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Pyrethroid pesticides are widely used in agriculture, aquaculture, and daily life in China, leading to concerns about their environmental residues. However, there is limited information available regarding the compositional distribution, bioaccumulation, and associated health and environmental risks of pyrethroids in the aquaculture areas of Eastern China. This study investigated the residues, distribution, and risk assessment of pyrethroids including deltamethrin, permethrin, fenvalerate, cypermethrin and bifenthrin in Yangcheng Lake using solid-phase extraction and gas chromatography-tandem mass spectrometry. The risk assessment of water, sediment, and aquatic products of Yangcheng Lake was conducted using various evaluation methods. The results revealed that pyrethroids were found at higher levels in both water and sediment in Yangcheng Lake with some seasonal variations observed in their distribution patterns. Compared with other watersheds in China, typical aquaculture areas of the Yangtze River Delta showed higher detection rates and quantities of pyrethroid pesticides. Ecological risk assessments indicated high risks to the environment from all five tested pyrethroids at Yangcheng Lake; deltamethrin posed the highest risk among them. Dietary assessment results showed no risks associated with aquatic products from Yangcheng Lake but drinking water at certain sites presented unacceptable health risks.
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Multifunctional materials with both antibacterial and antioxidant properties are highly desired in many scientific applications. The combination of polysaccharide and multi-chamber nanostructures offers a novel perspective for developing antibacterial and antioxidant nanomaterials. In this study, a new kind of tri-chamber eccentric Janus nanostructures (TEJNs) was fabricated through a single-step and straight forward tri-fluid side-by-side electrospinning. The all-in-one TEJNs contained an outer chitosan (CS) chamber, a middle and an inner ethylcellulose (EC)-based chamber loaded with curcumin (Cur) and vitamin E (VE), respectively. The side-by-side multiple-fluid electrospinning processes were implemented robustly and continuously based on a homemade spinneret. Transmission electron microscope and scanning electron microscope evaluations demonstrated the tri-chamber inner structures of TEJNs and the linear morphologies, respectively. The Fourier transform infrared and X-ray diffraction results verified that the components were compatible and coexisted in an amorphous state. In vitro dissolution tests indicated that the TEJNs could provide a sustained release of 90 % of the loaded Cur and VE for 34.30 h and 24.86 h, respectively. Antibacterial and antioxidant experiments demonstrated that the TEJNs were able to provide enhanced antibacterial and antioxidant effects compared to the traditional electrospun homogeneous nanofibers. In the future, the Janus nanofibers can be further developed for several human health applications, such as wound dressings, active food packaging membranes, dental implants and cosmetic films.
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Lactoferrin, lysozyme, and gelatin are three common basic proteins known for their ability to interact with acidic proteins (lactoglobulin, ovalbumin, casein, etc.) and form various supramolecular structures. Their basic nature makes them highly promising for interaction with other acidic proteins to form heteroprotein complex coacervation (HPCC) with a wide range of applications. This review extensively examines the structure, properties, and preparation methods of these basic proteins and delves into the internal and external factors influencing the formation of HPCC, including pH, ionic strength, mixing ratio, total protein concentration, temperature, and inherent protein properties. The applications of different HPCCs based on these three basic proteins are discussed, including the encapsulation of bioactive molecules, emulsion stabilization, protein separation and extraction, nanogel formation, and the development of formulas for infants. Furthermore, the challenges and issues that are encountered in the formation of heteroprotein complexes are addressed and summarized, shedding light on the complexities and considerations involved in utilizing HPCC technology in practical applications. By harnessing the basic proteins to interact with other proteins and to form complex coacervates, new opportunities arise for the development of functional food products with enhanced nutritional profiles and functional attributes.
