The cytochrome P4501A1 (CYP1A1) inhibitor bergamottin enhances host tolerance to multidrug-resistant Vibrio vulnificus infection.

PURPOSE: Vibrio vulnificus (V. Vulnificus) infection is characterized by rapid onset, aggressive progression, and challenging treatment. Bacterial resistance poses a significant challenge for clinical anti-infection treatment and is thus the subject of research. Enhancing host infection tolerance represents a novel infection prevention strategy to improve patient survival. Our team initially identified cytochrome P4501A1 (CYP1A1) as an important target owing to its negative modulation of the body's infection tolerance. This study explored the superior effects of the CYP1A1 inhibitor bergamottin compared to antibiotic combination therapy on the survival of mice infected with multidrug-resistant V. Vulnificus and the protection of their vital organs. METHODS: An increasing concentration gradient method was used to induce multidrug-resistant V. Vulnificus development. We established a lethal infection model in C57BL/6J male mice and evaluated the effect of bergamottin on mouse survival. A mild infection model was established in C57BL/6J male mice, and the serum levels of creatinine, urea nitrogen, aspartate aminotransferase, and alanine aminotransferase were determined using enzyme-linked immunosorbent assay to evaluate the effect of bergamottin on liver and kidney function. The morphological changes induced in the presence of bergamottin in mouse organs were evaluated by hematoxylin and eosin staining of liver and kidney tissues. The bacterial growth curve and organ load determination were used to evaluate whether bergamottin has a direct antibacterial effect on multidrug-resistant V. Vulnificus. Quantification of inflammatory factors in serum by enzyme-linked immunosorbent assay and the expression levels of inflammatory factors in liver and kidney tissues by real-time quantitative polymerase chain reaction were performed to evaluate the effect of bergamottin on inflammatory factor levels. Western blot analysis of IκBα, phosphorylated IκBα, p65, and phosphorylated p65 protein expression in liver and kidney tissues and in human hepatocellular carcinomas-2 and human kidney-2 cell lines was used to evaluate the effect of bergamottin on the nuclear factor kappa-B signaling pathway. One-way ANOVA and Kaplan-Meier analysis were used for statistical analysis. RESULTS: In mice infected with multidrug-resistant V. Vulnificus, bergamottin prolonged survival (p = 0.014), reduced the serum creatinine (p = 0.002), urea nitrogen (p = 0.030), aspartate aminotransferase (p = 0.029), and alanine aminotransferase (p = 0.003) levels, and protected the cellular morphology of liver and kidney tissues. Bergamottin inhibited interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α expression in serum (IL-1ß: p = 0.010, IL-6: p = 0.029, TNF-α: p = 0.025) and inhibited the protein expression of the inflammatory factors IL-1ß, IL-6, TNF-α in liver (IL-1ß: p = 0.010, IL-6: p = 0.011, TNF-α: p = 0.037) and kidney (IL-1ß: p = 0.016, IL-6: p = 0.011, TNF-α: p = 0.008) tissues. Bergamottin did not affect the proliferation of multidrug-resistant V. Vulnificus or the bacterial load in the mouse peritoneal lavage fluid (p = 0.225), liver (p = 0.186), or kidney (p = 0.637). CONCLUSION: Bergamottin enhances the tolerance of mice to multidrug-resistant V. Vulnificus infection. This study can serve as a reference and guide the development of novel clinical treatment strategies for V. Vulnificus.

Development and validation of a predictive model for acute-on-chronic liver failure after transjugular intrahepatic portosystemic shunt.

BACKGROUND: Transjugular intrahepatic portosystemic shunt (TIPS) is a cause of acute-on-chronic liver failure (ACLF). AIM: To investigate the risk factors of ACLF within 1 year after TIPS in patients with cirrhosis and construct a prediction model. METHODS: In total, 379 patients with decompensated cirrhosis treated with TIPS at Nanjing Drum Tower Hospital from 2017 to 2020 were selected as the training cohort, and 123 patients from Nanfang Hospital were included in the external validation cohort. Univariate and multivariate logistic regression analyses were performed to identify independent predictors. The prediction model was established based on the Akaike information criterion. Internal and external validation were conducted to assess the performance of the model. RESULTS: Age and total bilirubin (TBil) were independent risk factors for the incidence of ACLF within 1 year after TIPS. We developed a prediction model comprising age, TBil, and serum sodium, which demonstrated good discrimination and calibration in both the training cohort and the external validation cohort. CONCLUSION: Age and TBil are independent risk factors for the incidence of ACLF within 1 year after TIPS in patients with decompensated cirrhosis. Our model showed satisfying predictive value.

