Dynamic immunoediting by macrophages in homologous recombination deficiency-stratified pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease, notably resistant to existing therapies. Current research indicates that PDAC patients deficient in homologous recombination (HR) benefit from platinum-based treatments and poly-ADP-ribose polymerase inhibitors (PARPi). However, the effectiveness of PARPi in HR-deficient (HRD) PDAC is suboptimal, and significant challenges remain in fully understanding the distinct characteristics and implications of HRD-associated PDAC. We analyzed 16 PDAC patient-derived tissues, categorized by their homologous recombination deficiency (HRD) scores, and performed high-plex immunofluorescence analysis to define 20 cell phenotypes, thereby generating an in-situ PDAC tumor-immune landscape. Spatial phenotypic-transcriptomic profiling guided by regions-of-interest (ROIs) identified a crucial regulatory mechanism through localized tumor-adjacent macrophages, potentially in an HRD-dependent manner. Cellular neighborhood (CN) analysis further demonstrated the existence of macrophage-associated high-ordered cellular functional units in spatial contexts. Using our multi-omics spatial profiling strategy, we uncovered a dynamic macrophage-mediated regulatory axis linking HRD status with SIGLEC10 and CD52. These findings demonstrate the potential of targeting CD52 in combination with PARPi as a therapeutic intervention for PDAC.

Tankyrases inhibit innate antiviral response by PARylating VISA/MAVS and priming it for RNF146-mediated ubiquitination and degradation.

During viral infection, sensing of viral RNA by retinoic acid-inducible gene-I-like receptors (RLRs) initiates an antiviral innate immune response, which is mediated by the mitochondrial adaptor protein VISA (virus-induced signal adaptor; also known as mitochondrial antiviral signaling protein [MAVS]). VISA is regulated by various posttranslational modifications (PTMs), such as polyubiquitination, phosphorylation, O-linked ß-d-N-acetylglucosaminylation (O-GlcNAcylation), and monomethylation. However, whether other forms of PTMs regulate VISA-mediated innate immune signaling remains elusive. Here, we report that Poly(ADP-ribosyl)ation (PARylation) is a PTM of VISA, which attenuates innate immune response to RNA viruses. Using a biochemical purification approach, we identified tankyrase 1 (TNKS1) as a VISA-associated protein. Viral infection led to the induction of TNKS1 and its homolog TNKS2, which translocated from cytosol to mitochondria and interacted with VISA. TNKS1 and TNKS2 catalyze the PARylation of VISA at Glu137 residue, thereby priming it for K48-linked polyubiquitination by the E3 ligase Ring figure protein 146 (RNF146) and subsequent degradation. Consistently, TNKS1, TNKS2, or RNF146 deficiency increased the RNA virus-triggered induction of downstream effector genes and impaired the replication of the virus. Moreover, TNKS1- or TNKS2-deficient mice produced higher levels of type I interferons (IFNs) and proinflammatory cytokines after virus infection and markedly reduced virus loads in the brains and lungs. Together, our findings uncover an essential role of PARylation of VISA in virus-triggered innate immune signaling, which represents a mechanism to avoid excessive harmful immune response.

Dual External Field Strategy in Regulating the Superhalogen Characteristics of the Non-Noble Metal Constituted Tantalum Oxide Clusters.

