Przewaquinone A inhibits Angiotensin II-induced endothelial diastolic dysfunction activation of AMPK.

BACKGROUND: Endothelial dysfunction (ED), characterized by markedly reduced nitric oxide (NO) bioavailability, vasoconstriction, and a shift toward a proinflammatory and prothrombotic state, is an important contributor to hypertension, atherosclerosis, and other cardiovascular diseases. Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) is widely involved in cardiovascular development. Przewaquinone A (PA), a lipophilic diterpene quinone extracted from Salvia przewalskii Maxim, inhibits vascular contraction. PURPOSE: Herein, the goal was to explore the protective effect of PA on ED in vivo and in vitro, as well as the underlying mechanisms. METHODS: A human umbilical vein endothelial cell (HUVEC) model of ED induced by angiotensin II (AngII) was used for in vitro observations. Levels of AMPK, endothelial nitric oxide synthase (eNOS), vascular cell adhesion molecule-1 (VCAM-1), nitric oxide (NO), and endothelin-1 (ET-1) were detected by western blotting and ELISA. A mouse model of hypertension was established by continuous infusion of AngII (1000 ng/kg/min) for 4 weeks using osmotic pumps. Following PA and/or valsartan administration, NO and ET-1 levels were measured. The levels of AMPK signaling-related proteins in the thoracic aorta were evaluated by immunohistochemistry. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) were measured using the tail cuff method. Isolated aortic vascular tone measurements were used to evaluate the vasodilatory function in mice. Molecular docking, molecular dynamics, and surface plasmon resonance imaging (SPRi) were used to confirm AMPK and PA interactions. RESULTS: PA inhibited AngII-induced vasoconstriction and vascular adhesion as well as activated AMPK signaling in a dose-dependent manner. Moreover, PA markedly suppressed blood pressure, activated vasodilation in mice following AngII stimulation, and promoted the activation of AMPK signaling. Furthermore, molecular simulations and SPRi revealed that PA directly targeted AMPK. AMPK inhibition partly abolished the protective effects of PA against endothelial dysfunction. CONCLUSION: PA activates AMPK and ameliorates endothelial dysfunction during hypertension.

Unlocking Single Particle Anisotropy in Real-Time for Photoelectrochemistry Processes at the Nanoscale.

The key to rationally and rapidly designing high-performance materials is the monitoring and comprehension of dynamic processes within individual particles in real-time, particularly to gain insight into the anisotropy of nanoparticles. The intrinsic property of nanoparticles typically varies from one crystal facet to the next under realistic working conditions. Here, we introduce the operando collision electrochemistry to resolve the single silver nanoprisms (Ag NPs) anisotropy in photoelectrochemistry. We directly identify the effect of anisotropy on the plasmonic-assisted electrochemistry at the single NP/electrolyte interface. The statistical collision frequency shows that heterogeneous diffusion coefficients among crystal facets facilitate Ag NPs to undergo direction-dependent mass transfer toward the gold ultramicroelectrode. Subsequently, the current amplitudes of transient events indicate that the anisotropy enables variations in dynamic interfacial electron transfer behaviors during photothermal processes. The results presented here demonstrate that the measurement precision of collision electrochemistry can be extended to the sub-nanoparticle level, highlighting the potential for high-throughput material screening with comprehensive kinetics information at the nanoscale.

Hydrodynamics-Controlled Single-Particle Electrocatalysis.

Electrocatalysis is considered promising in renewable energy conversion and storage, yet numerous efforts rely on catalyst design to advance catalytic activity. Herein, a hydrodynamic single-particle electrocatalysis methodology is developed by integrating collision electrochemistry and microfluidics to improve the activity of an electrocatalysis system. As a proof-of-concept, hydrogen evolution reaction (HER) is electrocatalyzed by individual palladium nanoparticles (Pd NPs), with the development of microchannel-based ultramicroelectrodes. The controlled laminar flow enables the precise delivery of Pd NPs to the electrode-electrolyte interface one by one. Compared to the diffusion condition, hydrodynamic collision improves the number of active sites on a given electrode by 2 orders of magnitude. Furthermore, forced convection enables the enhancement of proton mass transport, thereby increasing the electrocatalytic activity of each single Pd NP. It turns out that the improvement in mass transport increases the reaction rate of HER at individual Pd NPs, thus a phase transition without requiring a high overpotential. This study provides new avenues for enhancing electrocatalytic activity by altering operating conditions, beyond material design limitations.

TaoHe ChengQi decoction ameliorates sepsis-induced cardiac dysfunction through anti-ferroptosis via the Nrf2 pathway.

