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Crotonaldehyde (CRA)—one of the major environmental pollutants from tobacco smoke and industrial pollution—is associated with vascular injury (VI). We used proteomics to systematically characterize the presently unclear molecular mechanism of VI and to identify new related targets or signaling pathways after exposure to CRA. Cell survival assays were used to assess DNA damage, whereas oxidative stress was determined using colorimetric assays and by quantitative fluorescence study; additionally, cyclooxygenase-2, mitogen-activated protein kinase pathways, Wnt3a, β-catenin, phospho-ErbB2, and phospho-ErbB4 were assessed using ELISA. Proteins were quantitated via tandem mass tag-based liquid chromatography-mass spectrometry and bioinformatics analyses, and 34 differentially expressed proteins were confirmed using parallel reaction monitoring, which were defined as new indicators related to the mechanism underlying DNA damage; glutathione perturbation; mitogen-activated protein kinase; and the Wnt and ErbB signaling pathways in VI based on Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and protein–protein interaction network analyses. Parallel reaction monitoring confirmed significant (p < 0.05) upregulation (> 1.5-fold change) of 23 proteins and downregulation (< 0.667-fold change) of 11. The mechanisms of DNA interstrand crosslinks; glutathione perturbation; mitogen-activated protein kinase; cyclooxygenase-2; and the Wnt and ErbB signaling pathways may contribute to VI through their roles in DNA damage, oxidative stress, inflammation, vascular dysfunction, endothelial dysfunction, vascular remodeling, coagulation cascade, and the newly determined signaling pathways. Moreover, the Wnt and ErbB signaling pathways were identified as new disease pathways involved in VI. Taken together, the elucidated underlying mechanisms may help broaden existing understanding of the molecular mechanisms of VI induced by CRA. [ABSTRACT FROM AUTHOR]

Background: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is the most frequent autoimmune paraneoplastic encephalitis, and is primarily associated with ovarian teratomas. Here, we report the first case of a patient diagnosed with chronic myelogenous leukemia (CML) during the recovery phase of anti-NMDAR encephalitis.Case Presentation: The patient was admitted with fever, headache, and seizures. Brain MRI revealed a cerebrospinal fluid (CSF)-containing arachnoid cyst in the left temporal lobe with no other abnormal signals. EEG showed diffuse background slowing in the delta-theta range. The patient tested positive for anti-NMDAR antibodies in both the serum and CSF. One year after the onset of encephalitis, the patient was referred to the Department of Hematology for extreme leukocytosis. Karyotype analysis showed the presence of Philadelphia chromosome t(9;22)(q34;q11). Quantitative reverse transcriptase PCR analysis further identified BCR/ABL1 fusion transcripts; thus, CML was diagnosed.Conclusions: To the best of our knowledge, this is the first case of anti-NMDAR encephalitis associated with CML. This report should alert clinicians to consider CML as a malignancy that is possibly associated with limbic encephalitis. [ABSTRACT FROM AUTHOR]

Semiquantum cryptography has drawn much attention in recent years since it simplifies the implementation of quantum cryptographic protocols. In this paper, we study semiquantum secure direct communication (SQSDC). Based on single-photons, we propose a two-step SQSDC protocol with identity authentication, which can be used to prevent impersonation and the man-in-the-middle attack. Different from previous protocols based on quantum entanglement or quantum memory, our protocol removes there restrictions for simplifying its physical implementation. We prove that our two-step SQSDC protocol is completely robust. That is, any adversarial attempting to learn some information on the secure message or identity strings will inevitably induce some errors that can be detected by communicators. [ABSTRACT FROM AUTHOR]

In search of direct targets of insulin-like growth factor ( IGF)-1 action, we discovered CCN5 ( WNT1 inducible signaling pathway protein 2 [ WISP2]) as a novel protein expressed in pancreatic β-cells. As a member of the ' CCN' ( Cysteine-rich angiogenic inducer 61 [ Cyr61], Connective tissue growth factor [ CTGF in humans], and Nephroblastoma overexpressed [ Nov; in chickens]) family, the expression of CCN5/WISP2 is stimulated by IGF-1 together with Wnt signaling. When overexpressed in insulinoma cells, CCN5 promotes cell proliferation and cell survival against streptozotocin-induced cell death. The cell proliferation effect seems to be caused by AKT phosphorylation and increased cyclin D1 levels. These properties resemble those of CCN2/CTGF, another isoform of the CCN family, although CCN5 is the only one within the family of six proteins that lacks the C-terminal repeat. Treatment of primary mouse islets with recombinant CCN5 protein produced similar effects to those of gene transfection, indicating that either as a matricellular protein or a secreted growth factor, CCN5 stimulates β-cell proliferation and regeneration in a paracrine fashion. This review also discusses the regulation of CCN5/WISP2 by estrogen and its involvement in angiogenesis and tumorigenesis. [ABSTRACT FROM AUTHOR]

