NKAIN1, as an oncogene, promotes the proliferation and metastasis of breast cancer, affecting its prognosis.

Na, K-ATPase interaction (NKAIN) is a transmembrane protein family, which can interact with Na, K-ATPase ß1 subunit. NKAIN1 plays an important role in alcohol-dependent diseases such as endometrial and prostate cancers. However, the relationship between NKAIN1 and human breast cancer has not been studied. Hence, this study aimed to explore the relationship between NKAIN1 expression and breast cancer. Data used in this study were mainly from the Cancer Genome Atlas, including differential expression analysis, Kaplan-Meier survival analysis, receiver operating characteristic curve analysis, multiple Cox regression analysis, co-expression gene analysis, and gene set enrichment analysis. Analyses were performed using reverse transcription-quantitative polymerase chain reaction, western blot analysis, and immunohistochemistry on 46 collected samples. The knockdown or overexpression of NKAIN1 in vitro in MCF-7 and MDA-MB-231 cell lines altered the proliferation and migration abilities of tumor cells. In vivo experiments further confirmed that NKAIN1 knockdown effectively inhibited the proliferation and migration of cancer cells. Therefore, our study identified NKAIN1 as an oncogene that is highly expressed in breast cancer tissues. The findings highlight the potential of NKAIN1 as a molecular biomarker of breast cancer.

Thrombosis of acute superior mesenteric artery in a patient with breast cancer receiving toremifene therapy: a case report and literature review.

It is widely recognized that cancer itself is related to increased risk of thromembolism. Venous thromboembolism is relatively common in breast cancer patients, but arterial thrombosis, especially acute superior mesenteric artery thrombosis (SMAT) associated with chemotherapy or endocrinotherapy, rarely occurs in breast cancer patients. There were few reports about acute SMAT in cancer patients who underwent chemotherapy, but no reports of acute SMAT caused by endocrine-therapy. We reported a 54-year-old patient with acute SMAT during toremifene treatment after breast cancer surgery. She underwent 4 cycles chemotherapy of TC regimen, then accepted toremifen endocrinotherapy because of positive estrogen receptor. She suffered from acute SMAT after 2 months toremifen treatment. Therefore, we consider that this case of acute SMAT may be a rare adverse event of toremifen. In view of the high risk and rarity of acute SMAT caused by toremifene, we suggest that except for venous thrombosis, arterial thrombosis in special position (ATSP) should be kept in mind during use of toremifene. Once a thrombotic event occurs, toremifene should be stopped immediately.

Revealing the potential of necroptosis-related genes in prognosis, immune characteristics, and treatment strategies for head and neck squamous cell carcinoma.

Necroptosis is a recently discovered apoptotic mechanism that has been linked to tumor formation, prognosis, and treatment response. However, the relationship between the TME and NRGs remains unclear. In this study, we analyzed the expression patterns of NRGs in 769 HNSCC cases from two distinct data sets. Our findings revealed distinct genetic groups and a correlation between patient clinical features, prognosis, TME cell infiltration characteristics, and NRG alterations. We then developed an NRG model to predict OS and confirmed its accuracy in predicting OS in HNSCC patients. Moreover, we have devised a precise nomogram that enhances the clinical utility of the NRG model substantially. The low-risk group had a better OS, and they were associated with immune suppression, more mutated genes, and higher TIDE scores. The risk score also had a significant correlation with the CSC index and susceptibility to anti-tumor agents. Our study provides insights into how NRGs affect prognosis, clinically significant features, TME, and immunotherapy response in HNSCC. With a better knowledge of NRGs in HNSCC, we could assess the prognosis and develop immunotherapy regimens that are more successful at opening up new doors.

Nickel exposure induces gut microbiome disorder and serum uric acid elevation.