The identification of the non-noble metal constituted TaO cluster as a potential analogue to the noble metal Au is significant for the development of tailored materials. It leverages the superatom concept to engineer properties with precision. However, the impact of incrementally integrating TaO units on the electronic configurations and properties within larger TaO-based clusters remains to be elucidated. By employing the density functional theory calculations, the global minima and low-lying isomers of the TanOn (n = 2-5) clusters were determined, and their structural evolution was disclosed. In the cluster series, Ta5O5 was found to possess the highest electron affinity (EA) with a value of 2.14 eV, based on which a dual external field (DEF) strategy was applied to regulate the electronic property of the cluster. Initially, the electron-withdrawing CO ligand was affixed to Ta5O5, followed by the application of an oriented external electric field (OEEF). The CO ligation was found to be able to enhance the Ta5O5 cluster's electron capture capability by adjusting its electron energy levels, with the EA of Ta5O5(CO)4 peaking at 2.58 eV. Subsequently, the introduction of OEEF further elevated the EA of the CO-ligated cluster. Notably, OEEF, when applied along the +x axis, was observed to sharply increase the EA to 3.26 eV, meeting the criteria for superhalogens. The enhancement of EA in response to OEEF intensity can be quantified as a functional relationship. This finding highlights the advantage of OEEF over conventional methods, demonstrating its capacity for precise and continuous modulation of cluster EAs. Consequently, this research has adeptly transformed tantalum oxide clusters into superhalogen structures, underscoring the effectiveness of the DEF strategy in augmenting cluster EAs and its promise as a viable tool for the creation of superhalogens.

A Rare Case of Benign Recurrent Intrahepatic Cholestasis Initially Diagnosed in Middle-age.

Background: Repeated episodes of jaundice and pruritus are common in a group of autosomal recessive liver diseases known as benign recurrent intrahepatic cholestasis. Benign recurrent intrahepatic cholestasis (BRIC) is divided into two types, type 1 and type 2, and is caused by mutations in the ATP8B1 and ABCB11 genes. Here, we report a rare case of BRIC type 2 mutation. Case presentation: A 45-year-old Chinese man had three frequent episodes of jaundice marked by extensive excoriation and severe pruritis, although he had no prior history of jaundice. Laboratory investigations showed no evidence of liver damage caused by viral, autoimmune, or acquired metabolic etiologies. The CT scan revealed an enlarged gallbladder with numerous punctate high-density shadows, while no wall thickening was observed. Endoscopic ultrasonography showed no evidence of dilation of the intrahepatic and extrahepatic bile duct, as well as the absence of gallstone. Diagnostic evaluation: Immunohistochemical examinations of liver biopsy samples showed cytokeratin-7 positive hepatocytes, suggesting chronic intrahepatic cholestasis. The reticulin fiberstaining demonstrated that the portions of the hepatic plate in the center of the lobule were asymmetrically organized,and somewhat enlarged, with collapsed areas indicating intralobular inflammation. Moreover, there were areas of collapse that indicated the presence of intralobular inflammation. Whole exome sequencing revealed mutations in the ABCB11 gene; c.3084A>G, p.A1028A homozygous mutation (chr2-169789016), and c.2594C>T, p.A865V heterozygous mutation (chr2-169801131). Based on these findings, the final diagnosis of the patient was metabolism-related jaundice. Treatment: Apart from receiving tapering dosage of prednisone to lower bilirubin levels, the patient received no extra care. Conclusion: The comprehensive diagnosis of a middle-aged male patient with BRIC-2, which involved extensive radiological, hematological, and genetic investigations, informed a tailored tapering prednisone regimen, highlighting the importance of personalized medicine in managing atypical presentations of this rare cholestatic disorder.

STING Agonist-Derived LNP-mRNA Vaccine Enhances Protective Immunity Against SARS-CoV-2.

Lipid nanoparticle (LNP)-mediated delivery of messenger RNA (mRNA) COVID-19 vaccines has provided large-scale immune protection to the public. To elicit a robust immune response against SARS-CoV-2 infections, antigens produced by mRNAs encoding SARS-CoV-2 Spike glycoprotein need to be efficiently delivered and presented to antigen-presenting cells such as dendritic cells (DCs). As concurrent innate immune stimulation can facilitate the antigen presentation process, a library of non-nucleotide STING agonist-derived amino lipids (SALs) was synthesized and formulated into LNPs for mRNA delivery. SAL12 lipid nanoparticles (SAL12-LNPs) were identified as most potent in delivering mRNAs encoding the Spike glycoprotein (S) of SARS-CoV-2 while activating the STING pathway in DCs. Two doses of SAL12 S-LNPs by intramuscular immunization elicited potent neutralizing antibodies against SARS-CoV-2 in mice.

