Background Mitochondrial dynamics imbalance is an essential pathological mechanism in heart failure (HF). The Chinese herbal formula Xin-Ji-Er-Kang (XJEK) has demonstrated good therapeutic effects in various cardiovascular disease models. However, whether XJEK treats HF by regulating mitochondrial dynamics homeostasis and its specific molecular mechanisms remain elusive. Purpose To investigate the effect of XJEK on restoring the disrupted mitochondrial dynamics homeostasis in HF and elucidate the potential regulatory mechanism. Study-design/methods A mouse model of myocardial ischemia-reperfusion (MIR)-induced HF was established to assess the cardioprotection of XJEK. Subsequently, network pharmacology was employed to predict the mechanism by which XJEK treated HF. Moreover, gene silencing was employed to explore the potential mechanisms behind the cardioprotective effects of XJEK in AC16 cells subjected to hypoxia/reoxygenation (H/R). Results XJEK treatment significantly attenuated myocardial fibrosis and ameliorated ventricular remodeling in post-MIR-induced HF mice. Network pharmacology analysis identified the estrogen receptor α (ERα) as a key regulator of XJEK-mediated cardioprotection. XJEK disordered mitochondrial dynamics in the hearts of MIR-induced HF mice. In addition, XJEK restored mitochondrial fusion-fission imbalance and facilitated ERα nuclear translocation to up-regulate sirtuin 3 (SIRT3) expression in the hearts of MIR-induced HF mice and H/R-induced AC16 cells. Notably, ERα depletion in cardiomyocytes completely abrogated the cardioprotective effects of XJEK. Conclusion XJEK safeguards the hearts in mice with MIR-induced HF by facilitating ERα nuclear translocation to up-regulate SIRT3 expression to rescue the mitochondrial fusion-fission imbalance. This study establishes a new theoretical basis for treating HF with XJEK.

Intervertebral disc (IVD) degeneration (IDD) is a primary cause of low-back pain in people, which is associated with nucleus pulposus-derived mesenchymal stem cells (NPMSCs). In this study, the involvement of lipopolysaccharide (LPS) in the pyroptosis of NPMSCs was investigated. The effect of RADKPS on the pyroptosis of NPMSCs and the underlying mechanism behind the impact of RADKPS on the proliferative capacity of NPMSCs were also studied. Pyroptosis of NPMSCs was induced with 10 & mu;g/mL LPS and its effects on the downstream signaling pathways were explored. The protective effect of RADKPS on NPMSCs under the action of LPS and its possible mechanism were explored, using different techniques such as immunohistochemical analysis, cell proliferation assay, quantitative real-time polymerase chain reaction (qPCR), and Western blot analysis. Accordingly, caspase1/p20/p10, a protein associated with pyroptosis, was found to be overexpressed in LPS-challenged NPMSCs, Furthermore, the qPCR results demonstrated that LPS promoted the expression of pyroptosis-related gene IL-1 & beta; (p < 0.0001), while downregulating the expression of Sox-9 (p < 0.001), which was a gene associated with the extracellular matrix. The immunohistochemical results identified lowered extracellular signal-regulated kinase 1/2 (ERK1/2) expression and phosphorylated (p-)ERK1/2 in the degenerated IVD tissues. In this study, the influence of RADKPS on the proliferative ability of NPMSCs was evaluated using two-dimensional (2D) and three-dimensional (3D) cultures. It was noted that RADKPS promoted the proliferation of NPMSCs in 2D and 3D cultures. The findings of the Western blot experiments revealed that RADKPS inhibited the expression of pyroptosis-related proteins, while it upregulated the p-ERK1/2 (p < 0.001), RhoA (p < 0.01), collagen II (p < 0.01), and Sox-9 (p < 0.01), whereas ERK inhibitor PD98059 and RhoA signaling pathway inhibitor CCG-1423 inhibited their expression. These findings reveal to us that RADKPS hydrogel may protect NPMSCs from pyroptosis. It was also noted that cell proliferation-related signaling pathways may promote the proliferation of NPMSCs. The results revealed that RADKPS hydrogel could be used as a potential therapeutic approach for IDD. Impact StatementRADKPS inhibits the pyroptosis of NPMSCs and promotes the production of extracellular matrix, which has the potential of intervertebral disc biotherapy.

