Different drugs in drug-eluting stents for peripheral artery disease: a systematic evaluation and Bayesian meta-analysis.

Drug-eluting stents (DESs) have become the first-line treatment for symptomatic peripheral arterial disease (PAD). Currently, there are many types of DESs on the market. The same type of DESs has different concentrations, and various drugs in them show uneven efficacy. The selection of DESs remains controversial. This study was aimed at comparing the long-term real-world outcomes of different DESs in the treatment of peripheral arterial occlusive disease (PAOD). The databases including Cochrane Library, Embase, and PubMed were searched with a time frame until March 25, 2023. The primary patency (PP) and target lesion revascularization (TLR) at 6 months were used as the primary endpoints. A total of 32 studies (5467 patients) were eligible. At the six-month follow-up, DES-Evero 1 ug/mm2 ranked first in terms of PP, with a significant difference from BMSs (RR [95% CI] = 1.6). DES-Siro 0.9 ug/mm2, DES-Siro 1.4 ug/mm2, DES-Siro 1.95 ug/mm2, DES-PTX 0.167 ug/mm2, DES-PTX 1 ug/mm2 and covered stents (CSs) showed significantly better PPs than BMSs. In terms of TLR, DES-Siro 0.9 ug/mm2 (0.31) ranked first, and DES-Evero 1 ug/mm2 ranked last. Among the treatment modalities for PAD, different DESs showed overall encouraging results in improving PP and TLR compared with BMSs. DES-Evero 1 ug/mm2 showed the best PP, but it had the highest reintervention rate at 6 months. Sirolimus-eluting stents were not always more effective with higher concentrations of sirolimus. Among various DESs, sirolimus-eluting stents and everolimus-eluting stents were superior to paclitaxel-eluting stents.

Network-based pharmacology-based research on the effect and mechanism of the Hedyotis diffusa-Scutellaria Barbata pair in the treatment of hepatocellular carcinoma.

The Hedyotis diffusa-Scutellaria officinalis pair (HD-SB) has therapeutic effects on a variety of cancers. Our study was to explore the mechanism of HD-SB in the treatment of hepatocellular carcinoma (HCC). A total of 217 active ingredients of HD-SB and 1196 HCC-related targets were reserved from the TCMSP and the SwissTarget Prediction database, and we got 63 intersection targets from GeneCards. We used a Venn diagram, and Cytoscape found that the three core ingredients were quercetin, luteolin, and baicalein. The PPI analysis showed that the core targets were TP53, CDK2, XPO1, and APP. Molecular docking results showed that these core ingredients had good binding potential with the core targets. HD-SB acts simultaneously on various HCC-related signaling pathways, including proteoglycans in cancer and the P53 signaling pathway. In vitro experiments confirmed that HD-SB can inhibit HepG2 cell proliferation by increasing TP53 and APP levels and decreasing XPO1 and CDK2 levels. This study analyzed active ingredients, core targets, and central mechanisms of HD-SB in the treatment of HCC. It reveals the role of HD-SB in targeting the P53 signaling pathway in the treatment of HCC. We hope that our research could provide a new perspective to the therapy of HCC and find new anticancer drugs.

Homo-oxidized HSPB1 protects H9c2 cells against oxidative stress via activation of KEAP1/NRF2 signaling pathway.

Several heat shock proteins are implicated in the endogenous cardioprotective mechanisms, but little is known about the role of heat shock protein beta-1 (HSPB1). This study aims to investigate the oxidation state and role of HSPB1 in cardiomyocytes undergoing oxidative stress and underlying mechanisms. Here, we demonstrate that hydrogen peroxide (H2O2) promotes the homo-oxidation of HSPB1. Cys137 residue of HSPB1 is not only required for it to protect cardiomyocytes against oxidative injury but also modulates its oxidation, phosphorylation at Ser15, and distribution to insoluble cell components after H2O2 treatment. Moreover, Cys137 residue is indispensable for HSPB1 to interact with KEAP1, thus regulating its oxidation and intracellular distribution, subsequently promoting the nuclear translocation of NRF2, and increasing the transcription of GLCM, HMOX1, and TXNRD1. Altogether, these findings provide evidence that Cys137 residue is indispensable for HSPB1 to maintain its redox state and antioxidant activity via activating KEAP1/NRF2 signaling cascade in cardiomyocytes.