Omental cancer-associated fibroblast-derived exosomes with low microRNA-29c-3p promote ovarian cancer peritoneal metastasis.

Ovarian cancer (OC) is characterized by frequent widespread peritoneal metastasis. Cancer-associated fibroblasts (CAFs) represent a critical stromal component of metastatic niche and promote omentum metastasis in OC patients. However, the role of exosomes derived from omental CAFs in metastasis remains unclear. We isolated exosomes from primary omental normal fibroblasts (NFs) and CAFs from OC patients (NF-Exo and CAF-Exo, respectively) and assessed their effect on metastasis. In mice bearing orthotopic OC xenografts, CAF-Exo treatment led to more rapid intraperitoneal tumor dissemination and shorter animal survival. Similar results were observed in mice undergoing intraperitoneal injection of tumor cells. Among the miRNAs downregulated in CAF-Exo, miR-29c-3p in OC tissues was associated with metastasis and survival in patients. Moreover, increasing miR-29c-3p in CAF-Exo significantly weakened the metastasis-promoting effect of CAF-Exo. Based on RNA sequencing, expression assays, and luciferase assays, matrix metalloproteinase 2 (MMP2) was identified as a direct target of miR-29c-3p. These results verify the significant contribution of exosomes from omental CAFs to OC peritoneal metastasis, which could be partially due to the relief of MMP2 expression inhibition mediated by low exosomal miR-29c-3p.

Antinuclear antibody (ANA) status predicts immune-related adverse events in liver cancer patients undergoing anti-PD-1 therapy.

Immune-related adverse events (irAEs) clinically resemble autoimmune diseases, indicating autoantibodies could be potential biomarkers for the prediction of irAEs. This study aimed to assess the predictive value of peripheral blood antinuclear antibody (ANA) status for irAEs, considering the time and severity of irAEs, as well as treatment outcome in liver cancer patients administered anti-PD-1 therapy. Ninety-three patients with advanced primary liver cancer administered anti-PD-1 treatment were analyzed retrospectively. They were divided into the ANA positive (ANA+, titer ≥ 1:100) and negative (ANA-, titer < 1:100) groups. Development of irAEs, progression-free survival (PFS), and overall survival (OS) were assessed. Compared with ANA- patients, ANA+ cases were more prone to develop irAEs (43.3% vs. 19.2%, P = 0.031). With the increase of ANA titers, the frequency of irAEs increased. The time interval between anti-PD-1 therapy and the onset of irAEs was significantly shorter in ANA+ patients compared with the ANA- group (median, 1.7 months vs. 5.0 months, P = 0.022). Moreover, the time between anti-PD-1 therapy and irAE occurrence decreased with increasing ANA titer. In addition, PFS and OS were decreased in ANA+ patients compared with the ANA- group (median PFS, 2.8 months vs. 4.2 months, P = 0.043; median OS, 21.1 months vs. not reached, P = 0.041). IrAEs occur at higher frequency in ANA+ liver cancer patients undergoing anti-PD-1 therapy. ANA titer could help predict irAE development and treatment outcome in these patients.

Efficacy and safety of moxibustion on cancer-related fatigue: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: The goal of this research was to review the literature from randomized controlled trials (RCTs) on the impacts of moxibustion on cancer-related fatigue (CRF) as well as provide credible evidence to guide clinical practice. METHODS: Three English electronic medical databases (PubMed, Embase, and the Cochrane Library) and two Chinese databases (China National Knowledge Infrastructure and Wanfang) were searched. Only randomized controlled trials on the effect of moxibustion on CRF were included in this systematic review. Study selection, data extraction, and validation were all carried out independently by two reviewers. The revised Cochrane Risk of Bias tool was used to assess the quality of the RCTs (RoB 2.0). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was applied to assess effect sizes in individual RCTs and pooled effect sizes in meta-analyses. Data were meta-analyzed using Stata (version 14.0). RESULTS: In a random-effects meta-analysis of 24 RCTs with 1894 participants, the aggregated standardized mean difference (SMD) revealed a statistically significant association between moxibustion and alleviation from cancer-related fatigue (SMD = - 1.66, 95% CI = - 2.05, - 1.28, p = 0.000). Pooled results, however, show significant heterogeneity (I2 = 92.5%), and the evidence is insufficient to determine whether this association varies systematically by measuring tools and moxibustion modalities. Furthermore, evidence ranging from very low to low showed that moxibustion had an immediate positive effect on patients with CRF. CONCLUSION: Moxibustion may have a therapeutic effect on cancer-related fatigue. However, further large-scale, multicenter, high-quality RCTs on moxibustion for fatigue relief and safety are still needed because of the handful of studies included and the low methodological quality.

