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1.
Int J Biol Macromol ; 209(Pt B): 2142-2150, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35500777

RESUMO

The development of multifunctional wound dressings has always been considered as a promising strategy to promote blood coagulation, inhibit bacterial infection, and accelerate wound healing. Herein, an antibacterial and hemostatic dressing (SA-PHMG) was developed based on sodium alginate (SA) nonwoven and polyhexamethylene guanidine hydrochloride (PHMG) through a completely green industrial route, including dipping, padding, and drying. According to studies, SA-PHMG dressings exhibited excellent liquid absorption capacity and water vapor permeability. Moreover, bactericidal assays have demonstrated that SA-PHMG dressings have ideal antibacterial activity against Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa and mixed bacteria, maintaining potent antibacterial activity even after 10 cycles of antibacterial trials or 50 times of washing or soaping. The in vitro evaluation of the hemostatic effect indicated that the SA-PHMG could significantly promote blood clotting by activating platelets, and in vitro and in vivo hemolysis, cytotoxicity and skin irritation studies demonstrated the ideal biocompatibility of the dressings. In addition, better wound closure and tissue regeneration were recorded using SA-PHMG nonwoven as the dressing based on an infected full-thickness wound model. In conclusion, this antibacterial, hemostatic, biocompatible, and environmentally friendly SA-PHMG nonwoven exhibit the potential for infected wound healing.

2.
Circ Res ; : 101161CIRCRESAHA122321050, 2022 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-35574856

RESUMO

BACKGROUND: Cellular redox control is maintained by generation of reactive oxygen/nitrogen species balanced by activation of antioxidative pathways. Disruption of redox balance leads to oxidative stress, a central causative event in numerous diseases including heart failure. Redox control in the heart exposed to hemodynamic stress, however, remains to be fully elucidated. METHODS: Pressure overload was triggered by transverse aortic constriction in mice. Transcriptomic and metabolomic regulations were evaluated by RNA-sequencing and metabolomics, respectively. Stable isotope tracer labeling experiments were conducted to determine metabolic flux in vitro. Neonatal rat ventricular myocytes and H9c2 cells were used to examine molecular mechanisms. RESULTS: We show that production of cardiomyocyte NADPH, a key factor in redox regulation, is decreased in pressure overload-induced heart failure. As a consequence, the level of reduced glutathione is downregulated, a change associated with fibrosis and cardiomyopathy. We report that the pentose phosphate pathway and mitochondrial serine/glycine/folate metabolic signaling, 2 NADPH-generating pathways in the cytosol and mitochondria, respectively, are induced by transverse aortic constriction. We identify ATF4 (activating transcription factor 4) as an upstream transcription factor controlling the expression of multiple enzymes in these 2 pathways. Consistently, joint pathway analysis of transcriptomic and metabolomic data reveals that ATF4 preferably controls oxidative stress and redox-related pathways. Overexpression of ATF4 in neonatal rat ventricular myocytes increases NADPH-producing enzymes whereas silencing of ATF4 decreases their expression. Further, stable isotope tracer experiments reveal that ATF4 overexpression augments metabolic flux within these 2 pathways. In vivo, cardiomyocyte specific deletion of ATF4 exacerbates cardiomyopathy in the setting of transverse aortic constriction and accelerates heart failure development, attributable, at least in part, to an inability to increase the expression of NADPH-generating enzymes. CONCLUSIONS: Our findings reveal that ATF4 plays a critical role in the heart under conditions of hemodynamic stress by governing both cytosolic and mitochondrial production of NADPH.