Catalytic Asymmetric Cascade Dearomatization of Indoles via a Photoinduced Pd-Catalyzed 1,2-Bisfunctionalization of Butadienes.

Photoinduced Pd-catalyzed bisfunctionalization of butadienes with a readily available organic halide and a nucleophile represents an emerging and attractive method to assemble versatile alkenes bearing various functional groups at the allylic position. However, enantiocontrol and/or diastereocontrol in the C-C or C-X bond-formation step have not been solved due to the open-shell process. Herein, we present a cascade asymmetric dearomatization reaction of indoles via photoexcited Pd-catalyzed 1,2-biscarbonfunctionalization of 1,3-butadienes, wherein asymmetric control on both the nucleophile and electrophile part is achieved for the first time in photoinduced bisfunctionalization of butadienes. This method delivers structurally novel chiral spiroindolenines bearing two contiguous stereogenic centers with high diastereomeric ratios (up to >20 : 1 dr) and good to excellent enantiomeric ratios (up to 97 : 3 er). Experimental and computational studies of the mechanism have confirmed a radical pathway involving excited-state palladium catalysis. The alignment and non-covalent interactions between the substrate and the catalyst were found to be essential for stereocontrol.

Microbiome dysbiosis by antibiotics protects cartilage degradation in OAOP mice.

The role of this study was to evaluate the impact of gut microbiota depletion on the progression of osteoarthritis (OA) and osteoporosis (OP). We conducted an experimental mouse model of OA and OP over an 8-week period. The model involved destabilization of the medial meniscus and bilateral ovariectomy (OVX). To deplete the gut microbiota, we administered a course of antibiotics for 8 weeks. The severity of OA was assessed through micro-CT scanning, X-rays, and immunohistochemical staining. Microbiome analysis was performed using PCR of 16S DNA on fecal samples, and the levels of serum lipopolysaccharide, interleukin 6, tumor necrosis factor-α (TNF-α), osteocalcin, and estrogen were measured using enzyme-linked immunosorbent assay. We found that in comparison to the OVX+OA group, the OVX+OA+ABT group exhibited increased bone mineral density (P < 0.0001), bone volume fraction (P = 0.0051), and trabecular number (P = 0.0023) in the metaphyseal bone. Additionally, cartilage injury and levels of matrix metalloproteinase 13 were reduced in the OVX+OA+ABT group compared to the OVX+OA group. Moreover, the OVX+OA+ABT group demonstrated decreased relative abundance of Bacteroidetes, serum lipopolysaccharide (P = 0.0005), TNF-α (P < 0.0001), CTX-1 (P = 0.0002), and increased expression of bone formation markers. These findings were further supported by correlation network analyses. Depletion of gut microbiota was shown to protect against bone loss and cartilage degradation by modulating the composition of the gut microbiota in osteoporosis and osteoarthritis.

Histological evaluation of pyrrolizidine alkaloid-induced hepatic sinusoidal obstruction syndrome: Correlation with Drum Tower Severity Scoring.

BACKGROUND: Hepatic sinusoidal obstruction syndrome induced by pyrrolizidine alkaloids (PA-HSOS) is a complication of drug-induced liver damage. Few studies have examined the relationship between pathological changes and clinical circumstances in PA-HSOS. The Drum Tower Severity Scoring System (DTSS) was developed using prognostic indicators from clinical treatment outcomes. We hypothesized that the severity of pathological damage is consistent with DTSS. AIMS: We aimed to improve our understanding and assessment of vascular liver injury disease histopathology by studying larger sample sizes of human histopathological samples. We also wanted to confirm the link between histopathological findings and DTSS. METHODS: The study included 62 patients with PA-HSOS who underwent transjugular liver biopsy. Their hepatic pathological tissues were evaluated. Analyses of linear regression and Spearman's correlation were employed to examine the relationship between DTSS and pathological characteristics. RESULTS: Clinical performance and the DTSS score were used to determine histopathological severity. The sinusoidal congestion area (SCA), central venous endothelial injury (CVEI), and fibrinoid exudation in congestion foci (FECF) were significant indicators. SCA was linearly related to the DTSS score. CONCLUSION: Our findings show that hepatic pathological characteristics correlate with DTSS scores in PA-HSOS. SCA, CVEI, and FECF may be helpful for determining PA-HSOS severity.

