CD147 Sparks Atherosclerosis by Driving M1 Phenotype and Impairing Efferocytosis.

BACKGROUND: Atherosclerosis is a globally prevalent chronic inflammatory disease with high morbidity and mortality. The development of atherosclerotic lesions is determined by macrophages. This study aimed to investigate the specific role of myeloid-derived CD147 (cluster of differentiation 147) in atherosclerosis and its translational significance. METHODS AND RESULTS: We generated mice with a myeloid-specific knockout of CD147 and mice with restricted CD147 overexpression, both in an apoE-deficient (ApoE-/-) background. Here, the myeloid-specific deletion of CD147 ameliorated atherosclerosis and inflammation. Consistent with our in vivo data, macrophages isolated from myeloid-specific CD147 knockout mice exhibited a phenotype shift from proinflammatory to anti-inflammatory macrophage polarization in response to lipopolysaccharide/IFN (interferon)-γ. These macrophages demonstrated a weakened proinflammatory macrophage phenotype, characterized by reduced production of NO and reactive nitrogen species derived from iNOS (inducible NO synthase). Mechanistically, the TRAF6 (tumor necrosis factor receptor-associated factor 6)-IKK (inhibitor of κB kinase)-IRF5 (IFN regulatory factor 5) signaling pathway was essential for the effect of CD147 on proinflammatory responses. Consistent with the reduced size of the necrotic core, myeloid-specific CD147 deficiency diminished the susceptibility of iNOS-mediated late apoptosis, accompanied by enhanced efferocytotic capacity mediated by increased secretion of GAS6 (growth arrest-specific 6) in proinflammatory macrophages. These findings were consistent in a mouse model with myeloid-restricted overexpression of CD147. Furthermore, we developed a new atherosclerosis model in ApoE-/- mice with humanized CD147 transgenic expression and demonstrated that the administration of an anti-human CD147 antibody effectively suppressed atherosclerosis by targeting inflammation and efferocytosis. CONCLUSIONS: Myeloid CD147 plays a crucial role in the growth of plaques by promoting inflammation in a TRAF6-IKK-IRF5-dependent manner and inhibiting efferocytosis by suppressing GAS6 during proinflammatory conditions. Consequently, the use of anti-human CD147 antibodies presents a complementary therapeutic approach to the existing lipid-lowering strategies for treating atherosclerotic diseases.

Exogenous melatonin as a treatment for secondary sleep disorders: A systematic review and meta-analysis.

Melatonin is a physiological indoleamine involved in circadian rhythm regulation and it is currently used for secondary sleep disorders supported by empirical evidence. A small amount of evidence and some controversial results have been obtained in some randomized controlled trials (RCT). The objective of this meta-analysis is to determine the efficacy of exogenous melatonin versus placebo in managing secondary sleep disorders. Literature retrieval of eligible RCT was performed in 5 databases (PubMed, Embase, Cochrane Library, ClinicalTrials.gov, and Web of Science). In total, 7 studies of 205 patients were included. Pooled data demonstrate that exogenous melatonin lowers sleep onset latency and increases total sleep time, whereas it has little if any effect on sleep efficiency. Although, the efficacy of melatonin still requires further confirmation, this meta-analysis clearly supports the use of melatonin as a management for patients with secondary sleep disorders.

Forkhead box O4 transcription factor in human neoplasms: Cannot afford to lose the novel suppressor.

Forkhead box O4 (FOXO4), a member of FOXO family, has been highlighted as an essential transcriptional regulator in many diverse carcinomas. Accumulated studies have demonstrated that FOXO4 is downregulated and associated with tumorigenesis, invasiveness, and metastasis of most human cancer. FOXO4 alteration is also closely linked to the prognosis of various types of cancer. The aim of this review is to comprehensively present the clinical and pathological significance of FOXO4 in human cancer. Additionally, the potential clinical applications of future FOXO4 research are discussed. Collectively, the information reviewed here should increase the potential of FOXO4 as a therapeutic target for cancer.

PGC-1: The Energetic Regulator in Cardiac Metabolism.

The peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1s (PGC-1s) can induce the expression of several downstream genes that play pivotal roles in the regulation of mitochondrial biogenesis and metabolism in the heart. Moreover, PGC-1 signaling pathways have also been reported to play a critical role in cardioprotection. Given the significance of PGC-1 coactivators, we summarize the current literature on the molecular mechanisms and roles of PGC-1s in cardiac metabolism. Thus, in this review, we first introduce the basic knowledge regarding PGC-1 signaling pathways. We then discuss their roles in heart metabolism. Moreover, we describe several significant treatments that target the PGC-1 signaling pathway. This review presents the significant roles of PGC-1s in cardiac metabolism and may contribute to the promotion of PGC-1 signaling pathway as a novel therapeutic target.

Nicorandil alleviates myocardial injury and post-infarction cardiac remodeling by inhibiting Mst1.

BACKGROUND: Cardiomyocyte autophagy and apoptosis are crucial events underlying the development of cardiac abnormalities and dysfunction after myocardial infarction (MI). A better understanding of the cell signaling pathways involved in cardiac remodeling may support the development of new therapeutic strategies for the treatment of heart failure (HF) after MI. METHODS: A cardiac MI injury model was constructed by ligating the left anterior descending (LAD) coronary artery. Neonatal cardiomyocytes were isolated and cultured to investigate the mechanisms underlying the protective effects of nicorandil on MI-induced injury. RESULTS: Nicorandil reduced cardiac enzyme release, mitigated left ventricular enlargement and cardiac dysfunction after MI, as evaluated by echocardiography and hemodynamic measurements. According to the results of the western blot analysis and immunofluorescence staining, nicorandil enhanced autophagic flux and reduced apoptosis in cardiomyocytes subjected to hypoxic injury. Interestingly, nicorandil increased Mst1 and p-Mst1 levels in cardiomyocytes subjected to MI injury. Mst1 knockout abolished the protective effects of nicorandil on cardiac remodeling and dysfunction after MI. Mst1 knockout also abolished the beneficial effects of nicorandil on cardiac enzyme release and cardiomyocyte autophagy and apoptosis. CONCLUSIONS: Nicorandil alleviates post-MI cardiac dysfunction and remodeling. The mechanisms were associated with enhancing autophagy and inhibiting apoptosis through Mst1 inhibition.

Polydatin ameliorates diabetic cardiomyopathy via Sirt3 activation.

BACKGROUND: Diabetic cardiomyopathy is identified as cardiac ventricular dysfunction induced by an insulin shortage in diabetic patients. Our previous studies have shown that Polydatin (PD) alleviates cardiac dysfunction after myocardial infarction (MI) injury. Nevertheless, the mechanism by which PD regulates diabetic cardiomyopathy has not been reported. METHODS: In this study, we demonstrated the effects and described the mechanisms of PD in diabetic cardiomyopathy in both adult mouse hearts and neonatal mouse cardiomyocytes. We injected streptozotocin (STZ) to induce the DM model in wild-type (WT) and Sirt3 knockout (Sirt3-/-) mice. Mitochondrial bioenergetics in diabetic mice were detected by measuring citrate synthase activity and ATP content. The extent of autophagy regulation by PD was investigated by detecting the levels of Beclin 1, Atg5, LC3 and p62. RESULTS: Compared to the WT mouse hearts, hearts from the diabetic mice exhibited better cardiac function and a higher level of autophagy. Moreover, mitochondrial function in the diabetic mouse hearts was improved after PD treatment. However, PD treatment had no effect on the Sirt3 knockout diabetic mouse hearts. Additionally, PD increased autophagy flux in the cardiomyocytes that were cultured in high-glucose medium for 48 h. In addition, PD had no effects on the cardiomyocytes under high-glucose conditions when we down-regulated Sirt3. CONCLUSIONS: Altogether, PD attenuated cardiac dysfunction, increased autophagy flux and improved mitochondrial bioenergetics by up-regulating Sirt3 in the diabetic mice.

Clinical and pathological significance of N-Myc downstream-regulated gene 2 (NDRG2) in diverse human cancers.

