Highly active lipid-lowering peptides were isolated from Tartary buckwheat through enzymatic hydrolysis, ultrafiltration, and reversed-phase high-performance liquid chromatography (RP-HPLC). Liquid chromatography-tandem mass spectrometry (LC-MS/MS) and molecular docking techniques were employed to identify and screen lipid-lowering peptide monomers. The lipid-lowering effects and underlying mechanisms were evaluated through molecular docking visualization, in vitro chemical assays, the 3 T3-L1 cell model, and the Caenorhabditis elegans(C. elegans) model. Five novel peptides were identified: FHWDYPQA, FHWDYPQALE, LFHWDYPQA, LPSYSNAPYI, and NAIIGPRW. These peptides bind to receptor proteins 1LPB and 1F6W via hydrogen bonds, hydrophobic interactions, and electrostatic interactions. These peptides significantly inhibited pancreatic lipase activity, effectively reduced lipid accumulation in 3 T3-L1 cells, and lowered triglycerides (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) levels. In addition, LI-10, FE-10, and LA-9 significantly elevated high-density lipoprotein cholesterol (HDLC) levels. Additionally, five peptides effectively reduced lipid accumulation in high-fat-fed C. elegans, decreased TG, glucose (GLU), and malondialdehyde (MDA) levels. Overall, these findings elucidate the lipid-lowering mechanisms of five novel peptides identified from Tartary buckwheat protein hydrolysates, providing a scientific foundation for the future development of Tartary buckwheat protein-derived functional products targeting hyperlipidemia.

Sepsis frequently leads to skeletal muscle atrophy, but its molecular mechanisms remain unclear. Using a mouse model of cecal ligation and puncture and LPS-treated C2C12 myotubes, we found that sepsis activates autophagy, the ubiquitin-proteasome system (UPS), and calpain pathways, resulting in muscle wasting and functional decline. These changes were linked to upregulated FoxO1/3a and NF-κB signaling and suppressed mTOR activity. Pharmacological inhibition or genetic deletion of key components in these pathways, especially MuRF1, mitigated muscle atrophy and preserved function. Our findings reveal that sepsis-induced muscle loss is driven by coordinated activation of proteolytic systems regulated by the FoxO1/3a, NF-κB, and mTOR signaling pathway, offering potential therapeutic targets.

RATIONALE:Impaired alveolar regeneration is a central feature of chronic lung diseases. Type 2 alveolar epithelial cells (AT2) serve as lung stem/progenitor cells that differentiate into type 1 cells (AT1) to restore gas exchange following injury. However, the metabolic determinants governing this regenerative process remain poorly understood. OBJECTIVES:This study aimed to determine the role of glutamine metabolism via glutaminase 1 (GLS1) in regulating AT2-to-AT1 differentiation and alveolar regeneration after lung injury. METHODS:We used primary murine AT2 cells, alveolar organoids, and lineage-tracing mouse models of bleomycin-induced lung injury. The effects of AT2-specific GLS1 deletion on epithelial differentiation were assessed in vitro and in vivo. Chloroquine and bafilomycin A1, two autophagy inhibitors with distinct molecular mechanisms of action, were used for mechanistic rescue experiments. MEASUREMENTS AND MAIN RESULTS:GLS1 expression increased during AT2-to-AT1 differentiation and was accompanied by metabolic reprogramming characterized by enhanced glycolysis and increased glutamine entry into the TCA cycle. AT2-specific GLS1 deletion impaired differentiation in vitro and in vivo, resulting in defective alveolar repair and exacerbated pulmonary fibrosis. Mechanistically, GLS1 deficiency induced excessive autophagy and promoted degradation of the Hippo pathway effectors YAP and TAZ, key regulators of epithelial cell fate decisions. Inhibition of autophagy with either chloroquine or bafilomycin A1 restored YAP/TAZ levels, rescued AT2-to-AT1 differentiation, reduced fibrosis, and improved lung function. CONCLUSIONS:GLS1-mediated glutaminolysis is essential for alveolar stem/progenitor cell differentiation through regulation of autophagy and YAP/TAZ stability. Modulation of autophagy may represent a therapeutic strategy to enhance lung regeneration in fibrotic lung diseases.

