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Stalled DNA replication fork restart after stress as orchestrated by ATR kinase, BLM helicase, and structure-specific nucleases enables replication, cell survival, and genome stability. Here we unveil human exonuclease V (EXO5) as an ATR-regulated DNA structure-specific nuclease and BLM partner for replication fork restart. We find that elevated EXO5 in tumors correlates with increased mutation loads and poor patient survival, suggesting that EXO5 upregulation has oncogenic potential. Structural, mechanistic, and mutational analyses of EXO5 and EXO5-DNA complexes reveal a single-stranded DNA binding channel with an adjacent ATR phosphorylation motif (T88Q89) that regulates EXO5 nuclease activity and BLM binding identified by mass spectrometric analysis. EXO5 phospho-mimetic mutant rescues the restart defect from EXO5 depletion that decreases fork progression, DNA damage repair, and cell survival. EXO5 depletion furthermore rescues survival of FANCA-deficient cells and indicates EXO5 functions epistatically with SMARCAL1 and BLM. Thus, an EXO5 axis connects ATR and BLM in directing replication fork restart.
Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Replicação do DNA/genética , DNA/genética , Exonucleases/genética , Instabilidade Genômica/genética , RecQ Helicases/genética , Linhagem Celular , Linhagem Celular Tumoral , Dano ao DNA/genética , DNA Helicases/genética , Análise Mutacional de DNA/métodos , Reparo do DNA/genética , Proteínas de Ligação a DNA/genética , Células HEK293 , Células HeLa , Humanos , Mutação/genética , Oncogenes/genética , Fosforilação/genética , Regulação para Cima/genéticaRESUMO
BACKGROUND: Persistent hemolytic anemia and a lack of oral treatments are challenges for patients with paroxysmal nocturnal hemoglobinuria who have received anti-C5 therapy or have not received complement inhibitors. Iptacopan, a first-in-class oral factor B inhibitor, has been shown to improve hemoglobin levels in these patients. METHODS: In two phase 3 trials, we assessed iptacopan monotherapy over a 24-week period in patients with hemoglobin levels of less than 10 g per deciliter. In the first, anti-C5-treated patients were randomly assigned to switch to iptacopan or to continue anti-C5 therapy. In the second, single-group trial, patients who had not received complement inhibitors and who had lactate dehydrogenase (LDH) levels more than 1.5 times the upper limit of the normal range received iptacopan. The two primary end points in the first trial were an increase in the hemoglobin level of at least 2 g per deciliter from baseline and a hemoglobin level of at least 12 g per deciliter, each without red-cell transfusion; the primary end point for the second trial was an increase in hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. RESULTS: In the first trial, 51 of the 60 patients who received iptacopan had an increase in the hemoglobin level of at least 2 g per deciliter from baseline, and 42 had a hemoglobin level of at least 12 g per deciliter, each without transfusion; none of the 35 anti-C5-treated patients attained the end-point levels. In the second trial, 31 of 33 patients had an increase in the hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. In the first trial, 59 of the 62 patients who received iptacopan and 14 of the 35 anti-C5-treated patients did not require or receive transfusion; in the second trial, no patients required or received transfusion. Treatment with iptacopan increased hemoglobin levels, reduced fatigue, reduced reticulocyte and bilirubin levels, and resulted in mean LDH levels that were less than 1.5 times the upper limit of the normal range. Headache was the most frequent adverse event with iptacopan. CONCLUSIONS: Iptacopan treatment improved hematologic and clinical outcomes in anti-C5-treated patients with persistent anemia - in whom iptacopan showed superiority to anti-C5 therapy - and in patients who had not received complement inhibitors. (Funded by Novartis; APPLY-PNH ClinicalTrials.gov number, NCT04558918; APPOINT-PNH ClinicalTrials.gov number, NCT04820530.).
