Ferulic acid suppresses the inflammation and apoptosis in Kawasaki disease through activating the AMPK/mTOR/NF-κB pathway.

Background: Kawasaki disease (KD) is a self-limiting and acute systemic vasculitis of unknown etiology, mainly affecting children. Ferulic acid (FA), a natural phenolic substance, has multiple pharmacological properties, including anti-inflammatory, anti-apoptosis, and anti-fibrosis, and so on. So far, the protective effects of FA on KD have not been explored. Methods: In this study, we established Candida albicans water soluble fraction (CAWS)-induced mouse coronary artery vasculitis of KD model and the tumor necrosis factor α (TNF-α)-induced human umbilical vein endothelial cells (HUVECs) injury model to investigate the anti-inflammatory and anti-apoptosis effects of FA on KD, and try to elucidate the underlying mechanism. Results: Our in vivo results demonstrated that FA exerted anti-inflammatory effects on KD by inhibiting the infiltration of CD45-positive leukocytes and fibrosis around the coronary artery. Additionally, FA downregulated the levels of inflammatory and chemotactic cytokines, alleviated splenomegaly, and exhibited anti-apoptotic effects on KD by reducing TUNEL-positive cells, downregulating BAX expression, and upregulating BCL-2 expression. In addition, Our in vitro findings showed that FA could effectively inhibit TNF-α-induced HUVEC inflammation like NF-κB inhibitor QNZ by downregulating the expression of pro-inflammatory cytokines as well as attenuated TNF-α-induced HUVEC apoptosis by reducing apoptotic cell numbers and the BAX/BCL-2 ratio, which could be reversed by the AMPK inhibitor compound c (CC). The further mechanistic study demonstrated that FA could restrain vascular endothelial cell inflammation and apoptosis in KD through activating the AMPK/mTOR/NF-κB pathway. However, FA alone is hard to completely restore KD into normal condition. Conclusion: In conclusion, FA has potential protective effects on KD, suggesting its promising role as an adjuvant for KD therapy in the future.

Gastrodin ameliorates acute pancreatitis by modulating macrophage inflammation cascade via inhibition the p38/NF-κB pathway.

Acute pancreatitis (AP) is a prevalent, destructive, non-infectious pancreatic inflammatory disease, which is usually accompanied with systemic manifestations and poor prognosis. Gastrodin (4-hydroxybenzyl alcohol 4-O-ß-d-glucopyranoside) has ideal anti-inflammatory effects in various inflammatory diseases. However, its potential effects on AP had not been studied. In this study, serum biochemistry, H&E staining, immunohistochemistry, immunofluorescence, western blot, real-time quantitative PCR (RT-qPCR) were performed to investigate the effects of Gastrodin on caerulein-induced AP pancreatic acinar injury model in vivo and lipopolysaccharide (LPS) induced M1 phenotype macrophage model in vitro. Our results showed that Gastrodin treatment could significantly reduce the levels of serum amylase and serum lipase while improving pancreatic pathological morphology. Additionally, it decreased secretion of inflammatory cytokines and chemokines, and inhibited the levels of p-p38/p38, p-IκB/IκB as well as p-NF-κB p-p65/NF-κB p65. Overall our findings suggested that Gastrodin might be a promising therapeutic option for patients with AP by attenuating inflammation through inhibition of the p38/NF-κB pathway mediated macrophage cascade.

Integrated single-cell RNA-seq analysis revealed podocyte injury through activation of the BMP7/AMPK/mTOR mediated autophagy pathway.

BACKGROUND: Nephrotic syndrome (NS) is a chronic kidney disease mainly caused by impaired podocytes, ultimately resulting in massive proteinuria or even end-stage renal disease (ESRD). METHODS: The objective of this study was to explore the potential pathogenesis of NS caused by podocyte injury, and further explore the underlying mechanism through data mining, bioinformatics analysis, and experimental verification. The integrated analyses including Seurat, CellChat, gene ontology (GO), and molecular docking were performed based on the single-cell RNA-seq data (scRNA-seq). The adriamycin (ADR)-induced podocyte injury model in vitro was established to conduct the experimental verification for bioinformatics analysis results through western blot and real-time quantitative PCR (RT-qPCR). RESULTS: The results of bioinformatics analysis revealed that the bone morphogenetic protein (BMP) signaling pathway was involved in the podocyte-to-podocyte communication, which plays a crucial role in podocyte injury. The expression of BMP7 was significantly increased in ADR-induced podocytes through activating the Adenosine-monophosphate activated-protein kinase/Mammalian target of rapamycin (AMPK/mTOR) mediated autophagy pathway, and these findings were confirmed by in vitro experiments. CONCLUSION: This study first demonstrated that BMP7 participated in ADR-induced podocyte injury. The BMP7/AMPK/mTOR mediated autophagy pathway may play a crucial role in podocyte injury, which may be the potential therapeutic target for NS patients.