Serum uric acid elevation has been found in long-term nickel (Ni) exposure occupational workers, but the mechanism is unclear. In this study, the relationship between Ni exposure and uric acid elevation was explored in a cohort of 109 participants composed of a Ni-exposed workers group and a control group. The results showed that Ni concentration (5.70 ± 3.21 µg/L) and uric acid level (355.95 ± 67.87 µmol/L) in the serum were increased in the exposure group with a significant positive correlation (r = 0.413, p < 0.0001). The composition of gut microbiota and metabolome revealed that the abundance of uric acid-lowering bacteria, such as Lactobacillus, Lachnospiraceae_Unclassfied and Blautia were reduced while pathogenic bacteria including Parabacteriadies and Escherichia-Shigella were enriched in Ni group, accompanied by impaired intestinal degradation of purines and upregulated biosynthesis of primary bile acids. Consistent with human results, the mice experiments showed that Ni treatment significantly promotes uric acid elevation and systemic inflammation. Lactobacillus and Blautia in gut microbiota were reduced and inflammation-related taxa Alistipes and Mycoplasma were enriched in the Ni treatment. In addition, LC-MS/MS metabolomic analysis indicated that purine nucleosides were accumulated in mice feces, which increased purine absorption and uric acid elevation in the serum. In summary, this study provides evidence that UA elevation was correlated with heavy metals exposure and highlighted the role of gut microbiota in intestinal purine catabolism and in the pathogenesis of heavy metal-induced hyperuricemia.

Safety and efficacy of remimazolam besylate in patients undergoing colonoscopy: A multicentre, single-blind, randomized, controlled, phase â ¢ trial.

Study objective: The objective of the study was to evaluate the safety and efficacy of remimazolam besylate versus propofol injection in patients undergoing colonoscopy. Design: A multicenter, randomized, non-inferiority, single-blind, parallel-controlled clinical trial. Setting: Operating room. Patients: Patients aged 18-65 years (American Society of Anesthesiologists [ASA] classification I-III) undergoing a diagnostic or therapeutic colonoscopy. Interventions: Patients were administered intravenous injection of remimazolam besylate or propofol (active comparator) for sedation. Measurements: Modified Observer's Assessment of Alertness/Sedation [MOAA/S] scores of the included patients were assessed before dosing, 1, 1.5, 2, 2.5, and 3 min after the start of dosing, and then every 1 min until the MOAA/S score reached 5 on three consecutive occasions. Main Results: A total of 360 patients received remimazolam and 120 patients received propofol. The incidence of adverse events (67.8% vs. 84.2%, p = 0.001) was significantly lower in patients administered remimazolam compared to propofol. There was no significant difference in sedation success rates (full analysis set [FAS]: 98.9% vs. 99.2%; remimazolam vs. propofol). Remimazolam had a significantly longer onset of action, but the difference was not considered clinically significant (1.45 min vs. 1.24 min, remimazolam vs. propofol). Propofol achieved a deeper level of sedation (mean MOAA/S score 0.5 vs. 0.2; remimazolam vs. propofol). Mean time to discharge after the end of the last administration of study drug (20.3 vs. 21.8 min, p = 0.020) and incidence of injection pain was significantly lower in patients administered remimazolam (2.3% vs. 35.3%, p < 0.0001). Incidence of oxygen desaturation was significantly higher in patients administered propofol compared to patients administered remimazolam (6.7% vs. 1.1%, p = 0.001). Similarly, incidence of hypotension was more frequent in patients administered propofol compared to patients administered remimazolam (29.2% vs. 10.6%, p < 0.0001). Conclusion: Remimazolam besylate had a better safety and tolerability profile and similar sedative efficacy to propofol in patients undergoing a diagnostic or therapeutic colonoscopy in China, suggesting that remimazolam besylate has potential as a sedative agent for colonoscopy.

A new technique for Asian nasal tip shaping: "twin tower" folding ear cartilage transplantation.

Rhinoplasty focuses on the establishment of the structural support of nasal cartilage and the shaping of the nasal tip. The purpose of this study was to explore the application of "double tower" folding ear cartilage transplantation for nasal tip shaping in rhinoplasty.

Small-Molecule Bi-DOTA Complex for High-Performance CT and Spectral CT Bioimaging.

OBJECTIVES: It is necessary to develop a high-performance and biocompatible contrast agent to accurately diagnose various diseases via in vivo computed tomography (CT) imaging. Here, we synthesized a small molecular Bi-DOTA complex as a high-performance contrast agent for in vitro and in vivo CT bioimaging. MATERIALS AND METHODS: In our study, Bi-DOTA was fabricated through a facile and one-pot synthesis strategy. The formed Bi-DOTA complex was characterized via different techniques. Furthermore, Bi-DOTA was used for in vitro and in vivo CT bioimaging to verify its X-ray attenuation ability, especially in vivo kidney imaging, gastrointestinal tract CT imaging, and spectral CT imaging. RESULTS: A small molecular Bi-DOTA complex with a molecular mass of 0.61 kDa was synthesized successfully, which exhibited outstanding dispersion, good biocompatibility, and superior X-ray attenuation ability. Meanwhile, we showed that the obtained contrast agent was quite biocompatible and safe in the given concentration range as confirmed by in vitro and in vivo cytotoxicity assay. Also, the proposed contrast agent can be rapidly excreted from the body via the urinary system, avoiding the potential side effects caused by long-term retention in vivo. Importantly, Bi-DOTA was successfully used in high-quality in vitro CT imaging, in vivo kidney imaging, gastrointestinal tract CT imaging, and spectral CT imaging. CONCLUSIONS: These superiorities allowed Bi-DOTA to be used as an efficient CT contrast agent and laid down a new way of designing high-performance CT contrast agents with great clinical transformation potential.

