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As methicillin-resistant Staphylococcus aureus (MRSA) exhibits formidable resistance to many drugs, the imperative for alternative therapeutic strategies becomes increasingly evident. At the heart of our study is the identification of a novel inhibitor through fluorescence anisotropy assays, specifically targeting the crucial multiple gene regulator A (MgrA) regulatory network in S. aureus. Isorhapontigenin (Iso), a natural compound, exhibits outstanding inhibitory efficacy, modulating bacterial virulence pathways without exerting direct bactericidal activity. This suggests a paradigm shift toward attenuating virulence instead of purely focusing on bacterial elimination. Through comprehensive in vitro and in vivo evaluations, we elucidated the complex interplay between Iso and MgrA, leading to reduced S. aureus adhesion, and overall virulence. At the cellular level, Iso offers significant protection to A549 cells infected with S. aureus, reducing cellular damage. Importantly, Iso augments the chemotaxis of neutrophils, curtailing the immune evasion capabilities of S. aureus. Furthermore, in vivo investigations highlight the notable effectiveness of Iso against MRSA-induced pneumonia and within the Galleria mellonella infection model, underscoring its pivotal role in the evolving realm of antibacterial drug discovery. Significantly, when Iso is used in combination with vancomycin, it outperforms its solo application, indicating a more pronounced therapeutic impact. This seminal research emphasizes Iso's potential as a primary defense against the surge of multidrug-resistant pathogens, heralding new prospects in antimicrobial therapy.
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Men who have sex with men (MSM) are at a high risk of HIV infection and should be offered effective preventive measures, such as pre-exposure prophylaxis (PrEP). However, PrEP uptake among eligible MSM was not as high as desired. Diverse research findings on how risky sexual behaviors affect PrEP uptake highlight the necessity for a comprehensive investigation. Understanding the interconnectedness of different sexual behaviors is crucial for evaluating their impact on PrEP uptake among eligible MSM. Using a proportional sampling method, we recruited 5877 MSM aged 16 years and above in mainland China according to PrEP eligibility criteria. Through latent class analysis (LCA), three distinct sexual behavior patterns were identified among eligible MSM. Demographic variances and PrEP uptake among the three distinct sexual behavior patterns were examined using chi-squared tests and multinomial logistic regression. LCA revealed three patterns: low-risk (4,815 MSM), medium-risk (516 MSM), and high-risk (546 MSM). MSM aged 25 years or older with a monthly income of ≥¥8,000 were more likely to be in the medium-risk group. Those from areas with high HIV prevalence and engaging as "top" in anal sex were more likely to be in the medium- and high-risk groups. The medium- and high-risk groups had a higher willingness, uptake, and adherence rates for PrEP than the low-risk group. LCA is effective in identifying diverse sexual behavior patterns among MSM, aiding targeted interventions to enhance PrEP uptake. Addressing demographic variations and tailoring interventions for specific risk groups are crucial for promoting PrEP dissemination and reducing HIV infection risk in eligible MSM.
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Pancreatic cancer, predominantly pancreatic ductal adenocarcinoma (PDAC), remains a highly lethal malignancy with limited therapeutic options and a dismal prognosis. By targeting the underlying molecular abnormalities responsible for PDAC development and progression, gene therapy offers a promising strategy to overcome the challenges posed by conventional radiotherapy and chemotherapy. This study sought to explore the therapeutic potential of small activating RNAs (saRNAs) specifically targeting the CCAAT/enhancer-binding protein alpha (CEBPA) gene in PDAC. To overcome the challenges associated with saRNA delivery, tetrahedral framework nucleic acids (tFNAs) were rationally engineered as nanocarriers. These tFNAs were further functionalized with a truncated transferrin receptor aptamer (tTR14) to enhance targeting specificity for PDAC cells. The constructed tFNA-based saRNA formulation demonstrated exceptional stability, efficient saRNA release ability, substantial cellular uptake, biocompatibility, and nontoxicity. In vitro experiments revealed successful intracellular delivery of CEBPA-saRNA utilizing tTR14-decorated tFNA nanocarriers, resulting in significant activation of tumor suppressor genes, namely, CEBPA and its downstream effector P21, leading to notable inhibition of PDAC cell proliferation. Moreover, in a mouse model of PDAC, the tTR14-decorated tFNA-mediated delivery of CEBPA-saRNA effectively upregulated the expression of the CEBPA and P21 genes, consequently suppressing tumor growth. These compelling findings highlight the potential utility of saRNA delivered via a designed tFNA nanocarrier to induce the activation of tumor suppressor genes as an innovative therapeutic approach for PDAC.
