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BACKGROUND: Hexokinase (HK) is the first rate-limiting enzyme of glycolysis, which can convert glucose to glucose-6-phosphate. There are several subtypes of HK, including HK2, which is highly expressed in a variety of different tumors and is closely associated with survival. METHODS: Non-small cell lung cancer (NSCLC) A549 cells with stable overexpression and knockdown of HK2 were obtained by lentivirus transfection. The effects of overexpression and knockdown of HK2 on proliferation, migration, invasion, and glycolytic activity of A549 cells were investigated. The effects on apoptosis were also analyzed using western blot and flow cytometry. In addition, the mitochondria and cytoplasm were separated and the expression of apoptotic proteins was detected by western blot respectively. RESULTS: Upregulation of HK2 could promote glycolysis, cell proliferation, migration, and invasion, which would be inhibited through the knockdown of HK2. HK2 overexpression contributed to cisplatin resistance, whereas HK2 knockdown enhanced cisplatin-induced apoptosis in A549 cells. CONCLUSIONS: Overexpression of HK2 can promote the proliferation, migration, invasion, and drug resistance of A549 cells by enhancing aerobic glycolysis and inhibiting apoptosis. Reducing HK2 expression or inhibiting HK2 activity can inhibit glycolysis and induce apoptosis in A549 cells, which is expected to be a potential treatment method for NSCLC.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/patologia , Cisplatino/farmacologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Hexoquinase/genética , Hexoquinase/metabolismo , Pulmão/patologia , Linhagem Celular Tumoral , Proliferação de Células , ApoptoseRESUMO
A series of tacrine-pyrazolo[3,4-b]pyridine hybrids were synthesised and evaluated as dual cholinesterase (ChE) and phosphodiesterase 4D (PDE4D) inhibitors for the treatment of Alzheimer's disease (AD). Compound 10j, which is tacrine linked with pyrazolo[3,4-b]pyridine moiety by a six-carbon spacer, was the most potent acetylcholinesterase (AChE) with IC50 value of 0.125⯵M. Moreover, compound 10j provided a desired balance of AChE and butylcholinesterase (BuChE) and PDE4D inhibition activities, with IC50 value of 0.449 and 0.271⯵M, respectively. The above results indicated that this hybrid was a promising dual functional agent for the treatment of AD.
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Doença de Alzheimer/tratamento farmacológico , Colinesterases/uso terapêutico , Inibidores de Fosfodiesterase/uso terapêutico , Piridinas/síntese química , Colinesterases/farmacologia , Humanos , Estrutura Molecular , Inibidores de Fosfodiesterase/farmacologia , Relação Estrutura-AtividadeRESUMO
A series of compounds with monoamine oxidase inhibition and biometal chelation activities were designed, synthesised and evaluated as agents against Alzheimer's disease. The in vitro assay shows that most target compounds exhibit good MAO-B activities with submicromolar IC50 values and antioxidant activity (1.49-5.67 ORAC-FL values). The selected compounds were used to determine the biometal chelating ability using UV-vis spectrometry and high-resolution mass spectrometry, which confirm that they can effectively interact with copper(II), iron(II) and zinc(II). The ThT fluorescence binding assay indicates that the synthetic compounds can inhibit Cu(II)-induced Aß1-42 aggregation. The parallel artificial membrane permeation assay shows that most target compounds can cross the BBB. Based on these results, compound 8a was selected as a potential multifunctional agent for the treatment of AD.
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Antioxidantes/síntese química , Quelantes/síntese química , Inibidores da Monoaminoxidase/síntese química , Monoaminoxidase/química , Selegilina/síntese química , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/química , Antioxidantes/farmacologia , Cátions Bivalentes , Permeabilidade da Membrana Celular , Quelantes/farmacologia , Cobre/química , Humanos , Ferro/química , Membranas Artificiais , Simulação de Acoplamento Molecular , Inibidores da Monoaminoxidase/farmacologia , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/química , Agregados Proteicos/efeitos dos fármacos , Espécies Reativas de Oxigênio/antagonistas & inibidores , Selegilina/farmacologia , Soluções , Zinco/químicaRESUMO
[This corrects the article DOI: 10.1016/j.isci.2024.109057.].
