ABSTRACT
Background: Drug-resistant microbes pose a global health concern, requiring the urgent development of effective antibacterial agents and strategies in clinical practice. Therefore, there is an urgent need to explore novel antibacterial materials to effectively eliminate bacteria. The synthesis of quaternary phosphonium salt in haloargentate systems, wherein the phosphorus atom is represented in a cationic form, is a possible strategy for the development of antibacterial materials. Methods: Using (triphenyl)phosphonium-based quaternary phosphorus salts with different spacer lengths (n=2, 4, 6) as a template, we designed three kinds of quaternary phosphorus salts as effective antibacterial agents against drug-resistant bacteria. Results: The synthesized quaternary phosphorus salt of (1,4-DBTPP)Br2 effectively prevented the formation of the bacterial biofilms, and degraded bacterial membranes and cell walls by promoting the production of reactive oxygen species, which exhibited effective therapeutic effects in a rat model of a superficial wound infected with methicillin-resistant Staphylococcus aureus. Conclusion: The quaternary phosphorus salt (1,4-DBTPP)Br2 demonstrated hemocompatibility and low toxicity, revealing its potential in the treatment of clinical infections.
Subject(s)
Methicillin-Resistant Staphylococcus aureus , Rats , Animals , Phosphorus , Salts/pharmacology , Microbial Sensitivity Tests , Anti-Bacterial Agents/pharmacology , Sodium Chloride/pharmacology , Wound HealingABSTRACT
Ischemic stroke can cause blood-brain barrier (BBB) injury, which worsens brain damage induced by stroke. Abnormal expression of tight junction proteins in endothelial cells (ECs) can increase intracellular space and BBB leakage. Selective inhibition of mitogen-activated protein kinase, the negative regulatory substrate of mitogen-activated protein kinase phosphatase (MKP)-1, improves tight junction protein function in ECs, and genetic deletion of MKP-1 aggravates ischemic brain injury. However, whether the latter affects BBB integrity, and the cell type-specific mechanism underlying this process, remain unclear. In this study, we established an adult male mouse model of ischemic stroke by occluding the middle cerebral artery for 60 minutes and overexpressed MKP-1 in ECs on the injured side via lentiviral transfection before stroke. We found that overexpression of MKP-1 in ECs reduced infarct volume, reduced the level of inflammatory factors interleukin-1ß, interleukin-6, and chemokine C-C motif ligand-2, inhibited vascular injury, and promoted the recovery of sensorimotor and memory/cognitive function. Overexpression of MKP-1 in ECs also inhibited the activation of cerebral ischemia-induced extracellular signal-regulated kinase (ERK) 1/2 and the downregulation of occludin expression. Finally, to investigate the mechanism by which MKP-1 exerted these functions in ECs, we established an ischemic stroke model in vitro by depriving the primary endothelial cell of oxygen and glucose, and pharmacologically inhibited the activity of MKP-1 and ERK1/2. Our findings suggest that MKP-1 inhibition aggravates oxygen and glucose deprivation-induced cell death, cell monolayer leakage, and downregulation of occludin expression, and that inhibiting ERK1/2 can reverse these effects. In addition, co-inhibition of MKP-1 and ERK1/2 exhibited similar effects to inhibition of ERK1/2. These findings suggest that overexpression of MKP-1 in ECs can prevent ischemia-induced occludin downregulation and cell death via deactivating ERK1/2, thereby protecting the integrity of BBB, alleviating brain injury, and improving post-stroke prognosis.
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Hepatocellular carcinoma (HCC) is a lethal malignancy with few effective options for therapeutic treatment in its advanced stages. While exosomal LINC00161 has been identified as a potential biomarker for HCC, its regulatory function and clinical values remain largely unknown. LINC00161 expressions in serum-derived exosomes from HCC patients and HCC cells were determined by qRT-PCR. The ability of proliferation, migration, and angiogenesis in HUVECs was assessed by MTT, Transwell, and tube formation. Luciferase reporter assay and AGO2-RIP assay were conducted to explore the interactions among LINC00161, miR-590-3p, and ROCK2. The level of ROCK signal-related proteins was examined by Western blotting and immunohistochemistry (IHC) assay. Subcutaneous tumor growth was observed in nude mice, in which in vivo metastasis was observed following tail vein injection of HCC cells. High levels of LINC00161 were detected in both serum-derived exosomes from HCC patients and the supernatants of HCC cell lines and were significantly associated with poor survival. Functional study demonstrated that exosomal LINC00161 derived from HCC-cells were significantly associated with enhanced proliferation, migration, and angiogenesis in HUVECs in vitro, all of which were effectively inhibited when LINC00161 was sliced with shRNA in HCC-cells. In vivo experiment showed that LINC00161 loss inhibited tumorigenesis and metastasis of HCC. Mechanistic study revealed that exosome-carried LINC00161 directly targeted miR-590-3p and induced its downstream target ROCK2, finally activating growth/metastasis-related signals in HCC. Exosome-carried LINC00161 promotes HCC tumorigenesis through inhibiting miR-590-3p to activate the ROCK2 signaling pathway, suggesting that LINC00161 may be used as potential targets to improve HCC treatment efficiency.
