Rspo1/Rspo3‐LGR4 signaling inhibits hepatic cholesterol synthesis through the AMPKα‐SREBP2 pathway

R‐spondins (Rspos) are endogenous ligands of leucine‐rich repeat‐containing G‐protein‐coupled receptor 4 (LGR4). Rspos‐LGR4 signaling plays important roles in embryogenesis, gastrointestinal homeostasis, and food intake. Here, we investigated the impacts of Rspos‐LGR4 on hepatic cholesterol synthesis. Rspo1/3 and Lgr4 knockdown mice were used to investigate the impacts of Rspo1/3‐LGR4 on hepatic cholesterol synthesis. AMPKα agonist, antagonist, and shRNA were used to explore the downstream targets of Rspos‐LGR4 signaling. In our study, we reported that LGR4, Rspo1, and Rspo3 were highly expressed in hepatocytes and their expressions were sensitive to energy states. Rspo1 and Rspo3 reversed OA‐induced cholesterol synthesis, accompanying with increased the phosphorylation of AMPKα Thr172, reduced SREBP2 nuclear translocation, and Srebf2 mRNA expression. Conversely, hepatic LGR4 knockdown increased hepatic cholesterol synthesis and decreased the phosphorylation of AMPKα both in vitro and in vivo. Activation or inhibition of AMPKα significantly abolished the effects of LGR4 deficiency or Rspos, respectively, on cholesterol synthesis. Knockdown of AMPKα1 or/and AMPKα2 repressed Rspos‐induced inhibition on cholesterol synthesis. Our study indicates that Rspo1/Rspo3‐LGR4 signaling in hepatocytes suppresses cholesterol synthesis via the AMPKα‐SREBP2 pathway.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163398/2/fsb221026.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163398/1/fsb221026_am.pd

Development and validation of case-finding algorithms for recurrence of breast cancer using routinely collected administrative data

Introduction Recurrence free survival is frequently investigated in cancer outcome studies, however is not explicitly documented in cancer registry data that is widely used for research. Patterns of events after initial treatment such as oncology visits, re-operation, chemotherapy or radiation may herald recurrence. Objectives and Approach This study aimed to develop and validate algorithms for identifying breast cancer recurrence using large administrative data.Two cohorts with high recurrence rates were used: 1) all young (≤ 40 years) breast cancer patients (2007-2010), and 2) all neoadjuvant chemotherapy patients (2012-2014) in Alberta, Canada. Health events after primary treatment were obtained from the Alberta cancer registry, physician billing claims, and vital statistics databases. Positive recurrence status (defined as either locoregional, distant or both) was ascertained by primary chart review. The cohort was divided into a developing (60%) and validating (40%) set. Development of algorithms geared towards high sensitivity, PPV and accuracy respectively were performed using classification and regression tree (CART) models. Key variables in the models included: a new round of chemotherapy, a second mastectomy, and a new cluster of radiologist, oncologist or general surgeon visits occurring after the primary treatment. Compared with chart review data, the sensitivity, specificity, PPV, NPV and accuracy of the algorithms were calculated. Results Of 606 patients, 121 (20%) had recurrence after a median follow-up 4 years. The high sensitivity algorithm had 94.2% (95% CI: 90.1-98.4%) sensitivity, 92.8% (90.5-95.1%) specificity, 76.5% (70.0-88.3%) PPV, 98.5% (97.3-99.6%) NPV and 93.1% (91.0-95.1%) accuracy. The high PPV algorithm had 74.4% (66.6-82.2%) sensitivity, 97.8% (96.5-99.2%) specificity, 90.0% (84.1-95.9%) PPV, 93.6% (91.4-95.7%) NPV and 92.9% (90.9-95.0%) accuracy. The high accuracy algorithm had 88.4% (82.7-94.1%) sensitivity, 97.1% (95.6-98.6%) specificity, 88.4% (82.7-94.1%) PPV, 97.1% (95.6-98.6%) NPV and 95.4% (93.7-97.1%) accuracy. Conclusion/Implications The proposed algorithms achieved favourably high validity for identifying recurrence using widely available administrative data. Further study may be needed for improving sensitivity and PPV, and validating the algorithms in larger data for widespread use

Abnormal glucose metabolism in virus associated sepsis

Sepsis is identified as a potentially lethal organ impairment triggered by an inadequate host reaction to infection (Sepsis-3). Viral sepsis is a potentially deadly organ impairment state caused by the host’s inappropriate reaction to a viral infection. However, when a viral infection occurs, the metabolism of the infected cell undergoes a variety of changes that cause the host to respond to the infection. But, until now, little has been known about the challenges faced by cellular metabolic alterations that occur during viral infection and how these changes modulate infection. This study concentrates on the alterations in glucose metabolism during viral sepsis and their impact on viral infection, with a view to exploring new potential therapeutic targets for viral sepsis

