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1.
Virus Genes ; 2024 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-39302542

RESUMO

Post-translational modifications (PTMs), as epigenetic modifications, are significant in the interaction between virus and its host. However, it is unclear whether rotavirus (RV) causes changes in both the host cell epigenetic protein modification and the regulatory mechanism of viral replication. Here, we analyzed the proteome of Caco-2 cells to determine if acetylation modification occurred within the cells after RV infection. We found that glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a protein involved in glycolysis, was deacetylated at lysine 219 via histone deacetylase 9 (HDAC9) in 50 h after the RV infection. Remarkably, the deacetylation of GAPDH promoted RV replication. Finally, we found that glycolysis was alterable in Caco-2 cells by RV or the deacetylation of GAPDH lysine 219, using the Seahorse XF Glycolysis Stress Test. In conclusion, our results demonstrate for the first time that RV infection promoted deacetylation of GAPDH at lysine 219 in order to increase its own viral replication in Caco-2 cells.

2.
Molecules ; 28(5)2023 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-36903326

RESUMO

Ficus pandurata Hance (FPH) is a Chinese herbal medicine widely used for health care. This study was designed to investigate the alleviation efficacy of the low-polarity ingredients of FPH (FPHLP), prepared by supercritical CO2 fluid extraction technology, against CCl4-induced acute liver injury (ALI) in mice and uncover its underlying mechanism. The results showed that FPHLP had a good antioxidative effect determined by the DPPH free radical scavenging activity test and T-AOC assay. The in vivo study showed that FPHLP dose-dependently protected against liver damage via detection of ALT, AST, and LDH levels and changes in liver histopathology. The antioxidative stress properties of FPHLP suppressed ALI by increasing levels of GSH, Nrf2, HO-1, and Trx-1 and reducing levels of ROS and MDA and the expression of Keap1. FPHLP significantly reduced the level of Fe2+ and expression of TfR1, xCT/SLC7A11, and Bcl2, while increasing the expression of GPX4, FTH1, cleaved PARP, Bax, and cleaved caspase 3. The results demonstrated that FPHLP protected mouse liver from injury induced by CCl4 via suppression of apoptosis and ferroptosis. This study suggests that FPHLP can be used for liver damage protection in humans, which strongly supports its traditional use as a herbal medicine.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Ferroptose , Ficus , Animais , Camundongos , Antioxidantes/farmacologia , Apoptose , Dióxido de Carbono/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Ficus/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fígado , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo
3.
Environ Monit Assess ; 195(1): 41, 2022 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-36301357

RESUMO

The amount of China's sulfur dioxide emission remains significantly large in recent years. To further reduce sulfur dioxide emission, the key is to find out the leading factors affecting sulfur dioxide emission and then take measures to control it accordingly. In order to investigate the influential factors of sulfur dioxide emission of various provinces, the data of sulfur dioxide emission of 30 provinces in China from 2001 to 2020 were collected. We established the symbolic regression model to explore the relationship between the GDP (x1), total population (x2), total energy consumption (x3), thermal power installed capacity (x4), and sulfur dioxide emission (dependent variable) for each province. The results show that the amount of China's total sulfur dioxide emission and sulfur dioxide emission in most provinces meet the environmental Kuznets curve (EKC). The influential degree of the factors affecting China's sulfur dioxide emission are GDP, total energy consumption, thermal power installed capacity, and total population. The provinces with the primary factor of GDP have the lowest average total energy consumption and average thermal power installed capacity, and their average sulfur dioxide emissions are also relatively low. The provinces with the primary factor of GDP do not show obvious geographical characteristics, but the provinces with the primary factor of total energy consumption are all distributed in southern China. Based on the research results, some control measures are also put forward.