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Aptâmeros de Nucleotídeos , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Receptores da Transferrina , Animais , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Carcinoma Ductal Pancreático/tratamento farmacológico , Aptâmeros de Nucleotídeos/química , Aptâmeros de Nucleotídeos/farmacologia , Receptores da Transferrina/metabolismo , Camundongos , Linhagem Celular Tumoral , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Proteínas Estimuladoras de Ligação a CCAAT/genética , Proliferação de Células/efeitos dos fármacos , Terapia Genética/métodos , RNA Interferente Pequeno/farmacologia , Camundongos NusRESUMO
Current in vitro models struggle to balance the complexity of human diseases with suitability for large-scale drug tests. While 3D cultures simulate human tissues, they lack cellular intricacy, and integrating these models with high-throughput drug screening remains a challenge. Here, we introduce a method that uses self-assembling nucleic acid nanostructures decorated living cells, termed NACs, to create spheroids with a customizable 3D layout. To demonstrate its uniqueness, our method effectively creates designer 3D spheroids by combining parenchymal cells, stromal cells, and immune cells, leading to heightened physiological relevance and detailed modeling of complex chronic diseases and immune-stromal interactions. Our approach achieves a high level of biological fidelity while being standardized and straightforward to construct with the potential for large-scale drug discovery applications. By merging the precision of DNA nanotechnology with advanced cell culture techniques, we are streamlining human-centric models, striking a balance between complexity and standardization, to boost drug screening efficiency.
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DNA , Avaliação Pré-Clínica de Medicamentos , Esferoides Celulares , Humanos , Esferoides Celulares/efeitos dos fármacos , DNA/química , Avaliação Pré-Clínica de Medicamentos/métodos , Nanotecnologia/métodos , Nanoestruturas/químicaRESUMO
Direct interspecies electron transfer (DIET) is essential for maintaining the function and stability of anaerobic microbial consortia. However, only limited natural DIET modes have been identified and DIET engineering remains highly challenging. In this study, an unnatural DIET between Shewanella oneidensis MR-1 (SO, electron donating partner) and Rhodopseudomonas palustris (RP, electron accepting partner) was artificially established by a facile living cell-cell click chemistry strategy. By introducing alkyne- or azide-modified monosaccharides onto the cell outer surface of the target species, precise covalent connections between different species in high proximity were realized through a fast click chemistry reaction. Remarkably, upon covalent connection, outer cell surface C-type cytochromes mediated DIET between SO and RP was achieved and identified, although this was never realized naturally. Moreover, this connection directly shifted the natural H2 mediated interspecies electron transfer (MIET) to DIET between SO and RP, which delivered superior interspecies electron exchange efficiency. Therefore, this work demonstrated a naturally unachievable DIET and an unprecedented MIET shift to DIET accomplished by cell-cell distance engineering, offering an efficient and versatile solution for DIET engineering, which extends our understanding of DIET and opens up new avenues for DIET exploration and applications.
