The TRIM28/miR133a/CD47 axis acts as a potential therapeutic target in pancreatic necrosis by impairing efferocytosis.

Efferocytosis, the clearance of apoptotic cells by macrophages, plays a crucial role in inflammatory responses and effectively prevents secondary necrosis. However, the mechanisms underlying efferocytosis in acute pancreatitis (AP) remain unclear. In this study, we demonstrated the presence of efferocytosis in injured human and mouse pancreatic tissues. We also observed significant upregulation of CD47, an efferocytosis-related the "do not eat me" molecule in injured acinar cells. Subsequently, we used CRISPR-Cas9 gene editing, anti-adeno-associated virus (AAV) gene modification, and anti-CD47 antibody to investigate the potential therapeutic role of AP. CD47 expression was negatively regulated by upstream miR133a, which is controlled by the transcription factor TRIM28. To further investigate the regulation of efferocytosis and reduction of pancreatic necrosis in AP, we used miR-133a-agomir and pancreas-specific AAV-shTRIM28 to modulate CD47 expression. Our findings confirmed that CD47-mediated efferocytosis is critical for preventing pancreatic necrosis and suggest that targeting the TRIM28-miR133a-CD47 axis is clinically relevant for the treatment of AP.

Development of an efficient, effective, and economical technology for proteome analysis.

We present an efficient, effective, and economical approach, named E3technology, for proteomics sample preparation. By immobilizing silica microparticles into the polytetrafluoroethylene matrix, we develop a robust membrane medium, which could serve as a reliable platform to generate proteomics-friendly samples in a rapid and low-cost fashion. We benchmark its performance using different formats and demonstrate them with a variety of sample types of varied complexity, quantity, and volume. Our data suggest that E3technology provides proteome-wide identification and quantitation performance equivalent or superior to many existing methods. We further propose an enhanced single-vessel approach, named E4technology, which performs on-filter in-cell digestion with minimal sample loss and high sensitivity, enabling low-input and low-cell proteomics. Lastly, we utilized the above technologies to investigate RNA-binding proteins and profile the intact bacterial cell proteome.

Adipose Triglyceride Lipase-Mediated Adipocyte Lipolysis Exacerbates Acute Pancreatitis Severity in Mouse Models and Patients.

Dyslipolysis of adipocytes has played a critical role in various diseases. Adipose triglyceride lipase (ATGL) is a rate-limiting enzyme in adipocyte autonomous lipolysis. However, whether the degree of adipocyte lipolysis relates to the prognoses in acute pancreatitis (AP) and the role of ATGL-mediated lipolysis in the pathogenesis of AP remain elusive. The visceral adipose tissue consumption rate in the acute stage was measured in both patients with AP and mouse models. Lipolysis levels and ATGL expression were detected in caerulein-induced AP models. CL316,243, a lipolysis stimulator, and adipose tissue-specific ATGL knockout mice were used to further investigate the role of lipolysis in AP. The ATGL-specific inhibitor, atglistatin, was used in C57Bl/6N and ob/ob AP models. This study found that increased visceral adipose tissue consumption rate in the acute phase was independently associated with adverse prognoses in patients with AP, which was validated in mice AP models. Lipolysis of adipocytes was elevated in AP mice. Stimulation of lipolysis could aggravate AP. Genetic blockage of ATGL specifically in adipocytes was able to alleviate the damage to AP. The application of atglistatin could effectively protect against AP in both lean and obese mice. These findings demonstrated that ATGL-mediated adipocyte lipolysis exacerbates AP and highlighted the therapeutic potential of ATGL as a drug target for AP.

Associations of Intrapancreatic Fat Deposition With Incident Diseases of the Exocrine and Endocrine Pancreas: A UK Biobank Prospective Cohort Study.

