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Geraniol, an acyclic monoterpene alcohol, has significant potential applications in various fields, including: food, cosmetics, biofuels, and pharmaceuticals. However, the current sources of geraniol mainly include plant tissue extraction or chemical synthesis, which are unsustainable and suffer severely from high energy consumption and severe environmental problems. The process of microbial production of geraniol has recently undergone vigorous development. Particularly, the sustainable construction of recombinant Escherichia coli (13.2 g/L) and Saccharomyces cerevisiae (5.5 g/L) laid a solid foundation for the microbial production of geraniol. In this review, recent advances in the development of geraniol-producing strains, including: metabolic pathway construction, key enzyme improvement, genetic modification strategies, and cytotoxicity alleviation, are critically summarized. Furthermore, the key challenges in scaling up geraniol production and future perspectives for the development of robust geraniol-producing strains are suggested. This review provides theoretical guidance for the industrial production of geraniol using microbial cell factories.
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Conductive hydrogels have been increasingly employed to construct wearable mechanosensors due to their excellent mechanical flexibility close to that of soft tissues. In this work, piezoelectric hydrogels are prepared through free radical copolymerization of acrylamide (AM) and acrylonitrile (AN) and further utilized in assembling flexible wearable mechanosensors. Introduction of the polyacrylonitrile (PAN) component in the copolymers endows the hydrogels with excellent piezoelectric properties. Meanwhile, significant enhancement of mechanical properties has been accessed by forming dipole-dipole interactions, which results in a tensile strength of 0.51 MPa. Flexible wearable mechanosensors are fabricated by utilizing piezoelectric hydrogels as key signal converting materials. Self-powered piezoelectric pressure sensors are assembled with a sensitivity (S) of 0.2 V kPa-1. Additionally, resistive strain sensors (gauge factor (GF): 0.84, strain range: 0-250%) and capacitive pressure sensors (S: 0.23 kPa-1, pressure range: 0-8 kPa) are fabricated by utilizing such hydrogels. These flexible wearable mechanosensors can monitor diverse body movements such as joint bending, walking, running, and stair climbing. This work is anticipated to offer promising soft materials for efficient mechanical-to-electrical signal conversion and provides new insights into the development of various wearable mechanosensors.
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Resinas Acrílicas , Hidrogéis , Dispositivos Eletrônicos Vestíveis , Hidrogéis/química , Resinas Acrílicas/química , Humanos , Resistência à Tração , Acrilamida/químicaRESUMO
The off-stoichiometric compound Na3.12Fe2.44(P2O7)2 (NFPO) is a highly promising, cost-effective, and structurally robust cathode material for sodium-ion batteries (SIBs). However, the slowing Na-ion migration kinetics and poor interface stability have seriously limited its rate capability and air stability. In this work, we successfully synthesis a sodium titanium pyrophosphate (NaTiP2O7 donated as NTPO) coating NFPO (denoted as NFPO-NTPO) cathode material via a liquid phase coating method for SIBs. After optimizing NTPO content, at 0.1C, NFPO-NTPO-4 % cathode achieves a reversible specific capacity of 108.4 mAh g-1. Remarkably, it maintains 88.39 % capacity at 10C comparing to 0.1C and stabilizes over 3000 cycles with 92.66 % retention rate. Moreover, it retains 88.89 % capacity after 5000 cycles at 20C, even after 28 days of air exposure. The NFPO-Ti cathode, alongside the complete battery system, exhibits remarkable electrochemical performance across a broad temperature range spanning from -40 to 60 â.
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CONTEXT: This work introduces a method for generating generalized structures of amorphous polymers using simulated polymerization and molecular dynamics equilibration, with a particular focus on amorphous polymers. The techniques and algorithms used in this method are described in the main text, and example input scripts are provided for the GMXPolymer code, which is based on the GROMACS molecular dynamics package. To demonstrate the efficacy of our method, we apply it to different glassy polymers exhibiting varying degrees of functionality, polarity, and rigidity. The reliability of the method is validated by comparing simulation results with experimental data in various structural and thermal properties, both of which show excellent agreement. METHODS: This work implements the GMXPolymer simulated polymerization algorithm on the GROMACS program. GMXPolymer code controls the main polymerization loop. The energy minimizations and molecular dynamics simulations use the GROMACS program called by the GMXPolymer code. A new ITP file is generated when a new bond is formed, and the necessary additions to the ITP file are made to include new bonds, angles, and dihedrals. In preparing the ITP file of the monomer, the charge of the reactive atom must be modified before the code runs so that it is a correct value after bonding.
