Influence of hypocalcemia on the prognosis of patients with multiple trauma.

BACKGROUND: Hypocalcemia is highly common in hospitalized patients, especially in those with trauma, On the other hand, abnormal calcium metabolism is an important metabolic challenge; however, it is often neglected and untreated, and certain factors may induce serious neurological and cardiovascular complications. AIM: To retrospectively analyze the impact of hypocalcemia on the prognosis of patients with multiple traumas. METHODS: The study was conducted from January 2020 to December 2021. Ninety-nine patients with multiple injuries were treated at the critical care medicine department of Fuyang People's Hospital. The selected indicators included sex, age, and blood calcium and hematocrit levels. Many indicators were observed, including within 24 h of hospitalization, and the prognosis was collected after 28 d. Based on the blood calcium levels, the patients were divided into the following two groups: Normocalcemia and hypocalcemia. Of the 99 patients included, 81 had normocalcemia, and 18 had hypocalcemia. Separate experiments were conducted for these two groups. RESULTS: There was an association between serum calcium levels and the prognosis of patients with polytrauma. CONCLUSION: Clinically, the prognosis of patients with multiple traumas can be preliminarily evaluated based on serum calcium levels.

Tanshinone IIA attenuates valvular interstitial cells' calcification induced by oxidized low density lipoprotein via reducing endoplasmic reticulum stress.

Recent studies revealed that endoplasmic reticulum (ER) stress played an emerging role of in valve calcification. Tanshinone IIA (TanIIA) has been a research hotspot in cardiovascular diseases. Previously we found that sodium TanIIA dampened the pathological phenotype transition of valvular interstitial cells (VICs) by affecting ER stress published in Chinese Journal. Here, we test the hypothesis that TanIIA attenuates the pro-osteogenic effects of oxidized low-density lipoprotein (oxLDL) in VICs by reducing induction of ER stress. Patients' aortic valve (AV) was collected, and porcine VICs were cultured for in vitro model. ER stress markers were tested in human leaflets by immunostaining. Immunoblotting were used to test the osteoblastic factors such as Runx2, osteocalcin, and ER stress markers GRP78, CHOP, XBP1, etc. Alkakine phosphate (ALP) activity assay were used to test the activity of ALP kinase. Pro-inflammatory gene expression was detected by polymerase chain reaction. As a result, ER stress markers were elevated in patients' calcified AVs. OxLDL induced osteogenesis and inflammation via promoting ER stress. TanIIA attenuated oxLDL induced ER stress. TanIIA also inhibited theosteoblastic factors and inflammatory cytokine expressions in VICs. In conclusion, our data provide evidence that TanIIA exerts anti-inflammation and anti-osteogenic effects in VICs by attenuating ER stress, and ER stress acts as an important regulator in oxLDL induced VICs' phenotype transition.

[Application of TightRope system combined with Locking-Loop biplane anatomical reconstruction technique for acute acromioclavicular joint dislocation].

