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BACKGROUND: The pathogenesis of Chlamydia trachomatis is associated with the induction of the host inflammatory response; however, the precise underlying molecular mechanisms remain poorly understood. METHODS: CT622, a T3SS effector protein, has an important role in the pathogenesis of C trachomatis; however, whether CT622 can induce a host inflammatory response is not understood. Our findings demonstrate that CT622 induces the expression of interleukins 6 and 8 (IL-6 and IL-8). Mechanistically, these effects involve the activation of the MAPK/NF-κB signaling pathways (mitogen-activated protein kinase/nuclear factor κB). RESULTS: Interestingly, we demonstrated that the suppression of toll-like receptor 4 using small interfering RNA markedly reduced the phosphorylation of ERK, p38, JNK, and IκBα, concomitant with a significant decrease in IL-6 and IL-8 secretion. Conversely, disruption of toll-like receptor 2 abrogated the CT622-induced upregulation of IL-8 and activation of ERK, whereas IL-6 expression and p38, JNK, and IκBα phosphorylation were unaffected. CONCLUSIONS: Taken together, these results indicate that CT622 contributes to the inflammatory response through the toll-like receptor 2/4-mediated MAPK/NF-κB pathways, which provides insight into the molecular pathology of C trachomatis infection.
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Chlamydia trachomatis , Citocinas , NF-kappa B , Receptor 2 Toll-Like , Receptor 4 Toll-Like , Humanos , Chlamydia trachomatis/imunologia , NF-kappa B/metabolismo , Receptor 2 Toll-Like/metabolismo , Receptor 2 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Receptor 4 Toll-Like/genética , Células THP-1 , Citocinas/metabolismo , Transdução de Sinais , Interleucina-6/metabolismo , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/genética , Infecções por Chlamydia/imunologia , Infecções por Chlamydia/microbiologia , Infecções por Chlamydia/metabolismo , Interleucina-8/metabolismo , Sistemas de Secreção Tipo III/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Sistema de Sinalização das MAP Quinases , FosforilaçãoRESUMO
Defect engineering is an effective strategy to enhance the enzyme-like activity of nanozymes. However, previous efforts have primarily focused on introducing defects via de novo synthesis and post-synthetic treatment, overlooking the dynamic evolution of defects during the catalytic process involving highly reactive oxygen species. Herein, a defect-engineered metal-organic framework (MOF) nanozyme with mixed linkers is reported. Over twofold peroxidase (POD)-like activity enhancement compared with unmodified nanozyme highlights the critical role of in situ defect formation in enhancing the catalytic performance of nanozyme. Experimental results reveal that highly active hydroxyl radical (â¢OH) generated in the catalytic process etches the 2,5-dihydroxyterephthalic acid ligands, contributing to electronic structure modulation of metal sites and enlarged pore sizes in the framework. The self-enhanced POD-like activity induced by in situ defect engineering promotes the generation of â¢OH, holding promise in colorimetric sensing for detecting dichlorvos. Utilizing smartphone photography for RGB value extraction, the resultant sensing platform achieves the detection for dichlorvos ranging from 5 to 300 ng mL-1 with a low detection limit of 2.06 ng mL-1. This pioneering work in creating in situ defects in MOFs to improve catalytic activity offers a novel perspective on traditional defect engineering.
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With alkyl halides (I, Br, Cl) as a coupling partner, an electrochemically driven strategy for para-selective C(sp2)-H alkylation of electron-deficient arenes (aryl esters, aldehydes, nitriles, and ketones) has been achieved to access diverse alkylated arenes in one step. The reaction enables the activation of alkyl halides in the absence of sacrificial anodes, achieving the formation of C(sp2)-C(sp3) bonds under mild electrolytic conditions. The utility of this protocol is reflected in high site selectivity, broad substrate scope, and scalable.
