Anti-inflammatory Factor IL-10 Research Articles

Baicalein ameliorates Alzheimer's disease via orchestration of CX3CR1/NF-κB pathway in a triple transgenic mouse model.

Alzheimer's disease (AD) is a common chronic neurodegenerative disease. Some studies have suggested that dysregulation of microglia activation and the resulting neuroinflammation play an important role in the development of AD pathology. Activated microglia have both M1 and M2 phenotypes and inhibition of M1 phenotype while stimulating M2 phenotype has been considered as a potential treatment for neuroinflammation-related diseases. Baicalein is a class of flavonoids with anti-inflammatory, antioxidant and other biological activities, but its role in AD and the regulation of microglia are limited. The purpose of this study was to investigate the effect of baicalein on the activation of microglia in AD model mice and the related molecular mechanism. Our results showed that baicalein significantly improved the learning and memory ability and AD-related pathology of 3×Tg-AD mice, inhibited the level of pro-inflammatory factors TNF-α, IL-1β and IL-6, promoted the production of anti-inflammatory factors IL-4 and IL-10, and regulated the microglia phenotype through CX3CR1/NF-κB signaling pathway. In conclusion, baicalein can regulate the phenotypic transformation of activated microglia and reduce neuroinflammation through CX3CR1/NF-κB pathway, thereby improving the learning and memory ability of 3×Tg-AD mice.

Effects of Yellow Mealworm (Tenebrio molitor) on Growth Performance, Hepatic Health and Digestibility in Juvenile Largemouth Bass (Micropterus salmoides).

This study investigated the effects of yellow mealworm meal (TM) on growth performance, hepatic health and digestibility in juvenile largemouth bass (Micropterus salmoides). The fish were fed with the basic feed and the test feed (70% basic feed and 30% raw materials) containing Cr2O3, and feces were collected for digestibility determination. The fish were fed with five isonitrogenous (47% crude protein) and isolipidic (13% crude lipid) diets, in which fishmeal (FM) was replaced with 0% (TM0), 12% (TM12), 24% (TM24), 36% (TM36) and 48% (TM48) TM. The fish were reared in cylindrical plastic tanks in a recirculating aquaculture system for 11 weeks. The apparent digestibility coefficients (ADC), of dry matter, crude protein and crude lipid, in largemouth bass of TM were 74.66%, 91.03% and 90.91%, respectively. The ADC of total amino acid (TAA) of TM in largemouth bass was 92.89%, and the ADC of essential amino acid (EAA) in TM in largemouth bass was 93.86%. The final body weight (FBW), weight gain rate (WGR) and specific growth rate (SGR) in the TM24 group were significantly higher than those in other groups. Similarly, the highest mRNA expression levels of hepatic protein metabolism genes (pi3k, mtor, 4ebp2 and got) and antioxidant enzyme (glutathione peroxidase, Gpx; catalase, Cat) activities were observed in the TM24 group. Moreover, the expression levels of anti-inflammatory factors (il-10 and tgf) in liver were up-regulated and the expression levels of pro-inflammatory factors (il-8 and il-1β) in liver were down-regulated. Quadratic regression model analysis, based on weight gain rate (WGR) against dietary TM level, indicated that the optimum level of dietary TM replacing FM in largemouth bass diet was 19.52%. Appropriate replacement levels (less than 36%) of FM by TM in the diets can enhance the antioxidant capacity and immunity of largemouth bass. However, high levels of FM substitution with TM (more than 48%) in the feeds can damage the liver health and inhibit the growth of largemouth bass. Notably, largemouth bass has high ADC and high utilization of TM, which indicates that it is feasible to use TM as feed protein source for largemouth bass.

Phenotypic Traits and Probiotic Functions of Lactiplantibacillus plantarum Y42 in Planktonic and Biofilm Forms.

Bacteria in planktonic and biofilm forms exhibit different phenotypic properties. In this study, the phenotypic traits and probiotic functions of Lactiplantibacillus plantarum Y42 in planktonic and biofilm forms were assessed. After 36 h of static culture, scanning electron microscopy and confocal laser scanning microscopy showed that the L. plantarum Y42 bacterial cells contained interconnected adhesive matter on the surface, forming a ~18 μm layer of dense biofilms. The surface properties of L. plantarum Y42 in biofilm form, including autoaggregation ability, hydrophobicity, acid-base charge, and adhesiveness, were all higher than those in the planktonic form. Biofilm L. plantarum Y42 showed a higher tolerance to adverse environmental conditions and a higher survival rate, enzymatic activity, and integrity after vacuum lyophilization. And biofilm L. plantarum Y42 had higher adhesion to human enterocyte HT-29 cell monolayers, inhibited the expressions of proinflammatory factors IL-6 and TNF-α, and promoted the expressions of the anti-inflammatory factor IL-10 and barrier proteins Claudin-1 and Occludin. In addition, L. plantarum Y42 in biofilm form can inhibit the adhesion and invasion of Listeria monocytogenes ATCC 19115 to HT-29 cell monolayers and is more effective in relieving the inflammatory reactions and injuries of HT-29 cells caused by L. monocytogenes ATCC 19115. In conclusion, L. plantarum Y42 in biofilm form exhibited better probiotic functions compared to that in planktonic form. This indicated that L. plantarum Y42 can form biofilms to enhance its probiotic functions, which provided a theoretical basis for better development and utilization of L. plantarum Y42.