Hyperforin Promotes Post-stroke Neuroangiogenesis via Astrocytic IL-6-Mediated Negative Immune Regulation in the Ischemic Brain

Hyperforin has been shown to be capable of promoting angiogenesis and functional recovery after ischemic stroke in our previous study. However, the exact mechanisms involved are not fully elucidated. In this study, adult male mice were subjected to 60-min transient middle cerebral artery occlusion followed by reperfusion for 28 days. Hyperforin was administrated to MCAO mice every 24 h for 2 weeks starting at 14 days post-ischemia (dpi). Then flow cytometry, quantitative Real-time PCR (RT-qPCR), western blotting, immunohistochemistry, and functional assays were performed to explore the molecular mechanisms in vivo and in vitro. Our data showed that hyperforin increased astrocytic interleukin (IL)-6 in the ischemic hemisphere via TLR4 at 28 dpi. The astrocytic IL-6 was essential to the promoting effects of hyperforin on the neural precursor cells proliferation, neuronal differentiation, angiogenesis, and functional recovery after stroke. Furthermore, hyperforin promoted the infiltration of regulatory T cells (Tregs) to the ischemic hemisphere and increased Tregs-derived cytokine IL-10 and transforming growth factor-β (TGF-β) in a manner that was dependent on astrocytic IL-6. Astrocytic IL-6 was critical to the role of hyperforin in promoting the infiltration of T-helper (Th) type 2 cells to the ischemic hemisphere and Th2-derived cytokine IL-4, relative to Th1 and Th1-derived cytokine interferon-γ (IFN-γ), which decreased during stroke recovery. After depletion of CD25+ Tregs, the promoting effects of hyperforin on post-stroke neurogenesis was attenuated. Moreover, blockade of IL-4 and TGF-β abrogated the promoting role of hyperforin in post-stroke neurogenesis, angiogenesis and functional recovery. Our results reveal a previously uncharacterized role of astrocytic IL-6-mediated negative immune regulation in the promoting effects of hyperforin on post-stroke neurovascular regeneration and functional recovery

Developing and validating a nomogram for cognitive impairment in the older people based on the NHANES

ObjectiveTo use the United States National Health and Nutrition Examination Study (NHANES) to develop and validate a risk-prediction nomogram for cognitive impairment in people aged over 60 years.MethodsA total of 2,802 participants (aged ≥ 60 years) from NHANES were analyzed. The least absolute shrinkage and selection operator (LASSO) regression model and multivariable logistic regression analysis were used for variable selection and model development. ROC-AUC, calibration curve, and decision curve analysis (DCA) were used to evaluate the nomogram’s performance.ResultsThe nomogram included five predictors, namely sex, moderate activity, taste problem, age, and education. It demonstrated satisfying discrimination with a AUC of 0.744 (95% confidence interval, 0.696–0.791). The nomogram was well-calibrated according to the calibration curve. The DCA demonstrated that the nomogram was clinically useful.ConclusionThe risk-prediction nomogram for cognitive impairment in people aged over 60 years was effective. All predictors included in this nomogram can be easily accessed from its’ user

Development and validation of a nomogram for the risk prediction of malignant cerebral edema after acute large hemispheric infarction involving the anterior circulation

BackgroundMalignant cerebral edema (MCE) is a life-threatening complication of large hemisphere infarction (LHI). Therefore, a fast, accurate, and convenient tool for predicting MCE can guide triage services and facilitate shared decision-making. In this study, we aimed to develop and validate a nomogram for the early prediction of MCE risk in acute LHI involving the anterior circulation and to understand the potential mechanism of MCE.MethodsThis retrospective study included 312 consecutive patients with LHI from 1 January 2019 to 28 February 2023. The patients were divided into MCE and non-MCE groups. MCE was defined as an obvious mass effect with ≥5 mm midline shift or basal cistern effacement. Least absolute shrinkage and selection operator (LASSO) and logistic regression were performed to explore the MCE-associated factors, including medical records, laboratory data, computed tomography (CT) scans, and independent clinic risk factors. The independent factors were further incorporated to construct a nomogram for MCE prediction.ResultsAmong the 312 patients with LHI, 120 developed MCE. The following eight factors were independently associated with MCE: Glasgow Coma Scale score (p = 0.007), baseline National Institutes of Health Stroke Scale score (p = 0.006), Alberta Stroke Program Early CT Score (p < 0.001), admission monocyte count (p = 0.004), white blood cell count (p = 0.002), HbA1c level (p < 0.001), history of hypertension (p = 0.027), and history of atrial fibrillation (p = 0.114). These characteristics were further used to establish a nomogram for predicting prognosis. The nomogram achieved an AUC-ROC of 0.89 (95% CI, 0.82–0.96).ConclusionOur nomogram based on LASSO-logistic regression is accurate and useful for the early prediction of MCE after LHI. This model can serve as a precise and practical tool for clinical decision-making in patients with LHI who may require aggressive therapeutic approaches