BACKGROUND AND AIMS:Nucleotide-binding oligomerization domain-containing protein (NOD)1 is an intracellular pattern recognition receptor that initiates immune responses upon ligation of molecules such as bacterial peptidoglycan containing a D-glutamyl-meso-diaminopimelic acid (iE-DAP) moiety. NOD1 ligation has been shown to promote vascular inflammation and atherosclerosis. In this study, we investigate the functional role of NOD1 in atherosclerotic plaques and characterize the vascular cells responsible for NOD1 expression and function. METHODS AND RESULTS:NOD1 was mainly expressed in a subtype of vascular smooth muscle cells (SMC) in human atherosclerotic lesions. In ex vivo cultures, human endarterectomy specimens reacted to NOD1 ligand by activation of mitogen-activated protein kinase (MAPK) p38 pathway, leading to cytokine expression. Levels of NOD1 mRNA were higher in carotid endarterectomy specimens obtained from symptomatic patients compared to asymptomatic ones. NOD1+ SMC were also found in arteries of atherosclerosis-prone Ldlr-/- mice. Challenging these mice with a NOD1 agonist resulted in transmural vascular inflammation, severe arterial damage, accelerated atherogenesis throughout the aorta, and evidence of occlusive coronary artery disease. In rats, mechanic injury to carotid arteries promoted NOD1+ SMC expansion and neointima formation. In vitro, neointima derived NOD1+ SMCs responded to NOD1 ligand exposure by enhanced migration, increased iNOS+ cells and amplified CCL5 production. CONCLUSION:Our findings show that NOD1 promotes vascular inflammation, vascular injury responses and atherosclerosis by acting on a NOD1+ subtype of SMC.

Salvia castanea Diels f. tomentosa Stib. (SCD) is a traditional Tibetan herbal medicine that is frequently employed in the treatment of cardiovascular disease. However, the mechanism of its effect on plateau hypoxia-induced right ventricular hypertrophy remains unclear. In the present study, we evaluated the antihypoxic effect of the alcoholic extract of Salvia castanea Diels f. tomentosa Stib. (SCDA) through a normal pressure hypoxia tolerance experiment in mice, and investigated the effect and possible mechanism of SCDA on hypoxia-induced right ventricular hypertrophy in rats. 0.3 and 0.6 g/kg SCDA were used to treat Sugen5416 + hypoxia-induced right ventricular hypertrophy in SD rats for 3 weeks. The findings indicated that SCDA (0.6 g/kg) could inhibit right ventricular hypertrophy, as evidenced by a reduction in heart weight/body weight, Fulton’s index, mean pulmonary artery pressure and hypertrophic markers. Furthermore, through network pharmacology in conjunction with transcriptomics and molecular docking as well as experimental validation, it was demonstrated that SCDA reduced lipid peroxidation products, mainly through inhibiting hypoxia-induced activation of the tumour proteins p53 (P53), spermine/ spermine N1 acetyltransferase 1 (SAT1) and arachidonate 15-lipoxygenase (ALOX15). Similarly, SCDA also increased levels of the antioxidant glutathione (GSH), which is associated with inhibition of P53 and promotion of the expression of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), resulting in an improved balance between antioxidant and oxidant systems. This provides new drugs and targets for the treatment of right ventricular hypertrophy.

