Senp7 deficiency impairs lipid droplets maturation in white adipose tissues via Plin4 deSUMOylation.

Lipid metabolism is important for the maintenance of physiological homeostasis. Several members of the small ubiquitin-like modifier (SUMO)-specific protease (SENP) family have been reported as the regulators of lipid homeostasis. However, the function of Senp7 in lipid metabolism remains unclear. In this study, we generated both conventional and adipocyte-specific Senp7 KO mice to characterize the role of Senp7 in lipid metabolism homeostasis. Both Senp7-deficient mice displayed reduced white adipose tissue mass and decreased size of adipocytes. By analyzing the lipid droplet morphology, we demonstrated that the lipid droplet size was significantly smaller in Senp7-deficient adipocytes. Mechanistically, Senp7 could deSUMOylate the perilipin family protein Plin4 to promote the lipid droplet localization of Plin4. Our results reveal an important role of Senp7 in the maturation of lipid droplets via Plin4 deSUMOylation.

HSK3486 Inhibits Colorectal Cancer Growth by Promoting Oxidative Stress and ATPase Inhibitory Factor 1 Activation.

BACKGROUND: HSK3486 (ciprofol), a new candidate drug similar to propofol, exerts sedative and hypnotic effects through gamma-aminobutyric acid type A receptors; however, its potential role in colorectal cancer is currently unknown. AIMS: This study aimed to evaluate the effects of HSK3486 on colorectal cancer cell proliferation. METHODS: Imaging was performed to detect reactive oxygen species and mitochondrial membrane potential. Western blotting was used to determine the expression of target signals. The HSK3486 molecular mechanism was investigated through ATPase inhibitory factor 1 knockdown and xenograft model experiments to assess mitochondrial function in colorectal cancer cells. RESULTS: Cell Counting Kit-8 and Annexin V/propidium iodide double staining assays showed that HSK3486 inhibited colorectal cancer cell proliferation in a concentration-dependent manner. In addition, HSK3486 treatment increased the expression of B-cell lymphoma-2-associated X, cleaved caspase 3, and cleaved poly (ADP-ribose) polymerase, whereas myeloid cell leukemia-1 and B-cell lymphoma 2 expression decreased. HSK3486 promoted mitochondrial dysfunction by inducing ATPase inhibitor factor 1 expression. Furthermore, HSK3486 promoted oxidative stress, as shown by the increase in reactive oxygen species and lactate dehydrogenase levels, along with a decrease in mitochondrial membrane potential and ATP levels. ATPase inhibitor factor 1 small interfering RNA pretreatment dramatically increased the mitochondrial membrane potential and tumor size in a xenograft model following exposure to HSK3486. CONCLUSION: Collectively, our findings revealed that HSK3486 induces oxidative stress, resulting in colorectal cancer cell apoptosis, making it a potential candidate therapeutic strategy for colorectal cancer.

Influence of Perioperative Anesthesia on Cancer Recurrence: from Basic Science to Clinical Practice.

PURPOSEOF REVIEW: In this review, we will summarize the effects of these perioperative anesthetics and anesthetic interventions on the immune system and tumorigenesis as well as address the related clinical evidence on cancer-related mortality and recurrence. RECENT FINDINGS: Cancer remains a leading cause of morbidity and mortality worldwide. For many solid tumors, surgery is one of the major therapies. Unfortunately, surgery promotes angiogenesis, shedding of circulating cancer cells, and suppresses immunity. Hence, the perioperative period has a close relationship with cancer metastases or recurrence. In the perioperative period, patients require multiple anesthetic management including anesthetics, anesthetic techniques, and body temperature control. Preclinical and retrospective studies have found that these anesthetic agents and interventions have complex effects on cancer outcomes. Therefore, well-planned, prospective, randomized controlled trials are required to explore the effects of different anesthetics and techniques on long-term outcomes after cancer surgery. Due to the conflicting effects of anesthetic management on cancer recurrence, further preclinical and clinical trials are required and beneficial to the development of systemic cancer therapies.

