Pyroptotic-Spatiotemporally Selective Delivery of siRNA against Pyroptosis and Autoimmune Diseases.

Small-interfering RNAs (siRNAs) offer promising prospects for treating pyroptosis-related autoimmune diseases. However, poor stability and off-target effects during in vivo transportation hinder their practical clinical applications. Precision delivery and adaptive release of siRNAs into inflamed tissues and immune cells could unleash their full therapeutic potential. This study establishes a pyroptotic-spatiotemporally selective siRNA delivery system (PMRC@siGSDME) that selectively targets inflammatory tissues, responds to pyroptosis, and exhibits remarkable therapeutic efficacy against various autoimmune diseases. Novel hybrid nanovesicles (NVs) are designed as a combination of pyroptotic macrophage membranes (PMs) and R8-cardiolipin-containing nanovesicles (RC-NVs). Evidence provides that PM-derived proteins involved in cell-cell interactions and membrane trafficking may contribute to the specificity of NVs to inflammatory tissue. In addition, cardiolipin anchored in the hybrid NVs increases its affinity for activated gasdermin E (GSDME) and achieves pyroptosis-adaptive release of siGSDME for the spatiotemporally selective suppression of immune responses. More importantly, PMRC@siGSDME displays significant anti-inflammatory and therapeutic effects in multiple mouse autoimmune disease models, including arthritis and inflammatory bowel disease (IBD). Collectively, an innovative siRNA delivery strategy precisely tailored for pyroptotic cells has been developed, paving the way for new treatments for autoimmune inflammatory diseases with minimal side effects and wide clinical applicability.

Self-adaptive pyroptosis-responsive nanoliposomes block pyroptosis in autoimmune inflammatory diseases.

Nanoliposomes have a broad range of applications in the treatment of autoimmune inflammatory diseases because of their ability to considerably enhance drug transport. For their clinical application, nanoliposomes must be able to realize on-demand release of drugs at disease sites to maximize drug-delivery efficacy and minimize side effects. Therefore, responsive drug-release strategies for inflammation treatment have been explored; however, no specific design has been realized for a responsive drug-delivery system based on pyroptosis-related inflammation. Herein, we report a pioneering strategy for self-adaptive pyroptosis-responsive liposomes (R8-cardiolipin-containing nanoliposomes encapsulating dimethyl fumarate, RC-NL@DMF) that precisely release encapsulated anti-pyroptotic drugs into pyroptotic cells. The activated key pyroptotic protein, the N-terminal domain of gasdermin E, selectively integrates with the cardiolipin of liposomes, thus forming pores for controlled drug release, pyroptosis, and inflammation inhibition. Therefore, RC-NL@DMF exhibited effective therapeutic efficacies to alleviate autoimmune inflammatory damages in zymosan-induced arthritis mice and dextran sulfate sodium-induced inflammatory bowel disease mice. Our novel approach holds great promise for self-adaptive pyroptosis-responsive on-demand drug delivery, suppressing pyroptosis and treating autoimmune inflammatory diseases.

Comparison of the ability of exosomes and ectosomes derived from adipose-derived stromal cells to promote cartilage regeneration in a rat osteochondral defect model.