3.
Saudi J Anaesth ; 16(2): 161-165, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35431758

RESUMO

Background: Post-operative analgesia is crucial in enhanced recovery after surgery and to minimize post-operative complications. There remains data paucity on the efficacy of preperitoneal analgesia (PPA) compared to patient-controlled analgesia (PCA). This study aims to examine the efficacy of preperitoneal infusion as analgesia following elective colorectal surgery. Methods: This is a prospective cross-sectional study of all patients which underwent elective colorectal surgeries, performed in a tertiary surgical referral center with dedicated colorectal unit. Patients from May 2017 to April 2021 who underwent elective colorectal surgery were included in this study. Pain scores were reviewed and analyzed at regular intervals post-operatively for comparison. Results: Amongst the 200 patients included, there were 174 patients in the PPA arm and 26 patients using PCA. Patients in the PPA group were older age (63.29 vs 56.00, P = 0.003). A total of 118 patients in PPA cohort (67.8%) and 21 from PCA cohort (80.8%) underwent open surgery and the remaining 82 patients underwent laparoscopic surgeries. Although postoperative pain scores were consistently below 5 and reduced in trend from 2 hours to 96 hours postoperatively in both groups, the pain scores on coughing markedly reduced in the PPA group when compared PCA alone. The total dosage of opioid required in PPA cohort was also significantly lower when compared to PCA group at the first 24 hours postoperatively 12.21 (±13.0) vs 20.0 (±14.43), P = 0.048. Conclusions: PPA is a comparable modality for analgesia after elective colorectal surgery that reduces the opioid requirement postoperatively giving adequate pain relief. PPA should be considered as an alternative modality for multi-modal analgesia.

4.
Acta Pharmacol Sin ; 2022 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-35388129

RESUMO

Lung adenocarcinoma (LUAD) characterized by high metastasis and mortality is the leading subtype of non-small cell lung cancer. Evidence shows that some microRNAs (miRNAs) may act as oncogenes or tumor suppressor genes, leading to malignant tumor occurrence and progression. To better understand the molecular mechanism associated with miRNA methylation in LUAD progression and clinical outcomes, we investigated the correlation between miR-148a-3p methylation and the clinical features of LUAD. In the LUAD cell lines and tumor tissues from patients, miR-148a-3p was found to be significantly downregulated, while the methylation of miR-148a-3p promoter was notably increased. Importantly, miR-148a-3p hypermethylation was closely associated with lymph node metastasis. We demonstrated that mitogen-activated protein (MAP) kinase kinase kinase 9 (MAP3K9) was the target of miR-148a-3p and that MAP3K9 levels were significantly increased in both LUAD cell lines and clinical tumor tissues. In A549 and NCI-H1299 cells, overexpression of miR-148a-3p or silencing MAP3K9 significantly inhibited cell growth, migration, invasion and cytoskeleton reorganization accompanied by suppressing the epithelial-mesenchymal transition. In a nude mouse xenograft assay we found that tumor growth was effectively inhibited by miR-148a-3p overexpression. Taken together, the promoter methylation-associated decrease in miR-148a-3p could lead to lung cancer metastasis by targeting MAP3K9. This study suggests that miR-148a-3p and MAP3K9 may act as novel therapeutic targets for the treatment of LUAD and have potential clinical applications.

5.
Arch Virol ; 167(5): 1325-1331, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35394245

RESUMO

We present here the results of the analysis of the complete genome sequence of a potentially temperate phage, vB_Sb_QDWS, which was isolated from wastewater samples collected in Qingdao, China. The genome of phage vB_Sb_QDWS is composed of a double-stranded DNA that is 47,902 bp in length with a G + C content of 63.16%. It is predicted to contain 69 putative protein-encoding genes. Microscopic and genomic analysis showed that vB_Sb_QDWS is a novel phage of the class Siphoviridae.


Assuntos
Bacteriófagos , Shewanella , Siphoviridae , Bacteriófagos/genética , DNA Viral/genética , Genoma Viral , Filogenia , Análise de Sequência de DNA , Shewanella/genética , Siphoviridae/genética , Siphoviridae/ultraestrutura
6.
Bioengineered ; 13(4): 10504-10517, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35443865

RESUMO

Colorectal cancer (CRC) is one of the most common malignancies and causes of cancer-related mortality worldwide. Cell proliferation and tumor metastasis as well as chemoresistance are correlated with poor survival of CRC. The interferon regulatory factor 6 (IRF6) is functioned as a tumor suppressor gene in several cancers and is associated with risk of CRC. We explored the role of IRF6 in CRC in the present study. The protein expressions of IRF6 in human CRC tissues, normal para-carcinoma tissue and liver metastases from CRC were measured. Cell proliferation, chemotherapeutic sensitivity, cell apoptosis, migration and invasion including the related markers along with IRF6 expression were explored. Our results indicated that IRF6 expression in CRC and liver metastasis were lower than normal tissues, which were correlated positively with E-cadherin and negatively with Ki67 expression in CRC tissue. IRF6 promoted CRC cell sensitivity to cisplatin to suppress cell proliferation, migration and invasion as well as aggravate cell apoptosis. Our study suggested that IRF6 may enhance chemotherapeutic sensitivity of cisplatin mediated by affecting cell proliferation, migration and invasion along with apoptosis through regulating E-cadherin and Ki67, while the identified molecular mechanisms remain to be further explored.


