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Current models of apoptosis regulation by the Bcl-2 family of proteins postulate that heterodimeric interactions between family members determine whether Bax and Bak are activated to trigger cell death. Thus, the relative abundance and binding affinities between pro- and anti-apoptotic proteins determines the outcome of these interactions. Examination of these interactions using purified mitochondria and liposomes with full-length recombinant proteins revealed that Bcl-xL inhibits apoptosis as a higher-order complex that binds multiple BH3 proteins. Allosteric regulation of this complex by the BH3 sensitizer Bad confers switch-like activity to the indirect activation of Bax. The BH3 activator cBid sequestered by Bcl-xL complexes changes from an inactive to an active form while bound to a Bcl-xL complex only when Bad is also bound. Bcl-xL complexes enable Bad to function as a non-competitive inhibitor of Bcl-xL and allosterically activate cBid, dramatically enhancing the pro-apoptotic potency of Bad.
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Proteína X Asociada a bcl-2/metabolismo , Proteína bcl-X/metabolismo , Regulación Alostérica , Animales , Apoptosis , Proteína Proapoptótica que Interacciona Mediante Dominios BH3/metabolismo , Línea Celular , Humanos , Ratones , Membranas Mitocondriales/metabolismo , Proteína Letal Asociada a bcl/metabolismo , Proteína bcl-X/químicaRESUMEN
The intrinsic apoptosis pathway, regulated by the BCL-2 protein family, is essential for embryonic development. Using mice lacking all known apoptosis effectors, BAX, BAK and BOK, we have previously defined the processes during development that require apoptosis. Rare Bok-/- Bax-/- Bak-/- triple knockout (TKO) mice developed to adulthood and several tissues that were thought to require apoptosis during development appeared normal. This raises the question if all apoptosis had been abolished in the TKO mice or if other BCL-2 family members could act as effectors of apoptosis. Here, we investigated the role of BID, generally considered to link the extrinsic and intrinsic apoptosis pathways, acting as a BH3-only protein initiating apoptosis upstream of BAX and BAK. We found that Bok-/- Bax-/- Bak-/- Bid-/- quadruple knockout (QKO) mice have additional developmental anomalies compared to TKO mice, consistent with a role of BID, not only upstream but also in parallel to BAX, BAK and BOK. Mitochondrial experiments identified a small cytochrome c-releasing activity of full-length BID. Collectively, these findings suggest a new effector role for BID in the intrinsic apoptosis pathway.
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Proteína Proapoptótica que Interacciona Mediante Dominios BH3 , Proteínas Proto-Oncogénicas c-bcl-2 , Proteína Destructora del Antagonista Homólogo bcl-2 , Animales , Ratones , Apoptosis , Proteína Destructora del Antagonista Homólogo bcl-2/genética , Proteína Destructora del Antagonista Homólogo bcl-2/metabolismo , Proteína X Asociada a bcl-2/genética , Proteína X Asociada a bcl-2/metabolismo , Proteína Proapoptótica que Interacciona Mediante Dominios BH3/genética , Proteína Proapoptótica que Interacciona Mediante Dominios BH3/metabolismo , Desarrollo Embrionario/genética , Ratones Noqueados , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismoRESUMEN
Thyroid cancer (THCA) is one of the most common malignancies of the endocrine system. Exosomes have significant value in performing molecular treatments, evaluating the diagnosis and determining tumor prognosis. Thus, the identification of exosome-related genes could be valuable for the diagnosis and potential treatment of THCA. In this study, we examined a set of exosome-related differentially expressed genes (DEGs) (BIRC5, POSTN, TGFBR1, DUSP1, BID, and FGFR2) by taking the intersection between the DEGs of the TCGA-THCA and GeneCards datasets. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of the exosome-related DEGs indicated that these genes were involved in certain biological functions and pathways. Proteinâprotein interaction (PPI), mRNAâmiRNA, and mRNA-TF interaction networks were constructed using the 6 exosome-related DEGs as hub genes. Furthermore, we analyzed the correlation between the 6 exosome-related DEGs and immune infiltration. The Genomics of Drug Sensitivity in Cancer (GDSC), the Cancer Cell Line Encyclopedia (CCLE), and the CellMiner database were used to elucidate the relationship between the exosome-related DEGs and drug sensitivity. In addition, we verified that both POSTN and BID were upregulated in papillary thyroid cancer (PTC) patients and that their expression was correlated with cancer progression. The POSTN and BID protein expression levels were further examined in THCA cell lines. These findings provide insights into exosome-related clinical trials and drug development.