Objective: To investigate the effectiveness of TightRope system combined with Locking-Loop biplane anatomical reconstruction technique in the treatment of acute acromioclavicular joint dislocation. Methods: A clinical data of 28 patients with acute acromioclavicular joint dislocation who met the selection criteria and admitted between June 2018 and December 2021 was retrospectively analyzed. There were 18 males and 10 females, with an average age of 47.7 years (range, 22-72 years). The causes of injury included falling (13 cases) and traffic accidents (15 cases). The acromioclavicular joint dislocation was rated as Rockwood type Ⅲ in 7 cases, type Ⅳ in 16 cases, and type Ⅴ in 5 cases. The time from injury to operation was 4-13 days, with an average of 9.5 days. The acromioclavicular joint dislocation was reconstructed with TightRope system and high-strength wire by Locking-Loop methods during operation. The operation time and complications were recorded. Visual analogue scale (VAS) score, Constant-Murley score, and active range of motion of shoulder (forward flexion and upward lift, abduction and upward lift, and external rotation) were recorded before operation and at 12 months after operation to evaluate the functional recovery of shoulder. The loss of acromioclavicular joint reduction was assessed by comparing the coracoclavicular distance (CCD) based on the anteroposterior X-ray films at 3 days and 12 months after operation. Results: The operation time was 58-100 minutes (median, 85 minutes). All incisions healed by first intention. All patients were followed up 12 months. During follow-up, 2 patients developed shoulder adhesion, which recovered after rehabilitation exercise. At 12 months after operation, the VAS score was significantly lower, the Constant-Murley score was significantly higher, and the range of motion of the shoulder joint (forward flexion and upward lift, abduction and upward lift, and external rotation) significantly increased when compared with preoperative ones ( P<0.05). X-ray films showed that the CCD was 8.4 (7.3, 9.4) and 9.2 (8.1, 10.1) mm at 3 days and 12 months after operation, respectively, with a significant difference ( Z=-4.665, P<0.001). During follow-up, there was no complication such as infection, titanium plate entrapment, fracture, internal fixation failure, or redislocation. Conclusion: The treatment of acute acromioclavicular joint dislocation with TightRope system combined with Locking-Loop biplane anatomical reconstruction has the advantages of small incision, joint reduction under direct vision, high fixation strength, and low incidence of postoperative complications, which can effectively relieve the pain of patients' shoulder joint and facilitate the recovery of shoulder joint function.

Imaging findings of hepatocellular carcinoma with portal vein tumor thrombosis secondary to hepatic portal vein collateral circulation: a cross-sectional study.

Background: Hepatic portal vein collateral circulation plays an important role in maintaining the perfusion of hepatic portal vein. However, at present, there is little research on collateral circulation of hepatic portal vein. Our study aims to analysis the imaging types and clinical value of hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) invading and completely blocking different branches of portal vein, secondary to hepatic portal vein collateral circulation. Methods: This study retrospectively analyzed Hepatocellular carcinoma (HCC) with PVTT diagnosed with enhanced CT examination of the upper abdomen in our hospital from May 2020 to October 2021.The inclusion criteria for patients were the following: (I) ultimately diagnosed with HCC, (II) accompanied by complete obstruction of the main portal vein or left/right branches, and (III) with collateral circulation of the hepatic portal vein established. All images were postprocessed by multiplanar reconstruction (MPR), maximum intensity projection (MIP), and other reconstruction techniques to obtain images of the abnormal portal vein system and the collateral vessels running toward the hepatic portal veins. Three physicians jointly judged the imaging anatomical classification of each collateral vessel. The qualitative variables were compared by chi-squared test. Results: A total of 125 hepatic portal vein collateral vessels were observed in MPR and MIP reconstruction images of 71 patients with portal vein cancer thrombosis with established hepatic portal vein collateral circulation. Common hepatic collateral branches in patients with PVTT mainly include the biliary collateral branch, gastric collateral branch, mesenteric collateral branch, accessory portal vein system and the splenic branch. The incidence rate was respectively 77.5%, 36.6%, 32.4%, 28.2%, 1.41%. Conclusions: The correct understanding of the imaging anatomical classification of the collateral vessels of the hepatic portal vein can provide clinicians with more information for diagnosis and treatment planning.

A protective factor against lymph node metastasis of papillary thyroid cancer: Female gender.

OBJECTIVE: Papillary thyroid carcinoma (PTC) is the most common pathological type of thyroid cancer, with good prognosis, but the rate of lymph node metastasis (LNM) is high, and the difference between men and women is significant. Therefore, the related risk factors for LNM of PTC based on gender were examined in this study in order to draw attention to gender factor in PTC. METHODS: We retrospectively analyzed the clinicopathological data of 2103 patients with surgically confirmed PTC at the Fourth affiliated Hospital of Hebei Medical University West Side between January 2016 and December 2019. RESULTS: LNM was detected in 1124 of the 2103 cases of PTC. Logistic regression analysis showed that LNM was associated with age (p < 0.001, OR:0.547), gender (p < 0.001, OR:2.609), tumor diameter (p < 0.001, OR:2.995), bilaterality (p=0.003, OR:1.683), and extrathyroid extension (p < 0.001, OR:1.657). After propensity score matching, female gender (p < 0.001, OR: 0.393) remained an independent factor of LNM in patients with PTC. LNM in men was only associated with diameter (p < 0.001, OR: 3.246). LNM in woman was associated with menopausal history (p = 0.012, OR=0.684), reproductive history (p < 0.001, OR=0.360), abortion history (p = 0.011, OR=0.725), tumor diameter >1 cm (p < 0.001, OR=2.807), bilaterality (p =0.006, OR:1.728), and extrathyroid extension (p < 0.001, OR=1.879). CONCLUSION: Although the invasion is high in female patients, the rate of LNM is significantly reduced due to the influence of sex hormones and reproductive factors. For female patients of childbearing age who were not pregnant and did not have children, it is suggested to take a positive attitude towards their lymph nodes.

