Nano-formulated delivery of active ingredients from traditional Chinese herbal medicines for cancer immunotherapy.

Cancer immunotherapy has garnered promise in tumor progression, invasion, and metastasis through establishing durable and memorable immunological activity. However, low response rates, adverse side effects, and high costs compromise the additional benefits for patients treated with current chemical and biological agents. Chinese herbal medicines (CHMs) are a potential treasure trove of natural medicines and are gaining momentum in cancer immunomodulation with multi-component, multi-target, and multi-pathway characteristics. The active ingredient extracted from CHMs benefit generalized patients through modulating immune response mechanisms. Additionally, the introduction of nanotechnology has greatly improved the pharmacological qualities of active ingredients through increasing the hydrophilicity, stability, permeability, and targeting characteristics, further enhancing anti-cancer immunity. In this review, we summarize the mechanism of active ingredients for cancer immunomodulation, highlight nano-formulated deliveries of active ingredients for cancer immunotherapy, and provide insights into the future applications in the emerging field of nano-formulated active ingredients of CHMs.

Discovery of new non-covalent and covalent inhibitors targeting SARS-CoV-2 papain-like protease and main protease.

Global coronavirus disease 2019 (COVID-19) pandemic still threatens human health and public safety, and the development of effective antiviral agent is urgently needed. The SARS-CoV-2 main protease (Mpro) and papain-like protease (PLpro) are vital proteins in viral replication and promising therapeutic targets. Additionally, PLpro also modulates host immune response by cleaving ubiquitin and interferon-stimulated gene product 15 (ISG15) from ISGylated host proteins. In this report, we identified [1,2]selenazolo[5,4-c]pyridin-3(2H)-one and benzo[d]isothiazol-3(2H)-one as attractive scaffolds of PLpro and Mpro inhibitors. The representative compounds 6c and 7e exhibited excellent PLpro inhibition with percent inhibition of 42.9% and 44.9% at 50 nM, respectively. The preliminary enzyme kinetics experiment and fluorescent labelling experiment results determined that 6c was identified as a covalent PLpro inhibitor, while 7e was a non-covalent inhibitor. Molecular docking and dynamics simulations revealed that 6c and 7e bound to Zn-finger domain of PLpro. Compounds 6c and 7e were also identified to potent Mpro inhibitors, and they exhibited potent antiviral activities in SARS-CoV-2 infected Vero E6 cells, with EC50 value of 3.9 µM and 7.4 µM, respectively. In addition, the rat liver homogenate half-life of 6c and 7e exceeded 24 h. These findings suggest that 6c and 7e are promising led compounds for further development of PLpro/Mpro dual-target antiviral drugs.

1,2-Isoselenazol-3(2H)-one derivatives as NDM-1 inhibitors displaying synergistic antimicrobial effects with meropenem on NDM-1 producing clinical isolates.

The New Delhi ß-Lactamase 1 (NDM-1), one of the most prevalent types of metallo-ß-lactamases, has attracted extensive attention since its discovery. Extensive efforts have been made to develop inhibitor of NDM-1, however, no inhibitor is available clinically so far. It is reported that Benzo[d][1,2]selenazol-3(2H)-one derivatives as covalent NDM-1 inhibitors can restore the efficacy of meropenem against NDM-1producing strains. In this study, 38 novel benzo or pyrido[d][1,2]selenazol-3(2H)-one derivatives were designed based on NDM-1 protein structure and structure-activity relationships study. Representative compound 15l exhibits significant synergistic antibacterial activity with meropenem against NDM-1 producing carbapenem-resistant Enterobacteriaceae (CRE) isolates, especially clinical CRE isolates (FIC indices ranging from 0.0625 to 0.25). ESI-MS analysis demonstrats that 15l covalently binds to NDM-1 enzyme, and the IC50 is 11.25 µM. In conclusion, this study has developed a novel scaffold with higher activity to enrich the structural types of benzo[d][1,2]selenazol-3(2H)-one derivatives. Compound 15l can be considered as a promising lead compound to restore the antibacterial effect of meropenem in combating life-threatening CRE.

