Pathologically successful conversion hepatectomy for advanced giant hepatocellular carcinoma after multidisciplinary therapy: A case report and review of literature.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the leading causes of death due to its complexity, heterogeneity, rapid metastasis and easy recurrence after surgical resection. We demonstrated that combination therapy with transcatheter arterial chemoembolization (TACE), hepatic arterial infusion chemotherapy (HAIC), Epclusa, Lenvatinib and Sintilimab is useful for patients with advanced HCC. CASE SUMMARY: A 69-year-old man who was infected with hepatitis C virus (HCV) 30 years previously was admitted to the hospital with abdominal pain. Enhanced computed tomography (CT) revealed a low-density mass in the right lobe of the liver, with a volume of 12.9 cm × 9.4 cm × 15 cm, and the mass exhibited a "fast-in/fast-out" pattern, with extensive filling defect areas in the right branch of the portal vein and an alpha-fetoprotein level as high as 657 ng/mL. Therefore, he was judged to have advanced HCC. During treatment, the patient received three months of Epclusa, three TACE treatments, two HAIC treatments, three courses of sintilimab, and twenty-one months of lenvatinib. In the third month of treatment, the patient developed severe side effects and had to stop immunotherapy, and the Lenvatinib dose had to be halved. Postoperative pathological diagnosis indicated a complete response. The patient recovered well after the operation, and no tumor recurrence was found. CONCLUSION: Multidisciplinary conversion therapy for advanced enormous HCC caused by HCV infection has a significant effect. Individualized drug adjustments should be made during any treatment according to the patient's tolerance to treatment.

FTO Knockdown-Mediated Maturation of miR-383-5p Inhibits Malignant Advancement of Pancreatic Cancer by Targeting ITGA3.

m6A demethylase FTO is confirmed to be involved in pancreatic cancer progression. FTO regulates miRNA processing. To investigate the regulatory effect of FTO on miR-383-5p and its role in pancreatic cancer. The expression of miR-383-5p, ITGA3, and FTO was predicted using bioinformatic analysis in tissues and was measured using qPCR in cells. Cell biological functions were investigated using MTT assay, Transwell assay, sphere formation assay, and qPCR. The targeting relationship between miR-383-5p and ITGA3 was evaluated using the dual-luciferase reporter assay. The effect of FTO on miR-383-5p processing was evaluated using RIP and MeRIP assay. FTO expression was upregulated in pancreatic cancer and silencing of FTO promoted the processing of miR-383-5p in an m6A-dependent manner. m6A-modified miRNA processing was recognized by IGF2BP1. Downregulation of miR-383-5p reversed FTO knockdown-induced inhibition of cellular processes. The FTO/miR-383-5p/ITGA3 axis facilitated cell viability, metastasis, and stemness in pancreatic cancer.

A novel TOX3-WDR5-ABCG2 signaling axis regulates the progression of colorectal cancer by accelerating stem-like traits and chemoresistance.

The eradication of cancer stem cells (CSCs) with drug resistance confers the probability of local tumor control after chemotherapy or targeted therapy. As the main drug resistance marker, ABCG2 is also critical for colorectal cancer (CRC) evolution, in particular cancer stem-like traits expansion. Hitherto, the knowledge about the expression regulation of ABCG2, in particular its upstream transcriptional regulatory mechanisms, remains limited in cancer, including CRC. Here, ABCG2 was found to be markedly up-regulated in CRC CSCs (cCSCs) expansion and chemo-resistant CRC tissues and closely associated with CRC recurrence. Mechanistically, TOX3 was identified as a specific transcriptional factor to drive ABCG2 expression and subsequent cCSCs expansion and chemoresistance by binding to -261 to -141 segments of the ABCG2 promoter region. Moreover, we found that TOX3 recruited WDR5 to promote tri-methylation of H3K4 at the ABCG2 promoter in cCSCs, which further confers stem-like traits and chemoresistance to CRC by co-regulating the transcription of ABCG2. In line with this observation, TOX3, WDR5, and ABCG2 showed abnormal activation in chemo-resistant tumor tissues of in situ CRC mouse model and clinical investigation further demonstrated the comprehensive assessment of TOX3, WDR5, and ABCG2 could be a more efficient strategy for survival prediction of CRC patients with recurrence or metastasis. Thus, our study found that TOX3-WDR5/ABCG2 signaling axis plays a critical role in regulating CRC stem-like traits and chemoresistance, and a combination of chemotherapy with WDR5 inhibitors may induce synthetic lethality in ABCG2-deregulated tumors.

