Diabetes and aortic dissection: unraveling the role of 3-hydroxybutyrate through mendelian randomization.

BACKGROUND: In observational and experimental studies, diabetes has been reported as a protective factor for aortic dissection. 3-Hydroxybutyrate, a key constituent of ketone bodies, has been found to favor improvements in cardiovascular disease. However, whether the protective effect of diabetes on aortic dissection is mediated by 3-hydroxybutyrate is unclear. We aimed to investigate the causal effects of diabetes on the risk of aortic dissection and the mediating role of 3-hydroxybutyrate in them through two-step Mendelian randomization. MATERIALS AND METHODS: We performed a two-step Mendelian randomization to investigate the causal connections between diabetes, 3-hydroxybutyrate, and aortic dissection and calculate the mediating effect of 3-hydroxybutyrate. Publicly accessible data for Type 1 diabetes, Type 2 diabetes, dissection of aorta and 3-hydroxybutyrate were obtained from genome-wide association studies. The association between Type 1 diabetes and dissection of aorta, the association between Type 2 diabetes and dissection of aorta, and mediation effect of 3-hydroxybutyrate were carried out separately. RESULTS: The IVW method showed that Type 1 diabetes was negatively associated with the risk of aortic dissection (OR 0.912, 95% CI 0.836-0.995), The weighted median, simple mode and weighted mode method showed consistent results. The mediated proportion of 3-hydroxybutyrate on the relationship between Type 1 diabetes and dissection of aorta was 24.80% (95% CI 5.12-44.47%). The IVW method showed that Type 2 diabetes was negatively associated with the risk of aortic dissection (OR 0.763, 95% CI 0.607-0.960), The weighted median, simple mode and weighted mode method showed consistent results. 3-Hydroxybutyrate does not have causal mediation effect on the relationship between Type 2 diabetes and dissection of aorta. CONCLUSION: Mendelian randomization study revealed diabetes as a protective factor for dissection of aorta. The protective effect of type 1 diabetes on aortic dissection was partially mediated by 3-hydroxybutyrate, but type 2 diabetes was not 3-hydroxybutyrate mediated.

Compare the effectiveness of extracorporeal shockwave and hyperbaric oxygen therapy on enhancing wound healing in a streptozotocin-induced diabetic rodent model.

Studies have revealed that both extracorporeal shock-wave therapy (ESWT) and hyperbaric oxygen therapy (HBOT) can accelerate wound healing. This study aimed to compare the effectiveness of ESWT and HBOT in enhancing diabetic wound healing. A dorsal skin defect in a streptozotocin-induced diabetes rodent model was used. Postoperative wound healing was assessed once every 3 days. Histologic examination was performed with hematoxylin and eosin staining. Proliferation marker protein Ki-67 (Ki-67), endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF), and 8-hydroxy-2-deoxyguanosine (8-OHdG) were evaluated with immunohistochemical (IHC) staining. The wound area was significantly reduced in the ESWT and HBOT groups compared to that in the diabetic controls. However, the wound healing time was significantly increased in the HBOT group compared to the ESWT group. Histological findings showed a statistical increase in neovascularization and suppression of the inflammatory response by both HBOT and ESWT compared to the controls. IHC staining revealed a significant increase in Ki-67, VEGF, and eNOS but suppressed 8-OHdG expression in the ESWT group compared to the HBOT group. ESWT facilitated diabetic wound healing more effectively than HBOT by suppressing the inflammatory response and enhancing cellular proliferation and neovascularization and tissue regeneration.

Combining Serum Procalcitonin Level, Thromboelastography, and Platelet Count to Predict Short-term Development of Septic Shock in Intensive Care Unit.