Ferroptosis has been implicated in skeletal muscle aging. Nevertheless, specific ferroptosis-related genes (FRGs) governing skeletal muscle aging remain unclear. The aim of this study was to identify ferroptosis-related marker genes associated with skeletal muscle aging, uncovering potential therapeutic targets for skeletal muscle aging. Data from GSE38718 was utilized to identify differentially expressed FRGs (DE-FRGs) in aging versus normal human skeletal muscle by the least absolute shrinkage and selection operator (LASSO) and the support vector machine recursive feature elimination (SVM-RFE) algorithms. Validation was conducted using RT-qPCR and Western blot in aging mouse muscle and D-galactose (D-gal)-treated C2C12 cells. SLC38A1 was identified as a significantly downregulated marker for aging skeletal muscle. Overexpression of SLC38A1 mitigated cellular aging in D-gal treated C2C12 cells. In both D-gal treated and sh-SLC38A1 C2C12 cells, increased ROS levels, elevated mtROS, higher intracellular iron concentrations, and intensified lipid peroxidation were observed. In contrast, SLC38A1 overexpression markedly reduced the accumulation of ROS, mtROS, iron concentration, and lipid peroxidation associated with D-gal treatment in these cells. In conclusion, through screening analyses and validation experiments, we identified SLC38A1 as a ferroptosis-related regulator for skeletal muscle aging.

Excessive Hedgehog (Hh) signaling activity contributes to fibrosis in multiple organs. However, its role in pancreatic stellate cell (PSC) activation and fibrosis development during chronic pancreatitis (CP) remains elusive. We show that GLI2 is one of the top-ranked effectors in the pancreas of CP patients and is highly expressed in activated PSCs. PSC-specific deletion of Gli2, but not Smo, significantly reduces fibrosis and the severity of the mouse CP, indicating that GLI2 in PSCs can be driven by non-canonical fashion during CP. In culture-activated primary PSCs, early nuclear translocation and increased GLI2 expression are observed promptly following in vitro culture. Whereas GLI2 inhibition reduces PSC activation, SMO inhibition dose not consistently affect changes in GLI2 levels or PSC activation. TGF-β1 promotes GLI2 activation and expression, while these processes and resultant PSC activation are reversed by TGF-β1/SMAD3 inhibition. Altogether, these findings demonstrate the activation of the non-canonical Hh pathway in PSCs during CP and highlight that GLI2 represents a promising therapeutic target for CP.

In this study, tea protein lipid-lowering peptides were prepared by enzymatic hydrolysis, and 3T3-L1 preadipocytes and high-fat mice were used to investigate its in vitro and in vivo lipid regulating effect. The results showed that tea protein lipid-lowering peptides could significantly inhibit the adipogenic differentiation of 3T3-L1 preadipocytes and reduce lipid accumulation. At the peptides concentration of 0.1 mg/mL, the content of total triglyceride, total cholesterol, low-density lipoprotein, and high-density lipoprotein of the cells decreased or increased by 38.57%, 47.71%, 46.68%, and 49.29%, respectively. Feeding lipid-lowering peptides could significantly inhibit the weight gain of high-fat mice, reduce fat accumulation and organ burden, and inhibit the degeneration of liver and epididymal fat. High concentration of lipid-lowering peptides (200 mg/kg) significantly reduced the atherosclerosis index and coronary artery risk index by 58.52% and 42.90%, respectively. Intestinal flora analysis showed that lipid-lowering peptides could increase the ratio of Firmicutes to Bacteroidetes, and increase the relative abundance of Muribaculaceae, while decreasing the overall abundance of Bacteroidetes. These changes help to restore the homeostasis of intestinal flora and thus have a positive regulatory effect on obesity and related metabolic disorders.