Transanal ileus catheter combined with nasal ileus catheter in the treatment of malignant ileus in 14 cases: a case series and literature review.

BACKGROUND: Malignant intestinal obstruction refers to intestinal obstruction caused by advanced primary tumors or secondary metastatic malignant tumors. Because surgical treatment cannot significantly improve the life cycle, non-surgical treatment is mostly used to improve the symptoms of intestinal obstruction; transanal intestinal obstruction catheter and transnasal intestinal obstruction catheter are palliative therapies for decompression and drainage. Transanal intestinal obstruction catheter is mostly used for rectal and left colon obstruction. Transnasal intestinal obstruction catheter is mostly used for small intestinal obstruction. The two catheters are generally used alone according to the site of obstruction and clinical manifestations, and there are few reports on the combined use of the two catheters. We try to use the two catheters to treat patients with complex conditions and explore a better treatment strategy for malignant intestinal obstruction. CASE DESCRIPTION: Retrospective analysis From January 2016 to April 2022, 14 patients with advanced cancer were diagnosed as malignant intestinal obstruction by imaging data and clinical manifestations. Under the premise of no improvement in the symptoms of placement of a catheter, nasal ileus catheter combined with transanal ileus catheter was used for common decompression and drainage. The efficacy of combined catheterization was evaluated by comparing the differences in imaging data before and after catheterization, as well as analyzing the degree of relief and prognosis of intestinal obstruction symptoms; of intestinal obstruction symptoms was completely relieved in 4 of 14 patients combined catheterization, and spontaneous defecation and exhaust could be performed; intestinal obstruction symptoms were significantly relieved in 3 patients, reexamination of image air-fluid level was reduced by more than 70%, abdominal distension and abdominal pain were significantly relieved, and intermittent defecation and exhaust could be performed; intestinal obstruction symptoms were relieved in 3 patients, reexamination of image air-fluid level was reduced by 20-50%, abdominal distension and abdominal pain were relieved, and defecation and exhaust could not be performed; intestinal obstruction symptoms were not relieved in 4 patients. CONCLUSIONS: Combined application of transanal ileus catheter and transnasal ileus catheter decompression and drainage can be used as a palliative treatment to relieve the symptoms of malignant ileus.

[Effectiveness of arthroscopic long head of biceps tendon transposition combined with Swivelock anchor double fixation for massive and irreparable rotator cuff tears].

Objective: To investigate the effectiveness of arthroscopic long head of biceps tendon (LHBT) transposition combined with Swivelock anchor double fixation in treatment of massive and irreparable rotator cuff tears. Methods: Between June 2019 and November 2021, 25 patients with massive and irreparable rotator cuff tears were treated by arthroscopic LHBT transposition combined with Swivelock anchor double fixation. There were 12 males and 13 females. The age ranged from 47 to 74 years (mean, 62.4 years). The disease duration ranged from 1 to 62 months (median, 7 months). The rotator cuff tears were classified as Hamada grade 2 in 25 cases and Goutallier grade 1 in 2 cases, grade 2 in 22 cases, and grade 3 in 1 case. Pre- and post-operative shoulder range of motion (ROM), visual analogue scale (VAS) score, University of California Los Angeles (UCLA) score, and Constant-Murley score were recorded. Postoperative complications were observed. The reconstructed tissue integrity was confirmed by MRI. Results: All operations were successfully completed. The operation time was 120-330 minutes (mean, 189.6 minutes). All incisions healed by first intention. All patients were followed up 10-36 months (mean, 22.0 months). At last follow-up, the ROM in forward flexion, abduction, and external rotation, VAS score, UCLA score, and Constant-Murley score were superior to those before operation, and the differences were significant ( P<0.05). According to UCLA scoring standard, shoulder joint function was rated as excellent in 5 cases, good in 18 cases, and poor in 2 cases, with an excellent and good rate of 92.0%. No other complications occurred except shoulder joint adhesion in 2 cases. At last follow-up, MRI examination showed no retear of rotator cuff, and LHBT was intact. Conclusion: For massive and irreparable rotator cuff tears, arthroscopic LHBT transposition combined with Swivelock anchor double fixation can increase the force of pressing the humeral head, effectively relieve the pain, improve the ROM of joints, maximize the recovery of shoulder function, and do not increase the number of anchor nails.