Effects of Genistein on Lipid Metabolism, Antioxidant Activity, and Immunity of Common Carp (Cyprinus carpio L.) Fed with High-Carbohydrate and High-Fat Diets.

A 56-day feeding trial was conducted to investigate the effects of genistein on growth, lipid metabolism, antioxidant capacity, and immunity of common carp fed with high-carbohydrate or high-fat diets. Five diets were used to feed fish: control diet (5% fat; CO), high-fat diet (11% fat; HF), high-carbohydrate diet (45% carbohydrate; HC), and HF or HC diet with 500 mg/kg genistein (FG or CG). Results showed that final body weight (FW) and specific growth rate (SGR) were significantly reduced, but the supplementation with genistein resulted in higher values of FW and SGR than the HF or HC group. Both high carbohydrate and high fat belong to high-energy diets, which may promote lipid deposition. Genistein obviously decreased liver triglyceride (TG) content and alleviated hepatic fat vacuolation in the HF and HC groups. The expression of lipid metabolism genes (cpt-1 and atgl) was markedly higher in the FG group than in the HF group. The lipid synthesis-related genes (fas, acc, and pparγ) were elevated in high-energy diets but recovered to the control level or reduced after genistein treatments. With respect to fatty acid transporter genes, fatp increased in the FG group, and cd36 increased in the CG group. Furthermore, the antioxidant and immune indexes, such as total antioxidant capacity (T-AOC), glutathione peroxidase (GSH-PX), superoxide dismutase (SOD), acid phosphatase (ACP), and lysozyme (LZM) activities, were decreased, while malonate aldehyde (MDA) content, activities of alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were enhanced in the HF and HC groups. The antioxidant and immunity values could be ameliorated by treatment with genistein. Moreover, the transcript levels of antioxidant-related genes (cat, gr, and nrf2) in the liver and anti-inflammatory factors (tgf-β and il-10) and lyz in the head kidney tissue were promoted, although the expression levels of proinflammatory factors (tnf-α and il-6) declined in the genistein supplementation group, which confirmed the antioxidant and immune-enhancing effects of genistein. Therefore, 500 mg/kg genistein could ameliorate the negative effects of high-energy diets on immunity.

Identification of biomarkers of hepatocellular carcinoma gene prognosis based on the immune-related lncRNA signature of transcriptome data

Long non-coding RNAs (lncRNAs) are well established to have an important role in cancer. The goal of this research was to investigate the prognostic usefulness of putative immune-related lncRNAs in hepatocellular carcinoma (HCC). The developed lncRNA signature was validated using 343 HCC patients from The Cancer Genome Atlas (TCGA) and 81 samples from Gene Expression Omnibus (GEO). Cox regression and Least Absolute Shrinkage and Selection Operator (LASSO) analysis were used to analyze immune-related lncRNAs for HCC prognosis. Patients in the low-risk group survived substantially longer than those in the high-risk group (P < 0.05). The discovered signal might be a useful prognostic factor for predicting patient survival. Overall survival predicted some clinical net improvements, according to the nomogram. Numerous enrichment approaches (including gene set enrichment analysis) were utilized to investigate the underlying mechanisms. Drug metabolism, mTOR, and p53 signaling pathways were associated with high-risk groups. When the expression of lncRNA PRRT3-AS1 was silenced in HepG2 cells, the proliferation, migration, and invasion abilities of HepG2 cells were decreased, and apoptosis was enhanced. In the supernatant from HepG2 cells with PRRT3-AS1 knockdown, the anti-inflammatory factors IL-10 and TGF-1 were induced, whereas the pro-inflammatory factors IL-1β, TNF-α, and IL-6 were reduced (P < 0.05). After PRRT3-AS1 knockdown, the protein expression of CD24, THY1, LYN, CD47, and TRAF2 in HepG2 cells was attenuated (P < 0.05). The discovery of five immune-related lncRNA signatures has significant therapeutic significance for predicting patient prognosis and directing personalized treatment for patients with HCC, which requires additional prospective confirmation.

