CPT1A-IL-10-mediated macrophage metabolic and phenotypic alterations ameliorate acute lung injury.

BACKGROUND: Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a common acute respiratory failure due to diffuse pulmonary inflammation and oedema. Elaborate regulation of macrophage activation is essential for managing this inflammatory process and maintaining tissue homeostasis. In the past decades, metabolic reprogramming of macrophages has emerged as a predominant role in modulating their biology and function. Here, we observed reduced expression of carnitine palmitoyltransferase 1A (CPT1A), a key rate-limiting enzyme of fatty acid oxidation (FAO), in macrophages of lipopolysaccharide (LPS)-induced ALI mouse model. We assume that CPT1A and its regulated FAO is involved in the regulation of macrophage polarization, which could be positive regulated by interleukin-10 (IL-10). METHODS: After nasal inhalation rIL-10 and/or LPS, wild type (WT), IL-10-/-, Cre-CPT1Afl/fl and Cre+CPT1Afl/fl mice were sacrificed to harvest bronchoalveolar lavage fluid, blood serum and lungs to examine cell infiltration, cytokine production, lung injury severity and IHC. Bone marrow-derived macrophages (BMDMs) were extracted from mice and stimulated by exogenous rIL-10 and/or LPS. The qRT-PCR, Seahorse XFe96 and FAO metabolite related kits were used to test the glycolysis and FAO level in BMDMs. Immunoblotting assay, confocal microscopy and fluorescence microplate were used to test macrophage polarization as well as mitochondrial structure and function damage. RESULTS: In in vivo experiments, we found that mice lacking CPT1A or IL-10 produced an aggravate inflammatory response to LPS stimulation. However, the addition of rIL-10 could alleviate the pulmonary inflammation in mice effectively. IHC results showed that IL-10 expression in lung macrophage decreased dramatically in Cre+CPT1Afl/fl mice. The in vitro experiments showed Cre+CPT1Afl/fl and IL-10-/- BMDMs became more "glycolytic", but less "FAO" when subjected to external attacks. However, the supplementation of rIL-10 into macrophages showed reverse effect. CPT1A and IL-10 can drive the polarization of BMDM from M1 phenotype to M2 phenotype, and CPT1A-IL-10 axis is also involved in the process of maintaining mitochondrial homeostasis. CONCLUSIONS: CPT1A modulated metabolic reprogramming and polarisation of macrophage under LPS stimulation. The protective effects of CPT1A may be partly attributed to the induction of IL-10/IL-10 receptor expression.

Angiotensin II type 2 receptor agonist attenuates LPS-induced acute lung injury through modulating THP-1-derived macrophage reprogramming.

Acute respiratory distress syndrome (ARDS) is a devastating respiratory disorder, characterized by overwhelming inflammation in the alveoli without effective pharmacological treatment. We aimed to investigate the effect and mechanism of angiotensin II type 2 receptor (AT2R) agonist, Compound 21 (C21), on the lipopolysaccharide (LPS)-induced acute lung injury (ALI) model. The protective effect of C21 was evaluated via enzyme-linked immunosorbent assay (ELISA), Western blot (WB), real-time PCR, and fluorescence microscopy in LPS-challenged THP1-derived macrophages. Besides, the in vivo efficacy of C21 was assessed using cell counting, ELISA, protein quantification, hematoxylin-eosin (H&E) staining, and WB in an LPS-induced ALI mouse model. The results showed that C21 significantly inhibited the secretion of pro-inflammatory cytokines (CCL-2, IL-6), overproduction of intracellular ROS, and activation of inflammatory pathways (NF-κB/NLRP3, p38/MAPK) in THP-1 cell-derived macrophages stimulated by LPS. In in vivo study, intraperitoneal injection of C21 could reduce airway leukocytes accumulation and chemokine/cytokine (keratinocyte chemoattractant (KC), IL-6) generation, as well as alleviate diffuse alveolar damage induced by LPS. Conclusively, the AT2R agonist C21 significantly inhibited LPS-stimulated excess inflammatory responses and oxidative stress in macrophages. Meanwhile, C21 could effectively alleviate acute inflammation and tissue damage in the lungs of ALI mice challenged by LPS. The results of this study bring new hope for the early treatment of ALI/ARDS.

Dopamine D1 receptor agonist alleviates acute lung injury via modulating inflammatory responses in macrophages and barrier function in airway epithelial cells.

