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1.
Arch Biochem Biophys ; 756: 110010, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38642632

RESUMEN

PARP1 plays a pivotal role in DNA repair within the base excision pathway, making it a promising therapeutic target for cancers involving BRCA mutations. Current study is focused on the discovery of PARP inhibitors with enhanced selectivity for PARP1. Concurrent inhibition of PARP1 with PARP2 and PARP3 affects cellular functions, potentially causing DNA damage accumulation and disrupting immune responses. In step 1, a virtual library of 593 million compounds has been screened using a shape-based screening approach to narrow down the promising scaffolds. In step 2, hierarchical docking approach embedded in Schrödinger suite was employed to select compounds with good dock score, drug-likeness and MMGBSA score. Analysis supplemented with decomposition energy, molecular dynamics (MD) simulations and hydrogen bond frequency analysis, pinpointed that active site residues; H862, G863, R878, M890, Y896 and F897 are crucial for specific binding of ZINC001258189808 and ZINC000092332196 with PARP1 as compared to PARP2 and PARP3. The binding of ZINC000656130962, ZINC000762230673, ZINC001332491123, and ZINC000579446675 also revealed interaction involving two additional active site residues of PARP1, namely N767 and E988. Weaker or no interaction was observed for these residues with PARP2 and PARP3. This approach advances our understanding of PARP-1 specific inhibitors and their mechanisms of action, facilitating the development of targeted therapeutics.


Asunto(s)
Antineoplásicos , Diseño de Fármacos , Simulación de Dinámica Molecular , Poli(ADP-Ribosa) Polimerasa-1 , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Humanos , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Poli(ADP-Ribosa) Polimerasa-1/antagonistas & inhibidores , Poli(ADP-Ribosa) Polimerasa-1/química , Inhibidores de Poli(ADP-Ribosa) Polimerasas/química , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Simulación del Acoplamiento Molecular , Dominio Catalítico , Poli(ADP-Ribosa) Polimerasas/metabolismo , Poli(ADP-Ribosa) Polimerasas/química , Enlace de Hidrógeno
2.
Phytomedicine ; 128: 155527, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38489888

RESUMEN

BACKGROUND: Pancreatic cancer, a tumor with a high metastasis rate and poor prognosis, is among the deadliest human malignancies. Investigating effective drugs for their treatment is imperative. Moracin D, a natural benzofuran compound isolated from Morus alba L., shows anti-inflammation and anti-breast cancer properties and is effective against Alzheimer's disease. However, the effect and mechanism of Moracin D action in pancreatic cancer remain obscure. PURPOSE: To investigate the function and molecular mechanism of Moracin D action in repressing the malignant progression of pancreatic cancer. METHODS: Pancreatic cancer cells were treated with Moracin D, and cell proliferation was evaluated by cell counting kit-8 (CCK-8) and immunofluorescence assays. The clonogenicity of pancreatic cancer cells was assessed based on plate colony formation and soft agar assay. Flow cytometry was used to detect cell apoptosis. The expression of proteins related to the apoptosis pathway was determined by Western blot analysis. Moracin D and XIAP were subjected to docking by auto-dock molecular docking analysis. Ubiquitination levels of XIAP and the interaction of XIAP and PARP1 were assessed by co-immunoprecipitation analysis. Moracin D's effects on tumorigenicity were assessed by a tumor xenograft assay. RESULTS: Moracin D inhibited cell proliferation, induced cell apoptosis, and regulated the protein expression of molecules involved in caspase-dependent apoptosis pathways. Moracin D suppressed clonogenicity and tumorigenesis of pancreatic cancer cells. Mechanistically, XIAP could interact with PARP1 and stabilize PARP1 by controlling its ubiquitination levels. Moracin D diminished the stability of XIAP and decreased the expression of XIAP by promoting proteasome-dependent XIAP degradation, further blocking the XIAP/PARP1 axis and repressing the progression of pancreatic cancer. Moracin D could dramatically improve the chemosensitivity of gemcitabine in pancreatic cancer cells. CONCLUSION: Moracin D repressed cell growth and tumorigenesis, induced cell apoptosis, and enhanced the chemosensitivity of gemcitabine through the XIAP/PARP1 axis in pancreatic cancer. Moracin D is a potential therapeutic agent or adjuvant for pancreatic cancer.


Asunto(s)
Apoptosis , Benzofuranos , Benzopiranos , Proliferación Celular , Neoplasias Pancreáticas , Poli(ADP-Ribosa) Polimerasa-1 , Proteína Inhibidora de la Apoptosis Ligada a X , Neoplasias Pancreáticas/tratamiento farmacológico , Proteína Inhibidora de la Apoptosis Ligada a X/metabolismo , Humanos , Apoptosis/efectos de los fármacos , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Animales , Benzofuranos/farmacología , Ratones Desnudos , Morus/química , Ratones , Antineoplásicos Fitogénicos/farmacología , Simulación del Acoplamiento Molecular , Ratones Endogámicos BALB C , Gemcitabina , Ensayos Antitumor por Modelo de Xenoinjerto
3.
Phytochemistry ; 213: 113766, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37343736

RESUMEN

The increased activity of PARP enzymes is associated with a deficiency of NAD+, as well as with a loss of NADPH and ATP, and consequent deterioration of the redox state in fruits. In this study, we checked whether treatment with nicotinamide (NAM) would affect PARP-1 expression and NAD+ metabolism in strawberry fruit during storage. For this purpose, strawberry fruits were treated with 10 mM NAM and co-treated with NAM and UV-C, and then stored for 5 days at 4 °C. Research showed that nicotinamide contributes to reducing oxidative stress level by reducing PARP-1 mRNA gene expression and the protein level resulting in higher NAD+ availability, as well as improving energy metabolism and NADPH levels in fruits, regardless of whether they are exposed to UV-C. The above effects cause fruits treated with nicotinamide to be characterised by higher anti-radical activity, and a lower level of reactive oxygen species in the tissue.