Previous reports have suggested that epidermal growth factor receptor (EGFR) is involved in microglia activation characterized by cell morphology changes, cytokine production and cell migration; and the biochemical regulation of the microglia migration is a potential therapeutic target following CNS inflammatory damages. However, the role of EGFR in microglia motility after inflammatory stimulation remains unknown. In the present study, lipopolysaccharide (LPS) was found to trigger rapid EGFR phosphorylation within 10 min, which was sustained during long-term stimulation in both primary microglial cells and the cultured BV2 microglial cells, furthermore, blocking EGFR phosphorylation by AG1478 significantly attenuated the LPS-induced chemotactic and chemokinetic migration of microglia. In addition, LPS could initiate calcium oscillation in microglia during live-cell recording, however, an intracellular calcium chelator and a selective inhibitor of calcium/calmodulin-dependent protein kinase II, but not an extracellular calcium chelator, remarkably suppressed the LPS-induced EGFR phosphorylation in BV2 microglia cells. As EGFR is not a traditional receptor for LPS, these findings suggest that the rapid phosphorylation of EGFR is attributed to the LPS-triggered intracellular calcium mobilization. By examining the downstream signals of EGFR, we further proved that extracellular signal-regulated kinase (ERK) is essential for EGFR-mediated microglia migration, because ERK inhibition attenuated the chemotactic and chemokinetic migration of microglia that had been induced by either LPS or EGF. Collectively, these results suggest that LPS could trigger the rapid phosphorylation of EGFR and subsequent ERK activation through mobilizing calcium activity, which underlies the microglia migration in an inflammatory condition. [ABSTRACT FROM AUTHOR]

The rice stem borer (RSB), Chilo suppressalis, a notorious rice pest in China, has evolved a high resistance level to commonly used insecticides. Tetraniliprole, a new anthranilic diamide insecticide, effectively controls multiple pests, including RSB. However, the potential resistance risk of RSB to tetraniliprole is still unknown. In this study, the tetraniliprole‐selection (Tet‐R) strain was obtained through 10 continuous generations of selection with tetraniliprole 30% lethal concentration (LC30). The realized heritability (h2) of the Tet‐R strain was 0.387, indicating that resistance of RSB to tetraniliprole developed rapidly under the continuous selection of tetraniliprole. The Tet‐R strain had a high fitness cost (relative fitness = 0.53). We established the susceptibility baseline of RSB to tetraniliprole (lethal concentration at LC50 = 0.727 mg/L) and investigated the resistance level of 6 field populations to tetraniliprole. All tested strains that had resistance to chlorantraniliprole exhibited moderate‐ to high‐level resistance to tetraniliprole (resistance ratio = 27.7−806.8). Detection of ryanodine receptor (RyR) mutations showed that the Y4667C, Y4667D, I4758M, and Y4891F mutations were present in tested RSB field populations. RyR mutations were responsible for the cross‐resistance between tetraniliprole and chlorantraniliprole. Further, the clustered regularly interspaced palindromic repeats (CRISPR) / CRISPR‐associated protein 9‐mediated genome‐modified flies were used to study the contribution of RyR mutations to tetraniliprole resistance. The order of contribution of a single RyR mutation to tetraniliprole resistance was Y4667D > G4915E > Y4667C ≈ I4758M > Y4891F. In addition, the I4758M and Y4667C double mutations conferred higher tetraniliprole resistance than single Y4667C mutations. These results can guide resistance management practices for diamides in RSB and other arthropods. [ABSTRACT FROM AUTHOR]

This study explores the low‐temperature pyrolysis kinetic of low metamorphic grade coal from Northern Shaanxi, utilizing Fourier transform infrared (FT‐IR) spectroscopy to analyze the characteristics of various functional groups over a 293–1023 K temperature range. A kinetic model, correlating with the pyrolysis behaviors of these groups, was developed through thermal analysis kinetics. Computational fluid dynamics (CFD) technology simulated the furnace's flow dynamics, allowing an examination of the physical field alterations and functional group evolution during pyrolysis. Results showed that the pyrolysis kinetic functions for aromatic C–H, C=C, C–O, and •OH, along with temperature, pressure, and velocity fields, were successfully integrated into the simulation. This integration provided detailed insights into the temperature profile, pressure distribution, flow velocities, and functional group distribution in the furnace. Aliphatics, exhibiting the largest mass fraction and wide pyrolysis temperature range, and •OH radicals with the highest activation energy were concentrated in the furnace's pyrolysis zone center. C=C's distribution was influenced by aromatic C–H and aliphatics, showing a complementary pattern. The oxygen‐containing groups C–O and C=O had similar pyrolysis mechanisms and uniform distribution. The functional groups' mass fractions were ranked from highest to lowest as follows: aliphatics > •OH > aromatic C–H > C–O > C=C > C=O. [ABSTRACT FROM AUTHOR]

CCN5/WISP2 is a matricellular protein, the expression of which is under the regulation of Wnt signaling and IGF-1. Our initial characterization supports the notion that CCN5 might promote the proliferation and survival of pancreatic β-cells and thus improve the metabolic profile of the animals. More recently, the roles of endogenous expression of CCN5 and its ectopic, transgenic overexpression on metabolic regulation have been revealed through two reports. Here, we attempt to compare the experimental findings from those studies, side-by-side, in order to further establish its roles in metabolic regulation. Prominent among the discoveries was that a systemic deficiency of CCN5 gene expression caused adipocyte hypertrophy, increased adipogenesis, and lipid accumulation, resulting in insulin resistance and glucose intolerance, which were further exacerbated upon high-fat diet feeding. On the other hand, the adipocyte-specific and systemic overexpression of CCN5 caused an increase in lean body mass, improved insulin sensitivity, hyperplasia of cardiomyocytes, and increased heart mass, but decreased fasting glucose levels. CCN5 is clearly a regulator of adipocyte proliferation and maturation, affecting lean/fat mass ratio and insulin sensitivity. Not all results from these models are consistent; moreover, several important aspects of CCN5 physiology are yet to be explored. [ABSTRACT FROM AUTHOR]

