Schisandrin inhibits VSMCs proliferation and migration by arresting cell cycle and targeting JAK2 to regulating the JAK2/STAT3 pathway.

Abnormal proliferation, migration, and foam cell formation of Vascular smooth muscle cells (VSMCs) each play a role in the development of atherosclerosis (AS). Schisandrin (Sch) is the active lignan ingredient with broad-spectrum pharmacological effects. However, the role of Sch in the AS process is not clear. Therefore, this study was proposed to explore the therapeutic effect and potential mechanism of Sch on VSMCs. Ox-LDL was selected to create an atherosclerosis injury environment for VSMCs and macrophages. The MTT assay, Oil red O staining, wound healing, transwell experiments and ELISA were used to investigate the phenotype effects of Sch. Network pharmacology, molecular docking, flow cytometry, and western blot were used to investigate the underlying mechanisms of Sch on AS progression. Our findings implied that Sch treatment inhibited the proliferation and migration of VSMCs, and suppressed the ROS production and inflammatory cytokines up-regulation of VSMCs and macrophages. Moreover, Sch reduced lipid uptake and foam cell formation through downregulating LOX-1. Mechanistically, we found that Sch can inhibit the activation of JAK2/STAT3 signaling by targeting JAK2, and arrest cell cycle in GO/G1 phase. In summary, Sch can inhibit VSMCs proliferation and migration by arresting cell cycle and targeting JAK2 to regulating the JAK2/STAT3 pathway. Sch may serve as a potential drug for patients with AS.

A double-blind pilot study of oral baricitinib in adult patients with lupus erythematosus panniculitis.

Lupus erythematosus panniculitis (LEP) is a chronic inflammatory skin disease with a significant impact on the overall well-being of patients. The safety and efficacy of oral baricitinib for the treatment of LEP have not been studied. This study aimed to explore the efficacy of oral baricitinib in patients with LEP who are recalcitrant or intolerant to conventional therapies. Patients (aged ≥18 years) with active LEP (with a revised cutaneous lupus erythematosus disease area and severity index [RCLASI]-active score ≥4] were randomly assigned 2:1 to baricitinib (4 mg) or placebo (once daily for 20 weeks). The placebo group was switched to baricitinib (4 mg) at week 13, and the final evaluation was conducted at week 24. The primary endpoint was the proportion of patients with an RCLASI-A score decreased by 20% at week 12. The secondary endpoints included the changes in the Cutaneous Lupus Erythematosus Disease Area and Severity Index active-(CLASI-A) score, the Dermatology Life Quality Index (DLQI), the Physician's Global Assessment (PGA) score, and safety. Five patients were enrolled. Three patients received baricitinib (4 mg), and two patients were treated with placebo. Two patients in the baricitinib treatment group showed a significant RCLASI-A decrease at week 12 and week 24. Two patients in the placebo group had no change in RCLASI-A at week 12 and a significant decrease at week 24. No new safety events were observed. Treatment with baricitinib was effective and well tolerated in patients with LEP.

Identification and mechanistic exploration of key anti-inflammatory molecules in American ginseng: Impacts on signal transducer and activator of transcription 3 STAT3 phosphorylation and macrophage polarization.

American ginseng (AG) has been reported to have anti-inflammatory effects in many diseases, but the key molecules and mechanisms are unclear. This study aims to evaluate the anti-inflammatory mechanism of AG and identify the key molecules by in vivo and in vitro models. Zebrafish was employed to assess the anti-inflammatory properties of AG and the compounds. Metabolomics was utilized to identify potential anti-inflammatory molecules in AG, while molecular dynamics simulations were conducted to forecast the interaction capabilities of these compounds with inflammatory targets. Additionally, macrophage cell was employed to investigate the anti-inflammatory mechanisms of the key molecules in AG by enzyme-linked immunosorbent assay and western blotting. Seven potential anti-inflammatory molecules were discovered in AG, with ginsenoside Rg1, ginsenoside Rs3 (G-Rs3), and oleanolic acid exhibiting the strongest affinity for signal transducer and activator of transcription 3. These compounds demonstrated inhibitory effects on macrophage migration in zebrafish models and the ability to regulate ROS levels in both zebrafish and macrophages. The cell experiments found that ginsenoside Rg1, ginsenoside Rs3, and oleanolic acid could promote macrophage M2/M1 polarization ratio and inhibit phosphorylation overexpression of signal transducer and activator of transcription 3. This study revealed the key anti-inflammatory molecules and mechanisms of AG, and provided new evidence of anti-inflammatory for the scientific use of AG.

