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1.
Sci Rep ; 12(1): 10772, 2022 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-35750870

RESUMO

Breast cancer is the most common malignancy in women and is a heterogeneous disease at molecular level. Early detection and specificity are the key prerequisite for the treatment of this deadly cancer. To address these issues attention on the breast cancer specific receptor protein(s) is the most realistic option. Herein estrogen (E) and progesterone (Pg) receptors(R) were considered to design fluorescent molecular probes with possible therapeutic option. We adopted QSAR technique to design a library of benzothiazole-purine hybrid molecules. Molecular docking offers us three screened molecules as most potential. Among these molecules one abbreviated as "CPIB" showed blue fluorescence and detected ER positive cancer cells at 1 nM concentration. At elevated concentration, CPIB induces apoptotic deaths of same cancer cells through targeting intracellular microtubules without affecting normal cells or ER negative cells. CPIB is one of its kind with two-in-one potential of "Detection and Destroy" ability targeting ER positive breast cancer cells.


Assuntos
Neoplasias da Mama , Receptores de Estrogênio , Benzotiazóis/farmacologia , Benzotiazóis/uso terapêutico , Neoplasias da Mama/patologia , Feminino , Corantes Fluorescentes/uso terapêutico , Humanos , Microtúbulos/patologia , Simulação de Acoplamento Molecular , Sondas Moleculares , Purinas/uso terapêutico , Receptores de Estrogênio/genética , Receptores de Progesterona/genética
2.
J Phys Chem B ; 126(24): 4483-4490, 2022 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-35679327

RESUMO

There is significant interest in developing suitable nucleoside analogs exhibiting high fluorescence and triplet yields to investigate the structure, dynamics, and binding properties of nucleic acids and promote selective photosensitized damage to DNA/RNA, respectively. In this study, steady-state, laser flash photolysis, time-resolved IR luminescence, and femtosecond broad-band transient absorption spectroscopies are combined with quantum chemical calculations to elucidate the excited-state dynamics of 2-oxopurine riboside in aqueous solution and to investigate its prospective use as a fluorescent or photosensitizer analog. The Franck-Condon population in the S1 (ππ*) state decays through a combination of solvent and conformational relaxation to its minimum in 1.9 ps. The population trapped in the 1ππ* minimum bifurcates to either fluoresce or intersystem cross to the triplet manifold within ca. 5 ns, while another fraction of the population decays nonradiatively to the ground state. It is demonstrated that 2-oxopurine riboside exhibits both high fluorescent (48%) and significant triplet (between 10% and 52%) yields, leading to a yield of singlet oxygen generation of 10%, making this nucleoside analog a dual fluorescent and photosensitizer analog for DNA and RNA research.


Assuntos
Fármacos Fotossensibilizantes , RNA , DNA , Fármacos Fotossensibilizantes/química , Estudos Prospectivos , Purinas
5.
Int J Mol Sci ; 23(11)2022 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-35682688

RESUMO

Intestinal microbiota dysbiosis is related to many metabolic diseases in human health. Meanwhile, as an irregular environmental light-dark (LD) cycle, short day (SD) may induce host circadian rhythm disturbances and worsen the risks of gut dysbiosis. Herein, we investigated how LD cycles regulate intestinal metabolism upon the destruction of gut microbes with antibiotic treatments. The growth indices, serum parameters, concentrations of short-chain fatty acids (SCFAs), and relative abundance of intestinal microbes were measured after euthanasia; intestinal contents, epithelial metabolomics, and hepatic transcriptome sequencing were also assessed. Compared with a normal LD cycle (NLD), SD increased the body weight, spleen weight, and serum concentration of aspartate aminotransferase, while it decreased high-density lipoprotein. Meanwhile, SD increased the relative abundance of the Bacteroidetes phylum while it decreased the Firmicutes phylum in the gut of ABX mice, thus leading to a disorder of SCFA metabolism. Metabolomics data revealed that SD exposure altered gut microbial metabolism in ABX mice, which also displayed more serious alterations in the gut epithelium. In addition, most differentially expressed metabolites were decreased, especially the purine metabolism pathway in epithelial tissue. This response was mainly due to the down-regulation of adenine, inosine, deoxyguanosine, adenylsuccinic acid, hypoxanthine, GDP, IMP, GMP, and AMP. Finally, the transcriptome data also indicated that SD has some negative effects on hepatic metabolism and endocrine, digestive, and disease processes. Overall, SD induced an epithelial and hepatic purine metabolism pathway imbalance in ABX mice, as well as the gut microbes and their metabolites, all of which could contribute to host metabolism and digestion, endocrine system disorders, and may even cause diseases in the host.


