Compromised endothelial Wnt/ß-catenin signaling mediates the blood-brain barrier disruption and leads to neuroinflammation in endotoxemia.

The blood-brain barrier (BBB) is a critical interface that maintains the central nervous system homeostasis by controlling the exchange of substances between the blood and the brain. Disruption of the BBB plays a vital role in the development of neuroinflammation and neurological dysfunction in sepsis, but the mechanisms by which the BBB becomes disrupted during sepsis are not well understood. Here, we induced endotoxemia, a major type of sepsis, in mice by intraperitoneal injection of lipopolysaccharide (LPS). LPS acutely increased BBB permeability, activated microglia, and heightened inflammatory responses in brain endothelium and parenchyma. Concurrently, LPS or proinflammatory cytokines activated the NF-κB pathway, inhibiting Wnt/ß-catenin signaling in brain endothelial cells in vitro and in vivo. Cell culture study revealed that NF-κB p65 directly interacted with ß-catenin to suppress Wnt/ß-catenin signaling. Pharmacological NF-κB pathway inhibition restored brain endothelial Wnt/ß-catenin signaling activity and mitigated BBB disruption and neuroinflammation in septic mice. Furthermore, genetic or pharmacological activation of brain endothelial Wnt/ß-catenin signaling substantially alleviated LPS-induced BBB leakage and neuroinflammation, while endothelial conditional ablation of the Wnt7a/7b co-receptor Gpr124 exacerbated the BBB leakage caused by LPS. Mechanistically, Wnt/ß-catenin signaling activation rectified the reduced expression levels of tight junction protein ZO-1 and transcytosis suppressor Mfsd2a in brain endothelial cells of mice with endotoxemia, inhibiting both paracellular and transcellular permeability of the BBB. Our findings demonstrate that endotoxemia-associated systemic inflammation decreases endothelial Wnt/ß-catenin signaling through activating NF-κB pathway, resulting in acute BBB disruption and neuroinflammation. Targeting the endothelial Wnt/ß-catenin signaling may offer a promising therapeutic strategy for preserving BBB integrity and treating neurological dysfunction in sepsis.

Adrenal pheochromocytoma impacts three main pathways: cysteine-methionine, pyrimidine, and tyrosine metabolism. / è‚¾ä¸Šè ºå—œé“¬ç»†èƒžç˜¤å½±å“ä¸‰æ¡ä¸»è¦ä»£è°¢é€šè·¯ï¼šåŠèƒ±æ°¨é ¸-è›‹æ°¨é ¸ä»£è°¢ã€å˜§å•¶ä»£è°¢å’Œé ªæ°¨é ¸ä»£è°¢é€šè·¯.

Pheochromocytomas and paragangliomas (PPGLs) cause symptoms by altering the circulation levels of catecholamines and peptide hormones. Currently, the diagnosis of PPGLs relies on diagnostic imaging and the detection of catecholamines. In this study, we used ultra-performance liquid chromatography (UPLC)/quadrupole time-of-flight mass spectrometry (Q-TOF MS) analysis to identify and measure the perioperative differential metabolites in the plasma of adrenal pheochromocytoma patients. We identified differentially expressed genes by comparing the transcriptomic data of pheochromocytoma with the normal adrenal medulla. Through conducting two steps of metabolomics analysis, we identified 111 differential metabolites between the healthy group and the patient group, among which 53 metabolites were validated. By integrating the information of differential metabolites and differentially expressed genes, we inferred that the cysteine-methionine, pyrimidine, and tyrosine metabolism pathways were the three main metabolic pathways altered by the neoplasm. The analysis of transcription levels revealed that the tyrosine and cysteine-methionine metabolism pathways were downregulated in pheochromocytoma, whereas the pyrimidine pathway showed no significant difference. Finally, we developed an optimized diagnostic model of two metabolites, L-dihydroorotic acid and vanylglycol. Our results for these metabolites suggest that they may serve as potential clinical biomarkers and can be used to supplement and improve the diagnosis of pheochromocytoma.

The complete chloroplast genome and phylogenetic analysis of Bauhinia glauca subsp. hupehana (Craib) T. C. Chen 1988.

