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1.
J Trace Elem Med Biol ; 86: 127516, 2024 Aug 30.
Artículo en Inglés | MEDLINE | ID: mdl-39226872

RESUMEN

BACKGROUND: Myocardial infarction (MI) is the result of reduced or stopped blood supply to a section of the myocardium. Regardless of its potential effectiveness in the treatment of several types of cancers, doxorubicin (DOX) capabilities are restricted because of its widespread cardiotoxic impact. AIM: In this study, the protective effect of zinc oxide nanoparticles against doxorubicin-induced myocardial infarction in rats is examined. METHODS: Zinc oxide nanoparticles (ZnO NPs) were synthesized and characterized using X-ray diffraction, transmission electron microscope, and UV-Vis spectral analysis. A total cumulative dose of DOX (18 mg/kg body weight, i.p.) was injected once daily on days 2, 4, 6, 8, 10, and 12 (i.p.) to induce MI in rats. 24 rats were divided into 4 groups; control, MI, and MI treated with two doses of ZnO NPs (45 and 22.5 mg/kg). RESULTS: The treatment with ZnO NPs restored ST-segment near normal, ameliorated the changes in cardiac troponin T, creatine kinase, lactate dehydrogenase, aspartate aminotransferase, alanine amino transferase, alkaline phosphatase, total proteins, malondialdehyde, nitric oxide, reduced glutathione, and catalase.The histological investigation revealed that ZnO NPs treated group showed marked improvement in the examined cardiac muscle and liver in numerous sections.The lower dose of ZnO NPs (22.5 mg/kg) was significantly more effective than the higher dose (45 mg/kg). CONCLUSION: The effect of ZnO NPs against doxorubicin-induced myocardial infarction in rats was assessed and the results revealed a successful cardioprotective potency through enhancing the antioxidant system and stimulating nitric oxide production in myocardial infarcted rats. This work implies that ZnO NPs could serve as promising agents for treating doxorubicin-induced cardiotoxicity.

2.
Heliyon ; 10(10): e31082, 2024 May 30.
Artículo en Inglés | MEDLINE | ID: mdl-38813143

RESUMEN

The reaction of sulfamethoxazolehydrazonoyl chloride with thiosemicarbazones, bis-thiosemicarbazones, or 4-amino-3-mercapto-1,2,4-triazole in dioxane in the presence of triethylamine as a basic catalyst at reflux resulted in the regioselective synthesis of thiazoles and bis-thiazoles linked to azo-sulfamethoxazole as novel hybrid molecules. The structures of the new compounds were confirmed using a range of spectra. Each compound's antibacterial properties were evaluated using the agar well-diffusion technique, and most of them demonstrated significant potency. In silico investigations revealed that the described compounds had strong interactions with the binding sites of MurE ligase, tyrosyl-tRNA synthetase, and dihydropteroate synthase, demonstrating inhibitory activity.

3.
J Inorg Biochem ; 253: 112488, 2024 04.
Artículo en Inglés | MEDLINE | ID: mdl-38325158

RESUMEN

Herein, we report the synthesis and biological evaluation of [Pd(L)(OH2)Cl] complex (where L = 2,2'-(pyridin-2-ylmethylene)bis(5,5-dimethylcyclohexane-1,3-dione) as a novel promising anticancer candidate. The complex was characterized by single-crystal X-ray diffraction and other various spectroscopic techniques. Besides, the optimized structure was determined through DFT calculations revealing that the coordination geometry of [Pd(L)(OH2)Cl] complex is square planar. The binding propensity of [Pd(L)(OH2)Cl] complex with DNA and BSA was assessed by the spectrophotometric method. The antimicrobial profile of the ligand and its [Pd(L)(OH2)Cl] complex was screened against clinically important bacterial strains. [Pd(L)(OH2)Cl] complex showed promising activity against these microorganisms. Pd(L)(OH2)Cl] complex exhibited a potent antiproliferative potential compared to its ligand against different human cancer cells (A549, HCT116, MDA-MB-231, and HepG2) with less toxic effect against normal cells (WI-38). Additionally, [Pd(L)(OH2)Cl] complex exerted its anticancer effects against the most responsive cells (HCT116 cells; IC50 = 11 ± 1 µM) through suppressing their colony-forming capabilities and triggering apoptosis and cell cycle arrest at S phase. Quantitative PCR analysis revealed a remarkable upregulation of the mRNA expression level of p53 and caspase-3 by 4.8- and 5.9-fold, respectively, relative to control. Remarkable binding properties and non-covalent interactions between L and its [Pd(L)(OH2)Cl] complex with the binding sites of different receptors including CDK2, MurE ligase, DNA, and BSA were established using molecular docking. Based on our results, [Pd(L)(OH2)Cl] complex is an intriguing candidate for future investigations as a potential anticancer drug for the treatment of colon cancer.