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BACKGROUND: Drugs targeting the spindle assembly checkpoint (SAC), such as inhibitors of Aurora kinase B (AURKB) and dual specific protein kinase TTK, are in different stages of clinical development. However, cell response to SAC abrogation is poorly understood and there are no markers for patient selection. METHODS: A panel of 53 tumor cell lines of different origins was used. The effects of drugs were analyzed by MTT and flow cytometry. Copy number status was determined by FISH and Q-PCR; mRNA expression by nCounter and RT-Q-PCR and protein expression by Western blotting. CRISPR-Cas9 technology was used for gene knock-out (KO) and a doxycycline-inducible pTRIPZ vector for ectopic expression. Finally, in vivo experiments were performed by implanting cultured cells or fragments of tumors into immunodeficient mice. RESULTS: Tumor cells and patient-derived xenografts (PDXs) sensitive to AURKB and TTK inhibitors consistently showed high expression levels of BH3-interacting domain death agonist (BID), while cell lines and PDXs with low BID were uniformly resistant. Gene silencing rendered BID-overexpressing cells insensitive to SAC abrogation while ectopic BID expression in BID-low cells significantly increased sensitivity. SAC abrogation induced activation of CASP-2, leading to cleavage of CASP-3 and extensive cell death only in presence of high levels of BID. Finally, a prevalence study revealed high BID mRNA in 6% of human solid tumors. CONCLUSIONS: The fate of tumor cells after SAC abrogation is driven by an AURKB/ CASP-2 signaling mechanism, regulated by BID levels. Our results pave the way to clinically explore SAC-targeting drugs in tumors with high BID expression.
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Neoplasias , Proteínas Serina-Treonina Quinasas , Humanos , Animales , Ratones , Proteínas Serina-Treonina Quinasas/genética , Aurora Quinasa B/genética , Aurora Quinasa B/metabolismo , Puntos de Control de la Fase M del Ciclo Celular , Línea Celular Tumoral , ARN Mensajero , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Proteínas Tirosina Quinasas/metabolismo , Proteínas de Ciclo Celular/genéticaRESUMEN
Ultraviolet C (UV-C) radiation induces apoptosis in mammalian cells via the mitochondrion-mediated pathway. The Bcl-2 family of proteins are the regulators of the mitochondrial pathway of apoptosis and appears responsive to UV-C radiation. It is unknown how the structure and, effectively, the function of these proteins are directly impacted by UV-C exposure. Here, we present the effect of UV-C irradiation on the structure and function of pro-apoptotic Bid-FL and anti-apoptotic Bcl-xlΔC proteins. Using a variety of biophysical tools, we show that, following UV-C irradiation, the structures of Bcl-xlΔC and Bid-FL are irreversibly altered. Bcl-xLΔC is found to be more sensitive to UV stress than Bid-FL Interestingly, UV-C exposure shows dramatic chemical shift perturbations in consequence of dramatic structural perturbations (α-helix to ß-sheet) in the BH3- binding region, a crucial segment of Bcl-xlΔC. Furter it has been shown that UV-exposed Bcl-xlΔC has reduced efficacy of its interactions with pro-apoptotic tBid.
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Proteínas Reguladoras de la Apoptosis , Apoptosis , Animales , Proteína bcl-X/metabolismo , Proteína Proapoptótica que Interacciona Mediante Dominios BH3/metabolismo , Mitocondrias/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Mamíferos/metabolismoRESUMEN
Calvarial bone healing is challenging, especially for individuals with osteoporosis because stem cells from osteoporotic patients are highly prone to adipogenic differentiation. Based on previous findings that chondrogenic induction of adipose-derived stem cells (ASCs) can augment calvarial bone healing, we hypothesized that activating chondroinductive Sox Trio genes (Sox5, Sox6, Sox9) and repressing adipoinductive genes (C/ebp-α, Ppar-γ) in osteoporotic ASCs can reprogram cell differentiation and improve calvarial bone healing after implantation. However, simultaneous gene activation and repression in ASCs is difficult. To tackle this problem, we built a CRISPR-BiD system for bi-directional gene regulation. Specifically, we built a CRISPR-AceTran system that exploited both histone acetylation and transcription activation for synergistic Sox Trio activation. We also developed a CRISPR interference (CRISPRi) system that exploited DNA methylation for repression of adipoinductive genes. We combined CRISPR-AceTran and CRISPRi to form the CRISPR-BiD system, which harnessed three mechanisms (transcription activation, histone acetylation, and DNA methylation). After delivery into osteoporotic rat ASCs, CRISPR-BiD significantly enhanced chondrogenesis and in vitro cartilage formation. Implantation of the engineered osteoporotic ASCs into critical-sized calvarial bone defects significantly improved bone healing in osteoporotic rats. These results implicated the potential of the CRISPR-BiD system for bi-directional regulation of cell fate and regenerative medicine.