Heavy macrophage infiltration identified by optical coherence tomography relates to plaque rupture.

OBJECTIVE: Risk stratification plays a critical role in patients with asymptomatic carotid atherosclerotic stenosis. Heavy macrophage infiltration (HMC) is an important factor of plaque destabilization. However, in vivo imaging technologies and screening criteria for HMC remain limited. We aimed to (i) introduce algorithms for in vivo detection of macrophage infiltrations using optical coherence tomography (OCT) and (ii) to investigate the threshold of HMC and its association with plaque vulnerability. METHODS: Ex vivo OCT images were co-registered with histopathology in 282 cross-sectional pairs from 19 carotid endarterectomy specimens. Of these, 197 randomly selected pairs were employed to define the parameters, and the remaining 85 pairs were used to evaluate the accuracy of the OCT-based algorithm in detecting macrophage infiltrations. Clinical analysis included 93 patients receiving carotid OCT evaluation. The prevalence and burden of macrophage infiltration were analyzed. Multivariable and subgroup analysis were performed to investigate the association between HMC and plaque rupture. RESULTS: The sensitivity and specificity of algorithm for detecting macrophage infiltration were 88.0% and 74.9%, respectively. Of 93 clinical patients, ruptured plaques exhibited higher prevalence of macrophage infiltration than nonruptured plaques (83.7% [36/43] vs 32.0% [16/50], p < 0.001). HMC was identified when the macrophage index was greater than 60.2 (sensitivity = 74.4%, specificity = 84.0%). Multivariable analysis showed that HMC and multiple calcification were independent risk factors for non-lipid-rich plaque rupture. INTERPRETATION: This study provides a novel approach and screening criteria for HMC, which might be valuable for atherosclerotic risk stratification.

Chicoric Acid Presented NLRP3-Mediated Pyroptosis through Mitochondrial Damage by PDPK1 Ubiquitination in an Acute Lung Injury Model.

Chicoric acid (CA), a functional food ingredient, is a caffeic acid derivative that is mainly found in lettuce, pulsatilla, and other natural plants. However, the anti-inflammatory effects of CA in acute lung injury (ALI) remain poorly understood. This study was conducted to investigate potential drug usage of CA for ALI and the underlying molecular mechanisms of inflammation. C57BL/6 mice were given injections of liposaccharide (LPS) to establish the in vivo model. Meanwhile, BMDM cells were stimulated with LPS+ATP to build the in vitro model. CA significantly alleviated inflammation and oxidative stress in both the in vivo and in vitro models of ALI through the inhibition of NLR family pyrin domain-containing 3 (NLRP3)-mediated pyroptosis. In addition, CA attenuated mitochondrial damage to suppress NLRP3-mediated pyroptosis in the in vivo and in vitro models of ALI by suppressing the production of reactive oxygen species (ROS) via inhibiting the Akt/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. CA inhibited the interaction between Akt at T308 and phosphoinositide-dependent kinase-1 (PDPK1) at S549, thus promoting the phosphorylation of the Akt protein. Furthermore, CA directly targeted the PDPK1 protein and accelerated PDPK1 ubiquitination, indicating that 91-GLY, 111-LYS, 126-TYR, 162-ALA, 205-ASP, and 223-ASP might be responsible for the interaction between PDPK1 and CA. In conclusion, CA from Lettuce alleviated NLRP3-mediated pyroptosis in the ALI model through ROS-induced mitochondrial damage by activating Akt/Nrf2 pathway via PDPK1 ubiquitination. The present study suggests that CA might be a potential therapeutic drug to treat or prevent ALI in pneumonia or COVID-19.

