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Using induced pluripotent stem cells, Ang et al. elucidate how a mutation in the transcription factor GATA4 causes congenital heart disease. They find that, although the recruitment of GATA4 to cardiac super-enhancers is retained, it no longer functions in partnership with another key transcription factor, leading to misexpression of non-cardiomyocyte genes.
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Fator de Transcrição GATA4/genética , Crise de Identidade , Coração , Humanos , Miócitos Cardíacos/metabolismo , Fatores de Transcrição/genéticaRESUMO
The mammalian heart has a remarkable regenerative capacity for a short period of time after birth, after which the majority of cardiomyocytes permanently exit cell cycle. We sought to determine the primary postnatal event that results in cardiomyocyte cell-cycle arrest. We hypothesized that transition to the oxygen-rich postnatal environment is the upstream signal that results in cell-cycle arrest of cardiomyocytes. Here, we show that reactive oxygen species (ROS), oxidative DNA damage, and DNA damage response (DDR) markers significantly increase in the heart during the first postnatal week. Intriguingly, postnatal hypoxemia, ROS scavenging, or inhibition of DDR all prolong the postnatal proliferative window of cardiomyocytes, whereas hyperoxemia and ROS generators shorten it. These findings uncover a protective mechanism that mediates cardiomyocyte cell-cycle arrest in exchange for utilization of oxygen-dependent aerobic metabolism. Reduction of mitochondrial-dependent oxidative stress should be an important component of cardiomyocyte proliferation-based therapeutic approaches.
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Pontos de Checagem do Ciclo Celular , Miócitos Cardíacos/citologia , Espécies Reativas de Oxigênio/metabolismo , Acetilcisteína/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Dano ao DNA , Sequestradores de Radicais Livres/farmacologia , Camundongos , Mitocôndrias/metabolismo , Miócitos Cardíacos/metabolismo , Peixe-ZebraRESUMO
Metabolic switches are a crucial hallmark of cellular development and regeneration. In response to changes in their environment or physiological state, cells undergo coordinated metabolic switching that is necessary to execute biosynthetic demands of growth and repair. In this Review, we discuss how metabolic switches represent an evolutionarily conserved mechanism that orchestrates tissue development and regeneration, allowing cells to adapt rapidly to changing conditions during development and postnatally. We further explore the dynamic interplay between metabolism and how it is not only an output, but also a driver of cellular functions, such as cell proliferation and maturation. Finally, we underscore the epigenetic and cellular mechanisms by which metabolic switches mediate biosynthetic needs during development and regeneration, and how understanding these mechanisms is important for advancing our knowledge of tissue development and devising new strategies to promote tissue regeneration.
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Diferenciação Celular , Proliferação de CélulasRESUMO
BACKGROUND: Adult mammalian cardiomyocytes have limited proliferative capacity, but in specifically induced contexts they traverse through cell-cycle reentry, offering the potential for heart regeneration. Endogenous cardiomyocyte proliferation is preceded by cardiomyocyte dedifferentiation (CMDD), wherein adult cardiomyocytes revert to a less matured state that is distinct from the classical myocardial fetal stress gene response associated with heart failure. However, very little is known about CMDD as a defined cardiomyocyte cell state in transition. METHODS: Here, we leveraged 2 models of in vitro cultured adult mouse cardiomyocytes and in vivo adeno-associated virus serotype 9 cardiomyocyte-targeted delivery of reprogramming factors (Oct4, Sox2, Klf4, and Myc) in adult mice to study CMDD. We profiled their transcriptomes using RNA sequencing, in combination with multiple published data sets, with the aim of identifying a common denominator for tracking CMDD. RESULTS: RNA sequencing and integrated analysis identified Asparagine Synthetase (Asns) as a unique molecular marker gene well correlated with CMDD, required for increased asparagine and also for distinct fluxes in other amino acids. Although Asns overexpression in Oct4, Sox2, Klf4, and Myc cardiomyocytes augmented hallmarks of CMDD, Asns deficiency led to defective regeneration in the neonatal mouse myocardial infarction model, increased cell death of cultured adult cardiomyocytes, and reduced cell cycle in Oct4, Sox2, Klf4, and Myc cardiomyocytes, at least in part through disrupting the mammalian target of rapamycin complex 1 pathway. CONCLUSIONS: We discovered a novel gene Asns as both a molecular marker and an essential mediator, marking a distinct threshold that appears in common for at least 4 models of CMDD, and revealing an Asns/mammalian target of rapamycin complex 1 axis dependency for dedifferentiating cardiomyocytes. Further study will be needed to extrapolate and assess its relevance to other cell state transitions as well as in heart regeneration.