OBJECTIVE: Despite the recent advances in diagnosis and treatment, sepsis continues to lead to high morbidity and mortality. Early diagnosis and prompt treatment are essential to save lives. However, most biomarkers can only help to diagnose sepsis, but cannot predict the development of septic shock in high-risk patients. The present study determined whether the combined measurement of procalcitonin (PCT), thromboelastography (TEG) and platelet (PLT) count can predict the development of septic shock. METHODS: A retrospective study was conducted on 175 septic patients who were admitted to the intensive care unit between January 2017 and February 2021. These patients were divided into two groups: 73 patients who developed septic shock were assigned to the septic shock group, while the remaining 102 patients were assigned to the sepsis group. Then, the demographic, clinical and laboratory data were recorded, and the predictive values of PCT, TEG and PLT count for the development of septic shock were analyzed. RESULTS: Compared to the sepsis group, the septic shock group had statistically lower PLT count and TEG measurements in the R value, K value, α angle, maximum amplitude, and coagulation index, but had longer prothrombin time (DT), longer activated partial thromboplastin time (APTT), and higher PCT levels. Furthermore, the Sequential Organ Failure Assessment (SOFA) score was higher in the septic shock group. The multivariate logistic regression analysis revealed that PCT, TEG and PLT count were associated with the development of septic shock. The area under the curve analysis revealed that the combined measurement of PCT, TEG and PLT count can be used to predict the development of septic shock with higher accuracy, when compared to individual measurements. CONCLUSION: The combined measurement of PCT, TEG and PLT count is a novel approach to predict the development of septic shock in high-risk patients.

Far-Infrared Therapy Accelerates Diabetic Wound Healing via Recruitment of Tissue Angiogenesis in a Full-Thickness Wound Healing Model in Rats.

Far-infrared ray (FIR) therapy has been applied in the tissue regeneration field. Studies have revealed that FIR could enhance wound healing. However, the biological effects of FIR on diabetic wounds remain unclear. Our study aims to investigate whether FIR could accelerate diabetic wound healing and analyze the biomechanisms. A dorsal skin defect (area, 6 × 5 cm2) in a streptozotocin (STZ)-induced diabetes rodent model was designed. Thirty-two male Wistar rats were divided into 4 groups (n = 8 each subgroup). Group 1 consisted of sham, non-diabetic control; group 2, diabetic control without treatment; group 3, diabetic rats received 20 min FIR (FIR-20, 20 min per session, triplicate/weekly for 4 weeks) and group 4, diabetic rats received 40 min FIR (FIR-40, 40 min per session, triplicate in one week for 4 weeks). The wound healing was assessed clinically. Skin blood flow was measured by laser Doppler. The vascular endothelial growth factor (VEGF), 8-hydroxy-2-deoxyguanosine (8-OHdG), eNOS, and Ki-67, were analyzed with immunohistochemical (IHC) staining. Laser Doppler flowmetry analysis of the blood flow of wounding area revealed the blood flow was higher in diabetic rats who received 40 min FIR (FIR-40) as compared to that in FIR-20 group. The wounding area was significantly reduced in the FIR-40 group than in the diabetic control groups. Histological findings of peri-wounding tissue revealed a significant increase in the neo-vessels in the FIR-treated groups as compared to the controls. IHC staining of periwounding biopsy tissue showed significant increases in angiogenesis expressions (VEGF, eNOS, and EGF), cell proliferation (Ki-67), and suppressed inflammatory response and oxygen radicles (CD45, 8-OHdG) expressions in the FIR-treated groups as compared to that in controls. Treatment with the optimal dosage of FIR significantly facilitated diabetic wound healing and associated with suppressed pro-inflammatory response and increased neovascularization and tissue regeneration.

Proteomic Analysis of Peri-Wounding Tissue Expressions in Extracorporeal Shock Wave Enhanced Diabetic Wound Healing in a Streptozotocin-Induced Diabetes Model.