Analysis of the causes of failed placement of nasoenteric tube under DSA guidance and treatment strategies for successful re-catheterization.

BACKGROUND: For patients with advanced cancer or patients who have undergone digestive tract reconstruction, enteral nutrition is the most important nutritional support therapy, which can reduce the risk of enteral infection and improve self-immunity; while digital subtraction angiography (DSA) guided nasoenteric tube placement is suitable for nutritional support and palliative treatment of most patients with advanced cancer, many doctors because the preoperative preparation is not sufficient or the intraoperative operation is not standardized, resulting in catheter failure can not achieve the purpose of nutritional supply, and we need to summarize the lessons of failure and optimize the catheterization strategy. METHODS: From February 2015 to July 2020, A total of 3,810 cases were treated with DSA guided nasoenteric feeding tube placement. According to the requirements that enteral nutrition could not be performed by the initial catheterization, 94 cases of catheterization failure were selected as the study subjects. The causes of catheterization failure were analyzed and summarized by analyzing the intraoperative image data and operation process; 42 cases of catheterization failure experienced successful catheterization after re-catheterization. By studying the relevant preoperative preparation and intraoperative operation, the treatment strategies and operation methods for successful re-catheterization were summarized. RESULTS: In 94 patients with primary catheterization failure, anastomotic stenosis or obstruction accounted for 20.2%, excessive dilatation of gastric lumen accounted for 17.0%, pyloric stenosis or obstruction of antrum accounted for 13.8%, efferent loop stenosis or obstruction accounted for 11.7%, and the above factors were the main causes of DSA guided feeding tube failure; of the 42 patients with successful recatheterization, 9 patients underwent adequate negative pressure drainage before surgery, 7 patients modified the projection angle by adjusting the C-arm, 5 patients applied cone-beam CT technique, 5 patients used balloon dilatation of the stenotic segment, and the above factors were the main strategy methods for successful recatheterization. CONCLUSIONS: The success rate of DSA guided nasoenteric feeding tube placement will be greatly improved by adequate gastrointestinal decompression and drainage and other related preoperative preparation as well as good intraoperative application of cone-beam CT technique or combined application of balloon, gastroscope, stent and other technical means.

Multiple interventional embolizations for hemostasis in hemorrhage following advanced colorectal cancer treatment: a case report.

Background: In recent years, the incidence of serious complications in patients with advanced colorectal cancer has been progressively increasing, and the fatality rate of secondary bleeding is the highest, while most patients cannot undergo surgical intervention due to physical weakness, while interventional embolization therapy has attracted more and more attention of clinicians because of its advantages of small trauma and quick effect. Among them, multiple cases of secondary hemorrhage of different arteries are very rare. In this case, the changes of vital signs of patients were significantly stabilized after each interventional embolization therapy. Interventional embolization therapy can be used as one of the first choices for secondary hemorrhage. Case Description: Retrospectively analyzed the clinical data of a patient with advanced colorectal cancer who successively developed 7 times of secondary hemorrhage within 10 months. The two times of hemorrhage had different degrees of hemorrhagic shock, and five times showed unexplained progressive decrease in hemoglobin. The location of each hemorrhage and the arteries invaded by the tumor were different, and the embolization materials and treatment methods used each time were not the same. The effect of interventional embolization each time could effectively stop bleeding, and the patient greatly improved the quality of life with tumor survival. The patient prolonged the survival cycle for up to 16 months from the first secondary hemorrhage. Conclusions: For patients with advanced colorectal cancer complicated with secondary hemorrhage, interventional embolization can be used to control the disease and prolong the life cycle, which is one of the preferred treatment methods in clinical application.