Asunto(s)
Antineoplásicos , Complejos de Coordinación , Ciclohexanonas , Humanos , Paladio/farmacología , Paladio/química , Simulación del Acoplamiento Molecular , Ligandos , Antineoplásicos/química , ADN/química , Complejos de Coordinación/química , Línea Celular Tumoral
4.
J Biomol Struct Dyn ; : 1-19, 2024 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-38373066

RESUMEN

In the light of anticancer drug discovery and development, a new series of cyanochalcones incorporating indole moiety (5a-g) were efficiently synthesized and characterized by different spectral analysis. MTT assay was used to evaluate the antiproliferative activity of the synthesized compounds towards different cancer cells (Hela, MDA-MB-231, A375, and A549) in parallel with normal cells (HSF). Trimethoxy and diethoxy-containing derivatives (5d and 5e) displayed the most selective cytotoxic activities against cervical Hela cells with IC50 values of 8.29 and 11.82 µM, respectively, with great safety pattern toward normal HSF cells (Selectivity index: 21.3 and 13.9, respectively). Therefore, 5d and 5e were chosen to study their effects on apoptosis, cell cycle arrest, and migration of Hela cells using flow cytometric analysis and wound healing assay. They induced apoptosis and cell cycle arrest at the S phase and impaired migration of HeLa cells. Regarding their effects on the expression profile of crucial genes related to the potential anticancer activities, 5d and 5e remarkably upregulated caspase 3 and Beclin1 and downregulated cyclin A1, CDK2, CDH2, MMP9, and HIF1A using qRT-PCR and ELISA techniques. UV-Vis spectral measurement demonstrated the ability of 5d and 5e to bind CT-DNA efficiently with Kb values of 3.7 × 105 and 1 × 105 M-1, respectively. Moreover, in silico molecular docking was performed to assess the binding affinities of the compounds toward the active sites of Bcl2, CDK2, and DNA. Therefore, cyanochalcones 5d and 5e might be promising anticancer agents and could offer a scientific basis for intensive research into cancer chemotherapy.Communicated by Ramaswamy H. Sarma.


A novel series of cyanochalcones incorporating indole moiety (5a­g) were designed and synthesized.Cytotoxic activities of the designed compounds were evaluated in vitro against different human cancer cell lines (Hela, MDA-MB-231, A375, and A549) in parallel with human normal cells (HSF).5d and 5e stimulated apoptosis (through deregulating Bcl2 and upregulating Cas3), cell cycle arrest at the S phase (by suppressing cyclin A and CDK2), and inhibited migration (through downregulating CDH2 and MMP9) of Hela cells.5d and 5e demonstrated good DNA binding affinities.Molecular docking was carried out to confirm the binding abilities of 5d and 5e toward Bcl2, CDK2, and DNA.

5.
Chem Biodivers ; 21(4): e202301341, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38314957

RESUMEN

In the light of advancement and potential extensive use of medication design and therapy, new bis(cyanoacrylamides) incorporating sulphamethoxazole derivatives (7 a-7 f) were synthesized and confirmed by different spectral tools. In vitro anticancer activity towards different human cancer cells (HCT116, MDA-MB-231 and A549) was assessed using MTT assay. Among all derivatives, 4C- and 6C-spacer derivatives (7 e and 7 f) had the most potent growth inhibitory activities against HCT116 cells with IC50 values of 39.7 and 28.5 µM, respectively. 7 e and 7 f induced apoptosis and suppressed migration of HCT116 cells. These compounds also induced a significant increase in caspase-3 and CDH1 activities, and a downregulation of Bcl2 using ELISA. pBR322 DNA cleavage activities of cyanoacrylamides were determined using agarose gel electrophoresis. Furthermore, 7 e and 7 f showed good DNA and BSA binding affinities using different spectroscopic techniques. Furthermore, molecular docking for 7 e and 7 f was performed to anticipate their binding capabilities toward various proteins (Bcl2, CDH1 and BSA). The docking results were well correlated with those of experimental results. Additionally, density functional theory and ADMET study were performed to evaluate the molecular and pharmacokinetic features of 7 e and 7 f, respectively. Thus, this work reveals promising antitumor lead compounds that merit future research and activity enhancement.