Bauhinia glauca subsp. hupehana (Craib) T. C. Chen 1988, a member of the Leguminosae family, Cercidoideae subfamily, and Bauhinia genus, has a rich history of traditional usage in Chinese medicine. Renowned for its analgesic properties, it is commonly employed for managing inflammation and pain. This study aimed to sequence the complete chloroplast genome of B. glauca subsp. hupehana using Illumina paired-end sequencing data. The chloroplast genome spans 156,967 bp and consists of four main regions: the large single-copy (LSC) region (89,185 bp), the small single-copy (SSC) region (19,146 bp), and a pair of inverted repeats (IRs) (24,318 bp). The overall GC content of the chloroplast genome is 36.19%, with specific values of 33.99%, 29.79%, and 42.76% for the LSC, SSC, and IR regions, respectively. A total of 128 genes were annotated in the chloroplast genome, including 83 protein-coding genes, 37 tRNA genes, and eight rRNA genes. Phylogenetic analysis revealed that B. glauca subsp. hupehana is closely related to Bauhinia racemose, indicating a sister taxon relationship between the two species. This study significantly contributes to the chloroplast genomic resource for Bauhinia, laying the groundwork for future phylogenetic investigations within the genus.

Healthy lifestyle decreases the risk of the first incidence of non-communicable chronic disease and its progression to multimorbidity and its mediating roles of metabolic components: a prospective cohort study in China.

OBJECTIVES: To identify the influence of healthy lifestyles on the incidence of the first NCD (FNCD), multiple chronic conditions (MCCs), and the progression from FNCD to MCCs. DESIGN: cohort study. SETTING: Zhejiang, China PARTICIPANTS: 10566 subjects (55.5 ± 13.5 years, 43.1% male) free of NCDs at baseline from the Zhejiang Metabolic Syndrome prospective cohort. MEASUREMENTS: Healthy lifestyle score (HLS) was developed by 6 common healthy lifestyle factors as smoking, alcohol drinking, physical activity, body mass index (BMI) and waist-to-hip ratio (WHR). Healthy lifestyle data and metabolic biomarkers collected via a face-to-face questionnaire-based interview, clinical health examination and routine biochemical determination. Biochemical variables were determined using biochemical auto-analyzer. Participants were stratified into four group based on the levels of HLS as ≤2, 3, 4 and ≥5. Multiple Cox proportional hazards model was applied to examine the relationship between HLS and the risk of FNCD, MCCs and the progression from FNCD to MCCs. The population-attributable fractions (PAF) were used to assess the attributable role of HLS. Mediating effect was examined by mediation package in R. RESULTS: After a median of 9.92 years of follow-up, 1572 participants (14.9%) developed FNCD, and 149 (1.4%) developed MCCs. In the fully adjusted model, the higher HLS group (≥5) was associated with lower risk of FNCD (HR = 0.68 and 95% CI: 0.56-0.82), MCCs (HR = 0.31 and 95%CI: 0.14-0.69); and the progression from FNCD to MCCs (HR = 0.39 and 95%CI: 0.18-0.85). Metabolic components (TC, TG, HDL-C, LDC-C, FPG, and UA) played the mediating roles with the proportion ranging from 5.02% to 22.2% for FNCD and 5.94% to 20.1% for MCCs. PAFs (95%CI) for poor adherence to the overall healthy lifestyle (HLS ≤ 3) were 17.5% (11.2%, 23.7%) for FNCD, 42.9% (23.4%, 61.0%) for MCCs, and 37.0% (15.5%, 56.3%) for the progression from FNCD to MCCs. CONCLUSIONS: High HLS decreases the risk of FNCD, MCCs, and the progression from FNCD to MCCs. These effects are partially mediated by metabolic components. Maintaining healthy lifestyles might reduce the disease burden of common chronic diseases.

Shape-recovery of implanted shape-memory devices remotely triggered via image-guided ultrasound heating.