Our former studies have demonstrated that extracorporeal shock wave therapy (ESWT) could enhance diabetic wound healing but the bio-mechanisms remain elusive. This study investigated the changes of topical peri-wounding tissue expressions after ESWT in a rodent streptozotocin-induced diabetic wounding model by using the proteomic analysis and elucidated the molecular mechanism. Diabetic rats receiving ESWT, normal control, and diabetic rats receiving no therapy were analyzed. The spots of interest in proteome analysis were subjected to mass spectrometry to elucidate the peptide mass fingerprints. Protein expression was validated using immunohistochemical staining and related expression of genes were analyzed using real-time RT-PCR. The proteomic data showed a significantly higher abundance of hemopexin at day 3 of therapy but down-regulation at day 10 as compared to diabetic control. In contrast, the level of serine proteinase inhibitor (serpin) A3N expression was significantly decreased at day 3 therapy but expression was upregulated at day 10. Using real-time RT-PCR revealed that serpin-related EGFR-MAPK pathway was involved in ESWT enhanced diabetic wound healing. In summary, proteome analyses demonstrated the expression change of hemopexin and serpin with related MAPK signaling involved in ESWT-enhanced diabetic wound healing. Modulation of hemopexin and serpin related pathways are good strategies to promote wound healing.

CCDC7 Activates Interleukin-6 and Vascular Endothelial Growth Factor to Promote Proliferation via the JAK-STAT3 Pathway in Cervical Cancer Cells.

OBJECTIVE: Tumor growth is one of the most lethal attributes of human malignancy. The expression of CCDC7, a novel gene which has multiple functions, has been shown to be associated with tumor growth and poor prognosis in patients with cancer. However, the specific functions of CCDC7 remain unclear. Here, we investigated the molecular mechanisms underlying the effects of CCDC7 on proliferation in cervical cancer. MATERIALS AND METHODS: The MTT and EdU assays were performed to evaluate the function of CCDC7. The immunohistochemical, quantitative real-time PCR (qRT-PCR), ELISA and Western blot assay were used to detect the gene and protein expression in tissues and cells. A xenograft test was conducted to detect the impact of CCDC7 on tumor development in vivo . RESULTS: In immunohistochemical analysis of 193 cases, normal cervical tissue and cervical cancer tissue show that CCDC7 expression is closely correlated with the development of cervical cancer and was positively correlated with the clinical stage and histological grade. Overexpression or knockdown of CCDC7 affected cell proliferation in cervical cancer cells in vitro. In a nude mouse xenograft model in vivo, knockdown of CCDC7 inhibited cell proliferation and tumor growth. Furthermore, CCDC7 overexpression upregulated interleukin (IL)-6 and vascular endothelial growth factor (VEGF) at mRNA and protein levels, and treatment with recombinant IL-6 or VEGF proteins also increased CCDC7 expression. In a case set of 80 patients with cervical cancer, we found that CCDC7, IL-6, and VEGF affected patient prognosis. Finally, inhibition of various signaling pathways using specific inhibitors indicated that CCDC7 blocked the decrease in cell proliferation observed following suppression of the JAK-STAT3 pathway, suggesting that CCDC7 functioned via this critical signaling network. CONCLUSION: Those findings indicated that CCDC7 may be a novel target for the treatment of cervical cancer and may have applications as a predictive marker for tumor growth in cervical carcinoma.

The Acceleration of Diabetic Wound Healing by Low-Intensity Extracorporeal Shockwave Involves in the GSK-3ß Pathway.

Previous studies have demonstrated that extracorporeal shock wave therapy (ESWT) could accelerate diabetic wound healing and that the inhibition of glycogen synthase kinase-3ß (GSK-3ß) is involved in epithelial differentiation during wound healing. This study investigated whether the enhancement of diabetic wound healing by ESWT is associated with the GSK-3ß-mediated Wnt/ß-catenin signaling pathway. A dorsal skin wounding defect model using streptozotocin-induced diabetic rodents was established. Rats were divided into 4 groups: group 1, normal controls without diabetes; group 2, diabetic controls without treatment; group 3, diabetic rats receiving ESWT; and group 4, rats receiving 6-bromoindirubin-3'oxime (BIO), a GSK-3ß inhibitor, to trigger Wnt/ß-catenin signaling. Tissue samples were collected and analyzed by immunohistochemical (IHC) staining and quantitative RT-PCR. The ESWT and BIO-treated groups both exhibited significant promotion of wound healing compared to the healing in controls without treatment. RT-PCR analysis of Wnt-1, -3a, -4, -5a, and -10 and ß-catenin expression showed significantly increased expression in the ESWT group. The IHC staining showed that Wnt-3a and -5a and ß-catenin levels were significantly increased in the ESWT and BIO treatment groups compared to the control groups. ESWT enhancement of diabetic wound healing is associated with modulation of the GSK-3ß-mediated Wnt/ß-catenin signaling pathway.