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Aspartato-Amônia Ligase , Desdiferenciação Celular , Fator 4 Semelhante a Kruppel , Miócitos Cardíacos , Animais , Camundongos , Aspartato-Amônia Ligase/genética , Aspartato-Amônia Ligase/metabolismo , Células Cultivadas , Miócitos Cardíacos/metabolismo , Carbono-Nitrogênio Ligases com Glutamina como Doadora de N-Amida/genética , Carbono-Nitrogênio Ligases com Glutamina como Doadora de N-Amida/metabolismoRESUMO
Despite significant advances in the treatment of colorectal cancer (CRC), identification of novel targets and treatment options are imperative for improving its prognosis and survival rates. The mitochondrial SIRT3 and SHMT2 have key roles in metabolic reprogramming and cell proliferation. This study investigated the potential use of the natural product apigenin in CRC treatment employing both in vivo and in vitro models and explored the role of SIRT3 and SHMT2 in apigenin-induced CRC apoptosis. The role of SHMT2 in CRC patients' survival was verified using TCGA database. In vivo, apigenin treatment restored the normal colon appearance. On the molecular level, apigenin augmented the immunohistochemical expression of cleaved caspase-3 and attenuated SIRT3 and SHMT2 mRNA expression CRC patients with decreased SHMT2 expression had improved overall and disease-free survival rates. In vitro, apigenin reduced the cell viability in a time-dependent manner, induced G0/G1 cell cycle arrest, and increased the apoptotic cell population compared to the untreated control. Mechanistically, apigenin treatment mitigated the expression of SHMT2, SIRT3, and its upstream long intergenic noncoding RNA LINC01234 in CRC cells. Conclusively, apigenin induces caspase-3-dependent apoptosis in CRC through modulation of SIRT3-triggered mitochondrial pathway suggesting it as a promising therapeutic agent to improve patient outcomes.
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Apigenina , Apoptose , Proliferação de Células , Neoplasias Colorretais , Sirtuína 3 , Apigenina/farmacologia , Humanos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/genética , Sirtuína 3/metabolismo , Sirtuína 3/genética , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Animais , Camundongos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Camundongos Nus , Linhagem Celular Tumoral , Transdução de Sinais/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Glicina HidroximetiltransferaseRESUMO
The newly discovered programmed iron-dependent necrosis, ferroptosis, is a novel pathway that is controlled by iron-dependent lipid peroxidation and cellular redox changes. It can be triggered intrinsically by low antioxidant enzyme activity or extrinsically by blocking amino acid transporters or activating iron transporters. The induction of ferroptosis involves the activation of specific proteins, suppression of transporters, and increased endoplasmic reticulum (ER) stress (a condition in which the ER, a crucial organelle involved in protein folding and processing, becomes overwhelmed by an accumulation of misfolded or unfolded proteins. This situation disrupts the normal functioning of the ER, leading to a cellular stress response known as the unfolded protein response), leading to lipid peroxidation byproduct accumulation and toxic reactive oxygen species (ROS), which are highly reactive molecules derived from diatomic oxygen and include various forms such as superoxide (O2â»), hydroxyl radicals (â¢OH), and hydrogen peroxide (H2O2). Ferroptosis is closely associated with signaling molecules in lung cancer, including epidermal growth factor receptor (EGFR), mitogen-activated protein kinase (MAPK), hypoxia-inducible factor 1-alpha (HIF-1α), and P53, and is regulated by epigenetic factors such as microRNAs (miRNAs). miRNAs are small non-coding RNA molecules that regulate gene expression by binding to target messenger RNAs (mRNAs), leading to translational repression or degradation. Several miRNAs have been found to modulate ferroptosis by targeting key genes involved in iron metabolism, lipid peroxidation, and antioxidant defense pathways. The research on ferroptosis has expanded to target its role in lung cancer treatment and resistance prevention. This review encapsulates the significance of ferroptosis in lung cancer. Understanding the mechanisms and implications of ferroptosis in lung cancer cells may lead to targeted therapies exploiting cancer cell vulnerabilities to ferroptosis Also, improving treatment outcomes, and overcoming resistance.
