Glutamine supplementation alleviated aortic atherosclerosis in mice model and in vitro.

This study aimed to clarify the role of glutamine in atherosclerosis and its participating mechanism. Forty C57BL/6J mice were divided into wild control (wild Con), ApoE- /- control (ApoE- /- Con), glutamine + ApoE- /- control (Glut + ApoE- /- Con), ApoE- /- high fat diet (ApoE- /- HFD), and glutamine + ApoE- /- HFD (Glut + ApoE- /- HFD) groups. The degree of atherosclerosis, western blotting, and multiomics were detected at 18 weeks. An in vitro study was also performed. Glutamine treatment significantly decreased the degree of aortic atherosclerosis (p = 0.03). O-GlcNAcylation (O-GlcNAc), IL-1ß, IL-1α, and pyruvate kinase M2 (PKM2) in the ApoE- /- HFD group were significantly higher than those in the ApoE- /- Con group (p < 0.05). These differences were attenuated by glutamine treatment (p < 0.05), and aggravated by O-GlcNA transferase (OGT) overexpression in the in vitro study (p < 0.05). Multiomics showed that the ApoE- /- HFD group had higher levels of oxidative stress regulatory molecules (guanine deaminase [GUAD], xanthine dehydrogenase [XDH]), proinflammatory regulatory molecules (myristic acid and myristoleic acid), and stress granules regulatory molecules (caprin-1 and deoxyribose-phosphate aldolase [DERA]) (p < 0.05). These differences were attenuated by glutamine treatment (p < 0.05). We conclude that glutamine supplementation might alleviate atherosclerosis through downregulation of O-GlcNAc, glycolysis, oxidative stress, and proinflammatory pathway.

Activation of macrophage TBK1-HIF-1α-mediated IL-17/IL-10 signaling by hyperglycemia aggravates the complexity of coronary atherosclerosis: An in vivo and in vitro study.

Our purpose was to study the effect of hyperglycemia on macrophage TBK1-HIF-1α-mediated IL-17/IL-10 signaling and its correlation with coronary atherosclerosis. A total of 135 patients with coronary heart disease (CHD) were divided into a stable CHD (SCHD) group (n = 30) and an acute myocardial infarction (AMI) group (n = 105) [nondiabetes mellitus (non-DM)-AMI, n = 60; DM-AMI, n = 45] from January to September 2020. The SYNTAX score and metabolic and inflammatory markers were quantified and compared. THP-1 cell studies and an animal study of coronary intimal hyperplasia were also carried out. We found that the DM-AMI group showed a higher SYNTAX score than the non-DM-AMI group (P < .05). The DM-AMI group showed the highest expression levels of TANK-binding kinase 1 (TBK1), hypoxia-inducible factor 1α (HIF-1α), and interleukin (IL)-17 and the lowest expression level of IL-10, followed by the non-DM-AMI group and the SCHD group (P < .05). THP-1 cell studies showed that BAY87-2243 (a HIF-1α inhibitor) reversed the increase in IL-17 and decrease in IL-10 expression induced by hyperglycemia. Amlexanox (a TBK1 inhibitor) reversed the increase in HIF-1α expression induced by hyperglycemia. Amlexanox treatment resulted in lower coronary artery intimal hyperplasia and a larger lumen area in a diabetic swine model. We conclude that hyperglycemia might aggravate the complexity of coronary atherosclerosis through activation of TBK1-HIF-1α-mediated IL-17/IL-10 signaling. Thus, TBK1 may be a novel drug therapy target for CHD complicated with DM.

"One-step" approach versus "Step-up" approach minimally invasive treatment for infected pancreatic necrosis: a study protocol for a single-center, prospective, randomized controlled trial.