Assuntos
Neoplasias Colorretais , Neoplasias Hepáticas , Apoptose/genética , Caderinas/genética , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Cisplatino/farmacologia , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , Antígeno Ki-67/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética
7.
Life Sci Alliance ; 5(8)2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35459739

RESUMO

Carboxylesterase 1d (Ces1d) is a crucial enzyme with a wide range of activities in multiple tissues. It has been reported to localize predominantly in ER. Here, we found that Ces1d levels are significantly increased in obese patients with type 2 diabetes. Intriguingly, a high level of Ces1d translocates onto lipid droplets where it digests the lipids to produce a unique set of fatty acids. We further revealed that adipose tissue-specific Ces1d knock-out (FKO) mice gained more body weight with increased fat mass during a high fat-diet challenge. The FKO mice exhibited impaired glucose and lipid metabolism and developed exacerbated liver steatosis. Mechanistically, deficiency of Ces1d induced abnormally large lipid droplet deposition in the adipocytes, causing ectopic accumulation of triglycerides in other peripheral tissues. Furthermore, loss of Ces1d diminished the circulating free fatty acids serving as signaling molecules to trigger the epigenetic regulations of energy metabolism via lipid-sensing transcriptional factors, such as HNF4α. The metabolic disorders induced an unhealthy microenvironment in the metabolically active tissues, ultimately leading to systemic insulin resistance.


Assuntos
Carboxilesterase , Diabetes Mellitus Tipo 2 , Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Animais , Carboxilesterase/genética , Carboxilesterase/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Dieta Hiperlipídica , Humanos , Camundongos
8.
Neoplasia ; 28: 100791, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35405500

RESUMO

With over 60,000 cases diagnosed annually in the US, ductal carcinoma in situ (DCIS) is the most prevalent form of early-stage breast cancer. Because many DCIS cases never progress to invasive ductal carcinomas (IDC), overtreatment remains a significant problem. Up to 20% patients experience disease recurrence, indicating that standard treatments do not effectively treat DCIS for a subset of patients. By understanding the mechanisms of DCIS progression, we can develop new treatment strategies better tailored to patients. The chemokine CCL2 and its receptor CCR2 are known to regulate macrophage recruitment during inflammation and cancer progression. Recent studies indicate that increased CCL2/CCR2 signaling in breast epithelial cells enhance formation of IDC. Here, we characterized the molecular mechanisms important for CCL2/CCR2-mediated DCIS progression. Phospho-protein array profiling revealed that CCL2 stimulated phosphorylation of MET receptor tyrosine kinases in breast cancer cells. Co-immunoprecipitation and proximity ligation assays demonstrated that CCL2-induced MET activity depended on interactions with CCR2 and SRC. Extracellular flux analysis and biochemical assays revealed that CCL2/CCR2 signaling in breast cancer cells enhanced glycolytic enzyme expression and activity. CRISPR knockout and pharmacologic inhibition of MET revealed that CCL2/CCR2-induced breast cancer cell proliferation, survival, migration and glycolysis through MET-dependent mechanisms. In animals, MET inhibitors blocked CCR2-mediated DCIS progression and metabolism. CCR2 and MET were significantly co-expressed in patient DCIS and IDC tissues. In summary, MET receptor activity is an important mechanism for CCL2/CCR2-mediated progression and metabolism of early-stage breast cancer, with important clinical implications.