Inhibition of ZIP4 reverses epithelial-to-mesenchymal transition and enhances the radiosensitivity in human nasopharyngeal carcinoma cells.

ZIP4 is a zinc transporter involved in epithelial cell morphology and migration in various cancers. In the epithelial-to-mesenchymal transition (EMT), epithelial cells transition into mesenchymal cells. The EMT plays a crucial role in invasiveness and metastasis during tumorigenesis. The aim of this study was to investigate the role of ZIP4 in the invasiveness and radiosensitivity of human nasopharyngeal carcinoma (NPC). In this study, results from 99 human patients with NPC showed that ZIP4 expression levels significantly correlated with a higher TN (tumor, lymph node) classification, as well as shorter overall survival (OS), recurrence-free survival (RFS), and distant metastasis-free survival (DMFS). Forced overexpression of ZIP4 promoted the migration and invasion of C666-1 cells through regulation of the EMT process. In contrast, ZIP4 silencing by lentivirus-mediated shRNA inhibited the EMT and metastasis of C666-1 cells in vitro and in vivo. Importantly, protein microarray analyses showed that downregulation of ZIP4 in C666-1 cells resulted in the decreased abundance of phosphoinositide 3-kinase (PI3K) p85 (Tyr607), phosphorylated (p)-Akt (Ser473), phosphorylated (p)-Akt (Thr308), and phosphorylated glycogen synthase kinase 3ß (pGSK3ß; Ser9). These data suggest that ZIP4 induces the EMT and promotes migration and invasion via the PI3K/Akt signaling pathway in NPC. Moreover, ZIP4 silencing significantly enhanced radiation-induced apoptosis and growth inhibition of human C666-1 cells in vitro and enhanced the antitumor activity of ionizing radiation (IR), leading to tumor growth inhibition in vivo. These results demonstrate that ZIP4 is a novel prognostic factor for malignant NPC progression. More importantly, targeting ZIP4, along with radiotherapy, may be an effective new treatment for NPC.

Hyaluronic Acid-Povidone-Iodine Compound Facilitates Diabetic Wound Healing in a Streptozotocin-Induced Diabetes Rodent Model.

BACKGROUND: This study investigated whether a hyaluronic acid-povidone-iodine compound can enhance diabetic wound healing. METHODS: A dorsal skin defect (6 × 5 cm) in a streptozotocin-induced diabetes rodent model was used. Seventy male Wistar rats were divided into seven groups: I, normal control; II, diabetic control, no treatment; III, diabetic rats, lower molecular weight (100 kDa) hyaluronic acid; IV, rats, higher molecular weight (1000 kDa) hyaluronic acid; V, rats, 0.1% povidone-iodine; VI, rats, lower molecular weight hyaluronic acid plus povidone-iodine; and VII, rats, higher molecular weight hyaluronic acid plus povidone-iodine. Histologic examination was performed with hematoxylin and eosin staining. CD45, Ki-67, prolyl 4-hydroxylase, and vascular endothelial growth factor were evaluated with immunohistochemical staining. RESULTS: Compared with the control, higher molecular weight hyaluronic acid plus povidone-iodine-treated rats had significantly reduced wound area (p < 0.001). Higher molecular weight hyaluronic acid plus povidone-iodine increased wound healing time when compared with higher molecular weight hyaluronic acid, povidone-iodine, or lower molecular weight hyaluronic acid plus povidone-iodine. Histology revealed significantly increased neovessels and suppressed inflammatory response in the higher molecular weight hyaluronic acid plus povidone-iodine group when compared with the control group. Immunohistochemical staining revealed significantly increased Ki67, prolyl 4-hydroxylase, and vascular endothelial growth factor expression, and suppressed CD45 expression in the higher molecular weight hyaluronic acid plus povidone-iodine group when compared with the other groups. CONCLUSION: Higher molecular weight hyaluronic acid plus povidone-iodine complex dressing significantly facilitated diabetic wound healing via increasing neovascularization and tissue regeneration and suppressing a proinflammatory response.