Chrysin Attenuates High Glucose-Induced BMSC Dysfunction via the Activation of the PI3K/AKT/Nrf2 Signaling Pathway.

PURPOSE: High glucose environment in diabetes mellitus induces the dysfunction of bone marrow-derived mesenchymal stromal cells (BMSCs) and impairs bone regeneration. Chrysin is a natural polyphenol with outstanding anti-inflammation and anti-oxidation ability. However, whether and how chrysin affects BMSCs in high glucose conditions remain poorly understood. The present study aimed to explore the effects and underlying mechanisms of chrysin on the BMSCs exposed to high glucose environment. MATERIALS AND METHODS: Cell viability was detected by cell counting kit 8 assay and 5-ethynyl-2'-deoxyuridine staining, while cell apoptosis was determined through flow cytometry using Annexin V-FITC/PI kit. The oxidative stress in BMSCs was evaluated by detecting the reactive oxygen species production, malondialdehyde content, and superoxide dismutase activity. Alkaline phosphatase staining, Alizarin Red staining, and quantitative real-time PCR were performed to determine the osteogenic differentiation. Western blot was used to examine the expression of the PI3K/ATK/Nrf2 signaling pathway. Furthermore, chrysin was injected into calvarial defects of type 1 diabetic SD rats to assess its in vivo bone formation capability. RESULTS: Chrysin reduced oxidative stress, increased cell viability, and promoted osteogenic differentiation in BMSCs exposed to high glucose. Blocking PI3K/ATK/Nrf2 signaling pathway weakened the beneficial effects of chrysin, indicating that chrysin at least partly worked through the PI3K/ATK/Nrf2 pathway. CONCLUSION: Chrysin can protect BMSCs from high glucose-induced oxidative stress via the activation of the PI3K/AKT/Nrf2 pathway, and promote bone regeneration in type 1 diabetic rats.

MiR-6869-5p Induces M2 Polarization by Regulating PTPRO in Gestational Diabetes Mellitus.

The role of microRNA (miRNA) in gestational diabetes mellitus has been widely investigated during the last decade. However, the altering effect of miR-6869-5p on immunity and placental microenvironment in gestational diabetes mellitus is largely unknown. In our study, the expression of miR-6869-5p was documented to be significantly decreased in placenta-derived mononuclear macrophages, which was also negatively related to PTPRO. Besides, PTPRO was negatively regulated by miR-6869-5p in placenta-derived mononuclear macrophages. In vitro, miR-6869-5p inhibited macrophage proliferation demonstrated by EdU and CCK-8 experiments. The inflammatory response in macrophages was also significantly inhibited by miR-6869-5p, which could regulate PTPRO as a target documented by luciferase reporter assay. Moreover, miR-6869-5p promoted M2 macrophage polarization and thus restrain inflammation. Accordingly, miR-6869-5p is involved in maintaining placental microenvironment balance by preventing from inflammation and inducing M2 macrophages in gestational diabetes mellitus.

Three-Dimensional Computed Tomography Scan Analysis of Secondary Labial Deformities in Patients With Unilateral Cleft Lip/Cleft Palate After Revisional Surgery.