MED27 plays a tumor-promoting role in breast cancer progression by targeting KLF4.

The mediator complex usually cooperates with transcription factors to be involved in RNA polymerase II-mediated gene transcription. As one component of this complex, MED27 has been reported in our previous studies to promote thyroid cancer and melanoma progression. However, the precise function of MED27 in breast cancer development remains poorly understood. Here, we found that MED27 was more highly expressed in breast cancer samples than in normal tissues, especially in triple-negative breast cancer, and its expression level was elevated with the increase in pathological stage. MED27 knockdown in triple-negative breast cancer cells inhibited cancer cell metastasis and stemness maintenance, which was accompanied by downregulation of the expression of EMT- and stem traits-associated proteins, and vice versa in non-triple-negative breast cancer. Furthermore, MED27 knockdown sensitized breast cancer cells to epirubicin treatment by inducing cellular apoptosis and reducing tumorsphere-forming ability. Based on RNA-seq, we identified KLF4 as the possible downstream target of MED27. KLF4 overexpression reversed the MED27 silencing-mediated arrest of cellular metastasis and stemness maintenance capacity in breast cancer in vitro and in vivo. Mechanistically, MED27 transcriptionally regulated KLF4 by binding to its promoter region at positions -156 to +177. Collectively, our study not only demonstrated the tumor-promoting role of MED27 in breast cancer progression by transcriptionally targeting KLF4, but also suggested the possibility of developing the MED27/KLF4 signaling axis as a potential therapeutic target in breast cancer.

BPTF inhibition antagonizes colorectal cancer progression by transcriptionally inactivating Cdc25A.

As the largest subunit of the nuclear remodeling factor complex, Bromodomain PHD Finger Transcription Factor (BPTF) has been reported to be involved in tumorigenesis and development in several cancers. However, to date, its functions and related molecular mechanisms in colorectal cancer (CRC) are still poorly defined and deserve to be revealed. In this study, we uncovered that, under the expression regulation of c-Myc, BPTF promoted CRC progression by targeting Cdc25A. BPTF was found to be highly expressed in CRC and promoted the proliferation and metastasis of CRC cells through BPTF specific siRNAs, shRNAs or inhibitors. Based on RNA-seq, combined with DNA-pulldown, ChIP and luciferase reporter assay, we proved that, by binding to -178/+107 region within Cdc25A promoter, BPTF transcriptionally activated Cdc25A, thus accelerating the cell cycle process of CRC cells. Meanwhile, BPTF itself was found to be transcriptionally regulated by c-Myc. Moreover, BPTF knockdown or inactivation was verified to sensitize CRC cells to chemotherapeutics, 5-Fluorouracil (5FU) and Oxaliplatin (Oxa), c-Myc inhibitor and cell cycle inhibitor not just at the cellular level in vitro, but in subcutaneous xenografts or AOM/DSS-induced in situ models of CRC in mice, while Cdc25A overexpression partially reversed BPTF silencing-caused tumor growth inhibition. Clinically, BPTF, c-Myc and Cdc25A were highly expressed in CRC tissues simultaneously, the expression of any two of the three was positively correlated, and their expressions were highly relevant to tumor differentiation, TNM staging and poor prognosis of CRC patients. Thus, our study indicated that the targeted inhibition of BPTF alone, or together with chemotherapy and/or cell cycle-targeted therapy, might act as a promising new strategy for CRC treatment, while c-Myc/BPTF/Cdc25A signaling axis is expected to be developed as an associated set of candidate biomarkers for CRC diagnosis and prognosis prediction.