Assuntos
Microbioma Gastrointestinal , Animais , Antibacterianos/farmacologia , Disbiose/metabolismo , Fígado/metabolismo , Camundongos , Purinas/farmacologia
6.
Cell Rep ; 39(11): 110945, 2022 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-35688145

RESUMO

SARS-CoV-2-infected subjects are generally asymptomatic during initial viral replication but may suffer severe immunopathology after the virus has receded and monocytes have infiltrated the airways. In bronchoalveolar lavage fluid from severe COVID-19 patients, monocytes express mRNA encoding inflammatory mediators and contain SARS-CoV-2 transcripts. We leverage a human small airway model of infection and inflammation, whereby primary blood monocytes transmigrate across SARS-CoV-2-infected lung epithelium to characterize viral burden, gene expression, and inflammatory mediator secretion by epithelial cells and monocytes. In this model, lung-infiltrating monocytes acquire SARS-CoV-2 from the epithelium and upregulate expression and secretion of inflammatory mediators, mirroring in vivo data. Combined use of baricitinib (Janus kinase inhibitor) and remdesivir (nucleoside analog) enhances antiviral signaling and viral clearance by SARS-CoV-2-positive monocytes while decreasing secretion of proneutrophilic mediators associated with acute respiratory distress syndrome. These findings highlight the role of lung-infiltrating monocytes in COVID-19 pathogenesis and their importance as a therapeutic target.


Assuntos
COVID-19 , Azetidinas , COVID-19/tratamento farmacológico , Humanos , Mediadores da Inflamação , Pulmão/patologia , Monócitos , Purinas , Pirazóis , SARS-CoV-2 , Sulfonamidas
7.
J Chem Theory Comput ; 18(6): 3637-3653, 2022 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-35652685

RESUMO

RNA modulation via small molecules is a novel approach in pharmacotherapies, where the determination of the structural properties of RNA motifs is considered a promising way to develop drugs capable of targeting RNA structures to control diseases. However, due to the complexity and dynamic nature of RNA molecules, the determination of RNA structures using experimental approaches is not always feasible, and computational models employing force fields can provide important insight. The quality of the force field will determine how well the predictions are compared to experimental observables. Stacking in nucleic acids is one such structural property, originating mainly from London dispersion forces, which are quantum mechanical and are included in molecular mechanics force fields through nonbonded interactions. Geometric descriptions are utilized to decide if two residues are stacked and hence to calculate the stacking free energies for RNA dinucleoside monophosphates (DNMPs) through statistical mechanics for comparison with experimental thermodynamics data. Here, we benchmark four different stacking definitions using molecular dynamics (MD) trajectories for 16 RNA DNMPs produced by two different force fields (RNA-IL and ff99OL3) and show that our stacking definition better correlates with the experimental thermodynamics data. While predictions within an accuracy of 0.2 kcal/mol at 300 K were observed in RNA CC, CU, UC, AG, GA, and GG, stacked states of purine-pyrimidine and pyrimidine-purine DNMPs, respectively, were typically underpredicted and overpredicted. Additionally, population distributions of RNA UU DNMPs were poorly predicted by both force fields, implying a requirement for further force field revisions. We further discuss the differences predicted by each RNA force field. Finally, we show that discrete path sampling (DPS) calculations can provide valuable information and complement the MD simulations. We propose the use of experimental thermodynamics data for RNA DNMPs as benchmarks for testing RNA force fields.