The scavenger receptor CD36 protects Nile tilapia (Oreochromis niloticus) against Streptococcus agalactiae infection and promotes the expression of inflammatory factors

To explore the role of CD36 (Cluster of Differentiation 36) in the antimicrobial immunity of Nile tilapia, the PCR was used to clone the CD36 gene (named OnCD36). The results showed that the ORF was 1407 bp, encoding 468 amino acids. Multiple sequence alignment revealed that OnCD36 was conserved among species. Subcellular localization proved that OnCD36 was distributed in the cell membrane. RT-PCR analysis presented that OnCD36 gene was expressed in all tissues of healthy tilapia, and the expression of OnCD36 gene was higher in immune tissues such as the head kidney, intestine, skin. After inactivated S. agalactiae and Poly I: C stimulated, the expression of OnCD36 in blood, head kidney, spleen and thymus showed a temporal expression. In vitro experiments showed that OnCD36 extracellular protein could bind to bacteria through the surface structure of bacteria LPS, LTA, PGN. In vivo experiments demonstrated that OnCD36 overexpression before S. agalactiae challenge, which could effectively reduce the bacterial load in the spleen and liver tissues, reduce the injury of immune tissues or organs to varying degrees. Moreover, the overexpression of CD36 in the activity of AKP, ACP, SOD in OnCD36 experimental group was significantly higher than that in the control group. OnCD36 also reduces inflammation and protects tilapia from S. agalactiae infection by increasing the expression of anti-inflammatory factors IL-10 and TGF-β and decreasing the expression of pro-inflammatory factors IL-6 and TNF-α. In conclusion, these studies indicate that OnCD36 may play a vital role in pathogen control and immune response in tilapia. However, the pathway mechanism involved in OnCD36 regulating the expression of inflammatory factors needs to be further studied.

Spinal cannabinoid receptor 2 activation alleviates neuropathic pain by regulating microglia and suppressing P2X7 receptor.

Neuropathic pain (NP) is the chronic pain in patients resulting from injuries or diseases in the somatosensory nervous system. However, effective treatment remains limited to opioids. Currently, there is an urgent need to develop new specific pharmaceuticals with low abuse potentiality. Cannabinoid receptor 2 (CB2R) is one of the significant receptors in the endocannabinoid system. It is widely expressed in the central nervous system, especially enriched in glial cells, and plays an important role in the occurrence and development of inflammation in the nervous system. CB2R activation has a neuroprotective effect on nerve injury. In this study, we report increased and more reactive microglia (with larger cell body, shorter processes, and fewer endpoints) observed in the spinal dorsal horn of spared nerve injury (SNI) rats. Continuous intrathecal administration of CB2R agonist PM226 attenuated mechanical and cold hyperalgesia in rats and prevented the transition of microglia to the proinflammatory stage. Thus, microglia transitioned into the neuroprotective stage. Meanwhile, the proinflammatory factors TNF-α and iNOS decreased, and the levels of anti-inflammatory factors Arg-1 and IL-10 increased. The content of P2X7 receptors in the spinal dorsal horn of rats increases with time after SNI. After continuous intrathecal administration of PM226, the content of P2X7 protein decreases significantly. The administration of P2X7 inhibitor A-438079 alleviated the mechanical hyperalgesia of rats, reduced the number of microglia, and decreased the content of P2X7. These results indicate that P2X7 is involved in the neuroprotective effect caused by CB2R activation. In conclusion, this study provides new insights into the neuroprotective mechanism of CB2R activation.

Prevention for moderate or severe BPD with intravenous infusion of autologous cord blood mononuclear cells in very preterm infants-a prospective non-randomized placebo-controlled trial and two-year follow up outcomes.