Transcutaneous Electrical Acupoints Stimulation Improves Spontaneous Voiding Recovery After Laparoscopic Cholecystectomy: A Randomized Clinical Trial.

BACKGROUND: Facilitating the recurrence of spontaneous voiding is considered to be a way to prevent urinary retention after surgery, which is of great importance in cholecystectomy. This study aimed to assess the effect of transcutaneous electrical acupoint stimulation (TEAS) on spontaneous voiding recovery after laparoscopic cholecystectom. METHODS: Participants who underwent elective laparoscopic cholecystectomy were randomly assigned to either the TEAS group or the sham group. Active TEAS or sham TEAS at specific acupuncture points was conducted intraoperatively and postoperatively. The primary outcome was the recovery speed of spontaneous voiding ability after surgery and secondary outcomes included postoperative urinary retention (POUR), voiding dysfunction, pain, anxiety and depression, and early recovery after surgery. RESULTS: A total of 1,948 participants were recruited and randomized to TEAS (n = 975) or sham (n = 973) between August 2018 and June 2020. TEAS shortens the time delay of the first spontaneous voiding after laparoscopic cholecystectomy (5.6 h [IQR, 3.7-8.1 h] in the TEAS group vs 7.0 h [IQR, 4.7-9.7 h] in the sham group) (p < 0.001). The TEAS group experienced less POUR (p = 0.020), less voiding difficulty (p < 0.001), less anxiety and depression (p < 0.001), reduced pain (p = 0.007), and earlier ambulation (p = 0.01) than the sham group. CONCLUSIONS: Our results showed that TEAS is an effective approach to accelerate the recovery of spontaneous voiding and reduce POUR which facilitates recovery for patients after laparoscopic cholecystectomy.

Dioscin induces osteosarcoma cell apoptosis by upregulating ROS-mediated P38 MAPK signaling.

Osteosarcoma is the most common primary malignant bone tumor in children and adolescents. Many patients with osteosarcoma readily develop resistance to chemotherapy and have an extremely dismal prognosis. Dioscin, a saponin, is known to exhibit potent anticancer activities and induce cellular death of a variety of cancer types. However, the inhibitory effect of dioscin on osteosarcoma cells and its underlying mechanisms have not been fully elucidated. We investigated the responses of human U2-OS and MG63 osteosarcoma cells to dioscin with regard to proliferation, apoptosis, migration, and invasion, and studied the effect of dioscin on MAPK-related proteins by western blot analysis assays. Dioscin inhibited osteosarcoma cell proliferation, migration, and invasion. Moreover, it induced osteosarcoma cell apoptosis via reactive oxygen species (ROS)-dependent apoptotic signaling. N-acetylcysteine, a reactive oxygen species inhibitor, suppressed dioscin-induced apoptosis, indicating that ROS play an essential role in dioscin-induced apoptosis. Western blot analysis assays showed that p38 MAPK was upregulated after dioscin treatment, and that dioscin induced apoptosis by upregulating ROS-mediated p38 MAPK signaling. Our study suggests that dioscin possesses antitumor activities against human osteosarcoma cells, inhibits osteosarcoma cell proliferation, migration and invasion, and induces osteosarcoma cell apoptosis through upregulating ROS-mediated p38 MAPK signaling. This study may provide a new therapeutic strategy and potential clinical applications for the treatment of osteosarcoma.

