Baicalin attenuates PD-1/PD-L1 axis-induced immunosuppression in piglets challenged with Glaesserella parasuis by inhibiting the PI3K/Akt/mTOR and RAS/MEK/ERK signalling pathways.

Infection of piglets with Glaesserella parasuis (G. parasuis) induces host immunosuppression. However, the mechanism underlying the immunosuppression of piglets remains unclear. Activation of the PD-1/PD-L1 axis has been shown to trigger host immunosuppression. Baicalin possesses anti-inflammatory and immunomodulatory functions. However, whether baicalin inhibits PD-1/PD-L1 activation and thus alleviates host immunosuppression has not been investigated. In this study, the effect of baicalin on the attenuation of piglet immunosuppression induced by G. parasuis was evaluated. Seventy piglets were randomly divided into the control group, infection group, levamisole group, BMS-1 group, 25 mg/kg baicalin group, 50 mg/kg baicalin group and 100 mg/kg baicalin group. Following pretreatment with levamisole, BMS-1 or baicalin, the piglets were challenged with 1 × 108 CFU of G. parasuis. Our results showed that baicalin, levamisole and BMS-1 modified routine blood indicators and biochemical parameters; downregulated IL-1ß, IL-10, IL-18, TNF-α and IFN-γ mRNA expression; and upregulated IL-2 and IL-8 mRNA expression in blood. Baicalin, levamisole and BMS-1 increased the proportions of CD3+ T cells, CD3+CD4+ T cells, CD3+CD8+ T cells and CD3-CD21+ B cells in the splenocyte population, increased the proportions of CD3+ T cells, CD3+CD4+ T cells and CD3+CD8+ T cells in the blood, and inhibited PD-1/PD-L1 and TIM-3 activation. Baicalin, levamisole and BMS-1 reduced p-PI3K, p-Akt, and p-mTOR expression, the p-MEK1/2/MEK1/2 and p-ERK1/2/ERK1/2 ratios and increased RAS expression. Baicalin, levamisole and BMS-1 provided substantial protection against G. parasuis challenge and relieved tissue histopathological damage. Our findings might provide new strategies for controlling G. parasuis infection and other immunosuppressive diseases.

Association Between Different Types of Physical Activity and Hepatic Steatosis and Liver Fibrosis: A Cross-Sectional Study Based on NHANES.

BACKGROUND AND AIMS: Many studies have shown a link between physical activity (PA) and nonalcoholic fatty liver disease (NAFLD). However, more research is needed to investigate the relationship between different types of PA and NAFLD. This study aimed to explore the potential link between different types of PA, hepatic steatosis, and liver fibrosis. STUDY: A cross-sectional study was conducted using the data set from the National Health and Nutrition Examination Survey (NHANES) from 2017 to 2020. A multiple linear regression model was used to examine the linear relationship between different types of PA, the controlled attenuation parameter (CAP), and liver stiffness measurement (LSM). In addition, smoothing curve fitting and threshold effect analysis were used to depict their nonlinear relationship. RESULTS: This study involved 5933 adults. Multiple linear regression analysis revealed a significantly negative correlation between leisure-time PA and CAP, while the relationship between occupation-related PA, transportation-related PA, and CAP was not significant. Subgroup analysis further revealed that leisure-time PA was significantly negatively correlated with CAP in women and younger age groups (under 60 y old), while the relationship was not significant in men and older age groups. In addition, there was a significant negative correlation between leisure-time PA and liver fibrosis in men. CONCLUSIONS: Leisure-time PA can prevent hepatic steatosis, and women and young people benefit more. Occupation-related PA is not associated with hepatic steatosis and cannot replace leisure-time PA. In men, increasing leisure-time PA is more effective in preventing liver fibrosis.

PDIA3-regulted inflammation and oxidative stress contribute to the traumatic brain injury (TBI) in mice.