Bronchopulmonary dysplasia (BPD) is the primary severe complication of preterm birth. Severe BPD was associated with higher risks of mortality, more postnatal growth failure, long term respiratory and neurological developmental retardation. Inflammation plays a central role in alveolar simplification and dysregulated vascularization of BPD. There is no effective treatment to improve BPD severity in clinical practice. Our previous clinical study showed autologous cord blood mononuclear cells (ACBMNCs) infusion could reduce the respiratory support duration safely and potential improved BPD severity. Abundant preclinical studies have reported the immunomodulation effect as an important mechanism underlying the beneficial results of stem cell therapies in preventing and treating BPD. However, clinical studies assessing the immunomodulatory effect after stem cells therapy were rare. This study was to investigate the effect of ACBMNCs infusion soon after birth on prevention for severe BPD and long term outcomes in very preterm neonates. The immune cells and inflammatory biomarkers were detected to investigate the underlying immunomodulatory mechanisms. This single-center, prospective, investigator-initiated, non-randomized trial with blinded outcome assessment aimed to assess the effect of a single intravenous infusion of ACBMNCs in preventing severe BPD (moderate or severe BPD at 36 weeks of gestational age or discharge home) in surviving very preterm neonates less than 32 gestational weeks. Patients admitted to the Neonatal Intensive Care Unit (NICU) of Guangdong Women and Children Hospital from July 01, 2018 to January 1, 2020 were assigned to receiving a targeted dosage of 5×107cells/kg ACBMNC or normal saline intravenously within 24h after enrollment. Incidence of moderate or severe BPD in survivors were investigated as the primary short term outcome. Growth, respiratory and neurological development were assessed as long term outcomes at corrected age of 18-24 month-old. Immune cells and inflammatory biomarkers were detected for potential mechanism investigation. The trial was registered at ClinicalTrials.gov (NCT02999373). Six-two infants were enrolled, of which 29 were enrolled to intervention group, 33 to control group. Moderate or severe BPD in survivors significantly decreased in intervention group (adjusted p=0.021). The number of patients needed to treat to gain one moderate or severe BPD-free survival was 5 (95% confidence interval: 3-20). Survivors in the intervention group had a significantly higher chance to be extubated than infants in the control group (adjusted p=0.018). There was no statistical significant difference in total BPD incidence (adjusted p=0.106) or mortality (p=1.000). Incidence of developmental delay reduced in intervention group in long term follow-up (adjusted p=0.047). Specific immune cells including proportion of T cells (p=0.04) and CD4+ T cells in lymphocytes (p=0.03), and CD4+ CD25+ forkhead box protein 3 (FoxP3)+ regulatory T cells in CD4+ T cells increased significantly after ACBMNCs intervention (p＜0.001). Anti-inflammatory factor IL-10 was higher (p=0.03), while pro-inflammatory factor such as TNF-a (p=0.03) and C reactive protein (p＜0.001) level was lower in intervention group than in control group after intervention. ACBMNCs could prevent moderate or severe BPD in surviving very premature neonates and might improve neurodevelopmental outcomes in long term. An immunomodulatory effect of MNCs contributed to the improvement of BPD severity. This work was supported by National Key R&D Program of China (2021YFC2701700), National Natural Science Foundation of China (82101817, 82171714, 8187060625), Guangzhou science and technology program (202102080104).

Comparison of the Effects between Tannins Extracted from Different Natural Plants on Growth Performance, Antioxidant Capacity, Immunity, and Intestinal Flora of Broiler Chickens.

In this study, four plant tannins, including AT (Acacia mearnsii tannin, 68%), CT (Castanea sativa tannin, 60%), QT (Schinopsis lorenzii tannin, 73%) and TT (Caesalpinia spinosa tannin, 50%) were added to broiler diets for 42 days to evaluate and compare their effects on growth performance, antioxidant capacity, immune performance and gut microbiota in broilers. The results showed that the supplementation of five tannins could increase the production of T-AOC, GSH-Px, SOD and CAT and reduce the production of MDA in the serum of broilers (p < 0.01), but the antioxidant effect of the AT group was lower than that of the other three groups (p < 0.01). All four tannins decreased the level of the pro-inflammatory factor IL-1β and increased the level of the anti-inflammatory factor IL-10 (p < 0.01). CT, QT and TT decreased the levels of pro-inflammatory factors IL-6 and TNF-α (p < 0.01), while AT and CT increased the level of IL-2 in serum (p < 0.01). Supplementation with four tannins also increased the levels of IgG, IgM, IgA and sIgA in serum (p < 0.01) and the levels of ZO-1, claudin-1 and occludin in the jejunum (p < 0.01). The detection results of ALT and AST showed that CT, QT and TT decreased the concentrations of ALT and AST in serum (p < 0.01). The results of the gut microbiota showed that the abundance of Clostridia and Subdoligranulum increased, and the abundance of Oscillospiraceae decreased, compared to the control group after adding the four tannins to the diets (p > 0.05). In addition, CT, QT and TT decreased the abundance of Lactobacillus and increased the abundance of Bacteroides compared to the control group, while AT showed the opposite result (p > 0.05). Overall, our study shows that tannins derived from different plants have their own unique effects on broilers. AT and CT can promote broilers' growth better than other tannins, CT has the best ability to improve immune and antioxidant properties, and QT and TT have the best effect on broilers' liver protection.

Microbe-Derived Antioxidants Alleviate Liver and Adipose Tissue Lipid Disorders and Metabolic Inflammation Induced by High Fat Diet in Mice.

Obesity induces lipodystrophy and metabolic inflammation. Microbe-derived antioxidants (MA) are novel small-molecule nutrients obtained from microbial fermentation, and have anti-oxidation, lipid-lowering and anti-inflammatory effects. Whether MA can regulate obesity-induced lipodystrophy and metabolic inflammation has not yet been investigated. The aim of this study was to investigate the effects of MA on oxidative stress, lipid disorders, and metabolic inflammation in liver and epididymal adipose tissues (EAT) of mice fed with a high-fat diet (HFD). Results showed that MA was able to reverse the HFD-induced increase in body weight, body fat rate and Lee's index in mice; reduce the fat content in serum, liver and EAT; and regulate the INS, LEP and resistin adipokines as well as free fatty acids to their normal levels. MA also reduced de novo synthesis of fat in the liver and EAT and promoted gene expression for lipolysis, fatty acid transport and β-oxidation. MA decreased TNF-α and MCP1 content in serum, elevated SOD activity in liver and EAT, induced macrophage polarization toward the M2 type, inhibited the NLRP3 pathway, increased gene expression of the anti-inflammatory factors IL-4 and IL-13 and suppressed gene expression of the pro-inflammatory factors IL-6, TNF-α and MCP1, thereby attenuating oxidative stress and inflammation induced by HFD. In conclusion, MA can effectively reduce HFD-induced weight gain and alleviate obesity-induced oxidative stress, lipid disorders and metabolic inflammation in the liver and EAT, indicating that MA shows great promise as a functional food.