Efficacy of keverprazan for duodenal ulcer: A phase II randomized, double-blind, parallel-controlled trial.

BACKGROUND AND AIM: Considering the limitation of varying acid suppression of proton pump inhibitors, this study was aimed to assess the efficacy, safety, and dose-effect relationship of keverprazan, a novel potassium-competitive acid blocker, in the treatment of duodenal ulcer (DU) compared with lansoprazole. METHODS: A randomized, double-blind, double-dummy, multicenter, low-dose, high-dose, and positive-drug parallel-controlled study was conducted to verify the non-inferiority of keverprazan (20 or 30 mg) to lansoprazole of 30 mg once daily for 4 to 6 weeks and dose-effect relationship of keverprazan in the treatment of patients with active DU confirmed by endoscopy. RESULTS: Of the 180 subjects randomized, including 55 cases in the keverprazan_20 mg group, 61 cases in the keverprazan_30 mg group, and 64 cases in the lansoprazole_30 mg group, 168 subjects (93.33%) completed the study. The proportions of healed DU subjects in the keverprazan_20 mg, keverprazan_30 mg, and lansoprazole_30 mg groups were respectively 87.27%, 90.16%, and 79.69% at week 4 (P = 0.4595) and were respectively 96.36%, 98.36%, and 92.19% at week 6 (P = 0.2577). The incidence of adverse events in the keverprazan_20 mg group was lower than that in the lansoprazole_30 mg (P = 0.0285) and keverprazan_30 mg groups (P = 0.0398). CONCLUSIONS: Keverprazan was effective and non-inferior to lansoprazole in healing DU. Based on the comparable efficacy and safety data, keverprazan of 20 mg once daily is recommended for the follow-up study of acid-related disorders. (Trial registration number: ChiCTR2100043455.).

Exploring the prognosis of neuroblastoma in adolescents and adults: a case series and literature review.

Neuroblastoma (NB) is one of the most common extracranial malignant solid tumors in childhood, and over 90% of NBs are diagnosed in children under the age of 10 years old. For patients between 14 and 18 years old or older than 18 years, due to the rarity of NB, few studies have been performed in this population. Defined "adolescent cases" as individuals in 14-18 years old and "adult cases" as older than 18 years old, we reported five NB cases of adolescents and adults in our hospital. 137 cases presented a review of published literature on this topic. Clinicopathological factors and treatment modalities used of the 142 patients were assessed for their prognostic value. Better outcomes were found in adolescent patients rather than adult patients (p=0.012). Patients diagnosed with neuroblastoma or ganglioneuroblastoma (nodular type) (p=0.006) and with distant metastasis (p<0.001) were characterized by poor outcomes. Distant metastasis was an independent adverse influencing factor for overall survival in adolescent and adult NB patients. Regarding treatment modalities, complete surgical resection was a significant factor improving the survival for such patients (p<0.001). For patients with distant metastasis, a significantly longer progression-free survival with chemotherapy than without chemotherapy (p=0.038), whereas chemotherapy did not show an advantage on patients with localized disease (p=0.039). The prognosis of NB in adolescent and adult patients was worse than that in children. These two groups also showed heterogeneity in clinical factors, genetic factors, and treatment tolerance. The rarity of adolescent and adult NB can lead to misdiagnosis and incorrect management. Further optimization of chemotherapy regimens and dosage for adolescent and adult NB patients is needed. The anti-GD2 immunotherapy may be an effective approach for treatment.

Water quality criteria and ecological risk assessment for ammonia in the Shaying River Basin, China.

