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1.
J Cardiovasc Pharmacol ; 84(1): 10-17, 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38547512

RESUMEN

ABSTRACT: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality globally. CVD and kidney disease are closely related, with kidney injury increasing CVD mortality. The pathogenesis of cardiovascular and renal diseases involves complex and diverse interactions between multiple extracellular and intracellular signaling molecules, among which transient receptor potential vanilloid 1 (TRPV1)/transient receptor potential ankyrin 1 (TRPA1) channels have received increasing attention. TRPV1 belongs to the vanilloid receptor subtype family of transient receptor potential ion channels, and TRPA1 belongs to the transient receptor potential channel superfamily. TRPV1/TRPA1 are jointly involved in the management of cardiovascular and renal diseases and play important roles in regulating vascular tension, promoting angiogenesis, antifibrosis, anti-inflammation, and antioxidation. The mechanism of TRPV1/TRPA1 is mainly related to regulation of intracellular calcium influx and release of nitric oxide and calcitonin gene-related peptide. Therefore, this study takes the TRPV1/TRPA1 channel as the research object, analyzes and summarizes the process and mechanism of TRPV1/TRPA1 affecting cardiovascular and renal diseases, and lays a foundation for the treatment of cardiorenal diseases.


Asunto(s)
Enfermedades Cardiovasculares , Enfermedades Renales , Transducción de Señal , Canal Catiónico TRPA1 , Canales Catiónicos TRPV , Humanos , Canal Catiónico TRPA1/metabolismo , Canales Catiónicos TRPV/metabolismo , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/fisiopatología , Animales , Enfermedades Renales/metabolismo , Enfermedades Renales/fisiopatología , Sistema Cardiovascular/metabolismo , Sistema Cardiovascular/fisiopatología , Sistema Cardiovascular/efectos de los fármacos , Riñón/metabolismo , Riñón/fisiopatología , Señalización del Calcio/efectos de los fármacos , Fármacos Cardiovasculares/uso terapéutico , Fármacos Cardiovasculares/farmacología
2.
J Nat Prod ; 87(4): 893-905, 2024 Apr 26.
Artículo en Inglés | MEDLINE | ID: mdl-38417166

RESUMEN

The bridged polycyclic sesquiterpenoids derived from sativene, isosativene, and longifolene have unique structures, and many chemical synthesis approaches with at least 10 steps have been reported. However, their biosynthetic pathway remains undescribed. A minimal biosynthetic gene cluster (BGC), named bip, encoding a sesquiterpene cyclase (BipA) and a cytochrome P450 (BipB) is characterized to produce such complex sesquiterpenoids with multiple carbon skeletons based on enzymatic assays, heterologous expression, and precursor experiments. BipA is demonstrated as a versatile cyclase with (-)-sativene as the dominant product and (-)-isosativene and (-)-longifolene as minor ones. BipB is capable of hydroxylating different enantiomeric sesquiterpenes, such as (-)-longifolene and (+)-longifolene, at C-15 and C-14 in turn. The C-15- or both C-15- and C-14-hydroxylated products are then further oxidized by unclustered oxidases, resulting in a structurally diverse array of sesquiterpenoids. Bioinformatic analysis reveals the BipB homologues as a discrete clade of fungal sesquiterpene P450s. These findings elucidate the concise and divergent biosynthesis of such intricate bridged polycyclic sesquiterpenoids, offer valuable biocatalysts for biotransformation, and highlight the distinct biosynthetic strategy employed by nature compared to chemical synthesis.


Asunto(s)
Sistema Enzimático del Citocromo P-450 , Familia de Multigenes , Estructura Molecular , Sistema Enzimático del Citocromo P-450/metabolismo , Sistema Enzimático del Citocromo P-450/genética , Sesquiterpenos/metabolismo , Sesquiterpenos/química , Vías Biosintéticas/genética , Sesquiterpenos Policíclicos/química , Sesquiterpenos Policíclicos/metabolismo , Estereoisomerismo
3.
Acta Pharmacol Sin ; 45(2): 238-247, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37803138

RESUMEN

The γ isoform of Class I PI3Ks (PI3Kγ) is primarily found in leukocytes and is essential for the function of myeloid cells, as it regulates the migration, differentiation, and activation of myeloid-lineage immune cells. Thus, PI3Kγ has been identified as a promising drug target for the treatment of inflammation, autoimmune disease, and immuno-oncology. Due to the high incidence of serious adverse events (AEs) associated with PI3K inhibitors, in the development of PI3Kγ inhibitors, isoform selectivity was deemed crucial. In this review, an overview of the development of PI3Kγ selective inhibitors in the past years is provided. The isoform selectivity of related drugs was achieved by different strategies, including inducing a specificity pocket by a propeller-shape structure, targeting steric differences in the solvent channel, and modulating the conformation of the Asp-Phe-Gly DFG motif, which have been demonstrated feasible by several successful cases. The insights in this manuscript may provide a potential direction for rational drug design and accelerate the discovery of PI3Kγ selective inhibitors.