INTRODUCTION: To investigate whether increased intrapancreatic fat deposition (IPFD) heightens the risk of diseases of the exocrine and endocrine pancreas. METHODS: A prospective cohort study was conducted using data from the UK Biobank. IPFD was quantified using MRI and a deep learning-based framework called nnUNet. The prevalence of fatty change of the pancreas (FP) was determined using sex- and age-specific thresholds. Associations between IPFD and pancreatic diseases were assessed with multivariate Cox-proportional hazard model adjusted for age, sex, ethnicity, body mass index, smoking and drinking status, central obesity, hypertension, dyslipidemia, liver fat content, and spleen fat content. RESULTS: Of the 42,599 participants included in the analysis, the prevalence of FP was 17.86%. Elevated IPFD levels were associated with an increased risk of acute pancreatitis (hazard ratio [HR] per 1 quintile change 1.513, 95% confidence interval [CI] 1.179-1.941), pancreatic cancer (HR per 1 quintile change 1.365, 95% CI 1.058-1.762) and diabetes mellitus (HR per 1 quintile change 1.221, 95% CI 1.132-1.318). FP was also associated with a higher risk of acute pancreatitis (HR 3.982, 95% CI 2.192-7.234), pancreatic cancer (HR 1.976, 95% CI 1.054-3.704), and diabetes mellitus (HR 1.337, 95% CI 1.122-1.593, P = 0.001). DISCUSSION: FP is a common pancreatic disorder. Fat in the pancreas is an independent risk factor for diseases of both the exocrine pancreas and endocrine pancreas.

Isoliquiritigenin limits inflammasome activation of macrophage via docking into Syk to alleviate murine non-alcoholic fatty liver disease.

Isoliquiritigenin (ISL) is a chalcone-type flavonoid derived from the root of licorice with antioxidant, anti-inflammatory, anti-tumour and neuroprotective properties. ISL has been proven to downregulate the productions of IL-1ß, TNF-α and IL-6 by macrophages. However, detailed molecular mechanisms of this modulation remain elusive. Here, ISL suppressed Syk phosphorylation and CD80, CD86, IL-1ß, TNF-α and IL-6 expressions in lipopolysaccharide-stimulated macrophages ex vivo. ApoC3-transgenic (ApoC3TG) mice had more activated macrophages. ISL was also able to downregulate the inflammatory activities of macrophages from ApoC3TG mice. Administration of ISL inhibited Syk activation and inflammatory activities of macrophages in ApoC3TG mice in vivo. The treatment of ISL further alleviated MCD-induced non-alcoholic fatty liver disease (NAFLD) in wild-type and ApoC3TG mice, accompanied by less recruitment and activation of liver macrophages. Due to the inhibition of Syk phosphorylation, ISL-treated macrophages displayed less production of cytoplasmic ROS, NLRP3, cleaved-GSDMD and cleaved-IL-1ß, suggesting less inflammasome activation. Finally, the molecular docking study demonstrated that ISL bound to Syk directly with the Kd of 1.273 × 10-8 M. When the Syk expression was knocked down by its shRNA, the inhibitory effects of ISL on activated macrophages disappeared, indicating that Syk was at least one of key docking-molecules of ISL. Collectively, ISL could alleviate MCD-induced NAFLD in mice involved with the inhibition of macrophage inflammatory activity by the blockade of Syk-induced inflammasome activation.

Naringenin Alleviates Radiation-Induced Intestinal Injury by Inhibiting TRPV6 in Mice.

SCOPE: Naringenin (NAR) possesses unique anti-inflammatory, antiapoptosis effects and various bioactivities; however, its role against radiation-induced intestinal injury (RIII) remains unclear. This study aims to investigate whether NAR has protective effects against radiation-induced intestinal injury and the underlying mechanisms. METHODS AND RESULTS: C57BL/6J mice are exposed to a single dose of 13 Gy X-ray total abdominal irradiation (TAI), then gavaged with NAR for 7 days. NAR treatment prolongs the survival rate, protects crypts and villi from damage, alleviates the level of radiation-induced inflammation, and mitigates intestinal barrier damage in the irradiated mice. Additionally, NAR reduces immune cell infiltration and intestinal epithelial cell apoptosis. NAR also shows radioprotective effects in human colon cancer cells (HCT116) and human intestinal epithelial cells (NCM460). It reduces cell damage by reducing intracellular calcium ion levels and reactive oxygen species (ROS) levels. NAR-mediated radioprotection is associated with the downregulation of transient receptor potential vanilloid 6 (TRPV6), and inhibition of apoptosis pathway. Notably, treatment with NAR fails to further increase the protective effects of the TRPV6 inhibitor 2-APB, indicating that TRPV6 inhibition is essential for NAR activity. CONCLUSION: NAR inhibits the apoptosis pathway by downregulating TRPV6 and reducing calcium ion level, thereby alleviating RIII. Therefore, NAR is a promising therapeutic drug for RIII.