Acute lung injury (ALI) or its severe form, acute respiratory distress syndrome (ARDS) is a life-threatening illness without effective therapeutic interventions currently. Multiple lines of evidence indicated that overwhelming inflammatory responses and impaired epithelial barrier contributed to the pathogenesis of ALI/ARDS. Recently, dopamine (DA) system was identified to participate in various pulmonary diseases. Here, we discovered that dopamine D1-like receptors mainly expressed in macrophages and airway epithelial cells (AECs), which were downregulated by lipopolysaccharide (LPS) challenge in ALI mouse lung. SKF38393 (SKF) is a selective agonist for D1-like receptors and was demonstrated to inhibit excessive inflammatory responses and oxidative stress in THP-1 cell-derived macrophages and Beas-2B cells, as well as improve airway epithelial barrier dysfunction induced by LPS stimulation. Moreover, SKF administration could effectively decrease pulmonary inflammation, ameliorate tissue damage in the LPS-triggered ALI mice. The broad protective actions of SKF might be attributed to the activation of Nrf2 antioxidative system by use of the specific inhibitor, ML385. This study offers evidence of potent immunoregulatory activity of SKF in macrophages, AECs as well as ALI mouse model, which opens novel therapeutic avenues for the intervention of ALI/ARDS.

L-carnitine reduces acute lung injury via mitochondria modulation and inflammation control in pulmonary macrophages

Acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) is a critical respiratory syndrome with limited effective interventions. Lung macrophages play a critical role in the pathogenesis of abnormal inflammatory response in the syndrome. Recently, impaired fatty acid oxidation (FAO), one of the key lipid metabolic signalings, was found to participate in the onset and development of various lung diseases, including ALI/ARDS. Lipid/fatty acid contents within mouse lungs were quantified using the Oil Red O staining. The protective effect of FAO activator L-carnitine (Lca, 50, 500, or 5 mg/mL) was evaluated by cell counting kit 8 (CCK-8) assay, real-time quantitative PCR (qPCR), ELISA, immunoblotting, fluorescence imaging, and fluorescence plate reader detection in lipopolysaccharide (LPS) (100 ng/mL)-stimulated THP-1-derived macrophages. The in vivo efficacy of Lca (300 mg/kg) was determined in a 10 mg/kg LPS-induced ALI mouse model. We found for the first time that lipid accumulation in pulmonary macrophages was significantly increased in a classical ALI murine model, which indicated disrupted FAO induced by LPS. Lca showed potent anti-inflammatory and antioxidative effects on THP-1 derived macrophages upon LPS stimulation. Mechanistically, Lca was able to maintain FAO, mitochondrial activity, and ameliorate mitochondrial dynamics. In the LPS-induced ALI mouse model, we further discovered that Lca inhibited neutrophilic inflammation and decreased diffuse damage, which might be due to the preservation of mitochondrial homeostasis. These results broadened our understanding of ALI/ARDS pathogenesis and provided a promising drug candidate for this syndrome.

ATRX status in patients with gliomas: Radiomics analysis.

MATERIAL AND METHODS: A cohort of 123 patients diagnosed with gliomas (World Health Organization grades II-IV) who underwent surgery and was treated at our center between January 2016 and July 2020, was enrolled in this retrospective study. Radiomics features were extracted from MR T1WI, T2WI, T2FLAIR, CE-T1WI, and ADC images. Patients were randomly split into training and validation sets at a ratio of 4:1. A radiomics signature was constructed using the least absolute shrinkage and selection operator (LASSO) to train the SVM model using the training set. The prediction accuracy and area under curve and other evaluation indexes were used to explore the performance of the model established in this study for predicting the ATRX mutation state. RESULTS: Fifteen radiomic features were selected to generate an ATRX-associated radiomic signature using the LASSO logistic regression model. The area under curve for ATRX mutation (ATRX(-)) on training set was 0.93 (95% confidence interval [CI]: 0.87-1.0), with the sensitivity, specificity and accuracy being 0.91, 0.82 and 0.88, while on the validation set were 0.84 (95% CI: 0.63-0.91), with the sensitivity, specificity and accuracy of 0.73, 0.86, and 0.79, respectively. CONCLUSIONS: These results indicate that radiomic features derived from preoperative MRI facilitat efficient prediction of ATRX status in gliomas, thus providing a novel evaluation method for noninvasive imaging biomarkers.