Asunto(s)
Enfermedades Autoinmunes , Fosfatidilinositol 3-Quinasas , Humanos , Inhibidores de las Quinasa Fosfoinosítidos-3/química , Enfermedades Autoinmunes/tratamiento farmacológico , Isoformas de Proteínas , Inflamación/tratamiento farmacológico
4.
Acta Pharmacol Sin ; 45(8): 1673-1685, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38641746

RESUMEN

Acute kidney injury (AKI) is defined as sudden loss of renal function characterized by increased serum creatinine levels and reduced urinary output with a duration of 7 days. Ferroptosis, an iron-dependent regulated necrotic pathway, has been implicated in the progression of AKI, while ferrostatin-1 (Fer-1), a selective inhibitor of ferroptosis, inhibited renal damage, oxidative stress and tubular cell death in AKI mouse models. However, the clinical translation of Fer-1 is limited due to its lack of efficacy and metabolic instability. In this study we designed and synthesized four Fer-1 analogs (Cpd-A1, Cpd-B1, Cpd-B2, Cpd-B3) with superior plasma stability, and evaluated their therapeutic potential in the treatment of AKI. Compared with Fer-1, all the four analogs displayed a higher distribution in mouse renal tissue in a pharmacokinetic assay and a more effective ferroptosis inhibition in erastin-treated mouse tubular epithelial cells (mTECs) with Cpd-A1 (N-methyl-substituted-tetrazole-Fer-1 analog) being the most efficacious one. In hypoxia/reoxygenation (H/R)- or LPS-treated mTECs, treatment with Cpd-A1 (0.25 µM) effectively attenuated cell damage, reduced inflammatory responses, and inhibited ferroptosis. In ischemia/reperfusion (I/R)- or cecal ligation and puncture (CLP)-induced AKI mouse models, pre-injection of Cpd-A1 (1.25, 2.5, 5 mg·kg-1·d-1, i.p.) dose-dependently improved kidney function, mitigated renal tubular injury, and abrogated inflammation. We conclude that Cpd-A1 may serve as a promising therapeutic agent for the treatment of AKI.


Asunto(s)
Lesión Renal Aguda , Ferroptosis , Ratones Endogámicos C57BL , Fenilendiaminas , Animales , Ferroptosis/efectos de los fármacos , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/metabolismo , Ratones , Masculino , Fenilendiaminas/farmacología , Fenilendiaminas/uso terapéutico , Ciclohexilaminas/farmacología , Ciclohexilaminas/uso terapéutico , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo
5.
Int J Mol Sci ; 25(12)2024 Jun 08.
Artículo en Inglés | MEDLINE | ID: mdl-38928070

RESUMEN

The GRAS gene family, responsible for encoding transcription factors, serves pivotal functions in plant development, growth, and responses to stress. The exploration of the GRAS gene family within the Orchidaceae has been comparatively limited, despite its identification and functional description in various plant species. This study aimed to conduct a thorough examination of the GRAS gene family in Cymbidum goeringii, focusing on its physicochemical attributes, phylogenetic associations, gene structure, cis-acting elements, and expression profiles under heat stress. The results show that a total of 54 CgGRASs were pinpointed from the genome repository and categorized into ten subfamilies via phylogenetic associations. Assessment of gene sequence and structure disclosed the prevalent existence of the VHIID domain in most CgGRASs, with around 57.41% (31/54) CgGRASs lacking introns. The Ka/Ks ratios of all CgGRASs were below one, indicating purifying selection across all CgGRASs. Examination of cis-acting elements unveiled the presence of numerous elements linked to light response, plant hormone signaling, and stress responsiveness. Furthermore, CgGRAS5 contained the highest quantity of cis-acting elements linked to stress response. Experimental results from RT-qPCR demonstrated notable variations in the expression levels of eight CgGRASs after heat stress conditions, particularly within the LAS, HAM, and SCL4/7 subfamilies. In conclusion, this study revealed the expression pattern of CgGRASs under heat stress, providing reference for further exploration into the roles of CgGRAS transcription factors in stress adaptation.