Asunto(s)
Almacenamiento de Alimentos , Fragaria , Frutas , Niacinamida , Catalasa , Producción de Cultivos/métodos , Complejo II de Transporte de Electrones , Almacenamiento de Alimentos/métodos , Fragaria/efectos de los fármacos , Fragaria/metabolismo , Fragaria/efectos de la radiación , Frutas/efectos de los fármacos , Frutas/metabolismo , Frutas/efectos de la radiación , Regulación de la Expresión Génica de las Plantas/efectos de los fármacos , Regulación de la Expresión Génica de las Plantas/efectos de la radiación , NAD/metabolismo , NADP/metabolismo , Niacinamida/farmacología , Oxidación-Reducción/efectos de los fármacos , Oxidación-Reducción/efectos de la radiación , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/efectos de la radiación , Poli(ADP-Ribosa) Polimerasa-1/genética , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Especies Reactivas de Oxígeno/metabolismo , ARN Mensajero , Superóxido Dismutasa , Rayos Ultravioleta
4.
Altern Ther Health Med ; 29(5): 410-416, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-37052975

RESUMEN

Objective: Poly (ADP-ribose) polymerase-1 (PARP-1) is a regulatory enzyme involved in DNA damage repair, gene transcription, cell growth, death and apoptosis. In our study, we aimed to explore the dynamic role of PARP-1 in chondrocyte (CH) degeneration in vitro. Methods: We used the primary CHs and treated them with interleukin-1 beta for up to 5 days. (IL-1ß) to induce degeneration. Meanwhile, we used AG-14361 (AG) to inhibit endogenous PARP-1 expression. Cell survival and collagen II expression were used to define the cell function of CHs. In addition, other metabolic indicators were measured containing the reactive oxygen species (ROS) level, 8-Hydroxy-2'-deoxyguanosine (8-OH-dG), IL-1ß, tumor necrosis factor alpha (TNF-α) and caspase 3/9 expression. Results: With IL-1ß treatment, the PARP1 expression of CHs was gradually increased from day 1 to day 5, accompanied by a reduction in cell survival and collagen II expression, and an increase in ROS, 8-OH-dG, IL-1ß, TNF-α and caspase 3/9 levels. We suppressed PARP1 expression on the first day of IL-1ß stimulation and found severe destruction of cell survival and collagen II content with a higher expression of caspase 3/9. However, when we cultured the CHs with AG from day 3 of the 5-day IL-1ß stimulation, cell survival and collagen II expression were rescued, and the ROS, 8-OH-dG, IL-1ß, TNF-α, and caspase 3/9 were downregulated. Conclusions: On day 1 of degeneration, increased PARP-1 played a protective role in CHs. However, from days 3 to 5 of degeneration, the accumulated PARP-1 presented a more destructive function in CHs.


Asunto(s)
Inhibidores de Poli(ADP-Ribosa) Polimerasas , Factor de Necrosis Tumoral alfa , Humanos , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Poli(ADP-Ribosa) Polimerasa-1/farmacología , Interleucina-1beta/metabolismo , Interleucina-1beta/farmacología , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/metabolismo , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Caspasa 3/metabolismo , Caspasa 3/farmacología , Condrocitos/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Especies Reactivas de Oxígeno/farmacología , 8-Hidroxi-2'-Desoxicoguanosina/metabolismo , 8-Hidroxi-2'-Desoxicoguanosina/farmacología , Apoptosis
5.
Cell Oncol (Dordr) ; 46(3): 761-776, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-36913068

RESUMEN

Accumulating evidence indicates that long noncoding RNAs (lncRNAs) are abnormal expression in various malignant tumors. Our previous research demonstrated that focally amplified long non-coding RNA (lncRNA) on chromosome 1 (FALEC) is an oncogenic lncRNA in prostate cancer (PCa). However, the role of FALEC in castration-resistant prostate cancer (CRPC) is poorly understood. In this study, we showed FALEC was upregulated in post-castration tissues and CRPC cells, and increased FALEC expression was associated with poor survival in post-castration PCa patients. RNA FISH demonstrated FALEC was translocated into nucleus in CRPC cells. RNA pulldown and followed Mass Spectrometry (MS) assay demonstrated FALEC directly interacted with PARP1 and loss of function assay showed FALEC depletion sensitized CRPC cells to castration treatment and restored NAD+. Specific PARP1 inhibitor AG14361 and NAD+ endogenous competitor NADP+ sensitized FALEC-deleted CRPC cells to castration treatment. FALEC increasing PARP1 meditated self PARylation through recruiting ART5 and down regulation of ART5 decreased CRPC cell viability and restored NAD+ through inhibiting PARP1meditated self PARylation in vitro. Furthermore, ART5 was indispensable for FALEC directly interaction and regulation of PARP1, loss of ART5 impaired FALEC and PARP1 associated self PARylation. In vivo, FALEC depleted combined with PARP1 inhibitor decreased CRPC cell derived tumor growth and metastasis in a model of castration treatment NOD/SCID mice. Together, these results established that FALEC may be a novel diagnostic marker for PCa progression and provides a potential new therapeutic strategy to target the FALEC/ART5/PARP1 complex in CRPC patients.