Subject(s)
Carcinoma, Hepatocellular/genetics , Liver Neoplasms/genetics , MicroRNAs/genetics , RNA, Long Noncoding/genetics , rho-Associated Kinases/genetics , Animals , Carcinogenesis/genetics , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Cell Proliferation/genetics , Exosomes/genetics , Gene Expression Regulation, Neoplastic/genetics , Heterografts , Humans , Liver Neoplasms/pathology , Mice , Neoplasm Metastasis , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/pathology , Proto-Oncogene Proteins c-akt/genetics , Signal TransductionABSTRACT
Aims: The actin-binding protein Drebrin is up-regulated in response to arterial injury and reduces smooth muscle cell (SMC) migration and proliferation through its interaction with the actin cytoskeleton. We, therefore, tested the hypothesis that SMC Drebrin inhibits angiotensin II-induced remodelling of the proximal aorta. Methods and results: Angiotensin II was administered via osmotic minipumps at 1000 ng/kg/min continuously for 28 days in SM22-Cre+/Dbnflox/flox (SMC-Dbn-/-) and control mice. Blood pressure responses to angiotensin II were assessed by telemetry. After angiotensin II infusion, we assessed remodelling in the proximal ascending aorta by echocardiography and planimetry of histological cross sections. Although the degree of hypertension was equivalent in SMC-Dbn-/- and control mice, SMC-Dbn-/- mice nonetheless exhibited 60% more proximal aortic medial thickening and two-fold more outward aortic remodelling than control mice in response to angiotensin II. Proximal aortas demonstrated greater cellular proliferation and matrix deposition in SMC-Dbn-/- mice than in control mice, as evidenced by a higher prevalence of proliferating cell nuclear antigen-positive nuclei and higher levels of collagen I. Compared with control mouse aortas, SMC-Dbn-/- aortas demonstrated greater angiotensin II-induced NADPH oxidase activation and inflammation, evidenced by higher levels of Ser-536-phosphorylated NFκB p65 subunits and higher levels of vascular cell adhesion molecule-1, matrix metalloproteinase-9, and adventitial macrophages. Conclusions: We conclude that SMC Drebrin deficiency augments angiotensin II-induced inflammation and adverse aortic remodelling.
Subject(s)
Angiotensin II , Aortic Diseases/metabolism , Hypertension/metabolism , Muscle, Smooth, Vascular/metabolism , Myocytes, Smooth Muscle/metabolism , Neuropeptides/metabolism , Vascular Remodeling , Animals , Aorta/metabolism , Aorta/pathology , Aorta/physiopathology , Aortic Diseases/genetics , Aortic Diseases/pathology , Aortic Diseases/physiopathology , Arterial Pressure , Cell Proliferation , Disease Models, Animal , Extracellular Matrix/metabolism , Extracellular Matrix/pathology , HEK293 Cells , Humans , Hypertension/genetics , Hypertension/pathology , Hypertension/physiopathology , Inflammation Mediators/metabolism , Mice, Inbred C57BL , Mice, Knockout , Muscle, Smooth, Vascular/pathology , Muscle, Smooth, Vascular/physiopathology , Myocytes, Smooth Muscle/pathology , NADPH Oxidases/metabolism , Neuropeptides/deficiency , Neuropeptides/genetics , Reactive Oxygen Species/metabolism , Signal TransductionABSTRACT
Objective: To explore the expression of PTK7 in pancreatic ductal adenocarcinoma and its clinical significance. Methods: The clinical and follow-up data of 85 patients with pancreatic ductal adenocarcinoma who underwent radical surgery at Tianjin Medical University Cancer Institute and Hospital from May 2011 to January 2016 were analyzed. The expression of PTK7 in 85 pancreatic cancer tissues and the corresponding para-cancer tissues was detected by immunohistochemistry, and the relationship between PTK7 expression level and the clinical pathological features and prognosis was analyzed. Results: Positive expression of PTK7 was observed mainly in the cytoplasm, presenting as brownish yellow granules. It was noted that expression of PTK7 in pancreatic ductal adenocarcinoma tissues and para-carcinoma tissues was 70.6% (60/85) and 52.9% (45/85), respectively, and the positive rate in pancreatic ductal adenocarcinoma tissues was significantly higher than that in para-carcinoma tissues; the difference was statistically significant (P<0.05). The abnormal expression of PTK7 was correlated with the tumor