Suppression of Oxygen Radicals Protects Diabetic Endothelium Damage and Tissue Perfusion in a Streptozotocin-Induced Diabetes Rodent Model.

BACKGROUND: Oxygen free radicals play a central role in diabetic angiopathy. This study investigated whether suppression of oxygen radicals could decrease endothelial damage and increase peripheral tissue circulation in a diabetic rodent model. METHODS: Sprague-Dawley rats were treated using streptozotocin to induce diabetes. The experiments were performed 4 weeks after diabetes induction: group 1: control, consisted of normal rats; group 2: diabetes, did not receive treatment; groups III (SOD10) and IV (SOD50): diabetes, received polyethylene glycol-conjugated superoxide dismutase (SOD), an antioxidant, 10 and 50 U/kg per day intraperitoneally for 4 weeks. Each subgroup consisted of 10 rats. Oxygen radicals in blood mononuclear cells were detected by flow cytometry. The blood lipid peroxidation byproduct malondialdehyde was measured. Tissue perfusion of hind limb was examined by laser Doppler. The expressions of oxygen radicals, as demonstrated by 8-hydroxyguanosine (8-OG), and constitutive endothelial nitric oxide synthase in distal femoral vessels were examined by immunohistochemical staining. RESULTS: Oxygen radicals, as demonstrated by H2O2 with 2',7'-dichlorofluorescin diacetate-conjugated expression, were significantly increased in diabetic rats. However, the SOD treatment groups significantly suppressed the H2O2 reaction. Diabetic-induced high malondialdehyde levels were significantly suppressed in the SOD50 group. The topical tissue blood perfusion was significantly increased as detected by laser Doppler in SOD10 and SOD50 groups, as compared with that in diabetes without treatment group (P < 0.05). The expression of 8-OG was markedly increased in the diabetic endothelium and subintima compared with that in normal vessels. Polyethylene glycol-conjugated SOD significantly suppressed 8-OG expression and protected endothelial nitric oxide synthase expression. CONCLUSIONS: Suppression of oxygen radicals, particularly with the higher dosage of polyethylene glycol-conjugated SOD at 50 U/kg per day, could have a positive effect to protect against endothelial damage and enhance peripheral perfusion in diabetes.

Modulation of vascular endothelial growth factor and mitogen-activated protein kinase-related pathway involved in extracorporeal shockwave therapy accelerate diabetic wound healing.

Extracorporeal shockwave therapy (ESWT) has a significant positive effect to accelerate chronic wound healing. This study investigated whether the vascular endothelial growth factor (VEGF)-related pathway has involved in ESWT enhancement of diabetic wound healing. A dorsal skin defect (area, 6 × 5 cm) in a streptozotocin-induced diabetes rodent model was used. Thirty-two male Wistar rats were divided into four groups. Group I consisted of nondiabetic control; group II, diabetic control without treatment; group III, diabetic rats received ESWT; and group IV, rats received Avastin (a VEGF monoclonal antibody) on day 0 (post-wounding immediately) to day 7 and ESWT on day 3 and day 7. The wound healing was assessed clinically. The VEGF, endothelial nitric oxide synthase (eNOS), and Ki-67 were analyzed with immunohistochemical staining. The mRNA expression of mitogen-activated protein kinase-related genes was measured by real-time quantitative real-time polymerase chain reaction. The results revealed wound size was significantly reduced in the ESWT-treated rats as compared to the diabetic control (p < 0.01). The positive effect of ESWT-increasing wound healing was significantly suppressed in pretreatment of the Avastin group. Histological findings revealed significant increase in neo-vessels in the ESWT group as compared to the control. In immunohistochemical stain, significant increases in VEGF, eNOS, and Ki-67 expressions were noted in the ESWT group as compared to that in controls. However, Avastin suppressed the shockwave effect and down-regulation of VEGF, eNOS, and Ki-67 expressions in the Avastin-ESWT group as compared to that in the ESWT alone group. We found that highly mRNA expression of Kras, Raf1, Mek1, Jnkk, Jnk, and Jun at early stage in the ESWT group, as compared to the diabetic control. These evidences indicated treatment with multiple sessions of ESWT significantly enhanced diabetic wound healing associated with increased neovascularization and tissue regeneration. The bio-mechanism of ESWT-enhanced wound healing is correlated with VEGF and mitogen-activated protein kinase-mediated pathway.