Asunto(s)
Regulación de la Expresión Génica de las Plantas , Respuesta al Choque Térmico , Familia de Multigenes , Orchidaceae , Filogenia , Proteínas de Plantas , Respuesta al Choque Térmico/genética , Orchidaceae/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Genoma de Planta , Perfilación de la Expresión Génica/métodos
6.
Int J Mol Sci ; 25(5)2024 Mar 06.
Artículo en Inglés | MEDLINE | ID: mdl-38474276

RESUMEN

Cymbidium sinense, a type of orchid plant, is more drought-resistant and ornamental than other terrestrial orchids. Research has shown that many members of the NUCLEAR FACTOR Y (NF-Y) transcription factor family are responsive to plant growth, development, and abiotic stress. However, the mechanism of the NF-Y gene family's response to abiotic stress in orchids has not yet been reported. In this study, phylogenetic analysis allowed for 27 CsNF-Y genes to be identified (5 CsNF-YAs, 9 CsNF-YBs, and 13 CsNF-YC subunits), and the CsNF-Ys were homologous to those in Arabidopsis and Oryza. Protein structure analysis revealed that different subfamilies contained different motifs, but all of them contained Motif 2. Secondary and tertiary protein structure analysis indicated that the CsNF-YB and CsNF-YC subfamilies had a high content of alpha helix structures. Cis-element analysis showed that elements related to drought stress were mainly concentrated in the CsNF-YB and CsNF-YC subfamilies, with CsNF-YB3 and CsNF-YC12 having the highest content. The results of a transcriptome analysis showed that there was a trend of downregulation of almost all CsNF-Ys in leaves under drought stress, while in roots, most members of the CsNF-YB subfamily showed a trend of upregulation. Additionally, seven genes were selected for real-time reverse transcription quantitative PCR (qRT-PCR) experiments. The results were generally consistent with those of the transcriptome analysis. The regulatory roles of CsNF-YB 1, 2, and 4 were particularly evident in the roots. The findings of our study may make a great contribution to the understanding of the role of CsNF-Ys in stress-related metabolic processes.


Asunto(s)
Arabidopsis , Proteínas de Plantas , Proteínas de Plantas/genética , Sequías , Filogenia , Genoma de Planta , Factor de Unión a CCAAT/genética , Arabidopsis/genética , Regulación de la Expresión Génica de las Plantas , Estrés Fisiológico
7.
Angew Chem Int Ed Engl ; 63(10): e202318628, 2024 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-38225206

RESUMEN

An anion-counterion strategy is proposed to construct organic mono-radical charge-transfer cocrystals for near-infrared photothermal conversion and solar-driven water evaporation. Ionic compounds with halogen anions as the counterions serve as electron donors, providing the necessary electrons for efficient charge transfer with unchanged skeleton atoms and structures as well as the broad red-shifted absorption (200-2000 nm) and unprecedented photothermal conversion efficiency (~90.5 %@808 nm) for the cocrystals. Based on these cocrystals, an excellent solar-driven interfacial water evaporation rate up to 6.1±1.1 kg ⋅ m-2 ⋅ h-1 under 1 sun is recorded due to the comprehensive evaporation effect from the cocrystal loading in polyurethane foams and chimney addition, such performance is superior to the reported results on charge-transfer cocrystals or other materials for solar-driven interfacial evaporation. This prototype exhibits the great potential of cocrystals prepared by the one-step mechanochemistry method in practical large-scale seawater desalination applications.

8.
J Nat Prod ; 86(10): 2333-2341, 2023 10 27.
Artículo en Inglés | MEDLINE | ID: mdl-37819880

RESUMEN

Linaridins are a family of underexplored ribosomally synthesized and post-translationally modified peptides despite the prevalence of their biosynthetic gene clusters (BGCs) in microbial genomes, as shown by bioinformatic studies. Our genome mining efforts reveal that 96 putative oxidoreductase genes, namely, LinC, are encoded in linaridin BGCs. We heterologously expressed two such LinC-containing linaridin BGCs, yan and ydn, from Streptomyces yunnanensis and obtained three new linaridins, named yunnanaridins A-C (1-3). Their structures are characterized by Z-configurations of the dehydrobutyrines and the presence of a variety of epimerized amino acid residues. Yunnanaridin A (1) is the sixth member of the family of type-B linaridins, whereas yunnanaridins B (2) and C (3) represent the first examples of expressed type-C linaridins. Interestingly, heterologous expression of the same BGCs with LinC in-frame knockouts produced the same compounds. This work expands the structural diversity of linaridins and provides evidence for the notion that the widespread LinCs may not be involved in linaridin biosynthesis.