BACKGROUND: Extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) offer promising prospects for stimulating cartilage regeneration. The different formation mechanisms suggest that exosomes and ectosomes possess different biological functions. However, little attention has been paid to the differential effects of EV subsets on cartilage regeneration. METHODS: Our study compared the effects of the two EVs isolated from adipose-derived MSCs (ASCs) on chondrocytes and bone marrow-derived MSCs (BMSCs) in vitro. Additionally, we loaded the two EVs into type I collagen hydrogels to optimize their application for the treatment of osteochondral defects in vivo. RESULTS: In vitro experiments demonstrate that ASC-derived exosomes (ASC-Exos) significantly promoted the proliferation and migration of both cells more effectively than ASC-derived ectosomes (ASC-Ectos). Furthermore, ASC-Exos facilitated a stronger differentiation of BMSCs into chondrogenic cells than ASC-Ectos, but both inhibited chondrocyte apoptosis to a similar extent. In the osteochondral defect model of rats, ASC-Exos promoted cartilage regeneration in situ better than ASC-Ectos. At 8 weeks, the hydrogel containing exosomes group (Gel + Exo group) had higher macroscopic and histological scores, a higher value of trabecular bone volume fraction (BV/TV), a lower value of trabecular thickness (Tb.Sp), and a better remodeling of extracellular matrix than the hydrogel containing ectosomes group (Gel + Ecto group). At 4 and 8 weeks, the expression of CD206 and Arginase-1 in the Gel + Exo group was significantly higher than that in the Gel + Ecto group. CONCLUSION: Our findings indicate that administering ASC-Exos may be a more effective EV strategy for cartilage regeneration than the administration of ASC-Ectos.

Electroacupuncture prevents the development or establishment of chronic pain via IL-33/ST2 signaling in hyperalgesic priming model rats.

BACKGROUND: Chronic pain is acomplexhealth issue. Compared to acute pain, which has a protective value, chronic pain is defined as persistent pain after tissue injury. Few clinical advances have been made to prevent the transition from acute to chronic pain. Electroacupuncture (EA), the most common form of acupuncture, is widely used in clinical practice to relieve pain. METHODS: The hyperalgesic priming model, established via a carrageenan injection followed by a prostaglandin E2 injection, was used to investigate the development or establishment of chronic pain. We observed the hyperalgesic effect of EA on rats and investigated the expression p38 mitogen-activated protein kinase, interleukin-33 (IL-33), and its receptor ST2 in astrocytes in the L4-L6 spinal cord dorsal horns (SDHs) after EA. The IL-33/ST2 signaling pathway in SDH is associated with the development of chronic pain. RESULTS: EA can reverse the pain threshold in hyperalgesic priming model rats and regulates the expression of phosphorylated p38, IL-33, and ST2 in astrocytes in the L4-L6 SDHs. We discovered that EA raises the pain threshold. This suggests that EA can prevent the development or establishment of chronic pain by inhibiting IL-33/ST2 signaling in the lower central nervous system. CONCLUSIONS: EA can alleviate the development or establishment of chronic pain by modulating IL-33/ST2 signaling in SDHs. Our findings will help clinicians understand the mechanisms of EA analgesia.

Laboratory and Greenhouse Performance of Five Commercial Light Traps for Capturing Mosquitoes in China.

Mosquito light traps for household use are popular because they are small, cheap, user friendly, and environment friendly. At present, there are many variations and specifications of mosquito traps intended for household use on the market. The light traps claim they are powerful, but research and evaluation are lacking. Key parameters such as capture rates in the laboratory and field of 5 popular mosquito traps were evaluated as intended for household use. This study found that in the laboratory experiments, the capture rate of the mosquito traps selected was between 34.7% and 65.0%. Field tests in greenhouses found that the 5 mosquito traps had high catch rates for Culex quinquefasciatus. The percentage of Cx. quinquefasciatus, Aedes albopictus, Anopheles sinensis, and other flying insects captured was 51.76%, 25.29%, 14.12%, and 8.82%, respectively. There was no significant difference in the capture rate of Ae. albopictus and An. sinensis by the 5 mosquito traps in the greenhouse, but a significant difference in the catch rate of Cx. quinquefasciatus. The analysis showed that the fan speed and design of the air guide of the traps are important factors that affect the mosquito catch rate and that the ultraviolet wavelength (395-400 nm) used by the traps did not impact mosquito catch rates. Therefore, the mosquito traps intended for household use can be improved by adjusting the fan speed and optimizing the air guide.

Electroacupuncture Alleviates Experimental Chronic Inflammatory Pain by Inhibiting Calcium Voltage-Gated Channel-Mediated Inflammation.