Assuntos
Dióxido de Carbono , Dióxido de Enxofre , Dióxido de Enxofre/análise , Dióxido de Carbono/análise , Monitoramento Ambiental , China , Desenvolvimento Econômico , Carbono
4.
J Med Virol ; 93(11): 6210-6219, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34260071

RESUMO

To investigate the role of miR-4301 in rotavirus (RV)-infected Caco-2 cells. In this experiment, RNAs of RV-infected Caco-2 cells were extracted, and the high-throughput second-generation sequencing was performed to detect the expression profiles of host microRNAs (miRNAs). Synthetic miRNA mimics and inhibitors were examined (quantitative polymerase chain reaction [qPCR], crystalline violet, immunofluorescence and electron microscopy) to evaluate the effect on RV replication. Target genes of miR-4301 were predicted by software analysis. The expression of target genes was evaluated by qPCR and Western blot after transfected with miRNA inhibitor/mimic, and crystalline violet and qPCR were used to detect the downregulation effects of target genes on RV replication. By transfecting miRNA inhibitors/mimics and detecting downstream target genes, the mechanism of miRNA affecting RV replication was analyzed. There were 78 known miRNAs with significant differential expression, including 39 upregulated miRNAs and 39 downregulated miRNAs. The results showed that miR-4301 exerted a key role in enhancing RV replication. PPP1R3D protein which can inhibit RV replication was predicted as the target gene of miR-4301 by software analysis. While upregulating miR-4301 by RV, the expression of PPP1R3D and glycogen synthase (GS) is suppressed. For the first time, the effect of miR-4301 on RV infection, and its influence on GS was investigated. Specifically, RV inhibits host cell glycogen synthesis to utilize the host intracellular glucose for promoting its own replication.


Assuntos
MicroRNAs/imunologia , Proteína Fosfatase 1/metabolismo , Infecções por Rotavirus/genética , Infecções por Rotavirus/imunologia , Rotavirus/imunologia , Replicação Viral/imunologia , Células CACO-2 , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Proteína Fosfatase 1/genética , Rotavirus/genética
5.
J Acoust Soc Am ; 149(3): 2027, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33765777

RESUMO

This paper presents a boundary element-based scheme for the sensitivity analysis of acoustic eigenfrequencies of both interior and exterior acoustic systems. The nonlinear eigenvalue problem generated by the acoustic boundary element method is first reformulated into a generalized eigenvalue problem of reduced dimension through a contour integral approach. The sensitivity formulations for acoustic eigenfrequencies are then derived based on an adjoint method that uses both the right and left eigenvectors. The adaptive cross approximation in conjunction with the hierarchical matrices is used to reduce the solution burden of the boundary element systems. The Burton-Miller-type combined formulation is applied to shift the spurious eigenfrequencies and their sensitivities, and the strategies to identify the spurious results are suggested. Three numerical examples are used to verify the accuracy and applicability of the developed scheme.

6.
Virus Genes ; 53(3): 367-376, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28289928

RESUMO

Rotavirus (RV) is the most common cause of severe gastroenteritis and fatal dehydration in human infants and neonates of different species. However, the pathogenesis of rotavirus-induced diarrhea is poorly understood. Secretory diarrhea caused by rotavirus may lead to a combination of excessive secretion of fluid and electrolytes into the intestinal lumen. Fluid absorption in the small intestine is driven by Na+-coupled transport mechanisms at the luminal membrane, including Na+/H+ exchanger (NHE). Here, we performed qRT-PCR to detect the transcription of NHEs. Western blotting was employed for protein detection. Furthermore, immunocytochemistry was used to validate the NHE's protein expression. Finally, intracellular Ca2+ concentration was detected by confocal laser scanning microscopy. The results demonstrated that the NHE6 mRNA and protein expressed in the human colon adenocarcinoma cell line (Caco-2). Furthermore, RV-Wa induced decreased expression of the NHE1 and NHE6 in Caco-2 cell in a time-dependent manner. In addition, intracellular Ca2+ concentration in RV-Wa-infected Caco-2 cells was higher than that in the mock-infected cells. Furthermore, RV-Wa also can downregulate the expression of calmodulin (CaM) and calmodulin kinase II (CaMKII) in Caco-2 cells. These findings provides important insights into the mechanisms of rotavirus-induced diarrhea. Further studies on the underlying pathophysiological mechanisms that downregulate NHEs in RV-induced diarrhea are required.