Traumatic brain injury (TBI) is a leading cause of death and disability throughout the world. However, the molecular mechanism contributing to TBI still remains unclear. Protein disulfide isomerases (PDI) are a family of redox chaperones, which catalyze formation or isomerization of disulfide bonds in proteins. PDIA3, a critical member of PDI family, is a multi-functional protein, playing critical roles in modulating inflammation, apoptosis and oxidative stress under various kinds of disease conditions. Nevertheless, its regulatory effects on TBI have far from to be known. In the present study, we attempted to explore the modulation of neuroinflammatory responses by PDIA3 and its contribution to oxidative stress and cell death after TBI in the wild type (PDIA+/+) and PDIA3 knockout (PDIA3+/+) C57BL/6 mice. Results here suggested that PDIA3 expression was markedly up-regulated in the late trauma human brain tissues, which was verified in the PDIA3+/+ mice at 24 h after TBI. PDIA-/- provided significant improvements in cognitive impairments and contusion volume induced by TBI. Apoptosis in brain samples was also alleviated in TBI mice with PDIA3 deficiency. Significantly, PDIA3-/- mitigated neuroinflammation after TBI in mice, as evidenced by the reduced expression of pro-inflammatory factors interleukin (IL)-6, tumor necrosis factor-α (TNF-α) and IL-1ß, while the enhanced anti-inflammatory regulator IL-10. These anti-inflammatory activities by PDIA3-/- were associated with the decrease in phosphorylated nuclear factor kappa B (NF-κB)/p65. PDIA3-/- mice following TBI showed attenuated oxidative stress, as proved by the restored superoxide dismutase (SOD) and glutathione (GSH) activities, and the down-regulated malondialdehyde (MDA) levels in brain samples. These effects regulated by PDIA3 were confirmed in OGDR-treated astrocytes. Collectively, these data demonstrated a detrimental role of PDIA3 in regulating TBI, providing an effective therapeutic target for TBI treatment in future.

Cdc42 Promotes Schwann Cell Proliferation and Migration Through Wnt/ß-Catenin and p38 MAPK Signaling Pathway After Sciatic Nerve Injury.

Schwann cells (SCs) are unique glial cells in the peripheral nerve and may secrete multiple neurotrophic factors, adhesion molecules, extracellular matrix molecules to form the microenvironment of peripheral nerve regeneration, guiding and supporting nerve proliferation and migration. Cdc42 plays an important regulatory role in dynamic changes of the cytoskeleton. However, there is a little study referred to regulation and mechanism of Cdc42 on glial cells after peripheral nerve injury. The present study investigated the role of Cdc42 in the proliferation and migration of SCs after sciatic nerve injury. Cdc42 expression was tested, showing that the mRNA and protein expression levels of Cdc42 were significantly up-regulated after sciatic nerve injury. Then, we isolated and purified SCs from injuried sciatic nerve at day 7. The purified SCs were transfected with Cdc42 siRNA and pcDNA3.1-Cdc42, and the cell proliferation, cell cycle and migration were assessed. The results implied that Cdc42 siRNA remarkably inhibited Schwann cell proliferation and migration, and resulted in S phase arrest. While pcDNA3.1-Cdc42 showed a contrary effect. Besides, we also observed that Cdc42 siRNA down-regulated the protein expression of ß-catenin, Cyclin D1, c-myc and p-p38, which were up-regulated by pcDNA3.1-Cdc42. Meanwhile, the inhibitor of Wnt/ß-catenin and p38 MAPK signaling pathway IWP-2 and SB203580 significantly inhibited the effect of pcDNA3.1-Cdc42 on cell proliferation and migration. Overall, our data indicate that Cdc42 regulates Schwann cell proliferation and migration through Wnt/ß-catenin and p38 MAPK signaling pathway after sciatic nerve injury, which provides further insights into the therapy of the sciatic nerve injury.

The C-terminal tail of polycystin-1 regulates complement factor B expression by signal transducer and activator of transcription 1.