BACKGROUND: Both experimental and clinical studies have shown that electroacupuncture (EA) administration ameliorates chronic inflammatory pain (CIP). However, the multifaceted mechanism underlying the effects of EA on CIP is poorly understood. In this study, the mRNA transcriptome was used to study various therapeutic targets of EA. METHODS: Using RNA-sequencing, protein-coding mRNA expression profiles of the L4-L5 dorsal root ganglion (DRG) were examined in the control (CN), complete Freund's adjuvant- (CFA-) induced CIP, and EA-treated CIP groups. A series of bioinformatics analyses was performed; "EA-reversed upregulated genes with CIP" (up-DEGs) and "EA-reversed downregulated genes with CIP" (down-DEGs) were identified. Thereafter, based on up-DEGs and down-DEGs, biological functions and signaling pathways were enriched using gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway analyses. RESULTS: In total, 189 DEGs were identified, including 134 up- and 55 down-DEGs, which were enriched in arachidonic acid metabolism (rno00590), glutamatergic synapse (rno04724), serotonergic synapse (rno04726), FoxO signaling pathway (rno04068), insulin signaling pathway (rno04910), amyotrophic lateral sclerosis (rno05014), cholinergic synapse (rno04725), ECM-receptor interaction (rno04512), and choline metabolism in cancer (rno05231). CONCLUSION: We identified a few GOs, pathways, and genes that could play key roles in the amelioration of CIP by EA. Hence, this study may provide a theoretical basis for CIP amelioration by EA.

Hamstring Co-Contraction in the Early Stage of Rehabilitation After Anterior Cruciate Ligament Reconstruction: A Longitudinal Study.

OBJECTIVE: Hamstring co-contraction may affect recovery from anterior cruciate ligament reconstruction. The aim of the study was to evaluate the changes in hamstring co-contraction during the early postoperative stages. DESIGN: Twenty-five patients with anterior cruciate ligament reconstruction were followed up for 1-3 mos postoperatively, during which the Lysholm and International Knee Documentation Committee questionnaires were completed and surface electromyograms were assessed during terminal knee extension maximum voluntary contraction and step-up tests. The integrated electromyogram of the tested muscles and co-contraction ratio were analyzed. RESULTS: Co-contraction ratio during terminal knee extension maximum voluntary contraction at 3 mos postoperatively was significantly less than that at 1 mo postoperatively (P < 0.0083), and it did not significantly differ from that of the uninvolved knee. In contrast, the co-contraction ratio during step-up was significantly higher at 2 and 3 mos postoperatively than that before surgery (P < 0.0167) and for the uninvolved knee (P < 0.05). Moreover, the postoperative hamstring co-contraction ratio in patients with a chronic injury was significantly higher during the step-up test than in patients with an early injury (P = 0.017). CONCLUSIONS: Hamstring co-contraction ratio during terminal knee extension maximum voluntary contraction recovers during the early postoperative stages. However, hamstring co-contraction ratio during step-up, which may be related to knee joint proprioception, remains high, particularly for patients with a chronic injury. CLINICAL TRIAL: ChiCTR-COC-17011167.

[Ingredients of Shuanghuanglian injection powder permeation through placental barrier of rat in pregnancy].

OBJECTIVE: Use HPLC to study the permeation of ingredients of Shuanghuanglian injection powder (SHL) through placental barriers of rats at different stages of pregnancy. METHOD: The pregnant rats were administered SHL for 5 d through caudalis vena at different stages of pregnancy. Plasma and embryonic tissues were obtained 12 h after the final administration of SHL. The componds in biological specimen were identified by HPLC. RESULT: Baicalin, luteolin and wogonoside were the main compounds in plasma. Wogonoside retained in first trimester embryonic tissues, and baicalin retained in the embryonic tissues of different pregnant stages. CONCLUSION: Baicalin is the main compound of SHL through placental barriers of rats. Embryotoxicity of baicalin should be considered as the key point to evaluate the safety of SHL.