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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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Fluorine possesses distinctive chemical characteristics, such as its strong electron-withdrawing ability and small atomic size, which render it an invaluable asset in the design and optimization of pharmaceuticals. The utilization of fluorine-enriched medications for combating cancer has emerged as a prominent approach in medicinal chemistry and drug discovery, offering improved clinical outcomes and enhanced pharmacological properties. This comprehensive review explores the synthetic approaches and clinical applications of approved 22 representative fluorinated anti-cancer drugs from 2019 to present, shedding light on their historical development, brand names, drug target activity, mechanism of action, preclinical pharmacodynamics, clinical efficacy, and toxicity. Additionally, the review provides an extensive analysis of the representative synthetic techniques employed. Overall, this review emphasizes the significance of incorporating fluorine chemistry into anti-cancer drug research while highlighting promising future prospects for exploring compounds enriched with fluorine in the battle against cancer.
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Antineoplásicos , Flúor , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Flúor/química , Neoplasias/tratamento farmacológico , Animais , Estrutura MolecularRESUMO
INTRODUCTION: Alzheimer's disease (AD) and atherosclerosis (AS) are widespread diseases predominantly observed in the elderly population. Despite their prevalence, the underlying molecular interconnections between these two conditions are not well understood. METHODS: Utilizing meta-analysis, bioinformatics methodologies, and the GEO database, we systematically analyzed transcriptome data to pinpoint key genes concurrently differentially expressed in AD and AS. Our experimental validations in mouse models highlighted the prominence of two genes, NKRF (NF-κB-repressing factor) and ZBTB17 (MYC-interacting zinc-finger protein 1). RESULTS: These genes appear to influence the progression of both AD and AS by modulating the NF-κB signaling pathway, as confirmed through subsequent in vitro and in vivo studies. CONCLUSIONS: This research uncovers a novel shared molecular pathway between AD and AS, underscoring the significant roles of NKRF and ZBTB17 in the pathogenesis of these disorders.
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Doença de Alzheimer , Aterosclerose , NF-kappa B , Transdução de Sinais , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Humanos , Animais , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , NF-kappa B/metabolismo , NF-kappa B/genética , Aterosclerose/genética , Aterosclerose/metabolismo , Camundongos , Transcriptoma , Perfilação da Expressão Gênica , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Camundongos TransgênicosRESUMO
BACKGROUND: Although evidence on the association between per- and polyfluoroalkyl substances (PFASs) and human health outcomes has grown exponentially, specific health outcomes and their potential associations with PFASs have not been conclusively evaluated. METHODS: We conducted a comprehensive search through the databases of PubMed, Embase, and Web of Science from inception to February 29, 2024, to identify systematic reviews with meta-analyses of observational studies examining the associations between the PFASs and multiple health outcomes. The quality of included studies was evaluated using the A Measurement Tool to Assess Systematic Reviews (AMSTAR) tool, and credibility of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) criteria. The protocol of this umbrella review (UR) had been registered in PROSPERO (CRD 42023480817). RESULTS: The UR identified 157 meta-analyses from 29 articles. Using the AMSTAR measurement tool, all articles were categorized as of moderate-to-high quality. Based on the GRADE assessment, significant associations between specific types of PFASs and low birth weight, tetanus vaccine response, and triglyceride levels showed high certainty of evidence. Moreover, moderate certainty of evidence with statistical significance was observed between PFASs and health outcomes including lower BMI z-score in infancy, poor sperm progressive motility, and decreased risk of preterm birth as well as preeclampsia. Fifty-two (33%) associations (e.g., PFASs and gestational hypertension, cardiovascular disease, etc) presented low certainty evidence. Additionally, eighty-five (55%) associations (e.g., PFASs with infertility, lipid metabolism, etc) presented very low certainty evidence. CONCLUSION: High certainty of evidence supported that certain PFASs were associated with the incidence of low birth weight, low efficiency of the tetanus vaccine, and low triglyceride levels.
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Fluorocarbonos , Revisões Sistemáticas como Assunto , Humanos , Gravidez , Estudos Observacionais como Assunto , Metanálise como Assunto , Recém-Nascido de Baixo Peso , Feminino , Poluentes Ambientais , Toxoide Tetânico , Triglicerídeos/sangueRESUMO
Objective: Co-occurrence of pediatric asthma and obesity has been widely reported, yet the causal directions between these two disorders are still not well-understood. The objective of this meta-analysis is to explore whether there is a possibility of a bidirectional association for these two disorders in children and adolescents. Methods: PubMed, Embase, Web of Science, and CENTRAL databases were searched up to August 2020. Cohort studies reporting the associations of obesity with risk of physician-diagnosed asthma or physician-diagnosed asthma with risk of obesity in children and adolescents were eligible for the review. Results: A total of 3,091 records were identified from the four databases, with final inclusion of nine. Six studies reported the association between obesity and risk of asthma; three studies reported the association between asthma and risk of childhood obesity. As evaluated by the Newcastle-Ottawa quality assessment scale, all studies were assessed as high-quality studies. There was a statistically significant association between obesity and increased risk of physician-diagnosed asthma in children and adolescents. The pooled RR was 1.39 (95% CI: 1.28, 1.50; p < 0.001), with significant heterogeneity across studies (I 2 = 81.7%; p heterogeneity < 0.001). The pooled RR in boys was 1.53 (95% CI: 1.17, 1.99; p = 0.002), but such a significant association was not observed in girls (RR = 1.17, 95% CI: 0.79, 1.72; p = 0.434). For the association of asthma with risk of childhood obesity, the pooled RR was 1.47 (95%CI: 1.25, 1.72; p < 0.001) without statistical heterogeneity (I 2 = 0%, p heterogeneity = 0.652). Conclusion: There is a bidirectional association between obesity and asthma during childhood and adolescence, suggesting that childhood obesity drives an increase in the onset of asthma; meanwhile, childhood asthma may also increase risk of obesity for children and adolescents.
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BACKGROUND: The prevalence of Mycoplasma pneumoniae pneumonia has increased considerably in recent years. To evaluate the efficacy of combined treatment of azithromycin with intravenous immunoglo-bulin (IVIG) or methylprednisolone in children with refractory Mycoplasma pneumoniae pneumonia (RMPP). METHODS: Children with RMPP were randomly allocated to group A [intravenous azithromycin (IA)+ methylprednisolone], group B (IA+IVIG) or group C (IA alone). Following a 7-day treatment, group C patients were randomly separated into two sub-groups: group C1 (IA+methylprednisolone) and group C2 (IA+IVIG). Temperature, respiratory symptoms and signs were examined. The average febrile period after treatment (F2), average total febrile period (F3), infiltration absorption, atelectasis resolution, pleural effusion disappearance were determined. The levels of C-reactive protein (CRP), D-dimer, and lactate dehydrogenase (LDH) were measured. RESULTS: Seven days after enrollment, the average F2 after treatment of group A was the shortest. Compared with the control group C, the combined treatment group A and B showed higher rates of infiltration absorption, atelectasis resolution and pleural effusion disappearance, while lower levels of serum CRP, D-dimer and LDH. Fourteen days after enrollment, all children with combined therapy clinically improved, and presented better laboratory results. Group C1 showed shorter F3 and lower levels of CRP and LDH than those of group C2. Overall, group A showed the shortest F3, also has the lowest CRP and LDH. CONCLUSIONS: Azithromycin with IVIG or methylprednisolone was better treatment for children with RMPP than azithromycin alone. IVIG treatment may be beneficial, especially when the efficacy of corticosteroids is insecure, thus could be considered as an alternative of primary therapeutic approaches.