stage, lymph node metastasis, and the vascular tumor embolus (P<0.05). The survival analysis suggested that the survival time or recurrence-free time of patients with PTK7 high expression in pancreatic duct adenocarcinoma was significantly shorter than in those with low expression (P<0.05, respectively). ShRNA interference of PTK7 was successfully established in the cell stabilizing system, verified by MTT and clone formation. Results indicated that cell survival was significantly lower in the shRNA experimental group compared to the control group (P<0.05), the number of colonies formed was significantly smaller in the shRNA experimental group compared to the control group (P<0.05), and the expression of proliferation-related proteins Ki-67 and PCNA was significantly lower in the shRNA experimental group compared to the control group (P<0.05, respectively). Conclusions: The up-regulation of PTK7 expression in pancreatic ductal ad-enocarcinoma tissues was associated with the tumor stage, lymph node metastasis, and the vascular tumor thrombus, suggesting poor prognosis. It was also found that in pancreatic cancer cell lines, PTK7 could promote the proliferation of pancreatic cancer cells by regulating the levels of proliferative factors Ki-67 and PCNA.
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Objective To study the clinical experience on pancreaticoduodenectomy (PD) in thepast three years from a single operation group at the Cancer Institute and Hospital of Tianjin Medical Universiy.Methods The clinical data of 118 patients who underwent PD from January 2015 to December 2017 were collected and analyzed retrospectively.Results Of the 118 patients who underwent PDs,102 underwent open pancreaticoduodenectomy (OPD) (86.4%),and 16 laparoscopic pancreaticoduodenectomy (LPD) (13.6%).There were 54.2% males with a age of (56.0±12.0) years (39.83% over 60 years).Malignancy was confirmed by pathology in 73.7% (87/118 patients).The operative time was (324.0±95.6) minutes.Intraoperative blood loss was (192.8±97.5) ml and R0 resection was achieved in all patients.The postoperative complication rate was 46.6% (55/118).The median postoperative hospital stay was (19.9±9.5) days.There was no perioperative mortality.The operation time of LPD was significantly longer than OPD,but there was no significant difference in intraoperative bleeding,lymph node clearance,postoperative complication rate and postoperative hospital stay (P>0.05).Conclusions PD is safe and feasible.The postoperative complication rate was relatively high but all patients were discharged from hospital after appropriate treatment.Compared with OPD,LPD is a better alternative for patients.
ABSTRACT
BACKGROUND: Sinus bradycardia is frequently observed in patients treated with crizotinib, a receptor tyrosine kinase inhibitor used for the treatment of anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). We investigated whether crizotinib could influence heart rate (HR) through direct cardiac effects. METHODS: The direct effect of crizotinib on HR was studied using ECG analysis of Langendorff-perfused mouse hearts. The whole-cell patch clamp technique was used to measure the effects of crizotinib on the hyperpolarization-activated funny current, If, in mouse sinoatrial node cells (SANCs) and hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) activity in HEK-293 cells stably expressing human HCN4. RESULTS: Crizotinib resulted in a dose-dependent reduction in HR in isolated intact mouse hearts with a half maximal inhibitory concentration (IC50) of 1.7 ± 0.4 µmol/L. Because ECG analysis revealed that crizotinib (0-5 µmol/L) resulted in significant reductions in HR in isolated mouse hearts without changes in PR, QRS, or QT intervals, we performed whole-cell patch clamp recordings of SANCs which showed that crizotinib inhibited If which regulates cardiac pacemaker activity. Crizotinib resulted in diminished current density of HCN4, the major molecular determinant of If, with an IC50 of 1.4 ± 0.3 µmol/L. Crizotinib also slowed HCN4 activation and shifted the activation curve to the left towards more hyperpolarized potentials. CONCLUSIONS: Our results suggest that crizotinib's effects on HCN4 channels play a significant role in mediating its observed effects on HR.
