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Van der Waals assembly enables the design of electronic states in two-dimensional (2D) materials, often by superimposing a long-wavelength periodic potential on a crystal lattice using moiré superlattices1-9. This twistronics approach has resulted in numerous previously undescribed physics, including strong correlations and superconductivity in twisted bilayer graphene10-12, resonant excitons, charge ordering and Wigner crystallization in transition-metal chalcogenide moiré structures13-18 and Hofstadter's butterfly spectra and Brown-Zak quantum oscillations in graphene superlattices19-22. Moreover, twistronics has been used to modify near-surface states at the interface between van der Waals crystals23,24. Here we show that electronic states in three-dimensional (3D) crystals such as graphite can be tuned by a superlattice potential occurring at the interface with another crystal-namely, crystallographically aligned hexagonal boron nitride. This alignment results in several Lifshitz transitions and Brown-Zak oscillations arising from near-surface states, whereas, in high magnetic fields, fractal states of Hofstadter's butterfly draw deep into the bulk of graphite. Our work shows a way in which 3D spectra can be controlled using the approach of 2D twistronics.
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Extracellular vesicles (EVs), emerging as novel mediators between intercellular communication, encapsulate distinct bioactive cargoes to modulate multiple biological events, such as epigenetic remodeling. In essence, EVs and epigenomic profiles are tightly linked and reciprocally regulated. Epigenetic factors, including histone and DNA modifications, noncoding RNAs, and protein post-translational modifications (PTMs) dynamically regulate EV biogenesis to contribute to EV heterogeneity. Alternatively, EVs actively modify DNA, RNA, and histone profiles in recipient cells by delivering RNA and protein cargoes for downstream epigenetic enzyme regulation. Moreover, EVs display great potential as diagnostic markers and drug-delivery vehicles for therapeutic applications. The combination of parental cell epigenomic modification with single EV characterization would be a promising strategy for EV engineering to enhance the epidrug loading efficacy and accuracy.
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Ion transport through nanoporous two-dimensional (2D) membranes is predicted to be tunable by controlling the charging status of the membranes' planar surfaces, the behavior of which though remains to be assessed experimentally. Here we investigate ion transport through intrinsically porous membranes made of 2D metal-organic-framework layers. In the presence of certain cations, we observe a linear-to-nonlinear transition of the ionic current in response to the applied electric field, the behavior of which is analogous to the cation gating effect in the biological ion channels. Specifically, the ionic currents saturate at transmembrane voltages exceeding a few hundreds of millivolts, depending on the concentration of the gating cations. This is attributed to the binding of cations at the membranes' surfaces, tuning the charging states there and affecting the entry/exit process of translocating ions. Our work also provides 2D membranes as candidates for building nanofluidic devices with tunable transport properties.
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White matter (WM) functional activity has been reliably detected through functional magnetic resonance imaging (fMRI). Previous studies have primarily examined WM bundles as unified entities, thereby obscuring the functional heterogeneity inherent within these bundles. Here, for the first time, we investigate the function of sub-bundles of a prototypical visual WM tract-the optic radiation (OR). We use the 7T retinotopy dataset from the Human Connectome Project (HCP) to reconstruct OR and further subdivide the OR into sub-bundles based on the fiber's termination in the primary visual cortex (V1). The population receptive field (pRF) model is then applied to evaluate the retinotopic properties of these sub-bundles, and the consistency of the pRF properties of sub-bundles with those of V1 subfields is evaluated. Furthermore, we utilize the HCP working memory dataset to evaluate the activations of the foveal and peripheral OR sub-bundles, along with LGN and V1 subfields, during 0-back and 2-back tasks. We then evaluate differences in 2bk-0bk contrast between foveal and peripheral sub-bundles (or subfields), and further examine potential relationships between 2bk-0bk contrast and 2-back task d-prime. The results show that the pRF properties of OR sub-bundles exhibit standard retinotopic properties and are typically similar to the properties of V1 subfields. Notably, activations during the 2-back task consistently surpass those under the 0-back task across foveal and peripheral OR sub-bundles, as well as LGN and V1 subfields. The foveal V1 displays significantly higher 2bk-0bk contrast than peripheral V1. The 2-back task d-prime shows strong correlations with 2bk-0bk contrast for foveal and peripheral OR fibers. These findings demonstrate that the blood oxygen level-dependent (BOLD) signals of OR sub-bundles encode high-fidelity visual information, underscoring the feasibility of assessing WM functional activity at the sub-bundle level. Additionally, the study highlights the role of OR in the top-down processes of visual working memory beyond the bottom-up processes for visual information transmission. Conclusively, this study innovatively proposes a novel paradigm for analyzing WM fiber tracts at the individual sub-bundle level and expands understanding of OR function.