Assuntos
Regulação para Baixo , Regulação da Expressão Gênica/genética , Rotavirus/patogenicidade , Trocador 1 de Sódio-Hidrogênio/genética , Trocadores de Sódio-Hidrogênio/genética , Animais , Células CACO-2 , Cálcio/análise , Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo , Calmodulina/genética , Calmodulina/metabolismo , Linhagem Celular , Citosol/química , Diarreia/virologia , Humanos , Macaca mulatta , RNA Mensageiro/análise , RNA Mensageiro/biossíntese , Infecções por Rotavirus/genética , Infecções por Rotavirus/virologia , Trocador 1 de Sódio-Hidrogênio/metabolismo , Trocadores de Sódio-Hidrogênio/metabolismo , Transcrição Gênica
7.
Toxicol Appl Pharmacol ; 298: 1-8, 2016 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-26965727

RESUMO

Methylmercury (MeHg) is a highly neurotoxic environmental chemical that can cause developmental impairments. Human fetuses and neonates are particularly susceptible to MeHg toxicity; however, the mechanisms governing its effects in the developing brain are unclear. In the present study, we investigated the effects of prenatal and lactational MeHg exposure on the developing cerebellum in rats. We demonstrated that exposure to 5ppm MeHg decreased postnatal expression of pre- and postsynaptic proteins, suggesting an impairment in synaptic development. MeHg exposure also reduced neurite outgrowth, as shown by a decrease in the expression of the neurite marker neurofilament H. These changes were not observed in rats exposed to 1ppm MeHg. In order to define the underlying mechanism, we investigated the effects of MeHg exposure on the tropomyosin receptor kinase (Trk) A pathway, which plays important roles in neuronal differentiation and synapse formation. We demonstrated suppression of the TrkA pathway on gestation day 20 in rats exposed to 5ppm MeHg. In addition, down-regulation of eukaryotic elongation factor 1A1 (eEF1A1) was observed on postnatal day 1. eEF1A1 knockdown in differentiating PC12 cells impaired neurite outgrowth and synaptic protein expression, similar to the results of MeHg exposure in the cerebellum. These results suggest that suppression of the TrkA pathway and subsequent decreases in eEF1A1 expression induced by prenatal exposure to MeHg may lead to reduced neurite outgrowth and synaptic protein expression in the developing cerebellum.


Assuntos
Cerebelo/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Compostos de Metilmercúrio/toxicidade , Neuritos/efeitos dos fármacos , Fator 1 de Elongação de Peptídeos/genética , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Receptor trkA/antagonistas & inibidores , Sinapses/efeitos dos fármacos , Animais , Western Blotting , Cerebelo/crescimento & desenvolvimento , Cerebelo/metabolismo , Cerebelo/patologia , Relação Dose-Resposta a Droga , Regulação para Baixo , Feminino , Masculino , Neuritos/patologia , Células PC12 , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/patologia , Ratos , Ratos Wistar , Sinapses/genética
8.
Yao Xue Xue Bao ; 51(10): 1622-8, 2016 10.
Artigo em Zh | MEDLINE | ID: mdl-29932618

RESUMO

The study was designed to generate an ophthalmic thermosensitive in situ gel with improved mechanical and mucoadhesive properties that may prolong the retention time to enhance the bioavalability of pearl hydrolyzate. The gene was comprised of poloxamer 407, poloxamer188 and Carbopol 934, which were optimized by central composite design and response surface methodology. The rheological properties, transcorneal permeability, retention time and in vitro release behaviors of the optimal gel formulation were investigated. The gel was Newtonian liquid at 25 ℃ and performed as a semisolid gel with non-Newtonian liquid property with a gelation time of 13 s at 35 ℃. Compared with a conventional eye drops, the ophthalmic in situ gel exhibited a sevenfold increase in retention with a sustained release behavior, which was observed with suitable permeability coefficient at 5.58 cm·s-1. In conclusion, the new gel of pearl hydrolyzate prolonged the release duration of drug, which may decrease the frequency of administration of pearl hydrolyzate.