BACKGROUND: The sympathoadrenergic system and its major effector PKA (protein kinase A) are activated to maintain cardiac output coping with physiological or pathological stressors. If and how PKA plays a role in physiological cardiac hypertrophy (PhCH) and pathological CH (PaCH) are not clear. METHODS: Transgenic mouse models expressing the PKA inhibition domain (PKAi) of PKA inhibition peptide alpha (PKIalpha)-green fluorescence protein (GFP) fusion protein (PKAi-GFP) in a cardiac-specific and inducible manner (cPKAi) were used to determine the roles of PKA in physiological CH during postnatal growth or induced by swimming, and in PaCH induced by transaortic constriction (TAC) or augmented Ca 2+ influx. Kinase profiling was used to determine cPKAi specificity. Echocardiography was used to determine cardiac morphology and function. Western blotting and immunostaining were used to measure protein abundance and phosphorylation. Protein synthesis was assessed by puromycin incorporation and protein degradation by measuring protein ubiquitination and proteasome activity. Neonatal rat cardiomyocytes (NRCMs) infected with AdGFP (GFP adenovirus) or AdPKAi-GFP (PKAi-GFP adenovirus) were used to determine the effects and mechanisms of cPKAi on myocyte hypertrophy. rAAV9.PKAi-GFP was used to treat TAC mice. RESULTS: (1) cPKAi delayed postnatal cardiac growth and blunted exercise-induced PhCH; (2) PKA was activated in hearts after TAC due to activated sympathoadrenergic system, the loss of endogenous PKIα (PKA inhibition peptide α), and the stimulation by noncanonical PKA activators; (3) cPKAi ameliorated PaCH induced by TAC and increased Ca 2+ influxes and blunted neonatal rat cardiomyocyte hypertrophy by isoproterenol and phenylephrine; (4) cPKAi prevented TAC-induced protein synthesis by inhibiting mTOR (mammalian target of rapamycin) signaling through reducing Akt (protein kinase B) activity, but enhancing inhibitory GSK-3α (glycogen synthase kinase-3α) and GSK-3β signals; (5) cPKAi reduced protein degradation by the ubiquitin-proteasome system via decreasing RPN6 phosphorylation; (6) cPKAi increased the expression of antihypertrophic atrial natriuretic peptide (ANP); (7) cPKAi ameliorated established PaCH and improved animal survival. CONCLUSIONS: Cardiomyocyte PKA is a master regulator of PhCH and PaCH through regulating protein synthesis and degradation. cPKAi can be a novel approach to treat PaCH.

Abstract Background Bawei Chenxiang Wan (BCW) is among the most effective and widely used therapies for coronary heart disease and angina pectoris in Tibet. However, whether it confers protection through a right-ventricle (RV) myocardial metabolic mechanism is unknown. Methods Male Sprague–Dawley rats were orally administrated with BCW, which was injected concurrently with a bolus of Sugen5416, and subjected to hypoxia exposure (SuHx; 5000 m altitude) for 4 weeks. Right ventricular hypertrophy (RVH) in high-altitude heart disease (HAHD) was assessed using Fulton’s index (FI; ratio of RV to left ventricle + septum weights) and heart-weight-to-body-weight ratio (HW/BW). The effect of therapeutic administration of BCW on the RVH hemodynamics was assessed through catheterization (mean right ventricular pressure and mean pulmonary artery pressure (mRVP and mPAP, respectively)). Tissue samples were used to perform histological staining, and confirmatory analyses of mRNA and protein levels were conducted to detect alterations in the mechanisms of RVH in HAHD. The protective mechanism of BCW was further verified via cell culture. Results BCW considerably reduced SuHx-associated RVH, as indicated by macro morphology, HW/BW ratio, FI, mPAP, mRVP, hypertrophy markers, heart function, pathological structure, and myocardial enzymes. Moreover, BCW can alleviate the disorder of glucose and fatty acid metabolism through upregulation of carnitine palmitoyltransferase1ɑ, citrate synthase, and acetyl-CoA and downregulation of glucose transport-4, phosphofructokinase, and pyruvate, which resulted in the reduced levels of free fatty acid and lactic acid and increased aerobic oxidation. This process may be mediated via the regulation of sirtuin 3 (SIRT3)-hypoxia-inducible factor 1α (HIF1α)-pyruvate dehydrogenase kinase (PDK)/pyruvate dehydrogenase (PDH) signaling pathway. Subsequently, the inhibition of SIRT3 expression by 3-TYP (a selective inhibitor of SIRT3) can reverse substantially the anti-RVH effect of BCW in HAHD, as indicated by hypertrophy marker and serum myocardial enzyme levels. Conclusions BCW prevented SuHx-induced RVH in HAHD via the SIRT3-HIF1ɑ-PDK/PDH signaling pathway to alleviate the disturbance in fatty acid and glucose metabolism. Therefore, BCW can be used as an alternative drug for the treatment of RVH in HAHD.