Asunto(s)
Antineoplásicos , Humanos , Relación Estructura-Actividad , Estructura Molecular , Simulación del Acoplamiento Molecular , Antineoplásicos/química , Proliferación Celular , ADN , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Ensayos de Selección de Medicamentos Antitumorales
6.
Chem Biodivers ; 19(9): e202100958, 2022 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-36045280

RESUMEN

The cyclocondensation reaction of aldehydes with dimedone and bis(6-aminopyrimidin-4-one) in acetic acid led to the formation of the corresponding bis(pyrimido[4,5-b]quinoline-4,6-diones) which are known as bis(sulfanediyl)bis(tetrahydro-5-deazaflavin) analogs in a single step. Also, bis(pyrimido[4,5-b]quinoline-4,6-diones) which are linked to naphthyl core via phenoxymethyl linkage is prepared. The interactions of the synthesized compounds with DNA and bovine serum albumin (BSA) were studied. Gel electrophoresis assay was used to show the capability of the compounds to photocleave the supercoiled pBR322 plasmid DNA in UV-A (365 nm). Besides, the most photocleavable compound, bis(tetrahydropyrimido[4,5-b]quinoline-4,6-dione) linked to pyridin-3-yl at position-5 exhibits good binding affinities toward CT-DNA and BSA as supported by UV/VIS spectral studies. In addition to the experimental findings, a molecular docking simulation was performed to collect detailed binding data for this compound to both biomolecules.


Asunto(s)
Quinolinas , Albúmina Sérica Bovina , Aldehídos , ADN/química , Flavinas , Simulación del Acoplamiento Molecular , Naftalenos , Unión Proteica , Quinolinas/química , Albúmina Sérica Bovina/química
7.
Neurotox Res ; 40(4): 1103-1114, 2022 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-35699891

RESUMEN

An inherent challenge that mitochondria face is the continuous exposure to diverse stresses which increase their likelihood of dysregulation. In response, human cells have evolved sophisticated quality control mechanisms to identify and eliminate abnormal dysfunctional mitochondria. One pivotal mitochondrial quality control pathway is PINK1/Parkin-dependent mitophagy which mediates the selective removal of the dysfunctional mitochondria from the cell by autophagy. PTEN-induced putative kinase 1 (PINK1) is a mitochondrial Ser/Thr kinase that was originally identified as a gene responsible for autosomal recessive early-onset Parkinson's disease (PD). Notably, upon failure of mitochondrial import, Parkin, another autosomal-recessive PD gene, is recruited to mitochondria and mediates the autophagic clearance of deregulated mitochondria. Importantly, recruitment of Parkin to damaged mitochondria hinges on the accumulation of PINK1 on the outer mitochondrial membrane (OMM). Normally, PINK1 is imported from the cytosol through the translocase of the outer membrane (TOM) complex, a large multimeric channel responsible for the import of most mitochondrial proteins. After import, PINK1 is rapidly degraded. Thus, at steady-state, PINK1 levels are kept low. However, upon mitochondrial import failure, PINK1 accumulates and forms a high-molecular weight > 700 kDa complex with TOM on the OMM. Thus, PINK1 functions as sensor, tagging dysfunctional mitochondria for Parkin-mediated mitophagy. Although much has been learned about the function of PINK1 in mitophagy, the biochemical and structural basis of negative regulation of PINK1 operation and functions is far from clear. Recent work unveiled new players as PTEN-l as negative regulator of PINK1 function. Herein, we review key aspects of mitophagy and PINK1/Parkin-mediated mitophagy with highlighting the role of negative regulation of PINK1 function and presenting some of the key future directions in PD cell biology.


