Hydrogen-Bonded Thiol Undergoes Unconventional Excited-State Intramolecular Proton-Transfer Reactions.

The chapter on the thiol-related hydrogen bond (H-bond) and its excited-state intramolecular proton-transfer (ESIPT) reaction was recently opened where compound 4'-diethylamino-3-mercaptoflavone (3NTF) undergoes ESIPT in both cyclohexane solution and solid, giving a 710 nm tautomer emission with an anomalously large Stokes shift of 12,230 cm-1. Considering the thiol H-bond to be unconventional compared to the conventional Pauling-type -OH or -NH H-bond, it is thus essential and timely to probe its fundamental difference between their ESIPT. However, thiol-associated ESIPT tends to be nonemissive due to the dominant nπ* character of the tautomeric lowest excited state. Herein, based on the 3-mercaptoflavone scaffold and π-elongation concept, a new series of 4'-substituted-7-diethylamino-3-mercaptoflavones, NTFs, was designed and synthesized with varied H-bond strength and 690-720 nm tautomeric emission upon ultraviolet (UV) excitation in cyclohexane. The order of their H-bonding strength was experimentally determined to be N-NTF < O-NTF < H-NTF < F-NTF, while the rate of -SH ESIPT measured by fluorescence upconversion was F-NTF (398 fs)-1 < H-NTF (232 fs)-1 < O-NTF (123 fs)-1 < N-NTF (101 fs)-1 in toluene. Unexpectedly, the strongest H-bonded F-NTF gives the slowest ESIPT, which does not conform to the traditional ESIPT model. The results are rationalized by the trend of carbonyl oxygen basicity rather than -SH acidity. Namely, the thiol acidity relevant to the H-bond strength plays a minor role in the driving force of ESIPT. Instead, the proton-accepting strength governs ESIPT. That is to say, the noncanonical thiol H-bonding system undergoes an unconventional type of ESIPT.

Comparison of Carotid Blood Flow Measured by Ultrasound and Cardiac Output in Patients Undergoing Cardiac Surgery.

BACKGROUND: In general, cerebral blood flow accounts for 10-15% of cardiac output (CO), of which about 75% is delivered through the carotid arteries. Hence, if carotid blood flow (CBF) is constantly proportional to CO with high reproducibility and reliability, it would be of great value to measure CBF as an alternative to CO. The aim of this study was to investigate the direct correlation between CBF and CO. We hypothesized that measurement of CBF could be a good substitute for CO, even under more extreme hemodynamic conditions, for a wider range of critically ill patients. METHODS: Patients aged 65-80 years, undergoing elective cardiac surgery were included in this study. CBF in different cardiac cycles were measured by ultrasound: systolic carotid blood flow (SCF), diastolic carotid blood flow (DCF), and total (systolic and diastolic) carotid blood flow (TCF). CO simultaneously was measured by transesophageal echocardiography. RESULTS: For all patients, the correlation coefficients between SCF and CO, TCF and CO were 0.45 and 0.30, respectively, which were statistically significant, but not between DCF and CO. There was no significant correlation between either SCF, TCF or DCF and CO, when CO was <3.5 L/min. CONCLUSIONS: Systolic carotid blood flow may be used as a better index to replace CO. However, the method of direct measurement of CO is essential when the patient's heart function is poor.

Management for lower limb malperfusion in acute type a aortic dissection patients.