Inhibition of the overactivated alternative complement pathway in autosomal dominant polycystic kidney disease (ADPKD) retards disease progression in animal models; however, it remains unknown how complement factor B (CFB) is upregulated in ADPKD. Here, we showed that the overexpression of CFB in cystic kidneys is associated with increased JAK2/STAT1 activity and enhanced expression of the polycystin-1 C-terminal tail (PC1-CTT). Overexpression or blockage of STAT1 increased or decreased CFB expression and CFB promoter activity. Moreover, overexpression of PC1-CTT induced JAK2/STAT1 activation and CFB upregulation in renal tubular epithelial cells. Furthermore, PC1-CTT overexpression increased human CFB promoter activity, whereas dominant negative STAT1 plasmids or mutation of putative STAT1 responsive elements decreased PC1-CTT-induced CFB promoter activity. The effect of CFB on macrophage differentiation was tested on a mouse macrophage cell line. Bioactive CFB dose dependently promoted macrophage M2 phenotype conversion. In addition, conditioned media from renal epithelial cells promoted macrophage M2 phenotype conversion which was blocked by STAT1 inhibition in a dose-dependent manner. Conditioned media from PC1-CTT-transfected renal epithelial cells further promoted macrophage M2 phenotype conversion, which was suppressed by fludarabine or a CFB antibody. In addition, we show that NF-κB acts downstream of PC1-CTT and may partly mediate PC1-CTT-induced CFB expression. In conclusion, our study reveals possible mechanisms of CFB upregulation in ADPKD and a novel role of PC1-CTT in ADPKD-associated inflammation. Furthermore, our study suggests that targeting STAT1 may be a new strategy to prevent inflammation in the kidney of patients with ADPKD.

Predictors for Massive Blood Loss During Posterior Correction of Congenital Scoliosis in Pre-school Children:A Retrospective Observation.

Objective To investigate the predictors for massive blood loss during posterior correction of congenital scoliosis in pre-school children. Methods Totally 124 children under six years of age,who received posterior correction of congenital scoliosis,were divided into two groups according to the ratio of intraoperative blood loss (BL) and estimated blood volume (EBV). Massive blood loss was defined as BL/EBV>0.15,and minor or moderate blood loss as BL/EBV≤0.15. All the records,including demographics,intraoperative fluids,pre- or postoperative laboratory parameters,and the length of hospital stay,were compared between these two groups. Results There were 57 children in the moderate or minor blood loss group and 67 children in the massive blood loss group. When compared with moderate or minor blood loss group,children in massive blood loss group had significantly lower body weight,shorter body height,longer anesthesia period,and more autologous or allogeneic transfusion (P<0.05). Binary Logistic regression analysis showed that body weight lower than 15 kg was the independent predictor for massive blood loss (OR=0.435,95% CI=0.197-0.962). Conclusions The incidence of massive blood loss is about 54% in children under six years of age who have received posterior correction of congenital scoliosis. The body weight of lower than 15 kg is an independent predictor for massive blood loss during the surgery.

Evaluation of risk factors for arytenoid dislocation after endotracheal intubation: a retrospective case-control study.

OBJECTIVE: To investigate the risk factors for postoperative arytenoid dislocation. METHODS: From September 2003 to August 2013, the records of 16 patients with a history of postoperative arytenoid dislocation were reviewed. Patients matched in terms of date and type of procedures were chosen as the controls (n=16). Recorded data for all patients were demographics, smoking status, alcoholic status, preoperative physical status, airway evaluation, intubation procedures, preoperative laboratory test results, anesthetic consumption and intensive care unit stay. For arytenoid dislocation cases, we further analyzed the incidences of the left and right arytenoid dislocation, and the outcomes of surgical repair and conservative treatment. Categorical variables were presented as frequencies and percentages, and were compared using the chi-squared test. Continuous variables were expressed as means±SD and compared using the Student's unpaired t-test. To determine the predictors of arytenoid dislocation, a logistic regression model was used for multivariate analysis. RESULTS: Sixteen patients with postoperative arytenoid dislocation were enrolled, with a median age of 52 years. Most postoperative arytenoid dislocation patients (15/16, 93.75%) received surgical repair, except one patient who recovered after conservative treatment. None of the postoperative arytenoid dislocation patients were smokers. Red blood cell (P=0.044) and hemoglobin (P=0.031) levels were significantly lower among arytenoid dislocation cases compared with the controls. CONCLUSIONS: Non-smoking and anemic patients may be susceptible to postoperative arytenoid dislocation. However, neither of them was independent risk factor for postoperative arytenoid dislocation.

Application of Intelligent Ultrasound in Real-Time Monitoring of Postoperative Analgesic Nerve Block.