Efficacy and safety of remimazolam tosilate versus propofol in patients undergoing day surgery: a prospective randomized controlled trial.

BACKGROUND: Remimazolam tosilate (RT) is a novel short-acting GABA (A) receptor agonist that has a rapid recovery from procedural sedation and can be fully reversed by flumazenil. To date, there have been relatively few articles comparing RT and propofol for general anesthesia. This study aimed to assess the efficacy and safety of RT with or without flumazenil compared with propofol in general anesthesia for day surgery. METHODS: 115 patients scheduled for day surgery were randomized into three groups: RT (n = 39), RT + flumazenil (n = 38) and propofol (n = 38). The primary endpoints were anesthesia induction time and time until fully alert. Anesthesia success rate, bispectral index (BIS) values, injection pain, opioid and vasopressor dosages, postoperative recovery profiles and perioperative inflammatory and cognitive changes were assessed. Any adverse events were recorded. RESULTS: Induction times were similar among the three groups (P = 0.437), but the median time until fully alert in patients treated with RT was longer than that of the propofol or RT + flumazenil groups (17.6 min vs. 12.3 min vs. 12.3 min, P < 0.001). The three groups had comparable postoperative recovery quality and inflammatory and cognitive state changes (P > 0.05). Smaller percentages of patients who received RT (26.3%) and RT + flumazenil (31.6%) developed hypotension during anesthesia maintenance compared with propofol (68.4%), and consequently less ephedrine (P < 0.001) and phenylephrine (P = 0.015) were needed in the RT group. Furthermore, serum triglyceride levels were lower (P < 0.001) and injection pain was much less frequent in the RT with or without flumazenil groups compared with the propofol group (5.3% vs. 0% vs. 18.4%). CONCLUSION: RT permits rapid induction and comparable recovery profile compared with propofol in general anesthesia for day surgery, but has a prolonged recovery time without flumazenil. The safety profile of RT was superior to propofol in terms of hypotension and injection pain. TRIAL REGISTRATION: The study was registered at Chinese Clinical Trial Registry http://www.chictr.org.cn/ (Registration date: 19/7/2021; Trial ID: ChiCTR2100048904).

The Deficiency of SCARB2/LIMP-2 Impairs Metabolism via Disrupted mTORC1-Dependent Mitochondrial OXPHOS.

Deficiency in scavenger receptor class B, member 2 (SCARB2) is related to both Gaucher disease (GD) and Parkinson's disease (PD), which are both neurodegenerative-related diseases without cure. Although both diseases lead to weight loss, which affects the quality of life and the progress of diseases, the underlying molecular mechanism is still unclear. In this study, we found that Scarb2-/- mice showed significantly reduced lipid storage in white fat tissues (WAT) compared to WT mice on a regular chow diet. However, the phenotype is independent of heat production, activity, food intake or energy absorption. Furthermore, adipocyte differentiation and cholesterol homeostasis were unaffected. We found that the impaired lipid accumulation of Adiponectin-cre; Scarb2fl/fl mice was due to the imbalance between glycolysis and oxidative phosphorylation (OXPHOS). Mechanistically, the mechanistic target of rapamycin complex 1 (mTORC1)/ eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1) pathway was down-regulated in Scarb2 deficient adipocytes, leading to impaired mitochondrial respiration and enhanced glycolysis. Altogether, we reveal the role of SCARB2 in metabolism regulation besides the nervous system, which provides a theoretical basis for weight loss treatment of patients with neurodegenerative diseases.

The Role of Pink1-Mediated Mitochondrial Pathway in Propofol-Induced Developmental Neurotoxicity.