OBJECTIVE: Acute type A aortic dissection (ATAAD) accompanied with lower limb malperfusion (LLM) is considered to be a catastrophic event, and remains a great challenge for cardiac surgeons. Here we introduce our experience in treating ATAAD patients accompanied with LLM. METHODS: 61 patients diagnosed with ATAAD accompanied by LLM enrolled in this study. All patients received aortic repair (Total-arch replacement or Hemi-arch replacement) as soon as possible on admission. Patients who still suffered LLM were performed extra-anatomic bypass using artificial vessels. All the discharged patients underwent the standard follow-up protocol. RESULTS: 38 patients (38/61, 62.3%) got satisfied reperfusion of the lower limbs after aortic repair while the others did not. Five patients had femorofemoral bypass, 16 received aortofemoral bypass, and two underwent aortofemoral bypass plus femorofemoral bypass. The ICU stay time was 5.4 ± 3.6 days. Fifty-five patients were discharged home successfully, while six patients died postoperatively with hospital mortality of 9.8%. Major postoperative complications included acute kidney injury requiring hemodialysis in seven patients, delayed wake-up (>3 days) in 5, prolonged ventilation (>4 days) in 8, and lower limb ischaemia in 1. Follow-up was successfully conducted in 50 patients with a mean follow-up time 4.9 ± 2.6 years. Five patients died during the follow-up. The estimated 5-year survival rate was 87.5 ± 6.1%. CTA images showed 100% patency of the extra-anatomic bypass. CONCLUSION: Aortic repair plus concomitant extra-anatomic bypass grafting in one operative setting could be a simple, safe and effective treatment on ATAAD patients with LLM.

A novel survival rat model of hyperkalemia and landiolol induced cardioplegic arrest and resuscitation via cardiopulmonary bypass.

OBJECTIVE: A small animal model would be an effective tool for research on the pathophysiology of cardiopulmonary bypass (CPB). However, numerous CPB models do not involve myocardial arrest and resuscitation. The aim of this research is to establish an easily achievable myocardial arrest and resuscitation CPB model through hyperkalemia and landiolol, simulating clinical cardiac surgery. MATERIALS AND METHODS: Ten Sprague-Dawley rats were chosen for CPB. Rats underwent sevoflurane inhalation induction anesthesia and were sustained in an anesthesia state by intubation and intraperitoneal injection's of esketamine and propofol. The entire CPB circuit include a reservoir, a membrane oxygenator and a roller pump, which were connected into a complete loop via silicon tubes and infusion tube.After CPB was established through the tail artery and internal jugular vein, cardioplegic arrest was induced and maintained for 5 min at a rectum temperature of 28.5 ± 0.5°C with hyperkalemia and landiolol. Calcium chloride, epinephrine and insulin were then used for resuscitation. RESULT: All rats successfully finished cardioplegic arrest, resuscitation procedure and survived 2 h postoperatively. Mean hematocrit during CPB was significantly lower than physiologic values of the baseline. The mean time of arrest-resuscitation and CPB was 5.4 ± 0.8 min and 98.5 ± 5.0 min. The blood gas at each detection point were in range with the normal standard requirement of CPB. CONCLUSION: The establishment of cardioplegic arrest and resuscitation procedure via hyperkalemia and landiolol during CPB of WD rat could be achieved successfully. This animal model could be an alternative organ injury research on organ injury of patients undergoing cardiac surgery.

Gold-Catalyzed [3+2]-Annulations of α-Aryl Diazoketones with the Tetrasubstituted Alkenes of Cyclopentadienes: High Stereoselectivity and Enantioselectivity.

This work reports gold-catalyzed [3+2]-annulations of α-diazo ketones with highly substituted cyclopentadienes, affording bicyclic 2,3-dihydrofurans with high regio- and stereoselectivity. The reactions highlights the first success of tetrasubstituted alkenes to undergo [3+2]-annulations with α-diazo carbonyls. The enantioselective annulations are also achieved with high enantioselectivity using chiral forms of gold and phosphoric acid. Our mechanistic analysis supports that cyclopentadienes serve as nucleophiles to attack gold carbenes at the more substituted alkenes, yielding gold enolates that complex with chiral phosphoric acid to enhance the enantioselectivity.

DynaPho: a web platform for inferring the dynamics of time-series phosphoproteomics.