BACKGROUND: Sepsis-induced cardiac dysfunction (SICD) is a serious complication of sepsis that is associated with increased mortality. Ferroptosis has been reported in the SICD. TaoHe ChengQi decoction (THCQD), a classical traditional Chinese medicinal formula, has multiple beneficial pharmacological effects. The potential effects of THCQD on the SICD remain unknown. PURPOSE: To investigate the effect of THCQD on SICD and explore whether this effect is related to the regulation of myocardial ferroptosis through nuclear factor erythroid 2-related factor 2 (Nrf2) activation. METHODS: We induced sepsis in a mouse model using cecal ligation and puncture (CLP) and administered THCQD (2 and 4 g/kg) and dexamethasone (40 mg/kg). Mice mortality was recorded and survival curves were plotted. Echocardiography, hematoxylin and eosin staining, and analysis of serum myocardial injury markers and inflammatory factors were used to evaluate cardiac pathology. Myocardial ferroptosis was detected by quantifying specific biomarker content and protein levels. Through HPLC-Q-Exactive-MS analysis, we identified the components of the THCQD. Network pharmacology analysis and Cellular Thermal Shift Assay (CETSA) were utilized to predict the targets of THCQD for treating SICD. We detected the expression of Nrf2 using Western blotting or immunofluorescence. An RSL3-induced ferroptosis model was established using neonatal rat cardiomyocytes (NRCMs) to further explore the pharmacological mechanism of THCQD. In addition to measuring cell viability, we observed changes in NRCM mitochondria using electron microscopy and JC-1 staining. NRF2 inhibitor ML385 and Nrf2 knockout mice were used to validate whether THCQD exerted protective effects against SICD through Nrf2-mediated ferroptosis signaling. RESULTS: THCQD reduced mortality in septic mice, protected against CLP-induced myocardial injury, decreased systemic inflammatory response, and prevented myocardial ferroptosis. Network pharmacology analysis and CETSA experiments predicted that THCQD may protect against SICD by activating the Nrf2 signaling pathway. Western blotting and immunofluorescence showed that THCQD activated Nrf2 in cardiac tissue. THCQDs consistently mitigated RSL3-induced ferroptosis in NRCM, which is related to Nrf2. Furthermore, the pharmacological inhibition of Nrf2 and genetic Nrf2 knockout partially reversed the protective effects of THCQD on SICD and ferroptosis. CONCLUSION: The effect of THCQD on SICD was achieved by activating Nrf2 and its downstream pathways.

Local Electric Potential-Driven Nanofluidic Ion Transport for Ultrasensitive Biochemical Sensing.

Nanofluidic biosensors have been widely used for detection of analytes based on the change of system resistance before and after target-probe interactions. However, their sensitivity is limited when system resistance barely changes toward low-concentration targets. Here, we proposed a strategy to address this issue by means of target-induced change of local membrane potential under relatively unchanged system resistance. The local membrane potential originated from the directional diffusion of photogenerated carriers across nanofluidic biosensors and gated photoinduced ionic current signal before and after target-probe interactions. The sensitivity of such biosensors for the detection of biomolecules such as circulating tumor DNA (ctDNA) and lysozyme exceeds that of applying a traditional strategy by more than 3 orders of magnitude under unchanged system resistance. Such biosensors can specifically detect the small molecule biomarker in the blood sample between prostate cancer patients and healthy humans. The key advantages of such nanofluidic biosensors are therefore complementary to traditional nanofluidic biosensors, with potential applications in a point-of-care analytical tool.

Multiphase Chemistry under Nanoconfinement: An Electrochemical Perspective.

Most relevant systems of interest to modern chemists rarely consist of a single phase. Real-world problems that require a rigorous understanding of chemical reactivity in multiple phases include the development of wearable and implantable biosensors, efficient fuel cells, single cell metabolic characterization techniques, and solar energy conversion devices. Within all of these systems, confinement effects at the nanoscale influence the chemical reaction coordinate. Thus, a fundamental understanding of the nanoconfinement effects of chemistry in multiphase environments is paramount. Electrochemistry is inherently a multiphase measurement tool reporting on a charged species traversing a phase boundary. Over the past 50 years, electrochemistry has witnessed astounding growth. Subpicoampere current measurements are routine, as is the study of single molecules and nanoparticles. This Perspective focuses on three nanoelectrochemical techniques to study multiphase chemistry under nanoconfinement: stochastic collision electrochemistry, single nanodroplet electrochemistry, and nanopore electrochemistry.

Ethyl ferulate suppresses post-myocardial infarction myocardial fibrosis by inhibiting transforming growth factor receptor 1.