BACKGROUND: Surgical reconstruction of secondary labial deformities associated with isolated unilateral cleft lip (UCL) and/or UCL and palate (UCLP) is challenging. There have been few studies in the literature looking at labial soft tissues quantitatively to assess surgical results. OBJECTIVE: To apply a novel computer-aided, 3-dimensional reconstruction technique based on CT scan images to conduct quantitative preoperative and postoperative assessments in patients with UCL/UCLP undergoing surgical revision of secondary labial deformities. METHODS: Preoperative and postoperative spiral computed tomographic (CT) scans of the face were performed in 21 randomly selected UCL or UCLP patients, who underwent secondary lip revision surgery. The data was then imported to the SimPlant 11.04 software system. Fixed point-to-point, linear distance, and angles were measured, statistically analyzed and used to assess the effect of the surgery. RESULTS: Preoperative measurements showed that the thickness of the upper vermilion at the apex of the Cupid's bow on the affected side was greater than that on the unaffected side. The distance from the apex of the Cupid's bow to the ipsilateral subnasal point of the affected side was smaller than that of the unaffected side (P < 0.05). After surgery, the subjects were rescanned at an average of 9 months, and the curative effects were evaluated. The statistically significant preoperative differences between the affected and unaffected sides were not found postoperatively indicating surgical success. CONCLUSIONS: This study demonstrates the utility of a novel method to measure and assess results in the surgical revision of UCL/UCLP patients with secondary lip deformities. This knowledge can aid the surgeon in selection of treatment techniques.

Complete genome sequence of a novel recombinant avian leukosis virus isolated from a three-yellow chicken.

In this study, an avian leukosis virus (ALV) strain (GX-2020-01) was isolated from a three-yellow chicken, and its complete genome was 7570 bp long with the typical organization "5'LTR-gag-pol-env-3'LTR." Phylogenetic analysis and sequence comparison revealed that it belongs to the ALV-J subgroup. However, the LTR region of GX-2020-01 is highly similar to that of reference strains of ALV-K/E (96.61%-97.10%), demonstrating that this novel isolate is a natural recombinant. The replication efficiency of GX-2020-01 was significantly lower than the previously isolated ALV-J strain (NX0101), indicating that the recombination event might have resulted in slower virus replication, making it harder for it to be detected through routine testing.

Electrochemical assays for determination of H2O2 and prostate-specific antigen based on a nanocomposite consisting of CeO2 nanoparticle-decorated MnO2 nanospheres.

A nanocomposite consisting of CeO2 nanoparticle-decorated MnO2 nanospheres (CeO2@MnO2) was synthesized for the first time via a hydrothermal method. CeO2@MnO2 was exploited to construct an electrochemical assays for detecting H2O2 and prostate-specific antigen (PSA) with square wave voltammetry (SWV). The electrochemical results proved that CeO2@MnO2 owned a better electrocatalytic effect towards H2O2 reduction than pure MnO2 NS and CeO2 NP due to the synergistic effect between MnO2 NS and CeO2 NP. Under optimized conditions, CeO2@MnO2-based assay can be applied to detect H2O2 in the range 1 to 3.0 × 103 µmol L-1. The label-free electrochemical immunoassay based on CeO2@MnO2 displayed linearly with concentrations of PSA from 0.005 to 50.0 ng mL-1. The electrochemical assays also possessed acceptable sensitivity, selectivity, and stability. The study showed that CeO2@MnO2 hold great potential as a biosensing platform and the clinical determination of tumor markers in human serum. Graphical abstract A nanocomposite consisting of CeO2 nanoparticles decorated MnO2 nanospheres (CeO2 @MnO2) was firstly synthesized via a hydrothermal method. CeO2@MnO2 was firstly exploited to construct electrochemical assays for detecting H2O2 and prostate-specific antigen (PSA) with square wave voltammetry (SWV), respectively. The electrochemical results proved that CeO2@MnO2 owned better electrocatalysis towards H2O2 reduction than pure MnO2 NS and CeO2 NP due to the synergistic effect between MnO2 NS and CeO2 NP. Under optimized conditions, CeO2@MnO2 based assay relative to the H2O2 system can be applied to detect H2O2 with range from 1 to 3.0 × 103 µmol L-1. The label-free electrochemical immunoassay based on CeO2@MnO2 relative to the H2O2 system displayed linearly with concentrations of PSA from 0.005 to 50.0 ng mL-1. The electrochemical assays also possessed acceptable sensitivity, selectivity and stability. The study showed that CeO2@MnO2 hold great potential for biosensing platform and the clinic determination of tumor markers in human serum.

microRNA-124 attenuates isoflurane-induced neurological deficits in neonatal rats via binding to EGR1.