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Química Click , Rodopseudomonas , Shewanella , Transporte de Elétrons , Shewanella/metabolismo , Shewanella/química , Rodopseudomonas/metabolismo , Rodopseudomonas/química , Azidas/química , Azidas/metabolismo , Alcinos/químicaRESUMO
Latuda® is a novel antipsychotic drug for schizophrenia and bipolar depression. A bioequivalence trial was performed to investigate the bioequivalence of Latuda® and its generic drug lurasidone. Two independent trials were carried out, each involving 28 subjects. In the fasting trial, subjects were randomly assigned to two groups (1:1 ratio), receiving either 40 mg of generic lurasidone or Latuda®. After a 7-day washout period, subjects entered the second period with a crossover administration of 40 mg of generic lurasidone or Latuda®. The postprandial study design was similar to that of the fasting study. In the fasting study, the pharmacokinetic (PK) parameter values of generic lurasidone and Latuda® were as follows: the Cmax was 28.84 ± 19.34 ng/ml and 28.22 ± 21.19 ng/ml, respectively; the AUC0-t was 121.39 ± 58.47 h*ng/ml and 118.35 ± 52.24 h*ng/ml, respectively; and the AUC0-∞ was 129.63 ± 63.26 h*ng/ml and 126.59 ± 57.99 h*ng/ml, respectively. The primary pharmacokinetic parameter, Cmax, was assessed for equivalence using reference-scaled average bioequivalence (RSABE), while other parameters (AUC0-t, AUC0-∞) were evaluated using average bioequivalence (ABE). The results indicate that both Cmax and AUC meet the equivalence criteria. In the postprandial study, the PK values of generic lurasidone and Latuda® were as follows: the Cmax was 74.89 ± 32.06 ng/ml and 83.51 ± 33.52 ng/ml, respectively; the AUC0-t was 274.77 ± 103.05 h*ng/ml and 289.26 ± 95.25 h*ng/ml, respectively; and the AUC0-∞ was 302.44 ± 121.60 h*ng/ml and 316.32 ± 109.04 h*ng/ml, respectively. The primary pharmacokinetic parameters (Cmax, AUC0-t, AUC0-∞) were assessed for equivalence using ABE, and both met the equivalence criteria. In the study, lurasidone and Latuda® both exhibited acceptable safety and tolerability. The results displayed that lurasidone and Latuda® were bioequivalent and safe in healthy Chinese participants. Clinical Trial Registry: This trial is registered at chinadrugtrials.org.cn (no.: CTR20191717, date: 2019.08.29).
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Recently, lead halide perovskite nanocrystals (NCs) have shown great potential and have been widely studied in lighting and optoelectronic fields. However, the long-term stability of perovskite NCs under irradiation is an important challenge for their application in practice. Mn2+ dopants are mostly proposed as substitutes for the Pb site in perovskite NCs synthesized through the hot-injection method, with the aim of improving both photo- and thermal stability. In this work, we employed a facile ligand-assisted reprecipitate strategy to introduce Mn ions into perovskite lattice, and the results showed that Mn3+ instead of Mn2+, even with a very low level of incorporation of 0.18 mol % as interstitial dopant, can enhance the photostability of perovskite binder film under the ambient conditions without emission change, and the photoluminescent efficiency can retain 70% and be stable under intensive irradiation for 12 h. Besides, Mn3+ incorporation could prolong the photoluminescent decay time by passivating trap defects and modifying the distortion of the lattice, which underscores the significant potential for application as light emitters.
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The development of a robust quasi-ohmic contact with minimal resistance, good stability and cost-effectiveness is crucial for perovskite solar cells. We introduce a generic approach featuring a Lewis-acid layer sandwiched between dopant-free semicrystalline polymer and metal electrode in perovskite solar cells, resulting in an ideal quasi-ohmic contact even at elevated temperature up to 85 °C. The solubility of Lewis acid in alcohol facilitates nondestructive solution processing on top of polymer, which boosts hole injection from polymer into metal by two orders of magnitude. By integrating the polymer-acid-metal structure into solar cells, devices exhibit remarkable resilience, retaining 96% ± 3%, 96% ± 2% and 75% ± 7% of their initial efficiencies after continuous operation in nitrogen at 35 °C for 2212 h, 55 °C for 1650 h and 85 °C for 937 h, respectively. Leveraging the Arrhenius relation, we project an impressive T80 lifetime of 26,126 h at 30 °C.