PHE-SICH-CT-IDS: A benchmark CT image dataset for evaluation semantic segmentation, object detection and radiomic feature extraction of perihematomal edema in spontaneous intracerebral hemorrhage.

BACKGROUND AND OBJECTIVE: Intracerebral hemorrhage is one of the diseases with the highest mortality and poorest prognosis worldwide. Spontaneous intracerebral hemorrhage (SICH) typically presents acutely, prompt and expedited radiological examination is crucial for diagnosis, localization, and quantification of the hemorrhage. Early detection and accurate segmentation of perihematomal edema (PHE) play a critical role in guiding appropriate clinical intervention and enhancing patient prognosis. However, the progress and assessment of computer-aided diagnostic methods for PHE segmentation and detection face challenges due to the scarcity of publicly accessible brain CT image datasets. METHODS: This study establishes a publicly available CT dataset named PHE-SICH-CT-IDS for perihematomal edema in spontaneous intracerebral hemorrhage. The dataset comprises 120 brain CT scans and 7,022 CT images, along with corresponding medical information of the patients. To demonstrate its effectiveness, classical algorithms for semantic segmentation, object detection, and radiomic feature extraction are evaluated. The experimental results confirm the suitability of PHE-SICH-CT-IDS for assessing the performance of segmentation, detection and radiomic feature extraction methods. RESULTS: This study conducts numerous experiments using classical machine learning and deep learning methods, demonstrating the differences in various segmentation and detection methods on the PHE-SICH-CT-IDS. The highest precision achieved in semantic segmentation is 76.31%, while object detection attains a maximum precision of 97.62%. The experimental results on radiomic feature extraction and analysis prove the suitability of PHE-SICH-CT-IDS for evaluating image features and highlight the predictive value of these features for the prognosis of SICH patients. CONCLUSION: To the best of our knowledge, this is the first publicly available dataset for PHE in SICH, comprising various data formats suitable for applications across diverse medical scenarios. We believe that PHE-SICH-CT-IDS will allure researchers to explore novel algorithms, providing valuable support for clinicians and patients in the clinical setting. PHE-SICH-CT-IDS is freely published for non-commercial purpose at https://figshare.com/articles/dataset/PHE-SICH-CT-IDS/23957937.

Soat2 inhibitor avasimibe alleviates acute pancreatitis by suppressing acinar cell ferroptosis.

Ferroptosis, characterized by lipid peroxidation, plays a significant role in the pathogenesis of acute pancreatitis (AP). While sterol O-acyltransferase 2 (Soat2) is known for its crucial regulatory role in cholesterol homeostasis, its involvement in the development of AP remains unreported. We conducted this study to identify the pivotal role of Soat2 in AP using transcriptomic databases. Subsequently, we confirmed its alterations through both in vitro and in vivo experimental models. Furthermore, we performed intervention with the Soat2 inhibitor avasimibe to evaluate pancreatic tissue pathology and serum enzymatic levels and observe inflammatory cell infiltration through immunohistochemistry. Additionally, changes in indicators related to ferroptosis were also observed. The results showed that in the AP mouse model, the protein and mRNA levels of Soat2 were significantly increased. Following avasimibe administration, there was a decrease in serum amylase levels, reduction in pancreatic tissue pathological damage, and attenuation of inflammatory cell infiltration. Furthermore, avasimibe administration resulted in downregulation of ferroptosis-related indicators. In conclusion, our findings suggest that the Soat2 inhibitor avasimibe protects against AP in mice through inhibition of the ferroptosis.

Prevalence and risk factors of fatigue and its association with quality of life among patients with chronic pancreatitis: A cross-sectional study.