The Acute Toxicities and Efficacy of Concurrent Chemotherapy With Docetaxel Plus Cisplatin, or Docetaxel, or Cisplatin and Helical Tomotherapy in Patients With Locoregionally Advanced Nasopharyngeal Carcinoma: A Randomized Single-Center Phase II Trial.

Objective: The objective of this trial is to evaluate and compare the acute toxicity in patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) treated with docetaxel plus cisplatin, or docetaxel, or cisplatin concurrently with helical tomotherapy during concurrent chemoradiotherapy (CCRT). Methods: In a prospective, single-center, open-label, randomized phase II study, after 2 cycles of induction chemotherapy with docetaxel plus cisplatin regimen, 125 patients with LA-NPC (stage III and IVA, UICC eighth) diagnosed pathologically from June 2017 to November 2019 were randomized into CCRT with docetaxel plus cisplatin group (25 patients), CCRT with docetaxel group (50 patients), and CCRT with cisplatin group (50 patients). The incidence of grade 3 or 4 acute toxicities and clinical efficacy were analyzed among the 3 groups. Results: Safety evaluation was completed in all the 125 patients, during the CCRT period, 66.4% of patients completed 3 cycles of chemotherapy, 24.0% completed 2 cycles of chemotherapy, and 9.6% completed 1 cycle of chemotherapy according to the research plan. The incidence of grade 3 or 4 acute toxicity in CCRT with docetaxel plus cisplatin (DP), docetaxel (D), and cisplatin (P) groups was 88.0%, 72.0%, and 56.0%, respectively. The incidence of grade 3 or 4 acute toxicities in the DP group was significantly higher than that in the D and P groups (P = .015), no significant difference was detected between the D and P groups (P = .096). The most common toxicities were mucositis (40.0%), leukopenia (29.6%), neutropenia (26.4%), and pharyngo-esophagitis (12.0%); compared to D and P groups, DP group did not significantly improved the 3-year overall survival (96.0% vs 87.0% and 87.6%), progression-free survival (92.0% vs 79.7% and,76.9%), locoregional failure-free survival (96.0% vs 91.8% and 92.7%), and distant failure-free survival (100% vs 90.0% and 89.0%), there were no significant difference in survival data among the 3 groups (all P > .05). Conclusions: Higher survival benefits did not achieve from intensified CCRT with DP, CCRT with P or D obtained similar short-term survival outcomes with similar acceptable toxicities in LA-NPC patients.

Relapsing cerebral atypical teratoid/rhabdoid tumor after trimodality therapy: A case report.

INTRODUCTION: Atypical teratoid rhabdoid tumor (AT/RT) is a high-grade embryonal malignant neoplasm of the central nervous system. It is rare and most often diagnosed in children <4 years of age. The biological manifestations of AT/RTs are highly malignant and have a very poor prognosis. Here, we present the case of a 16-year-old boy with AT/RT in the right parietal lobe and with a dismal outcome. PATIENT CONCERNS: A 16-year-old male boy presented with a headache after waking up for 1 year without obvious cause. The pain was persistent and dull, mainly in the right orbital, and was slightly relieved after pressing the orbital. Occasionally, nausea and vomiting occurred, and the vomiting was gastric contents. Examination and head computed tomography performed at a local hospital revealed a space-occupying lesion in the right parietal lobe. The patient was then transferred to our hospital for further diagnosis and treatment. DIAGNOSIS: The patient underwent craniotomy and gross total excision of the tumor. Further histologic examination of the tumor was identified (space-occupying lesion in the right parietal lobe) AT/RT, World Health Organization grade IV. INTERVENTIONS: The patient was transferred to the oncology department for radiotherapy and chemotherapy after surgery recovery. OUTCOMES: The patient did not comply with the advice for adjuvant chemotherapy regularly and the tumor recurred rapidly. Finally, the patient died after 18 months after the definitive surgery. CONCLUSION: In conclusion, in the presence of a tumor with peripheral cystic components or hemorrhage in young children, a diagnosis of AT/RT must always be considered. Patients must follow the doctor's advice for active treatment. All relevant data are within the paper and its Supporting Information files.

Carnitine Palmitoyltransferase System: A New Target for Anti-Inflammatory and Anticancer Therapy?