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Conectoma , Imageamento por Ressonância Magnética , Memória de Curto Prazo , Vias Visuais , Humanos , Memória de Curto Prazo/fisiologia , Conectoma/métodos , Vias Visuais/fisiologia , Vias Visuais/diagnóstico por imagem , Adulto , Masculino , Feminino , Percepção Visual/fisiologia , Substância Branca/diagnóstico por imagem , Substância Branca/fisiologia , Substância Branca/anatomia & histologia , Córtex Visual Primário/fisiologia , Córtex Visual Primário/diagnóstico por imagem , Corpos Geniculados/fisiologia , Corpos Geniculados/diagnóstico por imagem , Adulto Jovem , Córtex Visual/fisiologia , Córtex Visual/diagnóstico por imagemRESUMO
BACKGROUND: The combination of immune checkpoint inhibitors and antiangiogenic agents has been effective in treating multiple cancers. This was further explored in an open-label, multicenter phase 2 basket study (NCT04346381), which evaluated the antitumor activity and safety of camrelizumab (an anti-PD-1 antibody) plus famitinib (a receptor tyrosine kinase inhibitor) in patients with advanced solid tumors. We herein report the findings from the cohort of advanced NSCLC patients who progressed after treatment with platinum-doublet chemotherapy and immunotherapy. METHODS: Eligible patients were enrolled and treated with camrelizumab (200 mg once every 3 weeks via intravenous infusion) and oral famitinib (20 mg once daily). The primary endpoint was the objective response rate (ORR). Secondary endpoints included the disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Forty patients were enrolled in this cohort, with a median follow-up duration of 11.5 months. Three patients (7.5%) achieved a partial response, and 29 patients (72.5%) achieved stable disease. The ORR and DCR with this combination regimen were 7.5% (95% CI, 1.6-20.4) and 80.0% (95% CI, 64.4-90.9), respectively. The median DoR was 12.1 months (95% CI, 10.3-not reached). The median PFS was 5.4 months (95% CI, 4.1-7.5), and the median OS was 12.1 months (95% CI, 9.1-16.7). The estimated 12-month OS rate was 51.5% (95% CI, 34.9-65.9). The most frequent grade 3 or higher treatment-related adverse events occurring in more than 5% of patients included hypertension (27.5%), palmar-plantar erythrodysesthesia syndrome (10%), decreased neutrophil count (10%), and proteinuria (7.5%). CONCLUSION: Camrelizumab plus famitinib demonstrated favorable benefits in PFS and OS, along with manageable safety profiles, in patients with advanced NSCLC who progressed after platinum-doublet chemotherapy and immunotherapy. This finding warrants further exploration.
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Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Idoso , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Adulto , Sulfonamidas/uso terapêutico , Sulfonamidas/administração & dosagem , Imunoterapia/métodos , Indóis , PirróisRESUMO
Dielectrophoresis (DEP), which arises from the interaction between dielectric particles and an aqueous solution in a nonuniform electric field, contributes to the manipulation of nano and microparticles in many fields, including colloid physics, analytical chemistry, molecular biology, clinical medicine, and pharmaceutics. The measurement of the DEP force could provide a more complete solution for verifying current classical DEP theories. This review reports various imaging, fluidic, optical, and mechanical approaches for measuring the DEP forces at different amplitudes and frequencies. The integration of DEP technology into sensors enables fast response, high sensitivity, precise discrimination, and label-free detection of proteins, bacteria, colloidal particles, and cells. Therefore, this review provides an in-depth overview of DEP-based fabrication and measurements. Depending on the measurement requirements, DEP manipulation can be classified into assistance and integration approaches to improve sensor performance. To this end, an overview is dedicated to developing the concept of trapping-on-sensing, improving its structure and performance, and realizing fully DEP-assisted lab-on-a-chip systems.
