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Background Acute pancreatitis (AP) lacks targeted prevention and treatment measures. Some key points in the pathogenesis of AP remain unclear, such as early activation of pancreatic enzymes. Several recent reports have shown the protective effect of hydrogen on several AP animal models, and the mechanism is related to antioxidant activity. Heat shock protein 60 (Hsp60) is known to accompany pancreatic enzymes synthesis and secretion pathway of in pancreatic acinar cells, while role of hsp60 in AP remains a topic. Aim of this study was to investigate effect of hydrogen pretreatment on AP and the mechanisms, focusing on pancreatic oxidative stress and Hsp60 expression. Methods 80 mice were randomly assigned into four groups: HAP group, AP group, HNS group, and NS group and each group were set 3 observation time point as 1 h, 3 h and 5 h (n = 6–8). Mouse AP model was induced by intraperitoneal injection of 50 μg/kg caerulein per hour for 6 injections both in AP and HAP groups, and mice in NS group and HNS group given normal saline (NS) injections at the same way as control respectively. Mice in HAP group and HNS group were treated with hydrogen-rich gases inhalation for 3 days before the first injection of caerulein or saline, while mice in AP group and NS group in normal air condition. Histopathology of pancreatic tissue, plasma amylase and lipase, plasma IL-1 and IL-6, pancreatic glutathione (GSH) and malondialdehyde (MDA), and Hsp60 mRNA and protein expression were investigated. Comparisons were made by one-way analysis of variance. Results The pancreatic pathological changes, plasma amylase and lipase activity, and the increase of plasma IL-1 and IL-6 levels in AP mice were significantly improved by the hydrogen-rich gases pretreatment, Meanwhile, the pancreatic GSH content increased and the pancreatic MDA content decreased. And, the hydrogen-rich gases pretreatment improved the Hsp60 protein expression in pancreatic tissues of AP mice at 1 h and 5 h. Conclusions Pre-inhalation of hydrogen-rich gases have a good protective effect on AP mice, and the possible mechanisms of reduced oxidative stress and the early increased pancreatic Hsp60 protein deserve attention.

Background: The two main causes of body inflammation caused by lipopolysaccharide (LPS) -induced acute lung injury (ALI) are chronic inflammation and oxidant / antioxidant imbalances. Hydrogen (H2), a gaseous molecule without known toxicity, could react with hydroxyl radical to remove the reactive oxygen species (ROS). Both in vivo and vitro studies support the protective effect of hydrogen on injuries caused by oxidative stress and inflammations. Methods: In vivo study, mice were randomly divided into three groups: H2 control group, LPS group and LPS+H2 group. The mice were euthanized at the indicated time points and the specimens were collected. The 72h survival rates, cytokines contents, pathological changes, expression of Toll-like receptor 4(TLR4) and oxidative stress indicators were observed. In vitro study, according to different culture conditions, RAW 264.7 mouse macrophages were divided into the following groups: PBS group, LPS group and LPS+H2 group. The cell Viability, intracellular ROS, cytokines and expression of TLR4 and nuclear factor kappa-B (NF-κB) were observed. Results: In vivo, the 72h survival rate of hydrogen inhalation mice was increased to 80%, and H2 significantly lighten LPS-induced lung damages and decreased inflammatory cytokine release. Besides, H2 showed remarked anti-oxidative activity to reduce the MDA and NO contents in lung. In vitro, H2 down-regulated the levels of ROS, NO, TNF-α, IL-6 and IL-1β in LPS-stimulated macrophages. Second, H2 inhibited the expression of TLR4 and the activation of nuclear factor kappa-B (NF-κB). In summary, these findings supported that H2 attenuates LPS-induced inflammatory responses, which may be mediated by TLR4-NF-κB pathway.

Mounting evidence highlights long non‐coding RNAs (lncRNAs) as crucial regulators in multiple types of biological processes and contributing to tumourigenesis. LINC01133, located in chromosome 1q23.2, was a recently identified novel lncRNA with a length of 1154nt. It was involved in the development of colorectal cancer and non‐small cell lung cancer. However, its clinical relevance, biological functions and potential molecular mechanism in breast cancer are still unclear. In this study, we found that the LINC01133 expression was significantly down‐regulated in breast cancer samples and was associated with progression and poor prognosis of breast cancer. Further experiments demonstrated that overexpression of LINC01133 inhibited invasion and metastasis in breast cancer both in vitro and in vivo. Mechanistic investigations revealed that LINC01133 repressed SOX4 expression by recruiting EZH2 to SOX4 promoter. Moreover, rescue experiments further confirmed that LINC01133 functional acted as an anti‐oncogene, at least partly, via repressing SOX4 in breast cancer. Taken together, these findings imply that LINC01133 could serve as a novel prognostic biomarker and potential therapeutic target for breast cancer.