Long-time measurements of line-integrated plasma electron density using a two-color homodyne optical fiber interferometer.

A two-color homodyne Mach-Zehnder (M-Z) optical fiber interferometer with wavelengths of 1.55 and 1.31 µm was developed for long-time measurement of line-integrated plasma electron density. A novel phase difference demodulation algorithm based on a single 3 × 3 optical coupler was implemented in a two-color optical fiber interferometer scheme for the first time. Our laboratory tests showed that this new optical fiber interferometer could determine the phase shift due to the low-frequency ambient vibration and could maintain high phase resolution measurement. The resolution of the new interferometer was less than 0.04 rad in 1000 s, corresponding to a line-averaged electron density of less than 1.0 × 1019 m-2. Actual plasma discharge experiments performed on KTX-CTI, which is a new compact torus injector (CTI) constructed at the Keda Torus eXperiment (KTX), showed that this interferometer has excellent several-second stability.

Measurement of density profile and fluctuations using a multi-channel terahertz solid-state interferometer system on Keda Torus eXperiment (KTX).

A five-chord interferometer based on terahertz solid state sources has been successfully installed on the Keda Torus eXperiment (KTX), a reversed field pinch machine. The optical design has been carefully optimized for the uniform distribution of beam light to fully use the limited power source (∼2 mW). By setting the telescopic mirror unit, the beam waist is located in the center of the vacuum vessel and its diameter is in the range of the Rayleigh length. The beam width across the plasma area is improved to ∼20 mm to minimize crosstalk and beam energy loss. After careful beam alignment, the phase noise for each channel can reach 0.004π. The radial profiles of electron density on the KTX are inverted, and density fluctuation associated with instabilities is shown based on the forward-scattering signals.

Hybrids of aurantiamide acetate and isopropylated genipin as potential anti-inflammatory agents: The design, synthesis, and biological evaluation.

A novel series of hybrids designed on the basis of aurantiamide acetate and isopropylated genipin were synthesized and biologically evaluated as anti-inflammatory agents. Among them, compound 7o exhibited the best inhibitory activity against TNF-α secretion (IC50  = 16.90 µM) and was selected for further in vitro and in vivo functional study. The results demonstrated that 7o was capable of suppressing the expression of LPS-induced iNOS and COX-2, as well as reducing the production of NO at the concentration of 5 µM, which may be resulted from its regulation of NF-κB signaling and MAPK signaling. Moreover, compound 7o exhibited favorable in vivo anti-inflammatory activity with an inhibition rate of 53.32% against xylene-induced ear swelling in mice at the dose of 5 mg/kg.

Optical fiber interferometer application for high electron density measurements on compact torus plasmas.

An optical fiber Mach-Zehnder interferometer at a wavelength of 1.55 µm has been developed for measurements of high electron density on compact torus (CT) plasmas with a high time resolution of 0.1 µs and high phase resolution of 6.4 × 10-4 rad. To improve density measurement accuracy, the phase noise of the interferometer has been investigated in detail and optimized. In the bench test, the interferometer was calibrated using a piezoelectric ceramic actuator with known stroke. Initial results on CT plasma show that the optical fiber interferometer provides reliable density measurements at two spatial locations and the bulk velocity of plasma can be determined by the method of time of flight.

Discovery of talmapimod analogues as polypharmacological anti-inflammatory agents.