The mechanisms underlying propofol-induced toxicity in developing neurons are still unclear. The aim of present study was to explore the role of Pink1 mediated mitochondria pathway in propofol-induced developmental neurotoxicity. The primary Neural Stem Cells (NSCs) were isolated from the hippocampus of E15.5 mice embryos and then treated with propofol. The effects of propofol on proliferation, differentiation, apoptosis, mitochondria ultrastructure and MMP of NSCs were investigated. In addition, the abundance of Pink1 and a group of mitochondria related proteins in the cytoplasm and/or mitochondria were investigated, which mainly included CDK1, Drp1, Parkin1, DJ-1, Mfn1, Mfn2 and OPA1. Moreover, the relationship between Pink1 and these molecules was explored using gene silencing, or pretreatment with protein inhibitors. Finally, the NSCs were pretreated with mitochondrial specific antioxidant (MitoQ) or Drp1 inhibitor (Mdivi-1), and then the toxic effects of propofol on NSCs were investigated. Our results indicated that propofol treatment inhibited NSCs proliferation and division, and promoted NSCs apoptosis. Propofol induced significant NSCs mitochondria deformation, vacuolization and swelling, and decreased MMP. Additional studies showed that propofol affected a group of mitochondria related proteins via Pink1 inhibition, and CDK1, Drp1, Parkin1 and DJ-1 are the important downstream proteins of Pink1. Finally, the effects of propofol on proliferation, differentiation, apoptosis, mitochondrial ultrastructure and MMP of NSCs were significantly attenuated by MitoQ or Mdivi-1 pretreatment. The present study demonstrated that propofol regulates the proliferation, differentiation and apoptosis of NSCs via Pink1mediated mitochondria pathway.

The effects of erector spinae plane block on perioperative opioid consumption and rehabilitation in video assisted thoracic surgery.

BACKGROUND: This study aimed to determine whether ultrasound-guided continuous erector spinae plane block (ESPB) had an effect on opioid consumption and postoperative rehabilitation in patients undergoing video-assisted thoracic surgery (VATS). METHODS: In this prospective study, 120 patients aged 20-70 years who underwent elective VATS were randomly allocated to one of three groups: group C (general anesthesia with patient-controlled intravenous analgesia [PCIA]), group T (general anesthesia with patient-controlled epidural analgesia [PCEA]), or group E (general anesthesia with continuous ESPB and PCIA). Perioperative opioid consumption, visual analog scale (VAS) scores, preoperative and postoperative Quality of Recovery-15 scores, and postoperative opioid-related adverse events were all assessed. RESULTS: Intraoperative sufentanil consumption in groups T and E was significantly lower than that in group C (both P < 0.001), and the postoperative sufentanil consumption in group E was also significantly lower than that in group C (P = 0.001). Compared with group C, the VAS scores at rest or during coughing immediately out of the post-anesthesia care unit at 6 h, 12 h, and 24 h postoperatively were significantly lower in group T (P < 0.05). However, the VAS scores at rest at 6 h and 12 h postoperatively in group E were lower than those of group C (P < 0.05), but were significantly higher than those of group T at all study times (P < 0.05). CONCLUSION: Ultrasound-guided continuous ESPB significantly reduced perioperative opioid consumption during VATS and improved postoperative rehabilitation. However, these effects were inferior to those of thoracic epidural anesthesia. TRIAL REGISTRATION: The present study was prospectively registered at http://www.chictr.org/cn /(registration number: ChiCTR1900023050 ); registration date: May 82,019.

BIG1 mediates sepsis-induced lung injury by modulating lipid raft-dependent macrophage inflammatory responses.

Sepsis is a systemic inflammatory response syndrome with high mortality. It has been reported that brefeldin A-inhibited guanine nucleotide-exchange factor 1 (BIG1) is involved in the pathogenesis of sepsis. However, the mechanism is not fully elucidated. In the present study, we explored the role of BIG1 in mediating lipid raft-dependent macrophage inflammatory response and its impact on lung injury in murine sepsis. In vitro studies revealed that BIG1 deficiency reduces the upregulation and secretion of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and IL-1ß and inhibits the activation of the toll-like receptor 4 (TLR4)/myeloid differentiation primary response 88-dependent nuclear factor kappa-B signaling pathway induced by the lipopolysaccharide (LPS) treatment. Further experiments revealed that the inhibitory effects of BIG1 deficiency on LPS-induced inflammation are due to the upregulation of adenosine triphosphate-binding cassette transporter A1. This promotes the free-cholesterol efflux from lipid rafts and results in the reduction of lipid raft TLR4 content. The decrease in TLR4 content in lipid raft thereby inhibits the LPS-induced inflammatory response. Furthermore, using the cecal ligation and puncture-induced polymicrobial sepsis mouse model, we found that conditional knockout (cKO) of the myeloid cell BIG1 significantly reduced the serum concentrations of TNF-α, IL-6, and IL-1ß, and downregulated their mRNA expressions in the lungs. Pathological analysis confirmed that the BIG1 cKO alleviated the sepsis-induced lung injury. These results revealed the crucial new role of BIG1 in mediating lipid raft-dependent macrophage inflammatory response. Hence, BIG1 may be a potential promising therapeutic target for the treatment of septic lung injury.