Assuntos
Acrilatos/química , Géis/química , Soluções Oftálmicas/química , Poloxâmero/química , Animais , Preparações de Ação Retardada , Olho/efeitos dos fármacos , Reologia , Temperatura
9.
Arch Virol ; 160(6): 1421-33, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25877820

RESUMO

Rotavirus (RV) is the primary cause of severe dehydrating gastroenteritis and acute diarrheal disease in infants and young children. Previous studies have revealed that genistein can inhibit the infectivity of enveloped or nonenveloped viruses. Although the biological properties of genistein are well studied, the mechanisms of action underlying their anti-rotavirus properties have not been fully elucidated. Here, we report that genistein significantly inhibits RV-Wa replication in vitro by repressing viral RNA transcripts, and possibly viral protein synthesis. Interestingly, we also found that aquaporin 4 (AQP4) mRNA and protein expression, which was downregulated in RV-infected Caco-2 cells, can be upregulated by genistein in a time- and dose-dependent manner. Further experiments confirmed that genistein triggers CREB phosphorylation through PKA activation and subsequently promotes AQP4 gene transcription. These findings suggest that the pathophysiological mechanism of RV infection involves decreased expression of AQP4 and that genistein may be a useful candidate for developing a new anti-RV strategy by inhibiting rotavirus replication and upregulating AQP4 expression via the cAMP/PKA/CREB signaling pathway. Further studies on the effect of genistein on RV-induced diarrhea are warranted.


Assuntos
Antivirais/uso terapêutico , Aquaporina 4/biossíntese , Células CACO-2/virologia , Genisteína/uso terapêutico , Infecções por Rotavirus/tratamento farmacológico , Replicação Viral/efeitos dos fármacos , Adenilil Ciclases/metabolismo , Antivirais/farmacologia , Aquaporina 4/fisiologia , Células CACO-2/efeitos dos fármacos , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Eletroforese em Gel de Poliacrilamida , Técnica Indireta de Fluorescência para Anticorpo , Genisteína/farmacologia , Humanos , Immunoblotting , Reação em Cadeia da Polimerase em Tempo Real , Rotavirus/efeitos dos fármacos , Rotavirus/fisiologia , Regulação para Cima/efeitos dos fármacos
10.
J Environ Sci (China) ; 34: 107-15, 2015 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-26257353

RESUMO

In order to assess the potential health risks of Hg pollution, total mercury (T-Hg) and methyl mercury (MeHg) concentrations were determined in air, dust, surface soil, crops, poultry, fish and human hair samples from an electronic waste (e-waste) recycling area in Taizhou, China. High concentrations of T-Hg and MeHg were found in these multiple matrices, and the mean concentration was 30.7 ng/m(3) of T-Hg for atmosphere samples, 3.1 µg/g of T-Hg for soil, 37.6 µg/g of T-Hg for dust, 20.3 ng/g of MeHg for rice and 178.1 ng/g of MeHg for fish, suggesting that the e-waste recycling facility was a significant source of Hg. The inorganic Hg (I-Hg) levels (0.84 µg/g) in hair samples of e-waste workers were much higher than that in the reference samples. Pearson's correlation coefficients showed that strong positive correlations (p<0.01) between hair I-Hg and time staying in industrial area (r=0.81) and between MeHg and fish consumption frequency (r=0.91), imply that workers were mainly exposed to Hg vapor through long-time inhalation of contaminated air and dust, while other population mainly exposed to MeHg through high-frequency fish consumption. The estimated daily intakes of Hg showed that dietary intake was the major Hg exposure source, and Hg intakes from rice and fish were significantly higher than from any other foods. The estimated total daily intakes (TDIs) of MeHg for both children (696.8 ng/(kg·day)) and adults (381.3 ng/(kg·day)) greatly exceeded the dietary reference dose (RfD) of 230 ng/(kg·day), implying greater health risk for humans from Hg exposures around e-waste recycling facilities.