Dissecting the effects of paraquat-induced pulmonary injury in rats using UPLC-Q-TOF-MS/MS-based metabonomics.

Objective: Paraquat (PQ) is a toxic compound that selectively accumulates in the lungs, inducing severe pulmonary inflammation and fibrosis. However, data on the metabolomic changes induced by the PQ remain scant. This study aimed to determine the metabolic changes in Sprague-Dawley rats subjected to PQ using UPLC-Q-TOF-MS/MS. Methods: We established groups of PQ-induced pulmonary injury rats for 14 or 28 days. Results: Our data showed that PQ decreased the survival of the rats and induced pulmonary inflammation at day 14 or pulmonary fibrosis at day 28. There was upregulation of IL-1ß expression in the inflammation group as well as upregulation of fibronectin, collagen and α-SMA in the pulmonary fibrosis group. OPLS-DA revealed differential expression of 26 metabotites between the normal and the inflammation groups; 31 plasma metabotites were also differently expressed between the normal and the fibrosis groups. There was high expression of lysoPc160-, hydroxybutyrylcarnitine, stearic acid, and imidazolelactic acid in the pulmonary injury group compared to the normal group. Conclusion: Metabolomics analysis confirmed that the PQ-induced lung injury was not only related to the aggravation of inflammation and apoptosis but also to mediated histidine, serine, glycerophospholipid, and lipid metabolism. This study gives insights into the mechanisms of PQ-induced lung injury and highlights the potential therapeutic targets. Nonstructured abstract: The effect of PQ on lung injury in rats was detected by metabonomics, and the possible metabolic mechanism was investigated by KEGG analysis. OPLS-DA revealed the differential expression of 26 metabotites and 31 plasma metabotites between the normal and the pulmonary injury groups. Metabolomics analysis confirmed that the PQ-induced lung injury was not only related to the aggravation of inflammation and apoptosis but also to mediated histidine, serine, glycerophospholipid, and lipid metabolism. Oleoylethanolamine, stearic acid, and imidazolelactic acid are potential molecular markers in PQ-induced pulmonary injury.

Dynamic changes of serum metabolite profiling in septic mice based on high performance liquid chromatography of quadrupole time of flight mass spectrometry analysis.

The objective of this study is to gain insights into the underlying metabolic transformations that occurred during the whole progression of cecal ligation and puncture (CLP)-induced sepsis, thus providing new targets for its treatment. High-performance liquid chromatography of quadrupole time of flight mass spectrometry (HPLC-Q-TOF-MS/MS) combined with multivariate statistical techniques was used to detect the s in serum from septic mice. Fifty male mice were divided into two groups, including the sham group (n = 7) and the CLP-induced sepsis group (n = 43). Animals were sacrificed at 1, 3, 5, and 7 days post-CLP and then serum were collected for metabolomic analysis. Multivariate regression analysis was carried out through MetaboAnalyst 5.0, including principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA), to identify the s and screen out the related differential metabolites. Besides, the KEGG pathway analysis was used to analyze the related metabolic pathways in which the identified metabolites were involved. Based on the fold change (FC > 2.0 or <0.5), variable important in projection (VIP > 1.2), and P value (P < 0.05), we found 26, 17, 21, and 17 metabolites in septic mice at 1, 3, 5, and 7 days post-CLP, respectively, compared with that of the sham group. The PCA and PLS-DA pattern recognition showed a cluster-type distribution between the sham group and the CLP group. Dysregulated amino acid metabolism, as well as disturbed nucleotide metabolism, is observed. Several important metabolic pathways were identified between the sham group and the CLP group. Among them, phenylalanine metabolism, phenylalanine, tyrosine, and tryptophan biosynthesis showed striking at day 1 post-CLP. At day 3, phenylalanine, tyrosine, and tryptophan biosynthesis changed significantly. However, as the disease process, only pyrimidine metabolism showed the most significant alternation, compared to the sham group. Several differential metabolites were identified in the CLP group compared with that of the sham group and they were presented with dynamic alternation at different time points post-CLP, indicating metabolic disturbance occurred throughout the whole sepsis progression.

Insight into the mechanisms of therapeutic hypothermia for asphyxia cardiac arrest using a comprehensive approach of GC-MS/MS and UPLC-Q-TOF-MS/MS based on serum metabolomics.