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Regeneración Ósea , Condrogénesis , Tejido Adiposo , Animales , Regeneración Ósea/genética , Diferenciación Celular/genética , Condrogénesis/genética , Humanos , Ratas , Células Madre , Activación TranscripcionalRESUMEN
BACKGROUND: Generic competition is a vital health policy tool used in regulating the pharmaceutical market. Drug group HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl-coenzyme-A reductase) inhibitors, widely known as "statins," was the first drug group in Hungary in which generic prescriptions became mandatory. Our aim is to analyze the changes in the retail and wholesale margins through the generic competition regarding "statins". METHODS: Data was derived from the nationwide pharmaceutical database of the Hungarian National Health Insurance Fund Administration, the only health care financing agency in Hungary. We observed the turnover data regarding the HMG-CoA-reductase inhibitor "statins" from 2010 through 2019. As the drugs under review have a fixed price point in Hungary, we effectively calculated the margins. RESULTS: In 2010, the consumer expenditure of statins was 30.7 billion HUF ($148 million), which decreased by 59%, to 12.5 billion HUF ($42.9 million) in 2019. In 2010, the annual health insurance reimbursement of statins was 23.7 billion HUF ($114 million), which underwent a 63% decrease to 8.6 billion HUF ($29.7 million) in 2019. In 2010, the DOT turnover was 287 million days, and it increased to above 346 million days for 2019, which reflects a 20% increase over the past nine years. The monthly retail margins decreased from 334 million HUF ($1.6 million), (January, 2010) to 176 million HUF ($0.61 million), (December, 2019). The monthly wholesale margins decreased from 96.3 million HUF ($0.46 million), (January, 2010) to 41.4 million HUF ($0.14 million), (December, 2019). The most significant downturn in margins was due to the introduction of the first two blind bids. The combined DOT turnover in reference to the examined 43 products consistently increased. CONCLUSIONS: The decline in retail and wholesale margin and in health insurance expenditures was largely due to a reduction in the consumer price of generic medicines. DOT turnover of statins also increased significantly.
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Inhibidores de Hidroximetilglutaril-CoA Reductasas , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hungría , Seguro de Salud , Reembolso de Seguro de Salud , Medicamentos Genéricos , Preparaciones Farmacéuticas , Oxidorreductasas , Costos de los MedicamentosRESUMEN
Psoriasis is a chronic skin disease that affects millions of people worldwide. In 2014, psoriasis was recognized by the World Health Organization (WHO) as a serious non-communicable disease. In this study, a systems biology approach was used to investigate the underlying pathogenic mechanism of psoriasis and identify the potential drug targets for therapeutic treatment. The study involved the construction of a candidate genome-wide genetic and epigenetic network (GWGEN) through big data mining, followed by the identification of real GWGENs of psoriatic and non-psoriatic using system identification and system order detection methods. Core GWGENs were extracted from real GWGENs using the Principal Network Projection (PNP) method, and the corresponding core signaling pathways were annotated using the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Comparing core signaling pathways of psoriasis and non-psoriasis and their downstream cellular dysfunctions, STAT3, CEBPB, NF-κB, and FOXO1 are identified as significant biomarkers of pathogenic mechanism and considered as drug targets for the therapeutic treatment of psoriasis. Then, a deep neural network (DNN)-based drug-target interaction (DTI) model was trained by the DTI dataset to predict candidate molecular drugs. By considering adequate regulatory ability, toxicity, and sensitivity as drug design specifications, Naringin, Butein, and Betulinic acid were selected from the candidate molecular drugs and combined into potential multi-molecule drugs for the treatment of psoriasis.