Assuntos
Exposição Ambiental , Poluentes Ambientais/análise , Contaminação de Alimentos/análise , Mercúrio/análise , Compostos de Metilmercúrio/análise , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , China , Poeira/análise , Resíduo Eletrônico , Monitoramento Ambiental , Feminino , Cabelo/química , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Exposição Ocupacional , Reciclagem , Instalações de Eliminação de Resíduos , Adulto Jovem
11.
Arch Gynecol Obstet ; 289(6): 1225-34, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24318276

RESUMO

PURPOSE: The aim of this study was to evaluate the evidence for probiotic use in the treatment of bacterial vaginosis (BV) in adult women. METHODS: The Cochrane Library, PubMed, CINAHL and EMBASE databases were searched to identify the relevant randomized controlled trials that investigated the effects of probiotics for the treatment of BV. Two independent authors used an Excel file to extract data and assessed trial quality. The primary outcome measure was the cure rate of BV. The meta-analysis was performed with the fixed-effects model or random-effects model according to heterogeneity. RESULTS: A total of 1,304 patients from 12 trials were subjected to meta-analysis. The pooled result showed that probiotics supplementation can significantly improve the cure rate in adult BV patients [risk ratio (RR) 1.53; 95 % confidence interval (CI) 1.19-1.97]. Findings were slightly different when analyses were restricted to nine high-quality studies (RR 1.60; 95 % CI 1.16-2.22). In a subgroup meta-analysis, a statistically significant beneficial effect of probiotics was observed in Europe populations and short-term follow-up days. CONCLUSION: Compared with the control arm, the limited evidence suggests that probiotics show a beneficial effect in patients who are suffering from BV. However, the results should be interpreted cautiously because of the heterogeneity among study designs. Further large-scale, well-designed RCTs on this topic are urgently needed.


Assuntos
Probióticos/uso terapêutico , Vaginose Bacteriana/tratamento farmacológico , Administração Intravaginal , Administração Oral , Adulto , Anti-Infecciosos/uso terapêutico , Quimioterapia Combinada , Feminino , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
12.
Biomol Biomed ; 2024 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-39101759

RESUMO

MicroRNAs (miRNAs) represent a class of non-coding small RNAs that are prevalent in eukaryotes, typically comprising approximately 22 nucleotides, and have the ability to post-transcriptionally regulate gene expression. miRNAs exhibit diverse types and functions, with mechanisms of action that include cell differentiation, proliferation, apoptosis, and regulation of signaling pathways. Both viruses and their hosts can encode miRNAs, which serve as crucial effector molecules in the complex interaction between viruses and host cells. Host miRNAs can either directly interact with the virus genome to inhibit virus replication or facilitate virus replication by providing necessary substances. Viral miRNAs can directly bind to host mRNAs, thereby influencing translation efficiency, suppressing the immune response, and ultimately enhancing virus replication. This article comprehensively reviews the roles of miRNAs in virus-host interactions, aiming to provide valuable insights into viral pathogenic mechanisms and potential therapeutic approaches.

13.
Virology ; 594: 110039, 2024 06.
Artigo em Inglês | MEDLINE | ID: mdl-38492520

RESUMO

Porcine Epidemic Diarrhea Virus (PEDV) poses a significant threat to the global swine industry, demanding a thorough understanding of its cellular invasion mechanism for effective interventions. This study meticulously investigates the impact of O- and N-linked glycans on PEDV proteins and host cell interaction, shedding light on their influence on the virus's invasion process. Utilizing CRISPR-Cas9 technology to inhibit cell surface O- and N-linked glycan synthesis demonstrated no discernible impact on virus infection. However, progeny PEDV strains lacking these glycans exhibited a minor effect of O-linked glycans on virus infection. Conversely, a notable 40% reduction in infectivity was observed when the virus surface lacked N-linked glycans, emphasizing their pivotal role in facilitating virus recognition and binding to host cells. Additionally, inhibition studies utilizing kifunensine, a natural glycosidase I inhibitor, reaffirmed the significant role of N-linked glycans in virus infection. Inhibiting N-linked glycan synthesis with kifunensine substantially decreased virus entry into cells and potentially influenced spike protein expression. Assessment of the stability and recovery potential of N-linked glycan-deficient strains underscored the critical importance of N-glycans at various stages of the virus lifecycle. In vivo experiments infecting piglets with N-glycan-deficient strains exhibited milder clinical symptoms, reduced virus excretion, and less severe pathological lesions compared to conventional strains. These findings offer promising translational applications, proposing N-glycosylation inhibitors as potential therapeutic interventions against PEDV. The utilization of these inhibitors might mitigate virus invasion and disease transmission, providing avenues for effective antiviral strategies and vaccine development. Nonetheless, further research is warranted to elucidate the precise mechanisms of N-linked glycans in PEDV infection for comprehensive clinical applications.