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Chlamydia trachomatis persistent infection is the leading cause of male prostatitis and female genital tract diseases. Inhibition of host cell apoptosis is the key to maintaining Chlamydia survival in vivo, and long noncoding RNAs (lncRNAs) play important roles in its developmental cycle and pathogenesis. However, it is not clear how lncRNAs regulate persistent Chlamydia infection. Here, using a microarray method, we identified 1718 lncRNAs and 1741 mRNAs differentially expressed in IFN-γ-induced persistent C. trachomatis infection. Subsequently, 10 upregulated and 5 downregulated differentially expressed lncRNAs were verified by qRT-PCR to confirm the reliability of the chip data. The GO and KEGG analyses revealed that differentially regulated transcripts were predominantly involved in various signalling pathways related to host immunity and apoptosis response. Targeted silencing of three lncRNAs (MIAT, ZEB1-AS1 and IRF1) resulted in increased apoptosis rates. Furthermore, interference with lncRNA MIAT caused not only an obvious downregulation of the Bcl-2/Bax ratio but also a marked release of cytochrome c, resulting in a significantly elevated level of caspase-3 activation. Meanwhile, MIAT was involved in the regulation of chlamydial development during the persistent infection. Collectively, these observations shed light on the enormous complex lncRNA regulatory networks involved in mitochondria-mediated host cell apoptosis and the growth and development of C. trachomatis.
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Apoptose , Infecções por Chlamydia , RNA Longo não Codificante , Apoptose/genética , Infecções por Chlamydia/genética , Chlamydia trachomatis/patogenicidade , Feminino , Humanos , Masculino , Mitocôndrias/metabolismo , RNA Longo não Codificante/genética , Reprodutibilidade dos Testes , Regulação para Cima/genéticaRESUMO
BACKGROUND: Postconcussion symptoms (PCSs) are common complaints reported by patients after a mild traumatic brain injury (TBI), and these symptoms may lower quality of life. Previous investigations have primarily focused on PCSs in children, adults, and athletes. The frequency, and risk factors, and effects of PCSs for older adults with mild TBIs are unclear. PURPOSE: To investigate the frequency and risk factors of PCSs, and investigate their effects on quality of life over time after mild TBI in older adults. METHODS: A prospective longitudinal study was performed. All participants were enrolled from the emergency department or neurosurgical outpatient clinics of a medical center. The measurement tools were the Rivermead Post-Concussion Symptoms Questionnaire and the Quality of Life after Traumatic Brain Injury. Measurements were performed on the seventh day, at the first month, and at the sixth month after the head injury. A generalized estimating equation model was used for data analyses. RESULTS: One hundred and one older adults (mean age of 76.0 years) with mild TBIs with negative neuroimaging findings were included. Overall, 32.7%, 4%, and 15.8% of the sample reported PCS after 7 days, 1 month, and 6 months of head injury, respectively, revealing a U-shaped trend. We observed that comorbidity measured using the modified Charlson Comorbidity Index was associated with differences in PCSs ( P < .05). PCSs were an independent predictor of changes in postinjury quality of life ( P < .001). CONCLUSIONS: The results indicate that PCS after a mild TBI in older adults is prevalent, even in the chronic phase after a TBI, and PCSs significantly affected the quality of life of our cohort. Therefore, to improve patient quality of life, healthcare providers should employ effective interventions to manage PCSs at different phases after a TBI.
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Concussão Encefálica , Lesões Encefálicas Traumáticas , Síndrome Pós-Concussão , Idoso , Concussão Encefálica/diagnóstico , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/diagnóstico , Lesões Encefálicas Traumáticas/epidemiologia , Criança , Humanos , Estudos Longitudinais , Síndrome Pós-Concussão/complicações , Síndrome Pós-Concussão/diagnóstico , Síndrome Pós-Concussão/epidemiologia , Estudos Prospectivos , Qualidade de Vida , Fatores de RiscoRESUMO
The first synthesis of highly strained spirocyclobutane-pyrrolines via a palladium-catalyzed tandem Narasaka-Heck/C(sp3 or sp2)-H activation reaction is reported here. The key step in this transformation is the activation of a δ-C-H bond via an in situ generated σ-alkyl-Pd(II) species to form a five-membered spiro-palladacycle intermediate. The concerted metalation-deprotonation (CMD) process, rate-determining step, and energy barrier of the entire reaction were explored by density functional theory (DFT) calculations. Moreover, a series of control experiments was conducted to probe the rate-determining step and reversibility of the C(sp3)-H activation step.