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Psoriasis , Biología de Sistemas , Humanos , Reposicionamiento de Medicamentos , Psoriasis/tratamiento farmacológico , Psoriasis/genética , Análisis por Micromatrices , Redes Neurales de la ComputaciónRESUMEN
The COVID-19 pandemic has drastically affected the socioeconomic activities and peoples' daily life, resulting in a change in locational preferences in the real estate markets. Although enormous efforts have been devoted to examining the housing price impacts of the COVID-19 pandemic, little is known about the responses of the real estate markets to the evolving pandemic control measures. This study investigates the price gradient effects of various pandemic-related policy shocks using a hedonic price model on the district-level property transaction data in Shanghai, China over a 48-month period from 2018 to 2021. We found that these shocks have significantly altered the bid-rent curves. The price gradient for residential property units decreased in absolute value to - 0.433 after Wuhan's lockdown, demonstrating peoples' preferences to avoid the high infection risks in districts closer to the city center. However, in the post-reopening and post-vaccine periods, the price gradient increased to - 0.463 and - 0.486, respectively, implying rational expectations of a recovering real estate market for the low infection and mortality rates. In addition, we discovered that Wuhan's lockdown has steepened the price gradient for commercial property units, suggesting a decline in business volumes and an increase in operating costs in the low-density districts imposed by the strict pandemic control measures. This study contributes to the empirical literature on the price gradient effects of the COVID-19 pandemic by extending the study period to the post-vaccine era.
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Apoptosis is a naturally occurring process during the growth and development of multicellular organisms and is increasingly active during times of cellular stress such as in response to intracellular DNA damage when removal of the host cell is paramount to prevent cancer. Unfortunately, once formed, cancer cells become impervious to apoptosis, creating a desperate need to identify an approach to induce apoptosis in these cells. An attractive option is to focus efforts on developing and locating compounds which activate apoptosis using natural compounds. Curcumin is a natural component in turmeric and is well-known for its pharmacological effects in preventing and combating many ailments and has been shown to decrease the rapid proliferation of a wide variety of tumor cells. However, to date, the apoptotic intermediates and interactions through which curcumin exerts its cytotoxic effects are unknown. Motivated by reports linking the intracellular modulation of the concentrations of Bid and Bcl-xL, following curcumin administration to cancer cells, we set out to probe for potential intermolecular interactions of these proteins with curcumin. Using several biophysical techniques, most notably, fluorescence, circular dichroism and nuclear magnetic resonance spectroscopy, we reveal binding interactions of curcumin with both Bcl-xLΔC and full-length Bid (Bid-FL) and prove that this binding is hydrophobically driven and localized to well-known functional regions of each protein. Specifically, our NMR studies show that while Bid-FL interacts with curcumin through its hydrophobic and pore forming helices (α6-α7), Bcl-xLΔC interacts with curcumin via its BH3 binding pocket (α2-α3-α4-α5), a critical region for mediating apoptosis.
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Proteína Proapoptótica que Interacciona Mediante Dominios BH3/metabolismo , Curcumina/farmacología , Neoplasias/tratamiento farmacológico , Proteína bcl-X/metabolismo , Apoptosis , HumanosRESUMEN
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces death receptor-mediated extrinsic apoptosis, specifically in cancer cells, and Bid (BH3-interacting domain death agonist) plays an important role in TRAIL-induced apoptosis. Ferroptosis is a newly defined form of regulated cell death known to be distinct from other forms of cell death. However, our previous studies have shown that ferroptosis shares common pathways with other types of programmed cell death such as apoptosis. In this study, we investigated the role of Bid in the crosstalk between the ferroptotic agent-induced endoplasmic reticulum (ER) stress response and TRAIL-induced apoptosis. When human colorectal carcinoma HCT116 cells were treated with the ferroptosis-inducing agents artesunate and erastin in combination with TRAIL, TRAIL-induced activation of caspase-8 was enhanced, and subsequently, the truncation of Bid was increased. Similar results were observed when ovarian adenocarcinoma OVCAR-3 cells were treated with the ferroptotic agents in combination with TRAIL. Results from studies with Bid mutants reveal that the truncation of Bid and the presence of intact BH3 domains are critical for synergistic apoptosis. Nonfunctional Bid mutants were not able to activate the mitochondria-dependent apoptosis pathway, which is required for the conversion of p19 to p17, the active form of caspase-3. These results indicate that Bid plays a critical role in the crosstalk between the ferroptotic agent-induced ER stress response and TRAIL-induced apoptosis.