BACKGROUND: Fatigue is a debilitating symptom found in various chronic diseases and is associated with more severe symptoms and worse quality of life (QoL). However, this symptom has not been adequately addressed in chronic pancreatitis (CP), and there have been no studies on fatigue in patients with CP. METHODS: This cross-sectional study was conducted at the Changhai Hospital in Shanghai, China. Data on the patients' sociodemographic, disease, and therapeutic characteristics were collected. Fatigue was assessed using the Multidimensional Fatigue Inventory-20. QoL was assessed utilizing the European Organization for the Research and Treatment of Cancer of QoL questionnaire (EORTC-QLQ-C30). Sleep quality, anxiety and depression, and pain was assessed using Pittsburgh Sleep Quality Index, the Hospital Anxiety and Depression Scale, and the Brief Pain Inventory, respectively. RESULTS: The prevalence of fatigue among Chinese patients with CP was 35.51 % (87/245). Multivariate analysis showed that steatorrhea (OR = 2.638, 95 % CI: 1.117-6.234), history of smoking (OR = 4.627, 95 % CI: 1.202-17.802), history of endoscopic treatment (OR = 0.419, 95 % CI: 0.185-0.950), depression (OR = 5.924, 95 % CI: 2.462-14.255), and sleep disorder (OR = 6.184, 95 % CI: 2.543-15.034) were influencing factors for the presence of fatigue. The scores for global health and all functional dimensions in the EORTC-QLQ-C30 significantly decreased, whereas the scores for all symptom dimensions significantly increased in patients with fatigue. CONCLUSIONS: This study indicated that Fatigue is a common symptom and has a negative impact on the QoL of patients with CP. Steatorrhea, smoking history, endoscopic treatment, depression, and sleep disorders were associated with fatigue.

Calcium transferring from ER to mitochondria via miR-129/ITPR2 axis controls cellular senescence in vitro and in vivo.

Senescent cells are known to be accumulated in aged organisms. Although the two main characteristics, cell cycle arrest (for dividing cells) and secretion of senescence-associated secretory phenotype (SASP) factors, have been well described, the lack of sufficient senescent markers and incomplete understanding of mechanisms have limited the progress of the anti-senescence field. Calcium transferred from the endoplasmic reticulum (ER) via inositol 1, 4, 5-trisphosphate receptor type 2 (ITPR2) to mitochondria has emerged as a key player during cellular senescence and aging. However, the internal regulatory mechanisms, particularly those of endogenous molecules, remain only partially understood. Here we identified miRNA-129 (miR-129) as a direct repressor of ITPR2. Interestingly, miR-129 controlled a cascade of intracellular calcium signaling, mitochondrial membrane potential (MMP), reactive oxygen species (ROS), DNA damage, and consequently cellular senescence through ITPR2 and mitochondrial calcium uniporter (MCU). In addition, miR-129 was repressed in different senescence models and delayed bleomycin-induced cellular senescence. Importantly, intraperitoneal injection of miR-129 partly postponed bleomycin-accelerated lung aging and natural aging markers as well as reduced immunosenescence markers in mice. Altogether, these findings demonstrated that miR-129 regulated cellular senescence and aging markers via intracellular calcium signaling by directly targeting ITPR2.

AAV-mediated hepatic LPL expression ameliorates severe hypertriglyceridemia and acute pancreatitis in Gpihbp1 deficient mice and rats.

GPIHBP1 plays an important role in the hydrolysis of triglyceride (TG) lipoproteins by lipoprotein lipases (LPLs). However, Gpihbp1 knockout mice did not develop hypertriglyceridemia (HTG) during the suckling period but developed severe HTG after weaning on a chow diet. It has been postulated that LPL expression in the liver of suckling mice may be involved. To determine whether hepatic LPL expression could correct severe HTG in Gpihbp1 deficiency, liver-targeted LPL expression was achieved via intravenous administration of the adeno-associated virus (AAV)-human LPL gene, and the effects of AAV-LPL on HTG and HTG-related acute pancreatitis (HTG-AP) were observed. Suckling Gpihbp1-/- mice with high hepatic LPL expression did not develop HTG, whereas Gpihbp1-/- rat pups without hepatic LPL expression developed severe HTG. AAV-mediated liver-targeted LPL expression dose-dependently decreased plasma TG levels in Gpihbp1-/- mice and rats, increased post-heparin plasma LPL mass and activity, decreased mortality in Gpihbp1-/- rat pups, and reduced the susceptibility and severity of both Gpihbp1-/- animals to HTG-AP. However, the muscle expression of AAV-LPL had no significant effect on HTG. Targeted expression of LPL in the liver showed no obvious adverse reactions. Thus, liver-targeted LPL expression may be a new therapeutic approach for HTG-AP caused by GPIHBP1 deficiency.

Bile acid metabolomics identifies chenodeoxycholic acid as a therapeutic agent for pancreatic necrosis.