GAS41 mediates proliferation and GEM chemoresistance via H2A.Z.2 and Notch1 in pancreatic cancer.

PURPOSE: GAS41 is a YEATS domain protein that binds to acetylated histone H3 to promote the chromatin deposition of H2A.Z in non-small cell lung cancer. The role of GAS41 in pancreatic cancer is still unknown. Here, we aimed to reveal this role. METHODS: GAS41 expression in pancreatic cancer tissues and cell lines was examined using qRT-PCR, Western blotting and immunohistochemistry. MTT, colony formation, spheroid formation and in vivo tumorigenesis assays were performed to assess the proliferation, tumorigenesis, stemness and gemcitabine (GEM) resistance of pancreatic cancer cells. Mechanistically, co-immunoprecipitation (co-IP) and chromatin immunoprecipitation (ChIP) assays were used to evaluate the roles of GAS41, H2A.Z.2 and Notch1 in pancreatic cancer. RESULTS: We found that GAS41 is overexpressed in human pancreatic cancer tissues and cell lines, and that its expression increases following the acquisition of GEM resistance. We also found that GAS41 up-regulates Notch, as well as pancreatic cancer cell stemness and GEM resistance in vitro and in vivo. We show that GAS41 binds to H2A.Z.2 and activates Notch and its downstream mediators, thereby regulating stemness and drug resistance. Depletion of GAS41 or H2A.Z.2 was found to down-regulate Notch and to sensitize pancreatic cancer cells to GEM. CONCLUSION: Our data indicate that GAS41 mediates proliferation and GEM resistance in pancreatic cancer cells via H2A.Z.2 and Notch1.

TRIP4 transcriptionally activates DDIT4 and subsequent mTOR signaling to promote glioma progression.

In spite of significant advances in the understanding of glioma biology and pathology, survival remains poor. Therefore, it is still of great significance to further explore the key factors involved in tumorigenesis and development in glioma and find potential new therapeutic targets. Here, we show that thyroid hormone receptor interactor 4 (TRIP4) is highly expressed in glioma cells and tissues. Patients of glioma with high expression of TRIP4 possess poor overall survival. Knockdown of TRIP4 inhibited tumor cell proliferation, metastasis, and apoptosis suppression, whereas overexpression of TRIP4 displays the opposite effects. Further research showed that TRIP4 promoted glioma progression through regulating DDIT4 expression and subsequent activation of mTOR signaling. DDIT4 overexpression restored the inhibition of tumor growth by TRIP4 knockdown in vitro and in vivo. Consistently, mTOR activity inhibition reversed TRIP4 overexpression-mediated tumor promotion in vitro and in vivo. Moreover, molecular mechanism exploration demonstrates that TRIP4 functions as a specific transcriptional activator to anchor at the promoter region of DDIT4 gene (-196 to -11) to regulate its transcription and such regulation was affected by HIF1α. Clinically, TRIP4 expression is positively correlated with DDIT4 expression in glioma samples based on tissue microarray analysis and both of their high expression predicts the malignancy of the disease. Altogether, our findings identify TRIP4 as a critical promoter of glioma progression by targeting DDIT4 and mTOR signaling successively and suggest that TRIP4-DDIT4 axis has potential to be a novel therapeutic target in glioma treatment.

Transcatheter Arterial Infusion Combined With Radioactive Particles in the Treatment of Advanced Body/Tail Pancreatic Cancer: A Retrospective Cohort Study.