BackgroundDegenerative disc disease(DDD)is one of the most important causes of low back pain (LBP). Programmed death of human nucleus pulposus mesenchymal stem cells (NPMSCs) plays an important role in the progression of DDD. Growth differentiation factor-5 (GDF-5) is a protein that promotes chondrogenic differentiation, and has been reported to slow the expression of inflammatory factors in nucleus pulposus cells. Compared with those in normal rats, MRI T2-weighted images show hypointense in the central nucleus pulposus region of the intervertebral disc in GDF-5 knockout rats.Methods and resultsWe aimed to evaluate the role of GDF-5 and Ras homolog family member A (RhoA) in NPMSCs. We used lipopolysaccharide (LPS) to simulate the inflammatory environment in degenerative disc disease, and performed related experiments on the effects of GDF-5 on NPMSCs, including the effects of pyroptosis, RhoA protein, and the expression of extracellular matrix components, and the effects of GDF-5, on NPMSCs. In addition, the effect of GDF-5 on chondroid differentiation of NPMSCs was included. The results showed that the addition of GDF-5 inhibited the LPS-induced pyroptosis of NPMSCs, and further analysis of its mechanism showed that this was achieved by activating the RhoA signaling pathway.ConclusionThese findings suggest that GDF-5 plays an important role in inhibiting the pyroptosis of NPMSCs and GDF-5 may have potential for degenerative disc disease gene-targeted therapy in the future.

BackgroundExcessive oxidative stress has been accepted as one of the critical factors for intervertebral disc degeneration (IDD), which is associated with low back pain (LBP). Fisetin (Fis) is a bioactive flavonoid that possesses strong bioactive activity. In present study, we aimed to illuminate the role of Fis on nucleus pulposus mesenchymal stem cells (NPMSCs). MethodsNPMSCs were isolated and cultured from rat NP tissues and identified by flow cytometry and multilinear differentiation. The cytotoxicity of Fis, EX-527, and hydrogen peroxide (H2O2) on NPMSCs was validated using Cell Counting Kit-8 tests. Cell apoptosis was tested by flow cytometry and TUNEL assay. Inflammatory mediators were assessed by Elisa tests, RT-PCR. Extracellular matrix (ECM) metabolism was measured by Western blot analysis and RT-qPCR. The expression of the SIRT1 was evaluated by Western blot analysis. ResultsNPMSCs were successfully isolated and cultured from rat NP tissues, and it has been identified by flow cytometry and multilinear differentiation. The results showed that Fis attenuated H2O2-induced apoptosis, inflammation, and ECM degradation of NPMSCs. Moreover, the above protective effects of Fis can be inhibited by EX-527, a unique SIRT1 inhibitor, indicating that SIRT1 may involve in the mechanism of Fis in protecting NPMSCs from oxidative stress. ConclusionsAs a natural compound with little cytotoxicity on NPMSCs, Fis alleviate H2O2-induced apoptosis, inflammation, and ECM degradation by suppressing oxidative stress, this finding may add the theoretical basis for research on new treatment of IDD based on NPMSCs.

Purpose Adjacent segment degeneration (ASDeg) after anterior cervical discectomy and fusion (ACDF) seriously affects the long-term efficacy of the operation. Therefore, our team has done a lot of research on allograft intervertebral disc transplantation (AIDT) to prove its feasibility and safety. This study will compare the efficacy between AIDT and ACDF in the treatment of cervical spondylosis. Methods All patients who received ACDF or AIDT in our hospital from 2000 to 2016 and followed up for at least 5 years were recruited and divided into ACDF and AIDT groups. The clinical outcomes including functional scores and radiological data of both groups were collected and compared preoperatively and postoperatively at 1 week, 3 months, 6 months, 12 months, 24 months, 60 months and last follow-up. Functional scores included Japanese Orthopedic Association score (JOA), Neck Disability Index (NDI), Visual Analog Scale of Neck (N-VAS) and Arms (A-VAS) pain, the Short Form Health Survey-36 (SF-36) and imaging dates including digital radiographs in the lateral, hyperextension and flexion positions to assess the stability, sagittal balance and mobility of the cervical spine and magnetic resonance imaging (MRI) scans to assess the degeneration of adjacent segment. Results There were 68 patients with 25 in AIDT group and 43 in ACDF group. Satisfactory clinical results were obtained in both groups, but the long-term NDI score and N-VAS score in the AIDT group were better. The AIDT obtained the same stability and sagittal balance of the cervical spine as fusion surgery. The range of motion of adjacent segments can be restored to the preoperative level after transplantation, but this increases significantly after ACDF. There were significant differences in the superior adjacent segment range of motion (SROM) between two groups at 12 months ( P = 0.039), 24 months ( P = 0.035), 60 months ( P = 0.039) and the last follow-up ( P = 0.011). The inferior adjacent segment range of motion (IROM) and SROM had a similar trend in the two groups. The ratio value of the greyscale (RVG) of adjacent segments showed a downward trend. At the last follow-up, the RVG decreased more significantly in the ACDF group. At the last follow-up, there was a significant difference in the incidence of ASDeg between the two groups ( P = 0.000). And the incidence of adjacent segment disease (ASDis) is 22.86% in the ACDF group. Conclusion The allograft intervertebral disc transplantation may be as an alternative technique to traditional anterior cervical discectomy and fusion for the management of cervical degenerative diseases. For the more, the results showed it would improve cervical kinematics and reduce the incidence of adjacent segment degeneration.