Assuntos
Neoplasias da Mama , Carcinoma Ductal de Mama , Carcinoma Intraductal não Infiltrante , Quimiocina CCL2 , Proteínas Proto-Oncogênicas c-met , Receptores CCR2 , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Carcinoma Intraductal não Infiltrante/metabolismo , Carcinoma Intraductal não Infiltrante/patologia , Linhagem Celular Tumoral , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Progressão da Doença , Feminino , Humanos , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Receptores CCR2/metabolismo
9.
Front Pharmacol ; 13: 787032, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35281919

RESUMO

Introduction: Respiratory tract infections (RTIs) are a major cause of morbidity and mortality in some high-risk groups including children and older adults. There is evidence that Chinese herbal medicine has an effect on RTIs. Reynoutria japonica Houtt (better known under its synonym Fallopia japonica (Houtt.) Ronse Decr.) (F. japonica), a commonly used Chinese herbal medicine, has a high content of resveratrol and glycosides. In traditional Chinese medicine theory, F. japonica has the effect of clearing heat in the body, improving blood and qi circulation, eliminating phlegm, and relieving cough, so it may have an effect on RTIs. Methods: This systematic review was registered under PROSPERO CRD42020188604. Databases were searched for randomized controlled trials of F. japonica as a single herb, or as a component of a complex herbal formula for RTIs. Quality of methodology was assessed by two reviewers independently using the Cochrane Risk of Bias Tool. The primary outcome was symptom improvement rate. The secondary outcome measures were fever clearance time, Murray lung injury score and incidence of adverse effects. The extracted data were pooled and meta-analysed by RevMan 5.3 software. Results: Eight RCTs with 1,123 participants with acute RTIs were included in this systematic review, and all the RCTs used F. japonica as part of a herbal mixture. Only one included trial used F. japonica in a herbal mixture without antibiotics in the treatment group. The findings showed that herbal remedies that included F. japonica could increase the symptom improvement rate (risk ratio 1.14, 95% confidence intervals [1.09, 1.20], I2 = 0%, p < 0.00001, n = 7 trials, 1,013 participants), shorten fever duration, reduce Murray lung injury score and did not increase adverse events (RR 0.33, 95% CI [0.11, 1.00], I2 = 0%, p = 0.05, n = 5 trials, 676 participants). Conclusion: There is limited but some evidence that F. japonica as part of a herbal mixture may be an effective and safe intervention for acute RTIs in clinical practice. In future studies it would be preferable to evaluate the effectiveness and safety of using F. japonica without antibiotics for acute RTIs.

10.
Microb Cell Fact ; 21(1): 31, 2022 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-35248031

RESUMO

BACKGROUND: Converting carbon dioxide (CO2) into value-added chemicals using engineered cyanobacteria is a promising strategy to tackle the global warming and energy shortage issues. However, most cyanobacteria are autotrophic and use CO2 as a sole carbon source, which makes it hard to compete with heterotrophic hosts in either growth or productivity. One strategy to overcome this bottleneck is to introduce sugar utilization pathways to enable photomixotrophic growth with CO2 and sugar (e.g., glucose and xylose). Advances in engineering mixotrophic cyanobacteria have been obtained, while a systematic interrogation of these engineered strains is missing. This work aimed to fill the gap at omics level. RESULTS: We first constructed two engineered Synechococcus elongatus YQ2-gal and YQ3-xyl capable of utilizing glucose and xylose, respectively. To investigate the metabolic mechanism, transcriptomic and metabolomic analysis were then performed in the engineered photomixotrophic strains YQ2-gal and YQ3-xyl. Transcriptome and metabolome of wild-type S. elongatus were set as baselines. Increased abundance of metabolites in glycolysis or pentose phosphate pathway indicated that efficient sugar utilization significantly enhanced carbon flux in S. elongatus as expected. However, carbon flux was redirected in strain YQ2-gal as more flowed into fatty acids biosynthesis but less into amino acids. In strain YQ3-xyl, more carbon flux was directed into synthesis of sucrose, glucosamine and acetaldehyde, while less into fatty acids and amino acids. Moreover, photosynthesis and bicarbonate transport could be affected by upregulated genes, while nitrogen transport and assimilation were regulated by less transcript abundance of related genes in strain YQ3-xyl with utilization of xylose. CONCLUSIONS: Our work identified metabolic mechanism in engineered S. elongatus during photomixotrophic growth, where regulations of fatty acids metabolism, photosynthesis, bicarbonate transport, nitrogen assimilation and transport are dependent on different sugar utilization. Since photomixotrophic cyanobacteria is regarded as a promising cell factory for bioproduction, this comprehensive understanding of metabolic mechanism of engineered S. elongatus during photomixotrophic growth would shed light on the engineering of more efficient and controllable bioproduction systems based on this potential chassis.