Current Chinese surface water environmental quality standard GB3838-2002 for ammonia fails to take water quality factors and native organism distributions in different basins into consideration. In this study, ammonia toxicity tests were performed using three aquatic organisms native to the Shaying River Basin (China). Published ammonia toxicity data with pH and temperature, and toxicity data acquired in this study were used to establish water quality criteria. The final criterion maximum concentration (CMC) and criterion continuous concentration (CCC) for the Shaying River Basin were 5.09 and 1.36 (mg total ammonia nitrogen (TAN))/L (pH 7 and 20 °C), respectively. In addition, based on the corresponding relationship between ammonia toxicity and temperature and pH, the ecological risk assessment of ammonia was conducted in different seasons for the Shaying River using a tiered approach of both hazard quotient (HQ) and the joint probability (JPC) methods. Two methods gave consistent results: the ecological risks of ammonia to aquatic species in the Shaying River Basin were severe and the risk could be ranked as wet season > flat season > dry season. It is therefore indicating that monitoring, evaluation, and early warning of ammonia pollution need to be taken to prevent and control the risks posed by ammonia pollution, especially for wet season (because of high temperatures and pH) or flat season (because of high pH values). We hope the present work could provide valuable information to manage and control ammonia pollution in the Shaying River Basin.

Conversion of Fluorescence Signals into Optical Fingerprints Realizing High-Throughput Discrimination of Anionic Sulfonate Surfactants with Similar Structure Based on a Statistical Strategy and Luminescent Metal-Organic Frameworks.

To date, the effective discrimination of anionic sulfonate surfactants with tiny differences in structure, considered as environmentally noxious xenobiotics, is still a challenge for traditional analytical techniques. Fortunately, a sensor array becomes the best choice for recognizing targets with similar structures or physical/chemical properties by virtue of principal component analysis (PCA, a statistical technique). Herein, because of the beneficial construction of the statistical strategy and use of two types of luminescent metal-organic frameworks (LMOFs, NH2-UiO-66 and NH2-MIL-88) as sensing elements, high-throughput discrimination and detection of five anionic sulfonate surfactants and their mixtures are nicely realized for the first time. Significantly, the stacking interaction of aromatic rings and dynamic quenching play essential roles in the generation of diverse fluorescence responses and unique fingerprint maps for individual anionic sulfonate surfactants. Moreover, the mixtures of anionic sulfonate surfactants are also satisfactorily distinguished in environmental water samples, demonstrating the practicability of the sensor array. On the basis of the PCA method, this strategy converts general fluorescence signals into unique optical fingerprints of individual analytes, providing a new opportunity for the application of LMOFs in the field of analytes recognition.

Electroacupuncture Improves Cognition in Rats With Sepsis-Associated Encephalopathy.

BACKGROUND: Sepsis-associated encephalopathy (SAE) is a common complication of sepsis. Although sepsis is effectively managed with the administration of antibiotics and source control, which may include surgical intervention, SAE usually leads to prolonged cognitive dysfunction affecting the quality of life of the patients. In this study, we investigated the possible effect of electroacupuncture (EA) on cognition in a model of SAE induced by cecal ligation and puncture (CLP). MATERIALS AND METHODS: The rats were randomly divided into four groups: the control group, the CLP group, the CLP with EA treatment group (CLP + EA), and the CLP with sham EA treatment group (CLP + sham EA). EA at DU20, LI11, and ST36 or sham EA was performed 30 min daily for 10 consecutive days starting from 2 days before CLP. Then cognitive function was examined by the Morris water maze test. On day 14 after CLP surgery, the synaptic injury, neuron loss, and oxidative stress were studied. RESULTS: Rats with EA treatment showed improved survival rate, spatial learning, and memory abilities. The dendritic spine density, the synaptic proteins, and the hippocampal neuron number were also increased after EA treatment. Furthermore, EA suppressed oxidative stress through regulating the level of malondialdehyde and superoxide dismutase and enhanced the expression of antioxidant nuclear factor erythroid-2-related factor-2 and hemeoxygenase-1. But sham EA did not have the same effect. CONCLUSIONS: EA may protect against SAE-induced cognitive dysfunction by inhibiting synaptic injury, neuronal loss, and oxidative stress, and the nuclear factor erythroid-2-related factor-2/hemeoxygenase-1 signaling pathway may be involved in this effect.