Absorption and Transport Mechanism of Red Meat-Derived N-glycolylneuraminic Acid and Its Damage to Intestinal Barrier Function through the NF-κB Signaling Pathway.

N-glycolylneuraminic acid (Neu5Gc) is a specific factor in red meat that induces intestinal disease. Our aim was to investigate the effect of Neu5Gc on the intestinal barrier as well as its mechanism of endocytosis and exocytosis. Ten specific inhibitors were used to explore the mechanism of Neu5Gc endocytosis and exocytosis by Caco-2 cells. Amiloride hydrochloride and cytochalasin D had the strongest inhibitory effect on the endocytosis of Neu5Gc. Sodium azide, dynasore, chlorpromazine hydrochloride, and nystatin also inhibited Neu5Gc endocytosis. Dynasore exhibited a stronger inhibitory effect than that of chlorpromazine hydrochloride or nystatin alone. Exocytosis inhibitors, including nocodazole, brefeldin A, monensin, and bafilomycin A, inhibited the transmembrane transport of Neu5Gc. Monensin promoted the exocytosis of Neu5Gc from Caco-2 cells. In another experiment, we observed no significant inhibitory effects of monensin and brefeldin A. Dietary concentrations of Neu5Gc induced prominent damage to intestinal tight junction proteins zonula occludens-1 (ZO-1), occludin, and claudin-1 and promoted the phosphorylation of IκB-α and P65 to activate the canonical Nuclear Factor kappa-B (NF-κB) pathway. Neu5Gc increased the RNA levels of pro-inflammatory factors IL-1β, IL-6, and TNF-α and inhibited those of anti-inflammatory factors TGF-β and IL-10. BAY, an NF-κB signaling pathway inhibitor, attenuated these changes. Reductions in the levels of ZO-1, occludin, and claudin-1 were recovered in response to BAY. Our data reveal the endocytosis and exocytosis mechanism of Neu5Gc and prove that Neu5Gc can activate the canonical NF-κB signaling pathway, regulate the transcription of inflammatory factors, thereby damaging intestinal barrier function.

Quince extract resists atherosclerosis in rats by down-regulating the EGFR/PI3K/Akt/GSK-3β pathway

We identified the effective components and the underlying mechanisms of Quince (Cydonia oblonga Mill, COM) extract against atherosclerosis. The effective components of COM extract were identified with UHPLC-Q-TOF-MS/MS. Network pharmacology was performed. A rat model of atherosclerosis induced by high-fat emulsion combined with vitamin D3 was established. The anti-atherosclerosis effect of COM extract was evaluated from various aspects such as blood lipid regulation, anti-oxidative stress, anti-inflammatory response, and vascular protection function. We identified 14 serum components of COM extract using UHPLC-Q-TOF-MS/MS. Through prediction, 573 targets were obtained, among which 224 targets were atherosclerosis specific targets. The key targets included GSK3β, ESR1, EGFR, and HSP90AA1. The key signaling pathway was PI3K-Akt signaling pathway. Pharmacodynamics analysis showed that COM extract reduced the levels of TC, TG, and LDL-C as well as ALT and AST, while increased the level of HDL-C. Mechanistically, COM extract significantly increased serum SOD and GSH-Px activities, but decreased MDA content in atherosclerosis rats, showing antioxidant effects. Meanwhile, COM extract significantly down-regulated the levels of pro-inflammatory factors IL-1β, IL-6, TNF-α and CRP, but up-regulated anti-inflammatory factor IL-10. Additionally, COM extract increased the levels of NO, eNOS, and 6-keto-PGF1α; whereas, decreased the levels of ET-1 and TXB2. Furthermore, COM extract significantly inhibited the mRNA and protein levels of EGFR, p-PI3K, p-AKT, GSK-3β, Bax, and Caspase-3 as well as the Bax/Bcl-2 ratio. Conclusively, COM extract exerts hypolipidemic, anti-oxidative, anti-inflammatory, anti-thrombotic and vascular endothelium protective effects on atherosclerosis rat model, which may be related to the inhibition of EGFR/PI3K/AKT/GSK-3β signaling pathway.