Cardiac arrest (CA) is a severe worldwide health problem. Therapeutic hypothermia is widely used to reduce the cardiac injury and improve the neurological outcomes after CA. However, a few studies have reported the changes of serum metabolic characteristics after CA. The healthy male New Zealand Rabbits successfully resuscitated from 10-min asphyxia-induced CA were divided randomly into the normothermia (NT) group and mild therapeutic hypothermia (HT) group. The sham group underwent sham-operation. Survival was recorded and neurological deficit score (NDS) was assessed. The serum non-targeted metabolomics were detected using ultra-high-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS/MS) and gas chromatography tandem mass spectrometry (GC-MS/MS) at 15 min, 3 h, 6 h and 24 h after return of spontaneous circulation (ROSC). Our study showed that the heart rate (HR) significantly slowed down during 0.5-6 h post ROSC, consistent with the decreasing trend of body temperature in the HT group. Compared with the NT group, the levels of Lac and PCO2 at 24 h post ROSC were lower, while a significant increase in PO2 level at 24 h post ROSC was observed in the HT group. The survival rate of the HT group was significantly higher than that of the NT group, and NDS scores were remarkably increased at 24 h post ROSC in the NT group. Significant differences in metabolic profiles at 15 min, 3 h, 6 h and 24 h post ROSC were observed among the Sham, NT and HT groups. The differential metabolites detected by UPLC-Q-TOF-MS/MS and GC-MS/MS were screened for further study between every two groups (NT vs sham, HT vs sham and HT vs NT) at 15 min, 3 h, 6 h and 24 h post ROSC. Phenylalanine metabolism, alanine, aspartate and glutamate metabolism and tricarboxylic acid (TCA) cycle were enriched in NT vs sham, HT vs sham and HT vs NT respectively. Our study demonstrated that therapeutic hypothermia improves the survival and neurological outcomes in rabbit model of cardiac arrest, and firstly represents the dynamic metabolic changes in the hypothermia therapy for CA by comprehensive UPLC-Q-TOF-MS/MS- and GC-MS/MS-based metabolomics.

Shengjiang San alleviated sepsis-induced lung injury through its bidirectional regulatory effect.

BACKGROUND: Sepsis is a life-threatening organ dysfunction caused by dysregulated host responses to infection, for which effective therapeutic strategies are still absent. Shengjiang San (SJS), a well-known Traditional Chinese Medicine formula, has been widely used clinically. However, its role in sepsis-induced lung injury remains unclear. METHODS: To explore its specific mechanism, we firstly established a sepsis animal model using cecal ligation and puncture (CLP) and treated MH-S cells with LPS plus ATP. Then, UPLC/Q-TOF-MS/MS was utilized to identify its active ingredients. Network pharmacology analysis was performed to uncover the potential mechanism. HE staining and biochemical analysis were conducted to validate its therapeutic effect. ELISA was applied to detect the release of pro-inflammatory and anti-inflammatory cytokines. Western blot was utilized to detect the protein levels of GSDMD, NLRP3, P65, ASC and caspase-1. RESULTS: SJS could dramatically increase the survival rate of sepsis. In addition, it is able to inhibit the pro-inflammatory cytokines release at day 1 post CLP while promote their production at day 7, indicating SJS could attenuate uncontrolled inflammatory response in the early stage and improve immunosuppression in the late phase. Network pharmacology analysis showed that pyroptosis is the crucial action SJS exerted in the protection of sepsis-induced lung injury. Western blot data implicated SJS could attenuate pyroptosis in early sepsis while enhance in the late phase. CONCLUSIONS: SJS acted to alleviate sepsis-induced lung injury through its bidirectional regulatory effect.

HSPB1 Regulates Autophagy and Apoptosis in Vascular Smooth Muscle Cells in Arteriosclerosis Obliterans.