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Obesity increases the risk of kidney injury, involving various pathological events such as inflammation, insulin resistance, lipid metabolism disorders, and hemodynamic changes, making it a significant risk factor for the development and progression of chronic kidney disease. Diosmin, a natural flavonoid glycoside, exhibits anti-inflammatory, antioxidant, anti-lipid, and vasodilatory effects. However, whether diosmin has a protective effect on obesity-related kidney injury remains unclear. The molecular formula of diosmin was obtained, and diosmin and target genes related to obesity-related kidney injury were screened. The interaction between overlapping target genes was analyzed. GO functional enrichment and KEGG pathway enrichment analyses were performed on overlapping target genes. Molecular docking was employed to assess the binding strength between overlapping target genes. Palmitic acid-induced damage to HK-2 cells, which were then treated with diosmin. Subsequently, the expression levels of relevant mRNAs and proteins were measured. Network analysis identified 219 potential diosmin target genes, 6800 potential target genes related to obesity-related kidney injury, and 93 potential overlapping target genes. Protein-protein interaction networks and molecular docking results revealed that AKT1, TNF-α, SRC, EGFR, ESR1, CASP3, MMP9, PPAR-γ, GSK-3ß, and MMP2 were identified as key therapeutic targets, and they exhibited stable binding with diosmin. GO analysis indicated that these key targets may participate in inflammation, chemical stress, and protein phosphorylation. KEGG revealed that pathways in cancer, AGE-RAGE signaling pathway, PI3K-AKT signaling pathway, PPAR signaling pathway, and insulin resistance as crucial in treating obesity-related kidney injury. CCK-8 assay showed that diosmin significantly restored the viability of HK-2 cells affected by palmitic acid. Oil Red O staining demonstrated that diosmin significantly improved lipid deposition in HK-2 cells induced by palmitic acid. PCR results showed that diosmin inhibited the mRNA levels of AKT1, TNF-α, EGFR, ESR1, CASP3, MMP9, GSK-3ß, and MMP2 while promoting the mRNA level of PPAR-γ. Western blot analysis revealed that diosmin restored PPAR-γ protein expression, inhibited NF-kB p-p65 protein expression, and reduced TNF-α protein expression. Diosmin demonstrated multi-target and multi-pathway effects in the treatment of obesity-associated renal injury, with key targets including AKT1, TNF-α, EGFR, ESR1, CASP3, MMP9, PPAR-γ, GSK-3ß, and MMP2. The mechanism may be through the modulation of the PPAR-γ/NF-κB signaling pathway, which can attenuate inflammatory responses and protect the kidney.
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Renal calyceal neck atresia is a rare disorder. There is no clear guidance for standard treatment of this condition. The Memokath™ 045 temperature-controlled memory alloy stent is commonly used in the treatment of urethral strictures, but it has not been used for treating calyceal neck atresia. We present a case of a 44-year-old female patient with left lumbar pain who underwent two stages of treatment to resolve calyceal neck atresia located at the upper calyx of her left kidney. The first procedure was transurethral ureteroscopy combined with percutaneous recanalization of the left upper calyx calyceal neck atresia. One 6 F internal stent and one 8 F internal stent were placed, and she was discharged with a left nephrostomy tube. After her urinary tract infection was fully resolved, the patient returned for the second procedure of percutaneous upper renal calyx calyceal neck metal stent implantation. The temporary stents and nephrostomy tube were successfully removed. Our findings suggest that the Memokath™ 045 temperature-controlled memory alloy stent is an effective choice for treating calyceal neck atresia.