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Apoptosis , Neoplasias Ováricas , Humanos , Femenino , Línea Celular Tumoral , Neoplasias Ováricas/patología , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Proteína Proapoptótica que Interacciona Mediante Dominios BH3/genética , Proteína Proapoptótica que Interacciona Mediante Dominios BH3/metabolismo , Caspasa 8/metabolismo , Estrés del Retículo Endoplásmico , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Recovered senescent tumor cells harbor higher migration and invasion potential, owing to which they play a crucial role in tumor recurrence and drug resistance. The aim of this study was to explore the ability of BH3 mimetics in clearing senescent A549 cells and elucidate their underlying killing mechanism. Doxorubicin-induced cell senescence was determined using augmented senescence-associated beta-galactosidase (SA-ß-Gal) staining and increased P16 expression. CCK-8 and crystal violet staining demonstrated that A-1331852, BH3 mimetic, could kill senescent tumor cells without affecting the proliferating cells. A-1331852 induced caspase-dependent senescent cell death accompanied by nuclear concentration, decreased mitochondrial membrane potential, and cleavage of poly (ADP-ribose) polymerase. Most importantly, A-1331852 upregulated the expression of BID and BAX indicating their role in mediating A-1331852-induced apoptosis in senescent A549 cells. The results of fluorescence resonance energy transfer showed that A-1331852 loosened or even released the binding between BCL-xL and tBID, releasing tBID. In addition, A-1331852 also dissociated the binding between BCL-xL and BAX, eventually leading to BAX oligomerization in the mitochondria, and resulting in apoptosis via the mitochondrial pathway. In conclusion, our data demonstrate for the first time that A-1331852 promotes apoptosis of senescent A549 cells by influencing the interaction between BCL-xL and tBID and that between BCL-xL and BAX.
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Apoptosis , Proteína Proapoptótica que Interacciona Mediante Dominios BH3/metabolismo , Mitocondrias , Células A549 , Proteínas Reguladoras de la Apoptosis/metabolismo , Benzotiazoles , Humanos , Isoquinolinas , Mitocondrias/metabolismo , Poli(ADP-Ribosa) Polimerasas/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteína X Asociada a bcl-2/metabolismo , Proteína bcl-X/metabolismoRESUMEN
This study investigated the role of calpain in Eimeria tenella-induced host cell apoptosis. Chick embryo cecal epithelial cell culture technology, flow cytometry, enzyme-linked immunosorbent assays, and fluorescence quantitative PCR were used to detect the E. tenella host cell apoptotic rate, Bax and Bid expression levels, and calpain activity. The results demonstrated that Bax, Bid, and calpain levels were upregulated and apoptosis was increased following E. tenella infection at 24-120 h. Calpain levels were reduced by pharmacological inhibition of calpain using SJA6017 or by blocking Ca2+ entry into the cell using BAPTA/AM at 24-120 h. The mRNA and protein levels of Bax and Bid, the E. tenella infection rate, and the early apoptotic and late apoptotic (necrosis) rates were decreased by using SJA6017 at 24-120 h. These results indicated that E. tenella-promoted host cell apoptosis is regulated by calpain via Bid and Bax at 24-120 h. Thus, manipulation of calpain levels could be used to manage E. tenella infection in chickens in the middle and late developmental stages.