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Despite management efforts with standard surgery, radiation, and chemotherapy, glioblastoma multiform (GBM) remains resistant to treatment, which leads to tumor recurrence due to glioma stem cells (GSCs) and therapy resistance. In this study, we used random computer-based prediction and target identification to assess activities of our newly synthesized niclosamide-derived compound, NSC765689, to target GBM oncogenic signaling. Using target prediction analyses, we identified glycogen synthase kinase 3ß (GSK3ß), ß-Catenin, signal transducer and activator of transcription 3 (STAT3), and cluster of differentiation 44 (CD44) as potential druggable candidates of NSC765689. The above-mentioned signaling pathways were also predicted to be overexpressed in GBM tumor samples compared to adjacent normal samples. In addition, using bioinformatics tools, we also identified microRNA (miR)-135b as one of the most suppressed microRNAs in GBM samples, which was reported to be upregulated through inhibition of GSK3ß, and subsequently suppresses GBM tumorigenic properties and stemness. We further performed in silico molecular docking of NSC765689 with GBM oncogenes; GSK3ß, ß-Catenin, and STAT3, and the stem cell marker, CD44, to predict protein-ligand interactions. The results indicated that NSC765689 exhibited stronger binding affinities compared to its predecessor, LCC09, which was recently published by our laboratory, and was proven to inhibit GBM stemness and resistance. Moreover, we used available US National Cancer Institute (NCI) 60 human tumor cell lines to screen in vitro anticancer effects, including the anti-proliferative and cytotoxic activities of NSC765689 against GBM cells, and 50% cell growth inhibition (GI50) values ranged 0.23~5.13 µM. In summary, using computer-based predictions and target identification revealed that NSC765689 may be a potential pharmacological lead compound which can regulate GBM oncogene (GSK3ß/ß-Catenin/STAT3/CD44) signaling and upregulate the miR-135b tumor suppressor. Therefore, further in vitro and in vivo investigations will be performed to validate the efficacy of NSC765689 as a novel potential GBM therapeutic.
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Biologia Computacional/métodos , Glioblastoma/tratamento farmacológico , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Receptores de Hialuronatos/antagonistas & inibidores , Niclosamida/química , Fator de Transcrição STAT3/antagonistas & inibidores , beta Catenina/antagonistas & inibidores , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Diferenciação Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Simulação de Acoplamento Molecular , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Transdução de Sinais , Células Tumorais CultivadasRESUMO
Chlamydia trachomatis (C. trachomatis) is an obligate intracellular organism that depends on nutrients from the host cell for their replication and proliferation. Therefore, the interaction between this pathogen and host induces sustained endoplasmic reticulum (ER) stress in the infected cells. Unfolded protein response (UPR) has been demonstrated to be activated by chlamydial secreted effectors, allowing host cells to recover from the stressful state. In this study, we attempted to explore the role of the only secreted plasmid-encoded protein pORF5 of C. trachomatis between UPR and autophagy induction. The results showed that three branches of UPR (PERK, IRE1, and ATF6) were activated by pORF5. pORF5-induced autophagy was repressed by UPR inhibitors GSK2606414 and 4µ8C, while the autophagy inhibition was failed to influence pORF5-induced UPR significantly. MAPK/ERK inhibitor PD98059 partially suppressed the pORF5-induced autophagy, but had little effect on UPR, indicating that pORF5 actives UPR to induce autophagy via the MAPK/ERK signaling pathway. These observations provide clues on how the host maintains the cellular homeostasis during C. trachomatis infection.
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Autofagia , Proteínas de Bactérias/metabolismo , Chlamydia trachomatis/fisiologia , Resposta a Proteínas não Dobradas , Proteínas de Bactérias/genética , Chlamydia trachomatis/genética , Estresse do Retículo Endoplasmático , Células HeLa , Interações Hospedeiro-Parasita , Humanos , Sistema de Sinalização das MAP Quinases , Plasmídeos/genética , Plasmídeos/fisiologiaRESUMO
The past decades have witnessed significant progress in discovery and characterize cytosolic DNA sensing and signaling, especially the understanding of the stimulator of interferon genes (STING). This pathway to foreign nucleic acids enables the initiation of robust anti-pathogenic responses to protect the host, and provides a new understanding for therapeutic intervention in a growing infectious disease, including chlamydial infection. Chlamydiae are obligate intracellular pathogenic bacterium causing widespread human diseases such as sexually transmitted infections and respiratory tract infections. Previous studies have shown that IFN production and autophagy are well recognized as being two critical processes induced by STING, and these two processes were also activated during chlamydial infection. In this review, we summarize the important characteristics of the STING activation pathway and recent snapshots about the role of STING in chlamydial infection. Studying the role of STING in chlamydial infection could provide valuable information to further understand the pathogenesis and treatment of chlamydial infection.