Asunto(s)
Biología Computacional , Péptidos , Péptidos/química , Familia de Multigenes , Aminoácidos
9.
Exp Cell Res ; 420(1): 113341, 2022 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-36075445

RESUMEN

Esophageal squamous cell carcinoma (ESCC) is a major cause of cancer-related deaths. We have previously connected a non-sulfated glycosaminoglycan, hyaluronic acid (HA), with a common hydrogen sulfide (H2S) donor, 5-(4-hydroxyphenyl)-3H-1,2-dithiol-3-thione (ADT-OH), to reconstruct a novel conjugate, HA-ADT. In this study, we determined the effect of HA-ADT on the growth of ESCC. Our data suggested that HA-ADT exerted more potent effects than sodium hydrosulfide (NaHS, a fast H2S-releasing donor) and morpholin-4-ium (4-methoxyphenyl)-morpholin-4-ylsulfanylidenesulfido-λ5-phosphane (GYY4137, a slow H2S-releasing donor) on inhibiting the viability, proliferation, migration, and invasion of human ESCC cells. HA-ADT increased apoptosis by suppressing the protein expressions of phospho (p)-Ser473-protein kinase B (PKB/AKT), p-Tyr199/Tyr458-phosphatidylinositol 3-kinase (PI3K), and p-Ser2448-mammalian target of rapamycin (mTOR), but suppressed autophagy through the inhibition of the protein levels of p-Ser552-ß-catenin, p-Ser9-glycogen synthase kinase-3ß (GSK-3ß), and Wnt3a in human ESCC cells. In addition, HA-ADT was more effective in terms of the growth inhibition of human ESCC xenograft tumor than NaHS and GYY4137. In conclusion, HA-ADT can suppress ESCC progression via apoptosis promotion and autophagy inhibition. HA-ADT might be efficacious for the treatment of cancer.


Asunto(s)
Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Sulfuro de Hidrógeno , Apoptosis , Autofagia , Línea Celular Tumoral , Proliferación Celular , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Glucógeno Sintasa Quinasa 3 beta , Humanos , Ácido Hialurónico/farmacología , Sulfuro de Hidrógeno/farmacología , Morfolinas , Compuestos Organotiofosforados , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Sulfuros , Serina-Treonina Quinasas TOR/metabolismo , Tionas , beta Catenina
10.
Int J Mol Sci ; 24(18)2023 Sep 20.
Artículo en Inglés | MEDLINE | ID: mdl-37762622

RESUMEN

The TCP gene family are plant-specific transcription factors that play important roles in plant growth and development. Dendrobium chrysotoxum, D. nobile, and D. huoshanense are orchids with a high ornamental value, but few studies have investigated the specific functions of TCPs in Dendrobium flower development. In this study, we used these three Dendrobium species to analyze TCPs, examining their physicochemical properties, phylogenetic relationships, gene structures, and expression profiles. A total of 50 TCPs were identified across three Dendrobium species; they were divided into two clades-Class-I (PCF subfamily) and Class-II (CIN and CYC/TB1 subfamilies)-based on their phylogenetic relationships. Our sequence logo analysis showed that almost all Dendrobium TCPs contain a conserved TCP domain, as well as the existence of fewer exons, and the cis-regulatory elements of the TCPs were mostly related to light response. In addition, our transcriptomic data and qRT-PCR results showed that DchTCP2 and DchTCP13 had a significant impact on lateral organs. Moreover, changes in the expression level of DchTCP4 suggested its important role in the phenotypic variation of floral organs. Therefore, this study provides a significant reference for the further exploration of TCP gene functions in the regulation of different floral organs in Dendrobium orchids.