Summary: Large-scale phosphoproteomics studies have improved our understanding of dynamic cellular signaling, but the downstream analysis of phosphoproteomics data is still a bottleneck. We develop DynaPho, a useful web-based tool providing comprehensive and in-depth analyses of time-course phosphoproteomics data, making analysis intuitive and accessible to non-bioinformatics experts. The tool currently implements five analytic modules, which reveal the transition of biological pathways, kinase activity, dynamics of interaction networks and the predicted kinase-substrate associations. These features can assist users in translating their larger-scale time-course phosphoproteomics data into valuable biological discoveries. Availability and implementation: DynaPho is freely available at http://dynapho.jhlab.tw/ . Contact: hsuancheng@ym.edu.tw or yukijuan@ntu.edu.tw . Supplementary information: Supplementary data are available at Bioinformatics online.

Comparison of surgical and conservative treatment outcomes for type a aortic intramural hematoma.

OBJECTIVE: This study aimed to compare hospital and long-term clinical outcomes associated with various treatment methods for Stanford A type aortic intramural hematoma (IMH) to provide a reference for clinical decision-making. METHODS: In this single-center cohort study, we retrospectively analyzed 73 patients with Type A IMH treated at our center from August 1, 2018 to August 1, 2021. Among these patients, 26 were treated conservatively, and 47 underwent surgical intervention. We next compared this IMH cohort with 154 patients with acute type A aortic dissection (AD) who were treated surgically during the same study period. RESULTS: Computed tomography angiography revealed that the diameter of the ascending aorta of IMH patients treated with surgery was higher than IMH patients treated with conservative therapy (44.92 ± 7.58 mm vs. 51.22 ± 11.85 mm, P < 0.05), while there was no significant difference in other clinical parameters. The in-hospital mortality of patients with IMH who underwent surgical treatment was lower than those undergoing conservative treatment (0% vs. 11.5%, P < 0.05). The long-term mortality of the conservative IMH group was higher than the surgical IMH group (26.1% vs. 8.5%, P < 0.05). There was no significant difference in the surgical parameters and postoperative complications between AD and IMH surgery patients. The proportion of circulatory arrest time in the lower body (19.98 ± 9.39 min vs. 17.51 ± 3.97 min) and arch involvement (98 (63.6%) vs. 22 (46.8%)) in the IMH surgery group was lower than in the AD surgery group (P < 0.05). CONCLUSIONS: Compared with conservative treatment, surgical treatment of IMH significantly improves the survival rate of patients. Thus, surgical intervention should be considered the primary treatment option if feasible. Furthermore, The safety of IMH surgery can be guaranteed just like AD. But we still need in the future evidence on bigger samples.

Efficacy and safety of toripalimab with fruquintinib in the third-line treatment of refractory advanced metastatic colorectal cancer: results of a single-arm, single-center, prospective, phase II clinical study.

Background: The most effective treatment with immune checkpoint inhibitors (ICIs) is limited to the microsatellite instability high (MSI-H) subgroup of advanced colorectal cancer. ICIs are completely ineffective in microsatellite stabilized (MSS) patients with advanced colorectal cancer. Fruquintinib, a tyrosine kinase inhibitor (TKI) domestically made in China that specifically inhibits vascular endothelial growth factor receptors, is used to treat refractory metastatic colorectal cancer (mCRC). Researches showed that anti-angiogenic therapy combined with immunotherapy induces a long-lasting antitumor immune response. Here, we aimed to evaluate antitumor efficacy and safety of fruquintinib with anti-programmed death-1 (PD-1) antibody toripalimab in Chinese patients with non-MSI-H/mismatch repair proficient (pMMR) mCRC. Methods: This was a single-arm, single-center, prospective, phase II clinical trial. A total of 19 MSS patients with refractory or advanced mCRC were enrolled They received fruquintinib (5 mg, orally, once daily for 3 weeks followed by 1 week off in 4-week cycles) and toripalimab (240 mg, intravenously administered on day 1 once every 3 weeks) until disease progression or unacceptable toxicity. The objective response rate (ORR), progression-free survival (PFS), overall survival (OS), 1-year PFS rate, disease control rate (DCR), and toxicity were reviewed and evaluated. The Cox regression model was used to analyze the influence on OS and PFS. Results: Among the 19 patients, the median age was 52 years (range, 30-71 years); 4 patients (21.05%) achieved partial response, 10 patients (52.63%) experienced stable disease, and 4 patients (21.05%) experienced progressive disease. The ORR was 21.05%. The median PFS and OS were 5.98 months and 11.10 months, respectively. Patients with peritoneal metastasis received greater benefit from combination therapy, with a longer PFS (P=0.043) in the univariate analysis. The most common treatment-related adverse reactions were fatigue (57.89%), hepatic dysfunction (42.11%) and hypertension (36.84%). No serious adverse effects or adverse effect-related deaths were reported. Conclusions: Our study provides evidence supporting fruquintinib combined with an anti-PD-1 monoclonal antibody have the better effect than fruquintinib alone in the third-line setting for Chinese patients with MSS advanced colorectal cancer. Primary lesion excision and peritoneal metastasis were independent prognostic factors of PFS. Further well-designed, prospective, large-scale studies are needed to validate this outcome.