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This study examines the impact of cultural involvement on brand enriching benefits and consumers' willingness to pay a premium (WPP). Additionally, it explores the underlying mechanisms behind this impact. A partial least squares structural equation model was used to analyze the data collected from a pretest (N = 70) and an online survey (N = 1053) conducted in China. The moderating effect of brand type was examined using a multi-group analysis. The results indicate that cultural involvement has a significant and positive impact on brand enriching benefits, consequently enhancing consumers' WPP. Additionally, brand happiness mediates the relationship between brand enriching benefits and WPP. Through a multi-group analysis, the impact of brand culture on brand equity is found to be more pronounced in functional brands compared with symbolic brands. Additionally, high perceived quality facilitates the transformation of brand enriching benefits into WPP. Managers value the ability of a brand culture to create brand equity and implement differentiation strategies based on different brand types. It is critical for managers to use a culture and its rich benefits wisely and to consider consumer happiness in the brand experience. Although brand culture and its impact on brands are crucial, previous studies have only focused on qualitative analyses, while empirical research on the direct link between brand culture and equity has been lacking. This study empirically tests a conceptual model that elucidates the relationship between brand cultural involvement, brand enriching benefits, brand happiness, WPP, brand type, and perceived quality. It extends previous research and offers suggestions for academics and brand managers interested in effectively leveraging brand culture for brand building.
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ABSTRACT: The voltage-gated sodium channel NaV1.7 plays an important role in pain processing according to genetic data. Those data made NaV1.7 a popular drug target, especially since its relatively selective expression in nociceptors promised pain relief without the adverse effects associated with broader sodium channel blockade. Despite encouraging preclinical data in rodents, NaV1.7-selective inhibitors have not yet proven effective in clinical trials. Discrepancies between preclinical and clinical results should raise alarms. We reviewed preclinical and clinical reports on the analgesic efficacy of NaV1.7-selective inhibitors and found critical differences in several factors. Putting aside species differences, most preclinical studies tested young male rodents with limited genetic variability, inconsistent with the clinical population. Inflammatory pain was the most common preclinical chronic pain model whereas nearly all clinical trials focused on neuropathic pain despite some evidence suggesting NaV1.7 channels are not essential for neuropathic pain. Preclinical studies almost exclusively measured evoked pain whereas most clinical trials assessed average pain intensity without distinguishing between evoked and spontaneous pain. Nearly all preclinical studies gave a single dose of drug unlike the repeat dosing used clinically, thus precluding preclinical data from demonstrating whether tolerance or other slow processes occur. In summary, preclinical testing of NaV1.7-selective inhibitors aligned poorly with clinical testing. Beyond issues that have already garnered widespread attention in the pain literature, our results highlight the treatment regimen and choice of pain model as areas for improvement.
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Aristolochic acid (AA) is renowned for engendering nephrotoxicity and teratogenicity. Previous literature has reported that AA treatment resulted in heart failure (HF) via inflammatory pathways. Yet, its implications in HF remain comparatively uncharted territory, particularly with respect to underlying mechanisms. In our study, the zebrafish model was employed to delineate the cardiotoxicity of AA exposure and the restorative capacity of a phytogenic alkaloid palmatine (PAL). PAL restored morphology and blood supply in AA-damaged hearts by o-dianisidine staining, fluorescence imaging, and Hematoxylin and Eosin staining. Furthermore, PAL attenuated the detrimental effects of AA on ATPase activity, implying myocardial energy metabolism recovery. PAL decreased the co-localization of neutrophils with cardiomyocytes, implying an attenuation of the inflammatory response induced by AA. A combination of network pharmacological analysis and qPCR validation shed light on the therapeutic mechanism of PAL against AA-induced heart failure via upregulation of the epidermal growth factor receptor (EGFR) signaling pathway. Subsequent evaluations using a transcriptological testing, inhibitor model, and molecular docking assay corroborated PAL as an IKBKB enzyme activator. The study underscores the possible exploitation of the EGFR pathway as a potential therapeutic target for PAL against AA-induced HF, thus furthering the continued investigation of the toxicology and advancement of protective pharmaceuticals for AA.