Asunto(s)
Mitofagia , Enfermedad de Parkinson , Humanos , Mitocondrias/metabolismo , Fosfohidrolasa PTEN/metabolismo , Enfermedad de Parkinson/metabolismo , Proteínas Quinasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo
8.
Curr Protein Pept Sci ; 23(3): 129-132, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35598241

RESUMEN

One salient hallmark of neurodegeneration is the accumulation of toxic protein aggregates in neuronal cells. This proteotoxicity culminates in the deterioration of neuronal function. In AD and related tauopathies, the microtubule-associated protein tau becomes hyperphosphorylated. Hyperphosphorylated tau forms neurofibrillary tangles (NFTs) within neurons, which constitute a unique feature of tauopathies, including AD. A recent study has exploited a novel molecular strategy to counteract hyperphosphorylated tau and enhance its degradation. Analogous to the PROTAC methodology, a novel dephosphorylation targeting chimera (DEPTAC) was designed to promote the molecular interaction between tau and phosphatase, which, in turn, augments its degradation. Herein, we briefly discuss this novel finding and its potential therapeutic implications.


Asunto(s)
Enfermedad de Alzheimer , Tauopatías , Enfermedad de Alzheimer/metabolismo , Humanos , Ovillos Neurofibrilares/metabolismo , Neuronas/metabolismo , Fosforilación , Tauopatías/genética , Tauopatías/metabolismo , Proteínas tau/genética , Proteínas tau/metabolismo
9.
Physiol Rev ; 102(4): 1721-1755, 2022 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-35466694

RESUMEN

As a central hub for cellular metabolism and intracellular signaling, the mitochondrion is a pivotal organelle, dysfunction of which has been linked to several human diseases including neurodegenerative disorders and in particular Parkinson's disease. An inherent challenge that mitochondria face is the continuous exposure to diverse stresses that increase their likelihood of dysregulation. In response, eukaryotic cells have evolved sophisticated quality control mechanisms to monitor, identify, repair, and/or eliminate abnormal or misfolded proteins within the mitochondrion and/or the dysfunctional mitochondrion itself. Chaperones identify unstable or otherwise abnormal conformations in mitochondrial proteins and can promote their refolding to recover their correct conformation and stability. However, if repair is not possible, the abnormal protein is selectively degraded to prevent potentially damaging interactions with other proteins or its oligomerization into toxic multimeric complexes. The autophagic-lysosomal system and the ubiquitin-proteasome system mediate the selective and targeted degradation of such abnormal or misfolded protein species. Mitophagy (a specific kind of autophagy) mediates the selective elimination of dysfunctional mitochondria, to prevent the deleterious effects of the dysfunctional organelles within the cell. Despite our increasing understanding of the molecular responses toward dysfunctional mitochondria, many key aspects remain relatively poorly understood. Here, we review the emerging mechanisms of mitochondrial quality control including quality control strategies coupled to mitochondrial import mechanisms. In addition, we review the molecular mechanisms regulating mitophagy, with an emphasis on the regulation of PINK1/Parkin-mediated mitophagy in cellular physiology and in the context of Parkinson's disease cell biology.


Asunto(s)
Enfermedad de Parkinson , Autofagia , Humanos , Mitocondrias/metabolismo , Mitofagia/fisiología , Enfermedad de Parkinson/metabolismo , Proteínas Quinasas/metabolismo , Proteínas Quinasas/farmacología
10.
RSC Adv ; 12(3): 1871-1884, 2022 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-35425175

