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PURPOSE: To evaluate the effects of acupuncture on IVF-ET outcomes. METHODS: Digital databases, including Pubmed, Embase, the Cochrane Library, the Web of Science and ScienceDirect, were searched from their inception to July 2022. The MeSH terms we used included: acupuncture, in vitro fertilization, assisted reproductive technology and randomized controlled trial. The reference lists of relevant documents were also searched. The biases of included studies were assessed by the Cochrane Handbook 5.3. The major outcomes were clinical pregnancy rate (CPR) and live birth rate (LBR). The pregnancy outcomes reported in these trials were pooled and expressed as risk ratios (RR) with 95% confidence interval (CI) in the Review Manager 5.4 meta-analysis software. Heterogeneity of the therapeutic effect was evaluated with a forest plot analysis. Publication bias was assessed by a funnel plot analysis. RESULTS: Twenty-five trials (a total of 4757 participants) were included in this review. There were no significant publication biases for most of the comparisons among these studies. The pooled CPR (25 trials) of all the acupuncture groups (43.6%) was significantly higher than that of all the control groups (33.2%, P < 0.00001), and the pooled LBR (11 trials) of all the acupuncture groups (38.0%) was significantly higher than that of all the control groups (28.7%, P < 0.00001). Different acupuncture methods (manual acupuncture, electrical acupuncture and transcutaneous acupoint electrical stimulation), acupuncture time (before or during the time of controlled ovarian hyperstimulation and around the time of embryo transfer), and acupuncture courses (at least 4 sessions and less than 4 sessions) have respectively positive effects on IVF outcomes. CONCLUSION: Acupuncture can significantly improve CPR and LBR among women undergoing IVF. Placebo acupuncture can be a relatively ideal control measure.
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Terapia por Acupuntura , Resultado da Gravidez , Gravidez , Feminino , Humanos , Taxa de Gravidez , Fertilização in vitro/métodos , Transferência Embrionária , Nascido VivoRESUMO
Coumarins are natural products with benzopyran ring as the parent nucleus. Numerous coumarin derivatives exhibit a variety of pharmacological activities, including antibacterial, anti-inflammatory, antitumor, anti-coagulant, anti-osteoporotic, and insecticidal activities. Therefore, they play an important role in both medicine and agriculture. The development and utilization of coumarin derivatives have attracted increasing attention. The advancement of gene sequencing technology and the rapid progress in synthetic bio-logy have led to significant advancement in the biosynthesis of coumarin derivatives, and has received increasing attention from global researchers. This paper presents a comprehensive overview of the key biosynthesis-related enzymes of coumarin derivatives, such as cytochrome P450 enzyme(CYP450), prenyltransferase(PT), UDP-glucosyltransferase(UGT). Additionally, the pharmacological activities of these enzymes, including anti-tumor, anti-inflammatory, antioxidant, and antibacterial activities, are systematically summarized. This review aims to provide a valuable reference for the biosynthesis of coumarin derivatives and further exploration of their medicinal potential.
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Cumarínicos , Cumarínicos/química , Cumarínicos/farmacologia , Cumarínicos/metabolismo , Humanos , Animais , Dimetilaliltranstransferase/metabolismo , Dimetilaliltranstransferase/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Sistema Enzimático do Citocromo P-450/genética , Glucosiltransferases/genética , Glucosiltransferases/metabolismoRESUMO
Two new austocystin analogs, austocystin P (1) and austocystin Q (2), along with fourteen known compounds (3-16) were isolated from the fermentation extract of Aspergillus sp. WHUF05236. The planar structures of 1 and 2 were elucidated through 1D, 2D NMR and MS analyses. Their absolute configurations were determined by the time-dependent density functional (TDDFT)-ECD calculation. Compounds 3, 11, and 12 exhibited antimicrobial activities against Helicobacter pylori with MIC values ranging from 20.00 to 43.47â µM. Compounds 3, 6, and 7 showed cytotoxicities against the human colon cancer cell lines Hct-116 with IC50 values of 101.79, 65.46, and 36.72â µM, respectively.
