Diferenciação Celular , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Metabolismo dos Lipídeos/genética , Metabolismo dos Lipídeos/fisiologia , Lipídeos , Camundongos , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Proteínas de Sinalização YAP/genética , Proteínas de Sinalização YAP/metabolismo
6.
Math Biosci Eng ; 19(12): 14086-14101, 2022 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-36654081

RESUMO

Rolling bearings are the core components of mechanical and electrical systems. A practical fault diagnosis scheme is the key to ensure operational safety. There are excessive characteristic parameters with remarkable randomness and severe signal coupling in the rolling bearing operation, which makes the fault diagnosis to be challenging. To deal with this problem, the Gramian angular field (GAF) and DenseNet are combined to perform feature extraction and fault diagnosis. The GAF can convert 1-dimensional time series into an image, which can guarantee the completeness of feature information without temporal dependence. The GAF images are then trained by using the DenseNet to generate a data set network. In this process, the transfer learning (TL), which can solve the problem of insufficient samples, is integrated to the DenseNet to enhance its extensibility. The comparative simulations are carried out to illustrate the effectiveness of the proposed method.


Assuntos
Aprendizado Profundo
7.
Mol Cell Biochem ; 474(1-2): 243-261, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32789659

RESUMO

Skeletal muscle regeneration is a complex process, involving the proliferation, migration, and differentiation of myoblasts. Recent studies suggest that some natural flavanones stimulate myogenesis. However, the effect of plant estrogen, silibinin, on the regulation of myoblast behaviors is unclarified. In this study, we investigated the effects of silibinin on immortalized murine myoblast C2C12 in the aspects of proliferation, migration, differentiation along with underlying mechanisms. The results show that silibinin at concentrations below 50 µM enhanced the migration and differentiation of C2C12 cells, but had no effect on cell proliferation. Silibinin significantly promoted the production of ROS, which appeared to play important roles in the migration and differentiation of the myoblasts. Interestingly, among ROS, the superoxide anion and hydroxyl radical were associated with the migration, whereas hydrogen peroxide contributed to the myogenic differentiation. We used ER agonist and antagonist to explore whether estrogen receptors (ERs), which are affected by silibinin treatment in the silibinin-enhanced C2C12 migration and differentiation. Migration was independent of ERs, whereas the differentiation was associated with decreased ERα activity. In summary, silibinin treatment increases ROS levels, leading to the promotion of migration and myogenic differentiation. Negative regulation ERα of differentiation but not of migration may suggest that ERα represses hydrogen peroxide generation. The effect of silibinin on myoblast migration and differentiation suggests that silibinin may have therapeutic benefits for muscle regeneration.


Assuntos
Diferenciação Celular , Movimento Celular , Receptor alfa de Estrogênio/antagonistas & inibidores , Regulação da Expressão Gênica/efeitos dos fármacos , Desenvolvimento Muscular , Mioblastos/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Silibina/farmacologia , Animais , Antineoplásicos Fitogênicos/farmacologia , Proliferação de Células , Células Cultivadas , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Camundongos , Mioblastos/citologia , Mioblastos/efeitos dos fármacos
8.
J Cell Physiol ; 235(2): 1821-1837, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31432516

RESUMO

Extracellular matrix (ECM) has a marked influence on adipose tissue development. Adipose tissue formation is initiated with proliferation of preadipocytes and migration before undergoing further differentiation into mature adipocytes. Previous studies showed that collagen I (col I) provides a good substratum for 3T3-L1 preadipocytes to grow and migrate. However, it remains unclear whether and how col I regulates adipogenic differentiation of preadipocytes. This study reports that lipid accumulation, representing in vitro adipogenesis of the 3T3-L1 preadipocytes or the mouse primary adipocyte precursor cells derived from subcutaneous adipose tissue in the inguinal region is inhibited by the culture on col I, owing to downregulation of adipogenic factors. Previous study shows that col I enhances 3T3-L1 cell migration via stimulating the nuclear translocation of yes-associated protein (YAP). In this study, we report that downregulation of YAP is associated with in vitro adipogenesis of preadipocytes as well as with in vivo adipose tissue of high-fat diet fed mice. Increased expression of YAP in the cells cultured on col I-coated dishes is correlated with repression of adipogenic differentiation processes. The inactivation of YAP using YAP inhibitor, verteporfin, or YAP small-interfering RNA enhanced adipogenic differentiation and reversed the inhibitory effect of col I. Activation of YAP either by the transfection of YAP plasmid or the silence of large tumor suppressor 1 (LATS1), an inhibitory kinase of YAP, inhibited adipogenic differentiation. The results indicate that col I inhibits adipogenic differentiation via YAP activation in vitro.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adipócitos/metabolismo , Adipogenia/fisiologia , Proteínas de Ciclo Celular/metabolismo , Diferenciação Celular/fisiologia , Colágeno Tipo I/metabolismo , Células 3T3-L1 , Animais , Dieta Hiperlipídica , Camundongos , Células-Tronco/metabolismo , Proteínas de Sinalização YAP
9.
Food Funct ; 11(1): 328-338, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31799535