Asunto(s)
Neoplasias de la Próstata Resistentes a la Castración , ARN Largo no Codificante , Humanos , Masculino , Animales , Ratones , Neoplasias de la Próstata Resistentes a la Castración/patología , ARN Largo no Codificante/genética , NAD/metabolismo , Poli ADP Ribosilación , Ratones Endogámicos NOD , Ratones SCID , Poli(ADP-Ribosa) Polimerasa-1/genética
6.
Inflamm Res ; 72(1): 159-169, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-36357814

RESUMEN

OBJECTIVE: Paeonia lactiflora Pall has long been recognized as an anti-inflammatory traditional Chinese herbal medicine. We aimed to study the pharmacological action of albiflorin, an active ingredient extracted from the roots of Paeonia lactiflora Pall, on diabetic vascular complications. METHODS: Human umbilical vein endothelial cells (HUVECs) were stimulated with high glucose and treated with 5, 10, and 20 µM albiflorin. CCK-8 assay, EdU staining, Annexin V-FITC staining, transwell assay, scratch test, RT-PCR, ELISA, Western blot, and immunofluorescence were carried out. SwissTargetPrediction database was used for screening targets of albiflorin and molecular docking was done using Autodock Vina software. RESULTS: Albiflorin treatment dose-dependently alleviated high glucose-induced viability loss of HUVECs. In addition, albiflorin promoted the proliferation and migration, while inhibited apoptosis and the release of TNF-α, IL-6, and IL-1ß in HUVECs. PARP1 was predicted and confirmed to be a target for albiflorin in vitro. Albiflorin targeted PARP1 to inhibit the activation of NF-κB. Transfection of HUVECs with PARP1 overexpression plasmids effectively reversed the effects of albiflorin on high glucose-treated HUVECs. CONCLUSIONS: Albiflorin suppressed high glucose-induced endothelial cell apoptosis and inflammation, suggesting its potential in treating diabetic vascular complications. The action of albiflorin possibly caused by its regulation on inhibiting PARP1/NF-κB signaling.


Asunto(s)
Angiopatías Diabéticas , FN-kappa B , Humanos , FN-kappa B/metabolismo , Simulación del Acoplamiento Molecular , Transducción de Señal , Células Endoteliales de la Vena Umbilical Humana , Glucosa/farmacología , Glucosa/metabolismo , Apoptosis , Angiopatías Diabéticas/metabolismo , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Poli(ADP-Ribosa) Polimerasa-1/farmacología
7.
Mitochondrion ; 67: 59-64, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-36367519

RESUMEN

The low cerebral metabolic rate of oxygen despite the relatively preserved perfusion in Alzheimer's disease (AD) patients' medial temporal lobes suggest histotoxic hypoxia due to mitochondrial dysfunction that is independent of, but could precede, insulin resistance. Neuropathological, metabolomic, and preclinical evidence are consistent with the notion that this mitochondrial dysfunction may be contributed to by oxidative stress and DNA damage, leading to poly-(ADP-ribose)-polymerase-1 (PARP1) activation and consequent AMP accumulation, clogging of mitochondrial adenine nucleotide transporters (ANTs), matrix ADP deprivation, and ATP synthase inhibition. Complementary mechanisms may include mitochondrial-protein poly-ADP-ribosylation and mitochondrial-biogenesis suppression via PARPs outcompeting Sirtuin-1 (SIRT1) for nicotinamide-adenine-dinucleotide (NAD+).


Asunto(s)
Enfermedad de Alzheimer , Poli(ADP-Ribosa) Polimerasas , Humanos , Poli(ADP-Ribosa) Polimerasas/metabolismo , ATPasas de Translocación de Protón Mitocondriales/metabolismo , Estrés Oxidativo , NAD/metabolismo , Daño del ADN , Hipoxia , Adenosina Trifosfato/metabolismo , Adenosina Monofosfato , Adenosina Difosfato/metabolismo , Poli(ADP-Ribosa) Polimerasa-1/metabolismo
8.
Lab Invest ; 102(8): 872-884, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35361881

RESUMEN

Lupus nephritis (LN) is associated with extensive injury and nephron loss in the afflicted kidney. Evidence has revealed the involvement of dysregulated Yin Yang 1 (YY1), a reported inflammatory modulator, in LN-induced kidney injury, and our microarray profile identified downregulated YY1 expression. Therefore, this study explored the functional relevance and mechanism of YY1 in LN-induced kidney injury. LN was modeled in mice by intraperitoneal injection of pristane, and Jurkat cells (CD41 human T lymphocytes) were activated with TNF-α to mimic the inflammatory environment found in LN. The expression patterns of YY1 and bioinformatics predictions of the downstream factor IFN-γ were confirmed in renal tissues from the mice with LN using qRT-PCR and Western blot analyses. The contents of proinflammatory cytokines in mouse serum samples and cell supernatants were determined using enzyme-linked immunosorbent assays (ELISAs). Ectopic expression and depletion approaches were subsequently used in vitro and in vivo to examine the effects of the YY1/IFN-γ/Fra2/PARP-1/FOXO1 axis on TNF-α-induced inflammation and LN-induced kidney injury. The results showed downregulated expression of YY1 and FOXO1 in the kidney tissues of the mice with LN. Increased proinflammatory factor production was observed in the mice with LN and TNF-α-treated Jurkat cell supernatant, accompanied by increased cell apoptosis and a high ratio of Th17/Treg cells, and these effects were reversed by YY1 restoration. YY1 was further shown to inhibit IFN-γ expression and thereby downregulate Fra2 expression. Fra2 depletion then inhibited PARP-1 expression and promoted FOXO1 expression to suppress cell apoptosis and the release of inflammatory factors. Collectively, our findings revealed that YY1 may alleviate LN-induced renal injury via the IFN-γ/Fra2/PARP-1/FOXO1 axis.