Lipid metabolism involves multiple biological processes. As one of the most important lipid metabolic pathways, fatty acid oxidation (FAO) and its key rate-limiting enzyme, the carnitine palmitoyltransferase (CPT) system, regulate host immune responses and thus are of great clinical significance. The effect of the CPT system on different tissues or organs is complex: the deficiency or over-activation of CPT disrupts the immune homeostasis by causing energy metabolism disorder and inflammatory oxidative damage and therefore contributes to the development of various acute and chronic inflammatory disorders and cancer. Accordingly, agonists or antagonists targeting the CPT system may become novel approaches for the treatment of diseases. In this review, we first briefly describe the structure, distribution, and physiological action of the CPT system. We then summarize the pathophysiological role of the CPT system in chronic obstructive pulmonary disease, bronchial asthma, acute lung injury, chronic granulomatous disease, nonalcoholic fatty liver disease, hepatic ischemia-reperfusion injury, kidney fibrosis, acute kidney injury, cardiovascular disorders, and cancer. We are also concerned with the current knowledge in either preclinical or clinical studies of various CPT activators/inhibitors for the management of diseases. These compounds range from traditional Chinese medicines to novel nanodevices. Although great efforts have been made in studying the different kinds of CPT agonists/antagonists, only a few pharmaceuticals have been applied for clinical uses. Nevertheless, research on CPT activation or inhibition highlights the pharmacological modulation of CPT-dependent FAO, especially on different CPT isoforms, as a promising anti-inflammatory/antitumor therapeutic strategy for numerous disorders.

Association Between Stent Implantation and Progression of Nontarget Lesions in a Rabbit Model of Atherosclerosis.

BACKGROUND: Progression of nontarget lesions (NTLs) after percutaneous coronary intervention (PCI) has been reported. However, it remains unknown whether progression of NTLs was causally related to stenting. This study was undertaken to test the hypothesis that stent implantation triggers acute phase response and systemic inflammation which may be associated with progression of NTLs. METHODS: Thirty New Zealand rabbits receiving endothelial denudation and atherogenic diet were randomly divided into stenting, sham, and control groups. Angiography and intravascular ultrasonography were performed in the stenting and sham groups, and stent implantation performed only in the stenting group. Histopathologic study was conducted and serum levels of APPs (acute phase proteins) measured in all rabbits. Proteomics analysis was performed to screen the potential proteins related to NTLs progression after stent implantation. The serum levels of APPs and inflammatory cytokines were measured in 147 patients undergoing coronary angiography or PCI. RESULTS: Plaque burden in the NTLs was significantly increased 12 weeks after stent implantation in the stenting group versus sham group. Serum levels of APPs and their protein expression in NTLs were significantly increased and responsible for stenting-triggered inflammation. In patients receiving PCI, serum levels of SAA-1 (serum amyloid A protein 1), CRP (C-reactive protein), TNF (tumor necrosis factor)-α, and IL (interleukin)-6 were substantially elevated up to 1 month post-PCI. CONCLUSIONS: In a rabbit model of atherosclerosis, stent implantation triggered acute phase response and systemic inflammation, which was associated with increased plaque burden and pathological features of unstable plaque in NTLs. The potential mechanism involved vessel injury-triggered acute phase response manifested as increased serum levels of SAA-1, CRP, and LBP (lipopolysaccharide-binding protein) and their protein expression in NTLs. These findings provided a new insight into the relation between stent implantation and progression of NTLs, and further studies are warranted to clarify the detailed mechanism and clinical significance of these preliminary results. Registration: URL: http://www.chictr.org.cn; Unique identifier: ChiCTR1900026393. Graphic Abstract: A graphic abstract is available for this article.

Deletion of natriuretic peptide receptor C alleviates adipose tissue inflammation in hypercholesterolemic Apolipoprotein E knockout mice.