RESUMEN

A novel Pd(ii) double complex, [Pd(BAPP)][PdCl4], containing the 1,4-bis(3-aminopropyl)piperazine (BAPP) ligand is investigated. X-ray crystallography of a single crystal confirmed the structure of the [Pd(BAPP)][PdCl4] complex. The spectroscopic behavior was also elucidated using elemental analysis, nuclear magnetic resonance and Fourier-transform infrared spectroscopy, and mass spectrometry. The antimicrobial susceptibility of the [Pd(BAPP)][PdCl4] complex against all tested microbial strains was lower than that of the BAPP ligand except for C. albicans. The cytotoxic impacts of the BAPP ligand and its [Pd(BAPP)][PdCl4] complex were evaluated in vitro for HepG2, CaCo-2 and MCF7 cell lines as well as the WI-38 normal cell line. The anticancer activity was markedly improved by the complexation. The [Pd(BAPP)][PdCl4] complex could selectively inhibit the tested cancer cells in a safe way to the non-tumorigenic cell (WI-38). From the DNA binding studies with ultraviolet-visible spectrophotometry, the [Pd(BAPP)][PdCl4] complex interacts more efficiently with the calf thymus DNA than its BAPP ligand through the intercalative binding mode. In the absence of an external reductant, the [Pd(BAPP)][PdCl4] complex cleaved the intact supercoiled pBR322 DNA under physiological conditions in a concentration-dependent manner. Additionally, electrophoretic experiments were performed in the presence of different radical scavengers, namely DMSO, NaN3 and KI, and ruled out the hydrolytic mechanistic pathway of the reaction and suggested that the oxidative mechanism is the preferred one. The results of the binding affinity of the [Pd(BAPP)][PdCl4] complex to human DNA were modeled using a molecular docking study showing that the complex interacts more strongly with human DNA than the ligand. Finally, an in vitro pharmacokinetic study was assessed through in silico ADME predictions.

11.
Neurotox Res ; 40(1): 298-318, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-35043375

RESUMEN

Among the most salient features that underpin the development of aging-related neurodegenerative disorders are the accumulation of protein aggregates and the decrease in cellular degradation capacity. Mammalian cells have evolved sophisticated quality control mechanisms to repair or eliminate the otherwise abnormal or misfolded proteins. Chaperones identify unstable or abnormal conformations in proteins and often help them regain their correct conformation. However, if repair is not an option, abnormal proteins are selectively degraded to prevent undesired interactions with other proteins or oligomerization into toxic multimeric complexes. The autophagic-lysosomal system and the ubiquitin-proteasome system mediate the selective and targeted degradation of abnormal or aberrant protein fragments. Despite an increasing understanding regarding the molecular responses that counteract the formation and clearance of dysfunctional protein aggregates, the role of N-degrons in these processes is poorly understood. Previous work demonstrated that the Arg-N-end rule degradation pathway (Arg-N-degron pathway) mediates the degradation of neurodegeneration-associated proteins, thereby regulating crucial signaling hubs that modulate the progression of neurodegenerative diseases. Herein, we discuss the functional interconnection between N-degron pathways and proteins associated with neurodegenerative disorders, including Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease. We also highlight some future prospects related to how the molecular insights gained from these processes will help unveil novel therapeutic approaches.


Asunto(s)
Enfermedades Neurodegenerativas , Ubiquitina , Animales , Mamíferos/metabolismo , Chaperonas Moleculares/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteolisis , Ubiquitina/metabolismo
12.
Dalton Trans ; 50(42): 15389-15399, 2021 Nov 02.
Artículo en Inglés | MEDLINE | ID: mdl-34647551

RESUMEN

Reaction between [RuCl2(CO)2]n and 1H-benzimidazol-2-ylmethyl-(N-phenyl)amine ligands (LR) functionalized with various electron-donating and electron-withdrawing substituents on the phenyl ring (R = H, 4-CH3, 4-Cl, 4-COOCH3, and 3-COOCH3) afforded the dark-stable photoactivatable carbon monoxide prodrugs of the general formula [RuCl2(CO)2LR]. Release of the CO molecules from the Ru(II) compounds was examined by monitoring the electronic and IR spectra upon illumination at 365 nm. A noticeable decrease in the intensities of the two characteristic ν(CO) modes for Ru(CO)II2 species, and the growth of two new bands for the mono-carbonyl species and free CO, were the main features of the photolysis profiles. The cytotoxicity of the complexes towards breast cancer (MCF-7) cells was assessed with and without illumination at 365 nm. All the complexes except that with a 4-COOCH3 group (IC50 = 45.08 ± 3.5 µM) are nontoxic under dark conditions. Upon illumination, all the compounds acquired cytotoxicity in the following order: H > 4-COOCH3 > 4-CH3 > 4-Cl > 3-COOCH3. Investigation of the cytotoxicity of the CO-depleted fragments showed that the light-induced cytotoxicity can be attributed to the liberated CO and CO-depleted metal fragments, including the liberated benzimidazole ligands.


