Modulation of anti-cardiac fibrosis immune responses by changing M2 macrophages into M1 macrophages.

BACKGROUND: Macrophages play a crucial role in the development of cardiac fibrosis (CF). Although our previous studies have shown that glycogen metabolism plays an important role in macrophage inflammatory phenotype, the role and mechanism of modifying macrophage phenotype by regulating glycogen metabolism and thereby improving CF have not been reported. METHODS: Here, we took glycogen synthetase kinase 3ß (GSK3ß) as the target and used its inhibitor NaW to enhance macrophage glycogen metabolism, transform M2 phenotype into anti-fibrotic M1 phenotype, inhibit fibroblast activation into myofibroblasts, and ultimately achieve the purpose of CF treatment. RESULTS: NaW increases the pH of macrophage lysosome through transmembrane protein 175 (TMEM175) and caused the release of Ca2+ through the lysosomal Ca2+ channel mucolipin-2 (Mcoln2). At the same time, the released Ca2+ activates TFEB, which promotes glucose uptake by M2 and further enhances glycogen metabolism. NaW transforms the M2 phenotype into the anti-fibrotic M1 phenotype, inhibits fibroblasts from activating myofibroblasts, and ultimately achieves the purpose of treating CF. CONCLUSION: Our data indicate the possibility of modifying macrophage phenotype by regulating macrophage glycogen metabolism, suggesting a potential macrophage-based immunotherapy against CF.

Chemo-drugs in cell microparticles reset antitumor activity of macrophages by activating lysosomal P450 and nuclear hnRNPA2B1.

Macrophages in tumors (tumor-associated macrophages, TAMs), a major population within most tumors, play key homeostatic functions by stimulating angiogenesis, enhancing tumor cell growth, and suppressing antitumor immunity. Resetting TAMs by simple, efficacious and safe approach(s) is highly desirable to enhance antitumor immunity and attenuate tumor cell malignancy. Previously, we used tumor cell-derived microparticles to package chemotherapeutic drugs (drug-MPs), which resulted in a significant treatment outcome in human malignant pleural effusions via neutrophil recruitments, implicating that drug-MPs might reset TAMs, considering the inhibitory effects of M2 macrophages on neutrophil recruitment and activation. Here, we show that drug-MPs can function as an antitumor immunomodulator by resetting TAMs with M1 phenotype and IFN-ß release. Mechanistically, drug molecules in tumor MPs activate macrophage lysosomal P450 monooxygenases, resulting in superoxide anion formation, which further amplifies lysosomal ROS production and pH value by activating lysosomal NOX2. Consequently, lysosomal Ca2+ signaling is activated, thus polarizing macrophages towards M1. Meanwhile, the drug molecules are delivered from lysosomes into the nucleus where they activate DNA sensor hnRNPA2B1 for IFN-ß production. This lysosomal-nuclear machinery fully arouses the antitumor activity of macrophages by targeting both lysosomal pH and the nuclear innate immunity. These findings highlight that drug-MPs can act as a new immunotherapeutic approach by revitalizing antitumor activity of macrophages. This mechanistic elucidation can be translated to treat malignant ascites by drug-MPs combined with PD-1 blockade.

BCAT1 promotes lung adenocarcinoma progression through enhanced mitochondrial function and NF-κB pathway activation.

Lung cancer is one of the most prevalent and malignant cancers, among which lung adenocarcinoma (LUAD) accounts for the majority and remains a major cause of cancer-related mortality worldwide (Cui et al., 2019). Despite the growing intensity of research on the pathobiology and progression of lung cancer and the fact that many genes have been identified as potential drivers and targets for therapy (Luo et al., 2019; Zhang et al., 2019), the treatment and prognosis of lung cancer patients have hardly improved. Therefore, this study aimed to investigate the precise mechanism of lung cancer development and explore efficient diagnostic and therapeutic methods for clinical treatment.

Roles and potential clinical implications of tissue transglutaminase in cardiovascular diseases.

Cardiovascular disease (CVD)-related mortality and morbidity are among the most critical disease burdens worldwide. CVDs encompass many diseases and involve complex pathogenesis and pathological changes. While research on these diseases has advanced significantly, treatments and their efficacy remain rather limited. New therapeutic strategies and targets must, therefore, be explored. Tissue transglutaminase (TG2) is pivotal to the pathological development of CVDs, including participating in the cross-linking of extracellular proteins, activation of fibroblasts, hypertrophy and apoptosis of cardiomyocytes, proliferation and migration of smooth muscle cells (SMCs), and inflammatory reactions. Regulating TG2 activity and expression could ensure remarkable improvements in disorders like heart failure (HF), pulmonary hypertension (PH), hypertension, and coronary atherosclerosis. In this review, we summarize recent advances in TG2: we discuss its role and mechanisms in the progression of various CVDs and its potential as a diagnostic and therapeutic target.

BCAT1 knockdown-mediated suppression of melanoma cell proliferation and migration is associated with reduced oxidative phosphorylation.