The inflammation of adipose tissue is one of the most common secondary pathological changes in atherosclerosis, which in turn influences the process of atherosclerosis. Natriuretic peptides have been revealed important effect in regulating adipose metabolism. However, the relationship between natriuretic peptide receptor C and inflammation of adipose tissue in atherosclerosis remains unknown. This study aims to explore the effect natriuretic peptide receptor C exerts on the regulation of the adipose inflammation in atherosclerotic mice induced by western-type diet and its overlying mechanisms. To clarify the importance of NPRC of adipose inflammation in atherosclerotic mice, NPRC expression was measured in mice fed with chow diet and western-type diet for 12 weeks and we found a considerable increase in adipose tissue of atherosclerotic mice. Global NPRC knockout in mice was bred onto ApoE-/- mice to generate NPRC-/- ApoE-/- mice, which displayed remarked increase in browning of white adipose tissue and lipolysis of adipose tissue and decrease in adipose inflammation manifested by decreased macrophage invasion to form less CLS (crown-like structure), reduced oxidative stress and alleviated expression of TNFα, IL-6, IL-1ß and MCP1, but increased expression of adiponectin in adipose tissue. Moreover, our study showed that white adipose tissue browning in NPRC-/- ApoE-/- atherosclerotic mice was associated with decreased inflammatory response through cAMP/PKA signalling activation. These results identify NPRC as a novel regulator for adipose inflammation in atherosclerotic mice by modulating white adipose tissue browning.

Cytotoxic activity of Shp2 inhibitor fumosorinone in human cancer cells.

Fumosorinone (Fumos) isolated from entomogenous fungi Isaria fumosorosea exhibited selective inhibition of Src homology phosphotyrosine phosphatase 2 inhibitor (Shp2) in our previous study. The purpose of the present study was to investigate the effects of Fumos on cell cycle arrest, tumor cell migration and the in vitro antiproliferative activity of Fumos alone or in combination with the commonly used cytotoxic drugs 5-fluoracil (5-FU) and p38 inhibitor SB203580. Fumos exhibited cytotoxicity against selected human cancel lines, including HeLa, MDA-MB-231 and MDA-MB-453 cell lines. Fumos exerted selective cytotoxic effects on the human cell lines. Flow cytometric and DAPI assays showed that Fumos did not induce cell apoptosis, however it induced cell cycle arrest at the G1 phase. Fumos inhibited cell migration though reducing the phosphorylation of focal adhesion kinase (FAK) at tyrosine (Tyr)861 and marginally increasing the phosphorylation of FAK at Tyr397, however, Fumos did not affect the phosphorylation of FAK at Tyr576 or Tyr925. The present study also examined the combination effect of Fumos with other chemical agents, including 5-FU and p38 inhibitor SB203580. Fumos exhibited a marked synergistic effect with these agents, particularly with 5-FU. In conclusion, Fumos showed potential anticancer bioactivity, and the combination effect of Fumos with 5-FU or with p38 inhibitor offers a more effective anticancer strategy for carcinoma treatment.

PTP1B Inhibitors from the Entomogenous Fungi Isaria fumosorosea.

Protein tyrosine phosphatase 1B (PTP1B) is implicated as a negative regulator of insulin receptor (IR) signaling and a potential drug target for the treatment of type II diabetes and other associated metabolic syndromes. Thus, small molecule inhibitors of PTP1B can be considered as an attractive approach for the design of new therapeutic agents of type II diabetes and cancer diseases. In a continuing search for new PTP1B inhibitors, a new tetramic acid possessing a rare pyrrolidinedione skeleton named fumosorinone A (1), together with five known ones 2-6 were isolated from the entomogenous fungus Isaria fumosorosea. The structures of 2-6 were elucidated by extensive spectroscopic analysis. Fumosorinone A (1) and beauvericin (6) showed significant PTP1B inhibitory activity with IC50 value of 3.24 µM and 0.59 µM.

Diabetes promotes DMH-induced colorectal cancer by increasing the activity of glycolytic enzymes in rats.

The objective of the present study was to investigate the association between diabetes mellitus and colorectal carcinogenesis as well as the possible mechanism involved in this interaction. Diabetes rat models were induced with a low dose of STZ followed by a low dose of DMH to induce colorectal cancer. The formation of ACF in the colon and the incidence, number and size of tumors were measured. The activity of glycolytic enzymes in colonic tissues was also measured. The results demonstrated that both the total number of ACF and the number of foci that contain a different number of crypts were increased in diabetic rats. At the end of the experimental treatment, the incidence, number and size of tumors were also increased in diabetic rats. Overall, these data indicated that diabetes increased the risk of colorectal cancer. The activity of HK and PK in colonic tissues was increased in diabetic rats, whereas the activity of PDH was decreased. In addition, the activities of these enzymes in intratumor were higher than that of in peritumor. These data indicated that the high rate of glycolysis may play a role in colorectal carcinogenesis in diabetic rats.