Shape-memory materials hold great potential to impart medical devices with functionalities useful during implantation, locomotion, drug delivery, and removal. However, their clinical translation is limited by a lack of non-invasive and precise methods to trigger and control the shape recovery, especially for devices implanted in deep tissues. In this study, the application of image-guided high-intensity focused ultrasound (HIFU) heating is tested. Magnetic resonance-guided HIFU triggered shape-recovery of a device made of polyurethane urea while monitoring its temperature by magnetic resonance thermometry. Deformation of the polyurethane urea in a live canine bladder (5 cm deep) is achieved with 8 seconds of ultrasound-guided HIFU with millimeter resolution energy focus. Tissue sections show no hyperthermic tissue injury. A conceptual application in ureteral stent shape-recovery reduces removal resistance. In conclusion, image-guided HIFU demonstrates deep energy penetration, safety and speed.

Development of a therapeutic monoclonal antibody against circulating adipocyte fatty acid binding protein to treat ischaemic stroke.

BACKGROUND AND PURPOSE: Adipocyte fatty acid-binding protein (A-FABP) exacerbates cerebral ischaemia injury by disrupting the blood-brain barrier (BBB) through inducing expression of MMP-9. Circulating A-FABP levels positively correlate with infarct size in stroke patients. We hypothesized that targeting circulating A-FABP by a neutralizing antibody would alleviate ischaemic stroke outcome. EXPERIMENTAL APPROACH: Monoclonal antibodies (mAbs) against A-FABP were generated using mouse hybridoma techniques. Binding affinities of a generated mAb named 6H2 towards various FABPs were determined using Biacore. Molecular docking studies were performed to characterize the 6H2-A-FABP complex structure and epitope. The therapeutic potential and safety of 6H2 were evaluated in mice with transient middle cerebral artery occlusion (MCAO) and healthy mice, respectively. KEY RESULTS: Replenishment of recombinant A-FABP exaggerated the stroke outcome in A-FABP-deficient mice. 6H2 exhibited nanomolar to picomolar affinities to human and mouse A-FABP, respectively, with minimal cross-reactivities with heart and epidermal FABPs. 6H2 effectively neutralized JNK/c-Jun activation elicited by A-FABP and reduced MMP-9 production in macrophages. Molecular docking suggested that 6H2 interacts with the "lid" of the fatty acid binding pocket of A-FABP, thus likely hindering the binding of its substrates. In mice with transient MCAO, 6H2 significantly attenuated BBB disruption, cerebral oedema, infarction, neurological deficits, and decreased mortality associated with reduced cytokine and MMP-9 production. Chronic 6H2 treatment showed no obvious adverse effects in healthy mice. CONCLUSION AND IMPLICATIONS: These results establish circulating A-FABP as a viable therapeutic target for ischaemic stroke, and provide a highly promising antibody drug candidate with high affinity and specificity.

Serum thrombospondin-2 level changes with liver stiffness improvement in patients with type 2 diabetes.

OBJECTIVE: Baseline circulating thrombospondin-2 (TSP2) level was identified as a potential novel hepatic fibrosis biomarker that associates with development and progression of hepatic fibrosis in patients with nonalcoholic fatty liver disease and type 2 diabetes. Here, we investigated whether circulating TSP2 levels changed with improvement in liver stiffness (LS), which reflects liver fibrosis on transient elastography. DESIGN: Serum TSP2 levels were measured in participants from a randomized, open-label intervention study, at baseline and after 24-weeks treatment of either dapagliflozin 10 mg (N = 30) or sitagliptin 100 mg daily (N = 30). Vibration-controlled transient elastography was performed to evaluate the severity of hepatic fibrosis and steatosis using LS and controlled attenuation parameter (CAP), respectively. PATIENTS AND MEASUREMENTS: Among all 60 participants with similar clinical characteristics at baseline (mean HbA1c 8.9%, CAP 289 dB/m and LS 5.8 kPa), despite similar HbA1c lowering, treatment with dapagliflozin, but not sitagliptin, led to significant improvements in body weight (BW) (p = .012), CAP (p = .015) and LS (p = .011) after 24 weeks. RESULTS: Serum TSP2 level decreased significantly from baseline in dapagliflozin-treated participants (p = .035), whereas no significant change was observed with sitagliptin. In correlation analysis, change in serum TSP2 levels only positively correlated with change in LS (r = .487, p = .006), but not with changes in BW, CAP or HbA1c after dapagliflozin treatment. CONCLUSIONS: Serum TSP2 level decreased with LS after dapagliflozin treatment, and was independent of improvements in BW, glycemic control and hepatic steatosis, further supporting the potential of serum TSP2 level as a novel hepatic fibrosis biomarker in type 2 diabetes.