Effect of continuous subanesthetic esketamine infusion on postoperative fatigue in patients undergoing laparoscopic radical resection for colorectal cancer: a randomized controlled study.

This study aimed to examine the effect of subanesthetic esketamine on postoperative fatigue in patients who underwent laparoscopic colorectal surgery. A total of 62 patients, including 32 in the esketamine group and 30 in the control group, were analysed in this study. Compared with the control group, the patients in the esketamine group had reduced Identity-Consequence Fatigue Scale (ICFS) on the 3rd and 7th days after surgery (P<0.05). There were also significant differences in the Positive and Negative Affect Schedule (PANAS) scale between the two groups. The positive affect scale was higher on postoperative day 3 (POD3), while the negative affect scale was lower on POD3 and postoperative day 7 (POD7) in the esketamine group than in the control group. However, the scores of postoperative hand grip strength, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), Numeric Rating Scale (NRS) and Athens Insomnia Scale (AIS) were not significantly different between the two groups. Furthermore, mediation analysis showed that esketamine played an anti-fatigue role through improving emotional heath. Importantly, no adverse reactions occurred at this dosage of esketamine. Finally, our study suggested that subanesthetic esketamine improved postoperative fatigue, stabilized postoperative mood, reduced intraoperative remifentanil consumption, and promoted postoperative intestinal function recovery without increasing adverse reactions.

Perioperative pregabalin reduced fatigue scores after thoracoscopic pneumonectomy in a RCT of NSCLC patients.

Postoperative fatigue is prevalent, but non-small cell lung cancer (NSCLC) patients receive poor treatment after video-assisted thoracoscopic surgery (VATS). The main objective of the present trial is to observe the anti-fatigue function of pregabalin in NSCLC patients after surgery. Patients requiring VATS pneumonectomy were randomized into two groups (n=33): the experimental and control groups. The results showed that the experimental group's Identity-Consequence Fatigue Scale (ICFS) scores on days 1, 3, 7, and 30 after the operation decreased more than those of the control group. On days 1, 2, and 3 following surgery, there were significant differences in the Visual Analog Scale (VAS) scores, the incidence rate of anxiety and depression, and the Athens Insomnia Scale (AIS) scores between the two groups. Furthermore, we discovered that the ICFS scores were positively related to the VAS scores, Hospital Anxiety and Depression Scale (HADS) scores, and AIS scores. Postoperative fatigue and pain, on the other hand, were more closely related. Finally, this analysis suggested that perioperative pregabalin can reduce postoperative fatigue in NSCLC patients by relieving postoperative pain, anxiety, and depression, improving postoperative sleep quality, and promoting early recovery.

A comprehensive analysis of partial peristalsis recovery after peroral endoscopic myotomy in patients with achalasia.

OBJECTIVE: To determine whether peroral endoscopic myotomy (POEM) improves esophageal peristalsis and to investigate the association between recovery of esophageal peristalsis after POEM and clinical features of the patients. METHODS: In this single-center retrospective study, data were collected from medical records of the patients with achalasia who underwent POEM between January 2014 and May 2016. Demographics data, high-resolution esophageal manometry parameters, Eckardt score, and gastroesophageal reflux disease questionnaire (GERD-Q) score were collected. Weak and fragmented contraction was defined as partial recovery of esophageal peristalsis based on the Chicago classification version 3.0. Logistic regression analysis was used to identify variables associated with the partial recovery of peristalsis after POEM. RESULTS: A total of 103 patients were enrolled. Esophageal contractile activity was observed in the distal two-thirds of the esophagus in 24 patients. The Eckardt score, integrated relaxation pressure, and lower esophageal sphincter (LES) resting pressure were significantly decreased after POEM. Multivariate analysis revealed that preprocedural LES resting pressure (P = 0.013) and preprocedural Eckardt score (P = 0.002) were related to the partial recovery of peristalsis after POEM. Symptoms of gastroesophageal reflux and reflux esophagitis after POEM were less frequent in those with partial recovery of peristalsis (both P < 0.05). CONCLUSIONS: Normalization of esophagogastric junction relaxation pressure achieved by POEM is associated with the partial recovery of esophageal peristalsis in patients with achalasia. Preprocedural LES resting pressure and the Eckardt score are predictive of the recovery of esophageal peristalsis.