ABSTRACT
Polymorphisms in Disrupted-in-Schizophrenia 1 (DISC1) and Neuregulin 1 (NRG1) might be associated with schizophrenia; however, the conclusions of relevant studies were inconsistent across different ethnic populations. This population-based case-control study was carried out to determine whether polymorphisms in these two genes could be associated with schizophrenia in the Chinese population. A case-control study of 248 schizophrenia patients and 236 controls was performed with the Sequenom MassARRAY platform. The results revealed that the DISC1 rs821616 heterozygous (AT vs. AA: adjusted OR, 1.98, 95%CI: 1.30-3.02) and co-dominant (AT/TT vs. AA: adjusted OR=1.94; 95%CI: 1.29-2.92) patterns were associated with increased risk for developing schizophrenia in all participants and subgroups (stratified by sex and age at onset), respectively. Moreover, in the male subgroup, the DISC1 rs821597 genotype GA or GA/AA exhibited increased risk of schizophrenia. For NRG1 polymorphisms, in the early onset subgroup (≤25years), the rs3924999 G/G genotype was susceptible to schizophrenia. The interaction of DISC1 rs821616 T allele with the NRG1 rs3924999 A allele or that of DISC1 rs821597 A allele with NRG1 rs3924999 A allele had synergic effects on the development of schizophrenia. This study concluded that carriers of the DISC1 rs821616 T allele have increased risk for developing schizophrenia, and that the DISC1 rs821597 A allele was susceptible to schizophrenia for the male, and that there are marked interactions between the DISC1 rs821616 T and/or rs821597 A alleles and the NRG1 rs3924999 A allele for the development of schizophrenia.
Subject(s)
Asian People/genetics , Genetic Association Studies , Genetic Predisposition to Disease , Nerve Tissue Proteins/genetics , Neuregulin-1/genetics , Polymorphism, Single Nucleotide/genetics , Schizophrenia/genetics , Case-Control Studies , Demography , Female , Humans , Male , Middle AgedABSTRACT
The role of estrogen signaling in regulating prostate tumorigenesis is relatively underexplored. Although, an increasing body of evidence has linked estrogen receptor beta (ERß) to prostate cancer, the function of estrogen receptor alpha (ERα) in prostate cancer is not very well studied. We have discovered a novel role of ERα in the pathogenesis of prostate tumors. Here, we show that prostate cancer cells express ERα and estrogen induces oncogenic properties in prostate cancer cells through ERα. Importantly, ERα knockdown in the human prostate cancer PacMetUT1 cells as well as pharmacological inhibition of ERα with ICI 182,780 inhibited osteoblastic lesion formation and lung metastasis in vivo. Co-culture of pre-osteoblasts with cancer cells showed a significant induction of osteogenic markers in the pre-osteoblasts, which was attenuated by knockdown of ERα in cancer cells suggesting that estrogen/ERα signaling promotes crosstalk between cancer and osteoblastic progenitors to stimulate osteoblastic tumorigenesis. These results suggest that ERα expression in prostate cancer cells is essential for osteoblastic lesion formation and lung metastasis. Thus, inhibition of ERα signaling in prostate cancer cells may be a novel therapeutic strategy to inhibit the osteoblastic lesion development as well as lung metastasis in patients with advanced prostate cancer.
Subject(s)
Bone Neoplasms/metabolism , Cell Transformation, Neoplastic/metabolism , Estrogen Receptor alpha/antagonists & inhibitors , Estrogens/metabolism , Lung Neoplasms/metabolism , Osteoblasts/metabolism , Prostatic Neoplasms/metabolism , Animals , Bone Neoplasms/genetics , Bone Neoplasms/prevention & control , Bone Neoplasms/secondary , Cell Line, Tumor , Cell Proliferation , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/pathology , Coculture Techniques , Epithelial-Mesenchymal Transition , Estrogen Antagonists/pharmacology , Estrogen Receptor alpha/genetics , Estrogen Receptor alpha/metabolism , Estrogens/pharmacology , Gene Expression Regulation, Neoplastic , Humans , Lung Neoplasms/genetics , Lung Neoplasms/prevention & control , Lung Neoplasms/secondary , Male , Mice, Nude , Osteoblasts/drug effects , Osteoblasts/pathology , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/genetics , Prostatic Neoplasms/pathology , RNA Interference , Signal Transduction , Time Factors , Transfection , Xenograft Model Antitumor AssaysABSTRACT
Simultaneous substitution of three amino acid residues in the calmodulin binding domain (W3587A/L3591D/F3603A, ADA) of the cardiac ryanodine receptor ion channel (RyR2) impairs calmodulin inhibition of RyR2 and causes cardiac hypertrophy and early death of Ryr2ADA/ADA mice. To determine the physiological significance of growth promoting signaling molecules, the protein and phosphorylation levels of Ser/Thr kinase mTOR and upstream and downstream signaling molecules were determined in hearts of wild-type and Ryr2ADA/ADA mice. Phosphorylation of mTOR at Ser-2448, and mTOR downstream targets p70S6 kinase at Thr-389, S6 ribosomal protein at Ser-240/244, and 4E-BP1 at Ser-65 were increased. However, there was no increased phosphorylation of mTOR upstream kinases PDK1 at Ser-241, AKT at Thr-308, AMPK at Thr-172, and ERK1/2 at Thr-202/Tyr204. To confirm a role for mTOR signaling in the development of cardiac hypertrophy, rapamycin, an inhibitor of mTOR, was injected into wild-type and mutant mice. Rapamycin decreased mouse heart-to-body weight ratio, improved cardiac performance, and decreased phosphorylation of mTOR and downstream targets p70S6K and S6 in 10-day-old Ryr2ADA/ADA mice but did not extend longevity. Taken together, the results link a dysfunctional RyR2 to an altered activity of signaling molecules that regulate cardiac growth and function.