Levofloxacin alleviates blood-brain barrier disruption following cerebral ischemia and reperfusion via directly inhibiting A-FABP.

Reperfusion therapy is currently the most effective treatment for acute ischemic stroke, but often results in secondary brain injury. Adipocyte fatty acid-binding protein (A-FABP, FABP4, or aP2) was shown to critically mediate cerebral ischemia/reperfusion (I/R) injury by exacerbating blood-brain barrier (BBB) disruption. However, no A-FABP inhibitors have been approved for clinical use due to safety issues. Here, we identified the therapeutic effect of levofloxacin, a widely used antibiotic displaying A-FABP inhibitory activity in vitro, on cerebral I/R injury and determined its target specificity and action mechanism in vivo. Using molecular docking and site-directed mutagenesis, we showed that levofloxacin inhibited A-FABP activity through interacting with the amino acid residue Asp76, Gln95, Arg126 of A-FABP. Accordingly, levofloxacin significantly inhibited A-FABP-induced JNK phosphorylation and expressions of proinflammatory factors and matrix metalloproteinase 9 (MMP-9) in mouse primary macrophages. In wild-type mice with transient middle cerebral artery occlusion, levofloxacin substantially mitigated BBB disruption and neuroinflammation, leading to reduced cerebral infarction, alleviated neurological outcomes, and improved survival. Mechanistically, levofloxacin decreased MMP-9 expression and activity, and thus reduced degradation of extracellular matrix and endothelial tight junction proteins. Importantly, the BBB- and neuro-protective effects of levofloxacin were abolished in A-FABP or MMP-9 knockout mice, suggesting that the therapeutic effects of levofloxacin highly depended on specific targeting of the A-FABP-MMP-9 axis. Overall, our study demonstrates that levofloxacin alleviates A-FABP-induced BBB disruption and neural tissue injury following cerebral I/R, and unveils its therapeutic potential for the treatment of ischemic stroke.

Illicit drug use is associated with lower bone mineral density and bone strength.

Objectives: To evaluate the association of illicit drug use with bone mineral density (BMD) and hip geometric parameters at the narrow neck. Methods: This is a cross-sectional matched cohort study conducted in the Hong Kong Chinese population. Associations with illicit drug use were estimated using linear regression for BMD (lumbar spine and femoral neck) and hip geometrical parameters (cross-sectional area [CSA], cross-sectional moment of inertia [CSMI], section modulus [SM], average cortical thickness [ACT] and BMD at the narrow neck) after adjusting for age, body mass index (BMI), smoking status, drinking status, physical activity, and history of antipsychotic and antidepressant use. Mean difference and 95% confidence intervals (95% CI) were calculated between 108 illicit drug users and 108 controls using an adjusted linear model and cluster-robust standard errors after matching by age and sex. The false discovery rate was used to correct for multiple testing. Results: Illicit drug users had a significantly lower BMD (g/cm2) at the lumbar spine (mean difference: -0.062; 95% CI: -0.108 to -0.015), and femoral neck (mean difference: -0.058; 95% CI: -0.106 to -0.010) in the fully adjusted model. Illicit drug users also had a significantly lower CSA (mean difference: -0.238 cm2; 95% CI: -0.462 to -0.013), ACT (mean difference: -0.018 cm; 95% CI: -0.030 to -0.006) and BMD (mean difference: -0.070 g/cm2; 95% CI: -0.128 to -0.012) at the narrow neck. Conclusions: Illicit drug use is associated with lower BMD and bone strength. Future studies evaluating the risk of illicit drug use with fragility fracture are warranted.

Generating mutual support in multifamily therapy to promote father involvement and family communication quality of Chinese families of adolescents with attention deficit hyperactivity disorder: A qualitative study.