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Ácidos Aristolóquicos , Alcaloides de Berberina , Receptores ErbB , Insuficiência Cardíaca , Transdução de Sinais , Regulação para Cima , Peixe-Zebra , Animais , Ácidos Aristolóquicos/toxicidade , Receptores ErbB/metabolismo , Insuficiência Cardíaca/induzido quimicamente , Alcaloides de Berberina/farmacologia , Regulação para Cima/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Simulação de Acoplamento Molecular , Quinase I-kappa B/metabolismo , CardiotoxicidadeRESUMO
In this paper, three new iridium(III) complexes: [Ir(piq)2(DFIPP)]PF6 (piq = deprotonated 1-phenylisoquinoline, DFIPP = 3,4-difluoro-2-(1H-imidazo[4,5-f][1,10]phenenthrolin-2-yl)phenol, 3a), [Ir(bzq)2(DFIPP)]PF6 (bzq = deprotonated benzo[h]quinoline, 3b), and [Ir(ppy)2(DFIPP)]PF6 (ppy = deprotonated 1-phenylpyridine, 3c), were synthesized and characterized. The complexes were found to be nontoxic to tumor cells via 3-(4,5-dimethylthiazole-2-yl)-diphenyltetrazolium bromide (MTT) assay. Surprisingly, its liposome-entrapped complexes 3alip, 3blip, and 3clip on B16 cells showed strong cytotoxicity (IC50 = 13.6 ± 2.8, 9.6 ± 1.1, and 18.9 ± 2.1 µM). Entry of 3alip, 3blip, and 3clip into B16 cells decreases mitochondrial membrane potential, regulates Bcl-2 family proteins, releases cytochrome c, triggers caspase family cascade reaction, and induces apoptosis. In addition, we also found that 3alip, 3blip, and 3clip triggered ferroptosis and autophagy. In vivo studies demonstrated that 3blip inhibited melanoma growth in C57 mice with a high inhibitory rate of 83.95%, and no organic damage was found in C57 mice.
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Antineoplásicos , Apoptose , Complexos de Coordenação , Irídio , Lipossomos , Irídio/química , Irídio/farmacologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Camundongos , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Camundongos Endogâmicos C57BL , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/patologia , Melanoma Experimental/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacosRESUMO
Genome transcription and replication of influenza A virus (FluA), catalyzed by viral RNA polymerase (FluAPol), are delicately controlled across the virus life cycle. A switch from transcription to replication occurring at later stage of an infection is critical for progeny virion production and viral non-structural protein NS2 has been implicated in regulating the switch. However, the underlying regulatory mechanisms and the structure of NS2 remained elusive for years. Here, we determine the cryo-EM structure of the FluAPol-NS2 complex at ~3.0 Å resolution. Surprisingly, three domain-swapped NS2 dimers arrange three symmetrical FluPol dimers into a highly ordered barrel-like hexamer. Further structural and functional analyses demonstrate that NS2 binding not only hampers the interaction between FluAPol and the Pol II CTD because of steric conflicts, but also impairs FluAPol transcriptase activity by stalling it in the replicase conformation. Moreover, this is the first visualization of the full-length NS2 structure. Our findings uncover key molecular mechanisms of the FluA transcription-replication switch and have implications for the development of antivirals.
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AIM: To evaluate whether the ribosome-crosslinked collagen membrane (RCCM) is non-inferior to the natural collagen membrane (NCM) used in regeneration surgery in terms of clinical attachment level (CAL) gain at 6 months. METHODS: Eighty patients diagnosed as generalized periodontitis presenting with isolated infrabony defect (≥4 mm deep) were enrolled and randomized to receive regenerative surgery, either with NCM or RCCM, both combined with deproteinized bovine bone mineral (DBBM). CAL, pocket probing depth (PPD), and gingival recession (GR) were recorded at baseline, 3, and 6 months postoperatively. Periapical radiographs were taken at baseline, immediately, and 6 months after surgery. Early wound healing index (EHI) and patients' responses were recorded at 2 weeks postoperatively. RESULTS: At 6 months post-surgery, the mean CAL gain was 3.1 ± 1.5 mm in the NCM group and 2.9 ± 1.5 mm in the RCCM group, while the mean PPD was 4.3 ± 1.1 mm in the NCM group and 4.2 ± 1.0 mm in the RCCM group. Both groups demonstrated a statistically significant improvement from the baseline (p < .01). RCCM was non-inferior to NCM concerning the primary outcome (CAL gain at 6 months). The GR at 6 months postoperatively was 1.3 ± 1.2 and 1.2 ± 1.1 mm, which showed no difference compared with baseline. At 6 months follow-up, the radiographic linear bone fill (RLBF) was 6.5 ± 2.8 and 5.5 ± 2.6 mm (p > .05), while the bone fill percentage (BF%) was 102.3 ± 53.5% and 92.3 ± 40.1% (p > .05), in the NCM and RCCM groups, respectively. There was no significant difference in EHI and postoperative responses between two groups. CONCLUSION: RCCM + DBBM resulted in no-inferior clinical and radiographic outcomes to NCM + DBBM for the treatment of isolated infrabony defect in 6 months.