Asunto(s)
Dendrobium , Dendrobium/genética , Dendrobium/metabolismo , Filogenia , Factores de Transcripción/metabolismo , Transcriptoma , Perfilación de la Expresión Génica , Regulación de la Expresión Génica de las Plantas , Proteínas de Plantas/metabolismo
11.
Int J Mol Sci ; 24(24)2023 Dec 14.
Artículo en Inglés | MEDLINE | ID: mdl-38139293

RESUMEN

The PEBP gene family plays a significant role in regulating flower development and formation. To understand its function in Dendrobium chrysotoxum and D. nobile flowering, we identified 22 PEBP genes (11 DchPEBPs and 11 DnoPEBPs) from both species. We conducted analyses on their conserved domains and motifs, phylogenetic relationships, chromosome distribution, collinear correlation, and cis elements. The classification results showed that the 22 PEBPs were mainly divided into three clades, as follows: FT, MFT, and TFL1. A sequence analysis showed that most PEBP proteins contained five conserved domains, while a gene structure analysis revealed that 77% of the total PEBP genes contained four exons and three introns. The promoter regions of the 22 PEBPs contained several cis elements related to hormone induction and light response. This suggests these PEBPs could play a role in regulating flower development by controlling photoperiod and hormone levels. Additionally, a collinearity analysis revealed three pairs of duplicate genes in the genomes of both D. chrysotoxum and D. nobile. Furthermore, RT-qPCR has found to influence the regulatory effect of DchPEBPs on the development of flower organs (sepals, petals, lip, ovary, and gynostemium) during the flowering process (bud, transparent stage, and initial bloom). The results obtained imply that DchPEBP8 and DchPEBP9 play a role in the initial bloom and that DchPEBP7 may inhibit flowering processes. Moreover, DchPEBP9 may potentially be involved in the development of reproductive functionality. PEBPs have regulatory functions that modulate flowering. FT initiates plant flowering by mediating photoperiod and temperature signals, while TFL1 inhibits flowering processes. These findings provide clues for future studies on flower development in Dendrobium.


Asunto(s)
Dendrobium , Dendrobium/genética , Dendrobium/metabolismo , Proteínas de Plantas/metabolismo , Filogenia , Plantas/metabolismo , Hormonas
12.
Int J Mol Sci ; 24(9)2023 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-37175542

RESUMEN

Apostasia shenzhenica belongs to the subfamily Apostasioideae and is a primitive group located at the base of the Orchidaceae phylogenetic tree. However, the A. shenzhenica mitochondrial genome (mitogenome) is still unexplored, and the phylogenetic relationships between monocots mitogenomes remain unexplored. In this study, we discussed the genetic diversity of A. shenzhenica and the phylogenetic relationships within its monocotyledon mitogenome. We sequenced and assembled the complete mitogenome of A. shenzhenica, resulting in a circular mitochondrial draft of 672,872 bp, with an average read coverage of 122× and a GC content of 44.4%. A. shenzhenica mitogenome contained 36 protein-coding genes, 16 tRNAs, two rRNAs, and two copies of nad4L. Repeat sequence analysis revealed a large number of medium and small repeats, accounting for 1.28% of the mitogenome sequence. Selection pressure analysis indicated high mitogenome conservation in related species. RNA editing identified 416 sites in the protein-coding region. Furthermore, we found 44 chloroplast genomic DNA fragments that were transferred from the chloroplast to the mitogenome of A. shenzhenica, with five plastid-derived genes remaining intact in the mitogenome. Finally, the phylogenetic analysis of the mitogenomes from A. shenzhenica and 28 other monocots showed that the evolution and classification of most monocots were well determined. These findings enrich the genetic resources of orchids and provide valuable information on the taxonomic classification and molecular evolution of monocots.


Asunto(s)
Genoma Mitocondrial , Orchidaceae , Filogenia , Mitocondrias/genética , ARN Ribosómico/genética , Orchidaceae/genética
13.
Int J Mol Sci ; 24(12)2023 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-37373311