OBJECTIVES: This retrospective cohort study investigated the efficacy of routine intravenous chemotherapy (the control group), transcatheter arterial infusion (TAI) chemotherapy, and TAI combined with radioactive particles as therapeutic methods for advanced body/tail pancreatic cancer by assessing the short-term and overall survival rates. METHODS: We screened our prospective database for patients with advanced body/tail pancreatic cancer, which tumor deemed unresectable, and no other confirmed malignant tumors, patients were assigned into 3 groups according to their treatment: routine intravenous chemotherapy, TAI, and TAI combined with radioactive particles. RESULTS: The median survival time was 6 months in the control group, 10 months in the TAI group, and 13 months in the TAI combined group. The Kaplan-Meier estimates of the overall survival among the 3 groups, indicating that there is significant difference among 3 groups (P < 0.000). The clinical remission rates were 17.5% in the control group, 41.5% in the TAI group, and 48.0% in the TAI combined group. Covariates analyzed showed that different treatment methods and times affected the results significantly (P < 0.002). CONCLUSIONS: In the treatment of advanced body/tail pancreatic cancer, TAI and TAI combined with radioactive particles significantly improved the clinical outcomes in patients compared with routine intravenous chemotherapy.

Comparison of the postoperative pain change and spinal stenosis rate between percutaneous vertebroplasty combined with radiofrequency ablation and with 125I particle implantation in the treatment of metastatic spinal cord compression: A retrospective study.

Background context: Metastatic spinal cord compression (MSCC) seriously affects the survival rate. Objective: The therapeutic effects of two treatment strategies for MSCC: percutaneous vertebroplasty (PVP) combined with radiofrequency ablation (RFA) and PVP combined with 125I particle implantation, were compared. Study design: Retrospective study. Patient sample: 40 patients with MSCC were divided into two groups: 19 cases in the RFA group and 21 cases in the 125I group. Method: All patients were accessed to determine the differences in pain, which was evaluated using the visual analog scale (VAS) at 1 week, 1 month, and 3 months after the operation, and spinal stenosis rates (SSRs), which were measured at 1 and 3 months after the operation, between the two groups. Results: The VAS scores and SSRs at baseline were comparable between the RFA group and the 125I group (7.19 â€‹± â€‹2.07 vs 7.42 â€‹± â€‹1.95, 37.7% â€‹± â€‹11.2% vs 41.1% â€‹± â€‹11.4%). The VAS scores and SSRs at 1 month and 3 months after the operation were significantly reduced in both groups, compared with those at baseline. The VAS scores and SSRs in the 125I group were lower than those in the RFA group at 3 months after the operation (1.09 â€‹± â€‹0.97 vs 1.75 â€‹± â€‹1.06 p â€‹= â€‹0.048 and 12.3% â€‹± â€‹6.4% vs 18.1% â€‹± â€‹10.1% p â€‹= â€‹0.034), while the VAS scores at 1 week after the operation in the RFA group were lower than those in the 125I group (4.39 â€‹± â€‹1.34 vs 5.05 â€‹± â€‹1.82 p â€‹= â€‹0.049). Conclusion: PVP combined with RFA has a slight advantage in relieving pain in the short term, while PVP combined with 125I particle implantation may have a better effect in the relieving pain and decreasing the SSRs at 3 months after the operation.

TUG1 enhances high glucose-impaired endothelial progenitor cell function via miR-29c-3p/PDGF-BB/Wnt signaling.

BACKGROUND: Diabetes is associated with the dysfunction of endothelial progenitor cells (EPCs), characterized as impaired angiogenesis, a phenomenon thought to be involved in the development of diabetic foot. lncRNA plays an essential role in microvascular dysfunction and signaling pathways in patients with diabetes. lncRNA taurine upregulated gene 1 (TUG1) participates in angiogenesis in various cells. However, the mechanisms of TUG1 activity in EPCs have not been elucidated. METHODS: We isolated and then characterized EPCs from the peripheral blood of mice using immunofluorescence and flow cytometry. Western blot detected the wnt/ß-catenin pathway in high glucose-treated EPCs. Bioinformatics analysis predicted a putative binding site for TUG1 on miR-29c-3p. The interactions among TUG1, platelet-derived growth factor-BB (PDGF-BB), and miR-29c-3p were analyzed by luciferase assays. In vivo, diabetic mouse ischemic limb was treated with normal saline or TUG1 overexpression lentiviruses. RESULTS: We found that EPC migration, invasion, and tube formation declined after treatment with high glucose, but improved with TUG1 overexpression. Mechanically, wnt/ß-catenin pathway and autophagy were involved in the function of TUG1 overexpression in high glucose-treated EPCs. Moreover, TUG1 regulates the PDGF-BB/wnt pathway and function of high glucose-treated EPCs via miR-29c-3p. In vivo, injection of TUG1 lentivirus in a diabetic mouse ischemic limb model stimulated angiogenesis. CONCLUSIONS: Our findings suggest that TUG1 restores high glucose-treated EPC function by regulating miR-29c-3p/PDGF-BB/Wnt signaling.