Assuntos
Simulação de Dinâmica Molecular , RNA , DNA/química , Fosfatos de Dinucleosídeos/química , Conformação de Ácido Nucleico , Purinas , Pirimidinas , RNA/química , Termodinâmica
8.
Ann Med ; 54(1): 1616-1626, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35675334

RESUMO

BACKGROUND: Myeloid-derived suppressor cell (MDSC) mobilisation is an important immune event in acute myocardial infarction (AMI). The A2B adenosine receptor (A2BAR) plays key role in regulating MDSC function, but its specific involvement in MDSC mobilisation in AMI remains unclear. METHODS: In AMI patients, the circulating MDSC ratio and A2BAR mRNA expression were measured. A mouse AMI model was established by left anterior descending coronary artery (LADCA) ligation. MDSCs were analysed by FACS and immunofluorescence staining (of heart tissue). A2BAR mRNA expression was assessed by qRT-PCR. Myocardial injury was detected by HE staining. Myocardial cell apoptosis was analysed by immunohistochemistry. Cardiac systolic function was evaluated by transthoracic echocardiography. RESULTS: In AMI patients, the circulating MDSC ratio was increased and positively correlated with A2BAR mRNA expression (r = 0.86, p < 0.01). In AMI model mice, the percentage of MDSCs was increased in the circulation and infarcted heart and decreased in the spleen. MRS-1754-mediated A2BAR inhibition decreased the MDSC ratio in the circulation and infarcted heart and prevented the decrease in MDSC number in the spleens of mice with AMI. A2BAR blockade inhibited myocardial cell apoptosis, alleviated myocardial inflammatory injury, and improved myocardial systolic function in the AMI mouse model. Similar results were found in mice after splenectomy. Additionally, spleen-derived MDSC injection increased the MDSC ratio in the infarcted heart, increased myocardial cell apoptosis, aggravated myocardial injury, and decreased cardiac systolic function in mice with AMI. CONCLUSION: Blocking A2BAR alleviates myocardial damage and improves myocardial systolic function through inhibition of spleen-derived MDSC mobilisation after AMI. Key MessagesSpleen-derived MDSC mobilisation aggravates myocardial inflammatory injury within 24 h of AMI.A2BAR promotes spleen-derived MDSC mobilisation within 24 h of AMI.Blocking A2BAR improves myocardial systolic function through inhibition of spleen-derived MDSC mobilisation.


Assuntos
Antagonistas do Receptor A2 de Adenosina , Células Supressoras Mieloides , Infarto do Miocárdio , Receptor A2B de Adenosina , Acetamidas/farmacologia , Antagonistas do Receptor A2 de Adenosina/farmacologia , Animais , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/terapia , Purinas/farmacologia , RNA Mensageiro , Receptor A2B de Adenosina/metabolismo , Baço
9.
Ann Intern Med ; 175(6): JC64, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35667076

RESUMO

SOURCE CITATION: Ely EW, Ramanan AV, Kartman CE, et al. Efficacy and safety of baricitinib plus standard of care for the treatment of critically ill hospitalised adults with COVID-19 on invasive mechanical ventilation or extracorporeal membrane oxygenation: an exploratory, randomised, placebo-controlled trial. Lancet Respir Med. 2022;10:327-36. 35123660.