We reported previously that pancreas-specific ablation of IGF-I in mice induced an increased expression of regenerating family proteins Reg2 and Reg3β in the pancreas and protected them from streptozotocin (Stz)-induced β-cell damage. We, therefore, assessed the effect of ectopically introduced Reg2 on Stz-induced apoptosis in MIN6 mouse insulinoma cells and report here that Reg2 protects MIN6 cells from Stz-induced apoptosis by attenuating its ability to disrupt mitochondrial membrane integrity, activate caspase-3 and promote poly-ADP ribose polymerase cleavage, and induce apoptosis. These changes correlated with suppression of c-jun N-terminal kinase (JNK) phosphorylation by Stz. Reg2 inhibited Stz-induced proapoptotic events as well as the inactivation of JNK. Inclusion of chemical inhibitor of JNK to Reg2 expressing cells rendered them sensitive to Stz. These data demonstrate that Reg2 protects insulin-producing cells against Stz-induced apoptosis by interfering with its cytotoxic signaling upstream of the intrinsic proapoptotic events by preventing its ability to inactivate JNK. [ABSTRACT FROM AUTHOR]

Abstract: Irradiation-induced brain injury, leading to cognitive impairment several months to years after whole brain irradiation (WBI) therapy, is a common health problem in patients with primary or metastatic brain tumor and greatly impairs quality of life for tumor survivors. Recently, it has been demonstrated that a rapid and sustained increase in activated microglia following WBI led to a chronic inflammatory response and a corresponding decrease in hippocampal neurogenesis. Tamoxifen, serving as a radiosensitizer and a useful agent in combination therapy of glioma, has been found to exert anti-inflammatory response both in cultured microglial cells and in a spinal cord injury model. In the present study, we investigated whether tamoxifen alleviated inflammatory damage seen in the irradiated microglia in vitro and in the irradiated brain. Irradiating BV-2 cells (a murine microglial cell line) with various radiation doses (2–10 Gy) led to the increase in IL-1β and TNF-α expression determined by ELISA, and the conditioned culture medium of irradiated microglia with 10 Gy radiation dose initiated astroglial activation and decreased the number of neuronal cells in vitro. Incubation BV-2 cells with tamoxifen (1 μM) for 45 min significantly inhibited the radiation-induced microglial inflammatory response. In the irradiated brain, WBI induced the breakdown of the blood–brain barrier permeability at day 1 post irradiation and tissue edema formation at day 3 post-radiation. Furthermore, WBI led to microglial activation and reactive astrogliosis in the cerebral cortex and neuronal apoptosis in the CA1 hippocampus at day 3 post-radiation. Tamoxifen administration (i.p., 5 mg/kg) immediately post radiation reduced the irradiation-induced brain damage after WBI. Taken together, these data support that tamoxifen can decrease the irradiation-induced brain damage via attenuating the microglial inflammatory response. [Copyright &y& Elsevier]

Insulin and insulin-like growth factors (IGFs) mediate a variety of signals involved in mammalian development and metabolism. To study the metabolic consequences of IGF-I deficiency, we used the liver IGF-I-deficient (LID) mouse model. The LID mice show a marked reduction (approximately 75%) in circulating IGF-I and elevated growth hormone (GH) levels. Interestingly, LID mice show a fourfold increase in serum insulin levels (2.2 vs. 0.6 ng/ml in control mice) and abnormal glucose clearance after insulin injection. Fasting blood glucose levels and those after a glucose tolerance test were similar between the LID mice and their control littermates. Thus, the high levels of circulating insulin enable the LID mice to maintain normoglycemia in the presence of apparent insulin insensitivity. Insulin-induced autophosphorylation of the insulin receptor and tyrosine phosphorylation of insulin receptor substrate (IRS)-1 were absent in muscle, but were normal in liver and white adipose tissue of the LID mice. In contrast, IGF-I-induced autophosphorylation of its cognate receptor and phosphorylation of IRS-1 were normal in muscle of LID mice. Thus, the insulin insensitivity seen in the LID mice is muscle specific. Recombinant human IGF-I treatment of the LID mice caused a reduction in insulin levels and an increase in insulin sensitivity. Treatment of the LID mice with GH-releasing hormone antagonist, which reduces GH levels, also increased insulin sensitivity. These data provide evidence of the role of circulating IGF-I as an important component of overall insulin action in peripheral tissues. [ABSTRACT FROM AUTHOR]

Investigates the role of the area postrema in mediating the enhancement in baroreflex function in response to angiotensin II type 1 receptor blockade in rabbits with pacing-induced congestive heart failure (CHF). Effectiveness of area postrema lesions; Baroreflex function in normal and CHF rabbits.

Focuses on a study which assessed the importance of endocrine and autocrine/paracrine roles of insulin-like growth factor I (IGF-I) in growth and development. Generation and characterization of albumin-cre transgenic mice; Liver IGF-I expression in albumin-cre transgenic mice; Postnatal growth of mice exhibiting liver-specific deletion of IGF-I.

Reports on a study that investigated the role of liver-derived insulin-like growth factor I for postnatal body growth. Materials and methods; Results; Discussion.

Determines whether blockade of angiotensin 1 (AT1) receptors enhances baroreflex control of heart rate (HR) in conscious rabbits with heart failure. Effects of L-158,809 on the baroreflex control of HR in normal rabbits after autonomic blockade; Effects of chronic pacing on hemodynamics and baroreflex control of HR.

Studies the effects of nitric oxide on baroreflex control of heart rate and renal nerve activity in conscious rabbits. Surgical preparations; Implantation of renal sympathetic nerve recording electrodes; Sinoaortic denervation; Experimental protocols; Data analysis.

Investigates the effect of the neuronal nitric oxide (NO) synthase inhibitor 7-nitroindazole on the baroreflex control of heart rate (HR) and renal sympathetic nerve activity (RSNA) in the rabbit. Influence of blockade of neuronal NO synthase on baroreflex control of HR; Role of endogenous brain NO in decreasing the baroreflex control of HR.