BACKGROUND: With an increasing number of myocardial infarction (MI) patients, myocardial fibrosis is becoming a widespread health concern. It's becoming more and more urgent to conduct additional research and investigations into efficient treatments. Ethyl ferulate (EF) is a naturally occurring substance with cardioprotective properties. However, the extent of its impact and the underlying mechanism of its treatment for myocardial fibrosis after MI remain unknown. PURPOSE: The goal of this study was to look into how EF affected the signaling of the TGF-receptor 1 (TGFBR1) in myocardial fibrosis after MI. METHODS: Echocardiography, hematoxylin-eosin (HE) and Masson trichrome staining were employed to assess the impact of EF on heart structure and function in MI-affected mice in vivo. Cell proliferation assay (MTS), 5-Ethynyl-2'-deoxyuridine (EdU), and western blot techniques were employed to examine the influence of EF on native cardiac fibroblast (CFs) proliferation and collagen deposition. Molecular simulation and surface plasmon resonance imaging (SPRi) were utilized to explore TGFBR1 and EF interaction. Cardiac-specific Tgfbr1 knockout mice (Tgfbr1ΔMCK) were utilized to testify to the impact of EF. RESULTS: In vivo experiments revealed that EF alleviated myocardial fibrosis, improved cardiac dysfunction after MI and downregulated the TGFBR1 signaling in a dose-dependent manner. Moreover, in vitro experiments revealed that EF significantly inhibited CFs proliferation, collagen deposition and TGFBR1 signaling followed by TGF-ß1 stimulation. More specifically, molecular simulation, molecular dynamics, and SPRi collectively showed that EF directly targeted TGFBR1. Lastly, knocking down of Tgfbr1 partially reversed the inhibitory activity of EF on myocardial fibrosis in MI mice. CONCLUSION: EF attenuated myocardial fibrosis post-MI by directly suppressing TGFBR1 and its downstream signaling pathway.

Carnosic acid and rosemary extract reversed the lipid accumulation induced by bisphenol A in the 3T3-L1 preadipocytes and C57BL/6J mice via SIRT1/FoxO1 pathway.

Bisphenol A (BPA) is an endocrine-disrupting chemical, widely used to produce polycarbonate plastic. Carnosic acid (CA) is a rosemary diterpene with an anti-obesity effect. In this study, we investigated the anti-adipogenic effect of CA in BPA-treated 3T3-L1 preadipocytes and C57BL/6 J mice. In vitro experiments showed that CA inhibited lipid accumulation by BPA in 3T3-L1 preadipocytes. CA displayed anti-adipogenic effects through the downregulation of differentiation and adipogenesis-related proteins, along with the upregulation of lipolytic protein and SIRT1/FoxO1 pathway. In vivo experiments, mice treated with BPA exhibited an increase in body weight gain and epididymal adipose tissue mass when compared to the control group. CA treatment improved the epididymal adipose tissue mass induced by BPA. CA and rosemary extract (RE) treatment ameliorated dyslipidemia in BPA-treated mice. We further showed that CA and RE exerted anti-adipogenesis effects in liver tissues of BPA-treated mice via increasing SIRT1, FoxO1, and ATGL proteins and decreasing FAS and aP2 proteins. Moreover, SIRT1 inhibitor sirtinol blocked CA to increase SIRT1, FoxO1, FAS, and aP2 proteins, decrease Ac-FoxO1 protein, and reduce lipid accumulation in BPA-treated cells. These findings indicated that CA and RE could reverse BPA-induced lipid accumulation by regulating adipocyte differentiation, adipogenesis, and lipolysis through SIRT1/FoxO1 pathway.

Monitoring Photoinduced Interparticle Chemical Communication In Situ.

Monitoring interparticle chemical communication plays a critical role in the nanomaterial synthesis as this communication controls the final structure and stability of global nanoparticles (NPs). Yet most ensemble analytical techniques, which could only reveal average macroscopic information, are unable to elucidate NP-to-NP interactions. Herein, we employ stochastic collision electrochemistry to track the morphology transformation of Ag NPs in photochemical process at the single NP level. By further statistical analysis of time-resolved current transients, we quantitatively determine the dynamic chemical potential difference and interparticle communication between populations of large and small Ag NPs. The high sensitivity of stochastic collision electrochemistry enables the in situ investigation of chemical communication-dependent transformation kinetics of NPs in photochemical process, shedding light on designing nanomaterials.

Mass Transport and Electron Transfer at the Electrochemical-Confined Interface.

Single entity measurements based on the stochastic collision electrochemistry provide a promising and versatile means to study single molecules, single particles, single droplets, etc. Conceptually, mass transport and electron transfer are the two main processes at the electrochemically confined interface that underpin the most transient electrochemical responses resulting from the stochastic and discrete behaviors of single entities at the microscopic scale. This perspective demonstrates how to achieve controllable stochastic collision electrochemistry by effectively altering the two processes. Future challenges and opportunities for stochastic collision electrochemistry are also highlighted.