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Coccidiosis , Eimeria tenella , Enfermedades de las Aves de Corral , Animales , Apoptosis , Calpaína/genética , Embrión de Pollo , Pollos , Coccidiosis/metabolismo , Coccidiosis/veterinaria , Eimeria tenella/genética , Enfermedades de las Aves de Corral/genética , Proteína X Asociada a bcl-2/genéticaRESUMEN
Ammonia gas, a toxic environmental pollutant, is a vital component of PM2.5 aerosols, and can decrease human and animal immunity. Peripheral blood lymphocytes (PBLs) are main immune cells. Nevertheless, poisoning mechanism of PBLs under ammonia exposure remains unclear. Here, we established an ammonia poisoning model of chicken PBLs to explore poisoning mechanism of ammonia-caused apoptosis in chicken PBLs. Cell viability and apoptosis rate were detected using CCK8 assay and flow cytometry, respectively. Mitochondrial membrane potential (MMP) was observed using fluorescent staining. In addition, qRT-PCR was performed to measure mRNA levels of apoptosis-related genes (tumor necrosis factor-α (TNF-α), tumor necrosis factor receptor 1 (TNFR1), TNF receptor-associated death domain (TRADD), Fas-associated death domain (FADD), Caspase-8, BH3-interacting domain death agonist (Bid), Bcl-2-associated X protein (Bax), Bcl-2 homologous antagonist/killer (Bak), B-cell lymphoma-2 (Bcl-2), Cytochrome-c (Cytc), apoptotic protease activating factor-1 (APAF1), Caspase-9, and Caspase-3), immune-related genes (interferon-γ (IFN-γ), interleukin-2 (IL-2), IL-4, IL-6, IL-1ß, IL-10, transforming growth factor-ß1 (TGF-ß1), IL-17, IL-21, and IL-22), heat shock protein (HSP) genes (HSP25, HSP40, HSP60, HSP70, HSP90, and HSP110), as well as miR-27b-3p. Western blot was used to determine protein levels of apoptosis-related factors (TNF-α, Caspase-8, Bcl-2, Caspase-9, and Caspase-3), as well as HSPs (HSP40, HSP60, HSP70, and HSP90). The results indicated that TRADD, FADD, and APAF1 were target genes of miR-27b-3p, as well as miR-27b-3p participated in molecular mechanism of apoptosis through targeting TNF-α/TNFR1/Caspase-8 death receptor pathway-triggered Bid/Cytc/Caspase-9 mitochondrial pathway in ammonia-treated chicken PBLs. In addition, our findings demonstrated that excess ammonia led to immunosuppression via Th1/Th2 imbalance and Treg/Th17 imbalance. Simultaneously, ammonia stress activated HSPs. In summary, for the first time, our data demonstrated that HSPs-triggered immunosuppression led to apoptosis under ammonia exposure. Our findings provided a new insight into molecular mechanism of ammonia poisoning and an important reference for environmental risk assessment related to ammonia.
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Pollos , MicroARNs , Amoníaco/metabolismo , Amoníaco/toxicidad , Animales , Apoptosis/genética , Caspasa 3/metabolismo , Caspasa 8/metabolismo , Caspasa 9/metabolismo , Pollos/metabolismo , Proteínas de Choque Térmico/metabolismo , Terapia de Inmunosupresión , Linfocitos/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Neuromyelitis optica (NMO) is a rare disease usually presenting with bilateral or unilateral optic neuritis with simultaneous or sequential transverse myelitis. Autoantibodies directed against aquaporin-4 (AQP4-IgG) are found in most patients. They are believed to cross the blood−brain barrier, target astrocytes, activate complement, and eventually lead to astrocyte destruction, demyelination, and axonal damage. However, it is still not clear what the primary pathological event is. We hypothesize that the interaction of AQP4-IgG and astrocytes leads to DNA damage and apoptosis. We studied the effect of sera from seropositive NMO patients and healthy controls (HCs) on astrocytes' immune gene expression and viability. We found that sera from seropositive NMO patients led to higher expression of apoptosis-related genes, including BH3-interacting domain death agonist (BID), which is the most significant differentiating gene (p < 0.0001), and triggered more apoptosis in astrocytes compared to sera from HCs. Furthermore, NMO sera increased DNA damage and led to a higher expression of immunological genes that interact with BID (TLR4 and NOD-1). Our findings suggest that sera of seropositive NMO patients might cause astrocytic DNA damage and apoptosis. It may be one of the mechanisms implicated in the primary pathological event in NMO and provide new avenues for therapeutic intervention.
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Neuromielitis Óptica , Apoptosis , Acuaporina 4/metabolismo , Astrocitos/metabolismo , Autoanticuerpos , Humanos , Inmunoglobulina GRESUMEN
This study used a contingent valuation method to estimate residents' WTP for improved solid waste management in Hawassa city. The improvement in solid waste management includes the relocation of the current landfill and the switch from open donkey carts to covered tractors with a waste compactor for solid waste transportation. A method of iterative bidding was used to ask residents about their WTP, and ordinal logistic regression was used for data analysis. The result of the study indicated that the estimated average WTP of residents was Ethiopian Birr (ETB) 26.57 ($ 0.62) per month. Besides, the study findings showed that waste minimization practices such as reuse, recycle, waste separation and making compost from waste were uncommon at the household level in Hawassa city. The policy implications of the findings are that the Municipality of Hawassa should consider the residents' willingness for improved solid waste management service and adopt the solid waste management improvement project to prevent further public health risks and environmental impacts.