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Ligas , Cálices Renais , Stents , Humanos , Feminino , Adulto , Cálices Renais/cirurgia , Cálices Renais/anormalidades , Temperatura , Resultado do TratamentoRESUMO
Phosphodiesterases (PDEs) constitute a family of enzymes that play a pivotal role in the regulation of intracellular levels of cyclic nucleotides, including cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Dysregulation of PDE activity has been implicated in diverse pathological conditions encompassing cardiovascular disorders, pulmonary diseases, and neurological disorders. Small-molecule inhibitors targeting PDEs have emerged as promising therapeutic agents for the treatment of these ailments, some of which have been approved for their clinical use. Despite their success, challenges such as resistance mechanisms and off-target effects persist, urging continuous research for the development of next-generation PDE inhibitors. The objective of this review is to provide an overview of the synthesis and clinical application of representative approved small-molecule PDE inhibitors, with the aim of offering guidance for further advancements in the development of novel PDE inhibitors.
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Inibidores de Fosfodiesterase , Diester Fosfórico Hidrolases , Bibliotecas de Moléculas Pequenas , Animais , Humanos , Estrutura Molecular , Inibidores de Fosfodiesterase/farmacologia , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/química , Diester Fosfórico Hidrolases/metabolismo , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/síntese química , Relação Estrutura-Atividade , AMP Cíclico/química , AMP Cíclico/metabolismo , AMP Cíclico/farmacologiaRESUMO
BACKGROUND: A precise model for predicting outcomes is needed to guide perioperative management. With the developments of liver transplantation (LT) discipline, previous models may become inappropriate or noncomprehensive. Thus, we aimed to develop a novel model integrating variables from donors and recipients for quick assessment of transplant outcomes. METHODS: The risk model was based on Cox regression in a randomly selected derivation cohort and verified in a validation cohort. Perioperative data and overall survival were compared between stratifications grouped by X-tile. Receiver operating characteristic curve and decision curve analysis were used to compare the models. Violin and raincloud plots were generated to present post-LT complications distributed in different stratifications. RESULTS: Overall, 528 patients receiving LT from 2 centers were included with 2/3 in the derivation cohort and 1/3 in the validation cohort. Cox regression analysis showed that cold ischemia time (CIT) (P=0.012) and the Model for End-Stage Liver Disease (MELD) (P=0.007) score were predictors of survival. After comparison with the logarithmic models, the primitive algorithms of CIT and MELD were defined as the CIT-MELD Index (CMI). CMI was stratified by X-tile (grade 1 ≤1.06, 1.06< grade 2 ≤1.87, grade 3 >1.87). In both cohorts, CMI performed better in calculating transplant outcomes than the balance of risk score, including perioperative incidents and prevalence of complications. CONCLUSIONS: Model integrating variables from graft and recipient made the prediction more accurate and available. CMI provided new sight in outcome evaluation and risk factor management of LT.
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Organic room-temperature phosphorescence (RTP) and afterglow materials hold great potential for various applications, but there remain inherent trade-offs between the afterglow efficiency and the lifetime. Here, we propose a dual-mechanism design strategy, leveraging the RTP or thermally activated delayed fluorescence (TADF) mechanism for a high afterglow efficiency and the organic long-persistent luminescence (OLPL) mechanism for a prolonged afterglow duration. The intramolecular charge transfer (ICT)-type difluoroboron ß-diketonate molecules with a large S1 dipole moment are doped as the luminescent component into the organic matrix with a large dipole moment, and a series of TADF-type afterglow materials can be achieved with an afterglow efficiency of up to 88.7% and an afterglow lifetime of 200 ms. To prolong the afterglow duration, an electron donor is introduced as the third component to generate traps and facilitate charge separation. The obtained materials exhibit a dual afterglow mechanism, first exhibiting a TADF/RTP afterglow with an afterglow efficiency of up to 50.9%, followed by an hours-long OLPL afterglow emission with an afterglow efficiency of up to 13.1%. Further investigations reveal that an appropriate heavy-atom effect can facilitate the intersystem crossing process, which can promote the charge separation process and thus improve the OLPL afterglow performance. Additionally, rare-earth upconversion materials are introduced into OLPL materials to enable their near-infrared excitation properties, showcasing their potential applications in bioimaging.