Immunotherapeutic hydrogel for co-delivery of STAT3 siRNA liposomes and lidocaine hydrochloride for postoperative comprehensive management of NSCLC in a single application.

Despite standard treatment for non-small cell lung cancer (NSCLC) being surgical resection, cancer recurrence and complications, such as induction of malignant pleural effusion (MPE) and significant postoperative pain, usually result in treatment failure. In this study, an alginate-based hybrid hydrogel (SOG) is developed that can be injected into the resection surface of the lungs during surgery. Briefly, endoplasmic reticulum-modified liposomes (MSLs) pre-loaded with the signal transducer and activator of transcription 3 (STAT3) small interfering RNA and lidocaine hydrochloride are encapsulated in SOG. Once applied, MSLs strongly downregulated STAT3 expression in the tumor microenvironment, resulting in the apoptosis of lung cancer cells and polarization of tumor-associated macrophages towards the M1-like phenotype. Meanwhile, the release of lidocaine hydrochloride (LID) was beneficial for pain relief and natural killer cell activation. Our data demonstrated MSL@LID@SOG not only efficiently inhibited tumor growth but also potently improved the quality of life, including reduced MPE volume and pain relief in orthotopic NSCLC mouse models, even with a single administration. MSL@LID@SOG shows potential for comprehensive clinical management upon tumor resection in NSCLC, and may alter the treatment paradigms for other cancers.

LncRNA ZFPM2-AS1 promotes phyllodes tumor progression by binding to CDC42 and inhibiting STAT1 activation.

Breast phyllodes tumor (PT) is a rare fibroepithelial neoplasm with potential malignant behavior. Long non-coding RNAs (lncRNAs) play multifaceted roles in various cancers, but their involvement in breast PT remains largely unexplored. In this study, microarray was leveraged for the first time to investigate the role of lncRNA in PT. We identified lncRNA ZFPM2-AS1 was significantly upregulated in malignant PT, and its overexpression endowed PT with high tumor grade and adverse prognosis. Furthermore, we elucidated that ZFPM2-AS1 promotes the proliferation, migration, and invasion of malignant PT in vitro. Targeting ZFPM2-AS1 through nanomaterial-mediated siRNA delivery in patient-derived xenograft (PDX) model could effectively inhibit tumor progression in vivo. Mechanistically, our findings showed that ZFPM2-AS1 is competitively bound to CDC42, inhibiting ACK1 and STAT1 activation, thereby launching the transcription of TNFRSF19. In conclusion, our study provides evidence that ZFPM2-AS1 plays a pivotal role in the pathogenesis of breast PT, and suggests that ZFPM2-AS1 could serve as a prognostic indicator for patients with PT as well as a promising novel therapeutic target.

Thickness Measurements with EMAT Based on Fuzzy Logic.

Metal thickness measurements are essential in various industrial applications, yet current non-contact ultrasonic methods face limitations in range and accuracy, hindering the widespread adoption of electromagnetic ultrasonics. This study introduces a novel combined thickness measurement method employing fuzzy logic, with the aim of broadening the applicational scope of the EMAT. Leveraging minimal hardware, this method utilizes the short pulse time-of-flight (TOF) technique for initial thickness estimation, followed by secondary measurements guided by fuzzy logic principles. The integration of measurements from the resonance, short pulse echo, and linear frequency modulation echo extends the measurement range while enhancing accuracy. Rigorous experimental validation validates the method's effectiveness, demonstrating a measurement range of 0.3-1000.0 mm with a median error within ±0.5 mm. Outperforming traditional methods like short pulse echoes, this approach holds significant industrial potential.