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PURPOSE: The incomplete resection of non-muscle invasive bladder cancer (NMIBC) augments the risk of disease recurrence. Imaging-guided surgery by molecular probes represents a pivotal strategy for mitigating postoperative recurrence. Traditional optical molecular probes, primarily composed of antibodies/peptides targeting tumour cells and fluorescent groups, are challenged by the high heterogeneity of NMIBC cells, leading to inadequate probe sensitivity. We have developed a collagen-adhesive probe (CA-P) to target the collagen within the tumour microenvironment, aiming to address the issue of insufficient imaging sensitivity. METHODS: The distribution characteristics of collagen in animal bladder cancer models and human bladder cancer tissues were explored. The synthesis and properties of CA-P were validated. In animal models, the imaging performance of CA-P was tested and compared with our previously reported near-infrared probe PLSWT7-DMI. The clinical translational potential of CA-P was assessed using human ex vivo bladder tissues. RESULTS: The distribution of collagen on the surface of tumour cells is distinct from its expression in normal urothelium. In vitro studies have demonstrated the ability of the CA-P to undergo a "sol-gel" transition upon interaction with collagen. In animal models and human ex vivo bladder specimens, CA-P exhibits superior imaging performance compared to PLSWT7-DMI. The sensitivity of this probe is 94.1%, with a specificity of 81%. CONCLUSION: CA-P demonstrates the capability to overcome tumour cell heterogeneity and enhance imaging sensitivity, exhibiting favorable imaging outcomes in preclinical models. These findings provide a theoretical basis for the application of CA-P in intraoperative navigation for NMIBC.
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Chimeric antigen receptor (CAR)-modified T cell therapy has achieved remarkable efficacy in treating hematological malignancies, but it confronts many challenges in treating solid tumors, such as the immunosuppressive microenvironment of the solid tumors. These factors reduce the antitumor activity of CAR-T cells in clinical trials. Therefore, we used the immunocytokine interleukin-12 (IL-12) to enhance the efficacy of CAR-T cell therapy. In this study, we engineered CAR-IL12R54 T cells that targeted mesothelin (MSLN) and secreted a single-chain IL-12 fused to a scFv fragment R54 that recognized a different epitope on mesothelin. The evaluation of the anti-tumor activity of the CAR-IL12R54 T cells alone or in combination with anti-PD-1 antibody in vitro and in vivo was followed by the exploration of the functional mechanism by which the immunocytokine IL-12 enhanced the antitumor activity. CAR-IL12R54 T cells had potency to lyse mesothelin positive tumor cells in vitro. In vivo studies demonstrated that CAR-IL12R54 T cells were effective in controlling the growth of established tumors in a xenograft mouse model with fewer side effects than CAR-T cells that secreted naked IL-12. Furthermore, combination of PD-1 blockade antibody with CAR-IL12R54 T cells elicited durable anti-tumor responses. Mechanistic studies showed that IL12R54 enhanced Interferon-γ (IFN-γ) production and dampened the activity of regulatory T cells (Tregs). IL12R54 also upregulated CXCR6 expression in the T cells through the NF-κB pathway, which facilitated T cell infiltration and persistence in the tumor tissues. In summary, the studies provide a good therapeutic option for the clinical treatment of solid tumors.