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Pituitary adenomas (PAs) are an array of tumors originating from the pituitary gland. PAs are sorted as functional or nonfunctional according to their hormonal activity and classified according to size into microadenomas and macroadenomas. Still, the cellular events that trigger the transformations in pituitary neoplasms are not fully understood, and the current classification methods do not precisely predict clinical behavior. A rising number of researches have emphasized the role of miRNAs, that drawn more attention as oncogenic molecules or tumor suppressors. The etiopathological mechanisms of PAs include multiple molecular cascades that are influenced by different miRNAs. miRNAs control the cell cycle control, pro- or antiapoptotic processes, and tumor invasion and metastasis. miRNAs offer a novel perspective on tumor features and behaviors and might be valuable in prognostication and therapeutic plans. In pituitary adenomas, miRNAs showed a specific expression pattern depending on their size, cell origin, remission, and treatments. Screening miRNA expression patterns is promising to monitor and evaluate recurrence, as well as to investigate the efficacy of radiation and chemotherapy for PAs exhibiting aggressive behavior. Thus, the current review investigated the interplay of the miRNAs' pivotal role in offering new opportunities to translate these innovative epigenetic tools into healthcare applications.
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MicroRNAs (miRNAs), which are non-coding RNAs consisting of 18-24 nucleotides, play a crucial role in the regulatory pathways of inflammatory diseases. Several recent investigations have examined the potential role of miRNAs in forming Crohn's disease (CD). It has been suggested that miRNAs serve as diagnostics for both fibrosis and inflammation in CD due to their involvement in the mechanisms of CD aggravation and fibrogenesis. More information on CD pathophysiology could be obtained by identifying the miRNAs concerned with CD and their target genes. These findings have prompted several in vitro and in vivo investigations into the putative function of miRNAs in CD treatment. Although there are still many unanswered questions, the growing body of evidence has brought miRNA-based therapy one step closer to clinical practice. This extensive narrative study offers a concise summary of the most current advancements in CD. We go over what is known about the diagnostic and therapeutic benefits of miRNA mimicry and inhibition so far, and we see what additional miRNA family targets could be useful for treating CD-related inflammation and fibrosis.
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The metabolic switch from glycolysis to fatty acid oxidation in postnatal cardiomyocytes contributes to the loss of the cardiac regenerative potential of the mammalian heart. However, the mechanisms that regulate this metabolic switch remain unclear. The protein kinase complex mechanistic target of rapamycin complex 1 (mTORC1) is a central signaling hub that regulates cellular metabolism and protein synthesis, yet its role during mammalian heart regeneration and postnatal metabolic maturation is undefined. Here, we use immunoblotting, rapamycin treatment, myocardial infarction, and global proteomics to define the role of mTORC1 in postnatal heart development and regeneration. Our results demonstrate that the activity of mTORC1 is dynamically regulated between the regenerating and the non-regenerating hearts. Acute inhibition of mTORC1 by rapamycin or everolimus reduces cardiomyocyte proliferation and inhibits neonatal heart regeneration following injury. Our quantitative proteomic analysis demonstrates that transient inhibition of mTORC1 during neonatal heart injury did not reduce protein synthesis, but rather shifts the cardiac proteome of the neonatal injured heart from glycolysis towards fatty acid oxidation. This indicates that mTORC1 inhibition following injury accelerates the postnatal metabolic switch, which promotes metabolic maturation and impedes cardiomyocyte proliferation and heart regeneration. Taken together, our results define an important role for mTORC1 in regulating postnatal cardiac metabolism and may represent a novel target to modulate cardiac metabolism and promote heart regeneration.