Repression of TXNIP-NLRP3 axis restores intestinal barrier function via inhibition of myeloperoxidase activity and oxidative stress in nonalcoholic steatohepatitis.

Dysfunction of the intestinal barrier function occurs in hepatic injury, but the specific mechanisms responsible are largely unknown. Recently, NOD-like receptor 3 (NLRP3) inflammasome functions in impairing endothelial barrier function. In this study, we test the hypothesis that TXNIP-NLRP3 axis repression prevents against intestinal barrier function disruption in nonalcoholic steatohepatitis (NASH). First, lipopolysaccharide (LPS)-induced alterations in expression of ZO-1 and occludin, myeloperoxidase (MPO) activity, reactive oxygen species (ROS) level, and transepithelial electric resistance (TEER) in intestinal epithelial cells (IECs) isolated from C57BL/6 wild-type (WT) and TXNIP-/- mice were evaluated. The underlying regulatory mechanisms of TXNIP knockout in vivo were investigated with the detection of expressions of TXNIP, NLRP3 and ZO-1, and occludin, the interaction of TXNIP-NLRP3, MPO activity, ROS level, permeability of intestinal mucosa, levels of inflammatory factors in serum, and LPS concentration. We identified that TXNIP knockout promoted ZO-1 and occludin expression, yet reduced MPO activity, ROS level, and cell permeability in IECs, indicating restored the intestinal barrier function. However, LPS upregulated TXNIP and NLRP3 expression, as well as contributed to the interaction between TXNIP and NLRP3 in vitro. Furthermore, TXNIP was significantly upregulated in the intestinal mucosa of NASH mice and its knockout repaired the intestinal barrier disrupt, inhibited expression of inflammatory factors, and reduced LPS concentration as well as hepatic injury in vivo. Taken together, our findings demonstrated that inhibited the activation of the TXNIP-NLRP3 axis reduced MPO activity and oxidative stress and thus restoring the intestinal barrier function in NASH. TXNIP-NLRP3 axis may be a promising therapeutic strategy for the NASH treatment.

Galectin-3 deficiency protects lipopolysaccharide-induced chondrocytes injury via regulation of TLR4 and PPAR-γ-mediated NF-κB signaling pathway.

The aim of the present study was to identify the functional role of galectin-3 (Gal-3) in lipopolysaccharide (LPS)-induced injury in ATDC5 cells and to explore the probable molecular mechanisms. Here, we identified that LPS is sufficient to enhance the expression of Gal-3 in ATDC5 cells. In addition, repression of Gal-3 obviously impeded LPS-stimulated inflammation damage as exemplified by a reduction in the release of inflammatory mediators interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α, as well as the production of nitric oxide and prostaglandin E2 (PGE2) concomitant with the downregulation of matrix metalloproteinases (MMP)-13 and MMP-3 expression in ATDC5 cells after LPS administration. Moreover, ablation of Gal-3 dramatically augmented cell ability and attenuated cell apoptosis accompanied by an increase in the expression of antiapoptotic protein Bcl-2 and a decrease in the expression of proapoptotic protein Bax and caspase-3 in ATDC5 cells subjected with LPS. Importantly, we observed that forced expression of TLR4 or blocked PPAR-γ with the antagonist GW9662 effectively abolished Gal-3 inhibition-mediated anti-inflammatory and antiapoptosis effects triggered by LPS. Mechanistically, depletion of Gal-3 prevents the NF-κB signaling pathway. Taken together, these findings indicated that the absence of Gal-3 exerted chondroprotective properties dependent on TLR4 and PPAR-γ-mediated NF-κB signaling, indicating that Gal-3 functions as a protector in the development and progression of osteoarthritis.

SENP1-mediated deSUMOylation of USP28 regulated HIF-1α accumulation and activation during hypoxia response.