ABSTRACT
BACKGROUND: The purpose of this study was to determine the clinical value of three-dimensional (3D) computer reconstruction technology in pre-operative assessment and surgical planning for liver autotransplantation in patients with end-stage hepatic alveolar echinococcosis (HAE). STUDY DESIGN: Fifteen end-stage HAE patients received surgical treatment in our hospital between May 2011 and July 2014. 3D reconstruction and virtual surgeries were performed on diseased livers using a 3D reconstruction system for liver (IQQA-Liver). The feasibility and safety of liver autotransplantation were assessed for successful implementation of surgery. The results were compared with intraoperative conditions and computed tomography (CT) to verify the accuracy of pre-operative evaluation. RESULTS: Fifteen patients underwent liver resections and liver autotransplantation using surgical strategies consistent with pre-operative surgical planning in 3D reconstruction. Furthermore, there was no significant difference between whole-liver volume (2848.26 ± 798.41 vs. 2598.70 ± 822.45 cm(3), t = -4.635, P > 0.05) and lesion volume (1159.09 ± 789.47 vs. 1213.14 ± 813.76 cm(3), t = -1.959, P > 0.05) measured by 3D and traditional two-dimensional (2D) manual tracing from CT. The remaining liver volumes calculated by 3D and 2D CT were 810.47 ± 214.05 and 892.00 ± 262.36 cm(3) (t = -3.275, P > 0.05), with an average error rate of 6.2 and 16.5%, respectively. The pre-operative remaining liver volumes estimated by the two methods were positively correlated with the actual weight (783.67 ± 217.74 g) after the surgery (r three-dimensional = 0.976, r multislice CT = 0.883, P < 0.01). CONCLUSIONS: An individualized liver reconstruction technique can provide comprehensive anatomic information on livers of patients with end-stage HAE. Pre-operative virtual surgery can effectively improve the success rate of liver autotransplantation and reduce the risks of surgery.
Subject(s)
Echinococcosis, Hepatic/surgery , End Stage Liver Disease/surgery , Imaging, Three-Dimensional , Liver Transplantation/methods , Liver/pathology , Tomography, X-Ray Computed/methods , User-Computer Interface , Adult , Echinococcosis, Hepatic/complications , Echinococcosis, Hepatic/diagnostic imaging , End Stage Liver Disease/parasitology , Female , Hepatectomy , Humans , Liver/diagnostic imaging , Liver Transplantation/adverse effects , Male , Organ Size , Patient Care Planning , Preoperative Period , Transplantation, Autologous/adverse effectsABSTRACT
In cardiac muscle, calmodulin (CaM) regulates the activity of several membrane proteins involved in Ca(2+) homeostasis (CaV1.2; RyR2, SERCA2, PMCA). Three engineered amino acid substitutions in the CaM binding site of the cardiac ryanodine receptor (RyR2) in mice (Ryr2 (ADA/ADA) ) strongly affect cardiac function, with impaired CaM inhibition of RyR2, reduced SR Ca(2+) sequestration, and early cardiac hypertrophy and death (Yamaguchi et al., J Clin Invest 117:1344-1353, 2007). We have examined the ultrastructure and RyR2 immunolocalization in WT and Ryr2 (ADA/ADA) hearts at ~10 days after birth. The myocytes show only minor evidence of structural damage: some increase in intermyofibrillar space, with occasional areas of irregular SR disposition and an increase in frequency of smaller myofibrils, despite an increase of about 15 % in average myocyte cross sectional area. Z line streaming, a sign of myofibrillar stress, is limited and fairly rare. Immunolabeling with an anti-RyR2 antibody shows that RyR-positive foci located at the level of the Z lines are less frequent in mutant hearts. A dramatic decrease in the frequency and size of dyads, accompanied by a decrease in occupancy of the gap by RyR2, but without obvious alterations in location and general structure is a notable ultrastructural feature. The data suggest that the uneven distribution of dyads or calcium release sites within the cells resulting from an overall reduction in RyR2 content may contribute to the poor cardiac performance and early death of Ryr2 (ADA/ADA) mice. An unusual fragmentation of mitochondria, perhaps related to imbalances in free cytoplasmic calcium levels, accompanies these changes.