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AIMS: To assess the correlation between high-sensitivity C-reactive protein (Hs-CRP) and the prevalence of cardiovascular disease (CVD) among individuals with diabetes. METHODS: A total of 1,555 participants from the National Health and Nutrition Examination Survey were enrolled in this cross-sectional study after excluding individuals without diabetes and those who lacked data on Hs-CRP, diabetes and CVD. All participants were divided into four groups based on quartiles of Hs-CRP: Q1 (≤ 1.20 mg/L), Q2 (1.20-2.86 mg/L), Q3 (2.86-6.40 mg/L), and Q4 (> 6.40 mg/L). Logistic regression analysis, subgroup analysis and restricted cubic spline (RCS) analysis were used to evaluate the correlation between Hs-CRP and the prevalence of CVD in individuals with diabetes. RESULTS: In univariate logistic regression analysis, a higher level of Hs-CRP was associated with a higher prevalence of CVD (P < 0.05). In the multivariate logistic regression analysis adjusting for confounders, the correlation between Hs-CRP and the prevalence of CVD remained significant (Q3 vs. Q1, OR: 1.505, 95% CI: 1.056-2.147, P = 0.024; Q4 vs. Q1, OR: 1.711, 95% CI: 1.171-2.499, P = 0.006; log10(Hs-CRP), OR: 1.504, 95% CI: 1.168-1.935, P = 0.002). Further subgroup analysis showed that a higher Hs-CRP was independently associated with a higher prevalence of CVD in the < 60 years, male, non-hypertension and non-hypercholesterolemia subgroups (P < 0.05). Additionally, RCS analysis revealed a linear positive correlation between Hs-CRP and CVD prevalence (P for nonlinearity = 0.244). CONCLUSION: A higher level of Hs-CRP was closely related to a higher prevalence of CVD in people with diabetes.
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Biomarcadores , Proteína C-Reativa , Doenças Cardiovasculares , Diabetes Mellitus , Inquéritos Nutricionais , Humanos , Masculino , Proteína C-Reativa/análise , Proteína C-Reativa/metabolismo , Pessoa de Meia-Idade , Feminino , Estudos Transversais , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Prevalência , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/sangue , Diabetes Mellitus/diagnóstico , Biomarcadores/sangue , Adulto , Idoso , Fatores de Risco , Modelos Lineares , Análise Multivariada , Modelos Logísticos , Regulação para Cima , Razão de Chances , Medição de RiscoRESUMO
Bark beetles, major pests that bore into forest stems, cause significant economic damage to forests globally. (+)-α-Pinene is the precursor to (+)-cis-verbenol, a crucial component of the aggregation pheromones produced by bark beetles. This paper describes the de novo synthesis of (+)-cis-verbenol in Escherichia coli. Initially, the truncation position of (+)-α-pinene synthase (PtPS30 from Pinus taeda) and monoterpene precursor (geranyl diphosphate/neryl diphosphate) synthases were evaluated. Neryl diphosphate synthase from Solanum lycopersicum (SlNPPS1) and truncated (+)-α-pinene synthase (PtPS30-39) were selected as promising candidates. Subsequently, the titer of (+)-α-pinene was significantly increased 8.9-fold by using the fusion tag CM29, which enhanced the solubility of PtPS30-39. In addition, by optimizing expression elements (ribosomal binding sites, linkers, and up elements) and overexpressing CM29*PtPS30-39, a yield of 134.12 mg/L (+)-α-pinene was achieved. Finally, the first de novo synthesis of enantiopure (+)-cis-verbenol was achieved by introducing a cytochrome P450 mutant from Pseudomonas putida (P450camF89W,Y98F,L246A), resulting in a yield of 11.13 mg/L. This study lays the groundwork for developing verbenol-based trapping technology for controlling bark beetles.