Low back pain (LBP) is a common problem that causes enormous socioeconomic burden worldwide. Intervertebral disc degeneration (IDD) is considered to be a major cause of LBP. The specific mechanism of IDD is not fully understood; however, the decrease in the number of nucleus pulposus (NP) cells and loss of function are thought to be the main reasons for IDD. Therefore, the study of NP cell apoptosis plays an important role in the study of IDD. Autophagy, as a major intracellular lysosome-dependent degradation process, plays a key role in maintaining intracellular homeostasis and resisting environmental pressure, which may be a potential therapeutic target for IDD. Ferroptosis is a type of iron-dependent regulated cell death caused by disruption that occurs when oxidative stress and antioxidant defenses interact, and is subsequently driven by lipid peroxidation and plasma membrane ruptures. However, the potential links between autophagy and ferroptosis in IDD are unknown. Herein we postulate that SIRT1-autophagy axis can inhibit oxidative stress-induced NP cell ferroptosis. These findings may aid the development of novel therapeutic approaches for IDD treatment.

PurposeRecently, long noncoding RNA LINC01134 has been shown to reduce cell viability and apoptosis via the antioxidant stress pathway, thereby enhancing OXA resistance in hepatocellular carcinoma. However, the association of LINC01134 with ferroptosis and the underlying molecular mechanisms remain to be elucidated.MethodsBioinformatics analysis was employed to screen lncRNAs positively correlated with GPX4 and poor clinical prognosis. And Western blot and RT-PCR analysis in HCC cells confirmed the effect of LINC01134 on GPX4 expression. In addition, LINC01134 siRNA was transfected in HCC cells to detect the changes in cell viability, ROS, lipid peroxidation, MDA levels and GSH/GSSG levels. CCK-8, colony formation and apoptosis assays were performed to determine the effect of LINC01134 on cell death. The effect of LINC01134 and OXA on Nrf2 transcriptional binding to GPX4 was analyzed using dual luciferase reporter assay and CHIP. The expression of GPX4 and Nrf2 in HCC tissues was detected by FISH and IHC.ResultsLINC01134 is a novel lncRNA positively correlated with GPx4 and associated with poor clinical prognosis. Silenced LINC01134 conferred OXA sensitivity by enhancing total ROS, lipid ROS, MDA levels and decreasing GSH/GSSG ratio. Mechanistically, LINC01134 and OXA could promote Nrf2 recruitment to the GPX4 promoter region to exert transcriptional regulation of GPX4. Clinically, LINC01134 was positively correlated with GPX4 or Nrf2, demonstrating the clinical significance of LINC01134, Nrf2 and GPX4 in OXA resistance of HCC.ConclusionsWe identified LINC01134/Nrf2/GPX4 as a novel and critical axis to regulate HCC growth and progression. Targeting GPX4, knocking down LINC01134 or Nrf2 could be a potential therapeutic strategy for HCC.