Previous studies have suggested the negative impacts of attention deficit hyperactivity disorder (ADHD) on parent-adolescent interactions. Yet engaging parents, particularly the fathers, to participate in family-based interventions has been challenging in Chinese contexts given the traditional concerns about keeping the family's "face" and the influence of affiliate stigma. Empirical evidence supports multifamily therapy as an effective modality for parental engagement. This study explores the role of mutual support in promoting parental engagement and family communication quality of Chinese families of adolescents with ADHD. Inclusion criteria of the study were (a) Chinese family of at least one adolescent child having an ADHD diagnosis, (b) the adolescent child was aged between 11 and 15 years, and (c) the family participated in a multifamily therapy program. Families who had not completed a multifamily therapy program were excluded. Fourteen Chinese families of adolescents with ADHD who participated in a pilot multifamily therapy program from June 2017 to September 2018 were recruited for this qualitative study. Photo-elicited parent focus groups and photo-elicited individual interviews with adolescents were conducted. The thematic analysis revealed that a low level of hierarchy in the therapist-client relationship contributed to the building of mutual support among the families in the therapy process. The mutual support was found to play a key role in promoting acceptance, father involvement, and open communication within families of adolescents with ADHD. Discussion was conducted on the importance of the nonexpert stance of the therapist for promoting mutual support among Chinese families in a multifamily therapy process.

SCGN and STAT3 expressions are associated with the prognosis of ccRCC.

Clear cell renal cell carcinoma (ccRCC) is highly heterogeneous and accounts for about 70% of RCC. Its prognosis is worse than that of most histological types of RCC. In order to find potential biomarkers that may influence the prognosis and survival in ccRCC patients, we explored the expressions of STAT3, PDL1 and SCGN (secretagogin) in ccRCC based on the data of TCGA (n = 529), EMATAB-1980 (n = 99) and our own cohort (n = 99). Our study demonstrated that ccRCC patients with low STAT3 expression and high SCGN expression might have a better prognosis. No significant difference in the positive rate of SCGN expression was found when comparing the primary lesion with the matched metastatic liver lesions. The percentage of high SCGN expression in the primary lesion of metastatic ccRCC patients was significantly lower than that of patients with only the renal lesion. In view of the conclusion that STAT3 high expression cases are resistant to sunitinib, STAT3 immunohistochemistry results are essential for designing non-operative treatments. SCGN has the potential to become an indicator for subtype classification of ccRCC.

Single-Port Robot-Assisted Radical Prostatectomy with the Novel Shurui Single-Port Robotic Surgical System.

Purpose: The aim of this study was to explore the safety and efficacy of radical prostatectomy with a novel Shurui single-port (SR-SP) robotic surgical system. Methods: A total of 11 patients with prostate cancer were enrolled in this study. Extraperitoneal radical prostatectomy was performed using the SR-SP robotic surgical system for all patients. Clinicopathologic data, perioperative data, and short-term surgical outcomes were prospectively collected and analyzed. Results: Of the 11 patients, the median age was 65 years (range 52-73), and the median body mass index was 22.6 kg/m2 (range 20.2-26.7). The median operative time was 229 minutes (range 194-317), and the median console time was 167 minutes (range 141-265). The median blood loss was 40 mL (range 10-120), and none of the patients required intraoperative transfusion. There was no conversion to open surgery during the operation, and no assistant ports were added. The surgeons reported a good task load rating with a National Aeronautics and Space Administration Task Load Index (NASA-TLX) score of 25.1 ± 3.3 points. The median postoperative hospital stay time was 7 days (range 4-15). There were no severe intraoperative or postoperative complications (Clavien grade ≥3). Postoperative positive surgical margin occurred in 4 (36.4%) patients. No biochemical recurrence occurred within 1 month of surgery. The continence rate was 72.7% (8/11) 1 month after surgery. Conclusions: The new SR-SP robotic surgical system is safe, effective, flexible, and stable for application in radical prostatectomy.

Preliminary Experience of Partial Nephrectomy Through a New Single-Port Surgical Robot System.