The protective roles of allicin on type 1 diabetes mellitus through AMPK/mTOR mediated autophagy pathway.

Background: Type 1 diabetes mellitus (T1DM) is one of the most common endocrine and metabolic diseases in children. Pancreatic ß cells are thought to be critical cells involved in the progression of T1DM, and their injury would directly lead to impaired insulin secretion. Purpose: To investigate the protective effects of allicin on pancreatic ß cell injury and elucidate the underlying mechanism. Methods: The streptozotocin (STZ)-induced mouse T1DM model in vivo and STZ-induced pancreatic ß cell Min6 model in vitro were used to explore the effects of allicin on T1DM. The experiments include fasting blood glucose test, oral glucose tolerance detection, HE staining, immunohistochemistry, immunofluorescence, TUNEL staining, western blot, real-time quantitative PCR (RT-qPCR), and flow cytometry. Results: Allicin could significantly decrease blood glucose level, improve islet structure and insulin expression, and inhibit apoptosis to reduce STZ-induced pancreatic ß cell injury and loss through activating AMPK/mTOR mediated autophagy pathway. Conclusion: Allicin treatment significantly reduced STZ-induced T1DM progression, suggesting that allicin may be a potential therapy option for T1DM patients.

Downregulation of ACAN is Associated with the Growth hormone pathway and Induces short stature.

BACKGROUND: ACAN heterozygous mutations can cause short stature in patients with or without advanced bone age and have recently attracted researchers' attention. Growth hormone can be used to treat short stature induced by ACAN mutations; however, few studies have focused on the underlying mechanism of this treatment. METHODS: Four patients with new mutations were reported based on clinical data and genetic tests. We investigated the expression and Gene Ontology biological process enrichment of ACAN and GH pathways based on GTEx databases through bioinformatics analyses. The effect of ACAN on the growth hormone response evaluated in ATDC5 cells with a growth hormone stimulation test. RESULTS: Four mutations were reported in this study: c.619C > A, c.1967A > G, c.1888G > A, and c.1308_1309del. All patients' heights were under -2.5 SD, with one had advanced bone age, and two had GH deficiency. Two individuals received growth hormone therapy acquired variable levels of height SD score improvement. ACAN and the GH pathway were strongly associated; ACAN does not affect GHR but regulates the response to GH. Downregulating ACAN inhibited ATDC5 cell proliferation induced by GH. CONCLUSION: ACAN is associated with the GH pathway, revealing the potential mechanism underlying GH-targeted treatment for ACAN mutation-induced short stature. GH-promoting therapies may increase patients' heights.

Atrophy in subcortical gray matter in adult patients with moyamoya disease.

BACKGROUND: Acute cerebrovascular accidents, long-term hypoperfusion, and/or remote neuronal degeneration may lead to structural alterations in patients with moyamoya disease (MMD). This study sought to comprehensively investigate the distribution characteristics of subcortical gray matter volume and their correlations with angiographic changes in the intracranial artery in patients with MMD. METHOD: One hundred forty-two patients with MMD and 142 age- and sex-matched healthy controls underwent 3-dimensional high-resolution structural magnetic resonance imaging. Volumes of subcortical gray matter and subregions of the hippocampus and amygdala were calculated, and the degree of stenosis/occlusion of intracranial arteries in patients with MMD was evaluated on MR angiography. RESULTS: Volume reductions in the thalamus, caudate, putamen, hippocampus, amygdala, pallidum, and nucleus accumbens were found in patients with MMD. Hippocampal subfields and amygdala subnuclei in patients with MMD showed distinct vulnerability, and morphological alterations in specific subregions were more obvious than in the whole hippocampus/amygdala. Volume loss in several subcortical areas was related to disease duration and intracranial arterial changes. CONCLUSIONS: Our findings revealed structural alteration patterns of subcortical gray matter in MMD. The specific atrophy in subregions of the hippocampus and the amygdala suggested potential cognitive and affective impairments in MMD, which warrants further investigation. Chronic cerebral hemodynamic alterations in MMD may play a pivotal role in morphological changes in subcortical areas.

Enhanced cellulosic d-lactic acid production from sugarcane bagasse by pre-fermentation of water-soluble carbohydrates before acid pretreatment.