Assuntos
COVID-19 , Oxigenação por Membrana Extracorpórea , Adulto , Azetidinas , COVID-19/tratamento farmacológico , Humanos , Purinas , Pirazóis , SARS-CoV-2 , Sulfonamidas
10.
Spectrochim Acta A Mol Biomol Spectrosc ; 279: 121466, 2022 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-35696970

RESUMO

A novel polyethyleneimine (PEI)-based polymeric nanosensor (named PEIMP) was developed for specific fluorescence enhanced sensing of Pt4+ ion in aqueous media. The sensor was fabricated via "one-pot" three-component reaction using ortho-phthalaldehyde (OPA), PEI and mercaptopurine as raw materials, by which the formation of isoindole fluorophore and its chemical grafting onto PEI chain were achieved simultaneously. The morphology, size and structure of PEIMP have been characterized by various techniques. In buffered aqueous solution (pH 7.0), PEIMP had the ability to specifically bind with Pt4+ producing notable increase in fluorescence emission at 463 nm (excited at 395 nm). Based on investigations on the sensing mechanism, the fluorescence turn-on response towards Pt4+ was attributed to the binding of Pt4+ with purine group in PEIMP resulting in the inhibition of photoinduced electron transfer from purine to isoindole fluorophore. Under the optimal conditions (pH 7.0, incubated at 37 ℃ for 20 min) the detection of Pt4+ could be achieved with the linear range of 0.1-10 µM and the detection limit of 80 nM. The sensor had the advantages of low-cost raw materials, simple and environmental-friendly synthesis and analytical detection procedures. What's more, it could selectively and sensitively detect Pt4+ without the effects from common transition metal ions (Pb2+, Fe3+, Cr3+, Al3+, Ag+, Co2+, Hg2+, Cd2+, Cu2+, Mg2+, Ni2+, Mn2+, Zn2+), especially precious metalions of Pt2+ and Pd2+. The proposed method had been successfully applied to quantify Pt4+ in wastewater and urine samples, and also proved to be potential for monitoring Pt4+ in biological systems.


Assuntos
Corantes Fluorescentes , Polietilenoimina , Corantes Fluorescentes/química , Íons , Isoindóis , Polietilenoimina/química , Purinas , Espectrometria de Fluorescência
12.
Trop Anim Health Prod ; 54(4): 212, 2022 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-35689115

RESUMO

The present study evaluated the effect of supplementation alpha-linolenic fatty acid source (ALA) with different rumen undegradable to degradable protein ratios [low ratio (LR) = 26:74; high ratio (HR) = 36:64 based on CP%] on growth performance, nutrient digestibility, fecal score, animal feeding behavior, and urinary purine derivatives (PD) in young lambs during hot season. Forty 10-day-old lambs (averaging body weight of 7.9 ± 0.8 kg) were used in a completely randomized block design with a 2 × 2 factorial arrangement as following treatments (10 lambs/treatment): (1) no n-3 FA supplementation with LR diet (NALA-LR), (2) no ALA supplementation with HR diet (NALA-HR), (3) supplementation of ALA with LR diet (ALA-LR), and (4) supplementation of ALA with HR diet (ALA-HR). Results showed that ALA supplementation slightly increased feed efficiency (FE; tendency, P = 0.076), improved fecal score (P = 0.045), and reduced rectal temperature (tendency, P = 0.064) during pre-weaning period. The HR diets improved average daily gain (ADG; P < 0.01), wither height (post-weaning; P = 0.015), and final BW (P = 0.048) compared with LR diets. The greatest ADG (pre-weaning; P = 0.012), structural growth, and the lowest urinary nitrogen exertion (P = 0.043) were found in the ALA-HR treatment. No change was found for ruminal fermentation, nutrient digestibility, and animal behavior in lambs fed different experimental treatments. In summary, results indicated that concurrent feeding of ALA and high dietary RUP:RDP ratio can be recommendable that is likely due to more efficient nitrogen utilization when young lambs are raised during hot season. HIGHLIGHTS: • The interaction of n-3 FA and nitrogen was evaluated in pre-weaning lambs raised under heat condition. • Supplementation of n-3 FA increased FE and improved fecal score in heat-exposed lambs during pre-weaning period. • The high RUP:RDP ratio improved skeletal growth during post-weaning period. • Concurrent feeding of n-3 FA and high dietary RUP:RDP ratio is recommendable in young lambs raised during hot season.