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Anemia Hemolítica , Fator B do Complemento , Inativadores do Complemento , Hemoglobinas , Hemoglobinúria Paroxística , Humanos , Administração Oral , Anemia Hemolítica/complicações , Complemento C5/antagonistas & inibidores , Fator B do Complemento/antagonistas & inibidores , Inativadores do Complemento/administração & dosagem , Inativadores do Complemento/efeitos adversos , Inativadores do Complemento/uso terapêutico , Transfusão de Eritrócitos , Cefaleia/induzido quimicamente , Hemoglobinas/análise , Hemoglobinúria Paroxística/tratamento farmacológico , Hemoglobinúria Paroxística/etiologia , Ensaios Clínicos Fase III como Assunto , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Cancer is a complex disease displaying a variety of cell states and phenotypes. This diversity, known as cancer cell plasticity, confers cancer cells the ability to change in response to their environment, leading to increased tumor diversity and drug resistance. This review explores the intricate landscape of cancer cell plasticity, offering a deep dive into the cellular, molecular, and genetic mechanisms that underlie this phenomenon. Cancer cell plasticity is intertwined with processes such as epithelial-mesenchymal transition and the acquisition of stem cell-like features. These processes are pivotal in the development and progression of tumors, contributing to the multifaceted nature of cancer and the challenges associated with its treatment. Despite significant advancements in targeted therapies, cancer cell adaptability and subsequent therapy-induced resistance remain persistent obstacles in achieving consistent, successful cancer treatment outcomes. Our review delves into the array of mechanisms cancer cells exploit to maintain plasticity, including epigenetic modifications, alterations in signaling pathways, and environmental interactions. We discuss strategies to counteract cancer cell plasticity, such as targeting specific cellular pathways and employing combination therapies. These strategies promise to enhance the efficacy of cancer treatments and mitigate therapy resistance. In conclusion, this review offers a holistic, detailed exploration of cancer cell plasticity, aiming to bolster the understanding and approach toward tackling the challenges posed by tumor heterogeneity and drug resistance. As articulated in this review, the delineation of cellular, molecular, and genetic mechanisms underlying tumor heterogeneity and drug resistance seeks to contribute substantially to the progress in cancer therapeutics and the advancement of precision medicine, ultimately enhancing the prospects for effective cancer treatment and patient outcomes.
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Plasticidade Celular , Neoplasias , Humanos , Plasticidade Celular/genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal/genética , Transdução de SinaisRESUMO
We have examined the roles of yeast mRNA decapping-activators Pat1 and Dhh1 in repressing the translation and abundance of specific mRNAs in nutrient-replete cells using ribosome profiling, RNA-Seq, CAGE analysis of capped mRNAs, RNA Polymerase II ChIP-Seq, and TMT-mass spectrometry of mutants lacking one or both factors. Although the Environmental Stress Response (ESR) is activated in dhh1Δ and pat1Δ mutants, hundreds of non-ESR transcripts are elevated in a manner indicating cumulative repression by Pat1 and Dhh1 in wild-type cells. These mRNAs show both reduced decapping and diminished transcription in the mutants, indicating that impaired mRNA turnover drives transcript derepression in cells lacking Dhh1 or Pat1. mRNA degradation stimulated by Dhh1/Pat1 is not dictated by poor translation nor enrichment for suboptimal codons. Pat1 and Dhh1 also collaborate to reduce translation and protein production from many mRNAs. Transcripts showing concerted translational repression by Pat1/Dhh1 include mRNAs involved in cell adhesion or utilization of the poor nitrogen source allantoin. Pat1/Dhh1 also repress numerous transcripts involved in respiration, catabolism of non-preferred carbon or nitrogen sources, or autophagy; and we obtained evidence for elevated respiration and autophagy in the mutants. Thus, Pat1 and Dhh1 function as post-transcriptional repressors of multiple pathways normally activated only during nutrient limitation.