Objective: Small heat shock protein-1 (HSPB1) is a small heat shock protein that participates in many cellular processes and alleviates stress-induced cell injury. Autophagy protects cells from many types of stress and plays a key role in preventing stress in arteriosclerosis obliterans (ASO). However, the roles of HSPB1 in autophagy and apoptosis in the context of ASO pathogenesis remain unclear. Methods: In vivo and in vitro studies were used to determine whether HSPB1 is associated with ASO progression. The expression of HSPB1 was measured in normal and sclerotic blood vessels. The role of HSPB1 and its potential downstream signaling pathway were determined in VSMCs by overexpressing and silencing HSPB1. Results: A total of 91 ASO patients admitted to and treated at our hospital from Sep. 2020 to Sep. 2021 were selected, and plasma HSPB1 expression was assessed. We divided the patients with ASO into the grade I (n = 39), II (n = 29), III (n = 10), and IV (n = 13) groups according to Fontaine's classification. Plasma HSPB1 levels were markedly decreased in patients with grade III (n = 10) and IV (n = 13) ASO compared with patients with grade I ASO. Furthermore, HSPB1 expression was significantly decreased, and p62 and cleaved caspase-3 were increased in the sclerotic vasculature compared to the normal vasculature (p < 0.05). Overexpression of HSPB1 promoted apoptosis of VSMCs following ox-LDL treatment. Knockdown of HSPB1 led to a marked increase in the expression of LC3II and Beclin-1 in ox-LDL-stimulated VSMCs, whereas knockdown of HSPB1 attenuated these changes (p < 0.05). Importantly, overexpression of HSPB1 promoted the dephosphorylation of JNK in ox-LDL-stimulated VSMCs. Conversely, downregulation of HSPB1 induced the opposite change. Conclusion: Loss of HSPB1 promotes VSMC autophagy and inhibits VSMC apoptosis, which are associated with ASO. HSPB1 and its downstream signaling pathways could be potential therapeutic targets for ASO treatment.

Early predictive value of platelet function for clinical outcome in sepsis.

OBJECTIVE: Sepsis is the leading course of morbidity and mortality in critically ill patients. This study aimed to evaluate the predictive value of the platelet aggregation for mortality in patients with sepsis. In addition, the relationship between impaired mitochondria and the platelet aggregation was explored. METHOD: This was a prospective, observational cohort study. The platelet aggregation rate in response to adenosine diphosphate (ADP) was assessed. The primary outcome was 28-day mortality. Platelet mitochondrial parameters, including adenosine triphosphate(ATP), mitochondrial membrane potential (MMP) and mitochondrial permeability transition pore (mPTP) opening, were measured. Platelet mitochondrial ultrastructure was observed using transmission electron microscopy. RESULTS: 86 patients with 65 survivors and 21 non-survivors were enrolled. Platelets of non-survivors with sepsis were hyporesponsive to ADP, in terms of maximal aggregation rate (P < 0.001). Receiver operating characteristic curves analysis demonstrated that the AUC estimated 28-day mortality for platelet aggregation rate was 0.814. At the optimal cut-off value of 35.8% for platelet aggregation rate, the sensitivity was 86.2% and the specificity was 66.7%. Kaplan-Meier analysis showed that a platelet aggregation rate of less than 35.8% was associated closely with poor survival. After adjusting for lactate by Cox regression analysis, platelet aggregation rate was identified as an independent predictor for the probability of 28-day mortality. Compared with survivors, non-survivors showed a significant reduction in platelet ATP and MMP-index (both P < 0.001), and a remarkable increase in mPTP opening (P < 0.001). ATP and MMP-index were positively correlated with platelet aggregation rate (R square=0.75, R square=0.44, respectively). CONCLUSION: Platelet aggregation rate could be an early predictive biomarker for mortality in sepsis. Impaired platelet mitochondrial activity affects platelet aggregation and correlates with the severity of sepsis.

CCAAT/Enhancer-Binding Protein Homologous Protein (CHOP) Deficiency Attenuates Heatstroke-Induced Intestinal Injury.

The intestine is one of the main target organs involved in the pathological process of heatstroke. CCAAT/enhancer-binding protein homologous protein (CHOP) is involved in endoplasmic reticulum (ER) stress-induced apoptosis. This study aimed to explore the role of CHOP in heatstroke-induced intestinal injury and potential therapy. An in vitro heat stress (HS) model using Caco-2 cells was employed. We observed the role of CHOP in apoptosis-mediated intestinal epithelial cell injury secondary to HS by evaluating cell viability, lactate dehydrogenase release, apoptosis levels, and GRP78, PERK, ATF4, CHOP, Bcl-2, and BAX mRNA and protein expression. To further study the role of CHOP in HS-induced intestinal barrier dysfunction, we assessed transepithelial electrical resistance, paracellular tracer flux, ultrastructure of tight junctions, and protein expression of ZO-1 and occludin. Male wild-type mice and CHOP knockout mice were used for in vivo experiments. We evaluated serum d-lactate and diamine oxidase levels, histopathological changes, intestinal ultrastructure, and ZO-1 and occludin protein expression. HS activated the PERK-CHOP pathway and promoted apoptosis by upregulating BAX and downregulating Bcl-2; these effects were prevented by CHOP silencing. Intestinal epithelial barrier function was disrupted by HS in vitro and in vivo. CHOP silencing prevented intestinal barrier dysfunction in Caco-2 cells, whereas CHOP knockout mice exhibited decreased intestinal mucosal injury. The ER stress inhibitor 4-phenylbutyrate (4-PBA) prevented HS-induced intestinal injury in vitro and in vivo. This study indicated that CHOP deficiency attenuates heatstroke-induced intestinal injury and may contribute to the identification of a novel therapy against heatstroke associated with the ER stress pathway.