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Limitations in the clinical treatment of Staphylococcus aureus (S. aureus) infections have arisen due to the advent of antibiotic-resistant strains. Given the immense potential of therapeutic strategies targeting bacterial virulence, the role of MgrA as a pivotal virulence determinant in S. aureus-orchestrating resistance, adherence, and hundreds of virulence targets-becomes indispensable. In this investigation, leveraging advanced virtual screening and fluorescence anisotropy assays, we discerned methylophiopogonanone A (Mo-A), a flavonoid derivative, as a potent disruptor of the MgrA-DNA interaction nexus. Subsequent analysis revealed that Mo-A effectively inhibits the expression of virulence factors such as Hla and Pvl in S. aureus and markedly reduces its adhesion capability to fibrinogen. On a cellular landscape, Mo-A exerts a mitigating influence on the deleterious effects inflicted by S. aureus USA300 on A549 cells. Furthermore, our data indicate that Mo-A downregulates the transcription of genes associated with immune evasion, such as nucleases (nuc), Staphylococcal Chemotaxis Inhibitory Protein (chips), and Staphylococcal Complement Inhibitor (scin), thereby undermining immune escape and amplifying neutrophil chemotaxis. Upon application in an in vivo setting, Mo-A assumes a protective persona in a murine model of S. aureus USA300-induced pneumonia and demonstrates efficacy in the Galleria mellonella infection model. Of note, S. aureus displayed no swift acquisition of resistance to Mo-A, and the effect was synergistically enhanced when used in combination with vancomycin. Our findings add substantive weight to the expanding field of virulence-targeted therapeutic strategies and set the stage for more comprehensive exploration of Mo-A potential in combating antibiotic-resistant S. aureus.
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Benzodioxóis , Isoflavonas , Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Camundongos , Animais , Staphylococcus aureus/genética , Proteínas de Bactérias/genética , Fatores de Virulência/genética , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Antibacterianos/metabolismoRESUMO
Excessive induction of inflammatory and immune responses is widely considered as one of vital factors contributing to the pathogenesis and progression of central nervous system (CNS) diseases. Neutrophils are well-studied members of inflammatory and immune cell family, contributing to the innate and adaptive immunity. Neutrophil-released neutrophil extracellular traps (NETs) play an important role in the regulation of various kinds of diseases, including CNS diseases. In this review, current knowledge on the biological features of NETs will be introduced. In addition, the role of NETs in several popular and well-studied CNS diseases including cerebral stroke, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), and neurological cancers will be described and discussed through the reviewing of previous related studies.
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Doenças do Sistema Nervoso Central , Armadilhas Extracelulares , Esclerose Múltipla , Humanos , Sistema Nervoso Central , NeutrófilosRESUMO
Mpox (monkeypox) virus (MPXV), which causes a mild smallpox-like disease, has been endemic in Africa for several decades, with sporadic cases occurring in other parts of the world. However, the most recent outbreak of mpox mainly among men that have sex with men has affected several continents, posing serious global public health concerns. The infections exhibit a wide spectrum of clinical presentation, ranging from asymptomatic infection to mild, severe disease, especially in immunocompromised individuals, young children, and pregnant women. Some therapeutics and vaccines developed for smallpox have partial protective and therapeutic effects against MPXV historic isolates in animal models. However, the continued evolution of MPXV has produced multiple lineages, leading to significant gaps in the knowledge of their pathogenesis that constrain the development of targeted antiviral therapies and vaccines. MPXV infections in various animal models have provided a central platform for identification and comparison of diseased pathogenesis between the contemporary and historic isolates. In this review, we discuss the susceptibility of various animals to MPXV, and describe the key pathologic features of rodent, rabbit and nonhuman primate models. We also provide application examples of animal models in elucidating viral pathogenesis and evaluating effectiveness of vaccine and antiviral drugs. These animal models are essential to understand the biology of MPXV contemporary isolates and to rapidly test potential countermeasures. Finally, we list some remaining scientific questions of MPXV that can be resolved by animal models.