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Miócitos Cardíacos , Proteômica , Animais , Miócitos Cardíacos/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Animais Recém-Nascidos , Coração/fisiologia , Sirolimo , Ácidos Graxos/metabolismo , Proliferação de Células , Mamíferos/metabolismoRESUMO
We have previously shown that the long-acting ß2-adrenergic receptor (ß2-AR) agonist formoterol induced recovery from acute kidney injury in mice. To determine whether formoterol protected against diabetic nephropathy, the most common cause of end-stage kidney disease (ESKD), we used a high-fat diet (HFD), a murine type 2 diabetes model, and streptozotocin, a murine type 1 diabetes model. Following formoterol treatment, there was a marked recovery from and reversal of diabetic nephropathy in HFD mice compared with those treated with vehicle alone at the ultrastructural, histological, and functional levels. Similar results were seen after formoterol treatment in mice receiving streptozotocin. To investigate effects in humans, we performed a competing risk regression analysis with death as a competing risk to examine the association between Veterans with chronic kidney disease (CKD) and chronic obstructive pulmonary disease (COPD), who use ß2-AR agonists, and Veterans with CKD but no COPD, and progression to ESKD in a large national cohort of Veterans with stage 4 CKD between 2011 and 2013. Veterans were followed until 2016 or death. ESKD was defined as the initiation of dialysis and/or receipt of kidney transplant. We found that COPD was associated with a 25.6% reduction in progression from stage 4 CKD to ESKD compared with no COPD after adjusting for age, diabetes, sex, race-ethnicity, comorbidities, and medication use. Sensitivity analysis showed a 33.2% reduction in ESKD in Veterans with COPD taking long-acting formoterol and a 20.8% reduction in ESKD in Veterans taking other ß2-AR agonists compared with those with no COPD. These data indicate that ß2-AR agonists, especially formoterol, could be a treatment for diabetic nephropathy and perhaps other forms of CKD.NEW & NOTEWORTHY Diabetic nephropathy is the most common cause of ESKD. Formoterol, a long-acting ß2-adrenergic receptor (ß2-AR) agonist, reversed diabetic nephropathy in murine models of type 1 and 2 diabetes. In humans, there was an association with protection from progression of CKD in patients with COPD, by means of ß2-AR agonist intake, compared with those without COPD. These data indicate that ß2-AR agonists, especially formoterol, could be a new treatment for diabetic nephropathy and other forms of CKD.
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Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Falência Renal Crônica , Doença Pulmonar Obstrutiva Crônica , Humanos , Animais , Camundongos , Nefropatias Diabéticas/tratamento farmacológico , Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Estreptozocina , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Fumarato de Formoterol/uso terapêutico , Falência Renal Crônica/tratamento farmacológico , Falência Renal Crônica/etiologia , Receptores Adrenérgicos/uso terapêuticoRESUMO
Cancer associated drug resistance is a major cause for cancer aggravation, particularly as conventional therapies have presented limited efficiency, low specificity, resulting in long term deleterious side effects. Peptide based drugs have emerged as potential alternative cancer treatment tools due to their selectivity, ease of design and synthesis, safety profile, and low cost of manufacturing. In this study, we utilized the Red Sea metagenomics database, generated during AUC/KAUST Red Sea microbiome project, to derive a viable anticancer peptide (ACP). We generated a set of peptide hits from our library that shared similar composition to ACPs. A peptide with a homeodomain was selected, modified to improve its anticancer properties, verified to maintain high anticancer properties, and processed for further in-silico prediction of structure and function. The peptide's anticancer properties were then assessed in vitro on osteosarcoma U2OS cells, through cytotoxicity assay (MTT assay), scratch-wound healing assay, apoptosis/necrosis detection assay (Annexin/PI assay), RNA expression analysis of Caspase 3, KI67 and Survivin, and protein expression of PARP1. L929 mouse fibroblasts were also assessed for cytotoxicity treatment. In addition, the antimicrobial activity of the peptide was also examined on E coli and S. aureus, as sample representative species of the human bacterial microbiome, by examining viability, disk diffusion, morphological assessment, and hemolytic analysis. We observed a dose dependent cytotoxic response from peptide treatment of U2OS, with a higher tolerance in L929s. Wound closure was debilitated in cells exposed to the peptide, while annexin fluorescent imaging suggested peptide treatment caused apoptosis as a major mode of cell death. Caspase 3 gene expression was not altered, while KI67 and Survivin were both downregulated in peptide treated cells. Additionally, PARP-1 protein analysis showed a decrease in expression with peptide exposure. The peptide exhibited minimal antimicrobial activity on critical human microbiome species E. coli and S. aureus, with a low inhibition rate, maintenance of structural morphology and minimal hemolytic impact. These findings suggest our novel peptide displayed preliminary ACP properties against U2OS cells, through limited specificity, while triggering apoptosis as a primary mode of cell death and while having minimal impact on the microbiological species E. coli and S. aureus.