Nobiletin attenuates monocrotaline-induced pulmonary arterial hypertension through PI3K/Akt/STAT3 pathway.

OBJECTIVES: Nobiletin is a flavonoid found in the peel of Citrus sinensis (oranges). The purpose of this study is to investigate whether Nobiletin can alleviate the monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) and explore the underlying mechanisms. METHODS: The PAH rat model was replicated by subcutaneous injection of MCT. Nobiletin (1, 5 and 10 mg/kg) was administered by gavage from day 1 to day 21. After 21 days of MCT injection, the mean pulmonary artery pressure, pulmonary vascular resistance, Fulton Index, pulmonary artery remodelling, blood routine parameters, liver and kidney functions was measured. The level of inflammatory cytokines and PI3K/Akt/STAT3 were detected by qPCR, ELISA and western blot, the proliferation of pulmonary artery smooth muscle cells (PASMCs) was evaluated by CCK-8. KEY FINDINGS: Nobiletin (10 mg/kg) inhibited the MCT-induced increase in mean pulmonary artery pressure and pulmonary vascular resistance, right ventricular hypertrophy and pulmonary artery remodelling in rats. Nobiletin decreased the levels of inflammatory cytokines and phosphorylation level of PI3K/Akt/STAT3 in lungs of MCT-treated rats. Nobiletin inhibited the proliferation and lowered the inflammatory cytokines level induced by PDGF-BB in PASMCs. CONCLUSION: Nobiletin attenuates MCT-induced PAH, and the potential mechanism is to inhibit inflammation through PI3K/Akt/STAT3 pathway.

α-Mangostin Inhibited M1 Polarization of Macrophages/Monocytes in Antigen-Induced Arthritis Mice by Up-Regulating Silent Information Regulator 1 and Peroxisome Proliferators-Activated Receptor γ Simultaneously.

Background: α-Mangostin (MG) showed the potentials in alleviating experimental arthritis, inhibiting inflammatory polarization of macrophages/monocytes, and regulating peroxisome proliferators-activated receptor γ (PPAR-γ) and silent information regulator 1 (SIRT1) signals. The aim of this study was to analyze the correlations among the above-mentioned properties. Methods: Antigen-induced arthritis (AIA) was established in mouse, which was treated with MG in combination with SIRT1/PPAR-γ inhibitors to clarify the role of the two signals in the anti-arthritic actions. Pathological changes were systematically investigated. Phenotypes of cells were investigated by flow cytometry. Expression and co-localization of SIRT1 and PPAR-γ proteins in joint tissues were observed by the immunofluorescence method. Finally, clinical implications from the synchronous up-regulation of SIRT1 and PPAR-γ were validated by experiments in vitro. Results: SIRT1 and PPAR-γ inhibitors (nicotinamide and T0070097) reduced the therapeutic effects of MG on AIA mice, and abrogated MG-induced up-regulation of SIRT1/PPAR-γ and inhibition of M1 polarization in macrophages/monocytes. MG has a good binding affinity to PPAR-γ, and MG promoted the co-expression of SIRT1 and PPAR-γ in joints. Synchronously activating SIRT1 and PPAR-γ was revealed to be necessary by MG to repress inflammatory responses in THP-1 monocytes. Conclusion: MG binds PPAR-γ and excites this signaling to initiate ligand-dependent anti-inflammatory activity. Due to certain unspecified signal transduction crosstalk mechanism, it then promoted SIRT1 expression and further limited inflammatory polarization of macrophages/monocytes in AIA mice.

A novel modified McLaughlin surgery for treating locked chronic posterior shoulder dislocation.

