Mast cells (MCs) play a significant role in various diseases, and their activation and degranulation can trigger inflammatory responses and barrier damage. Several studies have indicated that vagus nerve stimulation (VNS) exerts ameliorates neurological injury, and regulates gut MC degranulation. However, there is limited research on the modulatory effect of VNS on MCs in both the gut and brain in brain ischemia-reperfusion (I/R) injury in this process. We aim to develop a minimally invasive, targeted and convenient VNS approach to assess the impact of VNS and to clarify the relationship between VNS and MCs on the prognosis of acute ischemic stroke. We utilized middle cerebral artery occlusion/reperfusion (MCAO/r) to induce brain I/R injury. After the experiment, the motor function and neurofunctional impairments of the rats were detected, and the gastrointestinal function, blood-brain barrier (BBB) and intestinal barrier damage, and systemic and local inflammation were evaluated by Nissl, TTC staining, Evans blue, immunofluorescence staining, transmission electron microscopy, western blot assays, ELISA, and fecal 16S rRNA sequencing methods. Our research confirmed that our minimally invasive VNS method is a novel approach for stimulating the vagus nerve. VNS alleviated motor deficits and gastrointestinal dysfunction while also suppressing intestinal and neuroinflammation. Additionally, VNS ameliorated gut microbiota dysbiosis in rats. Furthermore, our analysis indicated that VNS reduces chymase secretion by modulating MCs degranulation and improves intestinal and BBB damage. Our results showed that VNS treatment can alleviate the damage of BBB and colonic barrier after cerebral I/R by modulating mast cell degranulation, and alleviates systemic inflammatory responses.

Modern lifestyles have altered diet and metabolic homeostasis, with increased sugar intake, glycemic index, and prediabetes. A strong positive correlation between sugar consumption and diabetic incidence is revealed, but the underlying mechanisms remain obscure. Here we show that oral intake of long-term oscillating glucose (LOsG) (4 times/day) for 38 days, which produces physiological glycemic variability in rats, can lead to β-cells gaining metabolic memory in reactive oxygen species (ROS) stress. This stress leads to suppression of forkhead box O1 (FoxO1) signaling and subsequent upregulation of thioredoxin interacting protein, inhibition of insulin and SOD-2 expression, re-expression of Neurog3, and β-cell dedifferentiation and functional failure. LOsG-treated animals develop prediabetes exhibiting hypoinsulinemia and glucose intolerance. Dynamic and timely administration of antioxidant glutathione prevents LOsG/ROS-induced β-cell failure and prediabetes. We propose that ROS stress is the initial step in LOsG-inducing prediabetes. Manipulating glutathione-related pathways may offer novel options for preventing the occurrence and development of diabetes.

A predictive model for Corona Virus Disease 2019

Objective: Preeclampsia (PE) is a serious condition affecting pregnant women and placing both the mother and fetus at risk. While little is known about the pathogenesis of PE, there is evidence for involvement from the maternal innate immune system, specifically, signaling arising from monocytes. The present study was to explore the role of Toll-like receptor (TLR) 4 on peripheral blood monocyte in the pathogenesis of PE. Methods: This study included 22 patients with established preeclampsia and 23 healthy pregnant women (HP). All participants gave informed written consent for 4 mL of fresh venous blood to be collected into a tube containing heparin. The expression of TLR4 on monocytes was evaluated by flow cytometry (FCM). Monocytes were stimulated with LPS for 18 h and cytokine secretion (IL-6, IL-12P70, IL-10, and TNF-α) in supernatants was analyzed with Luminex platform (Luminex Corporation, Austin, TX). The expression of TLR4 and cytokine secretion (IL-6, IL-12P70, IL-10, and TNF-α) was compared between women with PE and healthy pregnant women. Results: Compared with controls, the percentage of TLR4+ monocytes was significantly higher in PE patients. Collected monocytes stimulated with lipopolysaccharide (LPS) to induce inflammation had increased cytokine production, and monocytes from PE patients produced more IL-6 and TNF-α, and less IL-10 than cells from healthy participants. PE patients also showed a positive correlation between the percentage of TLR4+ monocytes and serum levels of IL-6 and TNFα. Conclusions: These results suggest that TLR4 signaling may play a role in the pathogenesis of preeclampsia.

Regulatory CD19⁺CD24^hiCD27⁺ B cells were proved to be numerically decreased and functionally impaired in the peripheral blood (PB) from rheumatoid arthritis (RA), with the potential of converting into osteoclast-priming cells. However, the distribution and function of CD19⁺CD24^hiCD27⁺ B cells in RA synovial fluid (SF) were unclear. In this study, we investigated whether RA SF CD19⁺CD24^hiCD27⁺ B cells were increased and associated with bone destruction. We found that the proportion of RA SF CD19⁺CD24^hiCD27⁺ B cells was increased significantly, and was positively correlated with swollen joint counts, tender joint counts and disease activity. CXCL12, CXCL13, CCL19 contributed to the recruitment of CD19⁺CD24^hiCD27⁺ B cells in RA SF. Notably, CD19⁺CD24^hiCD27⁺ B cells in the SF from RA expressed significantly more RANKL compared to OA and that in the PB from RA. Critically, RA CD19⁺CD24^hiCD27⁺ B cells promoted osteoclast (OC) differentiation in vitro, and the number of OCs was higher in cultures with RA SF CD19⁺CD24^hiCD27⁺ B cells than in those derived from RA PB. Collectively, these findings revealed the accumulation of CD19⁺CD24^hiCD27⁺ B cells in SF and their likely contribution to joint destruction in RA. Modulating the status of CD19⁺CD24^hiCD27⁺ B cells might provide novel therapeutic strategies for RA.