Objectives: To investigate factors that may influence humoral immunity post-vaccination with a COVID-19-inactivated vaccine (SC2IV). Methods: A total of 1596 healthy individuals from the Seventh Affiliated Hospital, Sun Yat-sen University (1217) and Shenzhen Baotian Hospital (379) were enrolled in this study among which 694 and 218 participants were vaccinated with two-dose SC2IV, respectively. Physical examination indices were recorded. The levels of neutralizing antibody (NA), Spike IgG, receptor-binding domain (RBD) IgG, RBD IgG + IgM + IgA, and nucle-ocapsid IgG of SARS-CoV-2 were measured by a non-virus ELISA kit. Multiple statistical analyses were carried out to identify factors that influence humoral immunity post-vaccination. Results: The two-dosage vaccination could induce NA in more than 90 % of recipients. The NA has the strongest correlation with anti-RBD IgG. Age is the most important independent index that affects the NA level, while basophil count, creatine kinase-MB, mean corpuscular hemoglobin, the ratio of albumin to urine creatinine, and thyroglobulin antibody have relatively minor contributions. Indices that affect the NA level were different between males and females. Antibodies targeting other epitopes of SARS-CoV-2 were detected in recipients without anti-RBD. Conclusions: The factors identified in association with the NA level post-vaccination may help to evaluate the protective effect, risk of re-infection, the severity of symptoms, and prognosis for vaccine recipients in clinical.

Background and purpose: β-Arrestins are key regulators of G protein–coupled receptor (GPCR) signaling. Through their function as scaffolding proteins, β-arrestins mediate a range of cellular signaling events. However, the role of β-arrestins during myocardial ischemia remains incompletely understood. In this study, we explored the regulatory effects of β-arrestin-1 on autophagy following myocardial infarction and sought to identify the underlying mechanism. Methods: Acute myocardial infarction was induced by permanent left anterior descending coronary artery ligation. Cardiac function was assessed using echocardiography. β-Arrestin-1, autophagy-related 5 (ATG5), and liver kinase B1 (LKB1) were overexpressed or knocked down using lentivirus-mediated transduction of the gene or short hairpin RNA (shRNA) in cultured primary cardiomyocytes. Oxygen-glucose deprivation (OGD) in cardiomyocytes was used to simulate cardiac ischemia in vitro. Autophagy and apoptosis were assessed by western blot, flow cytometry, and transmission electron microscopy. Cell survival and lactate dehydrogenase (LDH) release were evaluated using the respective kits. Results: β-Arrestin-1 knockout (KO) increased myocardial infarction size, an effect that was associated with decreased autophagy and deterioration of cardiac function. The overexpression of β-arrestin-1 significantly increased autophagy levels and decreased cell apoptosis in cardiomyocytes exposed to OGD, whereas the knockdown of β-arrestin-1 exerted the opposite effect. The protective effect of β-arrestin-1 overexpression was abrogated by ATG5 knockdown. β-Arrestin-1 KO attenuated the myocardial infarction–induced phosphorylation of adenosine monophosphate (AMP)-activated protein kinase (AMPK). In cultured myocytes, the blockade of AMPK or the knockdown of LKB1 inhibited the β-arrestin-1–induced increase in the LC3-II/LC3-I ratio and beclin 1 expression levels and attenuated β-arrestin-1–mediated cardioprotective effects. Conclusions: Collectively, our findings suggested that β-arrestin-1 promotes cardiomyocyte survival under ischemic conditions via the regulation of LKB1/AMPK-dependent autophagy. These findings may be helpful in designing novel therapeutic strategies for myocardial ischemia.