BACKGROUND: Posterior shoulder dislocation is an uncommon orthopaedics injury and is frequently missed or misdiagnosed, accounting for 2%-4% of all shoulder dislocations, and is associated with the reverse Hill-Sachs lesion. Once posterior shoulder dislocation develops into a chronic disease, it will bring a lot of trouble to the treatment, especially in repairing the humeral defects. Surgical strategies are also developing and innovating to deal with this injury, including transfer of subscapularis tendon or lesser tubercle, humeral rotational osteotomy, autogenous bone graft or allograft. Shoulder replacement seems to be the ultimate and only option when the injury becomes irreparable, although some studies have shown unsatisfactory follow-up results. Considering no gold-standard treatment for locked posterior shoulder dislocation, we described a novel modified McLaughlin procedure for locked chronic posterior shoulder dislocation and evaluated the functional outcomes. METHODS: This study included five locked chronic posterior shoulder dislocation patients with an associated reverse Hill-Sachs lesion, in which the compression surface covered 30-40% of the humeral head. The mean period from injury to receiving surgery was 11.6 weeks (6-24 weeks). All five patients underwent the modified McLaughlin procedure, mainly divided into three steps, including open reduction, transfer of the partial lesser tuberosity and artificial bone to repair the reverse Hill-Sachs defects. The kernel technique was to fix the transferred tuberosity with two lag screws and strengthen it with two Ethibond sutures. The Constant-Murley score (CMS), the range of shoulder motion and the complications were recorded to assess and compare the functional situation of the shoulder postoperatively and postoperatively. RESULTS: After an average of 19.8 months (12-30) of follow-up, the mean CMS improved to 85.8 ± 4.9 (79-91) compared with 46.0 ± 4.5 (40-52) preoperatively, which showed a significant difference (p = 0.001). In the final follow-up, all five patients showed no symptoms of shoulder instability, and there was no pain or limited activity in daily life, thus all patients were satisfied with the results. CONCLUSION: Repairing the reverse Hill-Sachs lesion by transferring the partial lesser tuberosity combined with artificial bone fixed by lag screws and sutures can ensure shoulder stability and provide pain relief and good function in patients with locked chronic posterior shoulder dislocation associated with the humeral head defect.

Study on Increasing the Binding Amount of Rubber and Reinforcing Filler by Adding Aromatic Solvent Oil.

The binding amount of rubber and reinforcing filler directly affects the quality of rubber products. The effect of aromatic solvent oil (S-150) on the binding amount of rubber and reinforcing filler was studied. In order to determine the suitability of rubber after adding S-150, the curing characteristics, physical performance and tensile properties of rubber samples were tested and analyzed. Meanwhile, the microstructure of the composite was analyzed by scanning electron microscopy (SEM). The test results showed that the binding amount of rubber and reinforcing filler was increased after adding S-150. The density and Shore A hardness were decreased. When carbon black was 80 phr, after adding 40 phr of S-150, the rebound resilience of rubber increased by 13% on average, and the elongation at break increased by 88% on average. When white carbon black was between 10-70 phr, after adding 65 phr of S-150, the rebound resilience of rubber increased by 9% on average, and the elongation at break increased by 51% on average. Modulus at 100% and tensile strength were decreased. Meanwhile, it could be judged from the microstructure results that the reticulation space inside the rubber was increased, the agglomerate particles were relatively uniform, and no bubbles or holes were observed. The mechanism that S-150 could increase the binding amount of rubber was analyzed according to the like-dissolves-like principle. This research achievement could lead to improvements in the quality of rubber products and promote their practical application.

Meta-analysis of visual pretreatment for the prevention of emergence delirium in children undergoing ophthalmic surgery.

Objective: To evaluate the role of visual pretreatment in preventing emergence delirium in children receiving ophthalmic surgery. Methods: Four randomized controlled trials were identified in four databases, and a meta-analysis was conducted using RevMan 5.3. Results: The meta-analysis demonstrated a significantly lower incidence of postoperative emergence delirium (risk ratio: 0.39; 95% CI: 0.31-0.49) and propofol rescue (risk ratio: 0.29; 95% CI: 0.13-0.65) but comparable modified Yale Preoperative Anxiety Scale score (mean difference: -3.66; 95% CI: -9.96 to 2.65) and incidence of adverse events in the visual pretreatment group. Conclusion: Visual pretreatment is effective in preventing postoperative emergence delirium in children undergoing ophthalmic surgery without significant adverse effects and can also decrease the incidence of propofol rescue.

α-Mangostin Treats Early-Stage Adjuvant-Induced Arthritis of Rat by Regulating the CAP-SIRT1 Pathway in Macrophages.