BACKGROUND: Currently, the minimally invasive "Step-up" surgical strategy is still the main treatment for infected pancreatic necrosis (IPN). However, indiscriminate implementation of the "Step-up" strategy can lead to increased numbers of operations and prolonged hospital stay. The "Step-up" approach is not appropriate for some patients due to unavailabilty of a safe puncture path. Therefore, we developed the "One-step" surgical approach to treat IPN, which is safety. However, there is still a lack of comparison of the short and long-term efficacy between the "One-step" and "Step-up" approach. Consequently, we are conducting this clinical trial to provide a reference for IPN treatment. METHODS: This is an ongoing, single-center, randomized controlled trial of patients with IPN. The total sample size required for the trial (May 2021-December 2023) is approximately 128 patients. Patients will be randomly assigned to either an experimental group (One-step) or a control group (Step-up) at a ratio of 1:1 using the block randomization method. We used the case report forms and electronic data capture systems to obtain demographic information, preoperative laboratory examination, auxiliary examination results, surgery data, postoperative recovery outcomes, and follow-up outcomes. The patients will be followed up for 2 years after surgery. The primary endpoint is a composite endpoint, consisting of mortality and severe complications. The secondary endpoints include the incidence of organ dysfunction, the number of surgical procedures, mortality (the incidence of death in hospital and deaths within 30 days of discharge), hospital stay, intensive care unit stay, hospitalization costs, perioperative inflammatory marker changes, and short-and long-term complications. DISCUSSION: Compared with the "Step-up," the "One-step" minimally invasive surgery can significantly reduce the number of operations, reduce the length of hospital stay and hospitalization costs without increasing the incidence of composite endpoint events, and has better short- and long-term efficacy and safety. Additionally, there was no statistically significant difference in perioperative complications and mortality between "Step-up" and "One-step". This study will assist with the formulation of an effective and scientific "One-step" minimally invasive treatment strategy for IPN, and an understanding of this technique will facilitate clinical decision-making for IPN. Trial Registration ChiCTR2100044348. Trial status: Ongoing.

RETRACTED: Loss of microRNA-30e induced by extracellular vesicles from cancer-associated fibroblasts promotes breast cancer progression by binding to CTHRC1.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the authors as "some data in this study are not solid enough and need to be further explored". The authors stated that they "found abnormalities in the re-identification of CAF-EVs, the extracted extracellular vesicles may be polluted and the elliptical structure under electron microscope is not owned by CAF-EVs. The identification of CAF-EVs by Western Blots did not refer to the definition of international society." The authors informed the journal that, after the re-experiment, they found that "there is no vesicle specific protein expression, whether the results of subsequent experiments are generated by CAF-EVs needs to be re-tested".

Mst1 overexpression combined with Yap knockdown augments thyroid carcinoma apoptosis via promoting MIEF1-related mitochondrial fission and activating the JNK pathway.

BACKGROUND: Cancer cell viability is strongly modulated by the Hippo pathway, which includes mammalian STE20-like protein kinase 1 (Mst1) and yes-associated protein (Yap). Although the roles of Mst1 and Yap in thyroid carcinoma cell death have been fully addressed, no study has determined whether differential modification of Mst1 and Yap could further suppress thyroid carcinoma progression. The aim of our study was to explore the antiapoptotic effects exerted by combined Mst1 overexpression and Yap knockdown in thyroid carcinoma MDA-T32 cells in vitro. METHODS: Mst1 adenovirus and Yap shRNA were transfected into MDA-T32 cells to overexpress Mst1 and inhibit Yap, respectively. Cell viability and death were determined via an MTT assay, a TUNEL assay and western blotting. Mitochondrial function, mitochondrial fission and pathway studies were performed via western blotting and immunofluorescence. RESULTS: The results of our study showed that combined Mst1 overexpression and Yap knockdown further augmented MDA-T32 cell death by mediating mitochondrial damage. In addition, cancer cell migration and proliferation were suppressed by combined Mst1 overexpression and Yap knockdown. At the molecular level, mitochondrial membrane potential, ATP production, respiratory function, and caspase-9-related apoptosis were activated by combined Mst1 overexpression and Yap knockdown. Further, we found that fatal mitochondrial fission was augmented by combined Mst1 overexpression and Yap knockdown in a manner dependent on the JNK-MIEF1 pathway. Inhibition of JNK-MIEF1 pathway activity abolished the proapoptotic effects exerted by Mst1/Yap on MDA-T32 cells. CONCLUSIONS: Taken together, our data suggest that Mst1 activation and Yap inhibition coordinate to augment thyroid cancer cell death by controlling the JNK-MIEF1-mitochondria pathway, suggesting that differential regulation of the core Hippo pathway components is potentially a novel therapeutic tool for the treatment of thyroid cancer.

Silencing pancreatic adenocarcinoma upregulated factor (PAUF) increases the sensitivity of pancreatic cancer cells to gemcitabine.