RESUMEN

The small plant-specific YABBY gene family plays key roles in diverse developmental processes in plants. Dendrobium chrysotoxum, D. huoshanense, and D. nobile are perennial herbaceous plants belonging to Orchidaceae with a high ornamental value. However, the relationships and specific functions of the YABBY genes in the Dendrobium species remain unknown. In this study, six DchYABBYs, nine DhuYABBYs, and nine DnoYABBYs were identified from the genome databases of the three Dendrobium species, which were unevenly distributed on five, eight, and nine chromosomes, respectively. The 24 YABBY genes were classified into four subfamilies (CRC/DL, INO, YAB2, and FIL/YAB3) based on their phylogenetic analysis. A sequence analysis showed that most of the YABBY proteins contained conserved C2C2 zinc-finger and YABBY domains, while a gene structure analysis revealed that 46% of the total YABBY genes contained seven exons and six introns. All the YABBY genes harbored a large number of Methyl Jasmonate responsive elements, as well as anaerobic induction cis-acting elements in the promoter regions. Through a collinearity analysis, one, two, and two segmental duplicated gene pairs were identified in the D. chrysotoxum, D. huoshanense, and D. nobile genomes, respectively. The Ka/Ks values of these five gene pairs were lower than 0.5, indicating that the Dendrobium YABBY genes underwent negative selection. In addition, an expression analysis revealed that DchYABBY2 plays a role in ovary and early-stage petal development, while DchYABBY5 is essential for lip development and DchYABBY6 is crucial for early sepal formation. DchYABBY1 primarily regulates sepals during blooming. Furthermore, there is the potential involvement of DchYABBY2 and DchYABBY5 in gynostemium development. The results of a comprehensive genome-wide study would provide significant clues for future functional investigations and pattern analyses of YABBY genes in different flower parts during flower development in the Dendrobium species.


Asunto(s)
Dendrobium , Dendrobium/genética , Dendrobium/metabolismo , Filogenia , Estudio de Asociación del Genoma Completo , Flores/metabolismo , Regulación de la Expresión Génica de las Plantas , Proteínas de Plantas/metabolismo
14.
Acta Pharmacol Sin ; 43(1): 220-228, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33782542

RESUMEN

Checkpoint kinase 1 inhibitors (CHK1i) have shown impressive single-agent efficacy in treatment of certain tumors, as monotherapy or potentiators of chemotherapy in clinical trials, but the sensitive tumor types and downstream effectors to dictate the therapeutic responses to CHK1i remains unclear. In this study we first analyzed GDSC (Genomics of Drug Sensitivity in Cancer) and DepMap database and disclosed that hematologic malignancies (HMs) were relatively sensitive to CHK1i or CHK1 knockdown. This notion was confirmed by examining PY34, a new and potent in-house selective CHK1i, which exhibited potent anti-HM effect in vitro and in vivo, as single agent. We demonstrated that the downregulation of c-Myc and its signaling pathway was the common transcriptomic profiling response of sensitive HM cell lines to PY34, whereas overexpressing c-Myc could partially rescue the anticancer effect of PY34. Strikingly, we revealed the significant correlations between downregulation of c-Myc and cell sensitivity to PY34 in 17 HM cell lines and 39 patient-derived cell (PDC) samples. Thus, our results demonstrate that HMs are more sensitive to CHK1i than solid tumors, and c-Myc downregulation could represent the CHK1i efficacy in HMs.


Asunto(s)
Proteínas de Unión al ADN/antagonistas & inhibidores , Regulación hacia Abajo/efectos de los fármacos , Neoplasias Hematológicas/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Factores de Transcripción/antagonistas & inhibidores , Animales , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/antagonistas & inhibidores , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/deficiencia , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/patología , Humanos , Ratones , Ratones Endogámicos NOD , Ratones Desnudos , Ratones SCID , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Inhibidores de Proteínas Quinasas/química , Relación Estructura-Actividad , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
15.
Proc Natl Acad Sci U S A ; 116(44): 22347-22352, 2019 10 29.
Artículo en Inglés | MEDLINE | ID: mdl-31611410

RESUMEN

Observing the structure and regeneration of the myelin sheath in peripheral nerves following injury and during repair would help in understanding the pathogenesis and treatment of neurological diseases caused by an abnormal myelin sheath. In the present study, transmission electron microscopy, immunofluorescence staining, and transcriptome analyses were used to investigate the structure and regeneration of the myelin sheath after end-to-end anastomosis, autologous nerve transplantation, and nerve tube transplantation in a rat model of sciatic nerve injury, with normal optic nerve, oculomotor nerve, sciatic nerve, and Schwann cells used as controls. The results suggested that the double-bilayer was the structural unit that constituted the myelin sheath. The major feature during regeneration was the compaction of the myelin sheath, wherein the distance between the 2 layers of cell membrane in the double-bilayer became shorter and the adjacent double-bilayers tightly closed together and formed the major dense line. The expression level of myelin basic protein was positively correlated with the formation of the major dense line, and the compacted myelin sheath could not be formed without the anchoring of the lipophilin particles to the myelin sheath.