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Saccharomyces cerevisiae , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismo , Nutrientes , Estabilidade de RNA/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/metabolismo , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismoRESUMO
BACKGROUND: To determine whether the addition of durvalumab (anti-PD-L1) and oleclumab (anti-CD73) to standard-of-care treatment (FOLFOX and bevacizumab) enhances the anti-tumour effect in patients with metastatic colorectal cancer (mCRC). METHODS: COLUMBIA-1 (NCT04068610) was a Phase Ib (feasibility; Part 1)/Phase II (randomised; Part 2) trial in patients with treatment-naïve microsatellite stable mCRC. Patients in Part 2 were randomised to receive standard-of-care (control arm) or standard-of-care plus durvalumab and oleclumab (experimental arm). Primary objectives included safety and efficacy. RESULTS: Seven patients were enrolled in Part 1 and 52 in Part 2 (n = 26 in each arm). Grade ≥3 treatment-emergent adverse events (TEAE) occurred in 80.8% and 65.4% of patients in the control and experimental arms of Part 2, respectively, with 26.9% and 46.3% experiencing serious TEAEs. The confirmed objective response rate (ORR) was numerically higher in the experimental arm compared with the control arm (61.5% [95% confidence interval (CI), 40.6-79.8] vs 46.2% [95% CI, 26.6-66.6]) but did not meet the statistically significant threshold in either arm. CONCLUSION: The safety profile of FOLFOX and bevacizumab in combination with durvalumab and oleclumab was manageable; however, the efficacy results do not warrant further development of this combination in patients with microsatellite stable mCRC. REGISTRATION: NCT04068610.
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BACKGROUND: Inhibition of the adenosine 2A receptor (A2AR) diminishes the immunosuppressive effects of adenosine and may complement immune-targeting drugs. This phase 2 study evaluated the A2AR antagonist AZD4635 in combination with durvalumab or oleclumab in patients with metastatic castration-resistant prostate cancer. METHODS: Patients with histologically/cytologically confirmed disease progressing within 6 months on ≥ 2 therapy lines were randomly assigned to either Module 1 (AZD4635 + durvalumab) or Module 2 (AZD4635 + oleclumab). Primary endpoints were objective response rate per RECIST v1.1 and prostate-specific antigen (PSA) response rate. Secondary endpoints included radiological progression-free survival (rPFS), overall survival, safety, and pharmacokinetics. RESULTS: Fifty-nine patients were treated (Module 1, n = 29; Module 2, n = 30). Median number of prior therapies was 4. One confirmed complete response by RECIST (Module 1) and 2 confirmed PSA responses (1 per module) were observed. The most frequent adverse events (AEs) possibly related to AZD4635 were nausea (37.9%), fatigue (20.7%), and decreased appetite (17.2%) in Module 1; nausea (50%), fatigue (30%), and vomiting (23.3%) in Module 2. No dose-limiting toxicities or treatment-related serious AEs were observed. In Module 1, AZD4635 geometric mean trough concentration was 124.9 ng/mL (geometric CV% 69.84; n = 22); exposures were similar in Module 2. In Modules 1 and 2, median (95% CI) rPFS was 2.3 (1.6 -3.8) and 1.5 (1.3- 4.0) months, respectively. Median PFS was 1.7 versus 2.3 months for patients with high versus low blood-based adenosine signature. CONCLUSION: In this heavily pretreated population, AZD4635 with durvalumab or oleclumab demonstrated minimal antitumor activity with a manageable safety profile. CLINICAL TRIAL: gov identifier: NCT04089553.
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Anticorpos Monoclonais , Antineoplásicos , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Antígeno Prostático Específico , Antineoplásicos/uso terapêutico , Fadiga , Adenosina , Náusea/tratamento farmacológicoRESUMO
MAIN CONCLUSION: Integrated management strategies, including novel nematicides and resilient cultivars, offer sustainable solutions to combat root-knot nematodes, crucial for safeguarding global agriculture against persistent threats. Root-knot nematodes (RKN) pose a significant threat to a diverse range of host plants, with their obligatory endoparasitic nature leading to substantial agricultural losses. RKN spend much of their lives inside or in contact by secreting plant cell wall-modifying enzymes resulting in the giant cell development for establishing host-parasite relationships. Additionally, inflicting physical harm to host plants, RKN also contributes to disease complexes creation with fungi and bacteria. This review comprehensively explores the origin, history, distribution, and physiological races of RKN, emphasizing their economic impact on plants through gall formation. Management strategies, ranging from cultural and physical to biological and chemical controls, along with resistance mechanisms and marker-assisted selection, are explored. While recognizing the limitations of traditional nematicides, recent breakthroughs in non-fumigant alternatives like fluensulfone, spirotetramat, and fluopyram offer promising avenues for sustainable RKN management. Despite the success of resistance mechanisms like the Mi gene, challenges persist, prompting the need for integrative approaches to tackle Mi-virulent isolates. In conclusion, the review stresses the importance of innovative and resilient control measures for sustainable agriculture, emphasizing ongoing research to address evolving challenges posed by RKN. The integration of botanicals, resistant cultivars, and biological controls, alongside advancements in non-fumigant nematicides, contributes novel insights to the field, laying the ground work for future research directions to ensure the long-term sustainability of agriculture in the face of persistent RKN threats.