Assessment of 1-year Outcomes in Survivors of Severe Acute Respiratory Distress Syndrome Receiving Extracorporeal Membrane Oxygenation or Mechanical Ventilation: A Prospective Observational Study.

BACKGROUND: Little is known about the long-term outcomes of severe acute respiratory distress syndrome (ARDS) patients requiring extracorporeal membrane oxygenation (ECMO). This study aimed to investigate the 1-year outcomes of these patients or patients receiving mechanical ventilation (MV) and compare their health-related quality of life (HRQoL) to the general population. METHODS: Severe ARDS survivors admitted to two ICUs in China between January 2012 and January 2014 were enrolled. Of the severe ARDS survivors enrolled, 1-year postdischarge, HRQoL assessment using the Short-Form 36 (SF-36) and EuroQol questionnaire dimensions, 6-min walking distance, chest computed tomography scan, pulmonary function, and arterial blood gas analysis were compared for ARDS patients with or without ECMO. RESULTS: ARDS patients receiving ECMO had a significantly higher Acute Physiology and Chronic Health Evaluation II score (30.3 ± 6.7 vs. 26.5 ± 7.3, P= 0.036), lung injury score (3.3 ± 0.4 vs. 2.8 ± 0.5, P= 0.000), Sequential Organ Failure Assessment score (10.8 ± 3.5 vs. 7.9 ± 3.1, P= 0.000), lower PaO2/FiO2ratio ([mmHg, 1 mmHg = 0.133 kPa], 68.3 ± 16.1 vs. 84.8 ± 16.5, P= 0.000), and increased extrapulmonary organ failure (2 [1, 3] vs. 1 [1, 1], P= 0.025) compared with patients not receiving ECMO. ECMO and non-ECMO survivors showed similar pulmonary function, morphological abnormalities, resting arterial blood gas values, and 6-min walking distance. Mild pulmonary dysfunction and abnormal morphology were observed in a few survivors. In addition, ECMO and non-ECMO survivors showed a similar quality of life. ECMO survivors showed lower SF-36 physical functioning and role-physical domain scores (minimum clinically significant difference at least 5 points), and non-ECMO survivors had similar outcome. CONCLUSIONS: One-year posthospital discharge, severe ARDS survivors receiving ECMO or MV demonstrated comparable outcomes. Compared with the general population, ARDS survivors showed reduced HRQoL. Pulmonary function and lung morphology revealed sufficient recovery with minor lung impairment.

Interleukin-37 Enhances the Suppressive Activity of Naturally Occurring CD4+CD25+ Regulatory T Cells.

Naturally occurring CD4+CD25+ regulatory T cells (Tregs) are essential for the suppression of autoimmunity and can control the immune-mediated pathology during the early phase of sepsis. Our previous data showed that silencing interleukin-37 (IL-37) in human CD4+CD25+ Tregs obviously reduced the suppressive activity of CD4+CD25+ Tregs. Here, we found that rhIL-37 stimulation markedly enhanced the suppressive activity of CD4+CD25+ Tregs isolated from naive C57BL/6 J mice in the absence or presence of lipopolysaccharide (LPS). Treatment with rhIL-37 could significantly upregulate the expression of cytotoxic T-lymphocyte-associated antigen (CTLA)-4 and forkhead/winged helix transcription factor p3 (Foxp3) on CD4+CD25+ Tregs. Also, rhIL-37 stimulation promoted the production of transforming growth factor-ß1 (TGF-ß1) but not IL-10 in the supernatants of cultured CD4+CD25+ Tregs. Pretreated CD4+CD25+ Tregs with rhIL-37 in the presence or absence of LPS were cocultured with CD4+CD25- T cells, ratio of IL-4/interferon-γ in the supernatants obviously increased in IL-37-stimulated groups. In addition, early administration of IL-37 significantly improved the survival rate of septic mice induced by cecal ligation and puncture. Taken together, we concluded that rhIL-37 enhances the suppressive activity of CD4+CD25+ Tregs and might be a potential immunomodulator for the treatment of septic complications.