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Aspergillus , Fungos , Aspergillus/química , Fungos/química , Humanos , Espectroscopia de Ressonância Magnética , Estrutura MolecularRESUMO
BACKGROUND: The primary tumor, regional lymph nodes and distant metastasis (TNM) stage is an independent risk factor for 1-year hepatocellular carcinoma (HCC) recurrence but has insufficient predictive efficiency. We attempt to develop and validate a nomogram to predict 1-year recurrence in HCC and improve the predictive efficiency of the TNM stage. METHODS: A total of 541 HCC patients were enrolled in the study. The risk score (RS) model was established with the logistic least absolute shrinkage and selector operation algorithm. The predictive nomogram was further validated in the internal testing cohort and external validation cohort. The area under the receiver operating characteristic curves (AUCs), decision curves and clinical impact curves were used to evaluate the predictive accuracy and clinical value of the nomogram. RESULTS: In the training cohort, we identified a RS model consisting of five stage-related genes (NUP62, EHMT2, RANBP1, MSH6 and FHL2) for recurrence at 1 year. The 1-year disease-free survival of patients was worse in the high-risk group than in the low-risk group (P < 0.0001), and 1-year recurrence was more likely in the high-risk group (Hazard ratio: 3.199, P < 0.001). The AUC of the nomogram was 0.739, 0.718 and 0.693 in the training, testing and external validation cohort, respectively, and these values were larger than the corresponding AUC of the TNM stage (0.681, 0.688 and 0.616, respectively). CONCLUSIONS: A RS model consisting of five stage-related genes was successfully identified for predicting 1-year HCC recurrence. Then, a novel nomogram based on the RS model and TNM stage to predict 1-year HCC recurrence was also developed and validated.
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Global identification of protein C-termini is highly challenging due to their low abundance in conventional shotgun proteomics. Several enrichment strategies have been developed to facilitate the detection of C-terminal peptides. One major issue of previous approaches is the limited C-terminome coverage. Herein, we integrated LysargiNase digestion, chemical acetylation on neo-N-terminus, and a-ion-aided peptide matching into poly(allylamine)-based C-terminomics (termed as LAACTer). In this strategy, we leveraged LysargiNase, a protease with cleavage specificity N-terminal to Lys and Arg residues, to cover previously unidentifiable C-terminome and employed chemical acetylation and a-ion-aided peptide matching to efficiently boost peptide identifications. Triplicates of LAACTer identified a total of 834 C-termini from proteome of 293T cell, which expanded the coverage by 164% (643 more unique C-termini) compared with the parallel experiments using the original workflow. Compared with the largest human C-terminome data sets (containing 800-900 C-termini), LAACTer not only achieved comparable profiling depth but also yielded 465 previously unidentified C-termini. In a SILAC (stable isotope labeling with amino acids in cell culture)-based quantitative study for identification of GluC-cleaved products, LAACTer quantified 300% more C-terminal peptides than the original workflow. Using LAACTer and the original workflow, we performed global analysis for the C-terminal sequences of 293T cell. The original and processed C-termini displayed distinct sequence patterns, implying the "C-end rules" that regulates protein stability could be more complex than just amino acid motifs. In conclusion, we reason LAACTer could be a powerful proteomic tool for in-depth C-terminomics and would benefit better functional understanding of protein C-termini.
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Metaloproteases/química , Domínios Proteicos , Proteoma/análise , Linhagem Celular , Humanos , Marcação por Isótopo , Methanosarcina/enzimologia , Proteólise , Proteoma/química , Proteômica/métodosRESUMO
Hypermongones A-J (1-10), rare methylated polycyclic polyprenylated acylphloroglucinol derivatives, together with three known simple acylphloroglucinols (11-13) as their plausible biogenetic precursors, were identified from the flowers of Hypericum monogynum. The structures of 1-10 were elucidated by analysis of their 1D and 2D NMR spectroscopic data; the absolute configuration of their polycyclic skeleton was determined by the electronic circular dichroism exciton chirality method and was subsequently confirmed by an X-ray diffraction study of 1. The evaluation of their inhibitory effects on nitric oxide (NO) production in lipopolysaccharide-induced RAW264.7 cells revealed that compound 7 exhibited significant NO inhibition activity, with an IC50 value of 9.5 µM.