Clarifies the role of endogenous angiotensin II (ANG II) on baroreflex control of heart rate both in normal, conscious rabbits and conscious rabbits with pacing-induced heart failure. Sympathetic nerve activity; Arterial pressure; Suggestion of a role for ANG II in regulating cardiac sympathetic outflow in heart failure.

Investigates the role of nitric oxide in baroreflex control of heart rate and renal sympathetic nerve activity. Effects of these changes on the assessment of the central effects of nitric oxides on the baroreflex control of heart rate and renal sympathetic nerve activity.

In the past 15 years, gut microbiota emerged as a crucial player in health and disease. Enormous progress was made in the analysis of its composition, even in the discovery of novel species. It is time to go beyond mere microbiota-disease associations and, instead, provide more causal analyses. A key mechanism of metabolic regulation by the gut microbiota is through the production of short-chain fatty acids (SCFAs). Acting as supplemental nutrients and specific ligands of two G-protein-coupled receptors (GPCRs), they target the intestines, brain, liver, and adipose tissue, and they regulate appetite, energy expenditure, adiposity, and glucose production. With accumulating but sometimes conflicting research results, key questions emerged. Do SCFAs regulate pancreatic islets directly? What is the effect of β-cell-specific receptor deletions? What are the mechanisms used by SCFAs to regulate β-cell proliferation, survival, and secretion? The receptors FFA2/3 are normally expressed on pancreatic β-cells. Deficiency in FFA2 may have caused glucose intolerance and β-cell deficiency in mice. However, this was contrasted by a double-receptor knockout. Even more controversial are the effects of SCFAs on insulin secretion; there might be no direct effect at all. Unable to draw clear conclusions, this review reveals some of the recent controversies. [ABSTRACT FROM AUTHOR]

Background: Obesity occurs when the body's energy intake is constantly greater than its energy consumption and the pharmacological enhancing the activity of brown adipose tissue (BAT) and (or) browning of white adipose tissue (WAT) has been considered promising strategies to treat obesity. Methods: In this study, we took a multi-pronged approach to screen UCP1 activators, including in silico predictions, in vitro assays, as well as in vivo experiments. Results: Base on Connectivity MAP (CMAP) screening, we obtained multiple drugs that possess a remarkably correlating gene expression pattern to that of enhancing activity in BAT and (or) sWAT signature. Particularly, we focused on a previously unreported drug-indirubin, a compound obtained from the Indigo plant, which is now mainly used for the treatment of chronic myelogenous leukemia (CML). In the current study, our results shown that indirubin could enhance the BAT activity, as evidenced by up-regulated Ucp1 expression and enhanced mitochondrial respiratory function in vitro cellular model. Furthermore, indirubin treatment restrained high-fat diet (HFD)-induced body weight gain, improved glucose homeostasis and ameliorated hepatic steatosis which were associated with the increase of energy expenditure in the mice model. Moreover, we revealed that indirubin treatment increased BAT activity by promoting thermogenesis and mitochondrial biogenesis in BAT and induced browning of subcutaneous inguinal white adipose tissue (sWAT) of mice under HFD. Besides, our results indicated that indirubin induced UCP1 expression in brown adipocytes, at least in part, via activation of PKA and p38MAPK signaling pathways. Conclusions: Our results clearly show that as an effective BAT (as well as beige cells) activator, indirubin may have a protective effect on the prevention and treatment of obesity and its complications. [ABSTRACT FROM AUTHOR]

Metastatic cystic lesions may be considered as target lesions according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. However, cystic lesions are considered as non-measurable according to RECIST 1.0. Krukenberg tumors are cystic metastases from gastric cancer. The aim of the present case report was to address the question of whether a Krukenberg tumor can be considered as a target lesion. A 30-year-old female patient was diagnosed with stage IV gastric cancer 6 months after parturition. Subsequently, the patient received two courses of oxaliplatin/capecitabine plus trastuzumab (OCT) treatment. The response evaluation was considered as stable disease. However, after four courses of OCT, the cystic target lesion in the right pelvic cavity exhibited an increase in diameter of >40%. After one more cycle of OCT, contrast-enhanced magnetic resonance imaging (MRI) revealed that the diameter of the cystic mass lesion had decreased by >35% and a further two cycles of treatment were administered. After the last OCT cycle, the levels of the tumor markers cancer antigen (CA) 125, CA19-9 and CA153 had markedly increased, although the cystic mass had decreased in size. Eventually, positron emission tomography-computed tomography (PET/CT) was used to assess the efficacy of treatment. A new lesion was identified, indicating progressive disease. The present case demonstrated that the Krukenberg tumor may be considered as a non-target lesion. In addition, tumor markers and PET/CT yielded results complementary to those of contrast-enhanced MRI in the therapeutic assessment of advanced gastric cancer. [ABSTRACT FROM AUTHOR]

The rocket-based combined-cycle (RBCC) engine usually completes the transition process from ramjet to scramjet mode under the Ma ∞ = 5.5–6.0. The dual-mode (ramjet/scramjet) transient process is an important technology for engine operation. CFD modeling based on Reynolds average Navier-Stokes was for studying the influence of fuel injection position, high-temperature rocket jet and fuel throttling time on the combustion flow structure and transient characteristics of RBCC engine during the mode transiton. The results showed that whether RBCC engine could successfully achieve stable mode transition was mainly influenced by flame stability in the combustor. When the rocket shuts down, it was more suitable to choose the fuel injection arrangement which distributed downstream of the combustor to realize relatively smooth mode transition. The analysis shows that in the mode transition process, using the synergistic combustion-supporting effect of the cavity and the strut is beneficial to improve the fuel combustion efficiency and reduce the thrust fluctuation. Although the high temperature rocket jet with low mass flow rate cannot maintain the fuel combustion in the isolator at high Mach number, it can expand the high temperature combustion area width in the central flow of RBCC engine and increase the secondary fuel combustion efficiency. Therefore, keeping the rocket running at low mass flow rate can reduce the thrust drop caused by insufficient fuel heat release. When adopting a mode transition strategy that throttles the fuel linearly over time, the engine can go through the thrust dip more smoothly, but this correspondingly increases the time required for the internal flow field to stabilize. [ABSTRACT FROM AUTHOR]