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Agricultura , Doenças das Plantas , Raízes de Plantas , Animais , Doenças das Plantas/parasitologia , Doenças das Plantas/prevenção & controle , Raízes de Plantas/parasitologia , Agricultura/métodos , Tylenchoidea/fisiologia , Tylenchoidea/patogenicidade , Interações Hospedeiro-Parasita , Resistência à Doença , Produtos Agrícolas/parasitologia , Antinematódeos/farmacologiaRESUMO
The high rate of productivity observed in panicoid crops is in part due to their extensive root system. Recently, green foxtail (Setaria viridis) has emerged as a genetic model system for panicoid grasses. Natural accessions of S. viridis originating from different parts of the world, with differential leaf physiological behavior, have been identified. This work focused on understanding the physiological and molecular mechanisms controlling root hydraulic conductivity and root-to-shoot gas exchange signaling in S. viridis. We identified 2 accessions, SHA and ZHA, with contrasting behavior at the leaf, root, and whole-plant levels. Our results indicated a role for root aquaporin (AQP) plasma membrane (PM) intrinsic proteins in the differential behavior of SHA and ZHA. Moreover, a different root hydraulic response to low levels of abscisic acid between SHA and ZHA was observed, which was associated with root AQPs. Using cell imaging, biochemical, and reverse genetic approaches, we identified PM intrinsic protein 1;6 (PIP1;6) as a possible PIP1 candidate that regulates radial root hydraulics and root-to-shoot signaling of gas exchange in S. viridis. In heterologous systems, PIP1;6 localized in the endoplasmic reticulum, and upon interaction with PIP2s, relocalization to the PM was observed. PIP1;6 was predominantly expressed at the root endodermis. Generation of knockout PIP1;6 plants (KO-PIP1;6) in S. viridis showed altered root hydraulic conductivity, altered gas exchange, and alteration of root transcriptional patterns. Our results indicate that PIPs are essential in regulating whole-plant water homeostasis in S. viridis. We conclude that root hydraulic conductivity and gas exchange are positively associated and are regulated by AQPs.
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Aquaporinas , Setaria (Planta) , Setaria (Planta)/metabolismo , Água/metabolismo , Folhas de Planta/metabolismo , Membrana Celular/metabolismo , Aquaporinas/genética , Aquaporinas/metabolismo , Raízes de Plantas/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismoRESUMO
OBJECTIVES: To evaluate the role of combined intravoxel incoherent motion and diffusion kurtosis imaging (IVIM-DKI) and their machine-learning-based texture analysis for the detection and assessment of severity in prostate cancer (PCa). MATERIALS AND METHODS: Eighty-eight patients underwent MRI on a 3 T scanner after giving informed consent. IVIM-DKI data were acquired using 13 b values (0-2000 s/mm2) and analyzed using the IVIM-DKI model with the total variation (TV) method. PCa patients were categorized into two groups: clinically insignificant prostate cancer (CISPCa) (Gleason grade ≤ 6) and clinically significant prostate cancer (CSPCa) (Gleason grade ≥ 7). One-way analysis-of-variance, t test, and receiver operating characteristic analysis was performed to measure the discriminative ability to detect PCa using IVIM-DKI parameters. A chi-square test was used to select important texture features of apparent diffusion coefficient (ADC) and IVIM-DKI parameters. These selected texture features were used in an artificial neural network for PCa detection. RESULTS: ADC and diffusion coefficient (D) were significantly lower (p < 0.001), and kurtosis (k) was significantly higher (p < 0.001), in PCa as compared with benign prostatic hyperplasia (BPH) and normal peripheral zone (PZ). ADC, D, and k showed high areas under the curves (AUCs) of 0.92, 0.89, and 0.88, respectively, in PCa detection. ADC and D were significantly lower (p < 0.05) as compared with CISPCa versus CSPCa. D for detecting CSPCa was high, with an AUC of 0.63. A negative correlation of ADC and D with GS (ADC, ρ = -0.33; D, ρ = -0.35, p < 0.05) and a positive correlation of k with GS (ρ = 0.22, p < 0.05) were observed. Combined IVIM-DKI texture showed high AUC of 0.83 for classification of PCa, BPH, and normal PZ. CONCLUSION: D, f, and k computed using the IVIM-DKI model with the TV method were able to differentiate PCa from BPH and normal PZ. Texture features of combined IVIM-DKI parameters showed high accuracy and AUC in PCa detection.