Assuntos
Ácidos Graxos Ômega-3 , Rúmen , Ração Animal/análise , Animais , Dieta/veterinária , Proteínas na Dieta/metabolismo , Suplementos Nutricionais/análise , Digestão , Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Ômega-3/farmacologia , Temperatura Alta , Nitrogênio/metabolismo , Purinas/metabolismo , Purinas/farmacologia , Rúmen/metabolismo , Ovinos , Vitaminas/metabolismo
13.
J Appl Physiol (1985) ; 133(1): 1-10, 2022 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-35608201

RESUMO

Excess activation of circulating xanthine oxidoreductase (XOR) may contribute to the pathogenesis of widespread remote organ injury, including kidney injury. The purpose of this study was to determine the acute impact of marathon running on plasma XOR activity and to examine whether plasma XOR activity is associated with marathon-induced elevations in biomarkers of acute kidney injury (AKI). Twenty-three young men (aged 20-25 yr) who participated in the 38th Tsukuba Marathon were included. Blood and urine samples were collected before, immediately, 2 h (only blood sample), and 24 h after a full marathon run. Plasma XOR activity was evaluated using a highly sensitive assay utilizing a combination of [13C2,15N2] xanthine and liquid chromatography-triple quadrupole mass spectrometry. The levels of several AKI biomarkers, such as serum creatinine and urinary liver-type fatty acid-binding protein (L-FABP) were measured in each participant. Marathon running caused a transient elevation in plasma XOR activity and levels of purine degradation products (hypoxanthine, xanthine, and uric acid) as well as serum creatinine, urinary albumin, and urinary L-FABP levels. Immediately after the marathon, individual relative changes in plasma XOR activity were independently correlated with corresponding changes in serum creatinine and urinary L-FABP levels. In addition, the magnitude of marathon-induced elevation in plasma XOR activity and levels of purine degradation products were higher in individuals who developed AKI. These findings collectively suggest that marathon running substantially influences the purine metabolism pathway including XOR activity. Moreover, activated circulating XOR can be partly associated with elevated biomarkers of AKI after marathon running.NEW & NOTEWORTHY This study is the first to show marathon running transiently increases plasma XOR activity and levels of purine degradation products (hypoxanthine, xanthine, and uric acid), and further to demonstrate that activated plasma XOR may contribute to marathon-induced elevations in biomarkers of AKI. These findings significantly extend our prior knowledge of the purine metabolic pathway and several AKI biomarkers under strenuous exercise conditions.


Assuntos
Injúria Renal Aguda , Xantina Desidrogenase , Biomarcadores , Creatinina , Humanos , Hipoxantinas , Masculino , Corrida de Maratona , Purinas , Ácido Úrico/metabolismo , Xantina Desidrogenase/metabolismo
14.
Am J Physiol Renal Physiol ; 323(1): F20-F32, 2022 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-35532069