Dapagliflozin ameliorates diabetic renal injury through suppressing the self-perpetuating cycle of inflammation mediated by HMGB1 feedback signaling in the kidney

Dapagliflozin, the Sodium-glucose cotransporter 2 (SGLT2) inhibitor class of glucose-lowering agents, has shown the significantly nephroprotective effects to reduce the risk of kidney failure in diabetes. However, the underlying mechanisms are incompletely understood to explain the beneficial effects of dapagliflozin on kidney function. Here, we demonstrated that the administered of dapagliflozin for 12 weeks improved the proteinuria, histomorphology damage, oxidative stress, and macrophage infiltrations in the kidney of streptozotocin (STZ)-induced diabetic mice. Meanwhile, dapagliflozin attenuated the renal inflammation and fibrosis by reducing the pro-inflammatory factors interleukin-6 (IL-6), IL-1β, and tumor necrosis factor α (TNF-α) and anti-fiber factor fibronectin (FN) and elevating the anti-inflammatory factor IL-10. Our data revealed that dapagliflozin exerted anti-inflammatory effects by inhibiting the activation of high mobility group box 1 (HMGB1)/TLR2/4/NF-κB signaling pathway. Consistently, we found that dapagliflozin suppressed the expression of HMGB1 and downstream TLR2/4/NF-κB signaling proteins in the human proximal tubular (HK-2) stimulated by high glucose and lipids or HMGB1 and RAW264.7 cells stimulated by IL-1β, respectively. Further experiments were performed in the indirect co-culture model of RAW264.7 and HK-2 cells induced by high glucose and lipids. The results again confirmed the effects of dapagliflozin on alleviating inflammatory response and regulating the proportions of M1/M2 macrophage. It is indicated that the feedback signaling of HMGB1 between the tubules and macrophage involves in the persistence of the inflammation. These data demonstrate that dapagliflozin suppress the self-perpetuating inflammation by blocking the feedback loop of HMGB1 in the kidney, which contribute to ameliorate the renal injury in diabetes.

Preparation of Cod Skin Collagen Peptides/Chitosan-Based Temperature-Sensitive Gel and Its Anti-Photoaging Effect in Skin.

Photoaging decreases quality of life and increases the risk of skin cancer, underscoring the urgent need to explore natural, high-efficacy, anti-skin photoaging (SP) active substances. In this study, a gel (CS/CSCPs/β-GP gel) was prepared using chitosan (CS) and sodium β-glycerophosphate (β-GP) through crosslinking with small molecular CSCPs as the carried drug. We evaluated its structural characteristics and properties. The effect of CS/CSCPs/β-GP gel on the degree of ultraviolet (UV)-induced skin aging of mice was investigated through comparative analysis of skin damage, the integrity of collagen tissues and elastic fibers, levels of reactive oxygen species (ROS) and key inflammatory factors (tumor necrosis factor [TNF]-α and interleukin [IL]-1β, IL-6, and IL-10), and tissue expression of matrix metalloproteinase-3 (MMP-3) after repeated UV irradiation in a nude mice SP model. The results showed that CS/CSCPs/β-GP gel was successfully prepared and had the desired characteristics. Compared with CSCPs alone, the CS/CSCPs/β-GP gel more evidently improved typical photoaging characteristics on mouse dorsal skin. It also increased the moisture content, causing the skin to become glossy and elastic. Pathological skin analysis revealed that this peptide-carrying gel can effectively inhibit epidermal thickening, reduce tissue inflammatory infiltration, suppress collagen fiber degradation, increase the collagen content, alleviate structural elastic fiber damage, and significantly inhibit abnormal MMP-3 expression. In addition, biochemical analysis showed that the CS/CSCPs/β-GP gel can effectively inhibit the elevated expressions of ROS and key proinflammatory factors (TNF-α, IL-1β, IL-6) in photoaging skin tissues and promote expression of the anti-inflammatory factor IL-10. SP can cause many clinical skin diseases, such as solar freckle-like nevus, solar keratosis, cutaneous melanoma, and squamous cell carcinoma. CSCPs are a high-efficacy anti-SP natural active substance and CS/CSCPs/β-GP gel can synergistically enhance the CSCPs' anti-SP effect. The mechanism is likely related to the inhibited activation of ROS/nuclear transcription factor-κB signaling and the expression of downstream inflammatory factors.

Copper modified cobalt-chromium particles for attenuating wear particle induced-inflammation and osteoclastogenesis

The nature of aseptic prosthetic loosening mainly relates to the wear particles that induce inflammation and subsequent osteoclastogenesis. The ideal approach to impede wear particle-induced osteolysis should minimize inflammation and osteoclastogenesis. In this work, Co29Cr9W3Cu particles were used as a research model for the first time to explore the response of Co29Cr9W3Cu particles to inflammatory response and osteoclast activation in vitro and in vivo by using Co29Cr9W particles as the control group. In vitro studies showed that the Co29Cr9W3Cu particles could promote the generation of M2-phenotype macrophages and increase the expression level of anti-inflammatory factor IL-10, while inhibiting the formation of M1-phenotype macrophages and down-regulating the expression of inflammatory factors TNF-α, IL-6 and IL-1β; More importantly, the Co29Cr9W3Cu particles reduced the expression of NF-κB and downstream osteoclast related-specific transcription marker genes, such as TRAP, NFATc1, and Cath-K; In vivo results indicated that the Co29Cr9W3Cu particles exposed to murine calvarial contributed to decreasing the amount of osteoclast and osteolysis area. These findings collectively demonstrated that Cu-bearing cobalt-chromium alloy may potentially delay the development of aseptic prosthetic loosening induced by wear particles, which is expected to provide evidence of Co29Cr9W3Cu alloy as an alternative material of joint implants with anti-wear associated osteolysis.