Asunto(s)
Vaina de Mielina/ultraestructura , Regeneración Nerviosa , Traumatismos de los Nervios Periféricos/metabolismo , Animales , Axones/metabolismo , Axones/ultraestructura , Vaina de Mielina/metabolismo , Traumatismos de los Nervios Periféricos/patología , Ratas
16.
Proc Natl Acad Sci U S A ; 116(3): 890-899, 2019 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-30593567

RESUMEN

The AML1-ETO fusion protein, generated by the t(8;21) chromosomal translocation, is causally involved in nearly 20% of acute myeloid leukemia (AML) cases. In leukemic cells, AML1-ETO resides in and functions through a stable protein complex, AML1-ETO-containing transcription factor complex (AETFC), that contains multiple transcription (co)factors. Among these AETFC components, HEB and E2A, two members of the ubiquitously expressed E proteins, directly interact with AML1-ETO, confer new DNA-binding capacity to AETFC, and are essential for leukemogenesis. However, the third E protein, E2-2, is specifically silenced in AML1-ETO-expressing leukemic cells, suggesting E2-2 as a negative factor of leukemogenesis. Indeed, ectopic expression of E2-2 selectively inhibits the growth of AML1-ETO-expressing leukemic cells, and this inhibition requires the bHLH DNA-binding domain. RNA-seq and ChIP-seq analyses reveal that, despite some overlap, the three E proteins differentially regulate many target genes. In particular, studies show that E2-2 both redistributes AETFC to, and activates, some genes associated with dendritic cell differentiation and represses MYC target genes. In AML patients, the expression of E2-2 is relatively lower in the t(8;21) subtype, and an E2-2 target gene, THPO, is identified as a potential predictor of relapse. In a mouse model of human t(8;21) leukemia, E2-2 suppression accelerates leukemogenesis. Taken together, these results reveal that, in contrast to HEB and E2A, which facilitate AML1-ETO-mediated leukemogenesis, E2-2 compromises the function of AETFC and negatively regulates leukemogenesis. The three E proteins thus define a heterogeneity of AETFC, which improves our understanding of the precise mechanism of leukemogenesis and assists development of diagnostic/therapeutic strategies.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Leucemia Mieloide Aguda/etiología , Proteínas de Fusión Oncogénica/metabolismo , Proteína 1 Compañera de Translocación de RUNX1/metabolismo , Proteína 2 Similar al Factor de Transcripción 7/metabolismo , Diferenciación Celular , Línea Celular Tumoral , Humanos , Leucemia Mieloide Aguda/metabolismo , Recurrencia
17.
Int J Nurs Pract ; 28(6): e13082, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-35929026

RESUMEN

AIMS: To explore how family functioning and family resilience mediate the relationship between disability severity and quality of home-based care among families with disabled older adults. METHODS: A cross-sectional survey was conducted with 431 families with Uygur and Kazakh disabled older adults in Xinjiang, China, in 2020. The data were collected using the Katz Activity of Daily Living Scale; Mini-Mental State Examination; Family Adaptation, Partnership, Growth, Affection and Resolve Index Scale; Family Resilience Assessment Scale; and Family Caregiving Consequences Inventory Scale. All mediation effects were estimated in SPSS26.0. RESULTS: Disability severity, family functioning and family resilience were all significantly correlated with home-based care quality. Disability severity had a 46.16% direct effect on home-based care quality and a 53.84% indirect effect on home-based care quality independently and in series through family functioning and family resilience. CONCLUSIONS: Disability severity directly affected home-based care quality and had an indirect influence via family functioning and family resilience. Multidisciplinary care teams should focus on families with disabled older adults and help them improve family functioning and family resilience by implementing targeted interventions, so as to improve home-based care quality.


Asunto(s)
Personas con Discapacidad , Resiliencia Psicológica , Humanos , Anciano , Estudios Transversales , Salud de la Familia , China
18.
Zhongguo Zhong Yao Za Zhi ; 46(4): 951-965, 2021 Feb.
Artículo en Zh | MEDLINE | ID: mdl-33645102

RESUMEN

The Qinling-Daba Mountains area is the main producing areas of Gynostemma longipes for medicinal usage, and samples of wild whole plants in Pingli, Shaanxi Province and Qingchuan, Sichuan Province were collected. The ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry(UHPLC-Q-TOF-MS~E) was used to profile the chemical compositions and analyze the similarities and differences of G. longipes samples in these areas. Based on the accurate molecular weight and fragment information obtained from Q-TOF-MS~E, the structures of the main components were identified by combining with the mass spectra, chromatographic behaviors of reference standards and related literatures. The results showed that the components of wild G. longipes from different places among Qinling-Daba Mountains area were similar. Forty-five chemical components were identified in the whole plant of G. longipes from Pingli, Shaanxi Province, including 43 triterpenoid saponins and 2 flavonoids which contain all main peaks in its fingerprint. The main components are dammarane-type triterpenoid saponins, such asgypenoside ⅩLⅨ, gypenoside A and its malonylated product of glycosyl.