Molecular Dynamics Simulations of the Mechanical Properties of Cellulose Nanocrystals-Graphene Layered Nanocomposites.

Cellulose nanocrystals (CNCs) have received a significant amount of attention due to their excellent physiochemical properties. Herein, based on bioinspired layered materials with excellent mechanical properties, a CNCs-graphene layered structure with covalent linkages (C-C bond) is constructed. The mechanical properties are systematically studied by molecular dynamics (MD) simulations in terms of the effects of temperature, strain rate and the covalent bond content. Compared to pristine CNCs, the mechanical performance of the CNCs-graphene layered structure has significantly improved. The elastic modulus of the layered structure decreases with the increase of temperature and increases with the increase of strain rate and covalent bond coverage. The results show that the covalent bonding and van der Waals force interactions at the interfaces play an important role in the interfacial adhesion and load transfer capacity of composite materials. These findings can be useful in further modeling of other graphene-based polymers at the atomic scale, which will be critical for their potential applications as functional materials.

Outcomes of surgical treatment on type A acute aortic dissection accompanied with coronary artery involvement.

Background: Coronary artery (CA) involvement due to acute aortic dissection (AAD) is a catastrophic cardiovascular disease with high mortality. Two main surgery strategies, local coronary repair and coronary artery bypass grafting (CABG) can be applied to reestablish the blood flow in the aortic repair. This study was to evaluate the operative and long-term outcomes of type A AAD patients, who received aortic dissection repair plus CABG or local coronary repair. Method: We reviewed our database and screened 148 type A AAD patients with CA involvement from January 2001 to December 2021. Local coronary repair or CABG was performed concomitantly on these enrolled patients. Results: At the time of aortic repair, there were 58 patients with concomitant CABG (Group I) and 90 patients with local coronary repair (Group II). The basal characteristics of these two groups had no difference, except for acute myocardial ischemia (AMI) and CA involvement type. 45 patients with AMI in Group I, but none in Group II (P < 0.001). There was a higher frequency of type B and C lesions of CA involvement in Group I than that in Group II (P < 0.001). There was no difference in surgical procedures and complications, except for postoperative acute kidney injury (AKI) (34.5% vs. 8.9%, P < 0.001). Hospital mortality in Group I was higher than that in Group II, but without statistical difference (20.7% vs. 11.1%, P = 0.155). No significant difference was obtained in long-term survival rate between the two groups (82.5 ± 4.8% vs. 81.2 ± 6.9%, P = 0.19). Conclusion: CABG and local coronary repair suits different types of CA involvement, and their effects on perioperative results and long-term survival for type A AAD patients with CA involvement are equal.

Middle lobe preservation and fixation after right upper and lower lobectomy for synchronous lung cancer.