BACKGROUND: Studies have found that α-mangostin (MG) can relieve experimental arthritis by activating cholinergic anti-inflammatory pathway (CAP). It affects the polarization of macrophages and the balance of related immune cell subpopulations, but the specific mechanism is still unclear. It has been found that silent information regulator 1 (SIRT1) is closely related to macrophage activity. The purpose of this study is to explore the mechanism of MG intervening in macrophage polarization during treatment of early adjuvant-induced (AIA) rats through the CAP-SIRT1 pathway. METHODS: We investigated the polarization of M1 macrophages and the differentiation of Th1 in AIA rats by flow cytometry. Activity of acetylcholinesterase (AChE) and the level of nicotinic adenine dinucleotide (NAD+) in serum were also detected, and immunohistochemical was used to detect the levels of α7 nicotinic cholinergic receptor (α7nAChR) and SIRT1. Then in macrophages, the molecular mechanism of MG regulating the abnormal activation of macrophages in rats with early AIA through the CAP-SIRT1 pathway was studied. RESULTS: MG can significantly inhibit the polarization of M1 macrophages and the differentiation of Th1 in AIA rats in the acute phase of inflammation. MG can significantly inhibit the activity of AChE and increase the level of NAD+, thereby further up-regulated the expression levels of α7nAChR and SIRT1. Meanwhile, MG inhibited nuclear factor-κB (NF-κB)-mediated inflammation by activating the CAP-SIRT1 pathway in macrophages. CONCLUSION: In summary, the stimulation of MG induced CAP activation, which up-regulated SIRT1 signal, and thereby inhibited M1 polarization through the NF-κB pathway, and improved the pathological immune environment of early-stage AIA rats.

The Effect of α7nAChR Signaling on T Cells and Macrophages and Their Clinical Implication in the Treatment of Rheumatic Diseases.

Rheumatoid arthritis (RA) is one of the most common autoimmune disease and until now, the etiology and pathogenesis of RA is not fully understood, although dysregulation of immune cells is one of the leading cause of RA-related pathological changes. Based on current understanding, the priority of anti-rheumatic treatments is to restore immune homeostasis. There are several anti-rheumatic drugs with immunomodulatory effects available nowadays, but most of them have obvious safety or efficacy shortcomings. Therefore, the development of novel anti-rheumatic drugs is still in urgently needed. Cholinergic anti-inflammatory pathway (CAP) has been identified as an important aspect of the so-called neuro-immune regulation feedback, and the interaction between acetylcholine and alpha 7 nicotinic acetylcholine receptor (α7nAChR) serves as the foundation for this signaling. Consistent to its immunomodulatory functions, α7nAChR is extensively expressed by immune cells. Accordingly, CAP activation greatly affects the differentiation and function of α7nAChR-expressing immune cells. As a result, targeting α7nAChR will bring profound therapeutic impacts on the treatment of inflammatory diseases like RA. RA is widely recognized as a CD4+ T cells-driven disease. As a major component of innate immunity, macrophages also significantly contribute to RA-related immune abnormalities. Theoretically, manipulation of CAP in immune cells is a feasible way to treat RA. In this review, we summarized the roles of different T cells and macrophages subsets in the occurrence and progression of RA, and highlighted the immune consequences of CAP activation in these cells under RA circumstances. The in-depth discussion is supposed to inspire the development of novel cell-specific CAP-targeting anti-rheumatic regimens.

Network pharmacology for systematic understanding of Schisandrin B reduces the epithelial cells injury of colitis through regulating pyroptosis by AMPK/Nrf2/NLRP3 inflammasome.

Ulcerative colitis (UC) is a chronic inflammatory disease with increasing incidence and prevalence in many countries. The purpose of this study is to explore the function of Schisandrin B and its underlying molecular mechanisms in colitis. In this study, mice with colitis were induced by giving 2.0% dextran sulfate sodium (DSS, MP) in the drinking water for seven days. Furthermore, TCMSP server and GEO DataSets were used to analyze the mechanism of Schisandrin B in colitis. It was found that Schisandrin B presented colitis in mice model. At the same time, Schisandrin B not only reduced inflammation in vivo and vitro model of colitis, but also suppressed the nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 (NLRP3) inflammasome in vivo and vitro model of colitis. In addition, Schisandrin B induced AMP-activated protein kinase (AMPK) / Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway in model of colitis, and regulated AMPK protein at 316 sites. The inhibition of AMPK reduced the anti-inflammation effects of Schisandrin B on NLRP3 inflammasome. Apart from that, Schisandrin B decreased reactive oxygen species (ROS)-induced mitochondrial damage and reduced epithelial cells damage of colitis through regulating pyroptosis. Collectively, our novel findings for first time showed that, Schisandrin B suppressed NLRP3 inflammasome activation-mediated interleukin-1beta (IL-1ß) level and pyroptosis in intestinal epithelial cells of colitis model through the activation of AMPK/Nrf2 dependent signaling-ROS-induced mitochondrial damage, which may be a significant therapeutic approach in the treatment of acute colitis.