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Residuos Sólidos , Administración de Residuos , Ciudades , Etiopía , ReciclajeRESUMEN
BACKGROUNDS: miR-26a-5p is a short noncoding RNA that is abnormally expressed in drug-induced liver injury (DILI), but its pathophysiologic role in the mechanism of disease in DILI is still vague. METHODS: The expression of miR-26a-5p, viability of hepatic stellate cells (HSCs) proliferation, and apoptosis were explored via real-time PCR, CCK-8 assay, Tunel fluorescence, and flow cytometry. The expression of Bid was detected via Western blot assays, real-time PCR, and immunofluorescence. The apoptosis-associated proteins were determined through Western blot. The interaction between miR-26a-5p and Bid was measured via Dual luciferase reporter assay. RESULTS: miR-26a-5p expression was greatly decreased in HSCs and serum treated with azithromycin, simvastatin and diclofenac sodium, respectively. Hepatocyte viability was largely suppressed while hepatocyte apoptosis was markedly increased in DILI. Correspondingly, the apoptosis-associated proteins including Bid, caspase-8 and cytochrome C in HSCs were significantly upregulated when treated with either of these drugs. Moreover, miR-26a-5p interacted with Bid, and hepatocyte proliferation and apoptosis influenced by miR-26a-5p mimics were obviously reversed when co-treated with overexpressed Bid plasmids. CONCLUSIONS: miR-26a-5p played a protective role against DILI via targeting Bid.
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Enfermedad Hepática Inducida por Sustancias y Drogas , MicroARNs , Apoptosis/genética , Proteínas Reguladoras de la Apoptosis , Proliferación Celular , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Humanos , MicroARNs/genética , MicroARNs/metabolismoRESUMEN
Economic conditions within the market affect the likelihood of performing a business combination between firms. Indeed, the level of uncertainty during period of crisis plays a relevant role in M&A transactions. This paper is one of the first attempts to investigate the relationship between health crisis and business combinations. The findings show that while the bid premiums computed using the target's share price thirty days before the transaction announcement increase for M&A operations performed during health crises, the cumulative abnormal returns decrease.
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This paper examines the impact of COVID-19 related governments' interventions on the volatility and liquidity of American depository receipts (ADRs). Using a wide dataset of 387 ADRs from 34 countries around the globe, we provide an examination of the effect of economic and non-economic interventions on the quality of these cross-listed securities. Our results suggest that closures, restrictions, as well as containment health steps implemented during the outbreak period of the pandemic, seem to deteriorate the ADRs' liquidity and stability. The negative impact holds for different control variables and regression specifications and is not subsumed by the inclusion of the daily confirmed cases as a proxy for the severity of the pandemic. The information documented here may assist financial market participants in their risk management. The findings could also be important for policymakers for their preparedness plans in case of future crises.
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Increasing evidences have showed that autophagy played a significant role in oral squamous cell carcinoma (OSCC). Purpose of our study was to explore the prognostic value of autophagy-related genes (ATGs) and screen autophagy-related biomarkers for OSCC. RNA-seq and clinical data were downloaded from The Cancer Genome Atlas (TCGA) database following extracting ATG expression profiles. Then, differentially expressed analysis was performed in R software and a risk score model according to ATGs was established. Moreover, comprehensive bioinformatics analyses were used to screen autophagy-related biomarkers which were later verified in OSCC tissues and cell lines. A total of 232 ATGs were extracted, and 37 genes were differentially expressed in OSCC. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis demonstrated that these genes were mainly located in autophagosome membrane and associated with autophagy. Furthermore, the risk score on basis of ATGs was identified as potential independent prognostic biomarker. Moreover, ATG12 and BID were identified as potential autophagy-related biomarkers of OSCC. This study successfully constructed a risk model, and the risk score could predict the prognosis of OSCC patients accurately. Moreover, ATG12 and BID were identified as two potential independent prognostic autophagy-related biomarkers and might provide new OSCC therapeutic targets.