PMUT-Based System for Continuous Monitoring of Bolted Joints Preload.

In this paper, we present a bolt preload monitoring system, including the system architecture and algorithms. We show how Finite Element Method (FEM) simulations aided the design and how we processed signals to achieve experimental validation. The preload is measured using a Piezoelectric Micromachined Ultrasonic Transducer (PMUT) in pulse-echo mode, by detecting the Change in Time-of-Flight (CTOF) of the acoustic wave generated by the PMUT, between no-load and load conditions. We performed FEM simulations to analyze the wave propagation inside the bolt and understand the effect of different configurations and parameters, such as transducer bandwidth, transducer position (head/tip), presence or absence of threads, as well as the frequency of the acoustic waves. In order to couple the PMUT to the bolt, a novel assembly process involving the deposition of an elastomeric acoustic impedance matching layer was developed. We achieved, for the first time with PMUTs, an experimental measure of bolt preload from the CTOF, with a good signal-to-noise ratio. Due to its low cost and small size, this system has great potential for use in the field for continuous monitoring throughout the operative life of the bolt.

Circular SAW Resonators: Influence of Sensitive Element Dimensions on Strength Characteristics and First Experimental Samples.

In preceding research endeavors, the frequency characteristics of a ring resonator on surface acoustic waves made of various materials were studied. Investigations encompassed fixation techniques within the housing, the impact of external variables on these components, and the most efficient configuration of the interdigital transducer within the ring resonator to curtail bandwidth. This current study is dedicated to investigating the correlation between sensitivity and the highest measurable acceleration concerning the dimensions of these sensitive elements. Furthermore, it involves assessing the attributes of produced experimental samples to verify the simulation results. The results obtained represent the possibility of creating a micromechanical accelerometer that can be used in the automotive industry as a g-sensor shock, as well as in industries where the numerical value of high overloads is required.

Explore Ultrasonic-Induced Mechanoluminescent Solutions towards Realising Remote Structural Health Monitoring.

Ultrasonic guided waves, which are often generated and detected by piezoelectric transducers, are well established to monitor engineering structures. Wireless solutions are sought to eliminate cumbersome wire installation. This work proposes a method for remote ultrasonic-based structural health monitoring (SHM) using mechanoluminescence (ML). Propagating guided waves transmitted by a piezoelectric transducer attached to a structure induce elastic deformation that can be captured by elastico-ML. An ML coating composed of copper-doped zinc sulfide (ZnS:Cu) particles embedded in PVDF on a thin aluminium plate can be used to achieve the elastico-ML for the remote sensing of propagating guided waves. The simulation and experimental results indicated that a very high voltage would be required to reach the threshold pressure applied to the ML particles, which is about 1.5 MPa for ZnS particles. The high voltage was estimated to be 214 Vpp for surface waves and 750 Vpp for Lamb waves for the studied configuration. Several possible technical solutions are suggested for achieving ultrasonic-induced ML for future remote SHM systems.

Adaptation of Conductometric Monoenzyme Biosensor for Rapid Quantitative Analysis of L-arginine in Dietary Supplements.

The present study reports on the development, adaptation, and optimization of a novel monoenzyme conductometric biosensor based on a recombinant arginine deiminase (ADI) for the determination of arginine in dietary supplements with a high accuracy of results. Aiming for the highly sensitive determination of arginine in real samples, we studied the effect of parameters of the working buffer solution (its pH, buffer capacity, ionic strength, temperature, and protein concentration) on the sensitivity of the biosensor to arginine. Thus, it was determined that the optimal buffer is a 5 mM phosphate buffer solution with pH 6.2, and the optimal temperature is 39.5 °C. The linear functioning range is 2.5-750 µM of L-arginine with a minimal limit of detection of 2 µM. The concentration of arginine in food additive samples was determined using the developed ADI-based biosensor. Based on the obtained results, the most effective method of biosensor analysis using the method of standard additions was chosen. It was also checked how the reproducibility of the biosensor changes during the analysis of pharmaceutical samples. The results of the determination of arginine in real samples using a conductometric biosensor based on ADI clearly correlated with the data obtained using the method of ion-exchange chromatography and enzymatic spectrophotometric analysis. We concluded that the developed biosensor would be effective for the accurate and selective determination of arginine in dietary supplements intended for the prevention and/or elimination of arginine deficiency.