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Light-induced halide segregation constrains the photovoltaic performance and stability of wide-bandgap perovskite solar cells and tandem cells. The implementation of an intermixed two-dimensional/three-dimensional heterostructure via solution post-treatment is a typical strategy to improve the efficiency and stability of perovskite solar cells. However, owing to the composition-dependent sensitivity of surface reconstruction, the conventional solution post-treatment is suboptimal for methylammonium-free and cesium/bromide-enriched wide-bandgap PSCs. To address this, we develop a generic three-dimensional to two-dimensional perovskite conversion approach to realize a preferential growth of wider dimensionality (n ≥ 2) atop wide-bandgap perovskite layers (1.78 eV). This technique involves depositing a well-defined MAPbI3 thin layer through a vapor-assisted two-step process, followed by its conversion into a two-dimensional structure. Such a two-dimensional/three-dimensional heterostructure enables suppressed light-induced halide segregation, reduced non-radiative interfacial recombination, and facilitated charge extraction. The wide-bandgap perovskite solar cells demonstrate a champion power conversion efficiency of 19.6% and an open-circuit voltage of 1.32 V. By integrating with the thermal-stable FAPb0.5Sn0.5I3 narrow-bandgap perovskites, our all-perovskite tandem solar cells exhibit a stabilized PCE of 28.1% and retain 90% of the initial performance after 855 hours of continuous 1-sun illumination.
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Purpose: The purpose of this study was to examine the pharmacokinetics (PK), bioequivalence and safety of generic sunitinib and its original product Sutent® in healthy Chinese subjects through a phase-I clinical trial. Methods: The study selected two groups of 24 healthy Chinese subjects in a 1:1 ratio through random allocation. Each participant received either 12.5 mg of sunitinib or Sutent® per cycle. A total of 15 different time points were employed for blood sample collection during each cycle. Furthermore, a comprehensive assessment of the drugs' safety was consistently maintained throughout the trial. Results: The average adjusted geometric mean ratios (GMR) (90% CI) for the primary PK parameters Cmax, AUC0-t and AUC0-∞ were 97.04% (93.06%-101.19%), 98.45% (93.27%-103.91%) and 98.22% (93.15%-103.56%), respectively. The adjusted GMRs for essential pharmacokinetic (PK) parameters all met the requirements for bioequivalence, with values within the acceptable range of 80%-125%. In addition, the two drugs showed comparable results for the other PK parameters. These results indicate that the two drugs were bioequivalent. Furthermore, both drugs showed well safety. Conclusion: The research results proved that the PK and safety profiles of sunitinib in healthy Chinese subjects were comparable to those of Sutent®. These results advocate the clinical application of generic sunitinib as a potential alternative to original product Sutent® in the treatment of certain medical conditions.
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Aim: Our primary objective was to investigate the protective effects and mechanisms of isovanillic acid in mice infected with Staphylococcus aureus Newman. Methods: In vitro coagulation assays were used to validate vWbp and Coa as inhibitory targets of isovanillic acid. The binding mechanism of isovanillic acid to vWbp and Coa was investigated using molecular docking and point mutagenesis. Importantly, a lethal pneumonia mouse model was used to assess the effect of isovanillic acid on survival and pathological injury in mice. Results & Conclusion: Isovanillic acid reduced the virulence of S. aureus by directly binding to inhibit the clotting activity of vWbp and Coa, thereby reducing lung histopathological damage and improving the survival rate in mice with pneumonia.