Purpose: To explore the preliminary safety and efficacy of the Shurui single-port (SP) surgical robot in partial nephrectomy (PN). Methods: This study prospectively enrolled patients with T1a renal tumors who met the inclusion criteria from February to July 2022 in The First Affiliated Hospital School of Medicine Zhejiang University. The operative outcomes and perioperative data, including clinical and histological data, were prospectively collected and analyzed. Results: A total of 13 patients were included in this study, including 7 males and 6 females. The median age was 53 (33-74) years, and the average body mass index was 24.9 ± 4.2 kg/m2. There were 6 cases of left kidney tumors and 7 cases of right kidney tumors in the 13 patients. The average tumor diameter was 1.9 ± 0.9 cm. In all operations, the diseased tissue was removed according to the established surgical plan. The average warm ischemia time was 26.2 ± 9.7 minutes; the average device docking time was 3.6 ± 1.8 minutes; and the average robotic arm operation time was 124.7 ± 40.4 minutes. All operations were successfully completed; there was no conversion to open surgery during the operation; and no operation holes were added. The National Aeronautics and Space Administration Task Load Index (NASA-TLX) score was 26.3 ± 2.6 points, and no device-related adverse events occurred during the operation. The median time to discharge was 6 days (range, 4-11 days). Postoperative pathological examination showed that all tumor margins were negative. There were no Clavien grade ≥3 surgical complications in any of the patients during the perioperative period or at the 1-month postoperative follow-up. Conclusion: The new SP surgical robot system is safe, effective, flexible, and stable for application in PN.

Virtual care during the pandemic: Multi-family group sessions for Hong Kong Chinese families of adolescents with intellectual disabilities.

The suspension of social services in Hong Kong during the COVID-19 pandemic increased the caregiver strain for families of adolescent children with intellectual disabilities, possibly aggravating their family relationships. This article reports on an online Multi-Family Group (MFG) conducted during the pandemic for Hong Kong Chinese families of adolescents affected by mild-to-moderate intellectual disabilities. A thematic analysis of the experiences of the participating service users revealed three positive effects of the intervention model: improved family relationships, mutual helpful influences occurring among families, and a new understanding of family members with intellectual disabilities. The therapeutic group process used to promote family development is illustrated by a group vignette. The challenges and the practical considerations for conducting an MFG online are discussed.

[Clinical phenotype and genetic features of 16p11.2 microdeletion-related epilepsy in children]. / 16p11.2å¾®ç¼ºå¤±ç›¸å ³å„¿ç«¥ç™«ç—«çš„ä¸´åºŠè¡¨åž‹ä¸Žé—ä¼ å­¦ç‰¹å¾åˆ†æž.

OBJECTIVES: To study the clinical phenotype and genetic features of 16p11.2 microdeletion-related epilepsy in children. METHODS: The medical data of 200 children with epilepsy who underwent a genetic analysis of epilepsy by the whole exon sequencing technology were collected retrospectively, of whom 9 children with epilepsy had 16p11.2 microdeletion. The clinical phenotype and genetic features of the 9 children with 16p11.2 microdeletion were analyzed. RESULTS: The detection rate of 16p11.2 microdeletion was 4.5% (9/200). The 9 children with 16p11.2 microdeletion were 3-10 months old. They experienced focal motor seizures with consciousness disturbance, and some of the seizures developed into generalized tonic-clonic seizures. The interictal electroencephalogram showed focal or multifocal epileptiform discharge, and all 9 children responded well to antiepileptic drugs. The 9 children had a 16p11.2 deletion fragment size of 398-906 kb, and the number of deleted genes was 23-33 which were all pathogenic mutations. The mutation was of maternal origin in 2 children, of paternal origin in 1 child, and de novo in the other children. CONCLUSIONS: 16p11.2 microdeletion can be detected in some children with epilepsy. Most of the 16p11.2 microdeletion is de novo mutation and large gene fragment deletion. The onset of 16p11.2 microdeletion-related epilepsy in children is mostly within 1 year of life, and the epilepsy is drug-responsive.

C-Terminal Domains of Spider Silk Proteins Having Divergent Structures but Conserved Functional Roles.