Structural Optimization and Performance of a Low-Frequency Double-Shell Type-IV Flexural Hydroacoustic Transducer.

To amplify the displacement of the radiation shell, a double-shell type-IV curved hydroacoustic transducer was proposed. Through Ansys finite element simulation, the vibration modes of the transducer in different stages and the harmonic response characteristics in air and water were studied, and the bandwidth emission of the hydroacoustic transducer was achieved. By optimizing the size of each component, the resonant frequency of the transducer is 740 Hz, the maximum conductivity was 0.66 mS, and the maximum transmitting voltage response was 130 dB. According to the optimized parameters, a longitudinal acoustic transducer prototype was manufactured, and a physical test was conducted in an anechoic pool. The obtained resonant frequency was 750 Hz, the maximum conductivity was 0.44 mS, the maximum transmitting voltage response was 129.25 dB, and the maximum linear dimension was 250 mm, which match the simulated value of the virtual prototype and meet the expected requirements.

STAT4 Mediates IL-6 Trans-Signaling Arrhythmias in High Fat Diet Guinea Pig Heart.

Obesity is a major risk factor for the development of life-threatening malignant ventricular tachyarrhythmias (VT) and sudden cardiac death (SCD). Risks may be highest for patients with high levels of the proinflammatory cytokine interleukin (IL)-6. We used our guinea pig model of high-fat diet (HFD)-induced arrhythmias that exhibit a heightened proinflammatory-like pathology, which is also observed in human obesity arrhythmias, as well as immunofluorescence and confocal microscopy approaches to evaluate the pathological IL-6 trans-signaling function and explore the underlying mechanisms. Using blind-stick and electrocardiogram (ECG) techniques, we tested the hypothesis that heightened IL-6 trans-signaling would exhibit increased ventricular arrhythmia/SCD incidence and underlying arrhythmia substrates. Remarkably, compared to low-fat diet (LFD)-fed controls, HFD promoted phosphorylation of the IL-6 signal transducer and activator of transcription 4 (STAT4), leading to its activation and enhanced nuclear translocation of pSTAT4/STAT4 compared to LFD controls and pSTAT3/STAT3 nuclear expression. Overactivation of IL-6 trans-signaling in guinea pigs prolonged the QT interval, which resulted in greater susceptibility to arrhythmias/SCD with isoproterenol challenge, as also observed with the downstream Janus kinase (JAK) 2 activator. These findings may have potentially profound implications for more effective arrhythmia therapy in the vulnerable obese patient population.

Toll-like Receptor Homologue CD180 Ligation of B Cells Upregulates Type I IFN Signature in Diffuse Cutaneous Systemic Sclerosis.

Type I interferon (IFN-I) signaling has been shown to be upregulated in systemic sclerosis (SSc). Dysregulated B-cell functions, including antigen presentation, as well as antibody and cytokine production, all of which may be affected by IFN-I signaling, play an important role in the pathogenesis of the disease. We investigated the IFN-I signature in 71 patients with the more severe form of the disease, diffuse cutaneous SSc (dcSSc), and 33 healthy controls (HCs). Activation via Toll-like receptors (TLRs) can influence the IFN-I signaling cascade; thus, we analyzed the effects of the TLR homologue CD180 ligation on the IFN-I signature in B cells. CD180 stimulation augmented the phosphorylation of signal transducer and activator of transcription 1 (STAT1) in dcSSc B cells (p = 0.0123). The expression of IFN-I receptor (IFNAR1) in non-switched memory B cells producing natural autoantibodies was elevated in dcSSc (p = 0.0109), which was enhanced following anti-CD180 antibody treatment (p = 0.0125). Autoantibodies to IFN-Is (IFN-alpha and omega) correlated (dcSSc p = 0.0003, HC p = 0.0192) and were present at similar levels in B cells from dcSSc and HC, suggesting their regulatory role as natural autoantibodies. It can be concluded that factors other than IFN-alpha may contribute to the elevated IFN-I signature of dcSSc B cells, and one possible candidate is B-cell activation via CD180.