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Anti-Infecciosos , Antineoplásicos , Sais , Animais , Camundongos , Humanos , Caspase 3/genética , Caspase 3/metabolismo , Caspase 3/farmacologia , Survivina/genética , Survivina/metabolismo , Survivina/farmacologia , Escherichia coli/metabolismo , Peptídeos Antimicrobianos , Linhagem Celular Tumoral , Oceano Índico , Antígeno Ki-67/metabolismo , Staphylococcus aureus , Apoptose , Peptídeos/farmacologia , Peptídeos/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Anti-Infecciosos/farmacologia , Anexinas/farmacologiaRESUMO
Human astrovirus (HAstV) is a nonenveloped RNA virus and has been implicated in acute gastroenteritis among children and elderly. However, there exists a substantial dearth of information on HAstV strains circulating in Nigeria. Viral-like particles were purified from archived 254 stool samples of children with acute flaccid paralysis between January and December 2020 from five states in Nigeria, using the NetoVIR protocol. Extracted viral RNA and DNA were subjected to a reverse transcription step and subsequent random polymerase chain reaction amplification. Library preparation and Illumina sequencing were performed. Using the virome paired-end reads pipeline, raw reads were processed into genomic contigs. Phylogenetic and pairwise identity analysis of the recovered HAstV genomes was performed. Six near-complete genome sequences of HAstV were identified and classified as HAstV4 (n = 1), HAstV5 (n = 1), HAstV8 (n = 1), and MLB-3 (n = 3). The HAstV5 belonged to a yet unclassified sublineage, which we tentatively named HAstV-5d. Phylogenetic analysis of open reading frames 1a, 1b, and 2 suggested recombination events inside the MAstV1 species. Furthermore, phylogenetic analysis implied a geographic linkage between the HAstV5 strain from this study with two strains from Cameroon across all the genomic regions. We report for the first time the circulation of HAstV genotypes 4, 8, and MLB-3 in Nigeria and present data suggestive for the existence of a new sublineage of HAstV5. To further understand the burden, diversity, and evolution of HAstV, increased research interest as well as robust HAstV surveillance in Nigeria is essential.
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Infecções por Astroviridae , Mamastrovirus , Criança , Humanos , Idoso , Mamastrovirus/genética , Filogenia , Nigéria/epidemiologia , Infecções por Astroviridae/epidemiologia , Fezes , GenótipoRESUMO
More than half of the world's population is nourished by crops fertilized with synthetic nitrogen (N) fertilizers. However, N fertilization is a major source of anthropogenic emissions, augmenting the carbon footprint (CF). To date, no global quantification of the CF induced by N fertilization of the main grain crops has been performed, and quantifications at the national scale have neglected the CO2 assimilated by plants. A first cradle-to-grave life cycle assessment was performed to quantify the CF of the N fertilizers' production, transportation, and application to the field and the uses of the produced biomass in livestock feed and human food, as well as biofuel production. We quantified the direct and indirect inventories emitted or sequestered by N fertilization of main grain crops: wheat, maize, and rice. Grain food produced with N fertilization had a net CF of 7.4 Gt CO2eq. in 2019 after excluding the assimilated C in plant biomass, which accounted for a quarter of the total CF. The cradle (fertilizer production and transportation), gate (fertilizer application, and soil and plant systems), and grave (feed, food, biofuel, and losses) stages contributed to the CF by 2%, 11%, and 87%, respectively. Although Asia was the top grain producer, North America contributed 38% of the CF due to the greatest CF of the grave stage (2.5 Gt CO2eq.). The CF of grain crops will increase to 21.2 Gt CO2eq. in 2100, driven by the rise in N fertilization to meet the growing food demand without actions to stop the decline in N use efficiency. To meet the targets of climate change, we introduced an ambitious mitigation strategy, including the improvement of N agronomic efficiency (6% average target for the three crops) and manufacturing technology, reducing food losses, and global conversion to healthy diets, whereby the CF can be reduced to 5.6 Gt CO2eq. in 2100.
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Pegada de Carbono , Nitrogênio , Humanos , Fertilizantes/análise , Biocombustíveis , Agricultura , Solo , Produtos Agrícolas , Grão Comestível/química , China , Carbono/análiseRESUMO
PURPOSE OF REVIEW: To eradicate atherosclerotic diseases, novel biomarkers, and future therapy targets must reveal the burden of early atherosclerosis (AS), which occurs before life-threatening unstable plaques form. The chemical and biological features of microRNAs (miRNAs) make them interesting biomarkers for numerous diseases. We summarized the latest research on miRNA regulatory mechanisms in AS progression studies, which may help us use miRNAs as biomarkers and treatments for difficult-to-treat diseases. RECENT FINDINGS: Recent research has demonstrated that miRNAs have a regulatory function in the observed changes in gene and protein expression during atherogenesis, the process that leads to atherosclerosis. Several miRNAs play a role in the development of atherosclerosis, and these miRNAs could potentially serve as non-invasive biomarkers for atherosclerosis in various regions of the body. These miRNAs have the potential to serve as biomarkers and targets for early treatment of atherosclerosis. The start and development of AS require different miRNAs. It reviews new research on miRNAs affecting endothelium, vascular smooth muscle, vascular inflammation, lipid retention, and cholesterol metabolism in AS. A miRNA gene expression profile circulates with AS everywhere. AS therapies include lipid metabolism, inflammation reduction, and oxidative stress inhibition. Clinical use of miRNAs requires tremendous progress. We think tiny miRNAs can enable personalized treatment.