Assuntos
Infecções por Coronavirus , Vírus da Diarreia Epidêmica Suína , Doenças dos Suínos , Animais , Suínos , Vírus da Diarreia Epidêmica Suína/fisiologia , Internalização do Vírus , Processamento de Proteína Pós-Traducional , Polissacarídeos
14.
Lab Chip ; 24(17): 4073-4084, 2024 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-39115160

RESUMO

Microactuators, capable of executing tasks typically repetitive, hazardous, or impossible for humans, hold great promise across fields such as precision medicine, environmental remediation, and swarm intelligence. However, intricate motions of microactuators normally require high complexity in design, making it increasingly challenging to realize at small scales using existing fabrication techniques. Taking inspiration from the hierarchical-anisotropy principle found in nature, we program liquid crystalline elastomer (LCE) microactuators with multimodal actuation tailored to their molecular, shape, and architectural anisotropies at (sub)nanometer, micrometer, and (sub)millimeter scales, respectively. Our strategy enables diverse deformations with individual LCE microstructures, including expanding, contracting, twisting, bending, and unwinding, as well as re-programmable shape transformations of assembled LCE architectures with negative Poisson's ratios, locally adjustable actuation, and changing from two-dimensional (2D) to three-dimensional (3D) structures. Furthermore, we design tetrahedral microactuators with well-controlled mobility and precise manipulation of both solids and liquids in various environments. This study provides a paradigm shift in the development of microactuators, unlocking a vast array of complexities achievable through manipulation at each hierarchical level of anisotropy.

15.
Nanoscale ; 16(8): 4095-4104, 2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38333905

RESUMO

In recent years, tumor catalytic therapy based on nanozymes has attracted widespread attention. However, its application is limited by the tumor hypoxic microenvironment (TME). In this study, we developed oxygen-supplying magnetic bead nanozymes that integrate hemoglobin and encapsulate the photosensitizer curcumin, demonstrating reactive oxygen species (ROS)-induced synergistic breast cancer therapy. Fe3O4 magnetic bead-mediated catalytic dynamic therapy (CDT) generates hydroxyl radicals (˙OH) through the Fenton reaction in the tumor microenvironment. The Hb-encapsulated Fe3O4 magnetic beads can be co-loaded with the photosensitizer/chemotherapeutic agent curcumin (cur), resulting in Fe3O4-Hb@cur. Under hypoxic conditions, oxygen molecules are released from Fe3O4-Hb@cur to overcome the TME hypoxia, resulting in comprehensive effects favoring anti-tumor responses. Upon near-infrared (NIR) irradiation, Fe3O4-Hb@cur activates the surrounding molecular oxygen to generate a certain amount of singlet oxygen (1O2), which is utilized for photodynamic therapy (PDT) in cancer treatment. Meanwhile, we validated that the O2 carried by Hb significantly enhances the intracellular ROS level, intensifying the catalytic therapy mediated by Fe3O4 magnetic beads and inflicting lethal damage to cancer cells, effectively inhibiting tumor growth. Therefore, significant in vivo synergistic therapeutic effects can be achieved through catalytic-photodynamic combination therapy.