Self-Assembly of Lanthanide-Covalent Organic Polyhedra: Chameleonic Luminescence and Efficient Catalysis.

A series of multinuclear lanthanide-covalent organic polyhedra (LnCOPs), including pillar-typed triangular prisms 1-Ln3 and tetrahedra 2-Ln4 (Ln = LaIII, SmIII, EuIII), have been constructed for the first time, through either one-pot subcomponent self-assembly or postassembly metalation. In contrast to the known tetrahedral cages based on transition metals, the pillar-typed polyhedra were favored from the same organic components in the presence of lanthanides. Besides this, facile transmetalations between the 1-Ln3 polyhedra endow cascade chameleonic luminescence. Meanwhile, the open metal sites and pendent amine groups on 1-Ln3 enable these polyhedra to catalyze the Henry reaction efficiently.

Role and effect of vein-transplanted human umbilical cord mesenchymal stem cells in the repair of diabetic foot ulcers in rats.

Diabetic foot ulcer (DFU) is one of diabetic complications, which is frequently present and tormented in diabetes mellitus. Most multipotent mesenchymal stromal cells (MSCs) are capable of immune evasion, providing an allogeneic, ready-to-use, cell product option for therapeutic applications. The beneficial effect of MSCs for the treatment of a variety of traumatic injuries, such as open wounds, has been extensively explored. In this study, a rat DFU model was used to simulate the pathophysiology of clinical patients and to investigate the localization of human umbilical cord mesenchymal stem cells (hUC-MSCs) after intravenous transplantation and its role in DFU healing, so as to evaluate the potential of hUC-MSCs in the treatment of DFU. The diabetic rat model was established by streptozotocin injection, which was used to create full-thickness foot dorsal skin wounds to mimic DFU by a 6-mm skin biopsy punch and a Westcott scissor. The hUC-MSCs were transplanted through femoral vein, and the ulcer cicatrization situation and the fate of hUC-MSCs were evaluated. Our data suggest that intravenously transplantated hUC-MSCs have the ability to migrate and locate to the wound tissue and are helpful to wound healing in DFU rats, partly by regulating inflammation, trans-differentiation and providing growth factors that promote angiogenesis, cell proliferation and collagen deposition. Herein, we demonstrate that hUC-MSC transplantation is able to accelerate DFU healing in rats and transplantation of exogenous stem cells may be a potential strategy for clinical application in DFUs.

Exosomes derived from mmu_circ_0000250-modified adipose-derived mesenchymal stem cells promote wound healing in diabetic mice by inducing miR-128-3p/SIRT1-mediated autophagy.