Asunto(s)
Neoplasias de la Mama
13.
Anticancer Agents Med Chem ; 21(2): 246-253, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-32416702

RESUMEN

BACKGROUND: Identification of factors to detect and improve chemotherapy.response in cancer is the main concern. microRNA-372-3p (miR-372-3p) has been demonstrated to play a crucial role in cellular proliferation, apoptosis and metastasis of various cancers including Hepatocellular Carcinoma (HCC). However, its contribution towards Doxorubicin (Dox) chemosensitivity in HCC has never been studied. OBJECTIVE: This study aims to investigate the potential role of miR-372-3p in enhancing Dox effects on HCC cell line (HepG2). Additionally, the correlation between miR-372-3p and HCC patients who received Transarterial Chemoembolization (TACE) with Dox treatment has been analyzed. METHODS: Different cell processes were elucidated by cell viability, colony formation, apoptosis and wound healing assays after miR-372-3p transfection in HepG2 cells Furthermore, the miR-372-3p level has been estimated in the blood of primary HCC patients treated with TACE/Dox by quantitative real-time PCR assay. Receiver Operating Curve (ROC) analysis for serum miR-372-3p was constructed for its prognostic significance. Finally, the protein level of Mcl-1, the anti-apoptotic player, has been evaluated using western blot. RESULTS: We found a significantly higher level of miR-372-3p in the blood of the responder group of HCC patients who received TACE with Dox than of non-responders. Ectopic expression of miR-372-3p reduced cell proliferation, migration and significantly induced apoptosis in HepG2 cells which was coupled with a decrease of anti-apoptotic protein Mcl-1. CONCLUSION: Our study demonstrated that miR-372-3p acts as a tumor suppressor in HCC and can act as a predictor biomarker for drug response. Furthermore, the data referred for the first time its potential role in drug sensitivity that might be a therapeutic target for HCC.


Asunto(s)
Antibióticos Antineoplásicos/administración & dosificación , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Doxorrubicina/administración & dosificación , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , MicroARNs/genética , Antibióticos Antineoplásicos/farmacología , Antibióticos Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/diagnóstico , Quimioembolización Terapéutica , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Genes Supresores de Tumor/efectos de los fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/diagnóstico , Pronóstico
14.
Anticancer Agents Med Chem ; 21(2): 237-245, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-32357822

RESUMEN

BACKGROUND: Doxorubicin (DOX) is one of the most common drugs used in cancer therapy, including Hepatocellular Carcinoma (HCC). Drug resistance is one of chemotherapy's significant problems. Emerging studies have shown that microRNAs (miRNAs) could participate in regulating this mechanism. Nevertheless, the impact of miRNAs on HCC chemoresistance is still enigmatic. OBJECTIVE: Investigating the role of microRNA-520c-3p (miR-520c-3p) in the enhancement of the anti-tumor effect of DOX against HepG2 cells. METHODS: Expression profile for liver-related miRNAs (384 miRNAs) has been analyzed on HepG2 cells treated with DOX using qRT-PCR. miR-520c-3p, the most deregulated miRNA, was selected for combination treatment with DOX. The expression level for LEF1, CDK2, CDH1, VIM, Mcl-1 and p53 was evaluated in miR-520c-3p transfected cells. Cell viability, colony formation, wound healing as well as apoptosis assays have been demonstrated. Furthermore, Mcl-1 protein level was measured using the western blot technique. RESULTS: The present data indicated that miR-520c-3p overexpression could render HepG2 cells chemo-sensitive to DOX through enhancing its suppressive effects on proliferation, migration, and induction of apoptosis. The suppressive effect of miR-520c-3p involved altering the expression levels of some key regulators of cell cycle, proliferation, migration and apoptosis, including LEF1, CDK2, CDH1, VIM, Mcl-1 and p53. Interestingly, Mcl-1 was found to be one of the potential targets of miR-520c-3p, and its protein expression level was down-regulated upon miR-520c-3p overexpression. CONCLUSION: Our data referred to the tumor suppressor function of miR-520c-3p that could modulate the chemosensitivity of HepG2 cells towards DOX treatment, providing a promising therapeutic strategy in HCC.