Subject(s)
Calcium/metabolism , Calmodulin/metabolism , Myocardium/metabolism , Myocytes, Cardiac/metabolism , Ryanodine Receptor Calcium Release Channel/metabolism , Sarcoplasmic Reticulum/metabolism , Animals , Calmodulin/genetics , Mice , Mice, Mutant Strains , Myocardial Contraction , Myocardium/pathology , Myocytes, Cardiac/pathology , Ryanodine Receptor Calcium Release Channel/genetics , Sarcoplasmic Reticulum/geneticsABSTRACT
Mice with genetically modified cardiac ryanodine receptor (Ryr2 (ADA/ADA) mice) are impaired in regulation by calmodulin, develop severe cardiac hypertrophy and die about 2 weeks after birth. We hypothesized that the interleukin 6 (IL-6)/signal transducer and activator of transcription-3 (STAT3) signaling pathway has a role in the development of the Ryr2 (ADA/ADA) cardiac hypertrophy phenotype, and determined cardiac function and protein levels of IL-6, phosphorylation levels of STAT3, and downstream targets c-Fos and c-Myc in wild-type and RyR2 (ADA/ADA) mice, mice with a disrupted IL-6 gene, and mice treated with STAT3 inhibitor NSC74859. IL-6 protein levels were increased at postnatal day 1 but not day 10, whereas pSTAT3-Tyr705/STAT3 ratio and c-Fos and c-Myc protein levels increased in hearts of 10-day but not 1-day old Ryr2 (ADA/ADA) mice compared with wild type. Both STAT3 and pSTAT3-Tyr705 accumulated in the nuclear fraction of 10-day old Ryr2 (ADA/ADA) mice compared with wild type. Ryr2 (ADA /ADA) /IL-6(-/-) mice lived 1.5 times longer, had decreased heart to body weight ratio, and reduced c-Fos and c-Myc protein levels. The STAT3 inhibitor NSC74859 prolonged life span by 1.3-fold, decreased heart to body weight ratio, increased cardiac performance, and decreased pSTAT-Tyr705/STAT3 ratio and IL-6, c-Fos and c-Myc protein levels of Ryr2 (ADA /ADA) mice. The results suggest that upregulation of IL-6 and STAT3 signaling contributes to cardiac hypertrophy and early death of mice with a dysfunctional ryanodine receptor. They further suggest that STAT3 inhibitors may be clinically useful agents in patients with altered Ca(2+) handling in the heart.
ABSTRACT
In cardiac muscle, the release of calcium ions from the sarcoplasmic reticulum through ryanodine receptor ion channels (RyR2s) leads to muscle contraction. RyR2 is negatively regulated by calmodulin (CaM) and by phosphorylation of Ca2+/CaM-dependent protein kinase II (CaMKII). Substitution of three amino acid residues in the CaM binding domain of RyR2 (RyR2-W3587A/L3591D/F3603A, RyR2ADA) impairs inhibition of RyR2 by CaM and results in cardiac hypertrophy and early death of mice carrying the RyR2ADA mutation. To test the cellular function of CaMKII in cardiac hypertrophy, mutant mice were crossed with mice expressing the CaMKII inhibitory AC3-I peptide or the control AC3-C peptide in the myocardium. Inhibition of CaMKII by AC3-I modestly reduced CaMKII-dependent phosphorylation of RyR2 at Ser-2815 and markedly reduced CaMKII-dependent phosphorylation of SERCA2a regulatory subunit phospholamban at Thr-17. However the average life span and heart-to-body weight ratio of Ryr2ADA/ADA mice expressing the inhibitory peptide were not altered compared to control mice. In Ryr2ADA/ADA homozygous mice, AC3-I did not alter cardiac morphology, enhance cardiac function, improve sarcoplasmic reticulum Ca2+ handling, or suppress the expression of genes implicated in cardiac remodeling. The results suggest that CaMKII was not required for the rapid development of cardiac hypertrophy in Ryr2ADA/ADA mice.