More and more evidence advises that circular RNAs (circRNAs) function critically in regulating different disease microenvironments. Our previous study found that autotransplantation of adipose-derived mesenchymal stem cells (ADSCs) promotes diabetes wound healing. Exosomes derived in ADSCs play an important regulatory role. This study aimed to characterize if mmu_circ_0000250 played a role in ADSC-exosome-mediated full-thickness skin wound repair in diabetic rats. Endothelial progenitor cells (EPCs) were selected to study the therapeutic mechanism of exosomes in high-glucose (HG)-induced cell damage and dysfunction. Analysis and luciferase reporter assay were utilized to explore the interaction among mmu_circ_0000250, miRNA (miR)-128-3p, and sirtuin (SIRT)1. The diabetic rats were used to confirm the therapeutic effect of mmu_circ_0000250 against exosome-mediated wound healing. Exosomes containing a high concentration of mmu_circ_0000250 had a greater therapeutic effect on restoration of the function of EPCs by promotion autophagy activation under HG conditions. Expression of mmu_circ_0000250 promoted SIRT1 expression by miR-128-3p adsorption, which was confirmed via luciferase reporter assay and bioinformatics analysis. In vivo, exosomes containing a high concentration of mmu_circ_0000250 had a more therapeutic effect on wound healing when compared with wild-type exosomes from ADSCs. Immunohistochemistry and immunofluorescence detection showed that mmu_circ_0000250 increased angiopoiesis with exosome treatment in wound skin and suppressed apoptosis by autophagy activation. In conclusion, we verified that mmu_circ_0000250 enhanced the therapeutic effect of ADSC-exosomes to promote wound healing in diabetes by absorption of miR-128-3p and upregulation of SIRT1. Therefore, these findings advocate targeting the mmu_circ_0000250/miR-128-3p/SIRT1 axis as a candidate therapeutic option for diabetic ulcers.

Downregulated Circular RNA hsa_circ_0000291 Suppresses Migration And Proliferation Of Gastric Cancer Via Targeting The miR-183/ITGB1 Axis.

BACKGROUND: Circular RNAs are implicated in a variety of cancers. This investigation found that hsa_circ_0000291 expression was upregulated in gastric cancer (GC) cell lines, yet its role in GC has not yet been reported. OBJECTIVE: To explore the effects of hsa_circ_0000291 on GC cell proliferation and invasion. MATERIALS AND METHODS: In the current research, we used the gastric cancer cell lines MGC803 and MKN-28 to study hsa_circ_0000291 function. The relationship between hsa_circ_0000291, miR-183 and ITGB1 was analyzed by firefly luciferase analysis and Western blots, and qRT-PCR approaches were used for protein and gene expression analysis, respectively. Tumor growth and metastasis were determined in nude mice xenografts using MKN-28 cells, with or without hsa_circ_000r0291 downregulation. RESULTS: Our data showed that hsa_circ_0000291 was upregulated in GC cell lines, whereas hsa_circ_0000291 silencing suppressed cell metastasis and proliferation in in vivo and in vitro studies. Our results showed that the downregulation of hsa_circ_0000291 suppressed integrin beta 1 (ITGB1) expression via miR-183 "sponging," which was validated by rescue experiments using the luciferase reporter assay. Our observations suggested that hsa_circ_0000291 silencing suppressed the aggressive, metastatic GC phenotype. CONCLUSION: Taken together, hsa_circ_0000291 knockdown inhibited GC cell metastasis and growth by regulating the miR-183/ITGB1 axis. Importantly, this approach could provide a therapy target and potential biomarker for the diagnosis and treatment of GC.

Nanosphere-mediated co-delivery of VEGF-A and PDGF-B genes for accelerating diabetic foot ulcers healing in rats.

Diabetic ischemic ulcer is an intractable diabetic complication. Angiogenesis is a critical factor for wound healing in patients with diabetic foot wounds. Sustained gene delivery could be notably necessary in modulating gene expression in chronic ulcer healing and might be a promising approach for diabetic foot ulcers. In the present study, Sprague-Dawley rats were used to establish diabetic foot ulcer models by streptozotocin and skin biopsy punch. The plasmids expressing VEGF-A and PDGF-B were prepared and then incorporated with polylactic-co-glycolic acid (PLGA) nanospheres to upregulate genes expression. The aim of this study was to explore whether the engineered VEGF-A and PDGF-B based plasmid-loaded nanospheres could be upregulated in streptozotocin-induced diabetic rats and improve the wound healing. The cultured fibroblasts could be effectively transfected by means of nanosphere/plasmid in vitro. In vivo, the expression of VEGF-A and PDGF-B was significantly upregulated at full-thickness foot dorsal skin wounds and the area of ulceration was progressively and significantly reduced following treatment with nanosphere/plasmid. These results indicated that combined gene transfer of VEGF-A and PDGF-B could improve reparative processes in the wounded skin of diabetic rats and nanosphere may be a potential non-viral vector for gene therapy of the diabetic foot ulcer.