RESUMO

Acute kidney injury (AKI) is a common cause of morbidity after congenital heart disease surgery. Progress on diagnosis and therapy remains limited, however, in part due to poor mechanistic understanding and a lack of relevant translational models. Metabolomic approaches could help identify novel mechanisms of injury and potential therapeutic targets. In the present study, we used a piglet model of cardiopulmonary bypass with deep hypothermic circulatory arrest (CPB/DHCA) and targeted metabolic profiling of kidney tissue, urine, and serum to evaluate metabolic changes specific to animals with histological acute kidney injury. CPB/DHCA animals with acute kidney injury were compared with those without acute kidney injury and mechanically ventilated controls. Acute kidney injury occurred in 10 of 20 CPB/DHCA animals 4 h after CPB/DHCA and 0 of 7 control animals. Injured kidneys showed a distinct tissue metabolic profile compared with uninjured kidneys (R2 = 0.93, Q2 = 0.53), with evidence of dysregulated tryptophan and purine metabolism. Nine urine metabolites differed significantly in animals with acute kidney injury with a pattern suggestive of increased aerobic glycolysis. Dysregulated metabolites in kidney tissue and urine did not overlap. CPB/DHCA strongly affected the serum metabolic profile, with only one metabolite that differed significantly with acute kidney injury (pyroglutamic acid, a marker of oxidative stress). In conclusion, based on these findings, kidney tryptophan and purine metabolism are candidates for further mechanistic and therapeutic investigation. Urine biomarkers of aerobic glycolysis could help diagnose early acute kidney injury after CPB/DHCA and warrant further evaluation. The serum metabolites measured at this early time point did not strongly differentiate based on acute kidney injury.NEW & NOTEWORTHY This project explored the metabolic underpinnings of postoperative acute kidney injury (AKI) following pediatric cardiac surgery in a translationally relevant large animal model of cardiopulmonary bypass with deep hypothermic circulatory arrest. Here, we present novel evidence for dysregulated tryptophan catabolism and purine catabolism in kidney tissue and increased urinary glycolysis intermediates in animals who developed histological AKI. These pathways represent potential diagnostic and therapeutic targets for postoperative AKI in this high-risk population.


Assuntos
Injúria Renal Aguda , Procedimentos Cirúrgicos Cardíacos , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/etiologia , Animais , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Ponte Cardiopulmonar/efeitos adversos , Parada Circulatória Induzida por Hipotermia Profunda/efeitos adversos , Humanos , Rim , Purinas , Suínos , Triptofano
15.
Arthritis Res Ther ; 24(1): 112, 2022 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-35578304

RESUMO

BACKGROUND: Patients with systemic lupus erythematosus (SLE) have substantial unmet medical need. Baricitinib is a Janus kinase (JAK)1 and 2 inhibitor that was shown to have therapeutic benefit in patients with SLE in a phase II clinical trial. The purpose of this study was to evaluate the median change from baseline in conventional serologic biomarkers in subgroups and the overall population of baricitinib-treated patients with SLE, and the SLE Responder Index-4 (SRI-4) response by normalization of anti-dsDNA. METHODS: Data were assessed from the phase II trial I4V-MC-JAHH (NCT02708095). The median change from baseline in anti-dsDNA, IgG, and other conventional serologic markers was evaluated over time in patients who had elevated levels of markers at baseline, and in all patients for IgG. Median change from baseline for baricitinib treatments were compared with placebo. Among patients who were anti-dsDNA positive at baseline, SRI-4 responder rate was compared for those who stayed positive or achieved normal levels by week 24. RESULTS: Significant decreases of anti-dsDNA antibodies were observed in response to baricitinib 2 mg and 4 mg compared to placebo beginning at weeks 2 (baricitinib 2 mg = - 14.3 IU/mL, placebo = 0.1 IU/mL) and 4 (baricitinib 4 mg = - 17.9 IU/mL, placebo = 0.02 IU/mL), respectively, continuing through week 24 (baricitinib 2 mg = - 29.6 IU/mL, baricitinib 4 mg = - 15.1 IU/mL, placebo=3.0 IU/mL). Significant reductions from baseline of IgG levels were found for baricitinib 4 mg-treated patients compared to placebo at weeks 12 (baricitinib 4 mg = - 0.65 g/L, placebo = 0.09 g/L) and 24 (baricitinib 4 mg = - 0.60 g/L, placebo = - 0.04 g/L). For patients who were anti-dsDNA positive at baseline, no relationship between achieving SRI-4 responder and normalization of anti-dsDNA was observed by week 24. CONCLUSIONS: Baricitinib treatment resulted in a rapid and sustained significant decrease in anti-dsDNA antibodies compared to placebo among those with positive anti-dsDNA antibodies at baseline, as well as a significant decrease in IgG levels in the 4 mg group at weeks 12 and 24. These data suggest that baricitinib may influence B cell activity in SLE. Further studies are needed to evaluate if reductions in anti-dsDNA levels with baricitinib treatment reflect the impact of baricitinib on B cell activity. TRIAL REGISTRATION: NCT02708095 .


