Macrophage/Microglia Sirt3 Contributes to the Anti-inflammatory Effects of Resveratrol Against Experimental Intracerebral Hemorrhage in Mice.

Intracerebral hemorrhage (ICH) is a devastating stroke type with high mortality and disability. Inflammatory response induced by macrophages/microglia (M/Ms) activation is one of the leading causes of brain damage after ICH. The anti-inflammatory effects of resveratrol (RSV) have already been evaluated in several models of central nervous system disease. Therefore, we designed the current study to assess the role of RSV in ICH and explore its downstream mechanism related to Sirt3. The autologous artery blood injection was administrated to create an ICH mouse model. M/Ms-specific Sirt3 knockout Sirt3f/f; CX3CR1-Cre (Sirt3 cKO) mouse was used to evaluate the role of Sirt3 on RSV treatment. Neuronal function and hematoma volume were assessed to indicate brain damage. The pro-inflammatory marker (CD16) and cytokine (TNF) were measured to evaluate the inflammatory effects. Our results showed that RSV treatment alleviates neurological deficits, reduces cell death, and increases hematoma clearance on day 7 after ICH. In addition, RSV effectively suppressed CD16+ M/Ms activation and decreased TNF release. In Sirt3 cKO mice, the protective effects of RSV were abolished, indicating the potential mechanism of RSV was partially due to Sirt3 signaling activation. Therefore, RSV could be a promising candidate and therapeutic agent for ICH and Sirt3 could be a potential target to inhibit inflammation.

The causal effects of inflammatory bowel disease on primary biliary cholangitis: A bidirectional two-sample Mendelian randomization study.

BACKGROUND: Observational studies have indicated that the incidence of primary biliary cholangitis (PBC) is higher in inflammatory bowel disease (IBD) patients than that in healthy people. However, whether the correlation is causal remains unclear. METHODS: The genetic associations with IBD were obtained from publicly available genome-wide association studies (GWAS) of European ancestry with 31 665 cases and 33 977 controls, consisting of 17 897 Crohn's disease (CD) and 13 768 ulcerative colitis (UC) cases. The genetic associations with PBC were obtained from a European GWAS with 2764 cases and 10 475 controls. A bidirectional two-sample Mendelian randomization (MR) design was implemented to determine the causal relationship between IBD and PBC. In the forward MR, the IBD was treated as the exposure while the PBC was the exposure in the reverse MR. The inverse-variance-weighted (IVW) method was utilized as the main statistic method, and a series of sensitivity analyses were performed to detect heterogeneity and horizontal pleiotropy. RESULTS: A total of 99 valid instrumental variables (IVs) were selected for IBD and the number of IVs for PBC was 18. The forward MR analysis indicated that genetically predicted IBD (UC and CD) was significantly associated with an increased risk of PBC (IVW OR = 1.343; 95% CI: 1.220-1.466). Similar casual associations were observed in UC (IVW OR = 1.244; 95% CI: 1.057-1.430) and CD (IVW OR = 1.269; 95% CI: 1.159-1.379). Such results were still consistent in multiple MR methods. The reverse MR analysis implicated that genetic susceptibility to PBC might not alter the risk of IBD (IVW OR = 1.070; 95% CI: 0.984-1.164). CONCLUSION: Our study found that genetically predicted IBD can increase the risk of PBC while not vice versa in the European population, which may enlighten the aetiology of PBC, together with the IBD patient management.

Adhesion of Escherichia coli O157:H7 during sublethal injury and resuscitation: Importance of pili and surface properties.

Escherichia coli O157:H7 can recover from sublethally injured (SI) state, which causes threat of foodborne illness. Adhesion plays a key role in the carriage of pathogens in food. In this study, we investigated the adhesion ability of SI and recovered E. coli O157:H7 wildtype and its three pili-deficient mutants (curli, type 1 fimbriae, and type IV pili) on six food-related surfaces. Plate counting was used to determine adhesion population after washing and oscillating the surfaces. Spinach exhibited the stronger adhesion population of E. coli O157:H7 than the other fresh produces (p < 0.05). In addition, at least one key pili dominated adhesion on these surfaces, and curli was always included. The adhesion population and contribution of different types of pili were jointly affected by surface and physiological state. This can be attributed to high hydrophobicity and positive charge density on surface and different expression levels of csgB, fimA, fimC and ppdD in SI and recovered cells. Among glucose, mannose, maltose, fructose, lactose, and sucrose, addition of 0.5% mannose could reduce adhesion of cells at all physiological states on stainless steel. Overall, this research will provide support for controlling adhesion of SI and recovered E. coli O157:H7.