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Aprendizado de Máquina , Movimento (Física) , Neoplasias da Próstata , Humanos , Masculino , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologia , Idoso , Pessoa de Meia-Idade , Imagem de Difusão por Ressonância Magnética , Curva ROCRESUMO
The participation of both ligand and the metal center in the redox events has been recognized as one of the ways to attain the formal high valent complexes for the late 3d metals, such as Ni and Cu. Such an approach has been employed successfully to stabilize a Ni(III) bisphenoxyl diradical species in which there exist an equilibrium between the ligand and the Ni localized resultant spin. The present work, however, broadens the scope of the previously reported three oxidized equivalent species by conveying the approaches that tend to affect the reported equilibrium in CH3 CN at 233â K. Various spectroscopic characterization revealed that employing exogenous N-donor ligands like 1-methyl imidazole and pyridine favors the formation of the Ni centered localized spin though axial binding. In contrast, due to its steric hinderance, quinoline favors an exclusive ligand localized radical species. DFT studies shed light on the novel intermediates' complex electronic structure. Further, the three oxidized equivalent species with the Ni centered spin was examined for its hydrogen atom abstraction ability stressing their key role in alike reactions.
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This study aimed to investigate the three different methods for the fabrication of quercetin (1%-3% w/w of protein) incorporated soy protein isolate (SPI) films and their effect on material properties. The quercetin incorporated SPI films prepared by these methods were characterized by Fourier transform infrared (FTIR) spectroscopy, UV-Vis spectrophotometer, tensile properties, and water uptake and leaching properties. The cross-linking pattern was revealed by the FTIR spectrum that showed formation of an ester group because of interaction between the quercetin hydroxyl group and the carboxyl side chain of SPI amino acids. The tensile strength of SPI films were enhanced with the addition of quercetin as it increased to a maximum of 6.17 MPa while neat SPI film had tensile strength 4.13 MPa. The prepared films exhibit significant antibacterial activity against Listeria monocytogenes and Escherichia coli. The In-silico docking analysis demonstrates that covalent and non-covalent forces play crucial roles in binding interaction. It shows the formation of four hydrogen bonds, two salt bridges along with one pi-alkyl interaction. The simulation studies reflect the crucial amino acid residues involved in SPI-quercetin binding. The effect of quercetin binding with SPI on its stability and compactness is revealed by Root mean square deviation (RMSD) and radius of gyration studies.
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Quercetina , Proteínas de Soja , Proteínas de Soja/química , Simulação de Acoplamento Molecular , Quercetina/farmacologia , Resistência à Tração , Antibacterianos/farmacologiaRESUMO
OBJECTIVE: Rheumatoid arthritis (RA) has been associated with an elevated dementia risk. This study aimed to examine how different diagnostic dementia definitions perform in patients with RA compared to individuals without RA. METHODS: The study population included 2050 individuals (1025 with RA) from a retrospective, population-based cohort in southern Minnesota and compared the performance of 3 code-based dementia diagnostic algorithms with medical record review diagnosis of dementia. For the overall comparison, each patient's complete medical history was used, with no time frames. Sensitivity analyses were performed using 1-, 2-, and 5-year windows around the date that dementia was identified in the medical record (reference standard). RESULTS: Algorithms performed very similarly in persons with and without RA. The algorithms generally had high specificity, negative predictive values, and accuracy, regardless of the time window studied (> 88%). Sensitivity and positive predictive values varied depending on the algorithm and the time window. Sensitivity values ranged 56.5-95.9%, and positive predictive values ranged 55.2-83.1%. Performance measures declined with more restrictive time windows. CONCLUSION: Routinely collected electronic health record (EHR) data were used to define code-based dementia diagnostic algorithms with good performance (vs diagnosis by medical record review). These results can inform future studies that use retrospective databases, especially in the same or a similar EHR infrastructure, to identify dementia in individuals with RA.