Assuntos
Lúpus Eritematoso Sistêmico , Anticorpos Antinucleares , Azetidinas , Biomarcadores , DNA , Método Duplo-Cego , Humanos , Imunoglobulina G/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Purinas , Pirazóis , Índice de Gravidade de Doença , Sulfonamidas , Resultado do Tratamento
16.
PLoS Comput Biol ; 18(5): e1010113, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35617357

RESUMO

Hoogsteen (HG) base pairing is characterized by a 180° rotation of the purine base with respect to the Watson-Crick-Franklin (WCF) motif. Recently, it has been found that both conformations coexist in a dynamical equilibrium and that several biological functions require HG pairs. This relevance has motivated experimental and computational investigations of the base-pairing transition. However, a systematic simulation of sequence variations has remained out of reach. Here, we employ advanced path-based methods to perform unprecedented free-energy calculations. Our methodology enables us to study the different mechanisms of purine rotation, either remaining inside or after flipping outside of the double helix. We study seven different sequences, which are neighbor variations of a well-studied A⋅T pair in A6-DNA. We observe the known effect of A⋅T steps favoring HG stability, and find evidence of triple-hydrogen-bonded neighbors hindering the inside transition. More importantly, we identify a dominant factor: the direction of the A rotation, with the 6-ring pointing either towards the longer or shorter segment of the chain, respectively relating to a lower or higher barrier. This highlights the role of DNA's relative flexibility as a modulator of the WCF/HG dynamic equilibrium. Additionally, we provide a robust methodology for future HG proclivity studies.


Assuntos
DNA , Purinas , Pareamento de Bases , DNA/química , DNA/genética , Ligação de Hidrogênio , Conformação Molecular , Conformação de Ácido Nucleico , Termodinâmica
17.
Nat Commun ; 13(1): 2698, 2022 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-35577785

RESUMO

Purine nucleotides are necessary for various biological processes related to cell proliferation. Despite their importance in DNA and RNA synthesis, cellular signaling, and energy-dependent reactions, the impact of changes in cellular purine levels on cell physiology remains poorly understood. Here, we find that purine depletion stimulates cell migration, despite effective reduction in cell proliferation. Blocking purine synthesis triggers a shunt of glycolytic carbon into the serine synthesis pathway, which is required for the induction of cell migration upon purine depletion. The stimulation of cell migration upon a reduction in intracellular purines required one-carbon metabolism downstream of de novo serine synthesis. Decreased purine abundance and the subsequent increase in serine synthesis triggers an epithelial-mesenchymal transition (EMT) and, in cancer models, promotes metastatic colonization. Thus, reducing the available pool of intracellular purines re-routes metabolic flux from glycolysis into de novo serine synthesis, a metabolic change that stimulates a program of cell migration.


Assuntos
Nucleotídeos de Purina , Serina , Carbono , Movimento Celular , Purinas , Serina/metabolismo
18.
Nutrients ; 14(9)2022 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-35565687

RESUMO

OBJECTIVES: To investigate the association between dietary purine intake and mortality among Chinese adults. METHODS: Based on data from the 2004-2015 China Health and Nutrition Survey (CHNS) and the corresponding edition of China Food Composition, the average purine intake per day (mg/day) from 2004 to 2011 was calculated, and the surveyed population was divided into five groups by quintiles. The outcome event and timepoint of concern were defined as death and time, respectively, as reported by family members, recorded until the 2015 survey. Cox proportional hazards regression was used to estimate the hazard ratios (HRs) with 95% confidence intervals (CIs) for death. The possibly nonlinear relationship between purine intake and mortality was examined with restricted cubic splines. RESULTS: We included 17,755 subjects, and the average purine intake among them was 355.07 ± 145.32 mg/day. Purine intake was inversely associated with mortality (Ptrend < 0.001). Compared with the lowest quintiles of purine intake, the highest quintiles (HR = 0.60; 95% CI: 0.46, 0.77) showed a significant association with lower mortality. The negative association with mortality was mainly found in plant-derived purine (Ptrend = 0.001) and, weakly, in animal-derived purine (Ptrend = 0.052). In addition, a U-shaped relationship between purine intake and mortality was observed in males; however, there was no statistically significant dose-response relationship in females. Conclusion: Considering the low-purine-intake levels of the Chinese population, we observed a U-shaped relationship between purine intake and mortality in males, but purine intake may not relate to mortality in females. Future studies should investigate the causal relationship between purine intake and disease burden in China.