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Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/farmacologia , Hypericum/química , Floroglucinol , Animais , Medicamentos de Ervas Chinesas/química , Flores/química , Células HL-60 , Humanos , Concentração Inibidora 50 , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Camundongos , Estrutura Molecular , Óxido Nítrico/biossíntese , Ressonância Magnética Nuclear Biomolecular , Floroglucinol/análogos & derivados , Floroglucinol/química , Floroglucinol/isolamento & purificação , Floroglucinol/farmacologia , Difração de Raios XRESUMO
Six new limonoids with modified furan ring, khaysenelide A-F (1-6), together with six known limonoids (7-12) were isolated from the stem bark of Khaya senegalensis. The basic skeletons of these new limonoids belong to mexicanolide (1, 2) and rearrangement phragmalin (3-6), which were elucidated on the basis of spectroscopic methods including high resolution-electrospray ionization (HR-ESI)-MS, one and two dimensional (1D and 2D)-NMR and confirmed by single-crystal X-ray crystallography using CuKα radiation of 1 and 3. Their absolute configurations were determined by the X-ray crystallography data and comparison of their electronic circular dichroism spectra. The inhibitory effect on nitric oxide (NO) production in lipopolysaccaride-activated RAW264.7 macrophages of new compounds was also tested.
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Limoninas/farmacologia , Meliaceae/química , Óxido Nítrico/antagonistas & inibidores , Casca de Planta/química , Caules de Planta/química , Animais , Linhagem Celular , Dicroísmo Circular , Cristalografia por Raios X , Limoninas/química , Limoninas/isolamento & purificação , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Espectroscopia de Ressonância Magnética , Camundongos , Modelos Moleculares , Conformação Molecular , Óxido Nítrico/biossíntese , Relação Estrutura-AtividadeRESUMO
Eight new glucosylated coumaroyltyramine derivatives, teuvissides A-H (1-8), were isolated from whole plants of Teucrium viscidum. Their structures were elucidated using spectroscopic data and chemical methods. The antihyperglycemic activities of these compounds were evaluated in HepG2 cells and 3T3-L1 adipocytes, and all of the isolates elicited different levels of glucose consumption at a concentration of 2.0 µM. Teuvissides A (1), B (2), and F (6) induced 2.2-, 2.1-, and 2.2-fold changes, respectively, in the levels of glucose consumption in HepG2 cells and 2.5-, 2.1-, and 2.3-fold changes, respectively, in 3T3-L1 adipocytes relative to the basal levels.
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Ácidos Cumáricos/isolamento & purificação , Ácidos Cumáricos/farmacologia , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/farmacologia , Glicosídeos/isolamento & purificação , Glicosídeos/farmacologia , Hipoglicemiantes/isolamento & purificação , Hipoglicemiantes/farmacologia , Teucrium/química , Tiramina/análogos & derivados , Adipócitos/efeitos dos fármacos , Animais , Ácidos Cumáricos/química , Medicamentos de Ervas Chinesas/química , Glucose/análogos & derivados , Glucose/farmacologia , Glicosídeos/química , Células Hep G2 , Humanos , Hipoglicemiantes/química , Insulina/farmacologia , Camundongos , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Tiramina/química , Tiramina/isolamento & purificação , Tiramina/farmacologiaRESUMO
Two new neo-clerodane diterpenoids, teucvisins A and B (1, 2), and three new 19-nor-neoclerodane diterpenoids, teucvisins C-E (3-5), together with ten known constituents (6-15) were isolated from the whole plants of Teucrium viscidum. All the isolates were evaluated for their inhibitory activities of lipopolysaccharide (LPS)-induced nitric oxide production in RAW264.7 macrophages. The results indicated that compounds 11 and 15 showed moderate inhibition with an IC50 value of 21.9 and 22.4 µM, respectively.