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Infecções por Chlamydia/metabolismo , Chlamydia/fisiologia , Proteínas de Membrana/metabolismo , Animais , Chlamydia/genética , Infecções por Chlamydia/genética , Infecções por Chlamydia/microbiologia , Humanos , Proteínas de Membrana/genéticaRESUMO
OBJECTIVES: To compare the prevalence of sleep disturbances in older adults with traumatic brain injury (TBI) with that of age- and gender-matched controls and to determine the risk factors for post-TBI sleep disturbances and the effects of post-TBI disturbances on quality of life (QOL). DESIGN: Cross-sectional case-comparison study. PARTICIPANTS: Eighty older adults (aged ≥65 years) with first-time TBI more than 3 months since injury and 80 older adults controls without TBI who completed sleep and health-related QOL questionnaires. RESULTS: Older adults with TBI showed a higher prevalence of obstructive sleep apnea (OSA), insomnia, and daytime sleepiness than older adult controls. Being male, having higher levels of depression and pain, and the presence of insomnia were significantly correlated with the risks of OSA, insomnia, and daytime sleepiness following TBI, respectively. Both OSA and insomnia were significantly correlated with low QOL in older adults with TBI. CONCLUSIONS: Sleep disturbances are highly prevalent in older adults with TBI. Gender differences, depression severity, and pain level are correlated with the occurrence of post-TBI sleep disturbances. Both OSA and insomnia are regarded as major contributors to low QOL in older people with TBI. Interventions targeted at post-TBI sleep disturbances may improve QOL of older adults.
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Lesões Encefálicas Traumáticas , Distúrbios do Início e da Manutenção do Sono , Idoso , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/epidemiologia , Estudos Transversais , Humanos , Masculino , Qualidade de Vida , Sono , SonolênciaRESUMO
Chlamydia psittaci is an obligate intracellular pathogen with a biphasic developmental life cycle. It is auxotrophic for a variety of essential metabolites and obtains amino acids from eukaryotic host cells. Chlamydia can develop inside host cells within chlamydial inclusions. A pathway secreting proteins from inclusions into the host cellular cytoplasm is the type III secretion system (T3SS). The T3SS is universal among several Gram-negative bacteria. Here, we show that CPSIT_0959 of C. psittaci is expressed midcycle and secreted into the infected cellular cytoplasm via the T3SS. Recombinant CPSIT_0959 possesses cysteine desulfurase and PLP-binding activity, which removes sulfur from cysteine to produce alanine, and helps chlamydial replication. Our study shows that CPSIT_0959 improve the infectivity of offspring elementary bodies and seems to promote the replication by its product. This phenomenon has inhibited by the PLP-dependent enzymes inhibitor. Moreover, CPSIT_0959 increased expression of Bim and tBid, and decreased the mitochondrial membrane potential of host mitochondria to induce apoptosis in the latecycle for release of offspring. These results demonstrate that CPSIT_0959 has cysteine desulfurase and PLP-binding activity and is likely to contribute to apoptosis of the infected cells via a mitochondria-mediated pathway to improve the infectivity of progeny.
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Proteínas de Bactérias , Liases de Carbono-Enxofre , Chlamydophila psittaci , Psitacose , Sistemas de Secreção Tipo III , Animais , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Liases de Carbono-Enxofre/genética , Liases de Carbono-Enxofre/metabolismo , Chlamydophila psittaci/enzimologia , Chlamydophila psittaci/genética , Feminino , Células HeLa , Humanos , Potencial da Membrana Mitocondrial , Camundongos , Camundongos Endogâmicos BALB C , Mitocôndrias/metabolismo , Psitacose/genética , Psitacose/metabolismo , Sistemas de Secreção Tipo III/genética , Sistemas de Secreção Tipo III/metabolismoRESUMO
Glioblastoma multiforme represents one of the deadliest brain tumor types, manifested by a high rate of recurrence and poor prognosis. The presence of glioma stem cells (GSCs) can repopulate the tumor posttreatment and resist therapeutics. A better understanding of GSC biology is essential for developing more effective interventions. We established a CD133 promoter-driven dual reporter, expressing green fluorescent protein (GFP) and firefly luciferase (CD133-LG), capable for in vitro and in vivo imaging of CD133+ GSCs. We first demonstrated the reporter enabled in vitro analyses of GSCs. DBTRG-05MG (Denver Brain Tumor Research Group 05) carrying CD133-LG (DBTRG-05MG-CD133-LG) system reported increased GFP/luciferase activities in neurospheres. Additionally, we identified and isolated CD133+/GFP+ cells with increased tumorigenic properties, stemness markers, Notch1, ß-catenin, and Bruton's tyrosine kinase (Btk). Furthermore, prolonged temozolomide (TMZ) treatment enriched GSCs (reflected by increased percentage of CD133+ cells). Subsequently, Btk inhibitor, ibrutinib, suppressed GSC generation and stemness markers. Finally, we demonstrated real-time evaluation of anti-GSC function of ibrutinib in vivo with TMZ-enriched GSCs. Tumorigenesis was noninvasively monitored by bioluminescence imaging and mice that received ibrutinib showed a significantly lower tumor burden, indicating ibrutinib as a potential GSC inhibitor. In conclusion, we established a dual optical imaging system which enables the identification of CD133+ GSCs and screening for anti-GSC drugs.