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Aterosclerose , Biomarcadores , MicroRNAs , Humanos , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/diagnóstico , Aterosclerose/terapia , MicroRNAs/genética , MicroRNAs/metabolismo , Biomarcadores/metabolismo , Prognóstico , AnimaisRESUMO
OBJECTIVE: Substantial lymphovascular space invasion (LVSI) is an important predictor of lymph node (LN) involvement in women with endometrial carcinoma. We studied the prognostic significance of substantial LVSI in patients with 2009-FIGO stage-I uterine endometrioid adenocarcinoma (EC) who all had pathologic negative nodal evaluation (PNNE). METHODS: Pathologic specimens were retrieved and LVSI was quantified (focal or substantial) in women with stage-I EC who had a hysterectomy and PNNE. In addition to multivariate analysis (MVA), recurrence-free (RFS), disease-specific (DSS), and overall (OS) survival was compared between women with focal vs. substantial LVSI. RESULTS: 1052 patients were identified with a median follow-up of 9.7 years. 358 women (34%) received adjuvant radiotherapy. 907 patients (86.2%) had no LVSI, 87 (8.3%) had focal, and 58 (5.5%) had substantial LVSI. Five-year RFS was 93.3% (95% CI: 91.5-95.1), 76.8% (95% CI: 67.2-87.7) and 79.1% (95% CI: 67.6-95.3) for no, focal, and substantial LVSI(p < 0.0001). There was no statistically significant difference in 5-year RFS, DSS, OS, and in the patterns of initial recurrence between women with focal vs substantial LVSI. On MVA with propensity score matching, substantial LVSI was not independently associated with any survival endpoint compared to focal LVSI, albeit both were detrimental when compared to no LVSI. Age ≥ 60 years and higher grade were predictors of worse RFS, DSS, and OS. Additionally, comorbidity burden was an independent predictor for OS. CONCLUSIONS: Our results suggest that substantial LVSI does not predict worse survival endpoints or different recurrence patterns in women with stage-I EC with PNNE when compared to focal LVSI.
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Carcinoma Endometrioide , Invasividade Neoplásica , Estadiamento de Neoplasias , Humanos , Feminino , Pessoa de Meia-Idade , Idoso , Prognóstico , Carcinoma Endometrioide/patologia , Carcinoma Endometrioide/mortalidade , Carcinoma Endometrioide/terapia , Metástase Linfática , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/mortalidade , Neoplasias do Endométrio/terapia , Linfonodos/patologia , Adulto , Idoso de 80 Anos ou mais , Neoplasias Uterinas/patologia , Neoplasias Uterinas/mortalidade , Neoplasias Uterinas/terapia , Estudos Retrospectivos , HisterectomiaRESUMO
BACKGROUND: Antimicrobial resistance has emerged as a major global health threat, necessitating the urgent development of new antimicrobials through innovative methods to combat the rising prevalence of resistant microbes. With this view, we developed three novel nanoconjugates using microbial natural pigment for effective application against certain pathogenic microbes. RESULTS: A natural red pigment (RP) extracted from the endophyte Monascus ruber and gamma rays were applied to synthesize RP-ZnO, RP-CuO, and RP-MgO nanoconjugates. The synthesized nanoconjugates were characterized by different techniques to study their properties. The antimicrobial potential of these nanoconjugates was evaluated. Moreover, the antibiofilm, protein leakage, growth curve, and UV light irradiation effect of the synthesized nanoconjugates were also studied. Our results confirmed the nano-size, shape, and stability of the prepared conjugates. RP-ZnO, RP-CuO, and RP-MgO nanoconjugates showed broad antimicrobial potential against the tested bacterial and fungal pathogens. Furthermore, the RP-ZnO nanoconjugate possessed the highest activity, followed by the RP-CuO against the tested microbes. The highest % inhibition of biofilm formation by the RP-ZnO nanoconjugate. Membrane leakage of E. coli and S. aureus by RP-ZnO nanoconjugate was more effective than RP-MgO and RP-CuO nanoconjugates. Finally, UV light irradiation intensified the antibiotic action of the three nanoconjugates and RP-ZnO potential was greater than that of the RP-MgO, and RP-CuO nanoconjugates. CONCLUSION: These findings pave the way for exploiting the synthesized nanoconjugates as potential materials in biomedical applications, promoting natural, green, and eco-friendly approaches.