Piezoelectric Micromachined Microphone with High Acoustic Overload Point and with Electrically Controlled Sensitivity.

Currently, the most advanced micromachined microphones on the market are based on a capacitive coupling principle. Capacitive micro-electromechanical-system-based (MEMS) microphones resemble their millimetric counterparts, both in function and in performance. The most advanced MEMS microphones reached a competitive level compared to commonly used measuring microphones in most of the key performance parameters except the acoustic overload point (AOP). In an effort to find a solution for the measurement of high-level acoustic fields, microphones with the piezoelectric coupling principle have been proposed. These novel microphones exploit the piezoelectric effect of a thin layer of aluminum nitride, which is incorporated in their diaphragm structure. In these microphones fabricated with micromachining technology, no fixed electrode is necessary, in contrast to capacitive microphones. This specificity significantly simplifies both the design and the fabrication and opens the door for the improvement of the acoustic overload point, as well as harsh environmental applications. Several variations of piezoelectric structures together with an idea leading to electrically controlled sensitivity of MEMS piezoelectric microphones are discussed in this paper.

Computer-Aided Intra-Operatory Positioning of an MRgHIFU Applicator Dedicated to Abdominal Thermal Therapy Using Particle Swarm Optimization.

PURPOSE: Transducer positioning for liver ablation by magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU) is challenging due to the presence of air-filled organs or bones on the beam path. This paper presents a software tool developed to optimize the positioning of a HIFU transducer dedicated to abdominal thermal therapy, to maximize the treatment's efficiency while minimizing the near-field risk. METHODS: A software tool was developed to determine the theoretical optimal position (TOP) of the transducer based on the minimization of a cost function using the particle swarm optimization (PSO). After an initialization phase and a manual segmentation of the abdomen of 5 pigs, the program randomly generates particles with 2 degrees of freedom and iteratively minimizes the cost function of the particles considering 3 parameters weighted according to their criticality. New particles are generated around the best position obtained at the previous step and the process is repeated until the optimal position of the transducer is reached. MR imaging data from in vivo HIFU ablation in pig livers was used for ground truth comparison between the TOP and the experimental position (EP). RESULTS: As compared to the manual EP, the rotation difference with the TOP was on average -3.1 ± 7.1° and the distance difference was on average -7.1 ± 5.4 mm. The computational time to suggest the TOP was 20s. The software tool is modulable and demonstrated consistency and robustness when repeating the calculation and changing the initial position of the transducer.

Pharmacologic inhibition of Il6st/gp130 improves dermatological inflammation and pruritus.

Chronic dermatitis is a disease with large unmet need for pharmacological improvement. Dermatitis conditions are maintained and exacerbated by various cytokine actions in the context of inflammation. Interleukin 6 signal transducer (Il6st), also known as glycoprotein 130 (Gp130), is a key component for surface reception of a multitude of cytokines and transduction and amplification of their pro-inflammatory signals. We hypothesized accordingly that pharmacological inhibition of Il6st can alter dermatitis pathology. Treatment with SC-144 and bazedoxifene, two representative small molecule Il6st inhibitors with different binding modes led to moderate but significant improvement of skin conditions in a 1-chloro-2,4-dinitrobenzene animal model. Part of cytokine expressions indicating the dermatological index were normalized particularly when treated with SC-144. Pruritic behaviors were blunted, also possibly giving limited contribution to disease improvement. In psoriatic skin and itch of an imiquimod animal model, those two treatments appeared to be relatively moderate. Collectively, pharmacological inhibition of Il6st seems to lessen pathological irritation. Inversely, this experimental attempt newly implies that Il6st participates in pathological mechanisms. In conclusion, we suggest Il6st as a novel target for improving dermatitis, and that agents with suitable efficacy and safety for its modulation are translatable.

Evaluation of STAT3 Inhibition by Cancer Chemopreventive Trichothecenes Derived from Metabolites of Trichothecium roseum.