After several rounds of milling process for sugars extraction from sugarcane, certain amounts of water-soluble carbohydrates (WSC) still remain in sugarcane bagasse. It is a bottleneck to utilize WSC in sugarcane bagasse biorefinery, since these sugars are easily degraded into inhibitors during pretreatment. Herein, a simple pre-fermentation step before pretreatment was conducted, and 98 % of WSC in bagasse was fermented into d-lactic acid. The obtained d-lactic acid was stably preserved in bagasse and 5-hydroxymethylfurfural (HMF) generation was sharply reduced from 46.0 mg/g to 6.2 mg/g of dry bagasse, after dilute acid pretreatment. Consequently, a higher d-lactic acid titer (57.0 g/L vs 33.2 g/L) was achieved from the whole slurry of the undetoxified and pretreated sugarcane bagasse by one-pot simultaneous saccharification and co-fermentation (SSCF), with the overall yield of 0.58 g/g dry bagasse. This study gave an efficient strategy for enhancing lactic acid production using the lignocellulosic waste from sugar industry.

3D printing of essential oil/ß-cyclodextrin/popping candy modified atmosphere packaging for strawberry preservation.

In this study, lemongrass essential oil (LEO) was wrapped in ß-cyclodextrin (ß-CD) using a co-precipitation method to prepare an inclusion complex (LEO/ß-CD). A biological multifunctional preservation card was prepared by 3D printing and mixing the inclusion complex with sodium alginate (SA). The moisture generated by strawberry respiration melted the popping candy (PPC) and stimulated the release of CO2, a synergistic antibacterial compound formed with LEO. Hence, antibacterial activity and air regulation were achieved, and the fruit remained fresh. The results indicated that LEO was successfully encapsulated in ß-CD, and that LEO/ß-CD had a strong bacteriostatic effect on Aspergillus niger and Botrytis cinerea, with a high resistance to oxidation. The PPC could release CO2 and extend the shelf life of strawberries by reducing their respiration and inhibiting mold.

T-cell-specific Sel1L deletion exacerbates EAE by promoting Th1/Th17-cell differentiation.

Multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) are demyelinating neuroinflammatory diseases identified by the accumulation and aggregation of misfolded proteins in the brain. The Sel1L-Hrd1 complex comprising endoplasmic reticulum associated degradation (ERAD) is an ER-protein quality control system (ERQC) in the cell. Unfortunately, the contribution of ERAD to the development of these diseases has not been well explored. In this study, we used mice with a conditional deletion (KO) of Sel1L in T cells to dissect the role of ERAD on T cells and its contribution to the development of EAE. The results showed that Sel1L KO mice developed more severe EAE than the control wild type (WT) mice. Although, no obvious effects on peripheral T cells in steady state, more CD44-CD25+ double-negative stage 3 (DN3) cells were detected in the thymus. Moreover, Sel1L deficiency promoted the differentiation of Th1 and Th17 cells and upregulated the proliferation and apoptosis of CD4 T cells in vitro. Regarding the mechanism analyzed by RNA sequencing, 437 downregulated genes and 271 upregulated genes were detected in Sel1L deletion CD4 T cells, which covered the activation, proliferation, differentiation and apoptosis of these T cells. Thus, this study declared that the dysfunction of Sel1L in ERAD in T cells exacerbated the severity of EAE and indicated the important role of ERQC in maintaining immune homeostasis in the central nervous system.

Facile fabrication of sandwich-like anthocyanin/chitosan/lemongrass essential oil films via 3D printing for intelligent evaluation of pork freshness.

In this study, chitosan (CH), mulberry anthocyanin (MA), and lemongrass essential oils (LEO) were used as an interlayer using a 3D printer. Further, cassava starch (CS) was used as a protective layer to form indicator films. The indicator films containing LEO showed significant antioxidant and antibacterial properties, and the release rate of LEO increased with a rise in pH. When chilled pork spoiled, the color of the indicator films changed from red to gray-blue, and the RGB values could be automatically analyzed by a smartphone application to determine pork freshness. These films hold implications as easy-to-use indicators of meat freshness, with great potential for monitoring food spoilage, as part of an intelligent packaging system.

Regulation of thymic T regulatory cell differentiation by TECs in health and disease.