PRIMA-1Met suppresses colorectal cancer independent of p53 by targeting MEK

This work was supported by Grant No. 81201779 (Hua Xiong) from the National Natural Science Youth Foundation; Grant No. 81502118 (Yanmei Zou) from the National Natural Science Youth Foundation; Grant No. 2014CFB250 (Yanmei Zou) from the Natural Science Foundation of Hubei Province; Grant No. 81372434 (Huihua Xiong) from the National Natural Science Foundation.PRIMA-1Met is the methylated PRIMA-1 (p53 reactivation and induction of massive apoptosis) and could restore tumor suppressor function of mutant p53 and induce p53 dependent apoptosis in cancer cells harboring mutant p53. However, p53 independent activity of PRIMA-1Met remains elusive. Here we reported that PRIMA-1Met attenuated colorectal cancer cell growth irrespective of p53 status. Kinase profiling revealed that mitogen-activated or extracellular signal-related protein kinase (MEK) might be a potential target of PRIMA-1Met. Pull-down binding and ATP competitive assay showed that PRIMA-1Met directly bound MEK in vitro and in cells. Furthermore, the direct binding sites of PRIMA-1Met were explored by using a computational docking model. Treatment of colorectal cancer cells with PRIMA-1Met inhibited p53-independent phosphorylation of MEK, which in turn impaired anchorage-independent cell growth in vitro. Moreover, PRIMA-1Met suppressed colorectal cancer growth in xenograft mouse model by inhibiting MEK1 activity. Taken together, our findings demonstrate a novel p53-independent activity of PRIMA-1Met to inhibit MEK and suppress colorectal cancer growth.Publisher PDFPeer reviewe

BML-111 Reduces Neuroinflammation and Cognitive Impairment in Mice With Sepsis via the SIRT1/NF-κB Signaling Pathway

Sepsis is a life-threatening state of organ dysfunction caused by infection and which can induce severe neurological disorders that lead to neuroinflammation and cognitive impairment. Inflammation has been reported to cause neuronal apoptosis in sepsis, which can finally lead to cognitive impairment. Previous studies have suggested that BML-111 can exhibit anti-inflammatory and proresolution activities. Additionally, silent information regulator 1 (SIRT1) can inhibit the NF-κB signaling pathway in an inflammation state. However, the role of the SIRT1/NF-κB signaling pathway in the protective effects of BML-111 against sepsis-induced neuroinflammation and cognitive impairment remains unclear. This study aimed to determine the effects of BML-111 on neuroinflammation and cognitive impairment induced by sepsis. Male C57BL/6J mice were subjected to cecal ligation and puncture (CLP) or a sham operation. BML-111 was administered via intracerebroventricular injection (0.1 mg/kg) immediately after CLP. Boc-2 (50 μg/kg) was administered intracerebroventricularly 30 min before CLP, and EX527 (10 μg) was administered every 2 days for a total of three times before CLP, also intracerebroventricularly. Some of the surviving mice underwent open-field, novel-object-recognition, and fear-conditioning behavioral tests at 7 days after surgery. Some of the other surviving mice were killed at 24 h after surgery to assess synaptic damage (PSD95 and Synapsin1), markers of inflammation [tumor necrosis factor alpha (TNF-α) and interleukin (IL)-1β], cytoplasmic p65, nuclear p65, Ac- NF-κB and SIRT1. At 48 h after CLP, TUNEL and glia-activation by immunofluorescence investigations were performed on a separate cohort of surviving animals. The results suggested that sepsis resulted in cognitive impairment, which was accompanied by the decreased the expression of PSD95 and Synapsin1, increased amount of TUNEL-positive cells and the activation of glias, increased production of TNF-α and IL-1β, increased expression of nuclear p65, Ac- NF-κB, and decreased expression of SIRT1 and cytoplasmic p65. It is especially notable that these abnormalities could be reduced by BML-111 treatment. EX527, an SIRT1 inhibitor, abolished the effects of BML-111. These results demonstrate that BML-111 can reduce the neuroinflammation and cognitive impairment induced by sepsis via SIRT/NF-κB signaling pathway