Subject(s)
Calcium-Calmodulin-Dependent Protein Kinase Type 2/antagonists & inhibitors , Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism , Cardiomegaly/metabolism , Ryanodine Receptor Calcium Release Channel/metabolism , Animals , Calcium/metabolism , Calcium-Calmodulin-Dependent Protein Kinase Type 2/chemistry , Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics , Cardiomegaly/diagnosis , Cardiomegaly/genetics , Cardiomegaly/mortality , Disease Models, Animal , Echocardiography , Gene Expression , Mice , Mice, Transgenic , Mutation , Myocardium/metabolism , Myocardium/pathology , Peptide Fragments/pharmacology , Phosphorylation , Protein Kinase C/genetics , Protein Kinase C/metabolism , RNA, Messenger/geneticsABSTRACT
BACKGROUND: The aim of this study is to evaluate the clinical results of laparoscopic surgery compared with conventional surgery. METHODS: Records of patients who underwent surgery for liver hydatid disease between 2005 and 2011 were reviewed. Operative time, blood loss, conversion to open, postoperative morbidity, mortality, hospital stay, and recurrence rate were measured. RESULTS: Among 353 eligible patients, 60 were considered for laparoscopic and 293 for conventional surgery. Operative time was slightly increased in laparoscopic group. No major blood loss and blood transfusion were needed. Postoperative hospital stay was significantly short in laparoscopic group (3.8 ± 1.2 days) than that in conventional group (7.4 ± 1.4 days). The overall morbidity was 13.3 % (8/60) in laparoscopic and 19.8 % (58/293) in conventional group without significance. Both conversion rate and mortality was 0 %. One recurrence in laparoscopic (1.7 %, 1/60) and five in conventional group (1.7 %, 5/293) occurred within 48 months of follow-up. CONCLUSIONS: Laparoscopic treatment of liver hydatid disease is safe and effective in selected patients with all its advantages.
Subject(s)
Echinococcosis, Hepatic/surgery , Laparoscopy , Surgical Wound Infection/etiology , Albendazole/therapeutic use , Anticestodal Agents/therapeutic use , Blood-Nerve Barrier , Conversion to Open Surgery , Echinococcosis, Hepatic/drug therapy , Female , Hepatectomy/adverse effects , Hepatectomy/methods , Humans , Laparoscopy/adverse effects , Length of Stay , Male , Middle Aged , Operative Time , Recurrence , Retrospective StudiesABSTRACT
OBJECTIVE: The aim of this study was to provide a review of the world literature on the laparoscopic treatment of liver hydatid cyst. METHODS: We conducted a literature search using PubMed, screening all English language publications on the laparoscopic treatment of liver hydatid cysts. Operative characteristics, perioperative morbidity, and clinical outcomes were tabulated. RESULTS: A total of 57 published articles including 914 patients with 1116 hydatid cysts were identified. Of the resections done in the 914 patients, 89.17% were performed totally laparoscopically and 5.58% were gasless. The most common procedure was cystectomy (60.39%), followed by partial pericystectomy (14.77%) and pericystectomy (8.21%); the rest were segmentectomies. Conversion to open laparotomy occurred in 4.92% of reported cases (45/914). The common cause of conversion was anatomical limitations/inaccessible locations (16/45). The overall mortality was 0.22% (2/914 patients) and morbidity was 15.07%, with no intraoperative deaths reported. The most common complication was bile leakage (57/914). The postoperative recurrence was 1.09% (10/914 patients). CONCLUSIONS: The laparoscopic approach is safe with acceptable mortality and morbidity for both conservative and radical resections in selected patients. Clinical outcomes are comparable to open surgery, albeit in a selected group of patients.
Subject(s)
Anastomotic Leak/surgery , Bile Ducts, Intrahepatic/surgery , Echinococcosis, Hepatic/surgery , Laparoscopy/methods , Liver/surgery , Postoperative Complications , Adolescent , Adult , Aged , Anastomotic Leak/etiology , Anastomotic Leak/pathology , Animals , Bile Ducts, Intrahepatic/pathology , Child , Child, Preschool , Echinococcosis, Hepatic/mortality , Echinococcosis, Hepatic/parasitology , Echinococcosis, Hepatic/pathology , Echinococcus/physiology , Female , Humans , Laparoscopy/adverse effects , Length of Stay/statistics & numerical data , Liver/parasitology , Liver/pathology , Male , Middle Aged , Recurrence , Survival AnalysisABSTRACT
BACKGROUND/AIMS: To conduct a systematic review of observational studies to evaluate effectiveness of surgery for liver hemangioma. METHODOLOGY: Related studies were identified using different searching engines. Two reviewers independently extracted data on mortality, morbidity and symptoms recurrence and/or aggravation. RESULTS: Sixteen studies with a total of 1485 patients (402 in surgery and 1085 in observation group) were included in the analysis. Two deaths in surgical group (8.0%, 2/25) and two deaths in observation group (1.4%, 2/143) were reported. The RRs for mortality were not homogeneous (χ2=3.40, 1 d.f., P=0.07, I2=71 per cent). The RRs for morbidity were homogeneous across studies (x2=5.55, 12 d.f., P=0.94, I2=0 per cent). Morbidity in surgery group was significantly higher than that in observation group (RR=14.7, 95 per cent c.i. 9.56 to 45.63). Eight studies reported the symptom aggravation and RRs were heterogeneous (x2=31.03, 7 d.f., P<0.0001, I2=77 per cent), However, showed no statistical difference. CONCLUSION: The currently involved retrospective cohort studies of surgical series were likely to imply that surgery may take more risks than the benefits for non-emergency hemangioma patients.