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Triple-negative breast cancer (TNBC) has attracted attention due to its poor prognosis and limited treatment options. The mechanisms underlying the association between circular RNAs (circRNAs) and the occurrence and development of TNBC remain unclear. CircZCCHC2 is observed to be upregulated in TNBC cells, tissues, and plasma exosomes. Knockdown of circZCCHC2 inhibited the proliferation, migration, invasion, and epithelial-mesenchymal transition of TNBC cells in vitro and in vivo. Pirarubicin (THP) treatment downregulated circZCCHC2, and circZCCHC2 affected the sensitivity to THP. CircZCCHC2/miR-1200/translocated promoter region, the nuclear basket protein (TPR) pathway was cascaded and verified. It is demonstrated that circZCCHC2 plays a crucial role in the malignant progression of TNBC via the miR-1200/TPR axis, thereby activating the RAS-RAF-MEK-ERK pathway. The present results indicate that circZCCHC2 has the potential to serve as a novel prognostic biomarker for TNBC.
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A series of berberine-thiophenyl hybrids were designed, synthesised, and evaluated as inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) and ß-amyloid (Aß) aggregation and as antioxidants. Among these hybrids, compounds 4f and 4i, berberine linked with o-methylthiophenyl and o-chlorothiophenyl by a 2-carbon spacer, were observed to be potent inhibitors of AChE, with IC50 values of 0.077 and 0.042 µM, respectively. Of the tested compounds, 4i was also the most potent inhibitor of BuChE, with an IC50 value of 0.662 µM. Kinetic studies and molecular modelling simulations of the AChE-inhibitor complex indicated that a mixed-competitive binding mode existed for these berberine derivatives. The biological studies also demonstrated that these hybrids displayed interesting activities, including Aß aggregation inhibition and antioxidant properties.
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Acetilcolinesterase/química , Peptídeos beta-Amiloides/química , Antioxidantes/síntese química , Berberina/análogos & derivados , Berberina/química , Butirilcolinesterase/química , Inibidores da Colinesterase/síntese química , Fenóis/química , Compostos de Sulfidrila/química , Acetilcolinesterase/metabolismo , Peptídeos beta-Amiloides/metabolismo , Antioxidantes/química , Berberina/síntese química , Berberina/metabolismo , Sítios de Ligação , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/metabolismo , Desenho de Fármacos , Peróxido de Hidrogênio/química , Cinética , Simulação de Acoplamento Molecular , Ligação Proteica , Estrutura Terciária de ProteínaRESUMO
OBJECTIVE: Trastuzumab is the preferred drug for the treatment of breast cancer. However, research on the cellular mechanisms of trastuzumab's potential cardiotoxicity is insufficient. The purpose of this study was to explore the toxic effects and potential mechanism of action of trastuzumab on cardiomyocytes. METHOD: Human Cardiomyocyte (HCM) viability was assessed using the MTT method. HCM apoptosis was detected using the Hoechst33342/PI Fluorescent staining. The LDH and CK activities of the cell were measured using commercially available LDH and CK assay kits. The expression levels of Notch2, JAK2, STAT3, cleaved caspase 3, bax, and bcl 2 in HCMs were detected using western blotting. RESULTS: The results showed that 250 mg/L trastuzumab induced cardiomyocyte injury and apoptosis, inhibited viability, activated the Notch2 receptor, and inhibited JAK2/STAT3 expression in HCM. Inhibition of Notch2 expression in HCM by targeted siNotch2 transfection reversed the trastuzumab-induced injury and apoptosis, and the expression of JAK2/STAT3 returned to normal levels. CONCLUSIONS: Trastuzumab induces Notch2 expression by inhibiting the JAK2/STAT3 pathway of HCMs, promotes cell apoptosis, and causes cardiomyocyteinjury. Notch2 may be a potential target of trastuzumab-inducedmyocardial injury. This experiment reveals the mechanism of trastuzumab-induced cardiotoxicity, providing a theoretical basis for the application of trastuzumab.