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Diterpenos Clerodânicos/farmacologia , Macrófagos/efeitos dos fármacos , Teucrium/química , Animais , Diterpenos Clerodânicos/química , Diterpenos Clerodânicos/isolamento & purificação , Relação Dose-Resposta a Droga , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Macrófagos/metabolismo , Camundongos , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Despite the wide use of a three-month gonadotropin-releasing hormone agonist (3M GnRHa) for ovarian function suppression (OFS) in premenopausal breast cancer patients, it remains unclear whether it is as effective and safe as a one-month GnRHa regimen (1M GnRHa) when combined with selective estrogen receptor modulators (SERMs) or aromatase inhibitors (AIs), especially in younger patients. METHODS: This retrospective cohort study included 1109 premenopausal hormone receptor-positive (HR+) breast cancer patients treated with GnRHa plus SERM or AI. The estradiol (E2) inhibition rate within 1-24 months after treatment with 1M or 3M GnRHa in cohorts and different subgroups was analyzed. RESULTS: Following 1:1 propensity score matching, 950 patients with a mean age of 39 years and a median follow-up of 46 months were included. Both the 1M and 3M groups achieved >90% E2 inhibition within 24 months (94.53% vs 92.84%, 95% CI (-4.78%, 1.41%)), confirming the non-inferiority of 3M GnRHa. Both 1M and 3M GnRHa rapidly and consistently reduced E2 levels. 60 (6.3%) patients experienced incomplete ovarian function suppression (iOFS), with similar rates in the 1M and 3M groups (5.5% vs 7.2%). iOFS mainly occurred within the first 12 months, with age <40 years and no prior chemotherapy being the risk factors. Similar disease-free survival (DFS) and overall survival (OS) were found in the 1M and 3M groups, and in patients with complete and incomplete OFS (p > .05). CONCLUSIONS: The OFS with 3M GnRHa was not inferior to that with 1M GnRHa, regardless of age or combination with a SERM or an AI.
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The follicle is the functional unit of the ovary, whereby ovarian development is largely dependent on the development of the follicles themselves. The activation, growth, and progression of follicles are modulated by a diverse range of factors, including reproductive endocrine system and multiple signaling pathways. The Hippo pathway exhibits a high degree of evolutionary conservation between both Drosophila and mammalian systems, and is recognized for its pivotal role in regulating cellular proliferation, control of organ size, and embryonic development. During the process of follicle development, the components of the Hippo pathway show temporal and spatial variations. Recent clinical studies have shown that ovarian fragmentation can activate follicles. The mechanism is that the mechanical signal of cutting triggers actin polymerization. This process leads to the disruption of the Hippo pathway and subsequently induces the upregulation of downstream CCN and apoptosis inhibitors, thereby promoting follicle development. Thus, the Hippo pathway plays a crucial role in both the activation and development of follicles. In this article, we focused on the development and atresia of follicles and the function of Hippo pathway in these processes. Additionally, the physiological effects of Hippo pathway in follicle activation are also explored.