Intermittent fasting reduces neuroinflammation in intracerebral hemorrhage through the Sirt3/Nrf2/HO-1 pathway.

BACKGROUND: Inflammation contributes to the poor prognosis of intracerebral hemorrhage (ICH). Intermittent fasting (IF) has been shown to be protective against inflammation in multiple pathogenic processes. In the present study, we aimed to investigated the beneficial effects of IF in attenuating neuroinflammation and neurological deficits in a mouse model of ICH and to investigate the underlying mechanism. METHODS: ICH was modeled by intrastriatal injection of autologous blood and IF was modeled by every-other-day feeding in male control mice (C57BL/6), mice with and microglia specific knockout Sirt3f/f;Cx3cr1-Cre (Sirt3 cKO), and Sirt3f/f (wild-type) mice. Brain tissues and arterial blood were harvested at 1, 3, 7 and 28 days after ICH for immunohistochemistry analysis of Iba-1, DARPP-32 and HO-1, morphological analysis by HE staining and inflammatory factor release tests by ELISA. Neurological functions were approached by corner test and cylinder test. Fluorescent double-labeled staining of Iba-1 with CD16, Arg1 or Sirt3 was used to provide direct image of co-expression of these molecules in microglia. TUNEL, cleaved caspase-3 and Nissl staining was performed to evaluate cellular injuries. RESULTS: IF alleviated neurological deficits in both acute and chronic phases after ICH. Morphologically, IF enhanced hematoma clearance, reduced brain edema in acute phase and attenuated striatum atrophy in chronic phase. In addition, IF decreased the numbers of TUNEL+ cells and increased Nissl+ neuron number at day 1, 3 and 7 after ICH. IF suppressed CD16+Iba-1+ microglia activation at day 3 after ICH and reduced inflammatory releases, such as IL-1ß and TNF-α. The above effects of IF were attenuated by microglia Sirt3 deletion partly because of an inhibition of Nrf2/HO-1 signaling pathway. Interestingly, IF increased Iba-1+ microglia number at day 7 which mainly expressed Arg1 while decreased the proinflammatory factor levels. In mice with microglia-specific Sirt3 deletion, the effects of IF on Iba-1+ microglia activation and anti-inflammatory factor expressions were attenuated when compared with wild-type Sirt3f/f mice. CONCLUSIONS: IF protects against ICH by suppressing the inflammatory responses via the Sirt3/Nrf2/HO-1 pathway.

Family functioning and health-related quality of life of inpatients with coronary heart disease: a cross-sectional study in Lanzhou city, China.

BACKGROUND: A key outcome in coronary heart disease (CHD) is Health Related Quality of Life (HRQoL), and family functioning is important in the management of CHD. But few studies have examined both together, and little is known about them among inpatients with CHD in less developed areas of China. Therefore, this study aimed to assess the HRQoL and family functioning status of inpatients with CHD in Lanzhou from Northwest China, and identify the factors that affect their HRQoL. METHODS: A cross­sectional study was conducted in 224 CHD inpatients at one major hospital. Sociodemographic data and disease information of CHD inpatients were collected by face-to-face using a structured questionnaire and data were also obtained from patient medical records. HRQoL was measured using the Sickness Impact Profile (SIP). Family functioning was measured using the family APGAR index. Multiple binary logistic regression analysis (MBLRA) was used to explore potential risk factors associated with HRQoL, and Pearson's correlations were used to assess the relationship between family functioning and HRQoL. RESULTS: The overall, physical and psychosocial SIP scores were 25.03 ± 8.52, 18.61 ± 9.90 and 28.08 ± 9.64, respectively. The total family APGAR score was 6.11 ± 2.45. MBLRA found older age, poorer cardiac function and more severe disease were associated with poorer HRQoL, while better family functioning, higher monthly income, and urban living were associated with better HRQoL. Family functioning was weakly to moderately correlated with total and psychosocial HRQoL. CONCLUSIONS: Older and less affluent inpatients with lower educational level, less family support and more severe CHD have poorest quality of life, and health care providers should consider interventions to support them.