Resistance exercise promotes the resolution and recanalization of deep venous thrombosis in a mouse model via SIRT1 upregulation

BackgroundEarly exercise for acute deep venous thrombosis (DVT) improves the patient’s symptoms and does not increase the risk of pulmonary embolism. However, information about its effect on thrombus resolution is limited. The aim of this study was to investigate the role of resistance exercise (RE) in thrombus resolution and recanalization and determine its underlying mechanisms. MethodsNinety-six C57BL/6 J mice were randomly divided into four groups: Control group (C, n = 24); DVT group (D, n = 24); RE + DVT group (ED, n = 24); and inhibitor + RE + DVT group (IED, n = 24). A DVT model was induced by stenosis of the inferior vena cava (IVC). After undergoing IVC ultrasound within 24 h post-operation to confirm DVT formation, mice without thrombosis were excluded. Other mice were sacrificed and specimens were obtained 14 or 28 days after operation. Thrombus-containing IVC was weighed, and the thrombus area and recanalization rate were calculated using HE staining. Masson’s trichrome staining was used to analyze the collagen content. RT-PCR and ELISA were performed to examine IL-6, TNF-α, IL-10, and VEGF expression levels. SIRT1 expression was assessed using immunohistochemistry staining and RT-PCR. VEGF-A protein expression and CD-31-positive microvascular density (MVD) in the thrombus were observed using immunohistochemistry. ResultsRE did not increase the incidence of pulmonary embolism. It reduced the weight and size of the thrombus and the collagen content. Conversely, it increased the recanalization rate. It also decreased the levels of the pro-inflammatory factors IL-6 and TNF-α and increased the expression levels of the anti-inflammatory factor IL-10. RE enhanced VEGF and SIRT1 expression levels and increased the MVD in the thrombosis area. After EX527 (SIRT1 inhibitor) was applied, the positive effects of exercise were suppressed.ConclusionsRE can inhibit inflammatory responses, reduce collagen deposition, and increase angiogenesis in DVT mice, thereby promoting thrombus resolution and recanalization. Its underlying mechanism may be associated with the upregulation of SIRT1 expression.

Nanoemulsion of the Essential Oil from Blumea balsamifera (L.) DC. and Its Effect on Trauma Repair.

The essential oil, extracted from the Hmong medicine Blumea balsamifera (L.) DC. (BBO), is a purely natural wound repair agent. Its application has, however, been restricted due to its low solubility and high volatility properties. In this study, we have developed a nanoemulsion formulation to improve the characteristics of BBO. The particle size of the nanoemulsion was normally distributed, and 71% of its range was concentrated between 10-100 nm, with an average particle size of 62.8 nm and an encapsulation rate of 98%. After 7 days of application, the wound healing rate of the BBO nanoemulsion (BBO-NE) group was 1.5 times higher than that of the normal BBO group. Along with histological observations, nanoemulsion formulation has been demonstrated to significantly improve the efficacy of BBO for wound repair. In addition, inflammation-related TLR4, CD14 and IRAK-1 gene transcript levels were significantly reduced after the administration of BBO-NE compared to the BBO group, with downregulation of 47.8%, 35.7% and 57.8%, respectively, while the secretion of pro-inflammatory factors IL-6 and TNF-α was also significantly reduced by 83.8% and 32.7%, respectively, in the nanoformulation administration (BBO-NE) group compared to the BBO group. In contrast, the anti-inflammatory factor IL-10 was significantly increased by 4.2-fold. It was further found that the drug penetration per unit area increased significantly 6.30% to 19.5% at different time points after the application of the BBO-NE compared to the BBO. In conclusion, nano-formulation enhanced the drug penetration of the BBO, reduced inflammatory factors, increased the level of anti-inflammatory factors, and promoted collagen deposition, thereby accelerating wound repair.

The protective effect of Ganoderma atrum polysaccharide on intestinal barrier function damage induced by acrylamide in mice through TLR4/MyD88/NF-κB based on the iTRAQ analysis.