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Monoterpenos Bicíclicos , Escherichia coli , Pinus , Escherichia coli/genética , Escherichia coli/metabolismo , Monoterpenos Bicíclicos/química , Monoterpenos Bicíclicos/metabolismo , Pinus/química , Monoterpenos/metabolismo , Monoterpenos/química , Animais , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Proteínas de Plantas/química , Solanum lycopersicum/metabolismo , Engenharia MetabólicaRESUMO
BACKGROUND: Humankind have been struggling with colorectal cancer (CRC) for long period with its rapid progression and invasive metastasis. By hyperactivating IL-6/STAT3 signaling, CRC facilitates the capacity of angiogenesis to plunder massive nutrients and develops gradually under harsh condition. METHODS: The Cancer Genome Atlas database was analyzed for acquiring interferon-γ inducible protein 10 (IFITM10) expression levels and their correlation with clinical outcomes. The cell angiogenic ability were assessed by Cell Counting Kit-8 (CCK-8) and tube formation assay. Immunofluorescence, Western blot, and enzyme-linked immunosorbent assay (ELISA) assay were using to assess potential mechanism. RESULTS: In our study, we find that IFITM10 is upregulated in CRC and is positively related with tumor angiogenesis. We also find that IFITM inhibition decreased STAT3 phosphorylation level and IFITM10-mediated angiogenesis depends on STAT3 activation. Furthermore, our data suggests that IFITM10 may be a key prognostic biomarker in colorectal cancer. CONCLUSION: Together, our study suggests that IFITM10 enhance angiogenesis through STAT3 activation during CRC progression, which highlighting its potency as a therapeutic target for colorectal cancer.
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Neoplasias Colorretais , Progressão da Doença , Neovascularização Patológica , Fator de Transcrição STAT3 , Fator de Transcrição STAT3/metabolismo , Humanos , Neovascularização Patológica/metabolismo , Neovascularização Patológica/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/irrigação sanguínea , Linhagem Celular Tumoral , Transdução de Sinais , Regulação Neoplásica da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/metabolismo , Fosforilação , Prognóstico , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Angiogênese , Antígenos de DiferenciaçãoRESUMO
Cell therapy represents a promising treatment modality. A critical component in the production of cell therapy products is maintaining the sterility of cell therapy clean rooms (CTCRs). This study aimed to evaluate the environmental microbial load within CTCRs. We systematically monitored microbial load in CTCRs, following established guidelines. Cultured microbial samples underwent metagenomic sequencing, and alpha and beta diversity analyses, functional annotation, and resistance gene profiling were performed using various bioinformatics tools to assess microbial diversity and function. From November 2023 to January 2024, we collected 42 environmental microbial colony samples from various sources within the CTCR and performed metagenomic sequencing on 39 samples. Alpha diversity analysis revealed no significant differences among surface, settle_plate, and airborne categories, but significant disparities within surface subgroups were revealed. Beta diversity analysis showed notable differences between surface and airborne categories and among surface subgroups. Species distribution analysis identified Bacillus as the predominant genus on surfaces. Functional annotation and resistance gene analysis indicated distinct resistance patterns, with significant variations between subgroups, such as microscopes and transfer windows, and hands and other Grade_B environments. Resistance to hydrogen peroxide was notably higher in the transfer window group. These findings highlight the importance of stringent disinfection protocols and enhanced hand hygiene to maintain sterility in CTCRs. These findings provide valuable insights for implementing effective measures to maintain cleanliness throughout CTCRs. The annotation and study of resistance genes can help rapidly identify methods to control cellular contamination under circumstances of environmental microbial pollution.IMPORTANCEMaintaining the sterility of cell therapy clean rooms (CTCRs) is crucial for the production of safe and effective cell therapy products. Our study systematically evaluated the environmental microbial load within CTCRs, revealing significant microbial diversity and distinct resistance patterns to disinfection methods. These findings underscore the need for stringent disinfection protocols and enhanced hand hygiene practices to ensure CTCR sterility. By identifying key microbial species and their resistance genes, our research provides essential insights into controlling contamination and safeguarding the production environment, ultimately contributing to the reliability and success of cell therapy treatments.