PPM1D is a potential prognostic biomarker and correlates with immune cell infiltration in hepatocellular carcinoma.

BACKGROUND: Protein phosphatase magnesium-dependent 1 delta (PPM1D), also referred to as wild-type p53-induced phosphatase 1 (Wip1) or protein phosphatase 2C delta (PP2Cδ), is an oncogenic nuclear serine/threonine phosphatase belonging to the PP2C family. However, the knowledge regarding PPM1D mRNA expression, tumor immunity, and the prognosis in hepatocellular carcinoma (HCC) is scanty. METHODS: We analyzed PPM1D, including its expression in both the normal and tumor tissue using the Sangerbox database and Tumor Immune Estimation Resource (TIMER). We evaluated its correlation with prognosis in different tumor types by the Kaplan-Meier plotter and Gene Expression Profiling Interactive Analysis (GEPIA). The correlations between PPM1D and the cancer immune infiltrates were determined using TIMER. The correlations between PPM1D expression and gene marker sets of the immune infiltrates were established by both the TIMER and GEPIA. Immunohistochemistry was performed to detect the expression of Wip1 protein encoded by PPM1D in HCC, and the relationship between Wip1 expression and the prognosis of HCC were analyzed. RESULTS: We found out that PPM1D mRNA expression was significantly higher in several human cancers, including HCC, than in the corresponding normal human tissues. The PPM1D mRNA high expression in HCC was significantly correlated with poor prognosis. The expression was associated with progression-free survival (PFS) in multiple HCC patients' cohorts (PFS HR = 1.5, P = 0.0066). This was especially in early stage (stage 1) and AJCC_T 1 of HCC. Besides, PPM1D mRNA expression indicated a positive correlation with tumor-infiltrating Monocytes, tumor-associated macrophages (TAMs), M1 Macrophage, M2 Macrophage, dendritic cells (DCs), T-helper (Th) and Treg. Wip1 was higher in HCC than paracancerous tissue. High expression of Wip1 was associated with poor prognosis of HCC. CONCLUSION: Our findings suggested that PPM1D mRNA is critical in activating tumor immunity. Besides, they implied that PPM1D could be a potential prognostic biomarker for cancer progression. Moreover, it correlated with tumor immune cell infiltration in HCC.

Bmal1 Regulates the Redox Rhythm of HSPB1, and Homooxidized HSPB1 Attenuates the Oxidative Stress Injury of Cardiomyocytes.