Twenty novel talmapimod analogues were designed, synthesised and evaluated for the in vivo anti-inflammatory activities. Among them, compound 6n, the most potent one, was selected for exploring the mechanisms underlying its anti-inflammatory efficacy. In RAW264.7 cells, it effectively suppressed lipopolysaccharides-induced (LPS-induced) expressions of iNOS and COX-2. As illustrated by the western blot analysis, 6n downregulated both the NF-κB signalling and p38 MAPK phosphorylation. Further enzymatic assay identified 6n as a potent inhibitor against both p38α MAPK (IC50=1.95 µM) and COX-2 (IC50=0.036 µM). By virtue of the concomitant inhibition of p38α MAPK, its upstream effector, and COX-2, along with its capability to downregulate NF-κB and MAPK-signalling pathways, 6n, a polypharmacological anti-inflammatory agent, deserves further development as a novel anti-inflammatory drug.

Design, synthesis, biological evaluation and docking study of novel indole-2-amide as anti-inflammatory agents with dual inhibition of COX and 5-LOX.

In this work, a series of novel indole-2-amide compounds were designed, synthesized, characterized and the anti-inflammatory activity in vivo were evaluated. Compounds 8a, 10b, 12h, and 12l exhibited marked anti-inflammatory activity in 2,4-Dinitrofluorobenzenethe (DNFB) - induced mice auricle edema model. Further, compounds 8a, 10b and 12h exhibited potential in vitro COX-2 inhibitory activity (IC50 = 21.86, 23.3 and 23.21 nM, respectively), while the reference drug celecoxib was 11.20 nM. The most promising compound 10b was exhibited the highest selectivity for COX-2 (selectivity index (COX-1/COX-2) = 17.45) and moderate 5-LOX inhibitory activity (IC50 = 66 nM), which comparable to positive controlled zileuton (IC50 = 38.91 nM). In addition, the test results showed compounds 10b and 12h no significant cytotoxic activity on normal cells (RAW264.7). Further, at the active sites of the COX-1, COX-2 co-crystals, 3b and 4l showed higher binding forces in the molecular docking study, which consistent with the results of in vitro experiments. These results demonstrated that these compounds had dual inhibitory activity of COX/5-LOX, providing clues for further searching for safer and more effective anti-inflammatory drugs.

A parametric method for correcting polluted plasma current signal and its application on Keda Torus eXperiment.

We have developed a parametric method for eliminating the background component of the plasma current, which is measured by a Rogowski coil and polluted by the toroidal magnetic field in the vacuum vessel of the Keda Torus eXperiment (KTX) reversed field pinch (RFP) device. The method considers the toroidal magnetic field windings, the KTX vacuum chamber, and the Rogowski coil as a linear time-invariant system; in this case, a constant frequency response function characterizes the system. Using this response function, the current component caused by pollution from the toroidal magnetic field can be predicted exactly for an arbitrary input current to the toroidal magnetic field windings. Compared with the traditional proportional compensation method, the proposed method has great flexibility and universality and it is potentially applicable to cases in which the toroidal field current signal changes over time with plasma feedback signals. Furthermore, the method can be applied to other similarly affected signals, such as magnetic field signals. As an example, we have corrected the poloidal and toroidal magnetic field signals better to reveal the true physical processes for the RFP state.

An automatic beam alignment system based on relative reference points for Thomson scattering diagnosis system.

An automatic beam alignment system based on relative reference points is developed for the Thomson scattering system on Keda Torus eXperiment. Two critical apertures around the vacuum vessel are designed to shield stray light, and a probe beam is required to go through the centers of these two apertures, which are the reference points for alignment. Since these two apertures are coated with light absorbing materials, three fibers with glowing tips are employed to indicate the centers of two apertures. CMOS cameras are used to monitor beam deviations. The misalignment correction is achieved by driving piezomotor mirror mounts via a program developed with LabVIEW, which includes the image acquisition and processing module and the deviation correction module. As a result, this system can correct beam misalignment in less than 20 s and suppress the long-term drift of laser pointing in ±10 µrad. Also, this system has the capability to correct up to about 2.3 mm of camera shift with our experiment condition.

In situ relative self-dependent calibration of electron cyclotron emission imaging via shape matching.