The pulmonary benign metastasizing leiomyoma (BML) is an extremely rare disease case, of which the pathogenesis was not elucidated. The accumulation of additional case reports and analyses is needed. A case of pulmonary BML is presented. A 48-year-old asymptomatic female patient that underwent a hysteromyomectomy 11 years ago was found to have abnormal shadows on a chest X-ray during a regular health check-up in 2012. Multiple nodular was observed in both lungs and uterine under computed tomography (CT) examination. Transbronchial lung biopsy surgery with a resection of the lesion was performed. The results revealed the pulmonary nodule was formed by benign smooth muscle cells which displayed very low mitotic activity. The samples showed highly positive signals for α-smooth muscle actin (αSMA), Desmin and Vimentin. Estrogen receptor (ER) and progesterone receptor (PR) were also immunoreactive positive. HMB-45, CD117 (C-kit) and S-100 were found to be negative with low Ki-67 index in the tumor cells. The pathological diagnosis was pulmonary BML. A total hysterectomy with adnexectomy were performed for the multiple uterine leiomyomas and pulmonary BML one week after diagnosis was made. From then on, the pulmonary nodules in both lungs were stable in 7 years postoperation, based on chest CT scan. When a solitary lung nodule is detected in a patient with a history of uterine leiomyoma, as an option, pulmonary BML, accurately diagnosing and proper treatment to has important implications for clinical outcome.

Additional file of Pre-inhalation of hydrogen-rich gases protect against caerulein-induced mouse acute pancreatitis while enhance the pancreatic Hsp60 protein expression

Hypoxic/ischemic insult, a leading cause of functional brain defects, has been extensively studied in both clinical and experimental animal research, including its etiology, neuropathogenesis, and pharmacological interventions. Transient sublethal hypoxia (TSH) is a common clinical occurrence in the perinatal period. However, its effect on early developing brains remains poorly understood. The present study was designed to investigate the effect of TSH on the dendrite and dendritic spine formation, neuronal and synaptic activity, and cognitive behavior of early postnatal Day 1 rat pups. While TSH showed no obvious effect on gross brain morphology, neuron cell density, or glial activation in the hippocampus, we found transient hypoxia did cause significant changes in neuronal structure and function. In brains exposed to TSH, hippocampal neurons developed shorter and thinner dendrites, with decreased dendritic spine density, and reduced strength in excitatory synaptic transmission. Moreover, TSH-treated rats showed impaired cognitive performance in spatial learning and memory. Our findings demonstrate that TSH in newborn rats can cause significant impairments in synaptic formation and function, and long-lasting brain functional deficits. Therefore, this study provides a useful animal model for the study of TSH on early developing brains and to explore potential pharmaceutical interventions for patients subjected to TSH insult.

Background: Pulmonary sarcomatoid carcinoma (PSC) as a rare subtype of nonsmall cell lung cancer (NSCLC) is resistant to conventional chemotherapy and radiotherapy with poor prognosis. Nivolumab is a monoclonal antibody against PD-1 and might be a valuable therapy option for PSC, but limited case reports have shown good response. Case presentation: A 61-year-old man with PSC characterized with KRAS-G12C mutation and TP53 mutation received treatment of nivolumab synchronously combined with hydrogen inhalation. Clinical symptoms gradually relieved, and evaluation on imaging revealed a response after 1 year. Conclusion: This case suggests that immunotherapy combined with hydrogen inhalation may potentially be a promising strategy to treat PSC patients.

Highly effective targeted tumor recognition via vectors is crucial for cancer detection. In contrast to antibodies and proteins, peptides are direct targeting ligands with a low molecular weight. In the present study, a peptide magnetic nanovector platform containing a lipid bilayer was designed using a peptide amphiphile (PA) as a skeleton material in a controlled manner without surface modification. Fluorescein isothiocyanate-labeled epidermal growth factor receptor (EGFR) peptide nanoparticles (NPs) could specifically bind to EGFR-positive liver tumor cells. EGFR peptide magnetic vesicles (EPMVs) could efficiently recognize and separate hepatoma carcinoma cells from cell solutions and treated blood samples (ratio of magnetic EPMVs versus anti-EpCAM NPs: 3.5 ± 0.29). Analysis of the circulating tumor cell (CTC) count in blood samples from 32 patients with liver cancer showed that EPMVs could be effectively applied for CTC capture. Thus, this nanoscale, targeted cargo-packaging technology may be useful for designing cancer diagnostic systems.