Human primary CD34+ cells transplantation for critical limb ischemia.

BACKGROUND: The goal of this study was to characterize the properties of human CD34+ cells in culture and investigate the feasibility and efficacy of CD34+ transplantation in a mouse model of limb ischemia and in patients with no-option critical limb ischemia. METHODS: Human CD34+ cells isolated from peripheral blood and grown in culture for up to four passages stained positively for the surface markers CD34 and CD133 and showed high viability after cryopreservation and recovery. Seven days after surgery to induce limb ischemia, ischemic muscles of nude mice were injected with CD34+ cells. Two weeks later, mice were scored for extent of ischemic injury, and muscle tissue was collected for immunohistochemical analysis of vascular endothelial cells and RT-PCR analysis of cytokine expression. RESULTS: Injury scores of CD34+ -treated, but not control, mice were significantly different before and after transplantation. Vascular density and expression of VEGF and bFGF mRNAs were also significantly increased in the treated mice. Patients with severe lower extremity arterial ischemia were injected with their own CD34+ cells in the affected calf, foot, or toe. Significant improvements were observed in peak pain-free walking time, ankle-brachial index, and transcutaneous partial oxygen pressure. These findings demonstrate that growth of human CD34+ cells in vitro and cryopreservations are feasible. CONCLUSION: Such cells may provide a renewable source of stem cells for transplantation, which appears to be a feasible, safe, and effective treatment for patients with critical limb ischemia.

The NFκB signaling pathway serves an important regulatory role in Klebsiella pneumoniae liver abscesses.

The incidence of Klebsiella pneumoniae liver abscess (KPLA) has increased in a number of Asian countries over the past 30 years. Diabetes mellitus (DM) is a risk factor for KPLA. The prevalence and clinical features of KPLA in patients with and without DM have been well described; however, the underlying molecular mechanism responsible for the increased incidence of KPLA in patients with DM remains unclear. In the present study, a mouse model of DM was constructed and mice were infected with K. pneumoniae. Tissues were harvested for immunohistochemical and inflammatory factor expression analyses. The results revealed that the number of liver abscesses in mice with DM was greater than that observed in normal mice. The expression of interleukin (IL)-1ß, IL-2, IL-6, macrophage inflammatory protein-1α and tumor necrosis factor-α in the liver tissues of mice with DM was significantly higher compared with normal mice. Western blotting results revealed that the expression of phosphorylated (p)-inhibitor of nuclear factor κB (NFκB) kinase subunit ß, p-NFκB and p-inhibitor of NFκB was significantly increased in the liver tissue of mice with DM compared with that of normal mice. These results suggest that activation of the NFκB signaling pathways has a regulatory effect on the pathogenesis of K. pneumoniae bacteria liver abscesses and that high glucose conditions may promote the activation of NFκB signaling.

Human circular RNA­0054633 regulates high glucose­induced vascular endothelial cell dysfunction through the microRNA­218/roundabout 1 and microRNA­218/heme oxygenase­1 axes.