The influence of professional identity on work engagement among nurses working in nursing homes in China.

AIM: To assess the influence of professional identity on work engagement among nurses working in nursing homes in China. BACKGROUND: China is faced with an increasingly ageing population. There is a shortage of adequately trained nursing personnel and a high turnover rate among nurses. Work engagement is a key factor in improving nurses' performance and improving professional identity is critical to increase work productivity and satisfaction. METHODS: We conducted a cross-sectional survey of 272 nurses working in nursing homes. And the data were analysed by descriptive analyses, univariate analysis and Multiple regression analyses. RESULTS: The overall average work engagement score was 3.99 ± 1.04. Professional identity was the only factor that significantly influenced the 'vigour' and 'absorption' of nurses. Age, ethnicity and professional identity were significant predictors of 'dedication'. CONCLUSIONS: A positive professional identity can lead to a better work engagement among nurses working in nursing homes in China. IMPLICATIONS FOR NURSING MANAGEMENT: To enhance the work engagement of nurses working in nursing homes, nursing leaders should create a respectful and equal work environment, create a favourable image of the industry and the profession and strengthen training to improve the professional identity.

LncRNA MCF2L-AS1 aggravates the malignant development of colorectal cancer via targeting miR-105-5p/RAB22A axis.

BACKGROUND: Colorectal cancer (CRC) represents one of the major malignant cancers in the world. It has been demonstrated that long non-coding RNAs (lncRNAs) can cause great influences on various human cancers. Though MCF.2 cell line derived transforming sequence like antisense RNA 1 (MCF2L-AS1) and its carcinogenic effect in CRC has been elucidated by several previous researches, the underlying mechanism remains unknown. AIM: We aimed at exploring the function and regulatory mechanism of MCF2L-AS1 in CRC. METHODS: MCF2L-AS1 expression in CRC cells was tested via RT-qPCR assay. The effects of MCF2L-AS1 on the biological properties of CRC cells were testified through functional experiments. The molecular mechanism of MCF2L-AS1 was verified through mechanism experiments. RESULTS: MCF2L-AS1 was highly expressed in CRC cells, and it could enhance the proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) process of CRC cells. MiR-105-5p was sponged by MCF2L-AS1 in CRC cells and Ras-related protein Rab-22A (RAB22A) was verified to be the downstream target of miR-105-5p. It was verified through rescue assays that RAB22A overexpression or miR-105-5p silencing could reverse the repressive impact of MCF2L-AS1 silencing on CRC progression. CONCLUSION: MCF2L-AS1 accelerated the malignant development of CRC cells by targeting the miR-105-5p/RAB22A axis.

Alexithymia, social support, depression, and burnout among emergency nurses in China: a structural equation model analysis.

BACKGROUND: Several factors are associated with the incidence of burnout, including alexithymia, social support, and depression. The relative importance of these three key parameters as mediators of burnout, however, is not well understood. In addition, there have been few studies to date specifically examining the association between alexithymia and burnout among nurses in China. PURPOSE: To evaluate the relationship of burnout with alexithymia, social support, and depression across emergency department nurses in China. METHODS: This descriptive, cross-sectional survey was conducted using a convenience sampling methodology to survey nurses responsible for direct emergency care (n = 413) from 18 tertiary hospitals in Western, Eastern, Northern, and Southern China between May 2020 and June 2020. A structural equation modeling approach was then used to assess a hypothetical model wherein alexithymia both directly and indirectly affects burnout among emergency nurses via impacting the incidence of depression and perceived social support. RESULTS: Results supported all driving hypotheses. Alexithymia was positive direct correlated with burnout (ß = 0.35; P < 0.001) and depression (ß = 0.50; P < 0.001), and exhibited a negative direct effect on social support (ß = - 0.14; P = 0.041). Depression was associated with burnout, both directly (ß = 0.24; P < 0.001) and indirectly (ß = 0.15; P < 0.001) through its relationship with social support. Alexithymia was the factor most strongly associated with burnout, and it was able to affect burnout indirectly through depression and social support. CONCLUSIONS: We found that among emergency nurses in China, alexithymia was correlated with burnout, depression, and social support. Alexithymia was the factor most strongly associated with burnout. These data suggest that providing better social support and alleviating alexithymia may decrease rates of burnout among emergency nurses.