Tailored Chemodynamic Nanomedicine Improves Pancreatic Cancer Treatment via Controllable Damaging Neoplastic Cells and Reprogramming Tumor Microenvironment.

Pancreatic ductal adenocarcinoma (PDAC) strongly resists standard therapies since KRAS-mutated cancer cells harbor endogenous resistance toward chemotherapy-induced apoptosis and tumor-associated macrophages (TAMs) activate stroma cells to create the nearly impenetrable matrix. Herein, we developed a tailored nanocomplex through the self-assembly of synthetic 4-(phosphonooxy)phenyl-2,4-dinitrobenzenesulfonate and Fe3+ followed by hyaluronic acid decoration, realizing chemodynamic therapy (CDT) to combat PDAC. By controllably releasing its components in a GSH-sensitive manner under the distinctive redox homeostasis in cancer cells and TAMs, the nanocomplex selectively triggered a Fenton reaction to induce oxidative damage in cancer cells and simultaneously repolarized TAMs to deactivate stromal cells and thus attenuate stroma. Compared to gemcitabine, CDT remarkably inhibited tumor growth and prolonged animal survival in orthotopic PDAC models without noticeable side effects. This study provides a promising strategy to improve the treatment of PDAC through CDT-mediated controlled cancer cells damage and reprogramming of the stromal microenvironment.

Increased mu-opioid receptor expression is associated with reduced disease-free and overall survival in laryngeal squamous cell carcinoma.

BACKGROUND: Expression of the mu-opioid receptor (MOR) is associated with poor long-term outcomes in various types of cancer. The association between MOR expression and clinical outcomes in laryngeal squamous cell carcinoma (LSCC) is not clear. METHODS: This retrospective study included patients who underwent laryngectomy for LSCC. The expression pattern of the MOR protein and OPRM1 gene in tumours and corresponding adjacent non-carcinoma specimens was measured. Propensity score matching was used to minimise bias. The primary endpoints were overall survival (OS) and disease-free survival (DFS). The secondary endpoints were intraoperative sufentanil consumption, grade of surgical complications according to the Clavien-Dindo classification, and hospital length of stay. RESULTS: A total of 207 LSCC patients were enrolled. After propensity score matching, there was a significant difference in DFS between groups at 1, 3, and 5 yr (60.2% vs 81.2%, P=0.019; 39.4% vs 50.2%, P=0.026; 37.5% vs 42.5%, P=0.023, respectively) in patients with high MOR expression. The OS rates at 1, 3, and 5 yr were significantly lower in the high MOR expression group (81.2% vs 93.2%, P=0.027; 57.7% vs 78.3%, P<0.001; 42.5% vs 60.3%, P<0.001, respectively). The multivariate analysis indicated that high MOR expression was associated with worse DFS and OS (hazard ratio: 1.52, 95% confidence interval: 1.07, 2.25, P=0.034; hazard ratio: 1.42, 95% confidence interval: 1.17, 2.34, P=0.032). CONCLUSION: High MOR expression may be associated with poor prognosis in patients with LSCC, suggesting that MOR could be used as a valuable molecular biomarker to predict prognosis of LSCC patients.

Effects of different concentrations of isoflurane pretreatment on respiratory mechanics, oxygenation and hemodynamics in LPS-induced acute respiratory distress syndrome model of juvenile piglets.