Human N-Myc downstream-regulated gene 2 (NDRG2), located at chromosome 14q11.2, has been reported to be down-regulated and associated with the progression and prognosis of diverse cancers. Collectively, previous studies suggest that NDRG2 functions as a candidate tumor-suppressor gene; thus, up-regulation of NDRG2 protein might act as a promising therapeutic strategy for malignant tumors. The aim of this review was to comprehensively present the clinical and pathological significance of NDRG2 in human cancers.

SIRT1 activation by pterostilbene attenuates the skeletal muscle oxidative stress injury and mitochondrial dysfunction induced by ischemia reperfusion injury.

Ischemia reperfusion (IR) injury is harmful to skeletal muscles and causes mitochondrial oxidative stress. Pterostilbene (PTE), an analogue of resveratrol, has organic protective effects against oxidative stress. However, no studies have investigated whether PTE can protect against IR-related skeletal muscular injury. In this study, we sought to evaluate the protective effect of PTE against IR-related skeletal muscle injury and to determine the mechanisms in this process. Male Sprague-Dawley rats were pretreated with PTE for a week and then underwent limb IR surgery. The IR injury induced segmental necrosis and apoptosis, myofilament disintegration, thicker interstitial spaces, and inflammatory cell infiltration. Furthermore, mitochondrial respiratory chain activity in the muscular tissue was inhibited, methane dicarboxylic aldehyde concentration and myeloperoxidase activity were up-regulated, and superoxide dismutase was down-regulated after IR. However, these effects were significantly inhibited by PTE in a dose-dependent manner. The mechanism underlying IR injury is attributed to the down-regulation of silent information regulator 1 (SIRT1)-FOXO1/p53 pathway and the increase of the Bax/Bcl2 ratio, Cleaved poly ADP-ribose polymerase 1, Cleaved Caspase 3, which can be reversed with PTE. Furthermore, EX527, an SIRT1 inhibitor, counteracted the protective effects of PTE on IR-related muscle injury. In conclusion, PTE has protective properties against IR injury of the skeletal muscles. The mechanism of this protective effect depends on the activation of the SIRT1-FOXO1/p53 signaling pathway and the decrease of the apoptotic ratio in skeletal muscle cells.

Melatonin: the dawning of a treatment for fibrosis?

Fibrosis is a common occurrence following organ injury and failure. To date, there is no effective treatment for this condition. Melatonin targets numerous molecular pathways, a consequence of its antioxidant and anti-inflammatory actions that reduce excessive fibrosis. Herein, we review the multiple protective effects of melatonin against fibrosis. There exist four major phases of the fibrogenic response including primary injury to the organ, activation of effector cells, the elaboration of extracellular matrix (ECM) and dynamic deposition. Melatonin regulates each of these phases. Additionally, melatonin reduces fibrosis levels in numerous organs. Melatonin exhibits its anti-fibrosis effects in heart, liver, lung, kidney, and other organs. In addition, adhesions which occur following surgical procedures are also inhibited by melatonin. The information reviewed here should be significant to understanding the protective role of melatonin against fibrosis, contribute to the design of further experimental studies related to melatonin and the fibrotic response and shed light on a potential treatment for fibrosis.

UBE2S promotes glycolysis in hepatocellular carcinoma by enhancing E3 enzyme-independent polyubiquitination of VHL.

Background/Aims: Ubiquitination is widely involved in the progression of hepatocellular carcinoma (HCC) by regulating various cellular processes. However, systematic strategies for screening core ubiquitin-related genes, clarifying their functions and mechanisms, and ultimately developing potential therapeutics for patients with HCC are still lacking. Methods: Cox and LASSO regression analyses were performed to construct a ubiquitin-related gene prediction model for HCC. Loss- and gain-of-function studies, transcriptomic and metabolomics analysis were used to explore the function and mechanism of UBE2S on HCC cell glycolysis and growth. Results: Based on 1423 ubiquitin-related genes, a four-gene signature was successfully constructed to evaluate the prognosis of patients with HCC. UBE2S was identified in this signature with the potential to predict the survival of patients with HCC. E2F2 transcriptionally upregulated UBE2S expression by directly binding to its promoter. UBE2S positively regulated glycolysis in a HIF-1α-dependent manner, thus promoting the proliferation of HCC cells. Mechanistically, UBE2S enhanced K11-linkage polyubiquitination at lysine residues 171 and 196 of VHL independent of E3 ligase, thereby indirectly stabilizing HIF-1α protein levels by mediating the degradation of VHL by the proteasome. In particular, the combination of cephalomannine, a small molecule compound that inhibits the expression of UBE2S, and PX-478, an inhibitor of HIF-1α, significantly improved the anti-tumor efficacy. Conclusions: UBE2S is identified as a key biomarker in HCC among the thousands of ubiquitin-related genes and promotes glycolysis by E3 enzyme-independent ubiquitination, thus serving as a therapeutic target for the treatment of HCC.