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Glioma/diagnóstico por imagem , Células-Tronco Neoplásicas/citologia , Imagem Óptica/métodos , Antígeno AC133/metabolismo , Adenina/análogos & derivados , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Animais , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Eletroforese em Gel de Poliacrilamida , Citometria de Fluxo , Glioma/tratamento farmacológico , Glioma/patologia , Humanos , Luciferases de Vaga-Lume , Camundongos , Piperidinas , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Temozolomida/uso terapêuticoRESUMO
Chlamydia psittaci is an obligate intracellular pathogen with a broad host range that can lead to severe infectious disease by transferring from birds to humans. Vaccination has been considered the best way to prevent chlamydial infection; nevertheless, there is currently still no commercially available vaccine that can inhibit the spread of C. psittaci. In previous study, major outer membrane protein (MOMP) of C. psittaci was confirmed to be an appropriate candidate antigen for limiting C. psittaci respiratory infections in a murine model, and plasmid-encoded CPSIT_p6 also has functions similar to those of MOMP in our study. Therefore, according to bioinformatics analysis, we developed a recombinant peptide containing multiple antigenic epitopes from MOMP (24-32, 262-272) and CPSIT_p6 protein (109-119, 173-181) and evaluated the efficacy of peptide immunization. BALB/c mice were inoculated intraperitoneally with the recombinant multi-epitope antigens three times at 2-week intervals and subsequently intranasally infected with C. psittaci. We found that the recombinant multi-epitope antigens induced strong humoral and Th1 cellular immune responses by producing meaningfully high levels of antigen-specific antibodies, interferon-gamma (IFN-γ), or interleukin-2 (IL-2). Vaccination significantly reduced the bacterial burden and the degree of inflammation in the infected lungs and led to lower levels of IFN-γ and IL-6. Furthermore, adoptive transfer of CD4+ splenocytes harvested from the vaccinated mice produced a significantly lower chlamydial load, indicating the importance of the cellular immune response. Therefore, the recombinant multi-epitope antigens may provide the basis for a new peptide-based vaccine against C. psittaci infection.
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Proteínas da Membrana Bacteriana Externa/imunologia , Proteínas de Bactérias/imunologia , Vacinas Bacterianas/imunologia , Chlamydophila psittaci/imunologia , Epitopos/imunologia , Psitacose/prevenção & controle , Transferência Adotiva , Animais , Anticorpos Antibacterianos/sangue , Carga Bacteriana , Proteínas da Membrana Bacteriana Externa/genética , Proteínas de Bactérias/genética , Vacinas Bacterianas/administração & dosagem , Vacinas Bacterianas/genética , Linfócitos T CD4-Positivos/imunologia , Modelos Animais de Doenças , Epitopos/genética , Imunidade Celular , Imunidade Humoral , Esquemas de Imunização , Interferon gama/metabolismo , Interleucina-6/metabolismo , Leucócitos Mononucleares/imunologia , Camundongos Endogâmicos BALB C , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Resultado do Tratamento , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologiaAssuntos
Dermatite Atópica , Insuficiência Cardíaca , Distrofia Muscular de Duchenne , Adulto , Anticorpos Monoclonais Humanizados/uso terapêutico , Dermatite Atópica/complicações , Dermatite Atópica/diagnóstico , Dermatite Atópica/tratamento farmacológico , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/etiologia , Humanos , Masculino , Distrofia Muscular de Duchenne/complicações , Distrofia Muscular de Duchenne/diagnóstico , Distrofia Muscular de Duchenne/tratamento farmacológico , Resultado do Tratamento , Adulto JovemRESUMO