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Glycogen-autophagy ('glycophagy') is a selective autophagy process involved in delivering glycogen to the lysosome for bulk degradation. Glycophagy protein intermediaries include STBD1 as a glycogen tagging receptor, delivering the glycogen cargo into the forming phagosome by partnering with the Atg8 homolog, GABARAPL1. Glycophagy is emerging as a key process of energy metabolism and development of reliable tools for assessment of glycophagy activity is an important priority. Here we show that antibodies raised against the N-terminus of the GABARAPL1 protein (but not the full-length protein) detected a specific endogenous GABARAPL1 immunoblot band at 18kDa. A stable GFP-GABARAPL1 cardiac cell line was used to quantify GABARAPL1 lysosomal flux via measurement of GFP puncta in response to lysosomal inhibition with bafilomycin. Endogenous glycophagy flux was quantified in primary rat ventricular myocytes by the extent of glycogen accumulation with bafilomycin combined with chloroquine treatment (no effect observed with bafilomycin or chloroquine alone). In wild-type isolated mouse hearts, bafilomycin alone and bafilomycin combined with chloroquine (but not chloroquine alone) elicited a significant increase in glycogen content signifying basal glycophagy flux. Collectively, these methodologies provide a comprehensive toolbox for tracking cardiac glycophagy activity to advance research into the role of glycophagy in health and disease.
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PURPOSE: Shaping and assembling contemporary external fixators rapidly for the severe mandibular fractures remains a challenge, especially in emergency circumstance. We designed a novel external fixator that incorporates universal joints to provide the stabilization for mandibular comminuted fractures. This study aims to confirm the efficacy of this novel external fixator through biomechanical tests in vitro and animal experiments. METHODS: In vitro biomechanical tests were conducted using 6 fresh canine with mandibular defect to simulate critical comminuted fractures. Three mandibles were stabilized by the novel external fixator and other mandibles were fixed by 2.5 mm reconstruction plates. All fixed mandibles were subjected to loads of 350 N on the anterior regions of teeth and 550 N on the first molar of the unaffected side. The stability was evaluated based on the maximum displacement and the slope of the load-displacement curve. In animal experiments, 9 beagles with comminuted mandibular fractures were divided into 3 groups, which were treated with the novel external fixation, reconstruction plate, and dental arch bar, respectively. The general observation, the changes in animals' weight, and the surgical duration were recorded and compared among 3 groups. The CT scans were performed at various intervals of 0 day (immediately after the surgery), 3 days, 7 days, 14 days, 21 days, and 28 days to analyze the displacement of feature points on the canine mandible and situation of fracture healing at 28 days. The statistical significance was assessed by the two-way analysis of variance test followed by the Bonferroni test, enabling multiple comparisons for all tests using GraphPad Prism10.1.0 (GraphPad Inc, USA). RESULTS: The outcomes of the biomechanical tests indicated that no statistically significant differences were found in terms of the maximum displacement (p = 0.496, 0.079) and the slope of load displacement curves (p = 0.374, 0.349) under 2 load modes between the external and internal fixation groups. The animal experiment data showed that there were minor displacements of feature points between the external and internal fixation groups without statistic difference, while the arch bar group demonstrated inferior stability. The CT analysis revealed that the best fracture healing happened in the internal fixation group, followed by the external fixation and arch baring at 28 days after fixation. The external fixation group had the shortest fixation duration (25.67 ± 3.79) min compared to internal fixation ((70.67 ± 4.51) min, p < 0.001) and arch baring ((42.00 ± 3.00) min, p = 0.046). CONCLUSION: The conclusion of this study highlighted the efficacy and reliability of this novel external fixator in managing mandibular fractures rapidly, offering a viable option for the initial stabilization of comminuted mandibular fractures in the setting of emergency rescue.
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Fixadores Externos , Fixação de Fratura , Fraturas Cominutivas , Fraturas Mandibulares , Animais , Fraturas Mandibulares/cirurgia , Fraturas Mandibulares/diagnóstico por imagem , Fraturas Cominutivas/cirurgia , Cães , Fixação de Fratura/métodos , Fenômenos BiomecânicosRESUMO
This comprehensive review undertakes a meticulous scrutiny of the synthesis and clinical applications pertaining to small-molecule tyrosine kinase inhibitors (TKIs) directed towards the human epidermal growth factor receptor 2 (HER2), a pivotal protagonist in the pathogenesis of cancer. Focused on compounds like lapatinib, neratinib, and tucatinib, the review delves into the intricate synthesis strategies, emphasizing the challenges associated with their structural complexity. The clinical utilization of HER2 TKIs underscores noteworthy strides in the therapeutic landscape for HER2-positive breast and gastric malignancies. Lapatinib, a dual HER2/ epidermal growth factor receptor (EGFR) inhibitor, has demonstrated efficacy in combination therapies, addressing the need for overcoming resistance mechanisms. Neratinib, an irreversible HER2 inhibitor, presents a promising avenue for patients with refractory tumors. Tucatinib, strategically engineered to traverse the blood-brain barrier, epitomizes a groundbreaking advancement in the management of metastatic HER2-positive breast cancer manifesting cerebral involvement. Despite their success, challenges such as resistance mechanisms and off-target effects persist, urging continuous research for the development of next-generation HER2 TKIs. This comprehensive review serves as a valuable resource for pharmaceutical scientists, offering insights into the synthetic intricacies and clinical impact of small-molecule TKIs targeting HER2.