Isoflurane anesthesia induces neuroapoptosis in the development of the brain. In this study, neonatal rats and hippocampal neurons were subjected to isoflurane exposure, in which the effect of miR-124 on the neurological deficits induced by isoflurane was evaluated. Isoflurane anesthesia models were induced in neonatal SD rats aged 7 days and then treated with miR-124 agomir, miR-124 antagomir, or LV-CMV-early growth response 1 (EGR1) plasmids. Then, the spatial learning and memory ability of rats were evaluated by Morris water maze. Furthermore, primary hippocampal neurons cultured 7 days were also exposed to isoflurane and transfected with miR-124 agomir, miR-124 antagomir, or LV-CMV-EGR1 plasmids. The targeting relationship of miR-124 and EGR1 was verified by the dual-luciferase reporter gene assay. To identify the effect of miR-124 on neuron activities, the viability and apoptosis of hippocampal neurons were assessed. In response to isoflurane exposure, miR-124 expression was reduced and EGR1 expression was increased in the hippocampal tissues and neurons. The isoflurane anesthesia damaged rats' spatial learning and memory ability, and reduced viability, and promoted apoptosis of hippocampal neurons. EGR1 was targeted and negatively regulated by miR-124. The treatment of miR-124 agomir improved rats' spatial learning and memory ability and notably increased hippocampal neuron viability and resistance to apoptosis, corresponding to an increased brain-derived neurotrophic factor (BDNF) expression, inhibited expression of proapoptotic factors (cleaved-Caspase-3 and Bax), and enhanced the expression of antiapoptotic factor (Bcl-2). Upregulated miR-124 inhibited the expression of EGR1, by which mechanism miR-124 reduced the neurological deficits induced by isoflurane in neonatal rats through inhibiting apoptosis of hippocampal neurons.

KRT19 and CEACAM5 mRNA-marked circulated tumor cells indicate unfavorable prognosis of breast cancer patients.

AIM: To investigate the clinical and prognostic significance of circulated tumor cells (CTC) marked by cytokeratin 19 coding gene KRT19 mRNA and carcinoembryonic antigen coding gene CEACAM5 mRNA in preoperative peripheral blood of breast cancer patients and provide molecular markers for breast cancer metastasis risk. METHODS: The mRNA levels of KRT19 and CEACAM5 in preoperative peripheral blood of breast cancer patients without (n = 603) and with (n = 76) distant metastases at the time of initial diagnosis were detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The relationship between CTCKRT19, CTCCEACAM5 and clinicopathological features, local recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), or overall survival (OS) was statistically analyzed. RESULTS: In different pathological stages of breast cancer, the rates of CTCKRT19-pos and CTCCEACAM5-pos increased with the increase of the stages (P = 0.077 and P = 0.004). Preoperative CTCKRT19-pos in breast cancer patients was closely related to the lymph node metastasis statues (P < 0.0001), and had no significant correlation with other clinicopathological features. There was no significant correlation between CTCCEACAM5 and the clinicopathological features. Patients with high levels of CTC double-marked by KRT19 and CEACAM5 mRNA had shorter DMFS (P < 0.0001) and OS (P = 0.016) for patients with breast cancer. The 7-year DMFS rates for the low-, intermediate-, and high-risk groups were 90.7%, 67.5%, and 59.1%, respectively (P < 0.0001). The prognosis of patients with decreased KRT19 and CEACAM5 mRNA after treatment is better than that of patients who have not decreased, and the combination of the two indicators is better than the single one for predicting PFS (P = 0.002 compare with P = 0.036 or P = 0.047). CONCLUSION: Double-marked CTC by KRT19 and CEACAM5 mRNA is a prognostic index of breast cancer patients before surgery and after chemotherapy. Single-marked CTC by KRT19 mRNA indicates lymph node statues of preoperative patients. Therefore, the RT-qPCR-based molecular diagnosis of CTC could be used for prognostic prediction of breast cancer patients and guiding clinical treatment.

The prognostic significance of preoperative neutrophil-lymphocyte ratio in patients with hepatocellular carcinoma receiving hepatectomy: A systematic review and meta-analysis.