Regenerating gene 3α (Reg3α) protein is a trophic factor that stimulates cell and tissue proliferation, neogenesis and also acts against apoptosis and necrosis. In order to explore the potential roles of recombinant Reg3α (rReg3α), we produced a mature rReg3α polypeptide for direct administration in l -arginine (L-Arg) induced acute pancreatitis (AP) in mice. Our results showed that rReg3α stimulated cell proliferation through Erk1/2 and p38 phosphorylation and also cyclin D1 upregulation mediated by Akt/ATF-2 signaling. Moreover, rReg3α administration significantly reduced the pancreatic damage caused by L-Arg injection, as shown in histological examination and serum amylase, lipase and C-reactive protein (CRP) assays. Not only acinar cell necrosis but also apoptosis found in the pancreas of AP mice were alleviated by rReg3α. Finally, upregulated Bcl-2 and Bcl-xL and suppressed poly (ADP-ribose) synthetase/polymerase (PARP) levels were detected as being relevant to the mechanism of rReg3α protection. We therefore conclude that rReg3α acts as a protective polypeptide against AP in mice by enhancing Bcl-2 and Bcl-xL expressions and suppressing PARP level. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Optimal elevation of β-cell 11β-hydroxysteroid dehydrogenase type 1 is a compensatory mechanism that prevents high-fat diet-induced β-cell failure," by Turban et al. in a 2012 issue.

Lymphomatosis cerebri (LC) and cauda equina lymphoma are both rare forms of primary central nervous system lymphoma (PCNSL). LC is characterized by diffuse bilateral non-enhancing (or partially enhancing) inltrative lesions without mass effect, which can be easily confused with other forms of leukoencephalopathy and, thus, lead to delays in diagnosis. For the first time, a case of LC concomitant with cauda equina involvement confirmed by brain stereotactic biopsy is presented. This case highlights the necessity of using a multimodal strategy in diagnosing PCNSL, including multimodal magnetic resonance, cerebral spinal fluid cytology, flow cytometry and fluorodeoxyglucose positron emission tomography/computed tomography. [ABSTRACT FROM AUTHOR]

Background: In this study, we investigated the in vitro and in vivo chondrogenic capacity of kartogenin (KGN)–enhanced bone marrow–derived mesenchymal stem cells (BMSCs) for cartilage regeneration. Purpose: To determine (1) whether functionalized nanographene oxide (NGO) can effectively deliver KGN into BMSCs and (2) whether KGN would enhance BMSCs during chondrogenesis in vitro and in vivo in an animal model. Study Design: Controlled laboratory study. Methods: Functionalized NGO with line chain amine-terminated polyethylene glycol (PEG) and branched polyethylenimine (BPEI) were used to synthesize biocompatible NGO-PEG-BPEI (PPG) and for loading hydrophobic KGN molecules noncovalently via π–π stacking and hydrophobic interactions (PPG-KGN). Then, PPG-KGN was used for the intracellular delivery of hydrophobic KGN by simple mixing and co-incubation with BMSCs to acquire KGN-enhanced BMSCs. The chondrogenic efficacy of KGN-enhanced BMSCs was evaluated in vitro. In vivo, osteoarthritis (OA) was induced by anterior cruciate ligament transection in rats. A total of 5 groups were established: normal (OA treated with nothing), phosphate-buffered saline (PBS; intra-articular injection of PBS), PPG-KGN (intra-articular injection of PPG-KGN), BMSCs (intra-articular injection of BMSCs), and BMSCs + PPG-KGN (intra-articular injection of PPG-KGN–preconditioned BMSCs). At 6 and 9 weeks after the surgical induction of OA, the rats received intra-articular injections of PPG-KGN, BMSCs, or KGN-enhanced BMSCs. At 14 weeks after the surgical induction of OA, radiographic and behavioral evaluations as well as histological analysis of the knee joints were performed. Results: The in vitro study showed that PPG could be rapidly uptaken in the first 4 hours after incubation, reaching saturation at 12 hours and accumulating in the lysosome and cytoplasm of BMSCs. Thus, PPG-KGN could enhance the efficiency of the intracellular delivery of KGN, which showed a remarkably high chondrogenic differentiation capacity of BMSCs. When applied to an OA model of cartilage injuries in rats, PPG-KGN–preconditioned BMSCs contributed to protection from joint space narrowing, pathological mineralization, OA development, and OA-induced pain, as well as improved tissue regeneration, as evidenced by radiographic, weightbearing, and histological findings. Conclusion: Our results demonstrate that KGN-enhanced BMSCs showed markedly improved capacities for chondrogenesis and articular cartilage repair. We believe that this work demonstrates that a multifunctional nanoparticle-based drug delivery system could be beneficial for stem cell therapy. Our results present an opportunity to reverse the symptoms and pathophysiology of OA. Clinical Relevance: The intracellular delivery of KGN to produce BMSCs with enhanced chondrogenic potential may offer a new approach for the treatment of OA. [ABSTRACT FROM AUTHOR]