Asunto(s)
Antibióticos Antineoplásicos/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Doxorrubicina/farmacología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , MicroARNs/genética , Apoptosis/efectos de los fármacos , Carcinoma Hepatocelular/patología , Ciclo Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Genes Supresores de Tumor/efectos de los fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/patología
15.
Bioessays ; 43(2): e2000212, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33210303

RESUMEN

Autophagy functions in both selective and non-selective ways to maintain cellular homeostasis. Endoplasmic reticulum autophagy (ER-phagy) is a subclass of autophagy responsible for the degradation of the endoplasmic reticulum through selective encapsulation into autophagosomes. ER-phagy occurs both under physiological conditions and in response to stress cues, and plays a crucial role in maintaining the homeostatic control of the organelle. Although specific receptors that target parts of the ER membrane, as well as, internal proteins for lysosomal degradation have been identified, the molecular regulation of ER-phagy has been elusive. Recent work has uncovered novel regulators of ER-phagy that involve post-translational modifications of ER-resident proteins and functional cross-talk with other cellular processes. Herein, we discuss how morphology affects the function of the peripheral ER, and how ER-phagy modulates the turnover of this organelle. We also address how ER-phagy is regulated at the molecular level, considering implications relevant to human diseases.


Asunto(s)
Estrés del Retículo Endoplásmico , Proteínas de la Membrana , Autofagia , Retículo Endoplásmico/metabolismo , Humanos , Proteínas de la Membrana/metabolismo , Procesamiento Proteico-Postraduccional
17.
Dalton Trans ; 49(27): 9294-9305, 2020 Jul 17.
Artículo en Inglés | MEDLINE | ID: mdl-32578643

RESUMEN

Two series of photoinduced tricarbonyl manganese(i) compounds were prepared from the reaction of [MnBr(CO)3(2-C(H)[double bond, length as m-dash]O)] (2-C(H)[double bond, length as m-dash]O: quinoline-2-carboxaldehyde and pyridine-2-carboxaldehyde) and para-substituted aniline derivatives (X = OH, OCH3, Cl and NO2). Different electron-donating and electron-withdrawing substituents were introduced in the para-position of the phenyl ring to investigate their influence on the stability of the compounds in the dark and the photophysical properties upon illumination at 525 nm. When kept in the dark, the aerated solutions of the complexes in dimethyl sulfoxide (DMSO) and CH2Cl2 were stable. In the solution, the complexes bearing electron-withdrawing substituents, exchange their bromo ligands with DMSO solvent molecules, as evidenced from infrared and UV/Vis studies as well as time-dependent density functional theory (TDDFT) calculations. The complexes were assessed for their cytotoxicity, both in the dark and upon exposure to a 525 nm LED, against the human hepatocarcinoma cell line (HepG2). A marked reduction in the viability of HepG2 cells treated with the complex functionalized with quinoline and methoxy substituent was observed after illumination in a dose-dependent manner, with an IC50 value of 7.1 µM, making it the most phototoxic compound in our study.


Asunto(s)
Antineoplásicos/farmacología , Complejos de Coordinación/farmacología , Manganeso/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Monóxido de Carbono/análisis , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Teoría Funcional de la Densidad , Ensayos de Selección de Medicamentos Antitumorales , Células Hep G2 , Humanos , Manganeso/química , Conformación Molecular , Células Tumorales Cultivadas
18.
Curr Genet ; 66(4): 693-701, 2020 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-32157382