Bile acids are altered and associated with prognosis in patients with acute pancreatitis (AP). Here, we conduct targeted metabolomic analyses to detect bile acids changes in patients during the acute (n = 326) and the recovery (n = 133) phases of AP, as well as in healthy controls (n = 60). Chenodeoxycholic acid (CDCA) decreases in the acute phase, increases in the recovery phase, and is associated with pancreatic necrosis. CDCA and its derivative obeticholic acid exhibit a protective effect against acinar cell injury in vitro and pancreatic necrosis in murine models, and RNA sequencing reveals that the oxidative phosphorylation pathway is mainly involved. Moreover, we find that overexpression of farnesoid X receptor (FXR, CDCA receptor) inhibits pancreatic necrosis, and interfering expression of FXR exhibits an opposite phenotype in mice. Our results possibly suggest that targeting CDCA is a potential strategy for the treatment of acinar cell necrosis in AP, but further verification is needed.

Low-dose adropin stimulates inflammasome activation of macrophage via mitochondrial ROS involved in colorectal cancer progression.

Adropin is encoded by the energy homeostasis-associated (ENHO) gene and widely present in liver, pancreas, heart, kidney, brain, and vascular tissues. Abnormal adropin is associated with metabolic, inflammatory, immune, and central nervous disorders. Whether adropin is involved in the development of colorectal cancer (CRC) is still unclear. Here, decreased adropin expression of tumor-nest cells in advanced-stage CRC was demonstrated. Adropin expressed by carcinoma cells was negatively correlated with macrophage infiltration in the matrix of CRC tissues. However, tumor macrophages enhanced adropin expression and were positively correlated with tumor invasion and metastasis. ENHO gene transfection into colon cancer (MC38) cells inhibited tumor growth in vivo, accompanying the increase of M1 macrophages. Treatment with low-dose adropin (< 100 ng/mL) on macrophages ex vivo directly increased mitochondrial reactive oxygen species for inflammasome activation. Furthermore, ENHO-/- mice had less M1 macrophages in vivo, and ENHO-/- macrophages were inert to be induced into the M1 subset ex vivo. Finally, low-dose adropin promoted glucose utilization, and high-dose adropin enhanced the expression of CPT1α in macrophages. Therefore, variations of adropin level in carcinoma cells or macrophages in tumor tissues are differently involved in CRC progression. Low-dose adropin stimulates the antitumor activity of macrophages, but high-dose adropin facilitates the pro-tumor activity of macrophages. Increasing or decreasing the adropin level can inhibit tumor progression at different CRC stages.

HDL inhibits pancreatic acinar cell NLRP3 inflammasome activation and protect against acinar cell pyroptosis in acute pancreatitis.

BACKGROUND AND PURPOSE: Recent clinical studies have shown that serum high-density lipoprotein (HDL) levels are correlated with acute pancreatitis (AP) severity. We aimed to investigate the role of HDL in pancreatic necrosis in AP. EXPERIMENTAL APPROACH: ApoA-I is the main constitution and function component of HDL. The roles of healthy human-derived HDL and apoA-I mimic peptide D4F were demonstrated in AP models in vivo and in vitro. Constitutive Apoa1 genetic inhibition on AP severity, especially pancreatic necrosis was assessed in both caerulein and sodium taurocholate induced mouse AP models. In addition, constitutive (Casp1-/-) and acinar cell conditional (Pdx1CreNlrp3Δ/Δ and Pdx1CreGsdmdΔ/Δ) mice were used to explore the effects of HDL on acinar cell pyroptosis in AP. KEY RESULTS: Apoa1 knockout dramatically aggravated pancreatic necrosis. Human-derived HDL protected against acinar cell death in vivo and in vitro. We found that mimic peptide D4F also protected against AP very well. Constitutive Casp1 or acinar cell-conditional Nlrp3 and Gsdmd genetic inhibition could counteract the protective effects of HDL, implying HDL may exert beneficial effects on AP through inhibiting acinar cell pyroptosis. CONCLUSION AND IMPLICATIONS: This work demonstrates the protective role of HDL and apoA-I in AP pathology, potentially driven by the inhibition of NLRP3 inflammasome signaling and acinar cell pyroptosis. Mimic peptides have promise as specific therapies for AP.

Adherence to pancreatic enzyme replacement therapy among patients with chronic pancreatitis in East China: a mixed methods study.