Effect of probiotics on the incidence of ventilator-associated pneumonia in critically ill patients: a randomized controlled multicenter trial.

PURPOSE: To evaluate the potential preventive effect of probiotics on ventilator-associated pneumonia (VAP). METHODS: This was an open-label, randomized, controlled multicenter trial involving 235 critically ill adult patients who were expected to receive mechanical ventilation for ≥48 h. The patients were randomized to receive (1) a probiotics capsule containing live Bacillus subtilis and Enterococcus faecalis (Medilac-S) 0.5 g three times daily through a nasogastric feeding tube plus standard preventive strategies or (2) standard preventive strategies alone, for a maximum of 14 days. The development of VAP was evaluated daily, and throat swabs and gastric aspirate were cultured at baseline and once or twice weekly thereafter. RESULTS: The incidence of microbiologically confirmed VAP in the probiotics group was significantly lower than that in the control patients (36.4 vs. 50.4 %, respectively; P = 0.031). The mean time to develop VAP was significantly longer in the probiotics group than in the control group (10.4 vs. 7.5 days, respectively; P = 0.022). The proportion of patients with acquisition of gastric colonization of potentially pathogenic microorganisms (PPMOs) was lower in the probiotics group (24 %) than the control group (44 %) (P = 0.004). However, the proportion of patients with eradication PPMO colonization on both sites of the oropharynx and stomach were not significantly different between the two groups. The administration of probiotics did not result in any improvement in the incidence of clinically suspected VAP, antimicrobial consumption, duration of mechanical ventilation, mortality and length of hospital stay. CONCLUSION: Therapy with the probiotic bacteria B. Subtilis and E. faecalis are an effective and safe means for preventing VAP and the acquisition of PPMO colonization in the stomach.

YL4073 is a potent autophagy-stimulating antitumor agent in an in vivo model of Lewis lung carcinoma.

Cancer cells activate autophagy in response to anticancer therapies. Autophagy induction is a promising therapeutic approach to treat cancer. In a previous study, YL4073 inhibited the growth of liver cancer and induced liver cancer cell apoptosis. Here, we demonstrated the anticancer activity and specific mechanisms of YL4073 in Lewis lung carcinoma LL/2 cells. Our results show that YL4073-induced autophagy was followed by apoptotic cell death. The anticancer and autophagy stimulating efficacy was confirmed by several factors, including the appearance of autophagic vacuoles, formation of acidic vesicular organelles, recruitment of microtubule-associated protein 1 light chain 3 II (LC3-II) to the autophagosomes, conversion and cleavage of LC3-I to LC3-II, upregulation of Beclin 1 expression, and formation of the Atg12-Atg5 conjugate in LL/2 cells after YL4073 treatment for 24 or 48 h. Furthermore, P53 activation and p-histone H3 phosphorylation occurred after cell exposure to YL4073 for 48 h, suggesting that cell apoptosis had occurred. Pharmacological inhibition of autophagy using 3-methyladenine increased cell apoptosis. Molecular level studies revealed that YL4073 inhibited survival signalling by blocking the activation of Akt and mTOR phosphorylation and reduced the expression of p-mTOR downstream targets for phosphorylation, including p70S6K, p-TSC, p-MAPK, and p-AMPK. This suggests that the Akt/mTOR/p70S6K and TSC/MAPK/AMPK pathways are involved in the effects of YL4073 treatment in LL/2 cells. In addition, YL4073 significantly inhibited LL/2 tumor growth and induced apoptosis in vivo. These data suggest that YL4073 has a significant anticancer effect, with a pathway-specific mechanism of autophagy both in vitro and in vivo.