Asunto(s)
Riñón , Nefritis Lúpica , Linfocitos T Reguladores , Células Th17 , Factor de Transcripción YY1 , Animales , Proteína Forkhead Box O1 , Humanos , Interferón gamma/metabolismo , Riñón/metabolismo , Riñón/patología , Nefritis Lúpica/metabolismo , Ratones , Poli(ADP-Ribosa) Polimerasa-1 , Linfocitos T Reguladores/citología , Células Th17/citología , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Transcripción YY1/genética , Factor de Transcripción YY1/metabolismo
9.
Mol Cell ; 82(5): 889-890, 2022 03 03.
Artículo en Inglés | MEDLINE | ID: mdl-35245455

RESUMEN

Krastev et al. (2022) identify a cellular mechanism that counteracts cytotoxic trapping of PARP1 induced by clinical PARP inhibitors. SUMO-targeted ubiquitylation of trapped PARP1 is shown to trigger the enzymes' extraction from chromatin by the p97 ATPase.


Asunto(s)
Cromatina , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Cromatina/genética , Extractos Vegetales , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Ubiquitinación/efectos de los fármacos
10.
Int J Radiat Biol ; 98(7): 1222-1234, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-34919022

RESUMEN

PURPOSE: Poly (ADP-ribose) polymerase inhibitors (PARPi) are known to induce radiosensitization. However, the exact mechanisms of radiosensitization remain unclear. We previously reported that PARPi may have a unique radiosensitizing effect to enhance ß-components of the linear-quadratic model. The aim of this study was to evaluate PARPi in combination with high-dose-per-fraction radiotherapy and to elucidate the underlying mechanisms of its radiosensitization. MATERIALS AND METHODS: Radiosensitizing effects of PARPi PJ34, olaparib, and veliparib were measured using a colony-forming assay in the human cancer cell lines, HCT116, NCI-H460, and HT29. Six different radiation dose fractionation schedules were examined by tumor regrowth assay using three-dimensional multicellular spheroids of HCT116, NCI-H460, SW620, and HCT15. The mechanisms of radiosensitization were analyzed by measuring DNA double-strand breaks (DSB), DNA damage responses, chromosomal translocations, cellular senescence, and cell cycle analysis. RESULTS: Olaparib and PJ34 were found to show radiosensitization preferentially at higher radiation doses per fraction. Similar results were obtained using a mouse model bearing human tumor xenografts. A kinetic analysis of DNA damage responses and repairs showed that olaparib and PJ34 reduced the homologous recombination activity. However, a neutral comet assay showed that PJ34 treatment did not affect the physical rejoining of DNA-DSBs induced by ionizing radiation. Cell cycle analysis revealed that olaparib and PJ34 strikingly increased G1 tetraploid cells following irradiation, leading to premature senescence. The C-banding analysis of metaphase spreads showed that olaparib and PJ34 significantly increased ionizing radiation-induced dicentric chromosomes. The data suggests that PARPi olaparib and PJ34 altered the choice of DNA-DSB repair pathways rather than reducing the total amount of DNA-DSB repair, which resulted in increased repair errors. Increased quadratic misrepair was one of the mechanisms of PARP-mediated radiosensitization, preferentially at the higher dose range compared to the lower dose range. CONCLUSION: PARPi may be a promising candidate to combine with stereotactic hypofractionated radiotherapy, aiming at high-dose region-directed radiosensitization.


Asunto(s)
Neoplasias , Fármacos Sensibilizantes a Radiaciones , Adenosina Difosfato , Línea Celular Tumoral , ADN , Roturas del ADN de Doble Cadena , Reparación del ADN , Humanos , Cinética , Neoplasias/genética , Neoplasias/radioterapia , Poli(ADP-Ribosa) Polimerasa-1 , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Fármacos Sensibilizantes a Radiaciones/farmacología , Ribosa
11.
Biol Pharm Bull ; 44(12): 1837-1842, 2021 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-34615812

RESUMEN

Epstein-Barr virus (EBV), a human herpesvirus, is several human lymphoid malignancies-associated. Our earlier study found the effect of Polygonum cuspidatum root on promoting EBV-positive apoptosis. Therefore, this study investigated the effects of the Polygonum cuspidatum ethyl acetate subfraction containing emodin on EBV gene expression and anti-EBV tumor cells. Resultantly, the the Polygonum cuspidatum ethyl acetate subfraction containing emodin (F3a) promoted Raji cell death (50% cytotoxic concentration, CC50: 12.08 µg/mL); the 12.5 µg/mL F3a effect transcribed BRLF1 and BNLF1 and increased latent membrane protein 1 (LMP1), which may reduce the intracellular phospho-extracellular signal-regulated kinase (ERK) and phospho-inhibitor of Nuclear factor kappa B α (IκBα). Meanwhile, the Raji cells increased the intracellular reactive-oxygen species (ROS), activated the apoptosis-related proteins, cleaved caspase 3 and poly(ADP-ribose)polymerase (PARP), and increased the apoptosis percentage. Therefore, the Polygonum cuspidatum ethyl acetate subfraction containing emodin could be a therapeutic drug for EBV-related tumors.