Assuntos
Synechococcus , Transcriptoma , Engenharia Metabólica , Metabolômica , Fotossíntese , Synechococcus/genética , Synechococcus/metabolismo
11.
Acta Crystallogr C Struct Chem ; 78(Pt 2): 123-130, 2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-35119391

RESUMO

A novel zero-dimensional dinuclear zinc complex, di-µ-acetato-1:2κ4O:O'-(µ-2-acetyl-6-{[(Z)-2-bromo-3-oxoprop-1-en-1-yl]azanidyl}phenolato-1κ2O1,O2:2κ3O1,N,O6)(N,N-dimethylacetamide-1κO)dizinc(II), [Zn2(C11H8BrNO3)(CH3COO)2(C4H9NO)] or [Zn2(L)(CH3COO)2(DMA)], 1, was synthesized using (Z)-3-[(3-acetyl-2-hydroxyphenyl)amino]-2-bromoprop-2-enal (H2L), which was synthesized from 1-(3-amino-2-hydroxyphenyl)ethanone and 2-bromomalonaldehyde. H2L and 1 were characterized by single-crystal X-ray diffraction, FT-IR spectroscopy and elemental analysis. Theoretical calculations of the bond orders and excited state of H2L confirmed that there is extensive electron delocalization in the H2L molecules. Single-crystal X-ray diffraction shows that the two Zn atoms are pentacoordinated in distorted trigonal bipyramidal configurations in the crystals of 1. The thermogravimetric analysis of 1 shows that the main frame of the complex remains stable to about 190 °C. Powder X-ray diffraction (PXRD) analysis shows that 1 possesses high purity and acid and alkali resistance. The intermolecular interactions of H2L and 1 were analyzed using Hirshfeld surface analysis and the results indicate that the H...H and O...H interactions of H2L and 1 play a considerable role in stabilizing the self-assembly process.

12.
Front Genet ; 13: 822261, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35222541

RESUMO

Recent studies have identified a role for ALKBH7 in the occurrence and progression of cancer, and this protein is related to cellular immunity and immune cell infiltration. However, the prognostic and immunotherapeutic value of ALKBH7 in different cancers have not been explored. In this study, we observed high ALKBH7 expression in 17 cancers and low expression in 5 cancers compared to paired normal tissues. Although ALKBH7 expression did not correlate relatively significantly with the clinical parameters of age (6/33), sex (3/33) and stage (3/27) in the cancers studied, the results of the survival analysis reflect the pan-cancer prognostic value of ALKBH7. In addition, ALKBH7 expression was significantly correlated with the TMB (7/33), MSI (13/33), mDNAsi (12/33) and mRNAsi (13/33) in human cancers. Moreover, ALKBH7 expression was associated and predominantly negatively correlated with the expression of immune checkpoint (ICP) genes in many cancers. Furthermore, ALKBH7 correlated with infiltrating immune cells and ESTIMATE scores, especially in PAAD, PRAD and THCA. Finally, the ALKBH7 gene coexpression network is involved in the regulation of cellular immune, oxidative, phosphorylation, and metabolic pathways. In conclusion, ALKBH7 may serve as a potential prognostic pan-cancer biomarker and is involved in the immune response. Our pan-cancer analysis provides insight into the role of ALKBH7 in different cancers.