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There are two main types of carbon nanotubes (CNTs): metallic and semiconducting. Naturally grown CNTs are randomly distributed, posing challenges in distinguishing between the two types. Here, a novel approach for nanoscale high-resolution imaging and identification of CNTs was introduced by incorporating the heterodyne technique into high-harmonic electrostatic force microscopy (HH-EFM) on an atomic force microscopy (AFM) platform. In the developed heterodyne HH-EFM, a more localized high-order gradient of tip-sample nonlinear interaction force is used as signal channels, resulting in an improved spatial resolution, compared to the conventional HH-EFM. Furthermore, the heterodyne HH-EFM also has the capability to visualize material carrier density and assess qualitative carrier transport performance. Our work not only presents a new approach to identifying/exploring electrical properties of low-dimensional nanomaterials but also provides a solution for optimizing resolution in long-range interaction-based functional AFM technologies.
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The game between therapeutic monoclonal antibodies (mAbs) and continuously emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has favored the virus, as most therapeutic mAbs have been evaded. Addressing this challenge, we systematically explored a reproducible bispecific antibody (bsAb)-dependent synergistic effect in this study. It could effectively restore the neutralizing activity of the bsAb when any of its single mAbs is escaped by variants. This synergy is primarily attributed to the binding angle of receptor-binding domain (RBD)-5, facilitating inter-spike cross-linking and promoting cryptic epitope exposure that classical antibody cocktails cannot achieve. Furthermore, RBD-5 with RBD-2, RBD-6, and RBD-7, alongside RBD-8, also exhibit significantly enhanced effects. This study not only shifts the paradigm in understanding antibody interactions but paves the way for developing more effective therapeutic antibodies against rapidly mutating SARS-CoV-2, with Dia-19 already showing promise against emerging variants like BA.2.86, EG.5.1, and JN.1.
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Anticorpos Biespecíficos , Anticorpos Neutralizantes , Anticorpos Antivirais , COVID-19 , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , SARS-CoV-2/imunologia , Humanos , Anticorpos Biespecíficos/imunologia , Anticorpos Biespecíficos/farmacologia , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19/imunologia , COVID-19/virologia , COVID-19/terapia , Glicoproteína da Espícula de Coronavírus/imunologia , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Epitopos/imunologia , Ligação Proteica , AnimaisRESUMO
Anticancer activity has been extensively studies. In this article, three ligands 2-(6-bromobenzo[d][1,3]dioxol-5-yl)-1H-imidazo[4,5-f][1,10]phenanthroline (BDIP), 2-(7-methoxybenzo[d][1,3]dioxol-5-yl)-1H-imidazo[4,5-f][1,10]phenanthroline (MDIP), 2-(6-nitrobenzo[d][1,3]dioxol-5-yl)-1H-imidazo[4,5-f][1,10]phenanthroline (NDIP) and their iridium(III) complexes: [Ir(ppy)2(BDIP)](PF6) (ppy = deprotonated 2-phenylpyridine, 3a), [Ir(ppy)2(MDIP)](PF6) (3b) and [Ir(ppy)2(NDIP)](PF6) (3c) were synthesized. The cytotoxicity of 3a, 3b, 3c against Huh7, A549, BEL-7402, HepG2, HeLa, and non-cancer NIH3T3 was tested using 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) method. The results obtained from the MTT test stated clearly that these complexes demonstrated moderate or non-cytotoxicity toward Huh7, BEL-7402, HepG2 and HeLa except A549 cells. To improve the anticancer efficacy, we used white light to irradiate the mixture of cells and complexes for 30 min, the anticancer activity of the complexes was greatly enhanced. Particularly, 3a and 3b exhibited heightened capability to inhibit A549 cells proliferation with IC50 (half maximal inhibitory concentration) values of 0.7 ± 0.3 µM and 1.8 ± 0.1 µM, respectively. Cellular uptake has shown that 3a and 3b can be accumulated in the cytoplasm. Wound healing and colony forming showed that 3a and 3b significantly hinder the cell migration and growth in the S phase. The complexes open mitochondrial permeability transition pore (MPTP) channel and cause the decrease of membrane potential, release of cytochrome C, activation of caspase 3, and finally lead to apoptosis. In addition, 3a and 3b cause autophagy, increase the lipid peroxidation and lead to ferroptosis. Also, 3a and 3b increase the expression of calreticulin (CRT), high mobility group box 1 (HMGB1), heat shock protein 70 (HSP70), thereby inducing immunogenic cell death.
