Self-Assembled STING-Activating Coordination Nanoparticles for Cancer Immunotherapy and Vaccine Applications.

The cGAS-STING pathway plays a crucial role in innate immune activation against cancer and infections, and STING agonists based on cyclic dinucleotides (CDN) have garnered attention for their potential use in cancer immunotherapy and vaccines. However, the limited drug-like properties of CDN necessitate an efficient delivery system to the immune system. To address these challenges, we developed an immunostimulatory delivery system for STING agonists. Here, we have examined aqueous coordination interactions between CDN and metal ions and report that CDN mixed with Zn2+ and Mn2+ formed distinctive crystal structures. Further pharmaceutical engineering led to the development of a functional coordination nanoparticle, termed the Zinc-Mn-CDN Particle (ZMCP), produced by a simple aqueous one-pot synthesis. Local or systemic administration of ZMCP exerted robust antitumor efficacy in mice. Importantly, recombinant protein antigens from SARS-CoV-2 can be simply loaded during the aqueous one-pot synthesis. The resulting ZMCP antigens elicited strong cellular and humoral immune responses that neutralized SARS-CoV-2, highlighting ZMCP as a self-adjuvant vaccine platform against COVID-19 and other infectious pathogens. Overall, this work establishes a paradigm for developing translational coordination nanomedicine based on drug-metal ion coordination and broadens the applicability of coordination medicine for the delivery of proteins and other biologics.

STING agonist-loaded mesoporous manganese-silica nanoparticles for vaccine applications.

Cyclic dinucleotides (CDNs), as one type of Stimulator of Interferon Genes (STING) pathway agonist, have shown promising results for eliciting immune responses against cancer and viral infection. However, the suboptimal drug-like properties of conventional CDNs, including their short in vivo half-life and poor cellular permeability, compromise their therapeutic efficacy. In this study, we have developed a manganese-silica nanoplatform (MnOx@HMSN) that enhances the adjuvant effects of CDN by achieving synergy with Mn2+ for vaccination against cancer and SARS-CoV-2. MnOx@HMSN with large mesopores were efficiently co-loaded with CDN and peptide/protein antigens. MnOx@HMSN(CDA) amplified the activation of the STING pathway and enhanced the production of type-I interferons and other proinflammatory cytokines from dendritic cells. MnOx@HMSN(CDA) carrying cancer neoantigens elicited robust antitumor T-cell immunity with therapeutic efficacy in two different murine tumor models. Furthermore, MnOx@HMSN(CDA) loaded with SARS-CoV-2 antigen achieved strong and durable (up to one year) humoral immune responses with neutralizing capability. These results demonstrate that MnOx@HMSN(CDA) is a versatile nanoplatform for vaccine applications.

Effects of ultrasound combined with microbubbles on intracellular Ca 2+ homeostasis in carboplatin-treated microenvironment of A549 cell line / 中华超声影像学杂志

Objective To investigate the effects of ultrasound combined with microbubbles on intracellular Ca2+ homeostasis in carboplatin ( CBP )-treated A549 cell and its possible mechanisms of inhibiting A549 cell line activity . Methods According to whether SonoVue was used or not ,and the different dose of CBP ,the groups A-F were arranged as the ultrasound(US) group(group A) ,the ultrasound combined with microbubbles ( USMB) group( group B) ,the low dose CBP ( 100 μg/ml) + US group( group C) ,the low dose CBP+USMB group( group D) ,the high dose CBP ( 200 μg/ml)+ US group ( group E) and the high dose CBP+USMB group( group F) .A549 cells were bathed and washed by a calcium-free buffer , loaded with Ca2+ indicator fluo-4 AM . Real-time images were acquired using laser confocal microscopy .The fluorescence intensity of intracellular calcium ion concentration ([Ca2+ ]i) in individual living cell was observed and the calcium overload was analyzed . Results After ultrasound irradiation ,the normalized fluorescence intensity of [Ca2+ ]i increased rapidly ,then returned to a new homeostasis (selected cells in groups A ,B ,E ,F) or experienced a second calcium oscillation ( some cells in group C and D) . All the selected cells in group B and some cells in group C and D exhibited superimposed oscillations . The calcium overloading time in group D was longer than those of any other groups . Four cells in group A experienced delayed calcium oscillations . Compared with group A ,the selected cells in other groups exhibited a larger amplitude of calcium oscillation( all P < 0 .05) and the selected cells in group B and D exhibited calcium oscillation for a longer period of time( all P <0 .05) . Conclusions In the calcium-free buffer ,US ,USMB , CBP+ US ,CBP + USMB are direct stimuli of calcium overload in A 549 cells . SonoVue ,CBP ,CBP +SonoVue are all synergistic stimuli of calcium overload in A 549 cells irradiated by ultrasound .US ,USMB and CBP may synergistically induce calcium release from intracellular store sites in A 549 cells . Calcium overload is a possible mechanism of ultrasound combined with microbubbles in assisting CBP chemotherapy .