RESUMO

Skeletal muscle regeneration is a complicated process, requiring the proliferation, migration and differentiation of myoblasts whose processes are highly regulated by the extracellular matrix (ECM) surrounding the muscle tissues in vivo. However, the effects of respective ECM components on the regulation of myoblast behaviors are unknown. In this study, we report on the effect of collagen I, a major ECM component in muscle tissue and a popular food supplement, on mouse C2C12 myoblast proliferation, migration and differentiation as well as the underlying mechanisms. Collagen I (col 1) enhances the migration and myogenic differentiation of C2C12 cells, but has no effect on cell proliferation. Col I significantly promotes the production and release of interleukin-6 via nuclear translocation of nuclear factor κB (NF-κB) p65. The release of IL-6 plays a critical role in the col I-enhanced migration and differentiation of C2C12 cells. Furthermore, col I increases phosphorylation of focal adhesion kinase (FAK) that is involved in the nuclear translocation of NF-κB p65. Collectively, col I enhances the migration and differentiation of C2C12 cells through IL-6 release induced by FAK/NF-κB p65 activation.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Colágeno Tipo I/farmacologia , Quinase 1 de Adesão Focal/metabolismo , Interleucina-6/metabolismo , Mioblastos/efeitos dos fármacos , Fator de Transcrição RelA/metabolismo , Animais , Linhagem Celular , Camundongos , Desenvolvimento Muscular , Mioblastos/citologia
10.
Mol Cell Biochem ; 450(1-2): 1-23, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29916120

RESUMO

Preadipocyte migration is a fundamental and important process for the development of tissue organization, especially in the development of primitive adipose tissue and adipocyte tissue wound healing. However, excessive migration may result in abnormal development and fibrosis-related diseases such as hypertrophic scar. We previously reported that type I collagen (collagen I) enhanced migration of 3T3-L1 preadipocytes via phosphorylation and/or acetylation of NF-κB p65, and the enhanced cell migration is repressed by silibinin treatment through sirt1. It is known that sirt1 has an ability to deacetylate acetylated NF-κB p65, but little is known about the effect of sirt1 on phosphorylated NF-κB p65. This study aims to examine the potential effect of sirt1 on the regulation of phosphorylated NF-κB p65 and the underlying mechanism. Autophagy is involved in many physiological and pathological processes, including regulation of cell migration as well as in cellular homeostasis. The present study demonstrates that silibinin induces autophagy in a dose-dependent manner in 3T3-L1 cells. Autophagy is under the regulation of sirt1/AMPK pathway, and inhibits collagen I-enhanced migration of 3T3-L1 cells through negative regulation of NF-κB p65 phosphorylation but not acetylation. The expression of peroxisome proliferator-activated receptor α (PPARα) is up-regulated with silibinin accompanying up-regulation of autophagy through activating sirt1 in 3T3-L1 cells. Taken together, these findings indicate that silibinin-induced autophagy is mediated by up-regulation of PPARα-sirt1-AMPK, contributing to repression of type I collagen-enhanced migration in murine 3T3-L1 preadipocytes through down-regulation of phosphorylated NF-κB p65.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Adipócitos/metabolismo , Autofagia/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Colágeno Tipo I/metabolismo , PPAR alfa/metabolismo , Transdução de Sinais/efeitos dos fármacos , Silibina/farmacologia , Sirtuína 1/metabolismo , Células 3T3-L1 , Adipócitos/citologia , Animais , Camundongos , Fosforilação/efeitos dos fármacos , Fator de Transcrição RelA/metabolismo
11.
J Med Chem ; 61(23): 10814-10833, 2018 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-30433783

RESUMO

Cancer stem cells (CSCs) have been reported to be involved in tumorigenesis, tumor recurrence, cancer invasion, metastasis, and drug-resistance. Therefore, the development of drug molecules targeting CSCs has become an attractive therapeutic approach. However, the molecules which can selectively ablate CSCs are extremely rare. To explore the leading compounds targeting CSCs, 52 analogues of triterpenoic acids were synthesized in this study, whose biological activities were evaluated. On the basis of the results of tumorsphere assay, two compounds 48 and 51, derived from oleanolic acid, exhibited suppressive effect on elimination of different type of CSCs. Meanwhile, compounds 48 and 51 could significantly inhibit the growth of several tumors both in vitro and in vivo. Furthermore, treatment of cancer cells with both of two compounds would dramatically increase the level of ROS, which might eliminate the CSCs. Collectively, the leading compounds 48 and 51 were promising anti-CSCs agents that merited further validation as a novel class of chemotherapeutics.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Produtos Biológicos/química , Desenho de Fármacos , Células-Tronco Neoplásicas/efeitos dos fármacos , Triterpenos/química , Triterpenos/farmacologia , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Química Sintética , Ensaios de Seleção de Medicamentos Antitumorais , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Células-Tronco Neoplásicas/patologia , Espécies Reativas de Oxigênio/metabolismo , Triterpenos/síntese química
12.
Biochimie ; 150: 110-130, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29777737