Adipose-Derived Stem Cells Accelerate Diabetic Wound Healing Through the Induction of Autocrine and Paracrine Effects.

Cell-based therapy is an attractive approach for the treatment of chronic nonhealing wounds. This study investigated whether adipose-derived stem cells (ASCs) can accelerate diabetic wound healing and traffic in the engraftment of ASCs. Dorsal full-thickness skin wound defects (6 × 5 cm) were created in a streptozotocin (STZ)-induced diabetes rodent model. Group I served as a nondiabetic normal control, group II served as a diabetic control without ASCs, and group III included rats that were injected subcutaneously in the wound margin twice with nondiabetic ASCs (1 × 10(7) ASCs/dose). The wound healing was assessed clinically. Histological examination and immunohistochemical analyses of periwound tissue were performed. Green fluorescence protein (GFP)(+)-ASCs were used to examine the engraftment of these cells after injection. XenoLight DiR-labeled ASCs were implanted to detect migration ability using an IVIS imaging system. Results revealed that complete wound healing time statistically decreased in the ASC-treated group compared to the controls (p < 0.001). Histological examination revealed the ASC-treated group showed a significant reduction in the proinflammatory reaction, with significantly increased levels of EGF, VEGF, rPH, and Ki-67 expression compared to the controls. The populations of GFP(+)-ASCs in circulating blood significantly increased after ASC injection compared to those of controls. Immunofluorescence staining showed GFP(+)-ASCs significantly accumulated in the subdermal layer of the wound margin and increased angiogenesis via vWF and VEGF expression after injection. IVIS analysis revealed ASCs could exist and home into the periwound area up to 8 weeks postimplantation. In conclusion, ASCs significantly enhanced diabetic wound healing, engrafted into the local wound tissue, and implanted into circulating blood. ASC treatment stimulated neoangiogenesis and increased tissue regeneration through paracrine and autocrine mechanisms.

Expression of HMGB1/RAGE protein in renal carcinoma and its clinical significance.

OBJECTIVE: To investigate the expression of high mobility group protein B1 (HMGB1) and its receptor, receptor for advanced glycation end-product (RAGE), in renal cancer tissue and surrounding normal tissue and to analyze the relationship between the expression level of the protein and receptor as well as the clinical pathological characteristics and prognosis in renal cancer patients. METHODS: A total of 80 renal carcinoma patients who were surgically treated in our hospital from February 2004 to December 2012 were included in this study. Normal paratumoral tissues were collected as a control. All diagnoses were confirmed with a postoperative pathological examination. All patients had complete pathological data. The expression of HMGB1/RAGE proteins in renal cancer tissue and paratumoral tissue was examined using immunohistochemical methods. RESULTS: The positive expression rate of HMGB1 was 71% in renal cancer tissue, which was significantly higher than that in the paratumoral normal tissue (25%). The positive expression rate of RAGE was 72% in renal cancer tissue, which was significantly higher than that in the paratumoral normal tissue (27%). Further analysis did not indicate a correlation between the positive expression of HMGB1 and RAGE proteins and gender, age and tumor size (P > 0.05), whereas the expression patterns were shown to correlate with tumor differentiation, clinical stage and lymph node metastasis (P < 0.05). The expression of HMGB1 exhibited a significant positive correlation with RAGE level (P < 0.05), the expression of HMGB1/RAGE proteins exhibited a negative correlation with the prognosis of patients, and the five-year survival rate of patients with positive expression was significantly lower than that of patients with negative expression (P < 0.05). CONCLUSION: HMGB1/RAGE exhibited significantly elevated expression in renal cancer tissues that was closely related to the clinical prognosis of patients; thus, the expression levels may become a new target in the treatment of renal carcinoma.