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Imunoterapia Adotiva , Interleucina-12 , Mesotelina , Receptores de Antígenos Quiméricos , Animais , Interleucina-12/imunologia , Interleucina-12/genética , Humanos , Imunoterapia Adotiva/métodos , Imunoterapia Adotiva/efeitos adversos , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/genética , Linhagem Celular Tumoral , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto , Feminino , Proteínas Ligadas por GPI/imunologia , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/antagonistas & inibidores , Microambiente Tumoral/imunologia , Neoplasias/imunologia , Neoplasias/terapia , Receptores de Interleucina-12/genética , Receptores de Interleucina-12/imunologia , Linfócitos T/imunologiaRESUMO
CREB3 subfamily belongs to the bZIP transcription factor family and comprises five members. Normally they are located on the endoplasmic reticulum (ER) membranes and proteolytically activated through RIP (regulated intramembrane proteolysis) on Golgi apparatus to liberate the N-terminus to serve as transcription factors. CREB3L1 acting as one of them transcriptionally regulates the expressions of target genes and exhibits distinct functions from the other members of CREB3 family in eukaryotes. Physiologically, CREB3L1 involves in the regulation of bone morphogenesis, neurogenesis, neuroendocrine, secretory cell differentiation, and angiogenesis. Pathologically, CREB3L1 implicates in the modulation of osteogenesis imperfecta, low grade fibro myxoid sarcoma (LGFMS), sclerosing epithelioid fibrosarcoma (SEF), glioma, breast cancer, thyroid cancer, and tissue fibrosis. This review summarizes the upstream and downstream regulatory network of CREB3L1 and thoroughly presents our current understanding of CREB3L1 research progress in both physiological and pathological conditions with special focus on the novel findings of CREB3L1 in cancers.
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Fibrossarcoma , Humanos , Fibrossarcoma/genética , Fibrossarcoma/metabolismo , Fibrossarcoma/patologia , Fatores de Transcrição de Zíper de Leucina Básica , Biomarcadores Tumorais/genética , Proteínas do Tecido Nervoso , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genéticaRESUMO
In the field of inter-satellite laser communication, achieving high-quality communication and compensating for the Doppler frequency shift caused by relative motion necessitate lasers with narrow linewidths, low phase noise, and the ability to achieve mode-hop-free tuning within a specific range. To this end, this paper investigates a novel external cavity diode laser (ECDL) with a frequency-selective F-P etalon structure, leveraging the external cavity F-P etalon structure in conjunction with an auxiliary filter to achieve single longitudinal mode selection. The laser undergoes linewidth testing using a delayed self-heterodyne beating method, followed by the testing of its phase noise and frequency noise characteristics using a noise analyzer, yielding beat spectra and noise power spectral density profiles. Furthermore, the paper introduces an innovative bidirectional temperature-scanning laser method to achieve optimal laser-operating point selection and mode-hop-free tuning. The experimental results showcase that the single longitudinal mode spectral side-mode suppression ratio (SMSR) is around 70 dB, and the output power exceeds 10 mW. Enhancing the precision of the F-P etalon leads to a more pronounced suppression of low-frequency phase noise, reducing the Lorentzian linewidth from the initial 10 kHz level to a remarkable 5 kHz level. The bidirectional temperature-scanning laser method not only allows for the selection of the optimal operating point but also enables mode-hop-free tuning within 160 pm.
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BACKGROUND: Hot compressed water (HCW), also known as subcritical water (SCW), refers to high-temperature compressed water in a special physical and chemical state. It is an emerging technology for natural product extraction. The volatile organic compounds (VOCs) generated from the Maillard reaction between l-ascorbic acid (ASA) and l-cysteine (Cys) have attracted significant interest in the flavor and fragrance industry. This study aimed to explore the formation mechanism of VOCs from ASA and Cys and examine the effects of reaction parameters such as temperature, time, and pH in HCW. RESULTS: The identified VOCs were predominantly thiophene derivatives, polysulfides, and pyrazine derivatives in HCW. The findings indicated that thiophene derivatives were formed under various pH conditions, with polysulfide formation favored under acidic conditions and pyrazine derivative formation preferred under weak alkaline conditions, specifically at pH 8.0. CONCLUSION: The Maillard reaction between ASA and Cys mainly produced thiophene derivatives, polysulfides, and pyrazine derivatives in HCW. The generation mechanism was significantly dependent on the surrounding pH conditions. © 2024 Society of Chemical Industry.