Assuntos
Dieta , Purinas , Animais , China/epidemiologia , Estudos de Coortes , Feminino , Humanos , Masculino , Inquéritos Nutricionais , Modelos de Riscos Proporcionais , Fatores de Risco
19.
Molecules ; 27(9)2022 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-35566091

RESUMO

Rhabdomyosarcoma (RMS) is a highly malignant and metastatic pediatric cancer arising from skeletal muscle myogenic progenitors. Recent studies have shown an important role for AKT signaling in RMS progression. Aberrant activation of the PI3K/AKT axis is one of the most frequent events occurring in human cancers and serves to disconnect the control of cell growth, survival, and metabolism from exogenous growth stimuli. In the study reported here, a panel of five compounds targeting the catalytic subunits of the four class I PI3K isoforms (p110α, BYL-719 inhibitor; p110ß, TGX-221 inhibitor; p110γ, CZC24832; p110δ, CAL-101 inhibitor) and the dual p110α/p110δ, AZD8835 inhibitor, were tested on the RMS cell lines RD, A204, and SJCRH30. Cytotoxicity, cell cycle, apoptosis, and the activation of downstream targets were analyzed. Of the individual inhibitors, BYL-719 demonstrated the most anti-tumorgenic properties. BYL-719 treatment resulted in G1/G0 phase cell cycle arrest and apoptosis. When combined with CAL-101, BYL-719 decreased cell viability and induced apoptosis in a synergistic manner, equaling or surpassing results achieved with AZD8835. In conclusion, our findings indicate that BYL-719, either alone or in combination with the p110δ inhibitor, CAL-101, could represent an efficient treatment for human rhabdomyosarcoma presenting with aberrant upregulation of the PI3K signaling pathway.


Assuntos
Fosfatidilinositol 3-Quinases , Rabdomiossarcoma , Apoptose , Linhagem Celular Tumoral , Criança , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Purinas , Quinazolinonas , Rabdomiossarcoma/tratamento farmacológico , Rabdomiossarcoma/patologia
20.
Pol J Vet Sci ; 25(1): 175-182, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35575875

RESUMO

The effects of feeding, fasting, and re-feeding on the ruminal profile of growing cattle were studied. Ruminal fluid and urine samples were obtained from 12 crossbred steers weighing approximately 300 kg during the following periods: 11 h of normal feeding (postprandial period), 48 consecutive hours of fasting, and followed by 48 h of re-feeding. Fasting promotes changes in the ruminal profile, such as an increase in ruminal pH, reduction in the number of rumen protozoa and bacteria, and decrease in the urinary excretion of allantoin; however, it does not change the urinary uric acid excretion rate. The overall mean ruminal pH was higher during fasting (7.53±0.27) in comparison to those at normal feeding (6.72±0.25) and re-feeding (6.62±0.31) (p⟨0.05). During re-feeding, the ruminal profile returned to normal, except for the protozoa count, which despite a slight increase only after 48 h of re-feeding, did not recover to baseline values.


Assuntos
Ração Animal , Rúmen , Ração Animal/análise , Animais , Bovinos , Dieta/veterinária , Digestão , Jejum , Fermentação , Concentração de Íons de Hidrogênio , Purinas/metabolismo , Rúmen/metabolismo
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