Electron Cyclotron Emission Imaging (ECEI) is a diagnostic system which measures 2-D electron temperature profiles with high spatial-temporal resolution. Usually only the normalized electron temperature fluctuations are utilized to investigate the magnetohydrodynamics modes due to the difficulties of ECEI calibration. In this paper, we developed a self-dependent calibration method for 24 × 16 channel high-resolution ECEI on the Experimental Advanced Superconducting Tokamak. The technique of shape matching is applied to solve for the matrix of the calibration coefficients. The calibrated area is further expanded to an occupation ratio of 88% observation area by utilizing the features of sawtooth crash. The result is self-consistent and consistent with calibrated 1D ECE measurement.

Diagnostic capacity of electron cyclotron emission imaging system with continuous large observation area on EAST tokamak.

Electron cyclotron emission imaging on EAST provides direct measurements of the 2-D electron temperature dynamics in a continuous large observation area with high temporal and spatial resolution. Besides the normal MHD investigation, a system with a view field large enough to cover the core plasma region has been applied to extract more plasma information, such as the plasma center location, the deposition location of auxiliary heating, and the core toroidal rotation speed. These results solely based on electron cyclotron emission imaging (ECEI) data are consistent with the results of the equilibrium fitting (EFIT), numerical code, and other diagnostics, which indicate the powerful diagnostic capacity of this ECEI system.

Electromagnetic diagnostic system for the Keda Torus eXperiment.

A system for electromagnetic measurements was designed and installed on the Keda Torus eXperiment (KTX) reversed field pinch device last year. Although the unique double-C structure of the KTX, which allows the machine to be opened easily without disassembling the poloidal field windings, makes the convenient replacement and modification of the internal inductive coils possible, it can present difficulties in the design of flux coils and magnetic probes at the two vertical gaps. Moreover, the KTX has a composite shell consisting of a 6 mm stainless steel vacuum chamber and a 1.5 mm copper shell, which results in limited space for the installation of saddle sensors. Therefore, the double-C structure and composite shell should be considered, especially during the design and installation of the electromagnetic diagnostic system (EDS). The inner surface of the vacuum vessel includes two types of probes. One type is for the measurement of the global plasma parameters, and the other type is for studying the local behavior of the plasma and operating the new saddle coils. In addition, the probes on the outer surface of the composite shell are used for measurements of eddy currents. Finally, saddle sensors for radial field measurements for feedback control were installed between the conducting shell and the vacuum vessel. The entire system includes approximately 1100 magnetic probes, 14 flux coils, 4×26×2 saddle sensors, and 16 Rogowski coils. Considering the large number of probes and limited space available in the vacuum vessel, the miniaturization of the probes and optimization of the probe distribution are necessary. In addition, accurate calibration and careful mounting of the probes are also required. The frequency response of the designed magnetic probes is up to 200 kHz, and the resolution is 1 G. The EDS, being spherical and of high precision, is one of the most basic and effective diagnostic tools of the KTX and meets the demands imposed by requirements on basic machine operating information and future studies.

A multi-channel capacitive probe for electrostatic fluctuation measurement in the Madison Symmetric Torus reversed field pinch.

A 40-channel capacitive probe has been developed to measure the electrostatic fluctuations associated with the tearing modes deep into Madison Symmetric Torus (MST) reversed field pinch plasma. The capacitive probe measures the ac component of the plasma potential via the voltage induced on stainless steel electrodes capacitively coupled with the plasma through a thin annular layer of boron nitride (BN) dielectric (also serves as the particle shield). When bombarded by the plasma electrons, BN provides a sufficiently large secondary electron emission for the induced voltage to be very close to the plasma potential. The probe consists of four stalks each with ten cylindrical capacitors that are radially separated by 1.5 cm. The four stalks are arranged on a 1.3 cm square grid so that at each radial position, there are four electrodes forming a square grid. Every two adjacent radial sets of four electrodes form a cube. The fluctuating electric field can be calculated by the gradient of the plasma potential fluctuations at the eight corners of the cube. The probe can be inserted up to 15 cm (r/a = 0.7) into the plasma. The capacitive probe has a frequency bandwidth from 13 Hz to 100 kHz, amplifier-circuit limit, sufficient for studying the tearing modes (5-30 kHz) in the MST reversed-field pinch.