BACKGROUND Secreted protein acidic and rich in cysteine (SPARC) is implicated in cancer progression, but its role and associated molecular mechanism in the sorafenib sensitivity of hepatocellular carcinoma cells (HCC) remains elusive. METHODS Human HCC cell lines Hep3B and HepG2 were treated with sorafenib alone or combined with activator or inhibitor of ferroptosis. Cell viability assay, reactive oxygen species (ROS) assay, lactate dehydrogenase (LDH) assay and western blot were used to study the regulatory mechanism of SPARC on HCC cells. RESULTS Overexpression of SPARC enhanced the cytotoxic effect of sorafenib in Hep3B and HepG2 cells compared with parental cells. Depletion of SPARC decreased the cytotoxic effect of sorafenib in Hep3B and HepG2 cells compared with parental cells. Moreover, overexpression of SPARC significantly induced LDH release, whereas depletion of SPARC suppressed the release of LDH in Hep3B and HepG2 cells. Inhibition of ferroptosis exerted a clear inhibitory role against LDH release, whereas activation of ferroptosis promoted the release of LDH in HCC cells, as accompanied with deregulated expression of ferroptosis-related proteins. Furthermore, overexpression of SPARC induced oxidative stress, whereas depletion of SPARC suppressed the production of ROS. Deferoxamine (DFX)-induced inhibition of ferroptosis suppressed the production of ROS, while activation of ferroptosis promoted the contents of ROS in HCC cells exposed to sorafenib. CONCLUSION Our findings give a better understanding of ferroptosis and its molecular mechanism in HCC cells that is regulated by SPARC in response to sorafenib.

Cerebral ischemic/reperfusion injury is the most common neurological disorder and the second leading cause of death worldwide. Modulating microglia polarization from pro-inflammatory M1 phenotype to anti-inflammatory M2 state has been suggested as a potential therapeutic approach in the treatment of this injury. SRT2104, a novel activator of histone deacetylase Sirtuin-1 (Sirt1), has recently been shown to have anti-inflammation properties. However, the effect of SRT2104 on cerebral ischemic/reperfusion injury has not been elucidated. Here, we found that SRT2104 inhibited neuron and microglia death directly and indirectly through microglia condition medium from an oxygen glucose deprivation/reoxygenation (OGD/R) -induced cell injury models. Moreover, SRT2104 treatment modulated the microglia polarization shift from the M1 phenotype and skewed toward the M2 phenotype. Additionally, we found that SRT2104 could significant inhibit the activation of NF-κB and enhanced Sirt1 expression in microglia. Mechanism studies using the BV2 microglial cell line confirmed that knockdown Sirt1 significantly reduced the effect of SRT2104 on the activation of NF-κB pathway and microglial phenotype shift. Altogether, our result shows SRT2104 protect OGD/R-induced injury through shifting microglia phenotype, which may have potential in further studies as a novel neuroprotective agent for cerebral ischemic/reperfusion injury therapy.

Hypopharyngeal cancer is squamous cell carcinoma (SCC) with the worst prognosis among the head and neck cancers. Overall, the 5-year survival rate remains poor although diagnostic imaging, radiation, chemotherapy, and surgical techniques have been improved. The mortality of patients with hypopharyngeal cancer is partly due to an increased likelihood of developing a second primary malignancy and metastasis. In this study, we found that MLCK expression, compared to healthy tissue, was up-regulated in hypopharyngeal tumor tissue. Of particular interest, a low 5-year survival rate was positively correlated with MLCK expression. We hypothesized that MLCK might be a target for hypopharyngeal cancer prognosis and treatment. In order to explore the function of MLCK in the development of cancer, we knockdown MLCK in hypopharyngeal cancer FaDu cells. The results showed that MLCK knockdown reduced the migration and invasion of FaDu cells. 4-amino-2-trifluoromethyl-phenyl retinate (ATPR) is the derivative of all-trans retinoic acid (ATRA), which was able to reduce both MLCK expression and activity in FaDu cells. ATPR induced FaDu cells apoptosis in a dose-dependent manner and also inhibited cell growth both in vivo and in vitro. Further experiments showed that overexpression of MLCK reduced ATPR induced-migration inhibition while increase of ATPR induced apoptosis, which suggested that MLCK was involved in ATPR's anti-cancer function. In conclusion, MLCK is a novel prognostic marker and therapeutic target for hypopharyngeal cancer. By targeting MLCK, ATPR exhibits its potential application in the treatment of this type of cancer.