PURPOSE: This study was prospectively designed to investigate the effects of different concentrations of isoflurane (ISO) pretreatment on respiratory mechanics, oxygenation, and hemodynamics in lipopolysaccharide (LPS)-induced acute respiratory distress syndrome (ARDS) model of juvenile piglets. METHODS: Twenty-four piglets (9-14 kg, 5-6 weeks old) were randomly assigned to four groups (n = 6): LPS group, which was injected with LPS (20 µg/kg) to induce ARDS; 0.5 ISO-LPS, 1.0 ISO-LPS, and 1.3 ISO-LPS groups, which were pretreated with 0.5, 1.0, and 1.3 minimum alveolar concentrations (MAC) ISO for 30 min before immediate LPS infusion, respectively. After establishment of ARDS, respiratory mechanism, oxygenation and hemodynamics parameters were measured at baseline, and 0, 1, 2, 3, and 4 hours after induction of ARDS. RESULTS: After induction of ARDS, there were increases in alveolar-arterial oxygen difference (A-aDO2), oxygenation index (OI), mean airway pressure (MAP), dead space-to-tidal volume ratio, heart rate (HR), dP/dtmax, extravascular lung water index, pulmonary vascular permeability index, and PaCO2, and decreases in PaO2/FIO2, respiratory rate (RR), dynamic lung compliance (Cdyn), mean arterial blood pressure (MABP) and systemic vascular resistance (SVR) compared with baseline (P(time) < 0.05). Pretreatment with 1.0 and 1.3 MAC ISO alleviated changes in dP/dtmax and PaCO2 at ARDS 0-2 hours, SVR at 0-3 hours, PaO2/FIO2, RR, and MABP at 1-2 hours, HR at 2-3 hours, A-aDO2 at 3-4 hours, and OI at 4 hours (P(group) < 0.05). CONCLUSION: Pretreatment with 1.0 and 1.3 MAC ISO had protective effects on respiratory mechanics, oxygenation, and hemodynamics in piglets with LPS-induced ARDS.

HOXC6: A promising biomarker linked to an immunoevasive microenvironment in colorectal cancer based on TCGA analysis and cohort validation.

HOXC6 plays an essential part of the carcinogenesis of solid tumors, but its functional relevance within the immune contexture in patients with colorectal cancer (CRC) is still uncertain. We intended to investigate the predictive value of HOXC6 expression for survival outcomes and its correlation with immune contexture in CRC patients by utilizing the Cancer Genome Atlas database (n = 619). Validation was performed in cohorts from Zhongshan Hospital (n = 200) and Shanghai Cancer Center (n = 300). Immunohistochemical (IHC) staining was utilized to compare the levels of immunocytes infiltrating the tumor between the groups with high and low expression of HOXC6. Elevated levels of HOXC6 expression in CRC tissues were linked to malignant progression and poor prognosis. HOXC6 as a risk factor for survival of CRC patients was confirmed. Receiver operating characteristic analysis confirmed its diagnostic value, and a reliable prognostic nomogram was constructed. KEGG analysis and GSEA showed that HOXC6 participated in immune regulation, and its expression was tightly linked to the abundance of infiltrating immunocytes. HOXC6 was upregulated in patients diagnosed with CRC within the two cohorts, and high HOXC6 levels were correlated with a worse prognosis. The high-HOXC6 expression group showed increased infiltration of Treg cells, CD68+ macrophages, CD66b+ neutrophils, and CD8+ T-cells and elevated levels of PD-L1 and PD-1, but decreased levels of granzyme B and perforin. These findings suggest that HOXC6 abundance in patients with CRC determines a poor prognosis, promotes an immunoevasive environment, and directs CD8+ T-cell dysfunction. HOXC6 is expected to become a prospective biomarker for the outcome of CRC.

Association of vitamin B1 intake with geriatric cognitive function: An analysis of the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2014.