Chlamydia psittaci is a zoonotic pathogen with a broad host range that can lead to severe respiratory and systemic disease in humans. Currently, an effective commercial vaccine against C. psittaci infection is not available. The chlamydial plasmid is an important virulence factor and encodes plasmid proteins that play important roles in chlamydial infection and the corresponding immune response. In this study, we assessed the efficacy of vaccination with plasmid proteins at preventing C. psittaci lung infection in a murine model. BALB/c mice were immunized intraperitoneally, three times at 2-week intervals, with purified recombinant CPSIT_p8 protein and then infected with C. psittaci. Immunization significantly decreased chlamydial load in the lungs of infected mice, resulted in a lower level of IFN-γ, and reduced the extent of inflammation. In vivo or in vitro neutralization of C. psittaci with sera collected from immunized mice did not reduce the amount of viable C. psittaci in the lungs of mice, indicating that CPSIT_p8-specific antibodies do not have neutralizing capacity. Furthermore, confocal fluorescence microscopy using a mouse anti-CPSIT_p8 antibody revealed that CPSIT_p8 was localized inside the inclusion of C. psittaci 6BC-infected cells. Our results demonstrate that CPSIT_p8 protein induces significant protective immunity against challenge with C. psittaci in mice and represents a promising new vaccine candidate for the prevention of C. psittaci infection.
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Proteínas de Bactérias/imunologia , Vacinas Bacterianas/imunologia , Infecções por Chlamydia/prevenção & controle , Chlamydophila psittaci/imunologia , Plasmídeos/imunologia , Proteínas Recombinantes/imunologia , Animais , Anticorpos Antibacterianos/sangue , Carga Bacteriana , Proteínas de Bactérias/genética , Infecções por Chlamydia/imunologia , Clonagem Molecular , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Células HeLa , Humanos , Imunização , Interferon gama/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Recombinantes/genéticaRESUMO
Exposure to high environmental temperature leading to increased core body temperature above 40°C and central nervous system abnormalities such as convulsions, delirium, or coma is defined as heat stroke. Studies in humans and animals indicate that the heat shock responses of the host contribute to multiple organ injury and death during heat stroke. Heme oxygenase-1 (HO-1)-a stress-responsive enzyme that catabolizes heme into iron, carbon monoxide, and biliverdin-has an important role in the neuroprotective mechanism against ischemic stroke. Here, we investigated the role of endogenous HO-1 in heat-induced brain damage in rats. RT-PCR results revealed that levels of HO-1 mRNA peaked at 0 h after heat exposure and immunoblot analysis revealed that the maximal protein expression occurred at 1 h post-heat exposure. Subsequently, we detected the HO-1 expression in the cortical brain cells and revealed the neuronal cell morphology. In conclusion, HO-1 is a potent protective molecule against heat-induced brain damage. Manipulation of HO-1 may provide a potential therapeutic approach for heat-related diseases.
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Encéfalo/enzimologia , Golpe de Calor/enzimologia , Heme Oxigenase (Desciclizante)/metabolismo , Animais , Encéfalo/fisiopatologia , Córtex Cerebral/enzimologia , Córtex Cerebral/fisiopatologia , Regulação Enzimológica da Expressão Gênica , Golpe de Calor/fisiopatologia , Heme Oxigenase (Desciclizante)/genética , Masculino , Ratos Sprague-DawleyRESUMO
Although being applied as photosensitizers for photodynamic therapy, covalent organic frameworks (COFs) fail the precise fluorescence imaging in vivo and phototherapy in deep-tissue, due to short excitation/emission wavelengths. Herein, this work proposes the first example of NIR-II emissive and benzobisthiadiazole-based COF-980. Comparing to its ligands, the structure of COF-980 can more efficiently reducing the energy gap (ΔES1-T1) between the excited state and the triplet state to enhance photodynamic therapy efficiency. Importantly, COF-980 demonstrates high photostability, good anti-diffusion property, superior reactive oxygen species (ROS) generation efficiency, promising imaging ability, and ROS production in deep tissue (≈8 mm). Surprisingly, COF-980 combined with laser irradiation could trigger larger amount of intracellular ROS to high efficiently induce cancer cell death. Notably, COF-980 NPs precisely enable PDT guided by NIR-II fluorescence imaging that effectively inhibit the 4T1 tumor growth with negligible adverse effects. This study provides a universal approach to developing long-wavelength emissive COFs and exploits its applications for biomedicine.