Asunto(s)
Emodina/farmacología , Infecciones por Virus de Epstein-Barr/metabolismo , Fallopia japonica/química , Herpesvirus Humano 4/metabolismo , Neoplasias/virología , Extractos Vegetales/farmacología , Proteínas Virales/metabolismo , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/uso terapéutico , Apoptosis , Linfoma de Burkitt/virología , Línea Celular Tumoral , Emodina/uso terapéutico , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/virología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Expresión Génica , Humanos , Inhibidor NF-kappaB alfa/metabolismo , FN-kappa B/metabolismo , Fitoterapia , Extractos Vegetales/uso terapéutico , Raíces de Plantas/química , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Proteínas de la Matriz Viral/metabolismo
12.
Biosci Rep ; 41(10)2021 10 29.
Artículo en Inglés | MEDLINE | ID: mdl-34647577

RESUMEN

Coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has become a global health emergency. Although new vaccines have been generated and being implicated, discovery and application of novel preventive and control measures are warranted. We aimed to identify compounds that may possess the potential to either block the entry of virus to host cells or attenuate its replication upon infection. Using host cell surface receptor expression (angiotensin-converting enzyme 2 (ACE2) and Transmembrane protease serine 2 (TMPRSS2)) analysis as an assay, we earlier screened several synthetic and natural compounds and identified candidates that showed ability to down-regulate their expression. Here, we report experimental and computational analyses of two small molecules, Mortaparib and MortaparibPlus that were initially identified as dual novel inhibitors of mortalin and PARP-1, for their activity against SARS-CoV-2. In silico analyses showed that MortaparibPlus, but not Mortaparib, stably binds into the catalytic pocket of TMPRSS2. In vitro analysis of control and treated cells revealed that MortaparibPlus caused down-regulation of ACE2 and TMPRSS2; Mortaparib did not show any effect. Furthermore, computational analysis on SARS-CoV-2 main protease (Mpro) that also predicted the inhibitory activity of MortaparibPlus. However, cell-based antiviral drug screening assay showed 30-60% viral inhibition in cells treated with non-toxic doses of either MortaparibPlus or Mortaparib. The data suggest that these two closely related compounds possess multimodal anti-COVID-19 activities. Whereas MortaparibPlus works through direct interactions/effects on the host cell surface receptors (ACE2 and TMPRSS2) and the virus protein (Mpro), Mortaparib involves independent mechanisms, elucidation of which warrants further studies.


Asunto(s)
Antivirales/farmacología , Tratamiento Farmacológico de COVID-19 , Biología Computacional/métodos , Enzima Convertidora de Angiotensina 2/inmunología , Enzima Convertidora de Angiotensina 2/metabolismo , Antivirales/inmunología , COVID-19/inmunología , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos/métodos , Proteínas HSP70 de Choque Térmico/antagonistas & inhibidores , Humanos , Proteínas Mitocondriales/antagonistas & inhibidores , Poli(ADP-Ribosa) Polimerasa-1/antagonistas & inhibidores , SARS-CoV-2/inmunología , Serina Endopeptidasas/inmunología , Serina Endopeptidasas/metabolismo , Glicoproteína de la Espiga del Coronavirus/metabolismo , Internalización del Virus/efectos de los fármacos
13.
J Nanobiotechnology ; 19(1): 261, 2021 Sep 04.
Artículo en Inglés | MEDLINE | ID: mdl-34481495

RESUMEN

BACKGROUND: Chemodynamic therapy (CDT), employing Fenton or Fenton-like catalysts to convert hydrogen peroxide (H2O2) into toxic hydroxyl radicals (·OH) to kill cancer cells, holds great promise in tumor therapy due to its high selectivity. However, the therapeutic effect is significantly limited by insufficient intracellular H2O2 level in tumor cells. Fortunately, ß-Lapachone (Lapa) that can exert H2O2-supplementing functionality under the catalysis of nicotinamide adenine dinucleotide (phosphate) NAD(P)H: quinone oxidoreductase-1 (NQO1) enzyme offers a new idea to solve this problem. However, extensive DNA damage caused by high levels of reactive oxygen species can trigger the "hyperactivation" of poly(ADP-ribose) polymerase (PARP), which results in the severe interruption of H2O2 supply and further the reduced efficacy of CDT. Herein, we report a self-amplified nanocatalytic system (ZIF67/Ola/Lapa) to co-deliver the PARP inhibitor Olaparib (Ola) and NQO1-bioactivatable drug Lapa for sustainable H2O2 production and augmented CDT ("1 + 1 + 1 > 3"). RESULTS: The effective inhibition of PARP by Ola can synergize Lapa to enhance H2O2 formation due to the continuous NQO1 redox cycling. In turn, the high levels of H2O2 further react with Co2+ to produce the highly toxic ·OH by Fenton-like reaction, dramatically improving CDT. Both in vitro and in vivo studies demonstrate the excellent antitumor activity of ZIF67/Ola/Lapa in NQO1 overexpressed MDA-MB-231 tumor cells. Importantly, the nanocomposite presents minimal systemic toxicity in normal tissues due to the low NQO1 expression. CONCLUSIONS: This design of nanocatalytic system offers a new paradigm for combing PARP inhibitor, NQO1-bioactivatable drug and Fenton-reagents to obtain sustained H2O2 generation for tumor-specific self-amplified CDT.