The incidence of multiple lung cancer has been steadily increasing worldwide. Although cases of patients with lung cancers in the right upper and lower lobe have also become more frequently reported in clinical work, simultaneous right upper and lower lobectomy reports with the middle lobe preservation are still quite rare. A total of three patients with lung cancers in the right upper and lower lobe were included in the study. The patients underwent simultaneous right upper and lower lobectomy, whereas the remaining middle lobe was sutured and fixed to the intercostal muscle of the incision to prevent postoperative lobe torsion. There was no procedure to reduce residual space，such as phrenic nerve crush or thoracoplasty. All patients were discharged from the hospital 7 days after the operation. The chest tube was removed 5 days after the operation in two patients. One patient was discharged with the tube because of slight pulmonary leakage, and the tube was removed 2 weeks after the operation. Six months after the operation, the chest computer tomography showed that the middle lobe expanded well and no obvious cavity or pleural effusion was found. The suture of the remaining middle lobe and intercostal muscle of the incision is a simple and effective method that can be used to successfully avoid middle lobe torsion. This strategy is safe and can be used as the first choice for eligible patients.

Correction: N/O co-enriched graphene hydrogels as high-performance electrodes for aqueous symmetric supercapacitors.

[This corrects the article DOI: 10.1039/D1RA01863A.].

N/O co-enriched graphene hydrogels as high-performance electrodes for aqueous symmetric supercapacitors.

In this study, an easy one-pot hydrothermal strategy was used to prepare N/O co-enriched graphene hydrogels (NOGHs) using graphene oxide (GO) solution and n-propylamine as a reactant. The n-propylamine can be used not only as a reductant, nitrogen dopant and structure regulator, but also as a spacer to inhibit the agglomeration of graphene sheets. Benefiting from the synergistic effect between the heteroatoms (N, O), 3D porous structures and high specific surface area, the as-prepared NOGH samples present excellent electrochemical properties. Remarkably, the NOGH-140 based binder-free symmetric supercapacitor shows a high specific capacitance of 268.1 F g-1 at the current density of 0.3 A g-1 and retains 222.5 F g-1 (82.9% of its initial value) at 10.0 A g-1 in 6 M KOH electrolyte. Furthermore, the assembled device also displays a notable energy density (9.3 W h kg-1) and outstanding cycling performance (1.8% increase of its initial specific capacitance after 10 000 cycles at 10 A g-1). The simple preparation method and excellent electrochemical properties indicate that NOGHs can be used as electrode materials for commercial supercapacitors.

Successful Radical Pneumonectomy for a Primitive Neuroendodermal Tumor in the Lung: A Case Report and Review of the Literature.

Peripheral primitive neuroendodermal tumors (PNETs) and Ewing's sarcoma belong to the Ewing family of tumors and are small round-cell malignancies originating from spinal cord cells. These tumors account for 5% of all small round-cell malignant neoplasms. PNETs that arise from the lung parenchyma without pleural or chest wall involvement are very rare. We report a case of an adult female with a large pulmonary PNET who had given birth just 1 month prior to the diagnosis. She had cough and expectoration for 6 months, and the preoperative examination showed no metastases. Thus, we performed radical pneumonectomy and lymph node dissection. The patient recovered well without surgical complications and was discharged 7 days after the surgery. Postoperative pathology confirmed that the tumor was a small round-cell malignancy, and the tumor cells were positive for CD99, Friend leukemia virus integration 1 (FLI-1), and neuron-specific enolase (NSE), which was consistent with the diagnosis of a PNET. For primary large pulmonary PNETs, radical pneumonectomy may be a safe surgical method, worthy of further application in clinical practice.

Upregulated long-non-coding RNA DLEU2 exon 9 expression was an independent indicator of unfavorable overall survival in patients with esophageal adenocarcinoma.