[Effectiveness analysis of computer-aided technology in the treatment of primary elbow osteoarthritis combined with stiffness under arthroscopy].

Objective: To explore the effectiveness of computer-aided technology in the treatment of primary elbow osteoarthritis combined with stiffness under arthroscopy. Methods: The clinical data of 32 patients with primary elbow osteoarthritis combined with stiffness between June 2018 and December 2020 were retrospectively analyzed. There were 22 males and 10 females with an average age of 53.4 years (range, 31-71 years). X-ray film and three-dimensional CT examinations showed osteophytes of varying degrees in the elbow joint. Loose bodies existed in 16 cases, and there were 7 cases combined with ulnar nerve entrapment syndrome. The median symptom duration was 2.5 years (range, 3 months to 22.5 years). The location of bone impingement from 0° extension to 140° flexion of the elbow joint was simulated by computer-aided technology before operation and a three-dimensional printed model was used to visualize the amount and scope of impinging osteophytes removal from the anterior and posterior elbow joint to accurately guide the operation. Meanwhile, the effect of elbow joint release and impinging osteophytes removal was examined visually under arthroscopy. The visual analogue scale (VAS) score, Mayo elbow performance score (MEPS), and elbow range of motion (extension, flexion, extension and flexion) were compared between before and after operation to evaluate elbow function. Results: The mean operation time was 108 minutes (range, 50-160 minutes). All 32 patients were followed up 9-18 months with an average of 12.5 months. There was no other complication such as infection, nervous system injury, joint cavity effusion, and heterotopic ossification, except 2 cases with postoperative joint contracture at 3 weeks after operation due to the failure to persist in regular functional exercises. Loose bodies of elbow and impinging osteophytes were removed completely for all patients, and functional recovery was satisfactory. At last follow-up, VAS score, MEPS score, extension, flexion, flexion and extension range of motion significantly improved when compared with preoperative ones ( P<0.05). Conclusion: Arthroscopic treatment of primary elbow osteoarthritis combined with stiffness using computer-aided technology can significantly reduce pain, achieve satisfactory functional recovery and reliable effectiveness.

CircRNA ZNF609 promotes the growth and metastasis of thyroid cancer in vivo and in vitro by downregulating miR-514a-5p.

Thyroid cancer (TC) often manifests in the form of a painless cervical mass or nodule and continues to increase in incidence. Currently, much less is known about its pathogenesis in TC cells. This study sought to figure out what role the circular RNA (circRNA) ZNF609/miR-514a-5p might play in TC development and metastasis. In this study, the detection of circ-ZNF609 and miR-514a-5p expressions was carried out by qRT-PCR in TC cell lines. Cell proliferation assessment is employed by cell counting kit-8 (CCK-8) assay, colony formation, Western blot and immunofluorescence. Cell invasion and migration measurement were conducted applying wound healing and transwell. The relationship between circ-ZNF609 and miR-514a-5p was subjected to prediction with bioinformatics analysis and validated with the aid of luciferase reporter assay. Furthermore, xenograft animal experiment was adopted to confirm the role of circ-ZNF609/miR-514a-5p in TC in vivo. The data indicated that circ-ZNF609 was highly expressed, while miR-514a-5p was downregulated in TC cells. Circ-ZNF609 knockdown prevented the malignant biological behaviors of TPC-1 and IHH-4 cells. Besides, circ-ZNF609 sponged miR-514a-5p and miR-514a-5p knockdown reversed the suppressed impacts of circ-ZNF609 knockdown on TC cell malignant biological behaviors. In addition, the silence of circ-ZNF6091 significantly repressed, whereas miR-514a-5p silencing promoted TC tumorigenesis in vivo. The findings highlighted the importance of circ-ZNF609 function in facilitating TC cell development and metastasis in vitro and in vivo via binding to miR-514a-5p.