Assuntos
Neoplasias da Mama , Curcumina , Neoplasias , Fotoquimioterapia , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Oxigênio , Espécies Reativas de Oxigênio/farmacologia , Curcumina/farmacologia , Curcumina/uso terapêutico , Linhagem Celular Tumoral , Fotoquimioterapia/métodos , Neoplasias/tratamento farmacológico , Hipóxia , Fenômenos Magnéticos , Microambiente Tumoral , Peróxido de Hidrogênio/uso terapêutico
16.
Nat Biomed Eng ; 8(2): 177-192, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37872368

RESUMO

Cas13 can be used for the knockdown, editing, imaging or detection of RNA and for RNA-based gene therapy. Here by using RNA immunoprecipitation sequencing, transcriptome profiling, biochemical analysis, high-throughput screening and machine learning, we show that Cas13 can intrinsically target host RNA in mammalian cells through previously unappreciated mechanisms. Different from its known cis/trans RNA-cleavage activity, Cas13 can also cleave host RNA via mechanisms that are transcript-specific, independent of the sequence of CRISPR RNA and dynamically dependent on the conformational state of Cas13, as we show for several Cas13-family effectors encoded in one-vector and two-vector lentiviral systems. Moreover, host genes involved in viral processes and whose transcripts are intrinsically targeted by Cas13 contribute to constraining the lentiviral delivery and expression of Cas13. Our findings offer guidance for the appropriate use of lentiviral Cas13 systems and highlight the need for caution regarding intrinsic RNA targeting in Cas13-based applications.


Assuntos
Sistemas CRISPR-Cas , RNA , Animais , RNA/genética , Sistemas CRISPR-Cas/genética , Terapia Genética , Perfilação da Expressão Gênica , Lentivirus/genética , Mamíferos/genética
17.
Nat Commun ; 15(1): 5502, 2024 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-38951519

RESUMO

Resistance to chemotherapy has been a major hurdle that limits therapeutic benefits for many types of cancer. Here we systematically identify genetic drivers underlying chemoresistance by performing 30 genome-scale CRISPR knockout screens for seven chemotherapeutic agents in multiple cancer cells. Chemoresistance genes vary between conditions primarily due to distinct genetic background and mechanism of action of drugs, manifesting heterogeneous and multiplexed routes towards chemoresistance. By focusing on oxaliplatin and irinotecan resistance in colorectal cancer, we unravel that evolutionarily distinct chemoresistance can share consensus vulnerabilities identified by 26 second-round CRISPR screens with druggable gene library. We further pinpoint PLK4 as a therapeutic target to overcome oxaliplatin resistance in various models via genetic ablation or pharmacological inhibition, highlighting a single-agent strategy to antagonize evolutionarily distinct chemoresistance. Our study not only provides resources and insights into the molecular basis of chemoresistance, but also proposes potential biomarkers and therapeutic strategies against such resistance.


Assuntos
Antineoplásicos , Sistemas CRISPR-Cas , Resistencia a Medicamentos Antineoplásicos , Irinotecano , Oxaliplatina , Proteínas Serina-Treonina Quinases , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Oxaliplatina/farmacologia , Irinotecano/farmacologia , Sistemas CRISPR-Cas/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Neoplasias Colorretais/genética , Neoplasias Colorretais/tratamento farmacológico , Animais , Neoplasias/genética , Neoplasias/tratamento farmacológico , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Camundongos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
18.
Kidney Blood Press Res ; 38(1): 31-41, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24525835