RESUMO

In organ fibrosis, mechanical stress and transforming growth factor beta-1 (TGF-ß1) promote differentiation into myofibroblast from mesenchymal cells, leading to extracellular matrix (ECM) remodeling or active synthesis, deposition or degradation of ECM components. A major component of ECM, type I collagen (col I) triple helical molecules assemble into fibrils or are denatured to gelatin without triple-helicity in remodeling. However, whether changes of ECM components in remodeling have influence on mesenchymal cell differentiation remains elusive. This study adopted three states of collagen I existing in ECM remodeling: molecular collagen, fibrillar collagen and gelatin to see what are characteristics in the effects on two cell lines of mesenchymal origin, murine 3T3-L1 embryonic fibroblast and murine C2C12 myoblasts. The results showed that all three forms of collagen I were capable of inducing these two cells to differentiate into myofibroblasts characterized by increased expression of alpha-smooth muscle actin (α-SMA) mRNA. The expression of α-SMA is positively regulated by TGF-ß1. Nuclear translocation of Yes-associated protein (YAP) is involved in this process. Focal adhesion kinase (FAK) is activated in the cells cultured on molecular collagen-coated plates, contributing to YAP activation. On the other hand, in the cells cultured on fibrillar collagen gel or gelatin-coated plates, oxidative stress but not FAK induce YAP activation. In conclusion, the three physicochemically distinct forms of col I induce the differentiation of mesenchymal cells into myofibroblasts through different pathways.


Assuntos
Diferenciação Celular/fisiologia , Colágeno Tipo I/metabolismo , Fibroblastos/citologia , Fibroblastos/metabolismo , Miofibroblastos/citologia , Miofibroblastos/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Células 3T3-L1 , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Western Blotting , Proteínas de Ciclo Celular , Diferenciação Celular/genética , Linhagem Celular , Proliferação de Células/genética , Proliferação de Células/fisiologia , Colágeno Tipo I/genética , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Camundongos , Microscopia Confocal , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Fator de Crescimento Transformador beta1/genética , Proteínas de Sinalização YAP
13.
Free Radic Res ; 52(9): 913-928, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29768932

RESUMO

Reactive oxygen species (ROS) participate in various cell responses in association with cell proliferation, migration, differentiation, and death. Extracellular matrix (ECM) serves as cellular microenvironments for many kinds of cells, affecting cell activities. However, whether or not ECM influences cellular ROS levels has not been well studied. In this study, cells are cultured on collagen I molecule-coated (mol. coated) dishes and collagen I fibrous gel-covered (gel) dishes to explore their influence on cell behaviours. We found that the levels of ROS in murine 3T3-L1 preadipocytes increased both in cells on mol. coated and those on the gel. Much higher ROS levels were found in the cells cultured on the gel. Cell proliferation and migration were stimulated to opposite directions between the cells on mol. coated and the cells on gel. ROS in a moderate level were positive regulators in the proliferation and migration of cells on mol. coated; however, ROS in a high level served as negative regulators in the cells on gel. These opposite effects on cell proliferation and migration affected by different ROS levels are in parallel with opposite levels of NF-κB p65 activation.


Assuntos
Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Colágeno Tipo I/química , Meios de Cultura/química , Células 3T3-L1 , Animais , Colágeno Tipo I/farmacologia , Camundongos , NF-kappa B/química , Espécies Reativas de Oxigênio/química , Espécies Reativas de Oxigênio/farmacologia
14.
Nat Prod Res ; 32(22): 2625-2631, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28927292

RESUMO

Two new alkylated furan derivatives, 5-(undeca-3',5',7'-trien-1'-yl)furan-2-ol (1) and 5-(undeca-3',5',7'-trien-1'-yl)furan-2-carbonate (2), were isolated from the crude extract of the plant endophytic fungus Emericella sp. XL029 associated with the leaves of Panax notoginseng. The anti-agricultural pathogenic fungal assay indicated that compound 1 displayed significant activity against all tested fungi with minimum inhibitory concentrations (MIC) values from 25 to 3.1 µg/mL, while compound 2 displayed activity against all tested fungi except for Rhizoctonia solani and Fusarium oxysporum with MIC values from 50 to 12.5 µg/mL. Furthermore, compounds 1-2 also exhibited significant inhibitory activity against eight of thirteen tested bacteria with MIC values ranging from 50 to 6.3 µg/mL.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Emericella/química , Furanos/farmacologia , Panax notoginseng/microbiologia , Antibacterianos/isolamento & purificação , Antifúngicos/isolamento & purificação , Bactérias/efeitos dos fármacos , Furanos/isolamento & purificação , Fusarium/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Folhas de Planta/microbiologia , Rhizoctonia/efeitos dos fármacos
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