Silenced lncRNA DDX11-AS1 or up-regulated microRNA-34a-3p inhibits malignant phenotypes of hepatocellular carcinoma cells via suppression of TRAF5.

BACKGROUND: Studies have discussed long noncoding RNA DDX11-AS1 (DDX11-AS1)-mediated downstream mechanism in hepatocellular carcinoma (HCC). The goal of this study was to investigate the regulatory mechanism of DDX11-AS1-mediated microRNA-34a-3p (miR-34a-3p)/tumor necrosis factor receptor-associated factor 5 (TRAF5) axis on HCC cells. METHODS: DDX11-AS1, miR-34a-3p and TRAF5 expression levels in HCC were detected. The correlation of DDX11-AS1, miR-34a-3p and TRAF5 in HCC patients was analyzed by Pearson test. HCC cells were transfected with corresponding plasmid/oligonucleotide, and cell proliferation, migration, invasion, apoptosis and tumor formation ability were detected. Bioinformatics software, dual luciferase report experiment and RNA-pull down experiment analysis were applied to verify the targeting relationship between DDX11-AS1, miR-34a-3p and TRAF5. RESULTS: Elevated DDX11-AS1 and TRAF5 and reduced miR-34a-3p exhibited in HCC. Silenced DDX11-AS1 or up-regulated miR-34a-3p inhibited the proliferation, migration, invasion, promoted apoptosis of HCC cells and repressed the tumor growth in nude mice. In addition, DDX11-AS1 bound to miR-34a-3p to target TRAF5. Silencing TRAF5 or elevating miR-34a-3p expression mitigated up-regulated DDX11-AS1-mediated promotion of tumor growth. CONCLUSION: Silenced DDX11-AS1 or up-regulated miR-34a-3p inhibits HCC cell growth via elevation of TRAF5, which could be of great benefit to find early diagnostic markers for HCC patients.

Cervical carcinoma high-expressed long non-coding RNA 1 promotes papillary thyroid carcinoma cell proliferation and invasion.

BACKGROUND: Studies have shown that cervical carcinoma high-expressed long non-coding RNA 1 (lncRNA-CCHE1) may promote tumor development by regulating tumor migration and invasion in a variety of cancers; yet, the role of lncRNA-CCHE1 in papillary thyroid carcinoma (PTC) remains unclear. The purpose of this study was to explore the mechanism of lncRNA-CCHE1 in PTC. METHODS: The expression of lncRNA-CCHE1 in 51 PTC carcinoma tissues and normal adjacent tissues was measured using real-time quantitative polymerase chain reaction (RT-qPCR). Cell Counting Kit-8 (CCK8), plate cloning assay, transwell assay, and flow cytometry were used to analyze the effect of lncRNA-CCHE1 on PTC cell proliferation, invasion, and apoptosis in vitro. RESULTS: A higher expression of lncRNA-CCHE1 was found in PTC tissues than in adjacent tissues. High expression of lncRNA-CCHE1 was positively correlated with the number of tumors, extra-glandular invasion, and tumor stage. In addition, the down-regulation of lncRNA-CCHE1 reduced the proliferation and invasion of PTC cell lines and promoted cell apoptosis, while its up-regulation caused the opposite effect. These effects were regulated via the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway. CONCLUSIONS: The lncRNA-CCHE1 is closely related to PTC progression and may be used as a potential biomarker for early diagnosis and treatment of PTC.

Oxysophocarpine reduces oxidative stress and inflammation in tuberculosis-infected neutrophils and mouse lungs.