Malignant melanoma has a high mutational rate. As a result, resistance to current therapies is common. Consequently, there is an unmet medical need to develop novel therapies. Recent data suggest that branched-chain amino acid transaminase 1 (BCAT1) is overexpressed in multiple cancers, and such overexpressed BCAT1 is necessary for individual cancer progression. Therefore, BCAT1 appears to be a good target in cancer treatment. Additionally, because its expression in healthy tissues is highly restricted in adults and is limited to the brain, ovary, and placenta, BCAT1 is especially an ideal target in cancer therapies. Currently, the function of BCAT1 in malignant melanoma has not been demonstrated. Therefore, we investigated the role of BCAT1 in the proliferation and migration of malignant melanomas using human samples and mouse malignant B16 melanoma cell line. Our data showed that BCAT1 was overexpressed in malignant melanoma tissues both in humans and mice. Besides, BCAT1 knockdown suppressed melanoma cell proliferation and migration, which was associated with reduced oxidative phosphorylation. Collectively, our data indicate that BCAT1 is a promising therapeutic target for the treatment of malignant melanomas.

Correlations between aortic tortuosity, diameter and presence of acute type A aortic dissection.

BACKGROUND: Currently, only patients with ascending aorta diameter exceeding 55 mm will undergo prophylactic surgery. However, diameter alone is insufficient for precise risk stratification. An International Registry of Acute Aortic Dissections study showed that nearly 60% of patients with type A aortic dissection had a diameter <55 mm. This study aimed to compare the tortuosity of the ascending aorta between ATAAD patients and healthy controls and evaluate correlations between aortic tortuosity/diameter and presence of ATAAD. METHODS: A total of 75 cases in the ATAAD group and 83 cases in the Control group were enrolled. Tortuosity was calculated as the ratio of the total curve length (Lc) of the centerline to the linear distance (d) between its two endpoints, as assessed by an electronic caliper. The measurements were made on all patients by just one cardiovascular radiologist using 3-dimensional computerized tomographic imaging. ROC analysis was used to reckon the best cut-off level that prognosis occurrence of ATAAD. Correlation analysis was used to evaluate the correlation between ATAAD and tortuosity. Logistic regression was used to evaluate the relation between ATAAD and tortuosity. The tortuosity of ascending aorta was compared with a healthy control group using propensity score. RESULTS: According to the ROC analysis, the best cut-off level that prognosis occurrence of ATAAD was 0.135. In addition, the occurrence of ATAAD showed a strong correlation with maximum diameter of the ascending aorta (r=0.587, P<0.001), and moderate correlation with ascending aortic Tortuosity (r=0.425, P<0.001). Ninety-six patients were matched based on propensity scores (ATAAD N.=48, controls N.=48). The ascending aorta was more tortuous and more dilated in ATAAD patients compared with healthy controls (0.15±0.06 vs. 0.11±0.05, P<0.001, 37.96±7.31 mm vs. 31.67±2.78 mm, P<0.001, respectively). CONCLUSIONS: Our study found that the occurrence of ATAAD showed a strong correlation with maximum diameter of the ascending aorta, and moderate correlation with ascending aortic tortuosity. Adding tortuosity to the ATAAD prediction system will improve the ability to identify high-risk groups of ATAAD. When the tortuosity is more significant than 0.135, prophylactic surgical intervention should be considered.

SIRT3 as a potential therapeutic target for heart failure.

Heart failure causes significant morbidity and mortality worldwide. The underlying mechanisms and pathological changes associated with heart failure are exceptionally complex. Despite recent advances in heart failure research, treatment outcomes remain poor. The sirtuin family member sirtuin-3 (SIRT3) is involved in several key biological processes, including ATP production, catabolism, and reactive oxygen species detoxification. In addition to its role in metabolism, SIRT3 regulates cell death and survival and has been implicated in the pathogenesis of cardiovascular diseases. Emerging evidence also shows that SIRT3 can protect cardiomyocytes from hypertrophy, ischemia-reperfusion injury, cardiac fibrosis, and impaired angiogenesis. In this review article, we summarize the recent advances in SIRT3 research and discuss the role of SIRT3 in heart failure. We also discuss the potential use of SIRT3 as a therapeutic target in heart failure.

Lysine Acetylome Study of Human Hepatocellular Carcinoma Tissues for Biomarkers and Therapeutic Targets Discovery.

Lysine acetylation is a vital post-translational modification (PTM) of proteins, which plays an important role in cancer development. In healthy human liver tissues, multiple non-histone proteins were identified with acetylation modification, however, the role of acetylated proteins in hepatocellular carcinoma (HCC) development remains largely unknown. Here we performed a quantitative acetylome study of tumor and normal liver tissues from HCC patients. Overall, 598 lysine acetylation sites in 325 proteins were quantified, and almost 59% of their acetylation levels were significantly changed. The differentially acetylated proteins mainly consisted of non-histone proteins located in mitochondria and cytoplasm, which accounted for 42% and 24%, respectively. Bioinformatics analysis showed that differentially acetylated proteins were enriched in metabolism, oxidative stress, and signal transduction processes. In tumor tissues, 278 lysine sites in 189 proteins showed decreased acetylation levels, which occupied 98% of differentially acetylated proteins. Moreover, we collected twenty pairs of tumor and normal liver tissues from HCC male patients, and found that expression levels of SIRT1 (p = 0.002), SIRT2 (p = 0.01), and SIRT4 (p = 0.045) were significantly up-regulated in tumor tissues. Over-expression of possibly accounted for the widespread deacetylation of non-histone proteins identified in HCC tumor tissues, which could serve as promising predictors of HCC. Taken together, our work illustrates abundant differentially acetylated proteins in HCC tumor tissues, and offered insights into the role of lysine acetylation in HCC development. It provided potential biomarker and drug target candidates for clinical HCC diagnosis and treatment.