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Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer. In the absence of effective molecular markers for TNBC, there is an urgent clinical need for promising therapeutic target for TNBC. Histone deacetylases (HDACs), key regulators for chromatin remodeling and gene expression, have been suggested to play critical roles in cancer development. However, little is known ~the functions and implications of HDACs in TNBC treatment in the future. By analyzing the expression and prognostic significance of HDAC family members in TNBC through TCGA and METABRIC databases, HDAC7 was found to be downregulated in TNBC samples and the survival of patients with lower expression of HDAC7 was shorter. Furthermore, HDAC7 was negatively associated with NudC domain containing 1 (NudCD1) and γ-glutamyl hydrolase (GGH). Loss of NudCD1 or GGH predicted improved overall survival time (OS) of patients with TNBC. In vitro experiments showed that silencing of HDAC7 enhanced TNBC cell proliferation, while overexpression HDAC7 inhibited TNBC cell proliferation. The results of functional experiments confirmed that HDAC7 negatively modulated GGH and NudCD1 expression. Furthermore, decrease of NudCD1 or GGH inhibited cell proliferation. Notably, the HDAC7-NudCD1/GGH axis was found to be associated with NK cell infiltration. Overall, the present study revealed a novel role of HDAC7-NudCD1/GGH axis in TNBC, which might provide a promising treatment strategy for patients with TNBC.
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BACKGROUND: The Chinese herbal prescription Cuyun Recipe (CYR) has been widely used to treat clinical infertility and has shown good efficacy. Animal experiments have shown that CYR can promote implantation in mice, however, the exact mechanism underlying the implantation has not been elucidated. PURPOSE: To investigate the effect and mechanism of CYR on regulating macrophage polarization and hypercoagulability during the peri-implantation period in mice with ovarian hyperstimulation. METHODS: An ovarian hyperstimulation mouse model was developed, followed by treatment with CYR. Mice were sacrificed on day (D)4.5, D6, or D8 of gestation. The number of implantation sites, the pathological changes of the uterus and ovaries were assessed. The polarization of monocytes/macrophages in the spleen and endometrium, the expression and localization of cytokines were further detected. Furthermore, analyses of hypercoagulable state of the blood were also performed. RESULTS: Treatment with CYR increased the average number of implantation sites, promoted angiogenesis in endometrial, and regulated monocytes/macrophages and the cytokine levels. Moreover, CYR downregulated the overexpression of D-dimer and fgl2 after ovarian hyperstimulation. CONCLUSION: CYR facilitates embryo implantation by alleviating ovarian hyperstimulation, promoting endometrial decidualization and angiogenesis, regulating macrophage polarization, and reversing the hypercoagulable state of the blood.
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Implantação do Embrião , Trombofilia , Gravidez , Feminino , Camundongos , Animais , Útero , Endométrio , Trombofilia/tratamento farmacológico , Trombofilia/metabolismo , Trombofilia/patologia , MacrófagosRESUMO
The porcine-derived non-cross-linked collagen membrane Bio-gide® (BG) and the bovine-derived non-cross-linked collagen membrane Heal-all® (HA) were compared to better understand their in vitro biophysical characteristics and in vivo degradation patterns as a reference for clinical applications. It was showed that the porosity, specific surface area, pore volume and pore diameter of BG were larger than those of HA (64.5 ± 5.2% vs. 48.6 ± 6.1%; 18.6 ± 2.8 m2 /g vs. 2.3 ± 0.6 m2 /g; 0.114 ± 0.002 cm3 /g vs. 0.003 ± 0.001 cm3 /g; 24.4 ± 3.5 nm vs. 7.3 ± 1.7 nm, respectively); the average swelling ratio of BG was higher than that of HA (412.6 ± 41.2% vs. 270.0 ± 2.7%); the tensile strength of both dry and wet HA was higher than those of BG (18.26 ± 3.27 MPa vs. 4.02 ± 1.35 MPa; 2.24 ± 0.21 MPa vs. 0.16 ± 0.02 MPa, respectively); 73% of HA remained after 72 h in collagenase solution, whereas only 8.2% of BG remained. A subcutaneous rat implantation model revealed that, at 3, 7, 14, 28, and 56 days postmembrane implantation, there were more total inflammatory cells, especially more M1 and M2 polarized macrophages and higher M2/M1 ratio in BG than in HA; in addition, the fibrous capsule around BG was also thicker than that around HA. Moreover, concentrations of dozens of cytokines including interleukin-2(IL-2), IL-7, IL-10 and so forth. in BG were higher than those in HA. It is suggested that BG and HA might be suitable for different clinical applications according to their different characteristics.