Tuberculosis (TB) is a chronic inflammatory infectious disease caused by Mycobacterium tuberculosis (Mtb), which induces irreversible pulmonary damage. Oxysophocarpine (OSC) is a natural alkaloid that exhibits multiple pharmacological activities, including anti-inflammation; however, the protective effects of OSC against TB and the mechanisms involved are unknown. Here, we established murine and cellular models of TB with C3HeB/FeJ mice and neutrophils infected with H37Rv to investigate the biological functions of OSC in TB. We found that OSC reduced the mortality, inhibited the pulmonary H37Rv growth, and alleviated the lung pathology injury in the Mtb-infected mice. OSC also repressed neutrophil recruitment to the lesions of the Mtb-infected mice as evidenced by a decrease in the number and percentage of neutrophils in the lungs. OSC hampered the production of proinflammatory cytokines and chemokines, including tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), IL-6, macrophage inflammatory protein-2 (MIP-2), granulocyte colony stimulating factor (G-CSF), and keratinocyte chemoattractant (KC) in the lungs of Mtb-infected mice. The results of the in vitro experiments showed that OSC repressed the adhesion and F-actin polymerization of the Mtb-infected neutrophils by inhibiting the toll-like receptor 2/myeloid differentiation primary response gene 88/Src/extracellular signal-regulated kinase 1/2 signaling. Moreover, OSC abolished the Mtb-induced expression and release of TNF-α, IL-1ß, IL-6, MIP-2, G-CSF, and KC in neutrophils. Overall, these findings indicate that OSC can treat TB partly by lessening the neutrophilic recruitment and inflammation.

TLR4 induced Wnt3a-Dvl3 restrains the intensity of inflammation and protects against endotoxin-driven organ failure through GSK3ß/ß-catenin signaling.

BACKGROUND: Accumulating evidence suggests a regulatory role of Wnt proteins in innate immune responses. However, the effects of Wnt3a signaling on TLR4-mediated inflammatory responses are controversial and the signaling crosstalk between TLR4 and Wnt3a remains uncertain. METHODS: Gain- and Loss- of function approaches were utilized to determine the function of Wnt3a signaling in TLR4-mediated inflammatory responses. Cytokine production at protein and mRNA levels and phosphorylation of signaling molecules were measured by ELISA, qRT-PCR, and Western Blot, respectively. Endotoxemia mouse model was employed to assess the effect of Wnt3a on systemic inflammatory cytokine levels and neutrophil infiltration. RESULTS: LPS stimulation leads to an increase of Wnt3a expression and its downstream molecule, Dvl3, in primary monocytes. Inhibition or silence of Wnt3a or Dvl3 significantly increases the production of pro-inflammatory cytokines (IL-12, IL-6, TNFα), robustly reduces ß-catenin accumulation, and enhances the phosphorylation of NF-κB P65 and its DNA binding activity. These results were confirmed by multiple gain- and loss- of function approaches including specific siRNA and ectopic expression of Dvl3, GSK3ß, and ß-catenin in monocytes. Moreover, in vivo relevance was established in a murine endotoxin model, in which Wnt3a inhibition enhances the inflammatory responses by augmenting the systemic pro-inflammatory cytokine levels and neutrophil infiltration. CONCLUSIONS: TLR4 activation promotes Wnt3a-Dvl3 signaling, which acts as rheostats to restrain the intensity of inflammation through regulating GSK3ß-ß-catenin signaling and NF-κB activity. GENERAL SIGNIFICANCE: Wnt3a-Dvl3-ß-catenin signaling axis could be a potential interventional target for manipulating the direction and intensity of inflammatory responses.

MicroRNA-101 Targets CXCL12-Mediated Akt and Snail Signaling Pathways to Inhibit Cellular Proliferation and Invasion in Papillary Thyroid Carcinoma.

Escalating evidence suggests that microRNA-101 (miR-101) is implicated in the development and progression of various cancers, including papillary thyroid carcinoma (PTC). However, the biological function and molecular mechanisms of miR-101 in PTC are still unclear. In this study, we demonstrated that miR-101 expression was significantly decreased in PTC tissues and cell lines. Clinically, a low level of miR-101 was positively associated with advanced histological stages and lymph node and distant metastases. The expression of CXCL12 was negatively correlated with miR-101 level in PTC. CXCL12 was validated as a direct target of miR-101 in PTC cells. Functional experiments proved that miR-101 markedly reduced the proliferation, apoptosis escape, migration, and invasion of PTC cells. Moreover, CXCL12 restoration rescued the suppressive effects of miR-101 on PTC cells by activating Akt- and EMT-associated signaling pathways. Overall, miR-101 exerts oncostatic effects on PTC by downregulating CXCL12 and repressing its downstream Akt and Snail signaling pathways, suggesting that miR-101/CXCL12/Akt or Snail axis may serve as a potential therapeutic target for PTC.