13.
Cancer Metab ; 10(1): 6, 2022 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-35193687

RESUMO

BACKGROUND: Primary and posttreatment resistance to BRAFV600 mutation-targeting inhibitors leads to disease relapse in a majority of melanoma patients. In many instances, this resistance is promoted by upregulation of mitochondrial oxidative phosphorylation (OxPhos) in melanoma cells. We recently showed that a novel electron transport chain (ETC) complex I inhibitor, IACS-010759 (IACS), abolished OxPhos and significantly inhibited tumor growth of high-OxPhos, BRAF inhibitor (BRAFi)-resistant human melanomas. However, the inhibition was not uniform across different high OxPhos melanomas, and combination with BRAFi did not improve efficacy. METHODS: We performed a high-throughput unbiased combinatorial drug screen of clinically relevant small molecules to identify the most potent combination agent with IACS for inhibiting the growth of high-OxPhos, BRAFi-resistant melanomas. We performed bioenergetics and carbon-13 metabolite tracing to delineate the metabolic basis of sensitization of melanomas to the combination treatment. We performed xenograft tumor growth studies and Reverse-Phase Protein Array (RPPA)-based functional proteomics analysis of tumors from mice fed with regular or high-fat diet to evaluate in vivo molecular basis of sensitization to the combination treatment. RESULTS: A combinatorial drug screen and subsequent validation studies identified Atorvastatin (STN), a hydroxymethylglutaryl-coenzyme A reductase inhibitor (HMGCRi), as the most potent treatment combination with IACS to inhibit in vitro cell growth and induce tumor regression or stasis of some BRAFi-resistant melanomas. Bioenergetics analysis revealed a dependence on fatty acid metabolism in melanomas that responded to the combination treatment. RPPA analysis and carbon-13 tracing analysis in these melanoma cells showed that IACS treatment decreased metabolic fuel utilization for fatty acid metabolism, but increased substrate availability for activation of the mevalonate pathway by HMGCR, creating a dependence on this pathway. Functional proteomic analysis showed that IACS treatment inhibited MAPK but activated AKT pathway. Combination treatment with STN counteracted AKT activation. CONCLUSIONS: STN and other clinically approved HMGCRi could be promising combinatorial agents for improving the efficacy of ETC inhibitors like IACS in BRAFi-resistant melanomas.

14.
Biomed Chromatogr ; 36(6): e5356, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35178731

RESUMO

Untreated invasive fungal infection is one of the important risk factors affecting the prognosis of pediatric patients with hematologic tumors. Voriconazole (VOR) is the first-line antifungal drug for the treatment of Aspergillus infections. In order to reduce the risk of adverse drug reactions while producing an ideal antifungal effect, therapeutic drug monitoring was performed to maintain the VOR plasma concentration in a range of 1,000-5,500 ng/ml. In the present study, a reliable, accurate, sensitive and quick ultra-high performance liquid chromatograph-tandem mass spectrometry (UPLC-MS/MS) method was developed for the determination of the VOR level. Protein precipitation was performed using acetonitrile, and then the chromatographic separation was carried out by UPLC using a C18 column with the gradient mobile phases comprising 0.1% methanoic acid in acetonitrile (A) and 0.1% methanoic acid in water (B). In the selective reaction monitor mode, the mass spectrometric detection was carried out using an TSQ Endura triple quadruple mass spectrometer. The performance of this UPLC-MS/MS method was validated as per the National Medical Products Administration for Bioanalytical Method Validation. Additionally, the plasma concentrations of VOR in pediatric patients with hematologic tumors were detected using this method, and the analyzed results were used for personalized therapy.

15.
ACS Appl Mater Interfaces ; 14(3): 3885-3899, 2022 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-35014784

RESUMO

Due to the declined function of bone marrow mesenchymal stem cells (BMSCs), the repair of bone defects in the elderly is retarded. Elimination of senescent cells emerges as a promising strategy for treating age-related diseases. However, whether the local elimination of senescent BMSCs can promote bone regeneration in the elderly remains elusive. To tackle the above issue, we first screened out the specific senolytics for BMSCs and confirmed their effect of eliminating senescent BMSCs in vitro. Treatment with quercetin, which is determined the best senolytics for senescent BMSCs, efficiently removed senescent cells in the population. Moreover, the self-renewal capacity was restored as well as osteogenic ability of BMSCs after treatment. We then designed a microenvironment-responsive hydrogel based on the MMPs secreted by senescent cells. This quercetin-encapsulated hydrogel exhibited a stable microstructure and responsively released quercetin in the presence of senescence in vitro. In vivo, the quercetin-loaded hydrogel effectively cleared the local senescent cells and reduced the secretion of MMPs in the bone. Due to the removal of local senescent cells, the hydrogel significantly accelerated the repair of bone defects in the femur and skull of old rats. Taken together, our study revealed the role of removing senescent cells in bone regeneration and provided a novel therapeutic approach for bone defects in aged individuals.