The aim of the present study was to investigate the relative regulation of human circular RNA­0054633 (hsa_circ_0054633), microRNA­218 (miR­218), roundabout 1 (ROBO1) and heme oxygenase­1 (HO­1) in human umbilical vein endothelial cells (HUVECs) in high glucose conditions. Initially, the expression of hsa_circ_0054633 in HUVECs was detected in high glucose conditions by reverse transcription­quantitative polymerase chain reaction. Next, a small interfering RNA against hsa_circ_0054633 was constructed to investigate the function of jsa_circ_0054633 in HUVECs by transwell migration, cell counting kit­8, flow cytometry and tube formation assays. In addition, the effect of hsa_circ_0054633 on the expression levels of ROBO1, HO­1 and vascular endothelial growth factor were examined. The regulation effects of hsa_circ_0054633 on high glucose­induced HUVEC proliferation, migration, and angiopoiesis were also analyzed. Bioinformatics analysis and dual­luciferase assay were then used to confirm the direct or specific regulation of hsa_circ_0054633, miR­218, ROBO1 and HO­1. It was observed that high glucose levels increased the expression of hsa_circ_0054633, while downregulation of hsa_circRNA­0054633 increased the high glucose­induced endothelial cell dysfunction, including proliferation, migration and angiopoiesis suppression. Bioinformatics analysis revealed that the expression of circRNA­0054633 was able to inhibit miR­218 expression, which was clarified by the dual­luciferase assay. It was also demonstrated that downregulating the expression of miR­218 inhibited the high glucose­induced endothelial cell dysfunction by promoting the expression of ROBO1 and HO­1. These results suggest that the expression of hsa_circRNA­0054633 has a protective effect against high glucose­induced endothelial cell dysfunction by targeting ROBO1 and HO­1.

Exosomes from adipose-derived stem cells overexpressing Nrf2 accelerate cutaneous wound healing by promoting vascularization in a diabetic foot ulcer rat model.

Diabetic foot ulcers (DFU) increase the risks of infection and amputation in patients with diabetes mellitus (DM). The impaired function and senescence of endothelial progenitor cells (EPCs) and high glucose-induced ROS likely exacerbate DFUs. We assessed EPCs in 60 patients with DM in a hospital or primary care setting. We also evaluated the therapeutic effects of exosomes secreted from adipose-derived stem cells (ADSCs) on stress-mediated senescence of EPCs induced by high glucose. Additionally, the effects of exosomes and Nrf2 overexpression in ADSCs were investigated in vitro and in vivo in a diabetic rat model. We found that ADSCs that secreted exosomes promoted proliferation and angiopoiesis in EPCs in a high glucose environment and that overexpression of Nrf2 increased this protective effect. Wounds in the feet of diabetic rats had a significantly reduced ulcerated area when treated with exosomes from ADSCs overexpressing Nrf2. Increased granulation tissue formation, angiogenesis, and levels of growth factor expression as well as reduced levels of inflammation and oxidative stress-related proteins were detected in wound beds. Our data suggest that exosomes from ADSCs can potentially promote wound healing, particularly when overexpressing Nrf2 and therefore that the transplantation of exosomes may be suitable for clinical application in the treatment of DFUs.

MiR-31 regulates the function of diabetic endothelial progenitor cells by targeting Satb2.

Endothelial malfunctions in patients with diabetes are known to result in vascular diseases, and endothelial progenitor cells (EPCs) are indispensable for the functional preservation of the vascular endothelium. MicroRNA-31 (miR-31) has been found to be able to modulate the differentiation of stem cells. However, it is still unclear how miR-31 functions in diabetic EPCs. The aim of this study was to investigate how miR-31 regulates diabetic EPC function. In the current study, miR-31 expression was compared between normal and diabetic EPCs. Satb2 was recognized as a functionally related target of miR-31 in EPCs according to computational prediction. We also explored the role of miR-31 in terms of its anti-apoptotic effects. A remarkable elevation in miR-31 expression was found in diabetic EPCs, and this elevated expression resulted in suppressed cell proliferation under high glucose. It was also found that miR-31 targets Satb2, leading to the anti-apoptotic effect and maintenance of the functions of EPCs. Furthermore, knockdown of Satb2 exhibited an inhibitory effect on proliferation and migration of EPCs in both healthy and diabetic subjects, which showed the same trend as miR-31 overexpression. Conversely, overexpression of Satb2 showed the opposite effect. Moreover, overexpression of Satb2 attenuated the miR-31-induced migration and colony-forming ability reduction and apoptosis induction of EPCs in both healthy and diabetic subjects. In diabetic EPCs, elevated glucose level was found to up-regulate miR-31 expression, which in turn enhanced the malfunction and death of EPCs. In conclusion, our results indicate that up-regulation of miR-31 may underlie endothelial dysfunction in diabetes by targeting Satb2.