In this study, we aimed to explore the expression profiles of some known functional lncRNAs in esophageal adenocarcinoma (EAD) and to screening the potential prognostic makers, using data from The Cancer Genome Atlas (TCGA)-esophageal carcinoma (ESCA). Results showed that DLEU2 is a high potential OS related marker among 73 functional lncRNAs. DLEU2 and its intronic miR-15a and miR-16-1 expression were significantly upregulated in EAD compared with adjacent normal tissues. However, miR-15a and miR-16-1 expression were only weakly correlated with DLEU2 expression. Univariate and multivariate analysis confirmed that DLEU2 expression, but not miR-15a or miR-16-1 expression is an independent prognostic marker in terms of OS (HR:1.688, 95%CI: 1.085-2.627, p = 0.020) in EAD patients. The exon 9 of DLEU2 is very strongly co-expressed with DLEU2 (Pearson's r = 0.96) and showed better predictive value than total DLEU2 expression in predicting the OS of EAD patients. Multivariate analysis confirmed its independent prognostic value (HR:1.970, 95%CI: 1.266-3.067, p = 0.003), after adjustment of histologic grade, pathological stages and the presence of residual tumor. By checking the methylation status of DLEU2 gene, we excluded the possibility of the influence of two CpG sites near the DLEU2 exon 9 locus on its expression. In addition, although copy number alterations (CNAs) were observed DLEU2 gene, heterozygous loss (-1), low-level copy gain (+1) and high-level amplification (+2) had no significant association with DLEU2 transcription. Based on these findings, we infer that DLEU2 exon 9 expression might serve as a valuable biomarker of unfavorable OS in EAD patients.

MicroRNA expression profiles identify biomarkers for predicting the response to chemoradiotherapy in rectal cancer.

Neoadjuvant chemoradiotherapy (nCRT) following surgery significantly improves the survival rate of patients with rectal cancer. However, nCRT is associated with significant adverse symptoms and high medical costs. Therefore, it is important to investigate potential biomarkers for the prediction of the response to nCRT in patients with rectal cancer. The present study identified candidate biomarkers for predicting a complete response (CR) to nCRT in patients with rectal cancer and investigated the associated mechanisms. Microarray data (accession no. GSE29298) was downloaded from the Gene Expression Omnibus database. Differentially expressed microRNAs (miRNAs/miR) were screened between the pathological CR (pCR) group and no pCR (incomplete response) group. miRNA target genes were predicted using the miRWalk 2.0 online tool and subjected to Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. Furthermore, a miRNA co­regulatory network was constructed and disease­associated genes were predicted. The results demonstrated that a total of 36 upregulated and 5 downregulated miRNAs were identified between the two groups. Among these differentially expressed miRNAs, miR­548c­5p, miR­548d­5p and miR­663a were significantly associated with a CR to nCRT. The co­regulatory network and pathway analysis indicated that miR­548c­5p and miR­548d­5p may function together through stem cell pluripotency and ubiquitin­mediated proteolysis signaling pathways. Furthermore, the prediction of disease­associated genes demonstrated that miR­548c­5p/miR­548d­5p and miR­663a may regulate genes associated with rectal cancer, including mutated in colorectal cancers (MCC) and adenomatous polyposis coli (APC), and colorectal neoplasms, including interleukin­6 signal transducer (IL6ST), cell cycle checkpoint kinase 2 (CHEK2), marker of proliferation Ki­67 (MKI67), cadherin 7 (CDH7), calreticulin (CALR) and transforming growth factor ß1 (TGFB1). Therefore, miR­548c­5p, miR­548d­5p and miR­663a are promising candidate biomarkers for predicting a CR to nCRT. miR­548c­5p/miR­548d­5p may be associated with a CR by regulating IL6ST, CHEK2, MKI67 and MCC. In addition, it may function through the pluripotency of stem cells and ubiquitin­mediated proteolysis signaling pathways. miR­663a may be associated with a CR to nCRT by targeting CDH7, CALR, APC and TGFß1. Thus, the miRNA biomarkers investigated in the present study may represent novel therapeutic targets for the prediction and eventual improvement of the response to nCRT in patients with rectal cancer.

MFAP2 promotes epithelial-mesenchymal transition in gastric cancer cells by activating TGF-ß/SMAD2/3 signaling pathway.