Assuntos
Materiais Biocompatíveis/química , Células-Tronco Mesenquimais/química , Tecidos Suporte/química , Animais , Regeneração Óssea , Células Cultivadas , Senescência Celular , Teste de Materiais , Ratos , Engenharia Tecidual
16.
Cladistics ; 38(1): 59-82, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35049080

RESUMO

A new troodontid (LH PV39) recovered from the Upper Cretaceous Wulansuhai Formation, Inner Mongolia, China, is described, highlighting the dorsoventrally compressed sacral centra. The completely fused neurocentral junctions indicate that LH PV39 had reached adulthood at the time of death, but its size is nevertheless 20% smaller than that of the sympatric Philovenator, demonstrating that it is the second small-bodied troodontid recovered from the Wulansuhai Formation. Phylogenetic analyses scoring LH PV39 using different strategies and performed with different algorithms unambiguously recovered it as a troodontid. While the parsimony-based analysis scoring LH PV39 as an independent OTU with all of its available characteristics included recovered it as a basal troodontid, the Bayesian analysis suggests a closer relationship of LH PV39 to Almas and an unnamed troodontid from Ukhaa Tolgod, Mongolia (MPC-D100/1126+D100/3500). Body size analysis confirmed a single trend of gigantism throughout the evolution of troodontids, and suggests that the Late Cretaceous troodontids evolved in two directions: (i) several size-independent characteristics evolved while retaining the small sizes that are typical of the Early Cretaceous relatives, resulting in the Late Cretaceous small-bodied troodontids; and (ii) size-dependent characteristics (e.g., the elongation of the rostrum) evolved accompanying the size increase, resulting in large-bodied derived troodontids. The mosaic features of the Late Cretaceous small-bodied troodontids place them intermediate between their Early Cretaceous basal relatives and the Late Cretaceous large-bodied taxa in a well-resolved phylogeny, which is crucial for understanding the size and morphological evolution of troodontids.


Assuntos
Dinossauros , Animais , Teorema de Bayes , Tamanho Corporal , China , Dinossauros/anatomia & histologia , Filogenia
17.
G3 (Bethesda) ; 12(2)2022 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-35100332

RESUMO

Ananas comosus var. bracteatus f. tricolor (GL1) is a red pineapple accession whose mostly green leaves with chimeric white leaf margins turn red in spring and autumn and during flowering. It is an important ornamental plant and ideal plant research model for anthocyanin metabolism, chimeric leaf development, and photosynthesis. Here, we generated a highly contiguous chromosome-scale genome assembly for GL1 and compared it with other 3 published pineapple assemblies (var. comosus accessions MD2 and F153, and var. bracteatus accession CB5). The GL1 assembly has a total size of ∼461 Mb, with a contig N50 of ∼2.97 Mb and Benchmarking Universal Single-Copy Ortholog score of 97.3%. More than 99% of the contigs are anchored to 25 pseudochromosomes. Compared with the other 3 published pineapple assemblies, the GL1 assembly was confirmed to be more continuous. Our evolutionary analysis showed that the Bromeliaceae and Poaceae diverged from their nearest common ancestor ∼82.36 million years ago (MYA). Population structure analysis showed that while GL1 has not undergone admixture, bracteatus accession CB5 has resulted from admixture of 3 species of Ananas. Through classification of orthogroups, analysis of genes under positive selection, and analysis of presence/absence variants, we identified a series of genes related to anthocyanin metabolism and development of chimeric leaves. The structure and evolution of these genes were compared among the published pineapple assemblies with reveal candidate genes for these traits. The GL1 genome assembly and its comparisons with other 3 pineapple genome assemblies provide a valuable resource for the genetic improvement of pineapple and serve as a model for understanding the genomic basis of important traits in different pineapple varieties and other pan-cereal crops.


Assuntos
Ananas , Genoma de Planta , Pigmentação , Folhas de Planta , Ananas/genética , Quimera/genética , Genômica/métodos , Fotossíntese
18.
Eur J Med Chem ; 231: 114141, 2022 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-35092899

RESUMO

An efficient one-pot reaction for the synthesis of oxoaporphine alkaloids has been developed. Twenty-three compounds of oxoaporphine alkaloids were prepared and assessed for their antitumor activities. Most compounds inhibited the growth of T-24 tumor cells in vitro. Particularly, 4B displayed the most potent activity with an IC50 value of 0.5 µM, which was 19-fold more potent than the parent compound 4. The substitution at C3-position of oxoaporphine core by -NO2 significantly enhanced the anticancer activity. Mechanism studies indicated that 4 and 4B induced cell cycle arrest at G2/M phase; in contrast, 4V induced cell cycle arrest at the S phase. Increase of mitochondrial ROS/Ca2+ and decrease of MMP, accompanied by activation of caspase-3/9, were observed in T-24 cells after exposure to compounds 4, 4B and 4V, suggesting that the mitochondrial pathway was involved in the induced apoptosis. Moreover, compound 4B effectively inhibited tumor growth in a mouse xenograft model bearing T-24.