Subject(s)
Hemangioma/surgery , Liver Neoplasms/surgery , Hemangioma/mortality , Humans , Liver Neoplasms/mortality , MorbidityABSTRACT
The cardiac ryanodine receptor (RyR2) is inhibited by calmodulin (CaM) and S100A1. Simultaneous substitution of three amino acid residues (W3587A, L3591D, F3603A; RyR2ADA) in the CaM binding domain of RyR2 results in loss of CaM inhibition at submicromolar (diastolic) and micromolar (systolic) Ca²âº, cardiac hypertrophy, and heart failure in Ryr2ADA/ADA mice. To address whether cardiac hypertrophy results from the elimination of CaM and S100A1 inhibition at diastolic or systolic Ca²âº, a mutant mouse was generated with a single RyR2 amino acid substitution (L3591D; RyR2D). Here we report that in single-channel measurements RyR2-L3591D isolated from Ryr2D/D hearts lost CaM inhibition at diastolic Ca²âº only, whereas S100A1 regulation was eliminated at both diastolic and systolic Ca²âº. In contrast to the ~2-wk life span of Ryr2ADA/ADA mice, Ryr2D/D mice lived longer than 1 yr. Six-month-old Ryr2D/D mice showed a 9% increase in heart weight-to-body weight ratio, modest changes in cardiac morphology, and a twofold increase in atrial natriuretic peptide mRNA levels compared with wild type. After 4-wk pressure overload with transverse aortic constriction, heart weight-to-body weight ratio and atrial natriuretic peptide mRNA levels increased and echocardiography showed changes in heart morphology of Ryr2D/D mice compared with sham-operated mice. Collectively, the findings indicate that the single RyR2-L3591D mutation, which distinguishes the effects of diastolic and systolic Ca²âº, alters heart size and cardiac function to a lesser extent in Ryr2D/D mice than the triple mutation in Ryr2ADA/ADA mice. They further suggest that CaM inhibition of RyR2 at systolic Ca²âº is important for maintaining normal cardiac function.
Subject(s)
Calmodulin/metabolism , Cardiomegaly/metabolism , Ryanodine Receptor Calcium Release Channel/metabolism , S100 Proteins/metabolism , Action Potentials , Animals , Atrial Natriuretic Factor/genetics , Atrial Natriuretic Factor/metabolism , Binding Sites , Calcium/metabolism , Calcium Signaling , Cardiomegaly/pathology , Heart Failure/metabolism , Mice , Mice, Inbred C57BL , Mice, Mutant Strains , Mutation, Missense , Myocardial Contraction , RNA, Messenger/metabolism , Ryanodine Receptor Calcium Release Channel/chemistry , Ryanodine Receptor Calcium Release Channel/genetics , Ryanodine Receptor Calcium Release Channel/physiology , Transcription, GeneticABSTRACT
Surgery is still the main modality in the treatment of hepatic hydatid disease. Laparoscopic methods, with their low morbidity, have gained prominence in many fields and, in some cases, have nearly replaced open surgery. In this report, a laparoscopic method for the treatment of hepatic hydatid disease is described, and the results in the 46 cases are presented and the published articles were reviewed. The method involves laparoscopic cystectomy, pericystectomy, and liver resection for hydatid disease. The postoperative courses of the patients were very comfortable and no complication related to the laparoscopic technique occurred. The postoperative parameters and the early follow-up results (average, 18 mo) are very encouraging. Laparoscopic treatment of liver hydatid disease is safe and effective in selected patients and offers all the advantages of a laparoscopic surgery. In experienced hands, laparoscopic pericystectomy have lower morbidity and recurrence rate compared with cystectomy.