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Antineoplásicos , Inibidores de Proteínas Quinases , Receptor ErbB-2 , Humanos , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/síntese química , Estrutura Molecular , Neoplasias/tratamento farmacológico , Neoplasias/patologiaRESUMO
The putamen has been proposed to play a critical role in the development of obsessive-compulsive disorder (OCD). The primary objective of this study was to examine the resting-state regional activity and functional connectivity patterns of the putamen in individuals diagnosed with OCD. To achieve this, we employed resting-state functional magnetic resonance imaging (rs-fMRI) to collect data from a sample of 45 OCD patients and 53 healthy control participants. We aimed to use the regional amplitude of low-frequency fluctuation (ALFF) analysis to generate the ROI masks of the putamen and then conduct the whole brain functional connectivity of the putamen in individuals with OCD. Compared to controls, the OCD group demonstrated decreased ALFF in bilateral putamen. The right putamen also displayed decreased FC with the left putamen extending to the inferior frontal gyrus (IFG), bilateral precuneus extending to calcarine, the right middle occipital cortex extending to the right middle temporal cortex, and the left middle occipital gyrus. The decreased connectivity between the right putamen and the left IFG was negatively correlated with Yale-Brown Obsessive Compulsive scale (Y-BOCS) Obsession Scores. This study aimed to reveal the putamen changes in resting-state activity and connectivity in OCD patients, highlighting the significance of aberrant ALFF/FC of the putamen is a key characteristic of OCD.
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Imageamento por Ressonância Magnética , Vias Neurais , Transtorno Obsessivo-Compulsivo , Putamen , Humanos , Transtorno Obsessivo-Compulsivo/fisiopatologia , Transtorno Obsessivo-Compulsivo/diagnóstico por imagem , Transtorno Obsessivo-Compulsivo/patologia , Putamen/diagnóstico por imagem , Putamen/fisiopatologia , Masculino , Feminino , Adulto , Adulto Jovem , Vias Neurais/diagnóstico por imagem , Vias Neurais/fisiopatologia , Mapeamento Encefálico , Descanso , Processamento de Imagem Assistida por ComputadorRESUMO
Since gastric cancer shows no apparent signs in its early stages, most patients are diagnosed later with a poor prognosis. We therefore seek more sensitive and specific GC biomarkers. Small RNAs formed from tRNAs represent a novel class of non-coding RNAs that are highly abundant in bodily fluids and essential to biological metabolism. This study explores the potential of i-tRF-AsnGTT in gastric cancer diagnostics. To begin with, we sequenced i-tRF-AsnGTT using high-throughput methods. i-tRF-AsnGTT expression levels in GC were determined using real-time fluorescence PCR. Agarose gel electrophoresis, Sanger sequencing, and repeated freezing and thawing were performed to verify molecular properties. A correlation was found between clinical and pathological parameters and i-tRF-AsnGTT expression levels through the χ² test, and ROC was used to analyze its diagnostic value in GC. In serum, i-tRF-AsnGTT has a low and stable expression level. It can differentiate between patients with gastric cancer and gastritis and healthy donors with better diagnostic efficacy. In combination with clinicopathological parameters, i-tRF-AsnGTT correlates with tumor differentiation, infiltration depth of tumors, TNM stage, lymph node metastases, and neural/vascular invasion. Serum i-tRF-AsnGTT expression is low in GC patients. Serum from postoperative patients shows increased i-tRF-AsnGTT expression levels. Potentially, this could be used as a biomarker to help diagnose gastric cancer and monitor its prognosis.