The relationship between the type and intensities of lipids of blood and pancreas and the pathological changes in the pancreas during severe acute pancreatitis (SAP) remains unclear. In our study, we employed a rat model of SAP induced through intraperitoneal ornithine injections. We collected serum and pancreas samples at various time points (0–144 h) for histopathological and biochemical assessments, followed by lipidomic analyses using LC-MS/MS or in situ mass spectrometry imaging (MSI) To discern changes over time or at specific points, we employed time-course and univariate analyses for lipid screening, respectively. Our findings indicated that the peak inflammation in the Orn-SAP model occurred within the 24–30 h timeframe, with evident necrosis emerging from 24 h onwards, followed by regeneration starting at 48 h. Time-course analysis revealed an overall decrease in glycerophospholipids (PEs, PCs, LPEs, LPCs), while CEs exhibited an increase within the pancreas. Univariate analysis unveiled a significant reduction in serum TAGs containing 46–51 carbon atoms at 24 h, and CERs in the pancreas significantly increased at 30 h, compared with 0 h. Moreover, a substantial rise in TAGs containing 56–58 carbon atoms was observed at 144 h, both in serum and pancreas. MSI demonstrated the CERs containing saturated mono-acyl chains of 16 and 18 carbon atoms influenced pancreatic regeneration. Tracing the origin of FFAs hydrolyzed from pancreatic glycerophospholipids and serum TAGs during the early stages of inflammation, as well as FFAs utilized for CEs and CERs synthesis during the repair phase, may yield valuable strategies for diagnosing and managing SAP.

Background: A recent study suggests that systemic hypoxemia in adult male mice can induce cardiac myocytes to proliferate. The goal of the present experiments was to confirm these results, provide new insights on the mechanisms that induce adult cardiomyocyte cell cycle reentry, and to determine if hypoxemia also induces cardiomyocyte proliferation in female mice. Methods: EdU-containing mini pumps were implanted in 3-month-old, male and female C57BL/6 mice. Mice were placed in a hypoxia chamber, and the oxygen was lowered by 1% every day for 14 days to reach 7% oxygen. The animals remained in 7% oxygen for 2 weeks before terminal studies. Myocyte proliferation was also studied with a mosaic analysis with double markers mouse model. Results: Hypoxia induced cardiac hypertrophy in both left ventricular (LV) and right ventricular (RV) myocytes, with LV myocytes lengthening and RV myocytes widening and lengthening. Hypoxia induced an increase (0.01±0.01% in normoxia to 0.11±0.09% in hypoxia) in the number of EdU+ RV cardiomyocytes, with no effect on LV myocytes in male C57BL/6 mice. Similar results were observed in female mice. Furthermore, in mosaic analysis with double markers mice, hypoxia induced a significant increase in RV myocyte proliferation (0.03±0.03% in normoxia to 0.32±0.15% in hypoxia of RFP+ myocytes), with no significant change in LV myocyte proliferation. RNA sequencing showed upregulation of mitotic cell cycle genes and a downregulation of Cullin genes, which promote the G1 to S phase transition in hypoxic mice. There was significant proliferation of nonmyocytes and mild cardiac fibrosis in hypoxic mice that did not disrupt cardiac function. Male and female mice exhibited similar gene expression following hypoxia. Conclusions: Systemic hypoxia induces a global hypertrophic stress response that was associated with increased RV proliferation, and while LV myocytes did not show increased proliferation, our results minimally confirm previous reports that hypoxia can induce cardiomyocyte cell cycle activity in vivo.