MicroRNA-126 (miR-126) is an endothelial-specific microRNA that has shown beneficial effects on endothelial dysfunction. However, the underlying molecular mechanism is unclear. The present study evaluated the effects of miR-126 on the cell migration and underlying mechanism in HUVECs treated with palmitate. The present results demonstrated that overexpression of miR-126 was found to decrease cell migration in palmitate-treated HUVECs, with decreased MLCK expression and subsequent decreased phosphorylated MLC level. miR-126 also decreased the phosphorylation of MYPT1 in palmitate-treated HUVECs. In addition, it was demonstrated that miR-126 decreases expression of the NADPH oxidase subunits, p67 and Rac family small GTPase 1 with a subsequent decrease in cell apoptosis. Moreover, the phosphorylation of ERK was reduced by miR-126 in palmitate-induced HUVECs. Taken together, the present study showed that the effect of miR-126 on cell migration and cell apoptosis is mediated through downregulation of MLCK via the ERK/MAPK pathway.

4-Amino-2-trifluoromethyl-phenyl retinate (ATPR) is a novel All-trans Retinoid Acid (ATRA) derivative. The primary aim of this study was to characterize whether ATPR could contribute to growth arrest and apoptosis of breast cancer cell MDA-MB-231. MDA-MB-231 cells were exposed to ATPR. MTT assay was performed to detect the proliferation. Flow cytometry analysis was used to reveal the cell cycle distribution. RT-PCR was performed to reflect the transcription level of cell cycle protein p21 and cyclinD1. Hoechst staining was used to examine cell apoptosis. Western blot analysis was performed to detect the expression levels of p-p38, total p38, p53, iASPP, apoptosis-associated proteins Bcl-2, Bax, caspase-3. The cell proliferation was decreased in a concentration- and time-dependent manner by ATPR. The ATPR mediated G0-G1 phase arrest on MDA-MB-231 and promoted apoptosis of MDA-MB-231. In addition, the ATPR could increase the expression of p53 and decrease the expression of iASPP and the phosphorylation of p38. After combined with SB203580, ATPR could induce an enhancement of transcription level of p21, a reduction of transcription level of cyclinD1, an increase in Bax expression, a decrease in Bcl-2 level. Besides, the p53 was elevated while the expression of iASPP was declined more obviously, and that caused a further decrease in the phosphorylation of p38. These results suggested that ATPR contributed to apoptosis and growth inhibition of MDA-MB-231 in a time- and dose-dependently. The mechanism might be related to disruption of p38 signaling and activation of p53.

Endocan, which has been identified to be low expressed in gastric cancer, was found to be positively related to the differentiation level of gastric cancer in vivo and in vitro. In the present study, we aimed to investigate the role of endocan in gastric adenocarcinoma cell line SGC7901 by artificially upregualting or downregulating endocan expression using endocan recombinant vector or specific small interfering RNA (siRNA)-targeting endocan gene, respectively. The effects of endocan recombinant vector-mediated over-expressing and siRNA-mediated endocan silencing on the differentiation, migration, and apoptosis of SGC7901 cells were assessed. Furthermore, the primary molecular mechanisms of endocan were explored by testing the expression alterations of associated protein in SGC7901 along endocan over-expression or knockdown. We found that over-expression of endocan reduced the migration but promoted the differentiation and apoptosis of SGC7901 cells. While, knockdown of endocan did just the opposite. Some molecules were found to participate in endocan-mediated anti-tumor effects, such as p53, caspase 3, and MMP-9. In conclusion, our findings suggest that endocan plays an anti-carcinogenic role in gastric cancer development and progression and might serve as a prognostic biomarker as well as a potential therapeutic target for gastric cancer.