Novel role of COX6c in the regulation of oxidative phosphorylation and diseases.

Cytochrome c oxidase subunit VIc (COX6c) is one of the most important subunits of the terminal enzyme of the respiratory chain in mitochondria. Numerous studies have demonstrated that COX6c plays a critical role in the regulation of oxidative phosphorylation (OXPHOS) and energy production. The release of COX6c from the mitochondria may be a hallmark of the intrinsic apoptosis pathway. Moreover, The changes in COX6c expression are widespread in a variety of diseases and can be chosen as a potential biomarker for diagnosis and treatment. In light of its exclusive effects, we present the elaborate roles that COX6c plays in various diseases. In this review, we first introduced basic knowledge regarding COX6c and its functions in the OXPHOS and apoptosis pathways. Subsequently, we described the regulation of COX6c expression and activity in both positive and negative ways. Furthermore, we summarized the elaborate roles that COX6c plays in various diseases, including cardiovascular disease, kidney disease, brain injury, skeletal muscle injury, and tumors. This review highlights recent advances and provides a comprehensive summary of COX6c in the regulation of OXPHOS in multiple diseases and may be helpful for drug design and the prediction, diagnosis, treatment, and prognosis of diseases.

Pyroptosis-Related LncRNA Signature Predicts Prognosis and Is Associated With Immune Infiltration in Hepatocellular Carcinoma.

Pyroptosis is an inflammatory form of programmed cell death that is involved in various cancers, including hepatocellular carcinoma (HCC). Long non-coding RNAs (lncRNAs) were recently verified as crucial mediators in the regulation of pyroptosis. However, the role of pyroptosis-related lncRNAs in HCC and their associations with prognosis have not been reported. In this study, we constructed a prognostic signature based on pyroptosis-related differentially expressed lncRNAs in HCC. A co-expression network of pyroptosis-related mRNAs-lncRNAs was constructed based on HCC data from The Cancer Genome Atlas. Cox regression analyses were performed to construct a pyroptosis-related lncRNA signature (PRlncSig) in a training cohort, which was subsequently validated in a testing cohort and a combination of the two cohorts. Kaplan-Meier analyses revealed that patients in the high-risk group had poorer survival times. Receiver operating characteristic curve and principal component analyses further verified the accuracy of the PRlncSig model. Besides, the external cohort validation confirmed the robustness of PRlncSig. Furthermore, a nomogram based on the PRlncSig score and clinical characteristics was established and shown to have robust prediction ability. In addition, gene set enrichment analysis revealed that the RNA degradation, the cell cycle, the WNT signaling pathway, and numerous immune processes were significantly enriched in the high-risk group compared to the low-risk group. Moreover, the immune cell subpopulations, the expression of immune checkpoint genes, and response to chemotherapy and immunotherapy differed significantly between the high- and low-risk groups. Finally, the expression levels of the five lncRNAs in the signature were validated by quantitative real-time PCR. In summary, our PRlncSig model shows significant predictive value with respect to prognosis of HCC patients and could provide clinical guidance for individualized immunotherapy.

Endothelial genetic deletion of CD147 induces changes in the dual function of the blood-brain barrier and is implicated in Alzheimer's disease.