The thymus produces self-limiting and self-tolerant T cells through the interaction between thymocytes and thymus epithelial cells (TECs), thereby generating central immune tolerance. The TECs are composed of cortical and medullary thymic epithelial cells, which regulate the positive and negative selection of T cells, respectively. During the process of negative selection, thymocytes with self-reactive ability are deleted or differentiated into regulatory T cells (Tregs). Tregs are a subset of suppressor T cells that are important for maintaining immune homeostasis. The differentiation and development of Tregs depend on the development of TECs and other underlying molecular mechanisms. Tregs regulated by thymic epithelial cells are closely related to human health and are significant in autoimmune diseases, thymoma and pregnancy. In this review, we summarize the current molecular and transcriptional regulatory mechanisms by which TECs affect the development and function of thymic Tregs. We also review the pathophysiological models of thymic epithelial cells regulating thymic Tregs in human diseases and specific physiological conditions.

Endoplasmic Reticulum Quality Control in Immune Cells.

The endoplasmic reticulum quality control (ERQC) system, including endoplasmic reticulum-associated degradation (ERAD), the unfolded protein response (UPR), and autophagy, presides over cellular protein secretion and maintains proteostasis in mammalian cells. As part of the immune system, a variety of proteins are synthesized and assembled correctly for the development, activation, and differentiation of immune cells, such as dendritic cells (DCs), macrophages, myeloid-derived-suppressor cells (MDSCs), B lymphocytes, T lymphocytes, and natural killer (NK) cells. In this review, we emphasize the role of the ERQC in these immune cells, and also discuss how the imbalance of ER homeostasis affects the immune response, thereby suggesting new therapeutic targets for immunotherapy.

Finite element modelling of posterior occiput-axis fixation and biomechanical analysis of C2 intralaminar screw fixation with offset connectors.

PURPOSE: The occiput-axis crossing translaminar screw (C2LAM) fixation technique can help avoid vertebral injury, while the inclusion of offset connectors can facilitate implantation. This three-dimensional finite element (FE) study compared the stability of C2LAM using offset connectors (C2LAM + OF) with other methods. MATERIALS AND METHODS: Occipital and cervical spine computed tomography images of a healthy 30-year-old man were selected to build the FE model. Four internal fixation instruments including occiput plate-C2 pedicle (C2P) and pars (C2Pars) screws, as well as C2LAM and C2LAM + OF were applied consecutively to the model respectively to establish four new models, which were subjected to all states of motion and physiological loads to simulate normal movement, including the four kinds of basic activities of human such as flexion, extension, lateral bending, and axial rotation. Physiological measures and comparison included the range of motion (ROM) and stress distribution in the model. RESULTS: ROM between the fixation techniques was comparable, and the stability of the C2LAM + OF fixation technique was similar to that of C2P. Screw entry points, offset connectors and rods were the main stress distribution regions in the C2LAM + OF system. The mean von Mises stress of the inner wall was significantly smaller than that of the outer wall in flexion, extension, and rotation (p < 0.05); however, lateral bending was comparable, indicating a relatively small risk of damage to the inner wall. CONCLUSIONS: The results of this study indicate that the C2LAM + OF fusion technique can provide sufficient stability and can be used as an alternative to C2P under special circumstances.

[Simultaneous determination of 16 flavonoids in the ginkgo dietary supplement tea by high performance liquid chromatography-tandem mass spectrometry].

A method for the determination of 16 functional components of ginkgo dietary supplement tea such as catechin, vitexin, puerarin, isoflavoues aglycone, silymarin, quercetin, luteolin, apigenin, naringenin, hesperitin dihydrochalcone, kaempferol, hesperitin, isorhamnetin, baicalein, nobiletin and tangeretin by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was proposed. The conditions of chromatography and mass spectrometry were optimized. The 16 flavonoids were separated on a C18 chromatographic column with acetonitrile and water (additional 0.1% formic acid) as mobile phases under gradient elution at a flow rate of 0.25 mL/min. The determination was conducted by tandem mass spectrometry in positive ESI mode under multiple reaction monitoring (MRM) mode. Good linearities for all the compounds, with correlation coefficients over 0.996, were acquired. The recoveries were in the range of 70.9% to 100.0% (n = 6), while the relative standard deviations (RSDs) were less than 10%. The results showed that the nine flavonoids, which were kaempferol, quercetin, hesperitin, vitexin, luteolin, catechin, apigenin, naringenin and isorhamnetin, were higher in contents among the 16 flavonoids in real samples, and they constituted up to 99.6% of the total flavonoids. The contents of these nine flavonoids can be considered as the quality control index of the ginkgo dietary supplement tea. The method proved to be rapid, selective, sensitive and stable, and it can be applied to control the quality of the ginkgo dietary supplement tea.