BACKGROUND: The ubiquitin-specific protease 28 (USP28) is an oncogenic deubiquitinase, which plays a critical role in tumorigenesis via antagonizing the ubiquitination and degradation of tumor suppressor protein FBXW7-mediated oncogenic substrates. USP28 controls hypoxia-dependent angiogenesis and metastasis by preventing FBXW7-dependent hypoxia-inducible transcription factor-1α (HIF-1α) degradation during hypoxia. However, it remains unclear how USP28 activation and HIF-1α signaling are coordinated in response to hypoxia. METHODS: The in vitro deubiquitinating activity assay was used to determine the regulation of USP28 by hypoxia. The co-immunoprecipitation and GST Pull-down assays were used to determine the interaction between USP28 and SENP1. The in vivo deSUMOylation assay was performed to determine the regulation of USP28 by SENP1. The luciferase reporter assay was used to determine the transcriptional activity of HIF-1α. RESULTS: Here, we report that USP28 is a SUMOylated protein in normoxia with moderate deubiquitinating activity towards HIF-1α in vitro, while hypoxia and HIF-1α activate USP28 through SENP1-mediated USP28 deSUMOylation to further accumulate HIF-1α protein in cells. In agreement with this, a SUMOylation mutant USP28 showed enhanced ability to increase HIF-1α level as well as control the transcriptional activity of HIF-1α. CONCLUSION: Collectively, our results reveal a novel SENP1-USP28-HIF-1α positive feedback loop to maximize the concentration of HIF-1a protein and amplify its downstream effects during hypoxia response.

Identification of co-expression modules and pathways correlated with osteosarcoma and its metastasis.

BACKGROUND: Osteosarcoma is the most common bone tumor that occurs in children. METHODS: To identify co-expression modules and pathways correlated with osteosarcoma and its clinical characteristics, we performed weighted gene co-expression network analysis (WGCNA) on RNA-seq data of osteosarcoma with 52 samples. Then we performed pathway enrichment analysis on genes from significant modules. RESULTS: A total of 5471 genes were included in WGCNA, and 16 modules were identified. Module-trait analysis identified that a module involved in microtubule bundle formation, drug metabolism-cytochrome P450, and IL-17 signaling pathway was negatively correlated with osteosarcoma and positively correlated with metastasis; a module involved in DNA replication was positively correlated with osteosarcoma; a module involved in cell junction was positively correlated with metastasis; and a module involved in heparin binding negatively correlated with osteosarcoma. Moreover, expression levels in four of the top ten differentially expressed genes were validated in another independent dataset. CONCLUSIONS: Our analysis might provide insight for molecular mechanisms of osteosarcoma.

Stenosing tenosynovitis : Evaluation of percutaneous release with a specially designed needle vs. open surgery.

PURPOSE: The purpose of this study was to evaluate the effectiveness of conventional open surgery and percutaneous release with a specially designed needle for treating stenosing tenosynovitis in terms of cure, relapse and complication rates. METHODS: In this study 89 fingers from 76 patients were randomly assigned and allocated to one of the treatment groups. A total of 37 patients were treated with open surgery in group 1 and 39 patients with percutaneous release using a specially designed needle in group 2. A patient-based 4-inch visual analogue scale (VAS), Quinnell grading (QG), disability of arm shoulder and hand (DASH) score and finger total joint range of motion (FTROM) score were evaluated before treatment and after 7, 30 and 180 days. When finger QG scores were equal or greater than 2 points at follow-up at 180 days this was defined as recurrence.. RESULTS: There were no significant differences between the two groups (P > 0.05) in terms of VAS, DASH and QG scores and the degree of FTROM. At 7 days all the data were significantly different (p < 0.05) compared with preoperative data, 30 days was significantly different (p < 0.05) compared with 7 days while at 180 days no significant differences could be found (p > 0.05) compared with 30 days. The recurrence rate in group 1 was 4.65% and 6.55% in group 2. CONCLUSION: The percutaneous release and open surgery methods displayed similar effectiveness regarding the cure and recurrence of trigger finger disorder. The use of a specially designed needle for release is a safe and reliable method.