AIMS: The blood-brain barrier (BBB) is a specialized and indispensable structure in brain blood vessels that is damaged during Alzheimer's disease (AD). CD147 is expressed on the BBB and deeply engaged in the AD pathological process. In this study, we aimed to provide a better understanding of the roles of CD147 in BBB function in health and neurodegenerative disease. METHODS AND RESULTS: We measured CD147 expression in mouse brains and demonstrated that CD147 is exclusively expressed in brain endothelial cells (BECs), and its expression decreases with age. After constructing endothelial-specific CD147 knockout mice, we performed RNA-sequencing on BECs isolated from mice of different ages as well as a range of database analyses. We found that endothelial CD147 is essential for the dual functions of the BBB, including barrier maintenance and transporter regulation. This study also shows that CD147 plays a pivotal role in neurodegenerative diseases, particularly in AD. CONCLUSIONS: Our findings suggested that targeting CD147 in BECs may represent a novel therapeutic strategy, which promoted the design of future experimental investigations and the mechanistic understanding of neurodegenerative diseases.

Blockade of Macrophage CD147 Protects Against Foam Cell Formation in Atherosclerosis.

The persistence of macrophage-derived foam cells in the artery wall fuels atherosclerosis development. However, the mechanism of foam cell formation regulation remains elusive. We are committed to determining the role that CD147 might play in macrophage foam cell formation during atherosclerosis. In this study, we found that CD147 expression was primarily increased in mouse and human atherosclerotic lesions that were rich in macrophages and could be upregulated by ox-LDL. High-throughput compound screening indicated that ox-LDL-induced CD147 upregulation in macrophages was achieved through PI3K/Akt/mTOR signaling. Genetic deletion of macrophage CD147 protected against foam cell formation by impeding cholesterol uptake, probably through the scavenger receptor CD36. The opposite effect was observed in primary macrophages isolated from macrophage-specific CD147-overexpressing mice. Moreover, bioinformatics results indicated that CD147 suppression might exert an atheroprotective effect via various processes, such as cholesterol biosynthetic and metabolic processes, LDL and plasma lipoprotein clearance, and decreased platelet aggregation and collagen degradation. Our findings identify CD147 as a potential target for prevention and treatment of atherosclerosis in the future.

[Effects of precursor feeding and fungal elicitors on secondary metabolits in cell suspension culture of Cistanche deserticola].

OBJECTIVE: To investigate the effects of precursor feeding and fungal elicitors on cell growth and the contents of PeGs and Echin in the cell supension culture of Cistanche deserticola. METHODS: The combination of precursor feeding and fungal elicitors were added on the cell suspension culture. RESULTS: The combination of L-phenylalanine and L-Tyrosing were added with Cladosporium fulvum, the dry weight of cell and the contents of PeGs and Echin in suspention all reached the highest value, 14.69 gDW/L, 50.55 mg/g and 23.86 mg/g, which were 1.81, 4.18 and 3.99 times as much as the values of controls, respectively. CONCLUSIONS: Precursor feeding and fungal elicitors had obvious promotion effects on cell growth and contents of PeGs and Echin in cell suspension culture of C. deserticola.

Blossoming 20: The Energetic Regulator's Birthday Unveils its Versatility in Cardiac Diseases.

The peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α) was first identified in 1998 as a PGC-1 family member that regulates adaptive thermogenesis and mitochondrial function following cold exposure in brown adipose tissue. The PGC-1 family has drawn widespread attention over the past two decades as the energetic regulator. We recently summarized a review regarding PGC-1 signaling pathway and its mechanisms in cardiac metabolism. In this review, we elaborate upon the PGC-1 signaling network and highlight the recent progress of its versatile roles in cardiac diseases, including myocardial hypertrophy, peripartum and diabetic cardiomyopathy, and heart failure. The information reviewed here may be useful in future studies, which may increase the potential of this energetic regulator as a therapeutic target.

SOX11: friend or foe in tumor prevention and carcinogenesis?

Sex-determining region Y-related high-mobility-group box transcription factor 11 (SOX11) is an essential member of the SOX transcription factors and has been highlighted as an important regulator in embryogenesis. SOX11 studies have only recently shifted focus from its role in embryogenesis and development to its function in disease. In particular, the role of SOX11 in carcinogenesis has become of major interest in the field. SOX11 expression is elevated in a wide variety of tumors. In many cancers, dysfunctional expression of SOX11 has been correlated with increased cancer cell survival, inhibited cell differentiation, and tumor progression through the induction of metastasis and angiogenesis. Nevertheless, in a limited number of malignancies, SOX11 has also been identified to function as a tumor suppressor. Herein, we review the correlation between the expression of SOX11 and tumor behaviors. We also summarize the mechanisms underlying the regulation of SOX11 expression and activity in pathological conditions. In particular, we focus on the pathological processes of cancer targeted by SOX11 and discuss whether SOX11 is protective or detrimental during tumor progression. Moreover, SOX11 is highlighted as a clinical biomarker for the diagnosis and prognosis of various human cancer. The information reviewed here should assist in future experimental designs and emphasize the potential of SOX11 as a therapeutic target for cancer.