RESUMO

BACKGROUND/AIMS: An increasing body of evidence demonstrates that L-carnitine plays a pivotal role in lipid metabolism of hemodialysis (HD) patients. However, there are still some reservations about its benefits. Therefore, we performed a meta-analysis to assess the effects of L-carnitine supplementation on lipid profile in HD patients. METHODS: Literature search was performed to identify the relevant randomized controlled trials that investigated the effects of L-carnitine on the lipid profile of subjects. Two independent authors used an Excel file to extract data and assess trials quality. The primary effect measure was the difference in means of the final lipid measurements between the intervention and control groups. The meta-analysis was performed with the fixed-effects model or random-effects model according to heterogeneity. RESULTS: Twelve studies with a total of 391 patients met the inclusion criteria. The use of L-carnitine was not associated with a reduction in the total cholesterol (SMD, -0.11; 95% CI, -0.31 to 0.09), HDL-cholesterol (SMD, 0.01; 95% CI, -0.36 to 0.39), VLDL-cholesterol (SMD, 0.54; 95% CI, -0.06 to 1.14), and the serum triglycerides (SMD, -0.12; 95% CI, -0.36 to 0.12). However, L-carnitine can significantly decrease the LDL-cholesterol (SMD, -0.29; 95% CI, -0.53 to -0.06) in HD patients. In a subgroup meta-analysis, a significant LDL-cholesterol-lowering effect of L-carnitine supplementation was observed in intravenous application group, and patients with longer interventional duration and renal diseases. CONCLUSION: The limited evidence suggests that there was no effect of L-carnitine on serum total cholesterol, HDL-cholesterol, VLDL-cholesterol and serum triglycerides. By contrast, this meta-analysis suggests a promising effect of L-carnitine on LDL-cholesterol. Further large-scale, well-designed randomized controlled trials are urgently needed


Assuntos
Carnitina/farmacologia , Hipolipemiantes/farmacologia , Lipídeos/sangue , Diálise Renal , Complexo Vitamínico B/farmacologia , Animais , Suplementos Nutricionais , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Insuficiência Renal/sangue , Insuficiência Renal/terapia
19.
Nat Commun ; 14(1): 5386, 2023 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-37666839

RESUMO

Droplet rebound is ubiquitous on super-repellent surfaces. Conversion between kinetic and surface energies suggests that rebound suppression is unachievable due to negligible energy dissipation. Here, we present an effective approach to suppressing rebounds by incorporating bubbles into droplets, even in super-repellent states. This suppression arises from the counteractive capillary effects within bubble-encapsulated hollow droplets. The capillary flows induced by the deformed inner-bubble surface counterbalance those driven by the outer-droplet surface, resulting in a reduction of the effective take-off momentum. We propose a double-spring system with reduced effective elasticity for hollow droplets, wherein the competing springs offer distinct behavior from the classical single-spring model employed for single-phase droplets. Through experimental, analytical, and numerical validations, we establish a comprehensive and unified understanding of droplet rebound, by which the behavior of single-phase droplets represents the exceptional case of zero bubble volume and can be encompassed within this overarching framework.

20.
Biomed Pharmacother ; 169: 115941, 2023 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-38006619

RESUMO

Chaenomeles sinensis fruit polysaccharide (CSP) and carboxymethylated CSP (CSP-M) were prepared using ultrasound extraction and the sodium hydroxide-chloroacetic acid method. Structural analysis revealed that both CSP and CSP-M mainly consisted of glucose, arabinose, rhamnose, glucuronic acid, galactose, and xylose, and the introduction of carboxymethyl did not damage the polymer chain of CSP. In vivo studies verified that both CSP and CSP-M could remarkably alleviate the symptoms of ulcerative colitis (UC) mice and reduce intestinal epithelial cell depletion, along with the infiltration of inflammatory cells in colon tissue, by mediating the expression of myeloperoxidase (MPO), inflammatory factors [tumour necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and IL-6], and oxidative stress factors [malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), and nitric oxide (NO)]. Most importantly, the introduction of carboxymethyl significantly enhanced the anti-UC activity of CSP, confirming the efficacy of carboxymethylation as a method to enhance the biological activities of CSP, thereby suggesting the potential of CSP-M as a therapeutic option for UC.


Assuntos
Colite Ulcerativa , Colite , Rosaceae , Camundongos , Animais , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Sulfato de Dextrana/efeitos adversos , Inflamação/metabolismo , Colo/metabolismo , Estresse Oxidativo , Fator de Necrose Tumoral alfa/metabolismo , Glutationa/metabolismo , Polissacarídeos/efeitos adversos , Modelos Animais de Doenças , Colite/metabolismo
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