Allergic rhinitis (AR) is a common chronic inflammatory condition. It has been previously indicated that oxidative stress may contribute to allergic inflammation, including AR. Although molecular hydrogen (H2), an antioxidative agent, has been effective in treatment of numerous oxidative stress-associated diseases, the effect of inhalation of a high concentration of H2 on AR remains unknown. In the current study, female BALB/c mice were sensitized with ovalbumin (OVA) followed by intranasal OVA challenge to establish an animal model of AR. Mice were subjected to exposure to H2 and the inert gas helium at different frequencies and durations. The frequencies of sneezing/scratching and the body weights of mice were recorded. Histological analysis and multiplex cytokine assays were performed to evaluate the effects of H2 on AR. Challenge with OVA induced significant nasal mucosa inflammation. H2 inhalation reduced the infiltration of inflammatory cells into mucosa and lowered the levels of interleukin (IL)-5, IL-13 and monocyte chemoattractant protein-1 in serum. H2 inhalation slightly increased the level of interferon-γ, however the difference was not statistically significant. Treatment with H2 limited the weight increase in healthy mice and reversed the weight loss in mice with AR. Furthermore, H2 inhalation induced a therapeutic effect on AR in a dose-dependent manner. The current results demonstrate that H2 may demonstrate a therapeutic value for allergic diseases.

Mitogen-activated protein kinases (MAPKs) and phosphatidylinositol-3-kinase (PI3K)/Akt-mediated signaling pathways play critical roles in peripheral nerve injury. However, the mechanism by which activate these signaling is unclear. We examined the activation of MAPK and Akt pathways in the proximal segments of crushed rat sciatic nerve after 1-30 days injury. We found that the phosphorylation level of Erk was attenuated in protein level. Phosphorylation of JNK and p38 increased from day 1 to day 15 following injury. In addition, activation of Akt was up-regulated predominantly in the ipsilateral proximal nerves and located in Schwann cells. Furthermore, phosphorylated GSK3β (Ser9) and GSK3β (Tyr216) were highly augmented from the third day to the 30th day and from 3 to 7 days after injury, respectively. Moreover, mTOR/p70S6 were activated within 7 days injury. Taken together, our studies suggest that the PI3K/Akt signaling is required for the regulation of axon regeneration in Schwann cells in the proximal nerve segments after injury. Furthermore, the contralateral nerves have some compensable response to the injury, at least, including the changes of signaling molecules.

The incorporation of microcarriers as drug delivery vehicles into polymeric scaffold for bone regeneration has aroused increasing interest. In this study, the aminated mesoporous silica nanoparticles (MSNs-NH2) were prepared and used as microcarriers for dexamethasone (DEX) loading. Poly(l-lactic acid)/poly(e-caprolactone) (PLLA/PCL) nanofibrous scaffold was fabricated via thermally induced phase separation (TIPS) and served as template, onto which the drug-loaded MSNs-NH2 nanoparticles were deposited by electrophoretic deposition (EPD). The physicochemical and release properties of the prepared scaffolds (DEX@MSNs-NH2/PLLA/PCL) were examined, and their osteogenic activities were also evaluated through in vitro and in vivo studies. The release of DEX from the scaffolds revealed an initial rapid release followed by a slower and sustained one. The in vitro results indicated that the DEX@MSNs-NH2/PLLA/PCL scaffold exhibited good biocompatibility to rat bone marrow-derived mesenchymal stem cells (BMSCs). Also, BMSCs cultured on the DEX@MSNs-NH2/PLLA/PCL scaffold exhibited a higher degree of osteogenic differentiation than those cultured on PLLA/PCL and MSNs-NH2/PLLA/PCL scaffolds, in terms of alkaline phosphatase (ALP) activity, mineralized matrix formation, and osteocalcin (OCN) expression. Furthermore, the in vivo results in a calvarial defect model of Sprague-Dawley (SD) rats demonstrated that the DEX@MSNs-NH2/PLLA/PCL scaffold could significantly promote calvarial defect healing compared with the PLLA/PCL scaffold. Thus, the EPD technique provides a convenient way to incorporate osteogenic agents-containing microcarriers to polymer scaffold, and thus, prepared composite scaffold could be a potential candidate for bone tissue engineering application due to its capacity for delivery of osteogenic agents.

Chemokines are implicated in the neuroinflammation of several chronic neurodegenerative disorders. However, the precise role of chemokines in neurodegeneration is unknown. Thiamine deficiency (TD) causes abnormal oxidative metabolism in the brain as well as a well-defined microglia activation and neurodegeneration in the submedial thalamus nucleus (SmTN), which are common features of neurodegenerative diseases. We evaluated the role of chemokines in neurodegeneration and the underlying mechanism in a TD model. Among the chemokines examined, TD selectively induced neuronal expression of monocyte chemoattractant protein-1 (MCP-1) in the SmTN prior to microglia activation and neurodegeneration. The conditioned medium collected from TD-induced neurons caused microglia activation. With a neuron/microglia co-culture system, we showed that MCP-1-induced neurotoxicity required the presence of microglia, and exogenous MCP-1 was able to activate microglia and stimulated microglia to produce cytokines. A MCP-1 neutralizing antibody inhibited MCP-1-induced microglia activation and neuronal death in culture and in the thalamus. MCP-1 knockout mice were resistant to TD-induced neuronal death in SmTN. TD selectively induced the accumulation of reactive oxygen species in neurons, and antioxidants blocked TD-induced MCP-1 expression. Together, our results indicated an induction of neuronal MCP-1 during mild impairment of oxidative metabolism caused by microglia recruitment/activation, which exacerbated neurodegeneration.