Oxidative stress is the main cause of acute myocardial infarction (AMI), which is related to the disorder of the regulation of Bmal1 on the redox state. HSPB1 form homologous-oxidized HSPB1 (homooxidized HSPB1) to resist oxidative damage via S-thiolated modification. However, it is still unclarified whether there is an interaction between the circadian clock and HSPB1 in myocardial injury. A total of 118 AMI patients admitted and treated in our hospital from Sep. 2019 to Sep. 2020 were selected to detect the plasma HSPB1 expression and the redox state. We divided the AMI patients into three subgroups: morning-onset AMI (5 : 00 am to 8 : 00 am; Am-subgroup, n = 38), noon-onset AMI (12 : 00 pm to 15 : 00; Pm-subgroup, n = 45), and night-onset AMI (20 : 00 pm to 23 : 00 pm; Eve-subgroup, n = 35) according to the circadian rhythm of onset. The Am-subgroup had remarkably higher cardiac troponin I (cTnI), creatine kinase MB (CK-MB), and B-type natriuretic peptide (BNP) but lower left ventricular ejection fraction (LVEF) than the Pm-subgroup and Eve-subgroup. Patients complicated with cardiogenic shock were significantly higher in the Am-subgroup than in the other two groups. The homooxidized HSPB1 in plasma markedly decreased in the Am-subgroup. The HSPB1C141S mutant accelerated H9c2 cell apoptosis, increased reactive oxygen species (ROS), and decreased reduced-glutathione (GSH) and the ratio of reduced-GSH and GSSG during oxidative stress. Importantly, we found that the redox state of HSPB1 was consistent with the oscillatory rhythm of Bmal1 expression in normal C57B/L mice. The circadian rhythm disorder contributed to decrease Bmal1 and homooxidized HSPB1 in cardiomyocytes of C57BL/6 mice. In addition, Bmal1 and homooxidized HSPB1 decreased in neonatal rat cardiomyocytes exposed to H2O2. Knockdown of Bmal1 led to significant attenuation in homooxidized HSPB1 expression, whereas overexpression of Bmal1 increased homooxidized HSPB1 expression in response to H2O2. Our findings indicated that the homooxidized HSPB1 reduced probably the AMI patients' risk of shock and target organ damage, which was associated with Bmal1 regulating the redox state of HSPB1.

Xinmailong Attenuates Doxorubicin-Induced Lysosomal Dysfunction and Oxidative Stress in H9c2 Cells via HO-1.

The clinical use of doxorubicin (DOX) is limited by its cardiotoxicity, which is closely associated with oxidative stress. Xinmailong (XML) is a bioactive peptide extracted from American cockroaches, which has been mainly applied to treat chronic heart failure in China. Our previous study showed that XML attenuates DOX-induced oxidative stress. However, the mechanism of XML in DOX-induced cardiotoxicity remains unclear. Heme oxygenase-1 (HO-1), an enzyme that is ubiquitously expressed in all cell types, has been found to take antioxidant effects in many cardiovascular diseases, and its expression is protectively upregulated under DOX treatment. Lysosome and autophagy are closely involved in oxidative stress as well. It is still unknown whether XML could attenuate doxorubicin-induced lysosomal dysfunction and oxidative stress in H9c2 cells via HO-1. Thus, this study was aimed at investigating the involvement of HO-1-mediated lysosomal function and autophagy flux in DOX-induced oxidative stress and cardiotoxicity in H9c2 cells. Our results showed that XML treatment markedly increased cell proliferation and SOD activity, improved lysosomal function, and ameliorated autophagy flux block in DOX-treated H9c2 cells. Furthermore, XML significantly increased HO-1 expression following DOX treatment. Importantly, HO-1-specific inhibitor (Znpp) or HO-1 siRNA could significantly attenuate the protective effects of XML against DOX-induced cell injury, oxidative stress, lysosomal dysfunction, and autophagy flux block. These results suggest that XML protects against DOX-induced cardiotoxicity through HO-1-mediated recovery of lysosomal function and autophagy flux and decreases oxidative stress, providing a novel mechanism responsible for the protection of XML against DOX-induced cardiomyopathy.

Clinicopathological findings and imaging features of intraductal papillary neoplasms in bile ducts.

BACKGROUND: Intraductal papillary mucinous neoplasm of the bile duct (IPMN-B) is considered an uncommon tumor, and there is limited understanding of IPMN-B. This study aimed to investigate the prognosis and influential factors of the IPMN-B from 58 cases. METHODS: The clinical data of 58 patients with pathologically confirmed IPMN-B admitted to our hospital from January 1, 2012 to August 2017 were collected and analyzed. The patients were followed up by outpatient or telephone until January 1, 2019. SPSS 19.0 software was applied for data analysis. Survival analysis was performed using Kaplan-Meier method and parallel Log-rank test. Prognostic factors were analyzed by univariate analysis and multiple Cox regression model. RESULTS: Among of all the patients, 26 cases were benign tumors and 32 cases were malignant tumors. The preoperative tumor markers CA242 and CEA of malignant IPNM-B patients were significantly higher than those in benign tumors (P < 0.05). Survival analysis showed that patients with malignant tumors had a worse prognosis. The median survival time of malignant IPMN-B patients was 40.6 ±  3.0 months, yet median survival time of benign IPMN-B patients was not reached (P = 0.19). The one-year survival rate and three-year survival rate of benign IPMN-B were 84% and 74% respectively. The one-year survival rate and three-year survival rate of malignant IPMN-B were 88% and 64% respectively. Univariate analysis showed that combined lymph node metastasis, surgical method, and differentiation degree could affect patients' prognosis (P < 0.05). Multivariate analysis showed differentiation degree was an independent risk factor affecting prognosis (OR = 0.06, 95% confidence interval: 0.007∼0.486, P < 0.05). CONCLUSION: The levels of CEA and CA242 were helpful to identify benign and malignant of IPNM-B. Moreover, radical surgical resection could prolong patients' survival. Finally, differentiation degree was an independent risk factor affecting malignant IPNM-B prognosis.