Spider silk is self-assembled from silk proteins or spidroins. C-terminal domains (CTDs) of various types of spidroins are relatively conserved in amino acid sequences and are suggested to adopt similar structures and perform similar functional roles in spidroin storage and silk formation. Here, we solved the structure of the CTD from a capture-spiral silk protein (CTDFl) and characterized its stability and fibril formation in the presence and absence of a reducing agent at different pH values. CTDFl adopts a dimeric structure with 8 helices, but the CTDs of other types of spidroins exist in a domain-swapped dimeric structure with 10 helices. Despite the structural differences, CTDFl is pH-responsive in stability and fibril formation, similar to the CTDs from minor and major ampullate spidroins. Thus, the functional role of CTDs in silk fiber formation seems conserved. Comparing wild-type CTDFl and its mutants, we found that the pH-responsive behavior results from the protonation of H76, which is conserved from different spider species. In addition, the fibril formation rate of CTDFl correlates with its instability, suggesting that structural changes are involved in fibril formation.

The APPL1-Rab5 axis restricts NLRP3 inflammasome activation through early endosomal-dependent mitophagy in macrophages.

Although mitophagy is known to restrict NLRP3 inflammasome activation, the underlying regulatory mechanism remains poorly characterized. Here we describe a type of early endosome-dependent mitophagy that limits NLRP3 inflammasome activation. Deletion of the endosomal adaptor protein APPL1 impairs mitophagy, leading to accumulation of damaged mitochondria producing reactive oxygen species (ROS) and oxidized cytosolic mitochondrial DNA, which in turn trigger NLRP3 inflammasome overactivation in macrophages. NLRP3 agonist causes APPL1 to translocate from early endosomes to mitochondria, where it interacts with Rab5 to facilitate endosomal-mediated mitophagy. Mice deficient for APPL1 specifically in hematopoietic cell are more sensitive to endotoxin-induced sepsis, obesity-induced inflammation and glucose dysregulation. These are associated with increased expression of systemic interleukin-1ß, a major product of NLRP3 inflammasome activation. Our findings indicate that the early endosomal machinery is essential to repress NLRP3 inflammasome hyperactivation by promoting mitophagy in macrophages.

A-FABP in Metabolic Diseases and the Therapeutic Implications: An Update.

Adipocyte fatty acid-binding protein (A-FABP), which is also known as ap2 or FABP4, is a fatty acid chaperone that has been further defined as a fat-derived hormone. It regulates lipid homeostasis and is a key mediator of inflammation. Circulating levels of A-FABP are closely associated with metabolic syndrome and cardiometabolic diseases with imminent diagnostic and prognostic significance. Numerous animal studies have elucidated the potential underlying mechanisms involving A-FABP in these diseases. Recent studies demonstrated its physiological role in the regulation of adaptive thermogenesis and its pathological roles in ischemic stroke and liver fibrosis. Due to its implication in various diseases, A-FABP has become a promising target for the development of small molecule inhibitors and neutralizing antibodies for disease treatment. This review summarizes the clinical and animal findings of A-FABP in the pathogenesis of cardio-metabolic diseases in recent years. The underlying mechanism and its therapeutic implications are also highlighted.

Mutant CDKN2A regulates P16/p14 expression by alternative splicing in renal cell carcinoma metastasis.

OBJECTIVE: Metastatic renal cell carcinoma (mRCC) is the important factor for patient mortality, meanwhile gene mutation constantly changes cancer prognosis in tumor process. Exploring the driver mutation in mRCC process become more and more important. MATERIALS AND METHODS: We obtained the 15 paired primary and metastatic mRCC samples and analyzed specific mutation genes in the metastatic foci (SMGs) by next generation sequencing. Moreover, we explored the Correlated networks, Pathway and Gene Ontology (GO) enrichment results, prediction analysis of AS sites and prognosis of survival. RESULTS: We identify EPCAM, TMEM127, EZH2, EXT1, CDKN2A, PRF1, AIP, CDK4, PRKARIA as SMGs and find that CDKN2A mutation sites affect the prognosis of mRCC by altering splicing elements. Based on the differential analysis for SMGs in KIRC, we found that EPCAM, PRF1 and EZH2 were differential expression in both primary tumors with metastasis compared to primary tumors without metastasis or metastatic tissues. By the AS prediction analysis, we suggest that CDKN2A mutation sites play an important role for RCC metastasis by affecting the p16/p14 expression. CONCLUSIONS: The SMGs could provide new molecular cues associated with tumor metastasis and have potential clinical implications for cancer prognosis and treatment. Definitive conclusions await further validation and follow up.