Background: The association between dietary vitamin B1 intake and cognitive performance in the noninstitutionalized older adult population of the United States remains unclear. Purpose: This study aimed to investigate the association between vitamin B1 intake and cognitive performance in older adults in the United States. Methods: Vitamin B1 intake was assessed through two 24-h dietary recalls. Weighted logistic regression was used to evaluate the association between vitamin B1 intake and three cognitive scores (immediate recall test [IRT], animal fluency test [AFT], and digit symbol substitution test [DSST]). Cognitive performance was measured by these three tests, and individuals scoring below the lowest quartile were categorized as cognitive impairment. Sensitivity analysis, including dose-response curves, subgroup analyses, interaction effects, per 1 SD, and quartiles, were performed to ensure the accuracy of the conclusion. Results: A total of 2896 participants over the age of 60 were included in this study. In the adjusted final model, the association between vitamin B1 intake and low cognitive performance in old age was statistically significant, with the following odds ratios (ORs) and 95% confidence intervals (CIs): IRT, 0.75 (0.57, 0.97), P = 0.018; AFT, 0.68 (0.50, 0.92), P = 0.007; DSST, 0.71 (0.54, 0.92), P = 0.005. Subgroup analyses showed that this association was statistically significant among males, white, low-education, and no memory impairment. The results of the sensitivity analyses confirmed the association between VB1 and cognitive function in old age and the absence of interactions in the final calibrated model. Conclusion: Dietary vitamin B1 intake is negatively associated with cognitive performance in older adults.

Urokinase-coated chitosan nanoparticles for thrombolytic therapy: preparation and pharmacodynamics in vivo.

Blood reperfusion of affected limbs is the most effective therapy for peripheral vascular thrombotic disease, restoring nutrition and blood flow to threatened tissues. Because it is more cost-effective than other thrombolytics, urokinase (UK) is widely used to treat venous thrombosis in China. However, its use is limited because of the risk of UK-related hemorrhagic complications. UK-coated nanoparticles (NPs) may decrease adverse effects while simultaneously increasing thrombolytic benefits. The aim of this study was to combine the sustained-release properties of NPs with the clinical benefits of catheter-directed thrombolysis (CDT) to create a promising new therapy. NPs were prepared via self-assembled chitosan and tripolyphosphate, introduced into a thrombosis model in New Zealand white rabbits, and the ratio of the residual thrombus cross-sectional area to the vascular cross-sectional area was calculated. The NPs had a drug-bearing efficiency of 14.5 ± 1.3%, an encapsulation efficiency of 94.8 ± 2.1% while the particle size of UK-coated NPs was 236 nm. Transmission electron microscopy results showed that the shape of the NPs were spherical and regular. Whether delivered by intravenation or catheter, UK-coated NPs produced a significant increase in the thrombolytic effect compared with free UK and confirmed the superiority of CDT for improving clot lysis over drug-induced systemic thrombolysis. The intravenous NPs caused an abnormal increase in fibrinogen. In conclusion, a water-soluble UK-WCS-NP suspension with good encapsulation efficiency was easily prepared UK-WCS-NPs were capable of maintaining UK activity, provided sustained-release of UK and exhibited better thrombolytic function than free UK.

Depletion of Gsdma1/2/3 alleviates PMA-induced epidermal hyperplasia by inhibiting the EGFR-Stat3/Akt pathway.

Homeostasis of the skin barrier is essential for maintaining normal skin function. Gasdermin A (GSDMA) is highly expressed in the skin and is associated with many skin diseases, such as melanoma and psoriasis. In mice, GSDMA is encoded by three gene homologues, namely Gsdma1, Gsdma2, and Gsdma3. Although Gsdma3 gain-of-function mutations cause hair loss and skin inflammation, Gsdma3-deficient mice show no phenotypes in skin or hair structures. To explore the physiological function of GSDMA, we generated conventional Gsdma1/2/3 knockout (KO) mice. We found that Gsdma1/2/3 KO mice showed significantly decreased epidermal hyperplasia and inflammation induced by phorbol 12-myristate 13-acetate (PMA). Furthermore, we found that the alleviation of epidermal hyperplasia depends on Gsdma1/2/3 expressed specifically in keratinocytes. Mechanistically, Gsdma1/2/3 depletion downregulated epidermal growth factor receptor (EGFR) ligands, leading to decreased EGFR-Stat3/Akt signalling. These results demonstrate that depletion of Gsdma1/2/3 alleviates PMA-induced epidermal hyperplasia partially by inhibiting the EGFR-Stat3/Akt pathway.