AIMS:Dysregulation of microRNAs (miRNAs) plays a critical role in tumor growth and progression. In this study, we sought to explore the expression and biological roles of miR-539 in hepatocellular carcinoma (HCC).MAIN METHODS:The expression of miR-539 in human HCC tissues and cell lines was examined. The effects of miR-539 overexpression on cell growth, tumorigenicity, arsenic trioxide resistance of HCC cells were determined. The signaling pathways involved in the action of miR-539 in HCC were also investigated.KEY FINDINGS:miR-539 was downregulated in HCC tissues and cells, relative to corresponding controls. Overexpression of miR-539 inhibited HCC cell viability and colony formation in vitro and impaired tumorigenesis of HCC cells in vivo. Transfection with miR-539 mimic significantly induced apoptosis in HepG2 cells, which was coupled with reduced expression of anti-apoptotic proteins Bcl-2 and Bcl-xL and decreased phosphorylation of Stat3. Overexpression of a constitutively active form of Stat3 partially blocked miR-539-mediated apoptosis. Enforced expression of miR-539 resensitized arsenic trioxide-resistant HCC cells to arsenic trioxide. Intratumoral delivery of miR-539 mimic significantly retarded the growth of xenograft tumors from arsenic trioxide-resistant HCC cells by about 35%, compared to delivery of control miRNA (P<0.05). In combination with arsenic trioxide, miR-539 mimic yielded about 80% decrease in tumor burden.SIGNIFICANCE:miR-539 functions as a tumor suppressor in HCC and reexpression of this miRNA offers a potential therapeutic strategy for this disease.

The aim of the present study was to explore the role of miR-126 in palmitate-induced HUVECs apoptosis and the possible mechanisms. Palmitate inhibited miR-126 expression in HUVECs, increased reactive oxygen species (ROS) production, and induced apoptosis as determined by up-regulation of caspase-3 activity and DNA fragmentation. Overexpression of miR-126 decreased ROS production, TNF-α expression, and apoptosis in palmitate-stimulated HUVECs. In contrast, miR-126 antagomir enhanced palmitate-induced ROS production, TNF-α expression, and apoptosis. The induction of miR-126 correlated with a reduction in TRAF7. We further showed that miR-126 targeted and inhibited TRAF7 expression through target sites located in the 3′ untranslated region of TRAF7 mRNA. In concordance, miR-126 mimic reduced TRAF7 protein in HUVECs, whereas the inhibition of miR-126 increased it. This study demonstrates an anti-apoptotic role of miR-126 in HUVECs and identifies TRAF7 as a direct target of miR-126 in HUVECs.

4-Amino-2-trifluoromethyl-phenyl retinate (ATPR) is a novel all-trans retinoic acid (ATRA) derivative which was reported to have a superior antitumor effect in breast cancer cells. However, little is known about its antitumor effects on human gastric cancer cells and the mechanisms have not been fully elucidated. The results of the present study suggest that in the human gastric carcinoma cell line BGC-823, ATPR plays a more effective role than ATRA at the same dose in inhibiting proliferation, migration and inducing differentiation after the same treatment time. Furthermore, we investigated the preliminary mechanism of ATPR's anti-migration effect. Immunofluorescence assay demonstrated that claudin-18 positioned from cytoplasm to cell surface following ATPR stimuli. Real-time quantitative RT-PCR and western blot analyses showed that ATPR had significant effects on downregulation of the phosphorylation level of myosin light chain II (MLC II) by suppressing myosin light chain kinase (MLCK) and Rho-associated coiled-coil containing kinase (ROCK), as well as its regulation in the protein expression of RAR alpha and RAR beta. Moreover, ATPR increased the activity of myosin phosphatase by inhibiting ROCK. Consequently, ATPR showed more promising antitumor effects than ATRA in BGC-823 in vitro, and it may conduct its anti-migration effects by decreasing the phosphorylation level of MLC II, as well as by regulating MLCK and ROCK as downstream target genes.

The imbalance of CD4(+)CD25(+) regulatory T (Treg) cells and Th17 cells has shown to be involved in pathogenesis of atherosclerosis and acute coronary syndrome [ACS, including unstable angina (UA) and acute myocardial infarction (AMI)]. The purpose of this study is to explore the significance of Treg/Th17 ratio in early diagnosis for ACS. We detected expression of Treg and Th17 in patients with AMI, UA, stable angina, and subjects with normal coronary arteries at the time of admission. Our results showed that ACS patients have a significant increase of Th17 number, but a marked decline of Treg/Th17 ratio, Treg number, and Treg function. Significant positive correlations in Th17 frequency and negative correlation in Treg frequency, Treg/Th17 ratio were found to levels of oxidized low-density lipoprotein (Ox-LDL), high sensitive C-reactive protein (hsCRP), Lipoprotein (a) [Lp(a)], and Creatine kinase-MB(mass) (CK-MBmass) in serum. Receiver-operating characteristic curves shown that the predictive specificity and sensitivity of Treg/Th17 ratio for ACS and AMI was the highest among all the five markers: Ox-LDL, hsCRP, Lp(a), CK-MBmass, and Treg/Th17 ratio. In conclusion, Treg/Th17 ratio appeared to be a novel indicator for early diagnosis of ACS.