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Cardiotoxicidade , Miócitos Cardíacos , Humanos , Miócitos Cardíacos/metabolismo , Trastuzumab/efeitos adversos , Trastuzumab/metabolismo , Cardiotoxicidade/etiologia , Cardiotoxicidade/metabolismo , Receptor Notch2/metabolismo , Apoptose , Janus Quinase 2/metabolismo , Janus Quinase 2/farmacologia , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/farmacologiaRESUMO
A novel series of boron-containing compounds were designed, synthesized and evaluated as multi-target-directed ligands against Alzheimer's disease. The biological activity results demonstrated that these compounds possessed a significant ability to inhibit self-induced Aß aggregation (20.5-82.8%, 20 µM) and to act as potential antioxidants (oxygen radical absorbance capacity assay using fluorescein (ORAC-FL) values of 2.70-5.87). In particular, compound 17h is a potential lead compound for AD therapy (IC50 = 3.41 µM for self-induced Aß aggregation; ORAC-FL value = 4.55). Compound 17h also functions as a metal chelator. These results indicated that boron-containing compounds could be new structural scaffolds for the treatment of AD.
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Abstract Objective Trastuzumab is the preferred drug for the treatment of breast cancer. However, research on the cellular mechanisms of trastuzumab's potential cardiotoxicity is insufficient. The purpose of this study was to explore the toxic effects and potential mechanism of action of trastuzumab on cardiomyocytes. Method Human Cardiomyocyte (HCM) viability was assessed using the MTT method. HCM apoptosis was detected using the Hoechst33342/PI Fluorescent staining. The LDH and CK activities of the cell were measured using commercially available LDH and CK assay kits. The expression levels of Notch2, JAK2, STAT3, cleaved caspase 3, bax, and bcl 2 in HCMs were detected using western blotting. Results The results showed that 250 mg/L trastuzumab induced cardiomyocyte injury and apoptosis, inhibited viability, activated the Notch2 receptor, and inhibited JAK2/STAT3 expression in HCM. Inhibition of Notch2 expression in HCM by targeted siNotch2 transfection reversed the trastuzumab-induced injury and apoptosis, and the expression of JAK2/STAT3 returned to normal levels. Conclusions Trastuzumab induces Notch2 expression by inhibiting the JAK2/STAT3 pathway of HCMs, promotes cell apoptosis, and causes cardiomyocyteinjury. Notch2 may be a potential target of trastuzumab-inducedmyocardial injury. This experiment reveals the mechanism of trastuzumab-induced cardiotoxicity, providing a theoretical basis for the application of trastuzumab.
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Recently, phosphodiesterase-9 (PDE9) inhibitors and biometal-chelators have received much attention as potential therapeutics for the treatment of Alzheimer's disease (AD). Here, we designed, synthesized, and evaluated a novel series of PDE9 inhibitors with the ability to chelate metal ions. The bioassay results showed that most of these molecules strongly inhibited PDE9 activity. Compound 16 showed an IC50 of 34 nM against PDE9 and more than 55-fold selectivity against other PDEs. In addition, this compound displayed remarkable metal-chelating capacity and a considerable ability to halt copper redox cycling. Notably, in comparison to the reference compound clioquinol, it inhibited metal-induced Aß(1-42) aggregation more effectively and promoted greater disassembly of the highly structured Aß fibrils generated through Cu(2+)-induced Aß aggregation. These activities of 16, together with its favorable blood-brain barrier permeability, suggest that 16 may be a promising compound for treatment of AD.