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Acinetobacter species encode for extracellularly secreted Biofilm-associated protein (Bap), a multi-domain protein with variable molecular weights reaching several hundred kilodaltons. Bap is crucial for the development of multi-dimensional structures of mature biofilms. In our investigation, we analyzed 7338 sequences of A. baumannii from the NCBI database and found that Bap or Bap-like protein (BLP) was present in 6422 (87.52%) isolates. Further classification revealed that 12.12% carried Type-1 Bap, 68.44% had Type-2, 6.91% had Type-3, 0.05% had Type-6 or SDF-Type, and 12.51% lacked Bap or BLP. The majority of isolates with Type-1, Type-2, and Type-3 Bap belonged to ST1, ST2, and ST25, respectively. Phylogenetic analysis suggested that Type-1 Bap is the most ancient, while Type-3 and SDF-Type have evolved recently. Studying the interaction of predicted Bap structures with human CEACAM-1 and PIgR showed that Bap with its BIg13 and BIg6 domains interact with the N-terminal domain of CEACAM-1, involving Arg43 and Glu40, involved in CEACAM-1 dimerization. Also, we found that recently evolved Type-3 and SDF-Type Bap showed greater interaction with CEACAM-1 and PIgR. It can be asserted that the evolution of Bap has conferred enhanced virulence characteristics to A. baumannii with increased interaction with CEACAM-1 and PIgR. Using in silico approaches, this study explores the evolutionary, physicochemical, and structural features of A. baumannii Bap and unravels its crucial role in mediating interaction with human CEACAM-1 and PIgR through detailed structure modelling. These findings advance our understanding of A. baumannii Bap and highlight its role in pathogenesis.
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Acinetobacter baumannii , Proteínas de Bactérias , Biofilmes , Filogenia , Acinetobacter baumannii/genética , Acinetobacter baumannii/química , Acinetobacter baumannii/metabolismo , Biofilmes/crescimento & desenvolvimento , Proteínas de Bactérias/genética , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Humanos , Infecções por Acinetobacter/microbiologia , Evolução Molecular , Simulação por Computador , Modelos MolecularesRESUMO
BACKGROUND: Ketamine is increasingly used for treatment-resistant depression (TRD) while its mechanism of action is still being investigated. In this systematic review, we appraise the current evidence of metabolomic biomarkers for racemic ketamine and esketamine in patients with TRD and healthy controls (HCs). METHODS: A comprehensive search of several databases (Ovid MEDLINE®, Embase, and Epub Ahead of Print) was performed from each database's inception to June 29, 2022, in any language, was conducted. We included studies wherein the metabolomic biomarkers for racemic ketamine or esketamine were investigated in TRD or HCs. Our main outcomes were to examine changes in metabolites among patients treated with ketamine/esketamine and explore the association with response to ketamine/esketamine. RESULTS: A total of 1859 abstracts were screened of which 11 were included for full-text review. Of these, a total of five articles were included (N = 147), including three RCTs (n = 129) and two open-label trials (n = 18). All studies used racemic ketamine; one study additionally used esketamine. The included studies evaluated patients with treatment-resistant bipolar depression (n = 22), unipolar depression (n = 91), and HCs (n = 34). The included studies reported alteration in several metabolites including acylcarnitines, lipids, kynurenine (KYN), and arginine with ketamine in TRD. Studies suggest the involvement of energy metabolism, KYN, and arginine pathways. In HCs, acetylcarnitine decreased post-infusion, whereas inconsistent findings were observed after the ketamine infusion in TRD patients. CONCLUSIONS: This systematic review provides preliminary evidence that ketamine may cause changes in several important pathways involved in energy metabolism and inflammation. Larger and more rigorous studies are needed.