Apoptotic caspase-7 activation inhibits non-canonical pyroptosis by GSDMB cleavage.

GSDMB is associated with several inflammatory diseases, such as asthma, sepsis and colitis. GZMA is released by cytotoxic lymphocytes and cleaves GSDMB at the K244 site and to induce GSDMB N-terminus dependent pyroptosis. This cleavage of GSDMB is noncell autonomous. In this study, we demonstrated that the GSDMB-N domain (1-91 aa) was important for a novel cell-autonomous function and that GSDMB could bind caspase-4 and promote noncanonical pyroptosis. Furthermore, activated caspase-7 cleaved GSDMB at the D91 site to block GSDMB-mediated promotion of noncanonical pyroptosis during apoptosis. Mechanistically, the cleaved GSDMB-C-terminus (92-417 aa) binds to the GSDMB-N-terminus (1-91 aa) to block the function of GSDMB. During E. coli and S. Typhimurium infection, inhibition of the caspase-7/GSDMB axis resulted in more pyroptotic cells. Furthermore, in a septic mouse model, caspase-7 inhibition or deficiency in GSDMB-transgenic mice led to more severe disease phenotypes. Overall, we demonstrate that apoptotic caspase-7 activation inhibits non-canonical pyroptosis by cleaving GSDMB and provide new targets for sepsis therapy.

Trimethylamine N-oxide promotes atherosclerosis via regulating the enriched abundant transcript 1/miR-370-3p/signal transducer and activator of transcription 3/flavin-containing monooxygenase-3 axis.

Atherosclerosis (AS) is one of the main causes of cardiovascular diseases (CVDs). Trimethylamine N-oxide (TMAO) exacerbates the development of AS. This study aimed to investigate the roles of TMAO in AS. In this study, mice were fed with high fat food (HF) and/or injected with TMAO. Oil red O staining was applied for histological analysis. ELISA, qRT-PCR, and Western blot were conducted to determine the TMAO, serum, mRNA, and protein levels. CCK-8, colony formation assay, and flow cytometry assays were performed to detect the functions of human aortic endothelial cells (HUVECs). The results showed that TMAO induced thick internal and external walls and intimal plaques in vivo, and HUVEC dysfunction in vitro. TMAO and lncRNA enriched abundant transcript 1 (NEAT1) were increased in AS clinical samples and TMAO-HUVECs. Downregulated NEAT1 inhibited proliferation and promoted the apoptosis of HUVECs. NEAT1 regulated the expression of signal transducer and activator of transcription 3 (STAT3) via sponging miR-370-3p. Overexpression of miR-370-3p facilitated the effects of NEAT1 on the cellular functions of HUVECs, while STAT3 exerted opposing effects. The activation of STAT3 promoted the expression of flavin-containing monooxygenase-3 (FMO3). Taken together, our results show that TMAO-NEAT1/miR-370-3p/STAT3/FMO3 forms a positive feedback loop to exacerbate the development of AS. This novel feedback loop may be a promising therapeutic target for AS.

c-Myc participates in high glucose-mediated endothelial inflammation via upregulation of IRAK1 expression in diabetic nephropathy.