Recent evidence indicated that endocan may be a potential cell marker and a new target for cancers including acute leukemia since the serum endocan level in patients with acute leukemia was associated with the status of the disease, i.e., endocan was higly expressed in untreated acute leukemia, but decreased after chemotherapy and increased again during bone marrow regeneration. The present study showed that there was high level expression of endocan in cytoplasm of bone marrow blasts of patients with acute myeloid leukemia or acute lymphoblastic leukemia. The expression level of endocan was significantly decreased when the patients underwent remission after chemotherapy and re-bounces back when the acute leukemia relapsed. No obvious change in expression of endocan was observed before and after chemotherapy if the patients showed no remission after chemotherapy. (N-(4-Hydroxyphenyl)  retinamide), a potent anti-angiogenic agent, could not only down-regulate the expression of vascular epithelial growth factor, but also decrease endocan transcription and expression in NB4 cells, a human acute promyelocytic leukemia cell line. These observations suggest that endocan could act as a predictor for the severity and the prognosis of acute leukemia. The findings could be used as the basis for future targeted therapy directed against bone marrow angiogenesis in acute leukemia treatment.

BackgroundHigh-fat diet has been reported to be associated with cardiovascular diseases which is implicated in atherosclerosis. However, the underlying mechanisms remain unknown. MicroRNAs (miRNAs) are non-coding small RNAs that control gene expression at the post-transcriptional level. Dysregulated miRNAs have been shown to be involved in atherosclerosis.Methods and resultsThis study examined whether microRNA-29b (miR-29b) regulates high-fat diet induced endothelial permeability and apoptosis by targeting MT1, a known melatonin membrane receptor. In apoE knock-out mice, a high-fat diet increased miR-29b expression and induced apoptosis as determined by up-regulation of caspase-3 activity. However, a standard diet did not alter apoptosis. miR-29b antagomir decreased endothelial permeability and apoptosis in high-fat diet-stimulated mice. In contrast, a miR-29b mimic enhanced endothelial permeability and apoptosis. The induction of miR-29b correlated with a reduction in Bcl-2 and MT1 in high-fat diet-stimulated mice. miR-29b have an effect on the marker of inflammation (NF-κB) and cell adhesion molecule (ICAM-1). We further showed that miR-29b targeted and inhibited MT1 expression through a target site located in the 3′un-translational region of MT1 mRNA. This study demonstrates a role of miR-29b in atherosclerosis and identifies MT1 as a direct target of miR-29b.ConclusionsThe effect of miR-29b on endothelial permeability and apoptosis is mediated through the down-regulation of MT1. Thus, miR-29b may be a new therapeutic target for atherosclerosis.

Aims: This study was aimed to determine whether microRNA1 (miR1) plays a role in the activation of myosin light chain kinase (MLCK) mediated by oxLDL in human umbilical vein endothelial cells (HUVECs).Main methods: HUVECs were treated with oxLDL along with a control miR or miR1 mimic. MiR1 expression was assayed by miRNA plate assay kit and mirVana (TM) miRNA isolation kit. The MLCK protein, transcript, and kinase activity were measured by Western blot, real-time-polymerase chain reaction and gamma-P-32-ATP phosphate incorporation, respectively. In addition, phosphorylation of MLC, ERK and p38 was analyzed by Western blot.Key findings: The results showed that upon treatment with oxLDL, miR1 expression was decreased, whereas MLCK expression was increased, in a time- and dose-dependent manner. Consistent with this, miR1 mimic prevented MLCK expression and activation and attenuated the phosphorylation of MLC and ERK/p38 in oxLDL-treated HUVECs. Furthermore, we showed that miR1 was able to bind a site located at the 3'un-translational region of MLCK mRNA and inhibited its expression.Significance: Taken together, this study demonstrated that the effect of miR1 on hyperlipidemia is mediated through down-regulation of MLCK and the ERK/p38 MAPK pathway. (C) 2014 Elsevier Inc. All rights reserved.