[Role of mitochondrial-mediated cardiomyocytes injury in acute myocardial infarction with cardiogenic shock].

Acute myocardial infarction with cardiogenic shock (AMI-CS) refers to the rapid decrease in cardiac output in a short period of time, and it leads to severe insufficient perfusion of various organs and causes systemic microcirculatory dysfunction, which is the most common cause of the death of patients with acute myocardial infarction (AMI). At present, the main strategy for clinical treatment of AMI-CS is revascularization, which reduces the mortality of AMI-CS. However, myocardial ischemia and reperfusion can cause ischemia/reperfusion (I/R) injury, induce myocardial mitochondrial dysfunction, and a large amount of reactive oxygen species (ROS) accumulation. Mitochondrial-mediated apoptosis of cardiomyocytes is the main reason of cardiomyocyte death during reperfusion injury. This article summarizes the role of mitochondrial in AMI-CS, which focus on three aspects of mitochondrial permeability transition pore (mPTP) opening, mitochondrial autophagy and mitochondrial fusion/division. It is expected to provide new ideas for clinical AMI-CS and identify potential complications targets.

Curcumol inhibits the proliferation and metastasis of melanoma via the miR-152-3p/PI3K/AKT and ERK/NF-κB signaling pathways.

Melanoma is the most aggressive and treatment-resistant form of skin cancer. Curcumol is a Chinese medicinal herb traditionally used as a cancer remedy. However, the molecular mechanisms underlying the anticancer activity of curcumol in melanoma remains largely unknown. In the present study, we observed that Curcumol decreased mouse melanoma B16 cell proliferation and migration. The xenograft tumor assay showed that curcumol reduced melanoma volume and lung metastasis. Curcumol upregulated the expression of E-cadherin and downregulated the expression of N-cadherin, MMP2 and MMP9 in mouse melanoma B16 cell. Western blot analysis revealed that curcumol reduced the translocation of p65 to the nucleus and decreased p-ERK. Furthermore, curcumol attenuated c-MET, P13K and p-AKT protein expression and upregulated miR-152-3p gene expression. The dual-luciferase reporter assay indicated that c-MET was a target gene of miR-152-3p. Reduced expression of miR-152-3p partially attenuated the effect of curcumol on mouse melanoma B16 cell proliferation and migration. The decrease in c-MET, P13K and p-AKT protein expression following curcumol treatment in mouse melanoma B16 cells was notably attenuated by the miR-152-3p inhibitor. Taken together, our findings suggested that curcumol attenuated melanoma progression and concomitantly suppressed ERK/NF-κB signaling and promoted miR-152-3p expression to inactivate the c-MET/PI3K/AKT signaling pathway.

Ganoderma lucidum Triterpenoids (GLTs) Reduce Neuronal Apoptosis via Inhibition of ROCK Signal Pathway in APP/PS1 Transgenic Alzheimer's Disease Mice.