Effects of ultrasound combined with microbubbles on intracellular Ca 2+ homeostasis in carboplatin‐treated microenvironment of A549 cell line / 中华超声影像学杂志

To investigate the effects of ultrasound combined with microbubbles on intracellular Ca2+ homeostasis in carboplatin ( CBP )‐treated A549 cell and its possible mechanisms of inhibiting A549 cell line activity . Methods According to whether SonoVue was used or not ,and the different dose of CBP ,the groups A‐F were arranged as the ultrasound( US) group( group A ) ,the ultrasound combined with microbubbles ( USMB) group( group B) ,the low dose CBP ( 100 μg/ml) + US group( group C) ,the low dose CBP+USMB group( group D) ,the high dose CBP ( 200 μg/ml)+ US group ( group E) and the high dose CBP+USMB group( group F) .A549 cells were bathed and washed by a calcium‐free buffer , loaded with Ca2+ indicator fluo‐4 AM . Real‐time images were acquired using laser confocal microscopy . T he fluorescence intensity of intracellular calcium ion concentration ( [ Ca 2+ ] i ) in individual living cell was observed and the calcium overload was analyzed . Results After ultrasound irradiation ,the normalized fluorescence intensity of [ Ca2+ ] i increased rapidly ,then returned to a new homeostasis ( selected cells in groups A ,B ,E ,F ) or experienced a second calcium oscillation ( some cells in group C and D ) . All the selected cells in group B and some cells in group C and D exhibited superimposed oscillations . T he calcium overloading time in group D was longer than those of any other groups . Four cells in group A experienced delayed calcium oscillations . Compared with group A ,the selected cells in other groups exhibited a larger amplitude of calcium oscillation ( all P ＜ 0 .05 ) and the selected cells in group B and D exhibited calcium oscillation for a longer period of time( all P ＜0 .05) . Conclusions In the calcium‐free buffer ,US ,USMB , CBP+ US ,CBP + USMB are direct stimuli of calcium overload in A 549 cells . SonoVue ,CBP ,CBP +SonoVue are all synergistic stimuli of calcium overload in A 549 cells irradiated by ultrasound .US ,USMB and CBP may synergistically induce calcium release from intracellular store sites in A 549 cells . Calcium overload is a possible mechanism of ultrasound combined with microbubbles in assisting CBP chemotherapy .

A wearable multi-pad electrode prototype for selective functional electrical stimulation of upper extremities.

In this paper, a surface multi-pad stimulation electrode with selective characteristics was designed, it was safe to use and easy to mount. Then a wearable and distributed multi-pad functional electrical stimulation (FES) prototype combined with sensing, communication and smart technology was designed, which can achieve a fast, intelligent optimization to determine stimulation electrode sites and comfortable stimulation. In addition, in order to improve the application and convenience of FES in the rehabilitation at clinical and home-setting, an Android application (APP) based on smart phone was designed for running an algorithm of searching optimal stimulation site. The prototype has been validated by performing selective stimulation on one healthy subject, and showed that the FES system can automatically determine the stimulation site.