In order to monitor the effect of nerve block in postoperative analgesia more accurately, this paper puts forward the application research of ultrasonic real-time intelligent monitoring of nerve block in postoperative analgesia. Ultrasonic real-time intelligent monitoring of nerve block in upper limb surgery, lower limb surgery, and abdominal surgery combined with the nerve stimulator. The experiments show that there are 5 cases of adverse reactions when the nerve stimulator is only used, but no adverse reactions occur when combined with ultrasound-guided block. Continuous subclavian brachial plexus block with the ultrasound-guided nerve stimulator can clearly see the subclavian brachial plexus and its surrounding tissue structure, the direction of needle insertion in the plane, and the diffusion of narcotic drugs. The average success rate of block was up to 95.2%, which was significantly higher than that of nerve stimulator alone, and the success rate of recatheterization after the first failure was also improved. The average postoperative analgesia satisfaction was 85.6%, the average operation time was only 20 min, and the subclavian artery and pleura were avoided effectively. No pneumothorax and other complications occurred. The average success rate of ultrasound-guided subclavicular brachial plexus block in 1-2-year-old children was 97%, which was much higher than the average success rate of nerve stimulator localization with 63%. Ultrasound-guided nerve block not only directly blocks nerves under visual conditions but also helps to observe the structures around nerves and dynamically observe the diffusion of local anesthetics, which can significantly improve the accuracy and success rate of nerve block and reduce the incidence of complications.

SNX9 Inhibits Cell Proliferation and Cyst Development in Autosomal Dominant Polycystic Kidney Disease via Activation of the Hippo-YAP Signaling Pathway.

Autosomal dominant polycystic kidney disease (ADPKD) is a complex process, involving the alteration of multiple genes and signaling pathways, and the pathogenesis of ADPKD remains largely unknown. Here, we demonstrated the suppressive role of sorting nexin 9 (SNX9) during ADPKD development. Sorting nexin 9 expression was detected in the kidney tissues of ADPKD patients, for the first time, and SNX9 expression was also detected in Pkd1 knockout (Pkd1 -/-) and control mice. Subsequently, a series of gain- and loss-of-function studies were performed, to explore the biological roles and underlying molecular mechanisms of SNX9 in ADPKD progression. The expression of SNX9 was significantly downregulated in ADPKD patients and Pkd1 -/- mice compared with control individuals and wild-type mice (Pkd1+/+), respectively. The ectopic expression of SNX9 significantly inhibited ADPKD cell proliferation, renal cyst formation and enlargement, whereas these effects were promoted by SNX9 silencing. Mechanistically, we found that SNX9 interacted directly with yes-associated protein (YAP) and increased the large tumor suppressor kinase 1-mediated phosphorylation of YAP, resulting in the cytoplasmic retention of YAP, the decreased transcriptional activity of the YAP/TEA domain transcription factor 4 complex, and, consequently, the inhibition of Hippo target gene expression and ADPKD development. Taken together, our findings provided novel insights into the role played by SNX9 during ADPKD pathogenesis and may reveal novel therapeutic approaches for ADPKD and related kidney diseases.

Amputation of the first metatarsophalangeal joint due to a giant gouty tophi: A case report.

RATIONALE: The first metatarsophalangeal joint (MTP1) is the most frequent site of gouty tophi. We report an unusual case with a giant skin-perforating tophi. This is the first case of gouty tophi at MTP1 which accepts surgical debulking and amputation. PATIENT CONCERNS: A 42-year-old man presented with a seven-year history of gout and a giant tophi at MTP1. The patient was referred to hospital due to persistent pain and ulcerations on the surface of the left MTP1. This rounded, giant, swelling, tophaceous tophi severely interfered with his normal walking. DIAGNOSES: The patient was diagnosed with gouty arthritis seven years ago, and did not receive regular anti-gout treatments. OUTCOMES: Biochemical examination showed he had raised serum uric acid (SUA, 11.92 mg/dl) and creatinine (258 µmol/l). There was a severe joint destruction of MTP1 by X-ray examination. We controlled the skin infection by sulbenicillin. He was given febuxostat to reduce SUA. After 3 months of treatment, SUA fell to 6.8 mg/dl. Then we performed surgical debulking of MTP1 and amputation of hallux. Surgical operations obviously relieved the pain, and improved the function of his left foot. The visual closure after amputation was good. CONCLUSION: Surgical amputation of the gout lesion at MTP1 maximized the function, and reduced the pain of this patient. In the case of giant tophi with severe gouty arthritis or skin infections, surgical decisions need to weigh gains and losses carefully.