Asunto(s)
Antineoplásicos/farmacología , Nanoestructuras/química , Nanoestructuras/uso terapéutico , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Animales , Apoptosis , Línea Celular Tumoral , Daño del ADN/efectos de los fármacos , Humanos , Peróxido de Hidrógeno/metabolismo , Ratones , NAD(P)H Deshidrogenasa (Quinona) , Nanopartículas , Naftoquinonas , Poli(ADP-Ribosa) Polimerasa-1 , Especies Reactivas de Oxígeno/metabolismo
14.
J Cancer Res Clin Oncol ; 147(9): 2579-2590, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-34085099

RESUMEN

PURPOSE: Angiosarcoma (AS) is a rare vasoformative sarcoma, with poor overall survival and a high need for novel treatment options. Clinically, AS consists of different subtypes, including AS related to previous UV exposure (UV AS) which could indicate susceptibility to DNA damage repair inhibition. We, therefore, investigated the presence of biomarkers PARP1 (poly(ADP-ribose)polymerase-1) and Schlafen-11 (SLFN11) in UV AS. Based on experiences in other sarcomas, we examined (combination) treatment of PARP inhibitor (PARPi) olaparib and temozolomide (TMZ) in UV AS cell lines. METHODS: Previously collected UV AS (n = 47) and non-UV AS (n = 96) patient samples and two UV AS cell lines (MO-LAS and AS-M) were immunohistochemically assessed for PARP1 and SLFN11 expression. Both cell lines were treated with single agents PARPi olaparib and TMZ, and the combination treatment. Next, cell viability and treatment synergy were analyzed. In addition, effects on apoptosis and DNA damage were examined. RESULTS: In 46/47 UV AS samples (98%), PARP1 expression was present. SLFN11 was expressed in 80% (37/46) of cases. Olaparib and TMZ combination treatment was synergistic in both cell lines, with significantly increased apoptosis compared to single agent treatment. Furthermore, a significant increase in DNA damage marker γH2AX was present in both cell lines after combination therapy. CONCLUSION: We showed combination treatment of olaparib with TMZ was synergistic in UV AS cell lines. Expression of PARP1 and SLFN11 was present in the majority of UV AS tumor samples. Together, these results suggest combination treatment of olaparib and TMZ is a potential novel AS subtype-specific treatment option for UV AS patients.


Asunto(s)
Sinergismo Farmacológico , Hemangiosarcoma/tratamiento farmacológico , Proteínas Nucleares/metabolismo , Poli(ADP-Ribosa) Polimerasa-1/antagonistas & inhibidores , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Temozolomida/farmacología , Rayos Ultravioleta , Antineoplásicos Alquilantes/farmacología , Apoptosis , Proliferación Celular , Combinación de Medicamentos , Evaluación Preclínica de Medicamentos , Hemangiosarcoma/etiología , Hemangiosarcoma/patología , Humanos , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Pronóstico , Células Tumorales Cultivadas
15.
Int J Mol Sci ; 22(10)2021 May 12.
Artículo en Inglés | MEDLINE | ID: mdl-34066057

RESUMEN

Poly (ADP-ribose) polymerases (PARP) 1-3 are well-known multi-domain enzymes, catalysing the covalent modification of proteins, DNA, and themselves. They attach mono- or poly-ADP-ribose to targets using NAD+ as a substrate. Poly-ADP-ribosylation (PARylation) is central to the important functions of PARP enzymes in the DNA damage response and nucleosome remodelling. Activation of PARP happens through DNA binding via zinc fingers and/or the WGR domain. Modulation of their activity using PARP inhibitors occupying the NAD+ binding site has proven successful in cancer therapies. For decades, studies set out to elucidate their full-length molecular structure and activation mechanism. In the last five years, significant advances have progressed the structural and functional understanding of PARP1-3, such as understanding allosteric activation via inter-domain contacts, how PARP senses damaged DNA in the crowded nucleus, and the complementary role of histone PARylation factor 1 in modulating the active site of PARP. Here, we review these advances together with the versatility of PARP domains involved in DNA binding, the targets and shape of PARylation and the role of PARPs in nucleosome remodelling.


Asunto(s)
Proteínas de Ciclo Celular/química , Nucleosomas/metabolismo , Poli(ADP-Ribosa) Polimerasa-1/química , Poli(ADP-Ribosa) Polimerasas/química , Regulación Alostérica/efectos de los fármacos , Proteínas Portadoras/metabolismo , Proteínas de Ciclo Celular/metabolismo , Reparación del ADN , Humanos , Modelos Moleculares , Proteínas Nucleares/metabolismo , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Poli(ADP-Ribosa) Polimerasas/metabolismo , Dominios Proteicos/efectos de los fármacos
16.
Elife ; 102021 06 29.
Artículo en Inglés | MEDLINE | ID: mdl-34184634

RESUMEN

Retinitis pigmentosa (RP) and associated inherited retinal diseases (IRDs) are caused by rod photoreceptor degeneration, necessitating therapeutics promoting rod photoreceptor survival. To address this, we tested compounds for neuroprotective effects in multiple zebrafish and mouse RP models, reasoning drugs effective across species and/or independent of disease mutation may translate better clinically. We first performed a large-scale phenotypic drug screen for compounds promoting rod cell survival in a larval zebrafish model of inducible RP. We tested 2934 compounds, mostly human-approved drugs, across six concentrations, resulting in 113 compounds being identified as hits. Secondary tests of 42 high-priority hits confirmed eleven lead candidates. Leads were then evaluated in a series of mouse RP models in an effort to identify compounds effective across species and RP models, that is, potential pan-disease therapeutics. Nine of 11 leads exhibited neuroprotective effects in mouse primary photoreceptor cultures, and three promoted photoreceptor survival in mouse rd1 retinal explants. Both shared and complementary mechanisms of action were implicated across leads. Shared target tests implicated parp1-dependent cell death in our zebrafish RP model. Complementation tests revealed enhanced and additive/synergistic neuroprotective effects of paired drug combinations in mouse photoreceptor cultures and zebrafish, respectively. These results highlight the value of cross-species/multi-model phenotypic drug discovery and suggest combinatorial drug therapies may provide enhanced therapeutic benefits for RP patients.