Persistent acinar to ductal metaplasia (ADM) is a recently recognized precursor of pancreatic ductal adenocarcinoma (PDAC). Here we show that the ADM area of human pancreas tissue adjacent to PDAC expresses significantly higher levels of regenerating protein 3A (REG3A). Exogenous REG3A and its mouse homolog REG3B induce ADM in the 3D culture of primary human and murine acinar cells, respectively. Both Reg3b transgenic mice and REG3B-treated mice with caerulein-induced pancreatitis develop and sustain ADM. Two out of five Reg3b transgenic mice with caerulein-induced pancreatitis show progression from ADM to pancreatic intraepithelial neoplasia (PanIN). Both in vitro and in vivo ADM models demonstrate activation of the RAS-RAF-MEK-ERK signaling pathway. Exostosin-like glycosyltransferase 3 (EXTL3) functions as the receptor for REG3B and mediates the activation of downstream signaling proteins. Our data indicates that REG3A/REG3B promotes persistent ADM through binding to EXTL3 and activating the RAS-RAF-MEK-ERK signaling pathway. Targeting REG3A/REG3B, its receptor EXTL3, or other downstream molecules could interrupt the ADM process and prevent early PDAC carcinogenesis. Using several human and murine models, Zhang et al discover a role for the REG3A/REG3B proteins in acinar to ductal metaplasia (ADM), a precursor of pancreatic ductal adenocarcinoma (PDAC). They find that REG3B induces ADM through RAS-RAF-MEK-ERK signaling and identify EXTL3 as a REG3B receptor, providing new insights into PDAC development. [ABSTRACT FROM AUTHOR]

Both growth hormone and insulin-like growth factor (IGF)-I are essential for postnatal somatic growth, while exerting distinct effects on energy homeostasis. Although growth hormone controls IGF-I production, whether IGF-I was the exclusive mediator of its growth promotion is still debated. In order to further explore their in vivo interactions in somatic growth as well as in energy homeostasis, we have crossed mutant (MT-IGF) transgenic mice onto the GHR − / −  background. As expected, GHR gene deficiency caused growth retardation, including significant decreases in lumbar, femur and total body lengths, as well as decreased bone area, mineral content and mineral density. IGF-I overexpression alone in MT-IGF mice increased the weight, with no significant change in bone mineralization or longitudinal growth. Compared to GHR − / −  littermates, overexpressed IGF-I in bitransgenic mice (GHR − / −  and MT-IGF positive) exhibited fully restored body weight, lumbar (but not femur) and total body lengths, and normalized overall bone area, mineral content and density. On the other hand, there were significant changes in fasting glucose level, glucose tolerance, lean/fat masses and even adipose histology as a result of the transgenic/knockout double-crossing. IGF-I overexpression normalized glucose tolerance in GHR − / −  mice. Intriguingly, on GHR+/ −  background of partial growth hormone insensitivity, overexpression of IGF-I caused a significant weight gain. Our results thus establish that the growth defect and bone deficiency caused by lack of growth hormone signaling can be effectively restored by increasing IGF-I production in vivo. [ABSTRACT FROM AUTHOR]

Background: Osteosarcoma (OS) is the most common primary malignant bone tumor occurring in children and young adults. Drug-resistant osteosarcoma often results in chemotherapy failure. Therefore, new treatments aimed at novel therapeutic targets are urgently needed for the treatment of drug-resistant osteosarcoma. Mitochondria-targeted phototherapy, i.e., synergistic photodynamic/photothermal therapy, has emerged as a highly promising strategy for treating drug-resistant tumors. This study proposed a new nano-drug delivery system based on near-infrared imaging and multifunctional graphene, which can target mitochondria and show synergistic phototherapy, with preferential accumulation in tumors. Methods and results: Based on our previous study, (4-carboxybutyl) triphenyl phosphonium bromide (TPP), a mitochondria-targeting ligand, was conjugated to indocyanine green (ICG)-loaded, polyethylenimine-modified PEGylated nanographene oxide sheets (TPP-PPG@ICG) to promote mitochondrial accumulation after cellular internalization. Thereafter, exposure to a single dose of near-infrared irradiation enabled synergistic photodynamic and photothermal therapy, which simultaneously inhibited adenosine triphosphate synthesis and mitochondrial function. Induction of intrinsic apoptosis assisted in surmounting drug resistance and caused tumor cell death. After fluorescence imaging-guided synergistic phototherapy, the mitochondria-targeting, multifunctional graphene-based, drug-delivery system showed highly selective anticancer efficiency in vitro and in vivo, resulting in marked inhibition of tumor progression without noticeable toxicity in mice bearing doxorubicin-resistant MG63 tumor cells. Conclusion: The mitochondria-targeting TPP-PPG@ICG nanocomposite constitutes a new class of nanomedicine for fluorescence imaging-guided synergistic phototherapy and shows promise for treating drug-resistant osteosarcoma. [ABSTRACT FROM AUTHOR]

Investigates the role of liver-derived insulin-like growth factor (IGF)-I for carbohydrate and lipid metabolism by using mice with liver-specific IGF-I gene inactivation. Importance of IGF-I in glucose metabolism; Increase in serum leptin concentrations noted in the mice with concomitant decrease in fat mass.