Maternal hypothyroidism (MH) could adversely affect the cardiac disease responses of the progeny. This study tested the hypothesis that MH reduces early postnatal cardiomyocyte (CM) proliferation so that the adult heart of MH progeny has a smaller number of larger cardiac myocytes, which imparts adverse cardiac disease responses following injury. Thyroidectomy (TX) was used to establish MH. The progeny from mice that underwent sham or TX surgery were termed Ctrl (control) or MH (maternal hypothyroidism) progeny, respectively. MH progeny had similar heart weight (HW) to body weight (BW) ratios and larger CM size consistent with fewer CMs at postnatal day 60 (P60) compared with Ctrl (control) progeny. MH progeny had lower numbers of EdU+, Ki67+, and phosphorylated histone H3 (PH3)+ CMs, which suggests they had a decreased CM proliferation in the postnatal timeframe. RNA-seq data showed that genes related to DNA replication were downregulated in P5 MH hearts, including bone morphogenetic protein 10 (Bmp10). Both in vivo and in vitro studies showed Bmp10 treatment increased CM proliferation. After transverse aortic constriction (TAC), the MH progeny had more severe cardiac pathological remodeling compared with the Ctrl progeny. Thyroid hormone (T4) treatment for MH mothers preserved their progeny's postnatal CM proliferation capacity and prevented excessive pathological remodeling after TAC. Our results suggest that CM proliferation during early postnatal development was significantly reduced in MH progeny, resulting in fewer CMs with hypertrophy in adulthood. These changes were associated with more severe cardiac disease responses after pressure overload.NEW & NOTEWORTHY Our study shows that compared with Ctrl (control) progeny, the adult progeny of mothers who have MH (MH progeny) had fewer CMs. This reduction of CM numbers was associated with decreased postnatal CM proliferation. Gene expression studies showed a reduced expression of Bmp10 in MH progeny. Bmp10 has been linked to myocyte proliferation. In vivo and in vitro studies showed that Bmp10 treatment of MH progeny and their myocytes could increase CM proliferation. Differences in CM number and size in adult hearts of MH progeny were linked to more severe cardiac structural and functional remodeling after pressure overload. T4 (synthetic thyroxine) treatment of MH mothers during their pregnancy, prevented the reduction in CM number in their progeny and the adverse response to disease stress.

Early and accurate identification of patients with acute pancreatitis (AP) at high risk of persistent acute respiratory failure (PARF) is crucial. We sought to determine the accuracy of simplified Lung Injury Prediction Score (sLIPS) and simplified Early Acute Lung Injury (sEALI) for predicting PARF in ward AP patients. Consecutive AP patients in a training cohort from West China Hospital of Sichuan University (n = 912) and a validation cohort from The First Affiliated Hospital of Nanchang University (n = 1033) were analyzed. PARF was defined as oxygen in arterial blood/fraction of inspired oxygen < 300 mmHg that lasts for > 48 h. The sLIPS was composed by shock (predisposing condition), alcohol abuse, obesity, high respiratory rate, low oxygen saturation, high oxygen requirement, hypoalbuminemia, and acidosis (risk modifiers). The sEALI was calculated from oxygen 2 to 6 L/min, oxygen > 6 L/min, and high respiratory rate. Both indices were calculated on admission. PARF developed in 16