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Ácido Ascórbico , Cisteína , Temperatura Alta , Reação de Maillard , Compostos Orgânicos Voláteis , Água , Cisteína/química , Cisteína/análogos & derivados , Compostos Orgânicos Voláteis/química , Ácido Ascórbico/química , Água/química , Concentração de Íons de HidrogênioRESUMO
PURPOSE: To assess the relationship between dislocation and functional outcomes in supination-external rotation (SER) ankle fractures. METHODS: A retrospective case series study was performed on patients with ankle fractures treated surgically at a large trauma center from January 2015 to December 2021. The inclusion criteria were young and middle-aged patients of 18-65 years with SER ankle fractures that can be classified by Lauge-Hansen classification and underwent surgery at our trauma center. Exclusion criteria were serious life-threatening diseases, open fractures, fractures delayed for more than 3 weeks, fracture sites ≥2, etc. Then patients were divided into dislocation and no-dislocation groups. Patient demographics, injury characteristics, surgery-related outcomes, and postoperative functional outcomes were collected and analyzed. The functional outcomes of SER ankle fractures were assessed postoperatively at 1-year face-to-face follow-up using the foot and ankle outcome score (FAOS) and American orthopedic foot and ankle society score and by 2 experienced orthopedic physicians. Relevant data were analyzed using SPSS version 22.0 by Chi-square or t-test. RESULTS: During the study period, there were 371 ankle fractures. Among them, 190 (51.2%) were SER patterns with 69 (36.3%) combined with dislocations. Compared with the no-dislocation group, the dislocation group showed no statistically significant differences in gender, age composition, fracture type, preoperative complications with diabetes, smoking history, preoperative waiting time, operation time, and length of hospital stay (all p > 0.05), but a significantly higher Lauge-Hansen injury grade (p < 0.001) and syndesmotic screw fixation rate (p = 0.033). Moreover, the functional recovery was poorer, revealing a significantly lower FAOS in the sport/rec scale (p < 0.001). Subgroup analysis showed that among SER IV ankle fracture patients, FAOS was much lower in pain (p = 0.042) and sport/rec scales (p < 0.001) for those with dislocations. American orthopedic foot and ankle society score revealed no significant difference between dislocation and no-dislocation patients. CONCLUSION: Dislocation in SER ankle fractures suggests more severe injury and negatively affects functional recovery, mainly manifested as more pain and poorer motor function, especially in SER IV ankle cases.
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Objective: The open-label, phase II RATIONALE-209 study evaluated tislelizumab (anti-programmed cell death protein 1 antibody) as a tissue-agnostic monotherapy for microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) tumors. Methods: Adults with previously treated, locally advanced unresectable or metastatic MSI-H/dMMR solid tumors were enrolled. Patients received tislelizumab 200 mg intravenously every 3 weeks. Objective response rate (ORR; primary endpoint), duration of response (DoR), and progression-free survival (PFS) were assessed by independent review committee (Response Evaluation Criteria in Solid Tumors v1.1). Results: Eighty patients were enrolled and treated; 75 (93.8%) patients had measurable disease at baseline. Most had metastatic disease and received at least one prior therapy for advanced/metastatic disease (n=79; 98.8%). At primary analysis (data cutoff July 8, 2021; median follow-up 15.2 months), overall ORR [46.7%; 95% confidence interval (95% CI), 35.1-58.6; one-sided P<0.0001] and ORR across tumor-specific subgroups [colorectal (n=46): 39.1% (95% CI, 25.1-54.6); gastric/gastroesophageal junction (n=9): 55.6% (95% CI, 21.2-86.3); others (n=20): 60.0% (95% CI, 36.1-80.9)] were significantly greater with tislelizumab vs. a prespecified historical control ORR of 10%; five (6.7%) patients had complete responses. Median DoR, PFS, and overall survival were not reached with long-term follow-up (data cutoff December 5, 2022; median follow-up 28.9 months). Tislelizumab was well tolerated with no unexpected safety signals. Treatment-related adverse events (TRAEs) of grade ≥3 occurred in 53.8% of patients; 7.5% of patients discontinued treatment due to TRAEs. Conclusions: Tislelizumab demonstrated a significant ORR improvement in patients with previously treated, locally advanced unresectable or metastatic MSI-H/dMMR tumors and was generally well tolerated.