Diabetic nephropathy (DN) is a common vascular complication of diabetes. Endothelial adhesion molecules are involved in physiopathology of DN. Interleukin-1 receptor-associated kinase 1 (IRAK1) and c-Myc participate in inflammation in DN. We hypothesized c-Myc modulates IRAK1 expression, contributing to hyperglycemia-mediated endothelial inflammation. The expression of endothelial adhesion molecules and IRAK1 were increased in glomerular endothelium of DN patients and rats. Our cellular experiments indicated high glucose-induced endothelial cell inflammation was inhibited by si-IRAK1. Additionally, high glucose increased c-Myc expression. si-c-Myc inhibited high glucose-mediated increase of IRAK1 levels and endothelial cell inflammation. c-Myc overexpression-mediated endothelial cell inflammation was counteracted by si-IRAK1. c-Myc also interacted with lysine methyltransferase 5A (KMT5A). Furthermore, high glucose decreased KMT5A expression and histone H4 lysine 20 methylation (H4K20me1). KMT5A upregulation decreased high glucose-mediated increase of IRAK1 levels as well as endothelial inflammation. KMT5A silencing-mediated endothelial inflammation was reversed by si-IRAK1. Mechanistic research indicated that c-Myc and H4K20me1 occupied IRAK1 promoter region. KMT5A silencing augmented the active action of c-Myc on IRAK1 levels. Our in vivo experiments represented KMT5A is downregulated and c-Myc is upregulated in DN patients and rats. KMT5A interacts with c-Myc to modulate IRAK1 expression, thus contributing to hyperglycemia-mediated endothelial inflammation in DN.

Identification of a Chromosome 1 Substitution Line B6-Chr1BLD as a Novel Hyperlipidemia Model via Phenotyping Screening.

Hyperlipidemia is a chronic disease that seriously affects human health. Due to the fact that traditional animal models cannot fully mimic hyperlipidemia in humans, new animal models are urgently needed for basic drug research on hyperlipidemia. Previous studies have demonstrated that the genomic diversity of the wild mice chromosome 1 substitution lines was significantly different from that of laboratory mice, suggesting that it might be accompanied by phenotypic diversity. We first screened the blood lipid-related phenotype of chromosome 1 substitution lines. We found that the male HFD-fed B6-Chr1BLD mice showed more severe hyperlipidemia-related phenotypes in body weight, lipid metabolism and liver lesions. By RNA sequencing and whole-genome sequencing results of B6-Chr1BLD, we found that several differentially expressed single nucleotide polymorphism enriched genes were associated with lipid metabolism-related pathways. Lipid metabolism-related genes, mainly including Aida, Soat1, Scly and Ildr2, might play an initial and upstream role in the abnormal metabolic phenotype of male B6-Chr1BLD mice. Taken together, male B6-Chr1BLD mice could serve as a novel, polygenic interaction-based hyperlipidemia model. This study could provide a novel animal model for accurate clinical diagnosis and precise medicine of hyperlipidemia.

Effect of regulating macrophage polarization phenotype on intervertebral disc degeneration.

BACKGROUND: Macrophages are the only inflammatory cells that can penetrate the closed nucleus pulposus and their polarization plays an important role in intervertebral disc degeneration (IVDD). This paper attempted to investigate the pathogenesis of IVDD by altering the polarization state of macrophages. METHODS: Macrophage RAW264.7 cells were induced by interferonγ (IFN-γ) and lipopolysaccharide (LPS). The polarization of RAW264.7 cells was estimated by western blot and immunofluorescence. The expressions of inflammatory factors were detected by ELISA. Subsequently, RAW264.7 cells were treated with different concentrations of minocycline (Mino) and sinomenine (Sino), followed by the assessment of cell viability with cell counting kit-8 kit. Then, RAW264.7 cell culture medium was collected for the culture of human nucleus pulposus cells (NPCs). Toluidine blue staining and type II collagen staining were applied to assay the level of type II collagen. The cell apoptosis, oxidative stress, and nitric oxide (NO) level were appraised by TUNEL, oxidative stress kits and NO kit, respectively. Western blot was employed to test the levels of apoptosis- and oxidative stress-related proteins. RESULTS: IFN-γ and LPS could induce M1 polarization of RAW264.7 cells. Mino and Sino could reduce the polarization of RAW264.7 cells toward M1. M1-polarized medium inhibited LPS-induced activity, inflammation, and damage of NPCs, which were enhanced by Mino and Sino in medium. CONCLUSION: M1 polarization of macrophages promoted LPS-induced inflammation and damage of NPCs.