Asunto(s)
Medicamentos Herbarios Chinos , Saponinas , Cromatografía Líquida de Alta Presión , Gynostemma , Espectrometría de Masas
19.
Plant Cell Physiol ; 60(10): 2206-2219, 2019 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-31271439

RESUMEN

Photosynthetic induction, a gradual increase in photosynthetic rate on a transition from darkness or low light to high light, has ecological significance, impact on biomass accumulation in fluctuating light and relevance to photoprotection in strong light. However, the experimental quantification of the component electron fluxes in and around both photosystems during induction has been rare. Combining optimized chlorophyll fluorescence, the redox kinetics of P700 [primary electron donor in Photosystem I (PSI)] and membrane inlet mass spectrometry in the absence/presence of inhibitors/mediator, we partially estimated the components of electron fluxes in spinach leaf disks on transition from darkness to 1,000 �mol photons�m-2�s-1 for up to 10 min, obtaining the following findings: (i) the partitioning of energy between both photosystems did not change noticeably; (ii) in Photosystem II (PSII), the combined cyclic electron flow (CEF2) and charge recombination (CR2) to the ground state decreased gradually toward 0 in steady state; (iii) oxygen reduction by electrons from PSII, partly bypassing PSI, was small but measurable; (iv) cyclic electron flow around PSI (CEF1) peaked before becoming somewhat steady; (v) peak magnitudes of some of the electron fluxes, all probably photoprotective, were in the descending order: CEF1 > CEF2 + CR2 > chloroplast O2 uptake; and (vi) the chloroplast NADH dehydrogenase-like complex appeared to aid the antimycin A-sensitive CEF1. The results are important for fine-tuning in silico simulation of in vivo photosynthetic electron transport processes; such simulation is, in turn, necessary to probe partial processes in a complex network of interactions in response to environmental changes.


Asunto(s)
Transporte de Electrón , Oxígeno/metabolismo , Fotosíntesis/fisiología , Complejo de Proteína del Fotosistema I/metabolismo , Complejo de Proteína del Fotosistema II/metabolismo , Spinacia oleracea/fisiología , Antimicina A/farmacología , Dióxido de Carbono/metabolismo , Clorofila/metabolismo , Cloroplastos/metabolismo , Oscuridad , Fluorescencia , Cinética , Luz , Oxidación-Reducción , Hojas de la Planta/fisiología , Hojas de la Planta/efectos de la radiación , Spinacia oleracea/efectos de la radiación
20.
J Nat Prod ; 82(2): 169-176, 2019 02 22.
Artículo en Inglés | MEDLINE | ID: mdl-30714735

RESUMEN

A polysaccharide, Ali-1, was isolated from the roots of Eurycoma longifolia, a popular traditional medicinal herb in Malaysia. The structure of Ali-1 was characterized by monosaccharide, methylation, and NMR data analyses. The average molecular weight of Ali-1 is 14.3 ku, and it is composed of arabinose (14.31%), xylose (57.69%), galacturonic acid (13.03%), and glucuronic acid (14.86%). The main chain comprises (1→4)-linked xylose residues. It has branch points in the main chain; (1→2,4)-linked xylose residues, 1,2-linked glucuronic acid residues, and 1,2-linked arabinose residues form the branches, and the branches are terminated with T-linked galacturonic acid residues and T-linked arabinose residues. Ali-1 significantly improves the pinocytic and phagocytic abilities of RAW264.7 cells and facilitates cytokine secretion according to an immunostimulation assay. These results demonstrate that Ali-1 has potential as a functional supplement for people with compromised immune systems.


Asunto(s)
Eurycoma/química , Factores Inmunológicos/farmacología , Polisacáridos/aislamiento & purificación , Animales , Espectroscopía de Resonancia Magnética , Ratones , Conformación Molecular , Fagocitosis/efectos de los fármacos , Polisacáridos/química , Polisacáridos/farmacología , Células RAW 264.7
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