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In magnetic resonance examination, the interaction between implants and the radio frequency (RF) fields induces heating in human tissue and may cause tissue damage. To assess the RF-induced heating of implants, three steps should be executed, including electromagnetic model construction, electromagnetic model validation, and virtual human body simulations. The crucial step of assessing RF-induced heating involves the construction of a test environment for electromagnetic model validation. In this study, a hardware environment, comprised of a RF generation system, electromagnetic field measurement system, and a robotic arm positioning system, was established. Furthermore, an automated control software environment was developed using a Python-based software development platform to enable the creation of a high-precision automated integrated test environment. The results indicate that the electric field generated in this test environment aligns well with the simulated electric field, making it suitable for assessing the RF-induced heating effects of implants.
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Campos Eletromagnéticos , Temperatura Alta , Próteses e Implantes , Ondas de Rádio , Software , Humanos , Imageamento por Ressonância MagnéticaRESUMO
This Perspective highlights a malpractice during data processing in static noble gas mass spectrometry, viz. retrodicting the noble gas signals at "time zero" based on the linear fitting results of the time-varying analytical responses. Linear fitting is the most commonly used by noble gas analysts mainly on the consideration of high coefficient of determination (R2), while it poses risks of inaccurate estimation of required information. Here, we appeal to re-examining the signal variation mechanisms before deciding the way of fitting instead of merely choosing one with good R2. The primary processes during the static mass spectrometry measurement are considered, and a mechanism-based exponential fitting is recommended for the relevant data processing. For the same given data set, exponential fitting is a more robust processing strategy than linear fitting because not only does the former show perfect goodness of fitting but also it contributes to better consistence of retrodicted signals. For the sake of maintaining a high level of data quality in analytical science, we propose to apply the mechanism-based exponential fitting to retrodict the "time zero" signal in static noble gas mass spectrometry, and the commonly used linear fitting should be avoided.
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Manipulation of micro- and nanoscale objects is an essential procedure in many detection and sensing applications, including disease diagnosis and environmental monitoring. Induced-charge electro-osmotic (ICEO) vortices present excellent advantages in the enrichment and selection of micro/nanoscale particles for downstream detection due to gentle conditions and contactless operation, but the application of this method is currently constrained by the throughput. Double-layer charging at the ends of bipolar electrodes can maintain a continuous flow of electric current in the fluidically isolated channels, which provides a feasible method to manipulate particles using parallel ICEO vortices, promoting throughput of particle manipulation without compromising efficiency and overcoming the complicated ohmic contact of electrodes. Encouraged by these, we put forward a novel method with parallel ICEO vortices to manipulate micro/nanoscale samples for downstream detection. First, we study the extension regulation of the low-frequency electric field and mediating effect of the open BPEs on the extended electric field and characterize electric equilibrium states of microparticles and their voltage dependence. Afterward, we leverage this method to enrich nanoparticles for detection of low-abundance nanoparticles with about 20- and 40-fold fluorescence intensities by integrating with a simple fiber-optic sensor. Furthermore, this technique is engineered for the selection of targeted microalgae to continuously detect their proliferation behaviors by combining with a homemade electrical impedance spectroscopy device. This method can reinforce the throughput of ICEO vortices and enables it to integrate with simple and economical sensors to accomplish disease diagnosis and environmental monitoring.