Knockdown of LOXL1 inhibits TGF-ß1-induced proliferation and fibrogenesis of hepatic stellate cells by inhibition of Smad2/3 phosphorylation.

Liver fibrosis is pathological condition that seriously threatens human health. The lysyl oxidase (LOX) family has been reported to promote liver fibrosis. However, the effect of LOX-like 1 (LOXL1), a member of LOX family, on fibrogenesis of hepatic stellate cells (HSCs) remains unknown. The current study aimed to investigate the role of LOXL1 in liver fibrosis and the potential mechanism. We found that the mRNA and protein levels of LOXL1 were increased in transforming growth factor-beta 1 (TGF-ß1)-stimulated human hepatic stellate cell line LX-2. Knockdown of LOXL1 inhibited the proliferation of TGF-ß1-stimulated LX-2 cells. Knockdown of LOXL1 suppressed TGF-ß1-induced expression of metalloproteinase type 1 (TIMP1), α-smooth muscle actin (α-SMA), and collagen type I (Col-I), as well as phosphorylation of Smad2 and Smad3 in LX-2 cells. In addition, the cell proliferation and fibrogenesis mediated by TGF-ß1 stimulation and LOXL1 overexpression were abolished by knockdown of Smad2 and Smad3. Collectively, knockdown of LOXL1 suppressed cell proliferation and fibrogenesis in TGF-ß1-stimulated HSCs via regulating the phosphorylation of Smad2/3.

Hantaan virus triggers TLR4-dependent innate immune responses.

The innate immune response induced by Hantavirus is responsible for endothelial cell dysfunction and viral pathogenicity. Recent studies demonstrate that TLR4 expression is upregulated and mediates the secretion of several cytokines in Hantaan virus (HTNV)-infected endothelial cells. To examine viral interactions with host endothelial cells and characterize the innate antiviral responses associated with Toll-like receptors, we selected TLR4 as the target molecule to investigate anti-hantavirus immunity. TLR4 mRNA-silenced EVC-304 (EVC-304 TLR4-) cells and EVC-304 cells were used to investigate signaling molecules downstream of TLR4. The expression of the adaptor protein TRIF was higher in HTNV-infected EVC-304 cells than in EVC-304 TLR4- cells. However, there was no apparent difference in the expression of MyD88 in either cell line. The transcription factors for NF-κB and IRF-3 were translocated from the cytoplasm into the nucleus in HTNV-infected EVC-304 cells, but not in HTNV-infected EVC-304 TLR4- cells. Our results demonstrate that TLR4 may play an important role in the antiviral immunity of the host against HTNV infection through an MyD88-independent signaling pathway.

Dysregulation of the ß3 integrin-VEGFR2 complex in Hantaan virus-directed hyperpermeability upon treatment with VEGF.

Hantaviruses infect human endothelial cells (ECs) and are known to cause vascular-permeability-based diseases, including hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). The αvß3 integrins, which are highly expressed on the surface of ECs, serve as hantavirus receptors. Specifically, the ß3 integrin and vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) form a functional complex and interact with each other. Signaling through this complex causes cytoskeletal reorganization, which is one of the most important mechanisms underlying hyperpermeability. In this study, we show that VEGF dramatically enhances Hantaan virus (HTNV)-directed permeability and increases the reorganization of the cytoskeleton and the disruption of junctional organizations in an EC monolayer at 3 days postinfection. HTNV infection reduced the effect of VEGF on adhesion, migration, and the upregulation of ß3 expression, but the infection alone upregulated the expression of ß3 and VEGFR2. These results indicate that in addition to its role in blocking ß3 integrin activation as reported previously, HTNV blocks the function of the complex of VEGFR2 and ß3 integrin, and the dysfunction of the complex may contribute to cytoskeletal reorganization in an HTNV-directed hyperpermeability response to VEGF.