RESUMEN

Parkinson's disease (PD) is a progressive neurodegenerative condition characterized by a gradual loss of a specific group of dopaminergic neurons in the substantia nigra. Importantly, current treatments only address the symptoms of PD, yet not the underlying molecular causes. Concomitantly, the function of genes that cause inherited forms of PD point to mitochondrial dysfunction as a major contributor in the etiology of PD. An inherent challenge that mitochondria face is the continuous exposure to diverse stresses including high levels of reactive oxygen species and protein misfolding, which increase their likelihood of dysregulation. In response, eukaryotic cells have evolved sophisticated quality control mechanisms to identify, repair and/or eliminate abnormal dysfunctional mitochondria. One such mechanism is mitophagy, a process which involves PTEN-induced putative kinase 1 (PINK1), a mitochondrial Ser/Thr kinase and Parkin, an E3 ubiquitin ligase, each encoded by genes responsible for early-onset autosomal recessive familial PD. Over 100 loss-of-function mutations in the PTEN-induced putative kinase 1 (PINK1) gene have been reported to cause autosomal recessive early-onset PD. PINK1 acts upstream of Parkin and is essential for the mitochondrial localization and activation of Parkin. Upon mitochondrial damage, PINK1 builds up on the outer mitochondrial membrane (OMM) and mediates the activation of Parkin. Activated Parkin then ubiquitinates numerous OMM proteins, eliciting mitochondrial autophagy (mitophagy). As a result, damaged mitochondrial components can be selectively eliminated. Thus, PINK1 acts a sensor of damage via fine-tuning of its levels on mitochondria, where it activates Parkin to orchestrate the clearance of unhealthy mitochondria. Previous work has unveiled that the Arg-N-end rule degradation pathway (Arg-N-degron pathway) mediates the degradation of PINK1, and thus fine-tune PINK1-dependent mitochondrial quality control pathway. Herein, we briefly discuss the interconnection between N-end rule degradation pathways and mitophagy in the context of N-degron mediated degradation of mitochondrial kinase PINK1 and highlight some of the future prospects.


Asunto(s)
Mitocondrias/metabolismo , Proteínas Mitocondriales/metabolismo , Proteínas Quinasas/metabolismo , Animales , Glicina/metabolismo , Redes y Vías Metabólicas , Mitocondrias/genética , Membranas Mitocondriales/metabolismo , Proteínas Mitocondriales/genética , Mitofagia , Mutación , Enfermedad de Parkinson/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteínas Quinasas/genética , Proteolisis , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo
19.
Curr Genet ; 66(3): 501-505, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-32060627

RESUMEN

Mitochondrial dysregulation is a pivotal hallmark of aging-related disorders. Although there is a considerable understanding of the molecular counteracting responses toward damaged mitochondria, the molecular underpinnings connecting the abnormal aggregation of mitochondrial precursor protein fragments and abrogation of mitochondrial import machinery are far from clear. Recently, proteasomal-dependent degradation was unveiled as a pivotal fine-tuner of TOM machinery-dependent mitochondrial import. Herein, the role of proteasomal-mediated degradation in regulating fidelity of TOM-dependent import is briefly discussed and analyzed. The insights obtained from the characterization of this process may be applied to targeting mitochondrial import dysfunction in some neurodegenerative disorders.


Asunto(s)
Proteínas Portadoras/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Mitocondrias/metabolismo , Proteínas Mitocondriales/metabolismo , Animales , Proteínas Portadoras/genética , Humanos , Proteínas de Transporte de Membrana/genética , Mitocondrias/genética , Proteínas del Complejo de Importación de Proteínas Precursoras Mitocondriales , Proteínas Mitocondriales/genética , Proteolisis
20.
Protein Pept Lett ; 27(3): 251-255, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31738130

RESUMEN

A pivotal feature that underlies the development of neurodegeneration is the accumulation of protein aggregates. In response, eukaryotic cells have evolved sophisticated quality control mechanisms to identify, repair and/or eliminate the misfolded abnormal proteins. Chaperones identify any otherwise abnormal conformations in proteins and often help them to regain their correct conformation. However, if repair is not an option, the abnormal protein is selectively degraded to prevent its oligomerization into toxic multimeric complexes. Autophagiclysosomal system and the ubiquitin-proteasome system mediate the targeted degradation of the aberrant protein fragments. Despite the increasing understanding of the molecular counteracting responses toward the accumulation of dysfunctional misfolded proteins, the molecular links between the upstream physiological inputs and the clearance of abnormal misfolded proteins is relatively poorly understood. Recent work has demonstrated that certain physiological states such as vigorous exercise and fasting may enhance the ability of mammalian cells to clear misfolded, toxic and aberrant protein fragments. These findings unveil a novel mechanism that activates the cells' protein-disposal machinery, facilitating the adaptation process of cellular proteome to fluctuations in cellular demands and alterations of environmental cues. Herein, we briefly discuss the molecular interconnection between certain physiological cues and proteasomal degradation pathway in the context of these interesting findings and highlight some of the future prospects.


Asunto(s)
Chaperonas Moleculares/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteínas/química , Animales , Humanos , Fosforilación , Pliegue de Proteína , Proteolisis , Ubiquitinación
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