This study evaluated the ability of isolated or semisynthesized trichothecene sesquiterpenes to prevent cancer emergence and proliferation and inhibit signal transducer and activator of transcription-3 (STAT3) phosphorylation through in vitro assays. Trichothecinol A (TTC-A), which bears a hydroxy group at C3, exhibited greater cancer prevention, antiproliferation, and STAT3 phosphorylation inhibition effects than trichothecin (TTC), which lacks a hydroxy group at C3. Furthermore, trichothecinol B (TTC-B), which is a reduced derivative of TTC and has similar cytotoxic effect, showed substantially weaker chemoprotection and STAT3 phosphorylation inhibition effects than TTC. These results clearly indicate that the hydroxy group at C3 and carbonyl group at C8 are crucial for inducing both potent chemoprevention and STAT3 phosphorylation inhibition.

Determination of the absorbed acoustic power of longitudinal vibrations by measuring their amplitude in a chosen area of the waveguide system outside the load.

The way of determining the acoustic power of longitudinal ultrasonic vibrations going into the load by measuring the amplitude of longitudinal displacements using an electrodynamic sensor installed near the surface of the waveguide rod is considered. Two possibilities of using the developed method of measurement are analyzed in detail. One of them is based on the registration of the value of longitudinal displacements at the constant position of the electrodynamic sensor in two different states of the ultrasound system: with the load disconnected and after the load is connected, i.e. it uses two measurements at different moments of time, when the states of the system differ from each other. Another way uses two measurements of the amplitude of longitudinal oscillations at two chosen points of the oscillatory system, made at the same time. Formulas have been obtained that make it possible to determine the power entering the load from the measured values and other known values of the system parameters. The role of errors, both in the readings of the sensor and in determining its location on the oscillating system, on the accuracy of calculating the value of the power of the ultrasonic oscillations that went into the load is analyzed.

[Retracted] Puerarin improves graft bone defect through microRNA­155­3p­mediated p53/TNF­α/STAT1 signaling pathway.

Following the publication of the above paper, it has been drawn to the Editor's attention by a concerned reader that the immunohistochemical assay data shown in Fig. 4B on p. 245 were strikingly similar to data appearing in different form in another article written by different authors at different research institutes that had already been published in the journal International Journal of Biological Sciences prior to the submission of this paper to International Journal of Molecular Medicine. In view of the fact that the contentious data had already apparently been published previously, the Editor of International Journal of Molecular Medicine has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they agreed with the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Molecular Medicine 46: 239-251, 2020; DOI: 10.3892/ijmm.2020.4595].

Technical note: Impact of linear array transducer Doppler aperture location on spectral peak velocity measurements - A phantom study.

OBJECTIVE: Ultrasound beams sometimes need to be steered from the edge of linear array transducers to reach the sample volume with a desired Doppler angle in vascular exams. This phantom study aims to evaluate the impact of apertures located at the array edge on peak velocity (PV) measurements. METHODS: Three ultrasound scanner systems equipped with eight transducers from 3 major ultrasound vendors were tested using a flow phantom with a horizontal tube. Five spectral Doppler measurements with the aperture positioned at one edge of the array and 5 with the aperture at the center of the array were obtained using all available scanner-transducer combinations while maintaining all scan parameters and the sample volume in the same tube location. Differences in PVs between center and edge apertures were compared across 4 constant flow rates. RESULTS: The averaged PVs for all phantom flow rates ranged from 24.4 cm/s to 138.2 cm/s from the array center. The averaged PVs from the center aperture were significantly greater than the corresponding measurements from the edge aperture for each flow rate (all p < 0.001). The relative PV differences ranged from 6.7% to 19.4% across all transducers and flow rates. CONCLUSION: Significantly lower PVs were consistently shown with the Doppler beam aperture at the array edge compared to center among all tested systems. This may be due to a narrower aperture width, shifted central axis, and less intrinsic spectral broadening error at the array edge. Controlling variations in Doppler aperture location is important in clinical applications which depend on consistent velocity measurements.