INTRODUCTION: Microfibril-associated protein 2 (MFAP2) is an extracellular matrix protein that interacts with fibrillin to modulate the function of microfibrils. MFAP2 has been reported to play a significant role in obesity, diabetes, and osteopenia, and has been shown to be upregulated in head and neck squamous cell carcinoma. However, the molecular function and prognostic value of MFAP2 have never been reported in gastric cancer (GC) or any other tumors. METHODS: The current study investigated the expression patterns, prognostic significance, functional role, and possible mechanisms of MFAP2 in GC. RESULTS: We demonstrated that MFAP2 was overexpressed in GC tissues, and its overexpression was significantly correlated with poor overall and disease-free survival in patients with GC. Moreover, we found that MFAP2 promoted the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) phenotype in GC cells. MFAP2 might modulate EMT of GC cells by activating the TGF-ß/SMAD2/3 signaling pathway. CONCLUSION: These findings provide novel evidence that MFAP2 plays a crucial role in the progression of GC. Therefore, MFAP2 may be a promising prognostic marker and a potent anticancer agent.

MACC1 facilitates chemoresistance and cancer stem cell­like properties of colon cancer cells through the PI3K/AKT signaling pathway.

With regards to colon cancer, resistance to 5­fluorouracil (5­FU)­based chemotherapy and cancer stem cells (CSCs) are considered important factors underlying therapy failure. Metastasis­associated colon cancer 1 (MACC1) has been associated with poor prognosis and the promotion of metastasis within several types of cancer. However, the biological behavior of MACC1 in chemoresistance and CSC­like properties remains unclear. In the present study, various methods including gene knockdown, gene overexpression, western blotting, quantitative polymerase chain reaction and MTT assay, have been adopted. According to the results of the present study, MACC1 was depleted in two colon cancer cell lines resistant to 5­FU; subsequently, CSC­like properties and 5­FU sensitivity were investigated. Within 5­FU­resistant cells, cell death was facilitated by MACC1 knockdown. Furthermore, sphere formation and the expression levels of pluripotent markers, including cluster of differentiation (CD) 44, CD133 and Nanog were reduced due to MACC1 depletion. Additionally, it was indicated that the phosphoinositide 3­kinase/protein kinase B signaling pathway may be associated with 5­FU resistance and CSC­like properties via MACC1.

Activation of SphK1 by K6PC-5 Inhibits Oxygen-Glucose Deprivation/Reoxygenation-Induced Myocardial Cell Death.

In the current study, we evaluated the potential effect of a novel sphingosine kinase 1 (SphK1) activator, K6PC-5, on oxygen-glucose deprivation (OGD)/reoxygenation-induced damages to myocardial cells. We demonstrated that K6PC-5 increased intracellular sphingosine-1-phosphate (S1P) content and remarkably inhibited OGD/reoxygenation-induced death of myocardial cells (H9c2/HL-1 lines and primary murine myocardiocytes). SphK1 inhibitors, B-5354c and SKI-II, or SphK1-siRNA knockdown not only aggregated OGD/reoxygenation-induced cytotoxicity but also nullified the cytoprotection by K6PC-5. On the other hand, overexpression of SphK1 alleviated H9c2 cell death by OGD/reoxygenation, and K6PC-5-mediated cytoprotection was also enhanced in SphK1 overexpressed cells. Molecularly, OGD/reoxygenation activated the mitochondrial death pathway, evidenced by reactive oxygen species (ROS) production, mitochondrial membrane potential reduction, and p53-cyclophilin D (Cyp-D) association, which were all alleviated by K6PC-5 or overexpression of SphK1, but exacerbated by SphK1 knockdown. Furthermore, OGD/reoxygenation induced prodeath ceramide production in myocardial cells, which was largely suppressed by K6PC-5. In the meantime, adding a cell-permeable short-chain ceramide (C6) mimicked OGD/reoxygenation actions and induced ROS production and the mitochondrial death pathway in myocardial cells. Together, we conclude that K6PC-5 inhibits OGD/reoxygenation-induced myocardial cell death probably through activating SphK1. The results of the study indicate a potential benefit of K6PC-5 on ischemic heart disease.