The potential mechanism for the protective effect of Ganoderma atrum (G. atrum) polysaccharide (PSG-1) on acrylamide (AA) induced intestinal damage in mice was explored. Results showed that PSG-1 pretreatment prevented AA-induced injury by decreasing intestinal permeability and serum D-lactate acid (D-Lac) levels and increasing the number of small intestinal goblet cells and IgA secreting cells. In addition, PSG-1 pretreatment effectively reduced malondialdehyde (MDA) level and raised superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) activities in the intestine. Furthermore, PSG-1 administration decreased the levels of pro-inflammatory factors including IL-1β, TNF-α, and IL-6, while the anti-inflammatory factor IL-10 was elevated. Meanwhile, PSG-1 could increase the performance of tight junction (TJ) proteins such as Occludin, Claudin-1 and ZO-1. Moreover, according to the isobaric tag for relative and absolute quantitation (iTRAQ) and Western blot results, PSG-1 could reduce AA-induced intestinal injury through TLR4/MyD88/NF-κB signaling pathway. Overall, the present study suggested that PSG-1 protected intestinal permeability and barrier function in mice via reducing inflammation and oxidative stress, and effectively prevented AA-induced intestinal injury in mice.

Progesterone Enhances the Invasion of Trophoblast Cells by Activating PI3K/AKT Signaling Pathway to Prevent Preeclampsia

We aimed to explore whether the effect of progesterone on preeclampsia via the PI3K/AKT signaling pathway. First, we studied the role of progesterone in preeclampsia patients and HTR-8/Svneo cells by adding progesterone. Then PI3K inhibitor LY294002 was added. The effects of progesterone on preeclampsia were also studied in animals by constructing a preeclampsia rat model. CCK-8 and Transwell assay were applied to measure cell viability and invasion ability. ELISA was performed to measure progesterone, MMP-2, MMP-9, pro-inflammatory factors TNF-α, IL-1β, and anti-inflammatory factors IL-4, IL-10, and IL-13 levels. HE staining was used to detect the pathological changes in uterine spiral artery. Western blot was performed to detect Cyclin D1, PCNA, MMP-2, MMP-9, inflammatory factors TNF-α, IL-1β, IL-4, IL-10, IL-13, and PI3K/AKT signaling pathway related proteins AKT, p-AKT, PI3K, and p-PI3K expressions. Progesterone could reduce blood pressure and urine protein in pregnant women with preeclampsia. TNF-α and IL-1β levels were decreased, but IL-4, IL-10, IL-13, cyclin D1, and PCNA levels were increased in pregnant women with preeclampsia after using progesterone. After the use of progesterone, the symptoms of the PE model group were improved. Among them, the lumen of the placental uterine spiral artery was enlarged, and the fibrinoid necrosis of the uterine wall and acute atherosclerotic lesions were relieved. In addition, progesterone promoted HTR-8/Svneo cells proliferation and invasion. However, high expression of MMP-2, MMP-9, p-AKT, and p-PI3K in Normal and preeclampsia groups caused by progesterone was weakened after adding LY294002, indicating that progesterone could activate PI3K/AKT signaling pathway to regulate HTR-8/Svneo cells. Progesterone decreased urine protein and blood pressure of preeclampsia rats in a concentration-dependent manner. Moreover, progesterone activated the PI3K/AKT signaling pathway and inhibited the inflammatory response in preeclampsia rats.

Vascular endothelial growth factor attenuates neointimal hyperplasia of decellularized small-diameter vascular grafts by modulating the local inflammatory response.

Small-diameter vascular grafts (diameter <6mm) are in high demand in clinical practice. Neointimal hyperplasia, a common complication after implantation of small-diameter vascular grafts, is one of the common causes of graft failure. Modulation of local inflammatory responses is a promising strategy to attenuates neointimal hyperplasia. Vascular endothelial growth factor (VEGF) is an angiogenesis stimulator that also induces macrophage polarization and modulates inflammatory responses. In the present study, we evaluated the effect of VEGF on the neointima hyperplasia and local inflammatory responses of decellularized vascular grafts. In the presence of rhVEGF-165 in RAW264.6 macrophage culture, rhVEGF-165 induces RAW264.6 macrophage polarization to M2 phenotype. Decellularized bovine internal mammary arteries were implanted into the subcutaneous and infrarenal abdominal aorta of New Zealand rabbits, with rhVEGF-165 applied locally to the adventitial of the grafts. The vascular grafts were removed en-bloc and submitted to histological and immunofluorescence analyses on days 7 and 28 following implantation. The thickness of the fibrous capsule and neointima was thinner in the VEGF group than that in the control group. In the immunofluorescence analysis, the number of M2 macrophages and the ratio of M2/M1 macrophages in vascular grafts in the VEGF group were higher than those in the control group, and the proinflammatory factor IL-1 was expressed less than in the control group, but the anti-inflammatory factor IL-10 was expressed more. In conclusion, local VEGF administration attenuates neointimal hyperplasia in decellularized small-diameter vascular grafts by inducing macrophage M2 polarization and modulating the inflammatory response.