Assuntos
Antineoplásicos , Animais , Apoptose , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Mitocôndrias , Fase S
19.
mBio ; : e0317421, 2022 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-35038901

RESUMO

Quorum sensing (QS) is used to coordinate social behaviors, such as virulence and biofilm formation, across bacterial populations. However, the role of QS in regulating phage-bacterium interactions remains unclear. Preventing phage recognition and adsorption are the first steps of bacterial defense against phages; however, both phage recognition and adsorption are a prerequisite for the successful application of phage therapy. In the present study, we report that QS upregulated the expression of phage receptors, thus increasing phage adsorption and infection rates in Pseudomonas aeruginosa. In P. aeruginosa PAO1, we found that las QS, instead of rhl QS, upregulated the expression of galU for lipopolysaccharide synthesis. Lipopolysaccharides act as the receptor of the phage vB_Pae_QDWS. This las QS-mediated phage susceptibility is a dynamic process, depending on host cell density. Our data suggest that inhibiting QS may reduce the therapeutic efficacy of phages. IMPORTANCE Phage resistance is a major limitation of phage therapy, and understanding the mechanisms by which bacteria block phage infection is critical for the successful application of phage therapy. In the present study, we found that Pseudomonas aeruginosa PAO1 uses las QS to promote phage infection by upregulating the expression of galU, which is necessary for the synthesis of phage receptor lipopolysaccharides. In contrast to the results of previous reports, we showed that QS increases the efficacy of phage-mediated bacterial killing. Since QS upregulates the expression of virulence factors and promotes biofilm development, which are positively correlated with lipopolysaccharide production in P. aeruginosa, increased phage susceptibility is a novel QS-mediated trade-off. QS inhibition may increase the efficacy of antibiotic treatment, but it will reduce the effectiveness of phage therapy.

20.
Haematologica ; 107(1): 58-76, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33353284

RESUMO

MCL-1 and BCL-2 are both frequently overexpressed in acute myeloid leukemia and critical for the survival of acute myeloid leukemia cells and acute myeloid leukemia stem cells. MCL-1 is a key factor in venetoclax resistance. Using genetic and pharmacological approaches, we discovered that MCL-1 regulates leukemia cell bioenergetics and carbohydrate metabolisms, including the TCA cycle, glycolysis and pentose phosphate pathway and modulates cell adhesion proteins and leukemia-stromal interactions. Inhibition of MCL-1 sensitizes to BCL-2 inhibition in acute myeloid leukemia cells and acute myeloid leukemia stem/progenitor cells, including those with intrinsic and acquired resistance to venetoclax through cooperative release of pro-apoptotic BIM, BAX, and BAK from binding to anti-apoptotic BCL-2 proteins and inhibition of cell metabolism and key stromal microenvironmental mechanisms. The combined inhibition of MCL-1 by MCL-1 inhibitor AZD5991 or CDK9 inhibitor AZD4573 and BCL-2 by venetoclax greatly extended survival of mice bearing patient-derived xenografts established from an acute myeloid leukemia patient who acquired resistance to venetoclax/decitabine. These results demonstrate that co-targeting MCL-1 and BCL-2 improves the efficacy of and overcomes preexisting and acquired resistance to BCL-2 inhibition. Activation of metabolomic pathways and leukemia-stroma interactions are newly discovered functions of MCL-1 in acute myeloid leukemia, which are independent from canonical regulation of apoptosis by MCL-1. Our data provide new mechanisms of synergy and rationale for co-targeting MCL-1 and BCL-2 clinically in patients with acute myeloid leukemia and potentially other cancers.


Assuntos
Leucemia Mieloide Aguda , Proteína de Sequência 1 de Leucemia de Células Mieloides , Proteínas Proto-Oncogênicas c-bcl-2 , Animais , Apoptose , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Linhagem Celular Tumoral , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Camundongos , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Sulfonamidas/farmacologia
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