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Biomarcadores , Transtorno Depressivo Resistente a Tratamento , Ketamina , Metabolômica , Ketamina/farmacologia , Ketamina/uso terapêutico , Humanos , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Biomarcadores/metabolismo , Antidepressivos/farmacologiaRESUMO
Findings of early cerebral amyloid-ß deposition in mice after peripheral injection of amyloid-ß-containing brain extracts, and in humans following cadaveric human growth hormone treatment raised concerns that amyloid-ß aggregates and possibly Alzheimer's disease may be transmissible between individuals. Yet, proof that Aß actually reaches the brain from the peripheral injection site is lacking. Here, we use a proteomic approach combining stable isotope labeling of mammals and targeted mass spectrometry. Specifically, we generate 13 C-isotope-labeled brain extracts from mice expressing human amyloid-ß and track 13 C-lysine-labeled amyloid-ß after intraperitoneal administration into young amyloid precursor protein-transgenic mice. We detect injected amyloid-ß in the liver and lymphoid tissues for up to 100 days. In contrast, injected 13 C-lysine-labeled amyloid-ß is not detectable in the brain whereas the mice incorporate 13 C-lysine from the donor brain extracts into endogenous amyloid-ß. Using a highly sensitive and specific proteomic approach, we demonstrate that amyloid-ß does not reach the brain from the periphery. Our study argues against potential transmissibility of Alzheimer's disease while opening new avenues to uncover mechanisms of pathophysiological protein deposition.
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Doença de Alzheimer , Príons , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Humanos , Isótopos , Lisina , Mamíferos/metabolismo , Camundongos , Camundongos Transgênicos , Príons/metabolismo , ProteômicaRESUMO
Xanthomonas oryzae pv. oryzae (Xoo), the causative agent of bacterial blight (BB), has developed a unique strategy to infect rice by hijacking the host's methylglyoxal (MG) detoxification pathway. This results in an over-accumulation of MG, which facilitates tissue colonization and evasion of host's immune responses. While MG role in abiotic stresses is well-documented, its involvement in biotic stresses has not been extensively explored. Recently, Fu et al. (2024) provided the first evidence of MG role in promoting Xoo pathogenesis in rice. This new virulence strategy contributes to the pathogen's remarkable adaptability and survival. In this mechanism of hijacking of MG detoxification pathway, Xoo induces OsWRKY62.1 to inhibit OsGLY II expression, leading to MG overaccumulation in infected rice cells. This excess MG hinders plant cell organelle function, creating a favorable environment for Xoo by compromising the rice defense system. In this article, we have presented our perspectives on how the BB pathogen adapts its virulence mechanisms to infect and cause disease in rice.
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Oryza , Doenças das Plantas , Aldeído Pirúvico , Xanthomonas , Oryza/microbiologia , Oryza/metabolismo , Aldeído Pirúvico/metabolismo , Xanthomonas/patogenicidade , Xanthomonas/fisiologia , Doenças das Plantas/microbiologia , Virulência , Interações Hospedeiro-Patógeno , Inativação Metabólica , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Regulação da Expressão Gênica de PlantasRESUMO
Adhesion G protein-coupled receptor G4 (ADGRG4) is a G protein-coupled receptor (GPCR) that belongs to the adhesion family. Participation of ADGRG4 in cell adhesion and migration, signaling pathway activation, influence on angiogenesis, and modulation of immune responses are some of the possible ways through which it may contribute to oncogenesis. Conducting extensive omics studies poses budgetary challenges to small labs in peripheral areas, primarily due to restricted research funding and resource limitations. Here we propose a low-budget model for biomarker screening. A total of 11 ovarian cancer samples were sent for exome sequencing. Among various genes, ADGRG4 variants were present in all 11 samples and thus were chosen as a potential biomarker in the present population. However, the precise role of ADGRG4 in cancer is not fully understood. The present study aims to look at the association between the ADGRG4 gene variants and their risk of ovarian cancer in the North Indian region of Jammu and Kashmir, India. Overall, 235 individuals (115 cases and 120 healthy controls) were genotyped for the selected biomarker using Sanger sequencing. Logistic regression was used to assess the relationship between the variant and ovarian cancer. A statistically significant association was identified between the ADGRG4 variant rs5930932 polymorphism and the incidence of ovarian cancer among the study population. When corrected for age and BMI, the dominating OR of variant rs5930932 was 1.035 (1.003-1.069) under HWE patients (0.95) and controls (0.18), with a p-value of (0.03). According to the findings of the current investigation, the ADGRG4 gene variant rs5930932 increases the chance of developing ovarian cancer in the studied population.