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Monascus , Nanoconjugados , Monascus/metabolismo , Nanoconjugados/química , Biofilmes/efeitos dos fármacos , Pigmentos Biológicos/química , Fermentação , Cobre/química , Cobre/farmacologia , Endófitos/metabolismo , Endófitos/química , Óxido de Zinco/química , Óxido de Zinco/farmacologia , Testes de Sensibilidade Microbiana , Óxido de Magnésio/química , Óxido de Magnésio/farmacologia , Antibacterianos/farmacologia , Antibacterianos/química , Escherichia coli/efeitos dos fármacosRESUMO
In the current study, the effect of rGO ratio on the N-dopped TiO2has been synthesized through sol-gel method. The prepared N-doped TiO2/rGO composites were examined for humidity sensing applications. The relationship between optical properties and the humidity sensing properties was studied. The structure, morphology, and bonding interaction have been examined using XRD, FT-IR, PL and HRTEM respectively. The average particle size as estimated from XRD and HRTEM was found to be about 9 nm. The optical properties have been studied using UV/ Vis. Spectroscopy. Further, optical parameters including refractive index and optical band gap energy have been estimated. The humidity sensing behavior of the resultant composites were evaluated in a wide range of humidity (7%-97% RH) at different testing frequencies. The optical band gap was found to be decreased as the amount of rGO increase. Among all prepared samples, both the optical parameters and humidity sensing experiments confirmed that the 0.5% rGO@N-dopped TiO2sample is the best candidate for the humidity sensing applications. The best optimum testing frequency was demonstrated to be 50 Hz. The sensor demonstrates a fast response and recovery times of 13 s and 33 s with low hysteresis and large sensitivity. The humidity sensing mechanism was studied using complex impedance spectroscopy at different RH levels under testing frequency range from 50 Hz to 5 MHz and testing voltage of 1 VAC. The produced structure demonstrated a promising material for humidity measuring devices.
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BACKGROUND: Mitochondrial DNA (mtDNA) has become a significant tool for exploring genetic diversity and delineating evolutionary links across diverse taxa. Within the group of cold-water fish species that are native to the Indian Himalayan region, Schizothorax esocinus holds particular importance due to its ecological significance and is potentially vulnerable to environmental changes. This research aims to clarify the phylogenetic relationships within the Schizothorax genus by utilizing mitochondrial protein-coding genes. METHODS: Standard protocols were followed for the isolation of DNA from S. esocinus. For the amplification of mtDNA, overlapping primers were used, and then subsequent sequencing was performed. The genetic features were investigated by the application of bioinformatic approaches. These approaches covered the evaluation of nucleotide composition, codon usage, selective pressure using nonsynonymous substitution /synonymous substitution (Ka/Ks) ratios, and phylogenetic analysis. RESULTS: The study specifically examined the 13 protein-coding genes of Schizothorax species which belongs to the Schizothoracinae subfamily. Nucleotide composition analysis showed a bias towards A + T content, consistent with other cyprinid fish species, suggesting evolutionary conservation. Relative Synonymous Codon Usage highlighted leucine as the most frequent (5.18%) and cysteine as the least frequent (0.78%) codon. The positive AT-skew and the predominantly negative GC-skew indicated the abundance of A and C. Comparative analysis revealed significant conservation of amino acids in multiple genes. The majority of amino acids were hydrophobic rather than polar. The purifying selection was revealed by the genetic distance and Ka/Ks ratios. Phylogenetic study revealed a significant genetic divergence between S. esocinus and other Schizothorax species with interspecific K2P distances ranging from 0.00 to 8.87%, with an average of 5.76%. CONCLUSION: The present study provides significant contributions to the understanding of mitochondrial genome diversity and genetic evolution mechanisms in Schizothoracinae, hence offering vital insights for the development of conservation initiatives aimed at protecting freshwater fish species.