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Antineoplásicos , Complexos de Coordenação , Irídio , Neoplasias Pulmonares , Irídio/química , Irídio/farmacologia , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Células A549 , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Apoptose/efeitos dos fármacos , Luz , Animais , Camundongos , Proliferação de Células/efeitos dos fármacos , Células NIH 3T3RESUMO
Background: Although there is solid epidemiological evidence supporting the connection between hypertension and gout, little has been said about the relationship between diastolic and systolic blood pressure and gout, the causal relationship and direction associated are uncertain, so we aim to research the causal relationship between diastolic and systolic blood pressure and gout. Methods: We conducted a two-sample Mendelian randomization (MR) analysis to assess the causal effect between 2 blood pressure phenotypes (including diastolic blood pressure and systolic blood pressure) and 5 gout phenotypes (including gout, drug-induced gout, idiopathic gout, unspecified gout, and strictly defined gout) using genome-wide association study statistics. The inverse variance weighting method was used to generate the main results, while sensitivity analyses using MR-Egger, weighted median, Cochran's Q test, Egger intercept test, and leave-one-out analysis, were performed to assess the stability and reliability of the results. Results: After the screening, we found a causal relationship between diastolic blood pressure and gout, idiopathic gout, unspecified gout, and strictly defined gout, and a causal relationship between systolic blood pressure and gout, idiopathic gout, unspecified gout, and strictly defined gout. Conclusion: From a genetic predisposition, controlling blood pressure may reduce the risk of gout.
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Pressão Sanguínea , Estudo de Associação Genômica Ampla , Gota , Hipertensão , Análise da Randomização Mendeliana , Humanos , Gota/genética , Gota/epidemiologia , Pressão Sanguínea/genética , Hipertensão/genética , Hipertensão/epidemiologia , Predisposição Genética para Doença , Diástole , Sístole , Polimorfismo de Nucleotídeo Único , Fatores de RiscoRESUMO
Nanoparticle vaccines displaying mosaic receptor-binding domains (RBDs) or spike (S) from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or other sarbecoviruses are used in preparedness against potential zoonotic outbreaks. Here, we describe a self-assembling nanoparticle using lumazine synthase (LuS) as the scaffold to display RBDs from different sarbecoviruses. Mosaic nanoparticles induce sarbecovirus cross-neutralizing antibodies comparable to a nanoparticle cocktail. We find mosaic nanoparticles elicit a B cell receptor repertoire using an immunodominant germline gene pair of IGHV14-3:IGKV14-111. Most of the tested IGHV14-3:IGKV14-111 monoclonal antibodies (mAbs) are broadly cross-reactive to clade 1a, 1b, and 3 sarbecoviruses. Using mAb competition and cryo-electron microscopy, we determine that a representative IGHV14-3:IGKV14-111 mAb, M2-7, binds to a conserved epitope on the RBD, largely overlapping with the pan-sarbecovirus mAb S2H97. This suggests mosaic nanoparticles expand B cell recognition of the common epitopes shared by different clades of sarbecoviruses. These results provide immunological insights into the cross-reactive responses elicited by mosaic nanoparticles against sarbecoviruses.