Improvements on biological and antimicrobial properties of titanium modified by AgNPs-loaded chitosan-heparin polyelectrolyte multilayers.

Microbial infection around dental implants is a major cause for the loss of devices, including soft tissue infection in early period, post-operation peri-implantitis, and osseointegration failure. Silver nanoparticles (AgNPs) with wide antimicrobial spectrum, strong antimicrobial effect and hypotoxicity, as well as low incidence of antibiotic resistance, are widely involved in biomedical applications. Herein, firmly anchoring AgNPs onto the surface of implants through physical-chemical reaction is likely to relieve the above issues. In this study, AgNPs were biosynthesized by a simple and "green" method with chitosan (CS) as stabilizing and reducing agents. Then, AgNPs-loaded CS-heparin polyelectrolyte multilayers (PEMs) were constructed on alkali-heat treated titanium (Ti) substrates via layer-by-layer (LbL) self-assembly technique. The successful surface modification could be confirmed by scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS), and the constructed system could provide the continuous release of Ag+ over 28 days till mucosa healing. In short, this work revealed that the construction of multilayer coatings containing AgNPs on Ti substrates promoted adhesion and proliferation of human gingival fibroblasts (HGFs) and also enhanced the antimicrobial properties. This manifests the LbL technique is a viable and promising method for forming continuous antimicrobial coatings, to reduce microbial infection and improve the quality of peri-implant soft tissue seal. The preparation process of AgNPs-loaded CS-heparin PEMs on Ti substrate.

Helicobacter pylori induces caudal-type homeobox protein 2 and cyclooxygenase 2 expression by modulating microRNAs in esophageal epithelial cells.

Dysregulation of microRNAs (miRNAs) has been linked to virulence factors of Helicobacter pylori. The role of H. pylori in esophageal disease has not been clearly defined. We previously reported that H. pylori esophageal colonization promotes the incidence of Barrett's esophagus and esophageal adenocarcinoma in vivo. Here, we studied the direct effects of H. pylori on the transformation of esophageal epithelial cells, with particular focus on whether H. pylori exerts its effects by modulating miRNAs and their downstream target genes. The normal human esophageal cell line HET-1A was chronically exposed to H. pylori extract and/or acidified deoxycholic acid for up to 36 weeks. The miRNA profiles of the esophageal epithelial cells associated with H. pylori infection were determined by microarray analysis. We found that chronic H. pylori exposure promoted acidified deoxycholic acid-induced morphological changes in HET-1A cells, along with aberrant overexpression of intestinal metaplasia markers and tumorigenic factors, including caudal-type homeobox protein 2 (CDX2), mucin 2, and cyclooxygenase 2 (COX2). Helicobacter pylori modified the miRNA profiles of esophageal epithelial cells, particularly aberrant silencing of miR-212-3p and miR-361-3p. Moreover, in biopsies from Barrett's esophagus patients, esophageal H. pylori colonization was associated with a significant decrease in miR-212-3p and miR-361-3p expression. Furthermore, we identified COX2 as a target of miR-212-3p, and CDX2 as a target of miR-361-3p. Helicobacter pylori infection of esophageal epithelial cells was associated with miRNA-mediated upregulation of oncoprotein CDX2 and COX2. Our observations provide new evidence about the molecular mechanisms underlying the association between H. pylori infection and esophageal carcinogenesis.

Knockdown of SALL4 inhibits the proliferation and reverses the resistance of MCF-7/ADR cells to doxorubicin hydrochloride.