Targeted inhibition of STAT3 as a potential treatment strategy for atherosclerosis.

Atherosclerosis is the main pathological basis of ischemic cardiovascular and cerebrovascular diseases and has attracted more attention in recent years. Multiple studies have demonstrated that the signal transducer and activator of transcription 3 (STAT3) plays essential roles in the process of atherosclerosis. Moreover, aberrant STAT3 activation has been shown to contribute to the occurrence and development of atherosclerosis. Therefore, the study of STAT3 inhibitors has gradually become a focal research topic. In this review, we describe the crucial roles of STAT3 in endothelial cell dysfunction, macrophage polarization, inflammation, and immunity during atherosclerosis. STAT3 in mitochondria is mentioned as well. Then, we present a summary and classification of STAT3 inhibitors, which could offer potential treatment strategies for atherosclerosis. Furthermore, we enumerate some of the problems that have interfered with the development of mature therapies utilizing STAT3 inhibitors to treat atherosclerosis. Finally, we propose ideas that may help to solve these problems to some extent. Collectively, this review may be useful for developing future STAT3 inhibitor therapies for atherosclerosis.

Doxycycline Inducible Chimeric Antigen Receptor T Cells Targeting CD147 for Hepatocellular Carcinoma Therapy.

Chimeric antigen receptor T cell (CAR-T) therapy to hematological malignancies has demonstrated tremendous clinical outcomes. However, the therapeutic efficacy of CAR-T cells in solid tumors remains limited due to the scarcity of tumor-specific antigen targets and the poor infiltration of CAR-T cells into tumor tissue. In this study, we developed a novel inducible CAR-T cell system which targets CD147, a tumor-associated antigen for hepatocellular carcinoma (HCC). To minimize potential toxicities of CAR-T cell therapy, the Tet-On 3G system was introduced to induce CD147CAR expression in the right place at the right time. Specifically, Tet-CD147CAR lentiviral vector (LV-Tet-CD147CAR) was constructed, which comprised CD147CAR controlled by the Tet-On system. Tet-CD147CART cells were successfully generated from activated T cells by infection with LV-Tet-CD147CAR. Proliferation, cytotoxicity, and cytokine secretion of Tet-CD147CART cells were significantly increased against CD147-positive cancer cells in the presence of doxycycline (Dox) compared to Tet-CD147CART cells in the absence of Dox and PBMCs. Consistently, in vivo studies indicated that the tumor growth in nude mice was significantly inhibited by (Dox+) Tet-CD147CART cells through multiple intratumoral administration. Taken together, our results indicated that the expression and activity of CD147CAR were controlled by Dox both in vitro and in vivo, which facilitated decreased toxicity and adverse effects to CAR-T cell therapy. Moreover, this study provides viable evidence in support of the potential benefits and translation of this strategy of CAR-T cells targeting CD147 for the treatment of patients with HCC.

AMP-activated protein kinase sparks the fire of cardioprotection against myocardial ischemia and cardiac ageing.

AMP-activated protein kinase (AMPK) is a pivotal regulator of some endogenous defensive molecules in various pathological processes, particularly myocardial ischemia (MI), a high risk of myocardial infarction. Thereby it is of great significance to explore the inherent mechanism between AMPK and myocardial infarction. In this review, we first introduce the structure and role of AMPK in the heart. Next, we introduce the mechanisms of AMPK in the heart; followed by the energy regulation of AMPK in MI. Lastly, the attention will be expanded to some potential directions and further perspectives. The information compiled here will be helpful for further research and drug design in the future before AMPK might be considered as a therapeutic target of MI.