Glycogen synthase kinase 3β (GSK-3β) protein is a key regulator of neurogenesis, neuronal differentiation and polarisation during neurodevelopment. Sensory neurons in dorsal root ganglion (DRG) undergo a series of development stages during its maturation. In this study, we investigated the dynamic changes in GSK-3β expression and phosphorylation of its N-terminal serine-9 residue (p-GSK-3β (S9)) during DRG development. Sprague-Dawley (SD) rats were divided according to the following ages: Embryonic 13(th) (E13), E15, E19, Postnatal 1(st) (P1), P3, P7, P14, P21 and P60 days. GSK-3β was detected by immunohistochemistry and double immunofluorescence on DRGs. Western blotting was used to determine the quantity of GSK-3β and p-GSK-3β (S9) expression. It was found that GSK-3β immunopositive cells in the DRG appeared as early as E13 development phase, and gradually increased to a peak level at P3, at which almost all neurons were GSK-3β positive, and then stayed at a high level to the experiment day 60. GSK3β expression was cell-type-specific during DRG maturation and exhibited cytoplasmic staining in the neuronal cell body and the axon. Glial cells consistently remained negative in DRGs at all stages. Western blot analysis revealed that GSK3β expression stayed the same during DRG maturation. In contrast, p-GSK-3β (S9) expression was stage-specific and decreased from E13 to P60 (P0.01). Taken together, these results suggest that GSK-3β expression is stage-specific and cell-type-specific during DRG maturation.

Human embryonic stem cells (hESCs) are a promising model for the research of embryonic development and regenerative medicine. Since the first hESC line was established, many researchers have shown that pluripotent hESCs can be directed into many types of functional adult cells in culture. However, most of the reported methods have induced differentiation through the alteration of growth factors in the culture medium. These methods are time consuming; moreover, it is difficult to obtain a pure population of the desired cells because of the low efficiency of induction. In this study, we used a lentiviral-based inducible gene-expression system in hESCs to control the ectopic expression of MyoD, which is an essential transcription factor in skeletal muscle development. The induction of MyoD can efficiently direct the pluripotent hESCs into mesoderm in 24 h. The cells then become proliferated myoblasts and finally form multinucleated myotubes in vitro. The whole procedure took about 10 days, with an induction efficiency of over 90 %. To our knowledge, this is the first time that hESCs have been induced into terminally differentiated cells with only one factor. In the future, these results could be a potential resource for cell therapy for diseases of muscle dysfunction.

Several genes, including fibroblast growth factor 2 (FGF2), are up-regulated in the hypertrophic heart. However, the molecular mechanisms responsible for the angiotensin II (Ang II)-induced activation of FGF2 in cardiomyocyte hypertrophy are largely unknown. The purpose of this study was to determine the signaling cascades underlying the Ang II-induced transcriptional activation of FGF2 in neonatal rat cardiomyocytes. Real-time quantitative RT-PCR and Western blot showed that Ang II upregulates FGF2 expression and that these effects were attenuated by U0126 or SB203580, but not by SP600125. Deletion analyses revealed that the region between -845 and -666 is essential for Ang II-induced FGF2 promoter activity. The existence of an atypical GATA4-binding motif, located at position -752, was identified using electrophoretic mobility shift assay (EMSA). Using both EMSA and chromatin immunoprecipitation (ChIP) analyses, we also showed that Ang II increases binding of GATA4 to DNA, and that this effect is attenuated in the presence of U0126 or SB203580, but not in the presence of SP600125. GATA4 siRNA significantly reduced Ang II-induced FGF2 mRNA levels. Together, these results indicate that binding of GATA4 to DNA is increased by Ang II via extracellular signal-regulated protein kinase 1/2 (ERK 1/2) and p38 kinase, which increases FGF2 gene expression in neonatal rat cardiomyocytes.

ADAM23 modulates many cellular functions, alteration of expression causes a number of tumor types; however, the mechanisms controlling ADAM23 expression remain unknown. Here we have identified a SP1 binding site (-202/-190) that binds SP1 at the proximal promoter of human ADAM23 gene; furthermore, serum deprivation enhances open chromatin accessibility and help expose the SP1 binding site; finally, SP1 binding recruits RNA polymerase II, which in turn results in upregulation of endogenous ADAM23 expression. Therefore, the present study delineates the fundamental elements of a core promoter structure that will be helpful for future studies of the regulation of ADAM23 gene.