Alzheimer's disease (AD) is the most common cause of dementia among senior citizen. Ganoderma lucidum triterpenoids (GLTs) have nutritional health benefits and has been shown to promote health and longevity, but a protective effect of GLTs on AD damage has not yet been reported. The objective of this research was to elucidate the phylactic effect of GLTs on AD model mice and cells and to explore its underlying mechanisms. Morris water maze (MWM) test was conducted to detect changes in the cognitive function of mice. Hematoxylin-eosin (HE) staining was applied to observe pathological changes in the hippocampus. Silver nitrate staining was applied to observe the hippocampal neuronal tangles (NFTs). Apoptosis of the hippocampal neurons in mouse brain tissue was determined by TUNEL staining. The expression levels of apoptosis-related protein Bcl2, Bax, and caspase 3/cleaved caspase 3; antioxidative protein Nrf2, NQO1, and HO1; and ROCK signaling pathway-associated proteins ROCK2 and ROCK1 were measured by western blot. In vivo experiments show that 5-month-old APP/PS1 mice appeared to have impaired acquisition of spatial learning and GLTs could reduce cognitive impairment in AD mice. Compared to normal mice, the hippocampus of APP/PS1 mouse's brains was severely damaged, while GLTs could alleviate this symptom by inhibiting apoptosis, relieving oxidative damage, and inactivating the ROCK signaling pathway. In in vitro cell experiments, Aß 25-35 was applied to induce hippocampal neurons into AD model cells. GLTs promoted cell proliferation, facilitated superoxide dismutase (SOD) expression, and inhibited malondialdehyde (MDA) and lactic dehydrogenase (LDH) expression of neurons. Our study highlights that GLTs improve cognitive impairment, alleviate neuronal damage, and inhibit apoptosis in the hippocampus tissues and cells in AD through inhibiting the ROCK signaling pathway.

iNOS is associated with tumorigenicity as an independent prognosticator in human intrahepatic cholangiocarcinoma.

BACKGROUND: Inducible nitric oxide synthase (iNOS) has supposed to implicate in inflammation, infection, liver cirrhosis, and neoplastic diseases. This study was designed to explore the biological and clinical function of iNOS in intrahepatic cholangiocarcinoma (ICC). METHODS: RT-PCR (Real-time quantitative PCR) and immunohistochemical staining were used to analyze the expression of iNOS in ICC and adjacent tissues. CCK8, transwell assays, flow cytometry were conducted to detect the proliferation, apoptosis, cell cycle. Western blotting was performed to detect the expression of target proteins. Multivariate analyses were conducted to analysis associates between clinicopathological values and survival. RESULTS: We found that levels of iNOS mRNA and protein were dramatically increased in ICC samples and positively correlated with complicated bile duct stone, differentiation, pathology T, pathology M, Wip1, MMP-2, and MMP-9. iNOS expression was significantly correlated with the poor survival of ICC patients. Furthermore, iNOS was high expression in ICC cell lines (QBC-939, ICC-9810, SSP-25) compare with human normal biliary epithelium cell line (HIBEpic); both iNOS knockdown and iNOS inhibitor (1400 W) suppressed cell proliferation, invasion, and migration though nitric oxide production in ICC cells. Down-regulation of iNOS also induced G0/G1 cell cycle arrest and ICC cell apoptosis. Moreover, iNOS knockdown treatment significantly decreased Wip1, MMP-9, and MMP-2 gene expression. CONCLUSION: Lowly expressed iNOS-inhibited proliferation yet promoted apoptosis of ICC cells. Our data show targeted inhibition of iNOS in ICC may have therapeutic value.

Tangeretin inhibits hepatocellular carcinoma proliferation and migration by promoting autophagy-related BECLIN1.

Background: Hepatocellular carcinoma (HCC) is a particularly prevalent type of liver cancer and is one of the deadliest malignancies in Asia. Tangeretin is a biological compound extracted from traditional Chinese herbs and has been shown to have potential antitumour properties; however, its mechanism remains largely unknown. Therefore, we sought to determine the role of Tangeretin in HepG2 cells subjected to antitumour treatment. Materials and methods: Cell proliferation was quantified using CCK-8, EdU and colony formation assays, and cell migration was quantified using transwell migration and wound healing assays. Protein expression was assessed using Western blot analysis. Small interfering RNA was used to interfer protein expression. Immunoprecipitation was performed to detect the protein-protein interactions. Results: Tangeretin decreased cell proliferation and increased G2/M arrest. Tangeretin decreased cell migration. Tangeretin increased the LC3II/LC3I ratio and decreased p62 expression in HepG2 cells. Furthermore, the knockdown of BECLIN1 expression in HepG2 cells partially converted the Tangeretin-induced inhibition of proliferation, migration and autophagy. In addition, Tangeretin activated the JNK1/Bcl-2 pathway and disturbed the interaction between Bcl-2 and BECLIN1. Together, our findings demonstrate that Tangeretin inhibited the proliferation and migration of HepG2 cells through JNK/Bcl-2/BECLIN1 pathway-mediated autophagy. Conclusion: Our study contributes to the understanding of the inhibitory mechanism of Tangeretin on HCC development.