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Colágeno , Citocinas , Ratos , Animais , Bovinos , Suínos , Citocinas/metabolismo , Cicatrização , Membranas ArtificiaisRESUMO
Chinese medicine entered a significant period from foundation to maturity between Han and Tang dynasties when the Chinese traditional stomatology was a key stage. Sorting and analysis of existing literature and research outcomes have showed that current research on stomatology between Han and Tang dynasties focuses on oral physiology, pathology, diagnosis and treatment, and health care. It also involves stomatology history and explanation of termino-logies related to mouth and teeth recorded in medical books, use of simple methods, and thinking with citation and analysis of literature simply listed and reasoning preliminarily deducted. From the macro perspective, current research has not unveiled the whole picture of stomatology between the two dynasties and left a series of key issues unresolved. Thus, new methods should be developed and employed to carry out medical research on stomatology between Han and Tang dynasties given that is has a prosperous future.
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Boca , Medicina Bucal , Cognição , China , Medicina Tradicional ChinesaRESUMO
Endocrine resistance is a major challenge for breast cancer therapy. To identify the genes pivotal for endocrine-resistance progression, we screened five datasets and found 7 commonly dysregulated genes in endocrine-resistant breast cancer cells. Here we show that downregulation of serine protease inhibitor clade A member 3 (SERPINA3) which is a direct target gene of estrogen receptor α contributes to aromatase inhibitor resistance. Ankyrin repeat domain containing 11 (ANKRD11) works as a downstream effector of SERPINA3 in mediating endocrine-resistance. It induces aromatase inhibitor insensitivity by interacting with histone deacetylase 3 (HDAC3) and upregulating its activity. Our study suggests that aromatase inhibitor therapy downregulates SERPINA3 and leads to the ensuing upregulation of ANKRD11, which in turn promotes aromatase inhibitor resistance via binding to and activating HDAC3. HDAC3 inhibition may reverse the aromatase inhibitor resistance in ER-positive breast cancer with decreased SERPINA3 and increased ANKRD11 expression.
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Neoplasias da Mama , Serpinas , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Inibidores da Aromatase/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Histona Desacetilases/genética , Proteínas Repressoras , Serpinas/genéticaRESUMO
For nearly 20 years, dental stem cells (DSCs) have been successfully isolated from mature/immature teeth and surrounding tissue, including dental pulp of permanent teeth and exfoliated deciduous teeth, periodontal ligaments, dental follicles, and gingival and apical papilla. They have several properties (such as self-renewal, multidirectional differentiation, and immunomodulation) and exhibit enormous potential for clinical applications. To date, many clinical articles and clinical trials using DSCs have reported the treatment of pulpitis, periapical lesions, periodontitis, cleft lip and palate, acute ischemic stroke, and so on, and DSC-based therapies obtained satisfactory effects in most clinical trials. In these studies, no adverse events were reported, which suggested the safety of DSC-based therapy. In this review, we outline the characteristics of DSCs and summarize clinical trials and their safety as DSC-based therapies. Meanwhile, we also present the current limitations and perspectives of DSC-based therapy (such as harvesting DSCs from inflamed tissue, applying DSC-conditioned medium/DSC-derived extracellular vesicles, and expanding-free strategies) to provide a theoretical basis for their clinical applications.