Pancreatic enzyme replacement therapy (PERT) has been recommended as the preferred method for pancreatic exocrine insufficiency caused by chronic pancreatitis (CP). However, at present, the patient-related factors for the poor PERT management are not clear, and there are no studies on the adherence to PERT in patients with CP in East China. This was a mixed-method study following the principle of sequential explanatory design and included two parts: a quantitative and qualitative study. A cross-sectional survey of medication adherence (MA) was first carried out, followed by a semi-structured interview to further explore and explain the influencing factors of adherence to PERT. Of the 148 patients included in this study, 48.0% had poor MA and only 12.8% had good MA. Multivariate logistic regression showed that lower levels of education and income were contributing factors for non-adherence to PERT. Semi-structured interviews with 24 patients revealed that the reasons for non-adherence also included lack of knowledge, self-adjustment of PERT, lifetime of medication, side effects of PERT, forgetfulness, financial burdens, and accessibility issues. The adherence to PERT was poor among patients with CP in East China. Healthcare providers should personalize medication strategies to improve patients' MA.

Apolipoprotein C-III itself stimulates the Syk/cPLA2-induced inflammasome activation of macrophage to boost anti-tumor activity of CD8+ T cell.

Increased prevalence of cancer in obese individuals is involved with dyslipidemia- induced chronic inflammation and immune suppression. Although apolipoprotein C-III (ApoC3)-transgenic mice (ApoC3TG mice) or poloxamer 407 (P407)-treated mice had hyperlipidemia, CD8+ T cells with upregulated antitumor activities were observed in ApoC3TG mice, and decreased CD8+ T cell activities were observed in P407-treated mice. Increased ApoC3 expression in hepatocellular carcinoma was associated with increased infiltration of CD8+ T cells and predicted survival. Recombinant ApoC3 had no direct effects on CD8+ T cells. The upregulation of CD8+ T cells in ApoC3TG mice was due to cross-talk with context cells, as indicated by metabolic changes and RNA sequencing results. In contrast to dendritic cells, the macrophages of ApoC3TG mice (macrophagesTG) displayed an activated phenotype and increased IL-1ß, TNF-α, and IL-6 production. Coculture with macrophagesTG increased CD8+ T cell function, and the adoptive transfer of macrophagesTG suppressed tumor progression in vivo. Furthermore, spleen tyrosine kinase (Syk) activation induced by TLR2/TLR4 cross-linking after ApoC3 ligation promoted cellular phospholipase A2 (cPLA2) activation, which in turn activated NADPH oxidase 2 (NOX2) to promote an alternative mode of inflammasome activation. Meanwhile, mitochondrial ROS produced by increased oxidative phosphorylation of free fatty acids facilitated the classical inflammasome activation, which exerted an auxiliary effect on inflammasome activation of macrophagesTG. Collectively, the increased antitumor activity of CD8+ T cells was mediated by the ApoC3-stimulated inflammasome activation of macrophages, and the mimetic ApoC3 peptides that can bind TLR2/4 could be a future strategy to target liver cancer.

Psychometric validation of the fear of progression questionnaire-short form in acute pancreatitis patients.

Introduction: Fear of progression (FoP) is associated with the quality of life and behavioral change in acute pancreatitis (AP) patients, but lack of assessment tools. Aim: This study aimed to develop and evaluate the psychometric properties of the Fear of Progression Questionnaire-Short Form in AP patients (AP-FoP-Q-SF). Methods: Internal consistency, factorial structure, convergent validity, and criterion validity of AP-FoP-Q-SF were assessed. A receiver operating characteristic (ROC) curve analysis was performed to identify the cutoff value for high FoP. Associations between patient variables and FoP were evaluated using multiple logistic regression. Wilcox rank sum test was used to analyses the costs and length of hospital stay of the patients with high FoP. Results: The two-factor structure showed a good fit. Internal consistency was acceptable (Cronbach's α = 0.771). The cutoff of 26 identified 35.3% of patients with high FoP. High FoP scores were associated with age (OR = 0.96, 95%CI: 0.94-0.98), recurrence times (OR = 1.22, 95%CI: 1.02-1.45) and anxiety (OR = 1.27, 95%CI: 1.16-1.40). Patients with high FoP spent more cost and time in the hospital. Conclusions: The AP-FoP-Q-SF is a good FoP tool for AP patients in China. Implications for practice: Clinicians can use the AP-FoP-Q-SF to assess FoP and take promotion programs to avoid worse effects.