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Microalgas , Nanopartículas , Nanopartículas/química , Eletrodos , Eletricidade , Tecnologia de Fibra ÓpticaRESUMO
Portal hypertension (PT) commonly occurs in cirrhosis. Nitric oxide (NO) imbalance contributes to PT via reduced soluble guanylyl cyclase (sGC) activation and cGMP production, resulting in vasoconstriction, endothelial cell dysfunction, and fibrosis. We assessed the effects of BI 685509, an NO-independent sGC activator, on fibrosis and extrahepatic complications in a thioacetamide (TAA)-induced cirrhosis and PT model. Male Sprague-Dawley rats received TAA twice-weekly for 15 weeks (300-150 mg/kg i.p.). BI 685509 was administered daily for the last 12 weeks (0.3, 1, and 3 mg/kg p.o.; n = 8-11 per group) or the final week only (Acute, 3 mg/kg p.o.; n = 6). Rats were anesthetized to measure portal venous pressure. Pharmacokinetics and hepatic cGMP (target engagement) were measured by mass spectrometry. Hepatic Sirius Red morphometry (SRM) and alpha-smooth muscle actin (αSMA) were measured by immunohistochemistry; portosystemic shunting was measured using colored microspheres. BI 685509 dose-dependently increased hepatic cGMP at 1 and 3 mg/kg (3.92 ± 0.34 and 5.14 ± 0.44 versus 2.50 ± 0.19 nM in TAA alone; P < 0.05). TAA increased hepatic SRM, αSMA, PT, and portosystemic shunting. Compared with TAA, 3 mg/kg BI 685509 reduced SRM by 38%, αSMA area by 55%, portal venous pressure by 26%, and portosystemic shunting by 10% (P < 0.05). Acute BI 685509 reduced SRM and PT by 45% and 21%, respectively (P < 0.05). BI 685509 improved hepatic and extrahepatic cirrhosis pathophysiology in TAA-induced cirrhosis. These data support the clinical investigation of BI 685509 for PT in patients with cirrhosis. SIGNIFICANCE STATEMENT: BI 685509 is an NO-independent sGC activator that was tested in a preclinical rat model of TAA-induced nodular, liver fibrosis, portal hypertension, and portal systemic shunting. BI 685509 reduced liver fibrosis, portal hypertension, and portal-systemic shunting in a dose-dependent manner, supporting its clinical assessment to treat portal hypertension in patients with cirrhosis.
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Hipertensão Portal , Cirrose Hepática Experimental , Ratos , Masculino , Animais , Guanilil Ciclase Solúvel/farmacologia , Tioacetamida/efeitos adversos , Ratos Sprague-Dawley , Cirrose Hepática Experimental/induzido quimicamente , Cirrose Hepática Experimental/tratamento farmacológico , Hipertensão Portal/tratamento farmacológico , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/complicações , Fígado , GMP CíclicoRESUMO
Activation of soluble guanylate cyclase (sGC) to restore cyclic guanosine monophosphate (cGMP) and improve functionality of nitric oxide (NO) pathways impaired by oxidative stress is a potential treatment of diabetic and chronic kidney disease. We report the pharmacology of BI 685509, a novel, orally active small molecule sGC activator with disease-modifying potential. BI 685509 and human sGC α1/ß1 heterodimer containing a reduced heme group produced concentration-dependent increases in cGMP that were elevated modestly by NO, whereas heme-free sGC and BI 685509 greatly enhanced cGMP with no effect of NO. BI 685509 increased cGMP in human and rat platelet-rich plasma treated with the heme-oxidant ODQ; respective EC50 values were 467 nM and 304 nM. In conscious telemetry-instrumented rats, BI 685509 did not affect mean arterial pressure (MAP) or heart rate (HR) at 3 and 10 mg/kg (p.o.), whereas 30 mg/kg decreased MAP and increased HR. Ten days of BI 685509 at supratherapeutic doses (60 or 100 mg/kg p.o., daily) attenuated MAP and HR responses to a single 100 mg/kg challenge. In the ZSF1 rat model, BI 685509 (1, 3, 10, and 30 mg/kg per day, daily) coadministered with enalapril (3 mg/kg per day) dose-dependently reduced proteinuria and incidence of glomerular sclerosis; MAP was modestly reduced at the higher doses versus enalapril. In the 7-day rat unilateral ureteral obstruction model, BI 685509 dose-dependently reduced tubulointerstitial fibrosis (P < 0.05 at 30 mg/kg). In conclusion, BI 685509 is a potent, orally bioavailable sGC activator with clear renal protection and antifibrotic activity in preclinical models of kidney injury and disease. SIGNIFICANCE STATEMENT: BI 685509 is a novel small soluble guanylate cyclase (sGC) molecule activator that exhibits an in vitro profile consistent with that of an sGC activator. BI 685509 reduced proteinuria and glomerulosclerosis in the ZSF1 rat, a model of diabetic kidney disease (DKD), and reduced tubulointerstitial fibrosis in a rat 7-day unilateral ureteral obstruction model. Thus, BI 685509 is a promising new therapeutic agent and is currently in phase II clinical trials for chronic kidney disease and DKD.