BACKGROUND AND AIMS: Numerous reports have indicated that preoperative Neutrophil-Lymphocyte ratio (NLR) was correlated with the prognosis of hepatocellular carcinoma who underwent hepatectomy. However, the results still remained controversial. Therefore, the present meta-analysis of 17 studies was performed to evaluate the prognostic value of preoperative NLR in HCC patients. METHOD: Databases of PubMed, Embase, Cochrane Library and Web of Science were retrieved. Hazard Ratio (HR) or Odds Ratio (OR) with its 95% confidence intervals (CI) was used to evaluate the association between preoperative NLR and the prognosis or clinical features of HCC patients. RESULT: A total of 17 studies eventually were included in this meta-analysis. Elevated preoperative NLR had a close relationship with the overall survival (OS) (HR 1.52; 95% CI 1.37-1.69), recurrence-free survival (RFS) (HR 1.64; 95% CI 1.44-1.87) and disease-free survival (DFS) (HR 1.50; 95% CI 1.35-1.67) of hepatocellular carcinoma. Additionally, preoperative NLR was also associated with tumor vascular invasion (OR 2.08; 95% CI 1.60-2.70), HBV (OR 0.68; 95% CI 0.51-0.90) and large tumor size (OR: 4.07; 95% CI 2.60-6.37). CONCLUSION: The present meta-analysis indicated that preoperative NLR had significant association with the prognosis of hepatocellular carcinoma patients and may be an effectively prognostic indicator.

B7-H4 deficiency in salivary gland of patients with primary Sjögren's syndrome impairs the regulatory effect on T cells.

AIM: Our previous study confirmed the defect of B7-H4 expression in peripheral blood and salivary glands of patients with primary Sjögren's syndrome (pSS). The aim of this study was to analyze the effect of the deficit expression of B7-H4 on CD4+ T cells. METHODS: CD4+ T cells were purified by magnetic-activated cell sorting MACS. The proliferation and cytokine production of CD4+ T cells co-cultured with purified salivary gland epithelial cells (SGECs) from pSS or non-SS sicca syndrome were detected. RESULTS: By co-culturing the gland cells with CD4+ T cells, we found the proliferation of CD4+ T cells was significantly suppressed. The effect was weaker when SGECs from pSS patients were used compared to that from non-pSS sicca syndrome controls. Simultaneously, the productions of cytokines interleukin (IL)-5, IL-13, IL-17A, IL-6 in supernatant were reduced and also SGECs from pSS patients decreased them less than that from non-SS controls. CONCLUSIONS: The decrease of B7-H4 expression in salivary glands of SS patients contributes to the defect of negatively regulating the inflammation caused by CD4+ T cells, thereby providing new insights into the role of B7-H4 in the inflammatory process of salivary glands in SS.

Selective effect of cytokine-induced killer cells on survival of patients with early-stage melanoma.

Adoptive immunotherapy using cytokine-induced killer (CIK) cells has shown potential antitumor ability against several kinds of cancers, including melanoma. However, little is known about the achievable outcome of CIK cells in melanoma patients at different pathological stages. Here we recruited 55 patients treated with conventional therapy plus CIK cells as the CIK group, and 49 patients treated with conventional therapy alone as the control group. The pathological characteristics were comparable between two groups, with a follow-up period up to 40 months. Survival data and immune responses were evaluated after CIK cell treatment. In this study, CIK cells were successfully generated from peripheral blood of melanoma patients after in vitro culture for 14 days. The cultured CIK cells not only produced high levels of pro-inflammatory cytokines upon in vitro stimulation but also efficiently killed human melanoma cell lines. No serious side events were observed in all patients treated with CIK cells. Furthermore, infusions of CIK cells improved the quality of life in some patients, including advanced cases. More importantly, the CIK group exhibited better survival rates compared to the control group among early-stage melanoma patients, in consistent with the increased frequency of peripheral CD4+ T cells. However, the patients with advanced-stage melanoma did not benefit from the CIK cell therapy in terms of survival rate. In conclusion, CIK cells combined with conventional treatments may prolong the survival of early-stage melanoma patients and improve the quality of life for some advanced cases in a safe way.

Attenuating Hypoxia-Induced Apoptosis and Autophagy of Mesenchymal Stem Cells: the Potential of Sitagliptin in Stem Cell-Based Therapy.