Betatrophin [also known as lipasin, angiopoietin-like 8 (ANGPTL8), refeeding induced in fat and liver (RIFL), or hepatocellular carcinoma-associated gene TD26], a 22-kDa protein in the angiopoietin-like family, is a liver-derived hormone that promotes pancreatic β-cell proliferation and lipid metabolism. The aim of the present study was to investigate the effect of recombinant betatrophin on β-cell regeneration in a neonatal streptozotocin (STZ)-induced diabetic rat model. One-day-old Wistar rats were injected with STZ (100 mg/kg), followed by intraperitoneal administration of betatrophin to the STZ-injected rats for 6 days. Plasma glucose and body weight were monitored. On days 4 and 7, expression levels of pancreatic duodenal homeobox gene-1 (PDX-1), the Bax/B-cell lymphoma-2 (Bcl-2) ratio and plasma insulin were assessed, and the β-cell proliferation rate was determined. Pancreatic islet area and number were determined at 10 weeks. It was found that betatrophin treatment alleviated STZ-induced hyperglycemia, elevated pancreatic expression levels of Bcl-2, PDX-1, plasma insulin levels and the β-cell proliferation rate on days 4 and 7. Long-term betatrophin treatment improved glucose tolerance, associated with improved plasma insulin levels and β-cell mass. These results suggest that early administration of betatrophin promotes β-cell proliferation in STZ-induced diabetic neonates and prevents the development of diabetes in adults. [ABSTRACT FROM AUTHOR]

Pancreatic ß cell proliferation, survival and function are key elements that need to be considered in developing novel antidiabetic therapies. We recently identified CCN5/WISP2 to have potential growth promoting properties when overexpressed in ß cells; however, further investigations are needed to validate those properties. In this study, we demonstrated that exogenous treatment of insulinoma cells and primary islets with recombinant CCN5 (rh-CCN5) protein enhanced the proliferative capacity which was correlated with activation of cell-cycle regulators CDK4 and cyclin D1. Furthermore, pre-incubation of these cells with rh-CCN5 enhanced their survival rate after being exposed to harsh treatments such as streptozotocin and high concentrations of glucose and free fatty acids. CCN5 as well caused an upregulation in the expression of key genes associated with ß cell identity and function such as GLUT-2 and GCK. Finally, CCN5 activated FAK and downstream ERK kinases which are known to stimulate cell proliferation and survival. Hence, our results validate the growth promoting activities of rh-CCN5 in ß cells and open the door for further investigations in vivo. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the midterm results of the cementless S‐ROM modular femoral stem used with subtrochanteric transverse shortening osteotomy for the treatment of high hip dislocation secondary to hip pyogenic arthritis. Methods: We retrospectively reviewed the data of 49 patients (49 hips) with an average infection quiescent period of 37.4 years who underwent cementless total hip arthroplasty (THA) with simultaneous subtrochanteric transverse shortening osteotomy from July 2008 to June 2012. There were 23 men and 26 women with a mean age of 44.3 years at the time of surgery. The following clinical outcomes were evaluated: the Western Ontario and McMaster Universities Arthritis Index (WOMAC) score, Harris hip score (HSS), modified Merle d'Aubigne‐Postel hip (MAP) score, low back pain visual analog scale score, 12‐item short‐form health survey questionnaire score, limp, and Trendelenburg sign. Radiographic outcomes and complications were also evaluated. Results: The mean follow‐up period was 8.7 years (range, 5.5–10 years). No infection recurrence was observed after THA. The average HSS significantly improved from 45.0 to 84.8. The WOMAC score improved from 70.1 ± 3.5 (range, 65–76) to 43.1 ± 13.4 (range, 21–67). The modified MAP score improved from 5.9 ± 1.9 (range, 3–9) to 14.3 ± 2.4 (range, 11–18). The low back pain visual analog scale score, 12‐item short‐form health survey questionnaire score, limp, and Trendelenburg sign also improved significantly. The average limb length discrepancy decreased from 39.6 mm (range, 30–55 mm) to 7.2 mm (range, 0–22 mm). Two patients had temporary sciatic nerve paralysis but recovered within 6 months without any functional defects; one had an intraoperative fracture fixed by cerclage wires. One hip required revision surgery because of femoral stem aseptic loosening. Conclusions: The cementless S‐ROM modular femoral stem used with subtrochanteric transverse shortening osteotomy is safe and effective for high hip dislocation secondary to pyogenic arthritis and provides satisfactory midterm results. Significant improvements in clinical function were observed, as were high rates of stable fixation of the cementless implant, restoration of more normal limb lengths, and a low incidence of complications. [ABSTRACT FROM AUTHOR]

Aims: The potential effect of regenerating (Reg) proteins in the treatment of diabetes has been indicated in the past decade, but the clinical use of Reg proteins requires more advances in translational medicine. In the present study, we produced recombinant regenerating protein 2 (rReg2), to prove its protective effect against streptozocin (STZ)‐induced diabetes in BALB/c mice. Materials and Methods: rReg2 was administrated in STZ‐induced diabetic mice. Blood glucose, body weight, serum insulin and islet β‐cell loss were determined. However, Reg2 has also been reported to serve as an autoantigen that induces autoimmune attacks on islets and aggravates diabetic development in non‐obese diabetic mice. To address this contradiction, complete Freund's adjuvant was injected to generate a model that was hypersensitive to Reg2. In this model, islet CD8 T‐cell infiltration, serum Reg2 antibody and interleukin (IL)‐4 and IL‐10, and splenic CD4+/interferon (IFN)‐γ+ T cells were determined. Results: Direct rReg2 pretreatment preserved islet β‐cell mass against STZ and improved glycaemia, body weight and serum insulin content. The protection against cell death was further confirmed in cultured mouse islets and MIN6 cells. On the other hand, significant elevations of serum Reg2 antibody and splenic CD4+/IFN‐γ+ T cells, and decreases in serum IL‐4 and IL‐10 were detected in rReg2‐vaccinated mice, which may contribute to the accelerated diabetes. Interestingly, these mice, upon further rReg2 treatment, exhibited alleviated diabetic conditions with less islet CD8+ T‐cell infiltration. Conclusion: rReg2 treatment ameliorated STZ‐induced diabetes in normal BALB/c mice. By contrast, rReg2 vaccination exacerbated, but further rReg2 treatment alleviated, the severity of STZ‐induced diabetes. Thus, the protective effect of rReg2 is predominant over the autoantigenic β‐cell destruction, supporting the potential of rReg2 in the clinical treatment of diabetes. [ABSTRACT FROM AUTHOR]