Pancreatic adenocarcinoma upregulated factor (PAUF) is a new oncogene that activates signaling pathways that play a critical role in resistance to gemcitabine. We thus speculated that PAUF also plays a role in resistance to gemcitabine of pancreatic cancer cells. We established BxPC-3 cell lines with stable PAUF knockdown (BxPC-3_shPAUF) and controls (BxPC-3_shCtrl) and evaluated sensitivity to gemcitabine in vitro by MTT and flow cytometry. We established a xenograft model of human pancreatic cancer to examine PAUF function in gemcitabine resistance in vivo. Gene chip microarrays were performed to identify differentially expressed genes in BxPC-3_shPAUF and BxPC-3_shCtrl cells. Silencing PAUF increased the sensitivity of BxPC-3 cells to gemcitabine in vitro and in vivo. PAUF-knockdown BxPC-3 cell lines treated with gemcitabine showed increased proliferation inhibition and apoptosis compared with controls. Gemcitabine exhibited a more pronounced effect on reduction of BxPC-3_shPAUF tumors than BxPC-3_shCtrl tumors. Terminal deoxynucleotidyl transferase dUTP Nick-End Labeling (TUNEL) assays confirmed a significantly higher apoptotic rate of BXPC-3_shPAUF tumors compared with BXPC-3_shCtrl tumors. Gene array showed that PAUF function in gemcitabine sensitivity might involve MRP2, MRP3, MDR1, PIK3R1, and NFkB2 genes. PAUF could be considered as a key molecular target for sensitizing pancreatic cancer cells to gemcitabine.

Indoleamine 2,3-dioxygenase is upregulated in the brain of rats with acute pancreatitis.

BACKGROUND: Acute pancreatitis (AP) has an effect on both inflammatory/autoimmune processes and psychological states, but the pathophysiological causes of pancreatic encephalopathy in the brain are unclear. We hypothesized that the peripheral immune/inflammatory response during AP can affect indolamine 2,3-dioxygenase (IDO) expression and serotonin content in the brain. METHODS: About 210 male Sprague Dawley rats were randomly divided into five groups: control (0 h) and 6 h, 24 h, 48 h and 72 h experimental groups. Acute pancreatitis was induced by an injection of a sodium taurocholate solution via a cannulated bile-pancreatic duct. We measured the plasma TNF-α and IL-6 levels; serotonin, 5-HIAA and the protein concentration levels of IDO and monoamine oxidase A (MAO-A) were evaluated in the striatum, hippocampus and left prefrontal cortex. RESULTS: The IL-6 and the TNF-α levels increased in the 24 h, 48 h and 72 h groups. The IDO concentrations of both the 72 h group in the hippocampus and 48 h, 72 h groups in the prefrontal cortex increased; in the corpus striatum, the IDO concentrations fluctuated without statistical significance. The MAO-A protein concentration of the 6 h and 24 h groups decreased in the striatum, hippocampus and prefrontal cortex. There were no statistically significant differences found in the serotonin and 5-HIAA concentrations. CONCLUSIONS: During the process of AP, cytokines, such as IL-6 and TNF-α, may play a role in activation of neuronal pathways utilizing the metabolic enzyme IDO, which may play an important role in determining the mental symptomatology accompanying AP.

Research progress of acute coagulopathy of trauma-shock.

Acute coagulopathy of trauma-shock (ACoTS) occurs in 25% of patients with severe trauma in the early phase, and the mortality of those patients is four-fold higher than patients without coagulopathy. The pathophysiology of this complicated phenomenon has been focused on in recent years. Tissue injury and hypoperfusion, activated protein C and Complements play important roles in the early phase after trauma. While the use of blood products, hypothermia, acidosis and inflammation are the main mechanism in late phase. Supplementing coagulation factors and platelets to improve ACoTS are inefficient. Only positive resuscitation from shock and improving tissue hypoperfusion have expected benefits.

Analysis on the risk factors of intracranial infection secondary to traumatic brain injury.

OBJECTIVE: To discuss the characteristics and risk factors for intracranial infection post traumatic brain injury to prevent and better the clinical care. METHODS: Retrospective study of 520 patients with traumatic brain injury were included, 308 male and 212 female. The risky factors of intracranial infection were identified. RESULTS: Thirty two cases (6.54%, 32/520) of intracranial infection were diagnosed. Intracranial infection most likely happened 4-10 days after injury. Cerebrospinal fluid leakage, drainage, multiple craniotomies were significant related to intracranial infection. Logistic regression predicted cerebrospinal fluid leakage and drainage as independent factors. CONCLUSION: Intracranial infection is a serious complication after traumatic brain injury. Patients with drainage or cerebrospinal fluid leakage are more risky for intracranial infection. Aggressive precaution should be taken to better outcome.