Risk factors of poor prognosis in patients with pyrrolidine alkaloid-induced hepatic sinusoidal obstruction syndrome after transjugular intrahepatic portosystemic shunt.

AIMS: Transjugular intrahepatic portosystemic shunt (TIPS) is an effective method in treating patients with severe hepatic sinusoidal obstruction syndrome induced by pyrrolidine alkaloids (PA-HSOS). However, some patients still have poor postoperative prognosis. So, we aim to evaluate the predictors associated with poor outcomes in PA-HSOS patients receiving TIPS. METHODS: Patients who were diagnosed as PA-HSOS and received TIPS in our hospital between January 2013 and April 2019 were reviewed retrospectively. Baseline information and clinical data were collected. The hazard ratios (HRs) of factors associated with poor prognosis were analyzed by Cox proportional hazard analysis. The Kaplan-Meier method was used to analyze and compare the cumulative incidence of the poor results and survival rate of patients. RESULTS: During a median of 19.25-month follow-up, death occurred in 17 patients. We found that prothrombin time at baseline with an adjusted HR 1.110 (95% confidence interval 1.014-1.216, p = 0.024) and serum total bilirubin of 9 mg/dl 5 days after TIPS with an adjusted HR 1.114 (95% confidence interval 1.042-1.190, p = 0.001) were independent risk factors for death. The 1-year and 5-year survival rate were 86.2% and 82.1%, respectively. The 1-year survival rate in patients with prothrombin time > 17.85 s at baseline and serum total bilirubin > 9 mg/dl at 5 days after TIPS was significantly lower than that of patients below the corresponding threshold, respectively. CONCLUSIONS: Prolonged prothrombin time at baseline and increased serum total bilirubin levels 5 days after TIPS are independent risk factors for predicting death after TIPS treatment in PA-HSOS patients.

Current Status of Sarcopenia in the Disabled Elderly of Chinese Communities in Shanghai: Based on the Updated EWGSOP Consensus for Sarcopenia.

Our study aimed to investigate the prevalence and associated factors of sarcopenia in the disabled elderly in communities in Shanghai, China. A cross-sectional study was conducted in 2018. Five hundred and seventy two participants (≥60 years) were recruited through cluster sampling from Putuo District of Shanghai. Sarcopenia was defined according to the updated consensus of the European Sarcoma Working Group in 2019. The sarcopenia, depression, and nutrition status were assessed by using SARC-F, the Short Version of the Center for Epidemiological Studies Depression Scale (CES-D-10), and the Mini Nutritional Assessment-Short form (MNA-SF), respectively Physical activity was also assessed. Our results showed the prevalence of sarcopenia was 0.5%, but the prevalence of low handgrip strength was 37.2% (male, 5.5%; female, 39.1%). The modified Poisson regression model was used to evaluate the relationship among related variables and low handgrip strength. The risk for low handgrip strength was higher in the physically disabled subjects than in the visually disabled ones (aPR: 1.69, 95% CI: 1.88-2.42). Depressive symptoms (aPR: 1.31, 95% CI: 1.04-1.62) and PASE score (aPR: 0.99, 95% CI: 0.99-1.00) were independently associated with low handgrip strength. In summary, the prevalence of EWGSOP2-defined sarcopenia is low and the prevalence of declined muscle strength is high in the disabled elderly. The elderly participants with a physical disability had a higher prevalence of low hand handgrip strength than those with a visual disability. More studies with a larger sample size and longitudinal follow-up are needed to confirm our findings.