BACKGROUND/AIMS: Dipeptidyl peptidase-4 (DPP-4) inhibitors have pleiotropic effects on cardiovascular protection beyond the antidiabetic property. However, it remains unknown that the impact of one DPP-4 inhibitor sitagliptin on the survival of mesenchymal stem cells (MSCs) in hypoxia and serum deprivation (H/SD) environment. METHODS: The apoptosis and autophagy of MSCs were analyzed in different concentrations of sitagliptin under H/SD condition. For later studies, we tested the relationship between anti-apoptotic and anti-autophagic effects of sitagliptin. The level of cell apoptosis was analyzed by Annexin V-FITC/PI staining, western blot of Bcl-2 and Bax proteins. Autophagy flux was assessed by multiple autophagy related proteins and substrates. Cell autophagy was identified by acridine orange staining, western blot of Beclin 1 and light chain 3 protein, and transmission electron microscopy. RESULTS: We demonstrated that sitagliptin attenuated hypoxia-induced apoptosis and autophagy of MSCs. Furthermore, sitagliptin regulated cell autophagy by Bcl-2/ Beclin 1 pathway in H/SD condition. CONCLUSIONS: This study provides insight into the utility of the DPP-4 inhibitor sitagliptin for MSCs transplantation in the ischemic microenvironment that extends its antidiabetic property.

Clinical and laboratory profiles of primary Sjogren's syndrome in a Chinese population: A retrospective analysis of 315 patients.

AIM: To assess the clinical and laboratory features of primary Sjogren's syndrome (pSS) in a large teaching hospital in China. METHODS: Three hundred and fifteen pSS patients diagnosed according to American-European Classification Criteria and consecutively admitted to Anhui Provincial Hospital from 1 January 1999 to 30 September 2012 were retrospectively selected in this study. RESULTS: The median age was 46.8 ± 14.4 years (range 13-83 years) and the majority of patients were female (96.5%). The common clinical features at initial presentations were dry mouth (50.2%), dry eyes (31.4%) and joint pain (24.8%); 92.6% of patients had positive anti-SSA antibody and 49.2% patients had positive anti-SSB antibody. One hundred and eighteen patients underwent labial salivary gland biopsy. According to Chisholm grading criteria, grade 3 to 4 was present in 58.5% of the patients. The frequency of interstitial lung disease (ILD) occurred (20.9%) in the patients with systemic extraglandular manifestations. The patients with ILD were frequently associated with positive anti-SSA (P = 0.005) and low levels of C3. The most common impairment of lung function was small airway function abnormalities. Sixty-six pSS patients with ILD (pSS-ILD) were diagnosed with high-resolution computed tomography and treated with corticosteroids and/or immunosuppressants, in which 18 patients had improved pulmonary function. CONCLUSION: Labial salivary gland biopsy and anti-nuclear antibodies spectrum were important to the diagnosis of pSS. The pSS patients had high percentage of ILD, especially small airway function abnormalities. The combination of corticosteroids and immunosuppressants appears to be effective in treatment of pSS patients with ILD.

Atorvastatin treatment improves the effects of mesenchymal stem cell transplantation on acute myocardial infarction: the role of the RhoA/ROCK/ERK pathway.

BACKGROUND: Statins protect mesenchymal stem cells (MSCs) against the harsh microenvironment and improve the efficacy of MSC transplantation after acute myocardial infarction (AMI); however, the mechanism remains uncertain. Furthermore, the transdifferentiation potential of MSCs in the post-infarct heart remains highly controversial. The RhoA/Rho-associated coiled-coil-forming kinase (ROCK) pathway participates in many aspects of the damaged heart after AMI and related to the "pleiotropic" effects of statins. This study aimed to explore whether atorvastatin (ATV) facilitates the survival and therapeutic efficacy of MSCs via the inhibition of RhoA/ROCK pathway and subsequently its downstream molecular extracellular regulated protein kinase (ERK1/2), and to investigate the transdifferentiation potential of MSCs in vivo. METHODS AND RESULTS: Female rats received myocardial injections of male rat MSCs 30 min after AMI. Four weeks after AMI, ATV combined with MSC treatment resulted in improved cardiac function and reduced infarct area. ATV facilitated the MSC survival, as revealed by the increased expression of Y chromosomal genes and the increased number of Y chromosome-positive cells; however, no transdifferentiation markers were observed. ATV inhibited the production of inflammatory cytokines both in vitro and vivo, accompanied by suppression of ROCK and ERK activities. Geranylgeranyl pyrophosphate (GGPP) abrogated the effects of ATV in the H9c2 cells under hypoxia/serum deprivation (H/SD), while the ROCK inhibitor fasudil mimicked the benefits of ATV after AMI. CONCLUSIONS: ATV improves the post-infarct microenvironment via RhoA/ROCK/ERK inhibition and thus facilitates the survival and efficacy of implanted MSCs. Transdifferentiation may be not responsible for the cardiac benefits that follow MSC transplantation.