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Nanopartículas , Nanopartículas/química , Animais , Humanos , SARS-CoV-2/imunologia , Anticorpos Antivirais/imunologia , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Camundongos , Glicoproteína da Espícula de Coronavírus/imunologia , Glicoproteína da Espícula de Coronavírus/química , Reações Cruzadas/imunologia , Formação de Anticorpos/imunologia , COVID-19/imunologia , COVID-19/virologia , Domínios Proteicos , Camundongos Endogâmicos BALB C , Complexos Multienzimáticos/imunologia , Feminino , Epitopos Imunodominantes/imunologiaRESUMO
Peri-implant lesion is a grave condition afflicting numerous indi-viduals with dental implants. It results from persistent periodontal bacteria accumulation causing inflammation around the implant site, which can primarily lead to implant loosening and ultimately the implant loss. Early-stage peri-implant lesions exhibit symptoms akin to gum disease, including swelling, redness and bleeding of the gums surrounding the implant. These signs indicate infection and inflammation of the peri-implant tissues, which may result in bone loss and implant failure. To address this problem, a thermionic strategy was applied by designing a cuprorivaite-hardystonite bioceramic/alginate composite hydrogel with photothermal and Cu/Zn/Si multiple ions releasing property. This innovative approach creates a thermionic effect by the release of bioactive ions (Cu2+ and Zn2+ and SiO32-) from the composite hydrogel and the mild heat environment though the photothermal effect of the composite hydrogel induced by near-infrared light irradiation. The most distinctive advantage of this thermionic effect is to substantially eliminate periodontal pathogenic bacteria and inhibit inflammation, while simultaneously enhance peri-implant osseointegration. This unique attribute renders the use of this composite hydrogel highly effective in significantly improving the survival rate of implants after intervention in peri-implant lesions, which is a clinical challenge in periodontics. This study reveals application potential of a new biomaterial-based approach for peri-implant lesion, as it not only eliminates the infection and inflammation, but also enhances the osteointegration of the dental implant, which provides theoretical insights and practical guidance to prevent and manage early-stage peri-implant lesion using bioactive functional materials.
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Cardiovascular diseases (CVDs) persist as the predominant cause of mortality, urging the exploration of innovative pharmaceuticals. Mitochondrial dysfunction stands as a pivotal contributor to CVDs development. Sirtuin 3 (SIRT3), a prominent mitochondrial deacetylase known for its crucial role in protecting mitochondria against damage and dysfunction, has emerged as a promising therapeutic target for CVDs treatment. Utilizing isosteviol, a natural ent-beyerene diterpenoid, 24 derivatives were synthesized and evaluated in vivo using a zebrafish model, establishing a deduced structure-activity relationship. Among these, derivative 5v exhibited significant efficacy in doxorubicin-induced cardiomyopathy in zebrafish and murine models. Subsequent investigations revealed that 5v selectively elevated SIRT3 expression, leading to the upregulation of SOD2 and OPA1 expression, effectively preventing mitochondrial dysfunction, mitigating oxidative stress, and preserving cardiomyocyte viability. As a novel structural class of SIRT3 activators with robust therapeutic effects, 5v emerges as a promising candidate for further drug development.