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The FKBP (FK506-binding protein) gene family is an important member of the PPlase protease family and plays a vital role during the processes of plant growth and development. However, no studies of the FKBP gene family have been reported in cucumber. In this study, 19 FKBP genes were identified in cucumber, which were located on chromosomes 1, 3, 4, 6, and 7. Phylogenetic analysis divided the cucumber FKBP genes into three subgroups. The FKBP genes in the same subgroup exhibited similar structures and conserved motifs. The cis-acting elements analysis revealed that the promoters of cucumber FKBP genes contained hormone-, stress-, and development-related cis-acting elements. Synteny analysis of the FKBP genes among cucumber, Arabidopsis, and rice showed that 12 kinds of syntenic relationships were detected between cucumber and Arabidopsis FKBP genes, and 3 kinds of syntenic relationships were observed between cucumber and rice FKBP genes. The tissue-specific expression analysis showed that some FKBP genes were expressed in all tissues, while others were only highly expressed in part of the 10 types of tissues. The expression profile analysis of cucumber FKBP genes under 13 types of stresses showed that the CsaV3_1G007080 gene was differentially expressed under abiotic stresses (high temperature, NaCl, silicon, and photoperiod) and biotic stresses (downy mildew, green mottle mosaic virus, Fusarium wilt, phytophthora capsica, angular leaf spot, and root-knot nematode), which indicated that the CsaV3_1G007080 gene plays an important role in the growth and development of cucumber. The interaction protein analysis showed that most of the proteins in the FKBP gene family interacted with each other. The results of this study will lay the foundation for further research on the molecular biological functions of the cucumber FKBP gene family.
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Arabidopsis , Cucumis sativus , Cucumis sativus/genética , Cucumis sativus/metabolismo , Genoma de Planta/genética , Proteínas de Ligação a Tacrolimo/genética , Filogenia , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Plantas/metabolismo , Estresse Fisiológico/genéticaRESUMO
CDK4/6 inhibitors are the standard treatment in advanced HR+/HER2- breast cancer patients. Nevertheless, the resistance to CDK4/6 inhibitors is inevitable and the strategies to overcome resistance are of great interest. Here, we show that the palbociclib-resistant breast cancer cells expressed significantly higher levels of Cyclin D1 and CDK4 proteins because of upregulated protein synthesis. Silencing Cyclin D1 or CDK4 led to cell cycle arrest while silencing Cyclin E1 or CDK2 restored the sensitivity to palbociclib. Furthermore, PI3K/mTOR pathway was hyper-activated in palbociclib-resistant cells, leading to more phosphorylated 4E-BP1 and higher levels of Cyclin D1 and CDK4 translation. Targeting PI3K/mTOR pathway with a specific PI3Kα inhibitor (BYL719) or an mTOR inhibitor (everolimus) reduced the protein levels of Cyclin D1 and CDK4, and restored the sensitivity to palbociclib. The tumor samples expressed significantly higher levels of Cyclin D1, CDK4, p-AKT and p-4E-BP1 after progression on palbociclib treatment. In conclusion, our findings suggest that overexpressed Cyclin D1 and CDK4 proteins lead to the resistance to CDK4/6 inhibitor and PI3K/mTOR inhibitors are able to restore the sensitivity to CDK4/6 inhibitors, which provides the biomarker and rationale for the combinational use of CDK4/6 inhibitors and PI3K/mTOR inhibitors after CDK4/6 inhibitor resistance in breast cancer.
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Neoplasias da Mama , Ciclina D1 , Humanos , Feminino , Ciclina D1/genética , Ciclina D1/metabolismo , Ciclina D1/uso terapêutico , Inibidores de MTOR , Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Quinase 4 Dependente de Ciclina/uso terapêuticoRESUMO
A phytochemical investigation of the fruits of Citrullus colocynthis resulted in the isolation of 21 structurally diverse cucurbitane triterpenoids, including 9 previously undescribed ones, colocynins A-I (1-9). Their absolute configurations were elucidated by means of quantum chemical electronic circular dichroism (ECD) calculations, CD exciton chirality method, and single-crystal X-ray crystallography. Colocynins A-C (1-3) represent the first examples of nonanorcucurbitane-type triterpenoids. An anti-acetylcholinesterase activity assay showed that 6, 10, 13, 18, and 20 exhibited inhibitory activities, with IC50 values ranging from 5.0 to 21.7 µM. In addition, 18 and 21 showed significant cytotoxicity against PACA, A431, and HepG2 cells, with IC50 values ranging from 0.042 to 0.60 and 3.6-14.4 µM, respectively.