Photoreceptors are the cells responsible for vision. They are part of the retina: the light-sensing tissue at the back of the eye. They come in two types: rods and cones. Rods specialise in night vision, while cones specialise in daytime colour vision. The death of these cells can cause a disease, called retinitis pigmentosa, that leads to vision loss. Symptoms often start in childhood with a gradual loss of night vision. Later on, loss of cone photoreceptors can lead to total blindness. Unfortunately, there are no treatments available that protect photoreceptor cells from dying. Research has identified drugs that can protect photoreceptors in animal models, but these drugs have failed in humans. The classic way to look for new treatments is to find drugs that target molecules implicated in a disease, and then test them to see if they are effective. Unfortunately, many drugs identified in this way fail in later stages of testing, either because they are ineffective, or because they have unacceptable side effects. One way to reverse this trend is to first test whether a drug is effective at curing a disease in animals, and later determining what it does at a molecular level. This could reveal whether drugs can protect photoreceptors before research to discover their molecular targets begins. Tests like this across different species could maximise the chances of finding a drug that works in humans, because if a drug works in several species, it is more likely to have shared target molecules across species. Applying this reasoning, Zhang et al. tested around 3,000 drug candidates for treating retinitis pigmentosa in a strain of zebrafish that undergoes photoreceptor degeneration similar to the human disease. Most of these drug candidates already have approval for use in humans, meaning that if they were found to be effective for treating retinitis pigmentosa, they could be fast-tracked for use in people. Zhang et al. found three compounds that helped photoreceptors survive both in zebrafish and in retinas grown in the laboratory derived from a mouse strain with degeneration similar to retinitis pigmentosa. Tests to find out how these three compounds worked at the molecular level revealed that they interfered with a protein that can trigger cell death. The tests also found other promising compounds, many of which offered increased protection when combined in pairs. Worldwide there are between 1.5 and 2.5 million people with retinitis pigmentosa. With this disease, loss of vision happens slowly, so identifying drugs that could slow or stop the process could help many people. These results suggest that placing animal testing earlier in the drug discovery process could complement traditional target-based methods. The compounds identified here, and the information about how they work, could expand potential treatment research. The next step in this research is to test whether the drugs identified by Zhang et al. protect mammals other than mice from the degeneration seen in retinitis pigmentosa.


Asunto(s)
Fármacos Neuroprotectores/farmacología , Retinitis Pigmentosa/tratamiento farmacológico , Animales , Animales Modificados Genéticamente , Células Cultivadas/efectos de los fármacos , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 6/genética , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 6/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Regulación de la Expresión Génica/efectos de los fármacos , Ratones , Mutación , Poli(ADP-Ribosa) Polimerasa-1/genética , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Células Fotorreceptoras Retinianas Bastones/efectos de los fármacos , Pez Cebra
17.
Cell Death Dis ; 12(7): 651, 2021 06 25.
Artículo en Inglés | MEDLINE | ID: mdl-34172715

RESUMEN

Alzheimer's disease is the most common age-related neurodegenerative disorder. Familial forms of Alzheimer's disease associated with the accumulation of a toxic form of amyloid-ß (Aß) peptides are linked to mitochondrial impairment. The coenzyme nicotinamide adenine dinucleotide (NAD+) is essential for both mitochondrial bioenergetics and nuclear DNA repair through NAD+-consuming poly (ADP-ribose) polymerases (PARPs). Here we analysed the metabolomic changes in flies overexpressing Aß and showed a decrease of metabolites associated with nicotinate and nicotinamide metabolism, which is critical for mitochondrial function in neurons. We show that increasing the bioavailability of NAD+ protects against Aß toxicity. Pharmacological supplementation using NAM, a form of vitamin B that acts as a precursor for NAD+ or a genetic mutation of PARP rescues mitochondrial defects, protects neurons against degeneration and reduces behavioural impairments in a fly model of Alzheimer's disease. Next, we looked at links between PARP polymorphisms and vitamin B intake in patients with Alzheimer's disease. We show that polymorphisms in the human PARP1 gene or the intake of vitamin B are associated with a decrease in the risk and severity of Alzheimer's disease. We suggest that enhancing the availability of NAD+ by either vitamin B supplements or the inhibition of NAD+-dependent enzymes such as PARPs are potential therapies for Alzheimer's disease.


Asunto(s)
Enfermedad de Alzheimer/genética , Proteínas de Drosophila/genética , Mitocondrias/genética , Mutación , NAD/metabolismo , Neuronas/enzimología , Poli(ADP-Ribosa) Polimerasa-1/genética , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/enzimología , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Animales , Animales Modificados Genéticamente , Conducta Animal , Modelos Animales de Enfermedad , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Humanos , Metaboloma , Metabolómica , Mitocondrias/efectos de los fármacos , Mitocondrias/enzimología , Mitocondrias/ultraestructura , Actividad Motora , Degeneración Nerviosa , Neuronas/efectos de los fármacos , Neuronas/patología , Niacinamida/farmacología , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Polimorfismo de Nucleótido Simple
18.
Biomed Pharmacother ; 140: 111771, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-34058441