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Biomarcadores Tumorais , Neoplasias Ovarianas , Humanos , Feminino , Biomarcadores Tumorais/genética , Sequenciamento do Exoma , Genótipo , Neoplasias Ovarianas/genética , Receptores Acoplados a Proteínas G/genética , Índia/epidemiologiaRESUMO
This study presents the synthesis and bio-evaluation of new triazolylated dihydropyridine and tetrahydropyridine azasugar scaffolds (F1-14). Azasugar glycomimetics are the synthetic substances that mimic the structural and functional characteristics of natural carbohydrates showcasing promising potential as therapeutic agents for diabetes. The α-glucosidase inhibitory activity of synthesized final compounds were evaluated against the commercially available α-glucosidase enzyme. Majority of the screened compounds displayed excellent inhibition with IC50 values ranging from 2.12 to 75.11 µM, when compared to the standard drug Acarbose. Particularly, compound F5 with IC50 value of 2.12 µM was found to be the most active compound among the series. Further molecular docking studies of selected ligands were performed to investigate the binding interactions with enzyme active sites. Their specific binding patterns have been analysed with the binding sites of Saccharomyces cerevisiae α-glucosidase. These findings suggest these candidates as the potential leads for the anti-diabetic activity.
Assuntos
Inibidores de Glicosídeo Hidrolases , alfa-Glucosidases , Estrutura Molecular , Relação Estrutura-Atividade , Inibidores de Glicosídeo Hidrolases/química , Simulação de Acoplamento Molecular , alfa-Glucosidases/metabolismo , Saccharomyces cerevisiaeRESUMO
The properties of biocarriers significantly influence the performance of a moving bed-biofilm reactor (MBBR). This study aimed to assess the impact of media type, filling ratio, and hydraulic retention time (HRT) on biofilm formation and MBBR performance in both batch and continuous setups using real municipal wastewater. Two different media, high-density polyethylene (HDPE) and polypropylene (PPE), with varying surface area and properties were used. Biofilm growth and MBBR performance were monitored and optimized using response surface methodology. The effect of different media was investigated for three filling ratios of 20%, 40% and 60% and HRT of 4, 6 and 8 h. Results depicted a better biofilm growth on HDPE media in comparison to PPE carriers due to difference in media structure and surface properties. At all the conditions tested, HDPE media showed comparatively better performance for the removal of organic matter and nutrients than PPE media. The maximum organic matter removal efficiency was found as 77% and 75% at an HRT of 6 h and filling ratio of 40% for HDPE and PPE media, respectively. The ammonia removal was also found better for HDPE media due to its geometry and structure favoring the anoxic conditions with maximum removal of 89% achieved at 6-h HRT and 40% filling ratio. Overall, the system with HDPE media indicated more stability in terms of reactor performance than PPE carriers with variations in the operating conditions.
Assuntos
Eliminação de Resíduos Líquidos , Águas Residuárias , Eliminação de Resíduos Líquidos/métodos , Biofilmes , Polietileno , Reatores BiológicosRESUMO
Dye industry plays an essential role in industrial development, contributing significantly to economic growth and progress. However, its rapid expansion has led to significant environmental concerns, especially water pollution and ecosystem degradation due to the discharge of untreated or inadequately treated dye effluents. The effluents introduce various harmful chemicals altering water quality, depleting oxygen levels, harming aquatic organisms, and disrupting food chains. Dye contamination can also persist in the environment for extended periods, leading to long-term ecological damage and threatening biodiversity. Therefore, the complex effects of dye pollutants on aquatic ecosystems have been comprehensively studied. Recently, zebrafish (Danio rerio) has proved to be an effective biomedical model for this study due to its transparent embryos allowing real-time observation of developmental processes and genetic proximity (approx. 87%) to humans for studying diverse biological responses. This review highlights the various toxicological effects of industrial dyes, including cardiovascular toxicity, neurotoxicity, genotoxicity, hepatotoxicity, and developmental toxicity. These effects have been observed at different developmental stages and dye concentrations in zebrafish. The review underscores that the structure, stability and chemical composition of dyes significantly influence toxicological impact, emphasizing the need for detailed investigation into dye degradation to better understand and mitigate the environmental and health risks posed by dye pollutants.