Background: Measuring intra-abdominal pressure (IAP) is important for management of patients with severe acute pancreatitis (SAP). Intra-bladder pressure (IBP) is an indirect index that reflects IAP, but measuring techniques vary. We sought to optimise IBP measuring techniques in predicted SAP patients.Methods: Predicted SAP patients consecutively admitted between June 2018 and January 2020 were scrutinised. Eligible patients had their IBP monitored for the first 72 h at 6-h intervals, and were then sequentially allocated into three research scenarios: (1) in the supine position along with head of bed elevation(HoBE)of 0, 15 and 30 degrees at various points including the iliac crest the midaxillary line, pubic symphysis, and right atrium level, instilled with 25 mL normal saline (NS) at room temperature (RT); (2) NS instillation volume from 0, 10, 25, 40-50 mL at the iliac crest with HoBE15 at RT; and (3) NS instillation (25 mL) at either RT or 37 degrees C with HoBE15.Results: The dynamic IBP values measured at the pubic symphysis and iliac crest were fairly similar between HoBE0 and HoBE15 (all P > 0.05), but greatly increased at HoBE30 (all P < 0.01). IBP was significantly increased with escalating instillation volumes of NS (all P < 0.01 versus 0 mL NS), while there was no significant difference between 25 mL and 10 mL (P = 0.055). IBP was similar between NS at RT and under 37 degrees C (P = 0.643).Conclusion: In predicted SAP patients, measuring IBP at the iliac crest with HoBE15 after instilling 10 mL of NS seems to be appropriate for monitoring IAP.(c) 2022 The Authors. Published by Elsevier B.V. on behalf of IAP and EPC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Acute pancreatitis is a common gastrointestinal disease with increasing incidence worldwide. COVID-19 is a potentially life-threatening contagious disease spread throughout the world, caused by severe acute respiratory syndrome coronavirus 2. More severe forms of both diseases exhibit commonalities with dysregulated immune responses resulting in amplified inflammation and susceptibility to infection. Human leucocyte antigen (HLA)-DR, expressed on antigen-presenting cells, acts as an indicator of immune function. Research advances have highlighted the predictive values of monocytic HLA-DR (mHLA-DR) expression for disease severity and infectious complications in both acute pancreatitis and COVID-19 patients. While the regulatory mechanism of altered mHLA-DR expression remains unclear, HLA-DR−/low monocytic myeloid-derived suppressor cells are potent drivers of immunosuppression and poor outcomes in these diseases. Future studies with mHLA-DR-guided enrollment or targeted immunotherapy are warranted in more severe cases of patients with acute pancreatitis and COVID-19.

IntroductionAlveolar epithelial regeneration depends on the activity of resident quiescent progenitor cells. Alveolar epithelial type II (AT2) cells are known as the alveolar epithelial progenitor cells. They exit quiescent state, proliferate rapidly in response to injury and differentiate into alveolar epithelial type I (AT1) cells to regenerate the damaged alveolar epithelium. Although AT2 cell plasticity has been a very intense field of research, the role of CD8 T cell response and their released cytokine IFN-γ, in regulating AT2 cell plasticity and alveolar epithelial repair and regeneration after injury remains largely unknown.MethodsWe used flow cytometry to quantify the amount of CD8 T cells in mouse lungs after bacterial pneumonia caused by Streptococcus pneumoniae. To determine whether CD8 T cells and their released cytokine IFN-γ are necessary for AT2 cell activity during alveolar epithelial regeneration, we performed loss of function studies using anti-CD8 or anti-IFN-γ monoclonal antibody (mAb) treatment in vivo. We assessed the effects of CD8 T cells and cytokine IFN-γ on AT2 cell differentiation capacity using the AT2- CD8 T cell co-culture system in vitro.ResultsWe detected a transient wave of accumulation of CD8 T cells in mouse lungs, which coincided with the burst of AT2 cell proliferation during alveolar epithelial repair and regeneration in mice following bacterial pneumonia caused by Streptococcus pneumoniae. Depletion of CD8 T cells or neutralization of cytokine IFN-γ using anti-CD8 or anti-IFN-γ monoclonal antibody significantly reduced AT2 cell proliferation and differentiation into AT1 cells in mice after bacterial pneumonia. Furthermore, co-culture of CD8 T cells or cytokine IFN-γ with AT2 cells promoted AT2-to-AT1 cell differentiation in both murine and human systems. Conversely, blockade of IFN-γ signaling abrogated the increase in AT2-to-AT1 cell differentiation in the AT2- CD8 T cell co-culture system.DiscussionOur data demonstrate that CD8 T-cell response and cytokine IFN-γ are necessary for promoting AT2 cell activity during alveolar epithelial repair and regeneration after acute lung injury caused by bacterial pneumonia.