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Imagem Óptica , Fotoquimioterapia , Espécies Reativas de Oxigênio , Tiadiazóis , Fotoquimioterapia/métodos , Tiadiazóis/química , Tiadiazóis/farmacologia , Animais , Espécies Reativas de Oxigênio/metabolismo , Camundongos , Imagem Óptica/métodos , Linhagem Celular Tumoral , Humanos , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/farmacologia , Camundongos Endogâmicos BALB C , FemininoRESUMO
Oral biofilm is the leading cause of dental caries, which is difficult to completely eradicate because of the complicated biofilm structure. What's more, the hypoxia environment of biofilm and low water-solubility of conventional photosensitizers severely restrict the therapeutic effect of photodynamic therapy (PDT) for biofilm. Although conventional photosensitizers could be loaded in nanocarriers, it has reduced PDT effect because of aggregation-caused quenching (ACQ) phenomenon. In this study, we fabricated an oxygen self-sufficient nanodroplet (PFC/TPA@FNDs), which was composed of fluorinated-polymer (FP), perfluorocarbons (PFC) and an aggregation-induced emission (AIE) photosensitizer (Triphenylamine, TPA), to eradicate oral bacterial biofilm and whiten tooth. Fluorinated-polymer was synthesized by polymerizing (Dimethylamino)ethyl methacrylate, fluorinated monomer and 1-nonanol monomer. The nanodroplets could be protonated and behave strong positive charge under bacterial biofilm acid environment promoting nanodroplets deeply penetrating biofilm. More importantly, the nanodroplets had extremely high PFC and oxygen loading efficacy because of the hydrophobic affinity between fluorinated-polymer and PFC to relieve the hypoxia environment and enhance PDT effect. Additionally, compared with conventional ACQ photosensitizers loaded system, PFC/TPA@FNDs could behave superior PDT effect to ablate oral bacterial biofilm under light irradiation due to the unique AIE effect. In vivo caries animal model proved the nanodroplets could reduce dental caries area without damaging tooth structure. Ex vivo tooth whitening assay also confirmed the nanodroplets had similar tooth whitening ability compared with commercial tooth whitener H2O2, while did not disrupt the surface microstructure of tooth. This oxygen self-sufficient nanodroplet provides an alternative visual angle for oral biofilm eradication in biomedicine.
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Electroreduction mediated by organo-mediators has emerged as a concise and effective strategy, holding significant potential in the site-specific introduction of deuterium. In this study, we present an environmentally friendly electroreduction approach for anti-Markovnikov selective deuteroarylation of alkenes and aryl iodides with D2O as the deuterium source. The key to the protocol lies in the employment of a catalytic amount of 2,2'-bipyiridine as an efficient organo-mediator, which facilitates the generation of aryl radicals by assisting in the cleavage of the C-X (X = I or Br) bonds in aryl halides. Because its reduction potential matches that of aryl iodides, the organo-mediator can control the chemoselectivity of the reaction and avoid the side reactions of competitive substrate deuteration. These phenomena are theoretically supported by CV experiments and DFT calculations. Our protocol provides a series of mono-deuterated alkylarenes with excellent deuterium incorporation through two single-electron reductions (SER), without requiring metal catalysts, external reductants, and sacrificial anodes.
RESUMO
A cocrystallization strategy is used through incorporation of 1,2,4,5-tetracyanobenzene (TCNB) as an acceptor with halogen-substituent thioxanthone (TX) derivatives as donors. The resulting cocrystals TT-R (R = H, F, Cl, Br, or I) transform the thermally activated delayed fluorescence emission in the TT-H, TT-F, and TT-Cl cocrystals to room-temperature phosphorescence in the TT-Br and TT-I cocrystals. Definite crystal packing structures demonstrate a 1:1 alternative donor-acceptor stacking in the TT-H cocrystal, a 2:1 alternative donor-acceptor stacking in the TT-F and TT-Cl cocrystals, and a separate stacking of donor and acceptor in the TT-Br and TT-I cocrystals. A transformation law can be revealed that with an increase in atomic number from H, F, Cl, Br, to I, the cocrystals show the structural transformation of the number of aggregated TX-R molecules from monomers to dimers and finally to multimers. This work will facilitate an understanding of the effect of halogen substituents on the crystal packing structure and luminescence properties in the cocrystals.