The eddy current probe array for Keda Torus eXperiment.

In a reversed field pinch device, the conductive shell is placed as close as possible to the plasma so as to balance the plasma during discharge. Plasma instabilities such as the resistive wall mode and certain tearing modes, which restrain the plasma high parameter operation, respond closely with conditions in the wall, in essence the eddy current present. Also, the effect of eddy currents induced by the external coils cannot be ignored when active control is applied to control instabilities. One diagnostic tool, an eddy current probe array, detects the eddy current in the composite shell. Magnetic probes measuring differences between the inner and outer magnetic fields enable estimates of the amplitude and angle of these eddy currents. Along with measurements of currents through the copper bolts connecting the poloidal shield copper shells, we can obtain the eddy currents over the entire shell. Magnetic field and eddy current resolutions approach 2 G and 6 A, respectively. Additionally, the vortex electric field can be obtained by eddy current probes. As the conductivity of the composite shell is high, the eddy current probe array is very sensitive to the electric field and has a resolution of 0.2 mV/cm. In a bench test experiment using a 1/4 vacuum vessel, measurements of the induced eddy currents are compared with simulation results based on a 3D electromagnetic model. The preliminary data of the eddy currents have been detected during discharges in a Keda Torus eXperiment device. The typical value of toroidal and poloidal eddy currents across the magnetic probe coverage rectangular area could reach 3.0 kA and 1.3 kA, respectively.

Compact and lightweight support platform with electromagnetic disturbance elimination for interferometer on reversed field pinch Keda Torus eXperiment.

A compact and lightweight support platform has been used as a holder for the interferometer system on the Keda Torus eXperiment (KTX), which is a reversed field pinch device. The vibration caused by the interaction between the time-varying magnetic field and the induced current driven in the metal optical components has been measured and, following comparison with the mechanical vibration of the KTX device and the refraction effect of the ambient turbulent air flow, has been identified as the primary vibration source in this case. To eliminate this electromagnetic disturbance, nonmetallic epoxy resin has been selected as the material for the support platform and the commercially available metal optical mounts are replaced. Following these optimization steps and mechanical reinforcements, the stability of the interferometer platform has improved significantly. The phase shift caused by the vibration has been reduced to the level of background noise.

Design of interferometer system for Keda Torus eXperiment using terahertz solid-state diode sources.

A solid-state source based terahertz (THz) interferometer diagnostic system has been designed and characterized for the Keda Torus eXperiment (KTX). The THz interferometer utilizes the planar diodes based frequency multiplier (X48) to provide the probing beam at fixed frequency 0.650 THz, and local oscillator is provided by an independent solid-state diode source with tunable frequency (0.650 THz +/- 10 MHz). Both solid-state sources have approximately 1 mW power. The planar-diode mixers optimized for high sensitivity, ∼750 mV/mW, are used in the heterodyne detection system, which permits multichannel interferometer on KTX with a low phase noise. A sensitivity of ⟨nel⟩min = 4.5 × 10(16) m(-2) and a temporal resolution of 0.2 µs have been achieved during the initial bench test.

Woltjer-Taylor state without Taylor's conjecture: plasma relaxation at all wavelengths.

In the process of dissipative relaxation, there is strong astrophysical and laboratory evidence that plasmas tend to evolve towards the well-known Woltjer-Taylor state, specified by [nabla]×B=αB for constant α. To explain how such a state is reached, Taylor developed his famous theory based on the conjecture that relaxation is dominated by short wavelength fluctuations. However, there is no conclusive experimental or numerical evidence in support of Taylor's conjecture. A new theory is developed, which predicts that the system will evolve towards the Woltjer-Taylor state for an arbitrary fluctuation spectrum.