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Coagulase , Infecções Estafilocócicas , Camundongos , Animais , Coagulase/metabolismo , Staphylococcus aureus/metabolismo , Simulação de Acoplamento Molecular , Infecções Estafilocócicas/prevenção & controleRESUMO
BACKGROUND: Trastuzumab is a humanized anti-HER2 monoclonal antibody used in the treatment of breast cancer. This study compared the pharmacokinetics (PK), immunogenicity and safety of trastuzumab (Roche Pharma AG) and its biosimilar (Chia Tai Tianqing Pharmaceutical Group Co. Ltd) in healthy Chinese subjects. RESEARCH DESIGN AND METHODS: A randomized, parallel, double-blind, single-dose study was conducted. Healthy male subjects were randomized to receive trastuzumab (n = 43) or its biosimilar (n = 43) intravenously at a dose of 4 mg. Plasma drug concentrations were detected by enzyme-linked immunosorbent assay (ELISA), and PK parameters were statistically analyzed. Safety and immunogenicity were also evaluated. RESULTS: The geometric mean ratios (GMRs) of AUC0-t, Cmax and AUC0-∞ for trastuzumab and its biosimilar were 92.3%, 100.77% and 92.2%, respectively. The 90% CIs were all within 80%-125%, meeting the bioequivalence standards. No serious adverse events or immunogenicity were reported, and all the adverse events reported were mild and similar between the two treatment groups. CONCLUSIONS: Trastuzumab was well tolerated, showed a similar safety profile to its biosimilar, and demonstrated PK equivalence. CLINICAL TRIAL REGISTRATION: This trial was registered at the [anonymized].
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Medicamentos Biossimilares , Humanos , Masculino , Trastuzumab , Voluntários Saudáveis , Método Simples-Cego , Área Sob a Curva , Equivalência Terapêutica , Método Duplo-CegoRESUMO
High-throughput synthesis of solution-processable structurally variable small-molecule semiconductors is both an opportunity and a challenge. A large number of diverse molecules provide a possibility for quick material discovery and machine learning based on experimental data. However, the diversity of the molecular structure leads to the complexity of molecular properties, such as solubility, polarity, and crystallinity, which poses great challenges to solution processing and purification. Here, we first report an integrated system for the high-throughput synthesis, purification, and characterization of molecules with a large variety. Based on the principle "Like dissolves like," we combine theoretical calculations and a robotic platform to accelerate the purification of those molecules. With this platform, a material library containing 125 molecules and their optical-electronic properties was built within a timeframe of weeks. More importantly, the high repeatability of recrystallization we design is a reliable approach to further upgrading and industrial production.
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The ability to determine the distance to objects is an important feature of most visual systems, but little is known about the neuronal mechanisms for distance estimation. Larval zebrafish execute different visual behaviors depending on distance; at medium distances, they converge their eyes and approach, but when the prey is close enough, they execute a strike and suck the prey into their mouths. To study distance estimation, we developed a head-fixed strike assay. We found that we could evoke strike behavior in head-fixed larvae and quantify head movements to classify the behavior as a strike. Strikes were dependent on distance to prey, allowing us to use them to study distance estimation. Light intensity is rapidly attenuated as it travels through water, so we hypothesized that larvae could use intensity as a distance cue. We found that increasing stimulus intensity could cause larvae to strike at prey that would normally be out of range, and decreasing the intensity could lower the strike rate even for very proximal stimuli. In addition, stimulus contrast is a key parameter, and this could allow larvae to estimate distance over the range of natural illumination. Finally, we presented prey in the binocular vs. monocular visual field and found that monocular prey did evoke strikes, although the binocular input produced more. These results suggest that strike behavior is optimally evoked by bright UV dots in the binocular zone with minimal UV background light and provide a foundation to study the neuronal mechanisms of distance estimation.