BACKGROUND: Breast cancer is the most frequent malignancy in women and drug resistance is the major obstacle for its successful chemotherapy. In the present study, we analyzed the involvement of an oncofetal gene, sal-like 4 (SALL4), in the tumor proliferation and drug resistance of human breast cancer. RESULTS: Our study showed that SALL4 was up-regulated in the drug resistant breast cancer cell line, MCF-7/ADR, compared to the other five cell lines. We established the lentiviral system expressing short hairpin RNA to knockdown SALL4 in MCF-7/ADR cells. Down-regulation of SALL4 inhibited the proliferation of MCF-7/ADR cells and induced the G1 phase arrest in cell cycle, accompanied by an obvious reduction of the expression of cyclinD1 and CDK4. Besides, down-regulating SALL4 can re-sensitize MCF-7/ADR to doxorubicin hydrochloride (ADMh) and had potent synergy with ADMh in MCF-7/ADR cells. Depletion of SALL4 led to a decrease in IC50 for ADMh and an inhibitory effect on the ability to form colonies in MCF-7/ADR cells. With SALL4 knockdown, ADMh accumulation rate of MCF-7/ADR cells was increased, while the expression of BCRP and c-myc was significantly decreased. Furthermore, silencing SALL4 also suppressed the growth of the xenograft tumors and reversed their resistance to ADMh in vivo. CONCLUSION: SALL4 knockdown inhibits the growth of the drug resistant breast cancer due to cell cycle arrest and reverses tumor chemo-resistance through down-regulating the membrane transporter, BCPR. Thus, SALL4 has potential as a novel target for the treatment of breast cancer.

Upregulated LASP-1 correlates with a malignant phenotype and its potential therapeutic role in human cholangiocarcinoma.

LIM and SH3 protein 1 (LASP-1) is demonstrated to play a key role in occurrence and development of tumors. However, the expression and function of LASP-1 in cholangiocarcinoma (CCA) remain largely unexplored. This study aimed to investigate the effect of regulated LASP-1 expression on migration, invasion, proliferation, and apoptosis of CCA cells and on tumorigenesis in vivo, and to examine clinico-oncological correlates of LASP-1 expression. Expression of LASP-1 by immunohistochemistry was evaluated in CCA tissue samples. HCCC-9810 and RBE cells were transfected with the LASP-1 small interfering RNA (siRNA), and the effect of knocking down LASP-1 gene expression on cell migration, invasion, proliferation, and apoptosis were examined by wound healing, transwell assays, CCK-8 assays, colony formation, and flow cytometry assays, respectively. Xenograft tumor model was used to validate the effect of downregulated LASP-1 in vivo. Our results demonstrated that LASP-1 was over-expressed in CCA tissues, positively correlating with larger tumors, poor histological differentiation, lymph node metastasis, advanced TNM stage, and poor prognosis in CCA patients (P < 0.05). Downregulation of LASP-1 in HCCC-9810 and RBE cell lines significantly increased cell apoptosis and suppressed cell migration, invasion, and proliferation in vitro and tumorigenesis in vivo. Our results indicate that LASP-1 may essentially involve in the metastasis and growth of CCA and clinical significance of LASP-1 may reside in function as a biomarker to predict prognosis and as a promising therapeutic strategy for CCA patients by the inhibition of LASP-1 expression.

Influence of Water Activated by Far infrared Porous Ceramics on Nitrogen Absorption in the Pig Feed.

Under modern and, intensive feeding livestock and poultry density has increased, and brought a deterioration of the farm environment. The livestock and their excrement generate harmful gases such as ammonia, etc. which restricted the sustainable development and improvement of production efficiency of animal husbandry. In this paper, a new kind of far infrared porous ceramics was prepared to activate, the animal drinking water. The activated water and common water were then supplied to pigs, and the fresh pig feces of experimental group and:control group were collected on a regular basis. The residual protein content in feces was tested by Kjeldahl nitrogen method to study the influence law of the porous ceramics on absorbing nitrogen element in animal feces. The results showed that compared with the control group, the protein content in the experimental group decreased on average by 39.2%. The activated drinking water was conducive to the absorption of nitrogen in pig feed. The clusters of water molecules became smaller under the action of the porous ceramics. Hence, they were easy to pass through the water protein channel on the cell membrane for speeding up the metabolism.

[Salvia Miltiorrhiza reduces plasma levels of asymmetric ADMA in patients with non-ST elevation myocardial infarction undergoing percutaneous coronary intervention].