System design and experimental research of lower esophageal sphincter stimulator for treatment of gastroesophageal reflux disease.

Electrical stimulation therapy (EST) of lower esophageal sphincters (LES) is a new technique for the treatment of gastroesophageal reflux disease (GERD). In this paper, an implantable LES stimulator with wireless power transmission is proposed for the treatment of GERD. The LES stimulator is composed of an implantable pulse generator (IPG), an external controller, and a wireless power transmission module. The IPG, whose area is 31×21 mm2, is designed to generate voltage-regulated constant-current stimulation pulses. The external controller allows for wireless programming of the IPG via a Bluetooth Low Energy (BLE) module. The wireless power transmission module provides power for the IPG. According to the measurement of output stimulus waveforms, the proposed LES stimulator is capable of delivering electrical stimulations with a current ranging between 0 and 8 mA. To evaluate the safety and efficacy of the proposed LES stimulator, experiments were performed on 12 male New Zealand white rabbits. Esophageal manometry was performed before and after the procedure and the LES pressure (LESP) has been recorded. The mean LESP is increased significantly in the stimulation group than the sham group (stimulation group: 9.25±1.24 mmHg vs 13.99 ±1.28 mmHg, p<;0.05; sham group: 9.00±1.22 mmHg vs 9.23±1.27 mmHg, p=0.267). The results show that the electrical stimulation delivered by the LES stimulator can safely and effectively increase resting LES pressure in acute animal models, suggesting that the implantable LES stimulator is a perspective approach for treating GERD in clinics.

Proteomic signature of muscle fibre hyperplasia in response to faba bean intake in grass carp.

Fish muscle growth is important for the rapidly developing global aquaculture industry, particularly with respect to production and quality. Changes in muscle fibre size are accomplished by altering the balance between protein synthesis and proteolysis. However, our understanding regarding the effects of different protein sources on fish muscle proteins is still limited. Here we report on the proteomic profile of muscle fibre hyperplasia in grass carp fed only with whole faba bean. From the results, a total of 99 significantly changed proteins after muscle hyperplasia increase were identified (p < 0.05, ratio <0.5 or >2). Protein-protein interaction analysis demonstrated the presence of a network containing 56 differentially expressed proteins, and muscle fibre hyperplasia was closely related to a protein-protein network of 12 muscle component proteins. Muscle fibre hyperplasia was also accompanied by decreased abundance in the fatty acid degradation and calcium signalling pathways. In addition, metabolism via the pentose phosphate pathway decreased in grass carp after ingestion of faba bean, leading to haemolysis. These findings could provide a reference for the prevention and treatment of human glucose-6-phosphate dehydrogenase deficiency ("favism").

Application of multi-function moxibustion couch and its developing significance / 中国针灸

The basic structure and application manipulations of the multi-function moxibustion couch are introduced in this article. The designation of the couch is reasonable and its structure is simple. With easy manipulations and simple application, fumigation and moxibustion therapy is fulfilled by the moxa roll ignited under the couch. It has the characteristics of heat and medicine concentrating with strong penetration and extensive application area. And it can be applied especially on pain of the neck, shoulder, low back and leg, diseases of stomach and intestines, complicated gynaecological diseases as well as on health keeping.

Study on signal transmission characteristics of meridian based on electrical network theory and experiments / 中国针灸

Study on features of acupoints with resistance test in the past half century is reviewed in this article. Mechanism and technology of the method are introduced as well as its shortcomings. The determination method of signal transmission along meridians with the combination of electrical network theories and practice is advanced. And the result of a series experiments on one meridian at the superficial part of the body are given as well. Thus, it is concluded that the signals of the point-in/point-out and the signals along a non-meridian path with the same distance are significantly different, which gives a verification of the feasibility of the method by using electrical network theories to set out characteristics of signal transmission along meridians dynamically.