RESUMEN

Danhong injection (DHI) is a compound Chinese medicine widely used in China for treatment of ischemic cardio-cerebrovascular diseases. However, limited data are available regarding the protective effect of DHI on the ischemic penumbra in ischemic stroke. This study aimed to investigate the effect of intravenous DHI on neuronal injure in the ischemic penumbra after cerebral ischemia/reperfusion (CI/R), focusing especially on the involvement of intracellular energy metabolism coupling. Male Sprague-Dawley rats were subjected to right middle cerebral artery occlusion for 60 min followed by reperfusion with or without intravenous DHI (0.5, 1.0, or 2.0 mL/kg) once daily for 7 days. Post-treatment with DHI ameliorated neurological defects, diminished cerebral infarction, alleviated cerebral edema, improved microcirculatory perfusion after 7days of reperfusion, and inhibited apoptosis and enhanced neuronal survival in the ischemic penumbra. In addition, DHI significantly ameliorated oxidative stress, reduced DNA damage, and inhibited the activation of PARP1/AIF pathway, thereby restoring cytoplasmic glycolytic activity. Furthermore, this drug increased PDH activity by inhibiting the HIF1α/PDK1 signaling pathway, thus eliminating the inhibitory effect of CI/R on mitochondrial metabolism. The results of this study suggest that DHI can alleviate cerebral edema after CI/R and rescue the ischemic penumbra, and these protective effects are due to the regulation of intracellular energy metabolic coupling.


Asunto(s)
Medicamentos Herbarios Chinos/uso terapéutico , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/patología , Daño del ADN , Medicamentos Herbarios Chinos/farmacología , Edema/tratamiento farmacológico , Edema/metabolismo , Edema/patología , Metabolismo Energético/efectos de los fármacos , Subunidad alfa del Factor 1 Inducible por Hipoxia/antagonistas & inhibidores , Infarto de la Arteria Cerebral Media/metabolismo , Infarto de la Arteria Cerebral Media/patología , Cetona Oxidorreductasas/metabolismo , Masculino , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Poli(ADP-Ribosa) Polimerasa-1/antagonistas & inhibidores , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora/antagonistas & inhibidores , Ratas Sprague-Dawley
19.
Brief Bioinform ; 22(6)2021 11 05.
Artículo en Inglés | MEDLINE | ID: mdl-33940596

RESUMEN

The poly (ADP-ribose) polymerase-1 (PARP1) has been regarded as a vital target in recent years and PARP1 inhibitors can be used for ovarian and breast cancer therapies. However, it has been realized that most of PARP1 inhibitors have disadvantages of low solubility and permeability. Therefore, by discovering more molecules with novel frameworks, it would have greater opportunities to apply it into broader clinical fields and have a more profound significance. In the present study, multiple virtual screening (VS) methods had been employed to evaluate the screening efficiency of ligand-based, structure-based and data fusion methods on PARP1 target. The VS methods include 2D similarity screening, structure-activity relationship (SAR) models, docking and complex-based pharmacophore screening. Moreover, the sum rank, sum score and reciprocal rank were also adopted for data fusion methods. The evaluation results show that the similarity searching based on Torsion fingerprint, six SAR models, Glide docking and pharmacophore screening using Phase have excellent screening performance. The best data fusion method is the reciprocal rank, but the sum score also performs well in framework enrichment. In general, the ligand-based VS methods show better performance on PARP1 inhibitor screening. These findings confirmed that adding ligand-based methods to the early screening stage will greatly improve the screening efficiency, and be able to enrich more highly active PARP1 inhibitors with diverse structures.


Asunto(s)
Bases de Datos de Compuestos Químicos , Simulación del Acoplamiento Molecular , Poli(ADP-Ribosa) Polimerasa-1/antagonistas & inhibidores , Inhibidores de Poli(ADP-Ribosa) Polimerasas/química , Evaluación Preclínica de Medicamentos , Humanos , Poli(ADP-Ribosa) Polimerasa-1/química , Relación Estructura-Actividad
20.
Mol Cell ; 81(12): 2611-2624.e10, 2021 06 17.
Artículo en Inglés | MEDLINE | ID: mdl-33857404

RESUMEN

The Shieldin complex shields double-strand DNA breaks (DSBs) from nucleolytic resection. Curiously, the penultimate Shieldin component, SHLD1, is one of the least abundant mammalian proteins. Here, we report that the transcription factors THAP1, YY1, and HCF1 bind directly to the SHLD1 promoter, where they cooperatively maintain the low basal expression of SHLD1, thereby ensuring a proper balance between end protection and resection during DSB repair. The loss of THAP1-dependent SHLD1 expression confers cross-resistance to poly (ADP-ribose) polymerase (PARP) inhibitor and cisplatin in BRCA1-deficient cells and shorter progression-free survival in ovarian cancer patients. Moreover, the embryonic lethality and PARPi sensitivity of BRCA1-deficient mice is rescued by ablation of SHLD1. Our study uncovers a transcriptional network that directly controls DSB repair choice and suggests a potential link between DNA damage and pathogenic THAP1 mutations, found in patients with the neurodevelopmental movement disorder adult-onset torsion dystonia type 6.


Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Animales , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Proteínas de Ciclo Celular/genética , ADN/metabolismo , Roturas del ADN de Doble Cadena/efectos de los fármacos , Reparación del ADN por Unión de Extremidades/efectos de los fármacos , Reparación del ADN/genética , Distonía/genética , Femenino , Factor C1 de la Célula Huésped/metabolismo , Proteínas Mad2/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Reparación del ADN por Recombinación/efectos de los fármacos , Proteínas de Unión a Telómeros/metabolismo , Proteína 1 de Unión al Supresor Tumoral P53/metabolismo , Factor de Transcripción YY1/metabolismo
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