OBJECTIVE: To study changes of plasma ADMA levels of patients with non-ST elevation myocardial infarction (NSTEMI) undergoing percutaneous coronary intervention (PCI) and to explore the effect of Salvia Miltiorrhiza (SM) on them. METHODS: Totally 52 patients with confirmed NSTEMI undergoing PCI were randomly assigned to the SM treated group and the control group, 26 in each group. Patients in the SM treated group received the conventional therapy plus SM (1 g each time, three times per day till one month after PCI). Those in the control group only received the conventional therapy. Plasma ADMA levels were measured before PCI, and at day 1 and 30 after PCI. RESULTS: Plasma ADMA levels in both group obviously decreased at day 30 after PCI with statistical difference (P < 0.01). The decrement was more obviously seen in the SM treated group, with statistical difference when compared with the control group (P < 0.01). CONCLUSIONS: Patients with NSTEMI undergoing PCI could have plasma ADMA levels decreased. Administration of SM just before PCI might be associated with negative regulating plasma ADMA levels.

Comparative effects of exercise interventions and mindfulness-based interventions for cognitive impairment and quality of life in breast cancer survivors during or after cancer treatment: A systematic review and Bayesian network meta-analysis.

OBJECTIVE: The aim of this network meta-analysis was to compare the improvement effects of various exercise interventions and mindfulness-based interventions to determine the best interventions for the improvement of cognitive impairment. DESIGN: 7 databases were searched to screen RCTs of exercise interventions and mindfulness-based interventions to improve cognitive impairment. The network meta-analysis was performed using Revman 5.3, R 4.2.1 and ADDIS 1.16.8 software. RESULTS: 34 RCTs involving 14 interventions were included in the study. In terms of cognitive function, except for mindfulness-based stress reduction, all interventions showed significantly greater improvement in cognitive function compared with conventional therapy. Physical activity and Qigong showed better effect in improving executive function. In terms of improving verbal memory, compensatory cognitive training, neurofeedback training, Qigong and sham Qigong were more effective than other interventions. On performing surface under the cumulative ranking curve analysis, acceptance and commitment therapy, neurofeedback training, Qigong, and mediation had the best effects on cognitive function, quality of life, executive function, and processing speed, respectively. CONCLUSIONS: Mindfulness-based interventions were found to be more effective than exercise interventions for alleviating cognitive impairment. More robust RCTs focusing on acceptance and commitment therapy for cognitive impairment are required to support the current evidence.

Aspirin treatment for unruptured intracranial aneurysms: Focusing on its anti-inflammatory role.

Intracranial aneurysms (IAs), as a common cerebrovascular disease, claims a worldwide morbidity rate of 3.2%. Inflammation, pivotal in the pathogenesis of IAs, influences their formation, growth, and rupture. This review investigates aspirin's modulation of inflammatory pathways within this context. With IAs carrying significant morbidity and mortality upon IAs rupture and current interventions limited to surgical clipping and endovascular coiling, the quest for pharmacological options is imperative. Aspirin's role in cardiovascular prevention, due to its anti-inflammatory effects, presents a potential therapeutic avenue for IAs. In this review, we examine aspirin's efficacy in experimental models and clinical settings, highlighting its impact on the progression and rupture risks of unruptured IAs. The underlying mechanisms of aspirin's impact on IAs are explored, with its ability examined to attenuate endothelial dysfunction and vascular injury. This review may provide a theoretical basis for the use of aspirin, suggesting a promising strategy for IAs management. However, the optimal dosing, safety, and long-term efficacy remain to be established. The implications of aspirin therapy are significant in light of current surgical and endovascular treatments. Further research is encouraged to refine aspirin's clinical application in the management of unruptured IAs, with the ultimate aim of reducing the incidence of aneurysms rupture.

Long-chain fatty acids - The turning point between 'mild' and 'severe' acute pancreatitis.

Acute pancreatitis (AP) is an inflammatory disease characterized by localized pancreatic injury and a systemic inflammatory response. Fatty acids (FAs), produced during the breakdown of triglycerides (TGs) in blood and peripancreatic fat, escalate local pancreatic inflammation to a systemic level by damaging pancreatic acinar cells (PACs) and triggering M1 macrophage polarization. This paper provides a comprehensive analysis of lipases' roles in the onset and progression of AP, as well as the effects of long-chain fatty acids (LCFAs) on the function of pancreatic acinar cells (PACs). Abnormalities in the function of PACs include Ca2+ overload, premature trypsinogen activation, protein kinase C (PKC) expression, endoplasmic reticulum (ER) stress, and mitochondrial and autophagic dysfunction. The study highlights the contribution of long-chain saturated fatty acids (LC-SFAs), especially palmitic acid (PA), to M1 macrophage polarization through the activation of the NLRP3 inflammasome and the NF-κB pathway. Furthermore, we investigated lipid lowering therapy for AP. This review establishes a theoretical foundation for pro-inflammatory mechanisms associated with FAs in AP and facilitating drug development.