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Cardiotônicos , Diterpenos do Tipo Caurano , Desenho de Fármacos , Sirtuína 3 , Peixe-Zebra , Animais , Sirtuína 3/metabolismo , Sirtuína 3/antagonistas & inibidores , Diterpenos do Tipo Caurano/farmacologia , Diterpenos do Tipo Caurano/síntese química , Diterpenos do Tipo Caurano/química , Diterpenos do Tipo Caurano/uso terapêutico , Cardiotônicos/farmacologia , Cardiotônicos/síntese química , Cardiotônicos/química , Cardiotônicos/uso terapêutico , Relação Estrutura-Atividade , Camundongos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Humanos , Estresse Oxidativo/efeitos dos fármacos , Doxorrubicina/farmacologiaRESUMO
Nociceptive sensory neurons convey pain-related signals to the CNS using action potentials. Loss-of-function mutations in the voltage-gated sodium channel NaV1.7 cause insensitivity to pain (presumably by reducing nociceptor excitability) but clinical trials seeking to treat pain by inhibiting NaV1.7 pharmacologically have struggled. This may reflect the variable contribution of NaV1.7 to nociceptor excitability. Contrary to claims that NaV1.7 is necessary for nociceptors to initiate action potentials, we show that nociceptors can achieve similar excitability using different combinations of NaV1.3, NaV1.7, and NaV1.8. Selectively blocking one of those NaV subtypes reduces nociceptor excitability only if the other subtypes are weakly expressed. For example, excitability relies on NaV1.8 in acutely dissociated nociceptors but responsibility shifts to NaV1.7 and NaV1.3 by the fourth day in culture. A similar shift in NaV dependence occurs in vivo after inflammation, impacting ability of the NaV1.7-selective inhibitor PF-05089771 to reduce pain in behavioral tests. Flexible use of different NaV subtypes exemplifies degeneracy - achieving similar function using different components - and compromises reliable modulation of nociceptor excitability by subtype-selective inhibitors. Identifying the dominant NaV subtype to predict drug efficacy is not trivial. Degeneracy at the cellular level must be considered when choosing drug targets at the molecular level.
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Analgésicos , Benzenossulfonamidas , Nociceptores , Éteres Fenílicos , Animais , Analgésicos/farmacologia , Nociceptores/metabolismo , Nociceptores/efeitos dos fármacos , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.7/genética , Camundongos , Potenciais de Ação/efeitos dos fármacos , Dor/tratamento farmacológico , Humanos , Canais de Sódio/metabolismo , Canais de Sódio/genética , Canal de Sódio Disparado por Voltagem NAV1.8/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.8/genéticaRESUMO
Van der Waals (vdW) assembly of low-dimensional materials has proven the capability of creating structures with on-demand properties. It is predicted that the vdW encapsulation can induce a local high-pressure of a few GPa, which will strongly modify the structure and property of trapped materials. Here, we report on the structural collapse of carbon nanotubes (CNTs) induced by the vdW encapsulation. By simply covering CNTs with a hexagonal boron nitride flake, most of the CNTs (≈77%) convert from a tubular structure to a collapsed flat structure. Regardless of their original diameters, all the collapsed CNTs exhibit a uniform height of ≈0.7 nm, which is roughly the thickness of bilayer graphene. Such structural collapse is further confirmed by Raman spectroscopy, which shows a prominent broadening and blue shift in the Raman G-peak. The vdW encapsulation-induced collapse of CNTs is fully captured by molecular dynamics simulations of the local vdW pressure. Further near-field optical characterization reveals a metal-semiconductor transition in accompany with the CNT structural collapse. Our study provides not only a convenient approach to generate local high-pressure for fundamental research, but also a collapsed-CNT semiconductor for nanoelectronic applications.
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The development of solid-state electrolytes (SSEs) with outstanding comprehensive performance is currently a critical challenge for achieving high energy density and safer solid-state batteries (SSBs). In this study, a strategy of nano-confined in situ solidification is proposed to create a novel category of molten guest-mediated metal-organic frameworks, named MGM-MOFs. By embedding the newly developed molten crystalline organic electrolyte (ML20) into the nanocages of anionic MOF-OH, MGM-MOF-OH, characterized by multi-modal supramolecular interaction sites and continuous negative electrostatic environments within nano-channels, is achieved. These nanochannels promote ion transport through the successive hopping of Li+ between neighbored negative electrostatic environments and suppress anion movement through the chemical constraint of the hydroxyl-functionalized pore wall. This results in remarkable Li+ conductivity of 7.1 × 10-4 S cm-1 and high Li+ transference number of 0.81. Leveraging these advantages, the SSBs assembled with MGM-MOF-OH exhibit impressive cycle stability and a high specific energy density of 410.5 Wh kganode + cathode + electrolyte -1 under constrained conditions and various working temperatures. Unlike flammable traditional MOFs, MGM-MOF-OH demonstrates high robustness under various harsh conditions, including ignition, high voltage, and extended to humidity.