Zinc finger protein ZBTB17 controls cellular senescence via interacting with nuclear receptor RXRA and its downstream calcium signaling.

Cellular senescence is broadly known as a stable cell cycle arrest accompanied by a senescence-associated secretory phenotype (SASP). In the past decades, calcium signaling has emerged as a key mediator of cellular senescence. However, the transcriptional regulation of calcium signaling during cellular senescence remains partially understood. We have previously identified the nuclear receptor RXRA as a key senescence repressor through inhibiting the endoplasmic reticulum (ER) calcium release channel inositol 1,4,5-trisphosphate receptor, type 2 (ITPR2) mediated intracellular calcium signaling. Nevertheless, as a transcriptional recruiter, the mechanism by which RXRA inhibits ITPR2 during cellular senescence remains unclear. Here we identified the zinc finger protein ZBTB17 can interact with RXRA. Interestingly, knockdown of ZBTB17 induces a cascade of RXRA-dependent intracellular calcium signaling, mitochondrial membrane potential (MMP), reactive oxygen species (ROS) accumulation, DNA damages, and ultimately cellular senescence. Moreover, the signaling and senescence phenotype induced by knocking down of ZBTB17 can also be abolished after silencing ITPR2. Altogether, our work provides a new mechanism controlling intracellular calcium signaling and cellular senescence and unveils novel insight toward the role of zinc finger proteins.

Differential effects of PGAM5 knockout on high fat high fructose diet and methionine choline-deficient diet induced non-alcoholic steatohepatitis (NASH) in mice.

BACKGROUND: Phosphoglycerate mutase 5 (PGAM5), a phosphatase involved in mitochondrial homeostasis, is reported to be closely related to the metabolic stress induced by high-fat diet (HFD) or cold. In this study, we aimed to investigate the effects of PGAM5 on hepatic steatosis, inflammation and fibrosis in nonalcoholic steatohepatitis (NASH). METHODS AND RESULTS: We generated PGAM5 global knockout (GKO) mice and their wildtype (WT) littermates using CRISPR/CAS9. The mice were fed with a high fat high fructose (HFHF) diet for 12 weeks or a methionine choline-deficient (MCD) diet (methionine choline supplemented (MCS) as control) for 6 weeks. Hepatic PGAM5 expression was up-regulated in humans with NASH and WT mice fed with HFHF and MCS, and reduced in WT mice fed with MCD diet. In HFHF-fed mice, GKO had reduced body weight, hepatic triglyceride (TG) content and serum transaminase along with decreased hepatic pro-inflammatory and pro-fibrotic responses compared with their WT control. GKO had increased expression of antioxidative gene glutathione peroxidase-6 (GPX6) and activation of mammalian target of rapamycin (mTOR). In mice fed with MCS diet, GKO significantly increased serum TNF-α and IL-6 and decreased hepatic GPX6 mRNA expression. There was no difference in hepatic steatosis, inflammation or fibrosis between GKO and WT mice fed with MCD diet. We investigated the role of PGAM5 deficiency in a variety of cell types. In differentiated THP-1 cells, PGAM5 silencing significantly increased pro-inflammatory cytokine secretion and decreased antioxidative proteins, including nuclear factor erythroid 2- related factors (NRF2), heme oxygenase-1 (HO-1) and GPX6 without affecting mTOR activity. In HepG2 cells with steatosis, PGAM5 knockdown reduced insulin sensitivity, increased mTOR phosphorylation and reduced the expression of NRF2, catalase (CAT), HO-1 and GPX6. Conversely, PGAM5 knockdown reduced TG accumulation, increased insulin sensitivity, and increased antioxidative genes in 3T3-L1 cells, despite the up-regulation in mTOR phosphorylation. CONCLUSIONS: PGAM5-KO relieved hepatic steatosis and inflammation in HFHF model, promoted inflammation in MCS-fed mice and had no effects on the MCD-fed model. The distinct effects may be owing to the different effects of PGAM5-KO on anti-oxidative pathways in energy-dependent, possible involves mTOR, and/or cell type-dependent manner. Our findings suggest that PGAM5 can be a potential therapeutic target for NASH.