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Filogenia , Animais , Proteínas Mitocondriais/genética , Composição de Bases/genética , DNA Mitocondrial/genética , Uso do Códon/genética , Truta/genética , Truta/classificação , Códon/genética , Genoma Mitocondrial/genética , Evolução Molecular , Proteínas de Peixes/genética , Genômica/métodos , Variação Genética/genética , Cyprinidae/genética , Cyprinidae/classificaçãoRESUMO
Some heterocycles bearing a benzo[h]quinoline moiety were synthesized through treating a 3-((2-chlorobenzo[h]quinolin-3-yl)methylene)-5-(p-tolyl)furan-2(3H)-one with four nitrogen nucleophiles comprising ammonium acetate, benzylamine, dodecan-1-amine, and 1,2-diaminoethane. Also, thiation reactions of furanone and pyrrolinone derivatives were investigated. The insecticidal activity of these compounds against mosquito larvae (Culex pipiens L.) was evaluated. All tested compounds exhibited significant larvicidal activity, surpassing that of the conventional insecticide chlorpyrifos. In silico docking analysis revealed that these compounds may act as acetyl cholinesterase (AChE) inhibitors, potentially explaining their larvicidal effect. Additionally, interactions with other neuroreceptors, such as nicotinic acetylcholine receptor and sodium channel voltage-gated alpha subunit were also predicted. The results obtained from this study reflected the potential of benzo[h]quinoline derivatives as promising candidates for developing more effective and sustainable mosquito control strategies. The ADME (absorption, distribution, metabolism, and excretion) analyses displayed their desirable drug-likeness and oral bioavailability properties.
Assuntos
Culex , Inseticidas , Larva , Simulação de Acoplamento Molecular , Quinolinas , Animais , Culex/efeitos dos fármacos , Inseticidas/farmacologia , Inseticidas/química , Inseticidas/síntese química , Larva/efeitos dos fármacos , Relação Estrutura-Atividade , Quinolinas/farmacologia , Quinolinas/química , Quinolinas/síntese química , Estrutura Molecular , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Acetilcolinesterase/metabolismoRESUMO
This study presents a novel approach to manage vaginal infections due to Candidiasis, utilizing a novel silver secnidazole nano-hybrid emulsion (Ag-Secn-NHE)-based probiotics and free Ag-Secn-NHE. Ag-Secn-NHE was prepared by simple homogenizationâultrasonication technique and validated by using a ultravioletâvisible scan, dynamic light scattering, transmission electron microscopy (TEM), Fourier-transform infrared spectroscopy, and zeta potential. Saccharomyces cerevisiae (RCMB 002Y001) is the most effective probiotic-producing organism that demonstrates significant effects when combined with Ag-Secn-NHE. Ag-Secn-NHE-based probiotics showed significant antifungal effect compared to free Ag-Secn-NHE, silver nitrate, silver nanoparticles, secnidazole, secnidazole nanoemulsion, and commercial vaginal wash against multidrug-resistant vaginal pathogens. The highest inhibitory effect was achieved with Ag-Secn-NHE-based probiotic against Candida auris, Candida albicans, and Cryptococcus neoformans with minimal inhibitory concentration (MIC) 0.625 ± 0.002, 0.00625:1.25 ± 0.012 and 0.00625:1.25 ± 0.032 mg/mL, respectively, in comparison with Ag-Secn-NHE that show MIC at 0.00625:1.25 ± 0.612, 0.0125:2.5 ± 0.812, and 0.0125:2.5 ± 0.112 mg/mL (Ag:Secn). Ag-Secn-NHE-based- probiotic show minimum fungicidal concentration (MFC) at range from 2.5 to 20 mg/mL, wherever free Ag-Secn-NHE show MFC range from 5 to >20 mg/mL. Additionally, Ag-Secn-NHE-based probiotics have 75% inhibition of biofilm formation against C. auris and 60% inhibition of biofilm formation against both Cryptococcus neoformans and C. albicans in comparison with free Ag-Secn-NHE. Time-kill curves showed that the antifungal effect of Ag-Secn-NHE-based probiotics was fungistatic at 2MIC value after 4 h and after 16 h for Ag-Secn-NHE. TEM photographs showed that C. auris cells treated with Ag-Secn-NHE-based probiotic formula revealed severe deformations and distored ultrastructural changes. furthermore, results indicated that the Gamma radiation up to 15 kGy increases production of Ag-Secn-NHE in comparison with non-irradiated one.