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Insuficiência Renal Crônica , Obstrução Ureteral , Ratos , Humanos , Animais , Guanilil Ciclase Solúvel/metabolismo , Guanilato Ciclase/metabolismo , Obstrução Ureteral/patologia , Rim/metabolismo , Progressão da Doença , Proteinúria/tratamento farmacológico , Fibrose , Enalapril/uso terapêutico , Óxido Nítrico/metabolismo , GMP Cíclico/metabolismoRESUMO
A series of trimetallic cyanidometal-bridged compounds [Men Cp(dppe)FeII -(µ-NC)-RuII (MeOpy)4 -(µ-CN)-FeII (dppe)CpMen ] - [PF6 ]2 (N[PF6 ]2 , n=0, N =1; n=1, N=2; n=3, N=3; Cp=cyclopentadiene, dppe=1,2-bis(diphenylphosphino)ethane, MeOpy=4-methoxypyridine) and their one- and two-electron oxidized compounds N3+ and N4+ were synthesized and characterized. Meanwhile, a series of corresponding linear cyanido-bridged pentanuclear compounds [Men Cp(dppe)FeIII -(µ-NC)-RuII (MeOpy)4 -(µ-NC)-AgI -(µ-CN)-RuII (MeOpy)4 -(µ-CN)-FeIII (dppe)CpMen ][BF4 ]5 (M[BF4 ]5 , n=0, M=4; n=1, M=5; n=3, M=6) were also obtained and well characterized. The investigations suggest that in the trinuclear system there exists remote interaction between the two Fe centers, but no significant interactions exist across the central silver unit between the metals on the two sides of the silver center in the pentanuclear system. In both the trinuclear N4+ and the pentanuclear M5+ complexes, there exists the neighboring RuII âFeIII MM'CT transitions, and the MM'CT energy in the corresponding trinuclear system is higher than those in the pentanuclear system in which no remote metal-metal interaction occurs. Meanwhile, as the substituted methyl groups on the cyclopentadiene increases, the redox potential of the ruthenium in the trinuclear N4+ series increases, but that in the pentanuclear M5+ complexes decreases.
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Alzheimer's disease (AD) is a complex neurodegenerative disease that is prevalent around the world. Both Apelin-13 and proliferator-activated receptor-γ (PPARγ)/PPARγ co-activator 1α (PGC-1α) are regarded as candidate targets for treating AD. The investigation examined whether Apelin-13 exerts neuroprotective effects via PGC-1α/PPARγ signaling. In this study, Apelin-13 improved cognitive deficits in AD mice, while SR-18,292 (a PGC-1α inhibitor) interfered with the therapeutic effects of Apelin-13. Mechanistically, Apelin-13, PGC-1α and PPARγ were decreased in AD mice and oxygen-glucose deprivation (OGD)-induced neuronal cells. Apelin-13 bound to PGC-1α and negatively regulated the expression of PGC-1α and PPARγ. In turn, PGC-1α accelerated the accumulation of Apelin-13 and PPARγ. Additionally, neuronal apoptosis was inhibited, and the abundance of apoptosis-related proteins (Bax, Bcl-2, and cleaved caspase 3) was induced. The content of reactive oxygen species (ROS), malondialdehyde (MDA) and superoxide dismutase (SOD) fluctuated. The level of inflammatory factors (interleukin-6, IL-6, IL-10, tumor necrosis factor-α, TNF-α) was regulated. In short, Apelin-13 exerted anti-apoptosis, anti-oxidant stress and anti-inflammatory effects. Interestingly, PGC-1α silencing promoted neuronal apoptosis, oxidant stress and inflammation, and overexpression of PGC-1α exhibited the opposite. More importantly, inhibition of PGC-1α attenuated Apelin-13-enhanced cognitive impairment and neuronal damage. Therefore, our findings suggested that Apelin-13 exerted neuroprotective effects in part via the PGC-1α/PPARγ pathway.