Toll-like receptor 2 deficiency promotes the generation of alloreactive γδT17 cells after cardiac transplantation in mice.

Homograft rejection is the main cause of heart transplantation failure. The role of TLR2, a major member of the toll-like receptor (TLR) family, in transplantation rejection is has yet to be elucidated. In this study, we used a mouse model of acute cardiac transplantation rejection to investigate whether the TLR2 signalling pathway can regulate cardiac transplantation rejection by regulating alloreactive IL-17+γδT (γδT17) cells. We found that the expression of TLR2 on the surface of dendritic cells (DCs) and macrophages increased during acute transplantation rejection. In addition, our investigation revealed that γδT17 cells exert a significant influence on acute cardiac transplantation rejection. TLR2 gene knockout resulted in an increase in alloreactive γδT17 cells in the spleen and heart grafts of recipient mice compared with wild-type recipient mice and an increase in the mRNA expression of IL-17, IL-1ß, CCR6, and CCL20 in the heart grafts. In an in vitro experiment, a mixed lymphocyte reaction was conducted to assess the impact of TLR2 deficiency on the generation of γδT17 cells, which further substantiated a significant increase compared to that in wild-type controls. Furthermore, the mixed lymphocyte reaction showed that TLR2 regulated the production of γδT17 cells by regulating the ability of DCs to secrete IL-1ß. These results suggest that TLR2 signalling is important for regulating the generation of γδT17 cells after cardiac allograft transplantation.

Impairment of Autophagic Flux After Hypobaric Hypoxia Potentiates Oxidative Stress and Cognitive Function Disturbances in Mice.

Acute hypobaric hypoxic brain damage is a potentially fatal high-altitude sickness. Autophagy plays a critical role in ischemic brain injury, but its role in hypobaric hypoxia (HH) remains unknown. Here we used an HH chamber to demonstrate that acute HH exposure impairs autophagic activity in both the early and late stages of the mouse brain, and is partially responsible for HH-induced oxidative stress, neuronal loss, and brain damage. The autophagic agonist rapamycin only promotes the initiation of autophagy. By proteome analysis, a screen showed that protein dynamin2 (DNM2) potentially regulates autophagic flux. Overexpression of DNM2 significantly increased the formation of autolysosomes, thus maintaining autophagic flux in combination with rapamycin. Furthermore, the enhancement of autophagic activity attenuated oxidative stress and neurological deficits after HH exposure. These results contribute to evidence supporting the conclusion that DNM2-mediated autophagic flux represents a new therapeutic target in HH-induced brain damage.

Shank3 ameliorates neuronal injury after cerebral ischemia/reperfusion via inhibiting oxidative stress and inflammation.

Shank3, a key molecule related to the development and deterioration of autism, has recently been found to downregulate in the murine brain after ischemia/reperfusion (I/R). Despite this discovery, however, its effects on neuronal injury and the mechanism underlying the effects remain to be clarified. To address this, in this study, based on genetically modified mice models, we revealed that the expression of Shank3 showed a time-dependent change in murine hippocampal neurons after I/R, and that conditional knockout (cko) of Shank3 in neurons resulted in aggravated neuronal injuries. The protective effects of Shank3 against oxidative stress and inflammation after I/R were achieved through direct binding STIM1 and subsequent proteasome-mediated degradation of STIM1. The STIM1 downregulation induced the phosphorylation of downstream Nrf2 Ser40, which subsequently translocated to the nucleus, and further increased the expression of antioxidant genes such as NQO1 and HO-1 in HT22 cells. In vivo, the study has further confirmed that double knockout of Shank3 and Stim1 alleviated oxidative stress and inflammation after I/R in Shank3cko mice. In conclusion, the present study has demonstrated that Shank3 interacts with STIM1 and inhibits post-I/R neuronal oxidative stress and inflammatory response via the Nrf2 pathway. This interaction can potentially contribute to the development of a promising method for I/R treatment.