Background We performed a systematic review and meta-analysis to evaluate the risk of immune-related endocrine disorders associated with PD-1 inhibitors therapy for solid tumors. Methods An Embase and PubMed search through December 6, 2017, using the following keywords was performed: immune-related endocrine disorders, and PD-1 inhibitors, etc. The data were analyzed using R 3.4.3 (R Project) and the metafor package. Patients treated with chemotherapy alone were used as control for the purpose of comparison. Results A total of 12 clinical trials including 5577 patients were found eligible for the meta-analysis. Compared with chemotherapy, the risk ratios of all-grade endocrine disorders are 13.89, (95% CI: 5.35–36.05, p  < 0.001) for nivolumab therapy, and 9.85, (95% CI: 5.65–17.17, p  < 0.001) for pembrolizumab therapy. The risk of all-grade hypothyroidism and hyperthyroidism incidence was increased for nivolumab therapy (hypothyroidism: RR 10.07, 95% CI: 3.37–30.11, p  < 0.001; hyperthyroidism: RR 4.29, 95% CI: 1.13–16.30, p  = 0.034) and for pembrolizumab therapy (hypothyroidism: RR 7.73, 95% CI: 3.86–15.49, p  < 0.001; hyperthyroidism: RR 5.09, 95% CI: 2.36–10.97, p  < 0.001). There was a significant increase in the risk of grade 1–5 endocrine disorders incidence for ipilimumab-nivolumab combination therapy (versus ipilimumab, RR 3.20, 95% CI: 2.08–4.91, p  < 0.001; versus nivolumab, RR 2.54, 95% CI: 1.70–3.80, p  < 0.001). Conclusions Both nivolumab and pembrolizumab therapy could result in a higher risk of all-grade immune-related endocrine disorders than chemotherapy. Nivolumab and ipilimumab combination therapy could result in an even higher risk of all-grade immune-related endocrine disorders than ipilimumab or nivolumab alone. Awareness of these side effects could guide clinicians to better manage the patients treated with anti-PD-1 inhibitors therapy for solid tumors. [ABSTRACT FROM AUTHOR]

Background: The reductions of perioperative blood loss and inflammatory response are important in total knee arthroplasty. Tranexamic acid reduced blood loss and the inflammatory response in several studies. However, the effect of epinephrine administration plus tranexamic acid has not been intensively investigated, to our knowledge. In this study, we evaluated whether the combined administration of low-dose epinephrine plus tranexamic acid reduced perioperative blood loss or inflammatory response further compared with tranexamic acid alone.Methods: This randomized placebo-controlled trial consisted of 179 consecutive patients who underwent primary total knee arthroplasty. Patients were randomized into 3 interventions: Group IV received intravenous low-dose epinephrine plus tranexamic acid, Group TP received topical diluted epinephrine plus tranexamic acid, and Group CT received tranexamic acid alone. The primary outcome was perioperative blood loss on postoperative day 1. Secondary outcomes included perioperative blood loss on postoperative day 3, coagulation and fibrinolysis parameters (measured by thromboelastography), inflammatory cytokine levels, transfusion values (rate and volume), thromboembolic complications, length of hospital stay, wound score, range of motion, and Hospital for Special Surgery (HSS) score.Results: The mean calculated total blood loss (and standard deviation) in Group IV was 348.1 ± 158.2 mL on postoperative day 1 and 458.0 ± 183.4 mL on postoperative day 3, which were significantly reduced (p < 0.05) compared with Group TP at 420.5 ± 188.4 mL on postoperative day 1 and 531.1 ± 231.4 mL on postoperative day 3 and Group CT at 520.4 ± 228.4 mL on postoperative day 1 and 633.7 ± 237.3 mL on postoperative day 3. Intravenous low-dose epinephrine exhibited a net anti-inflammatory activity in total knee arthroplasty and did not induce an obvious hypercoagulable status. Transfusion values were significantly reduced (p < 0.05) in Group IV, but no significant differences were observed in the incidence of thromboembolic complications, wound score, range of motion, and HSS score among the 3 groups (p > 0.05).Conclusions: The combined administration of low-dose epinephrine and tranexamic acid demonstrated an increased effect in reducing perioperative blood loss and the inflammatory response compared with tranexamic acid alone, with no apparent increased incidence of thromboembolic and other complications.Level Of Evidence: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. [ABSTRACT FROM AUTHOR]

The bioactive, signaling lipid, sphingosine-1-phosphate (S1P), and its analog, fingolimod (FTY720), have previously shown neuroprotective effects against ischemic brain injury. However, the underlying mechanisms have not yet been fully clarified. The roles of autophagy in ischemic stroke are being increasingly recognized. In the present study, we sought to determine whether the S1P pathway is involved in neuronal autophagy and investigate its possible mechanisms following stroke. Interestingly, we found that FTY720 significantly attenuates infarct volumes and reduces neuronal apoptosis on days 1 and 3 post stroke, accompanied by amelioration of functional deficits. Additionally, FTY720 was found to decrease the induction of autophagosome proteins, microtubule-associated protein 1 light chain 3(LC3-II) and Beclin1, following ischemic stroke in a dose-dependent manner. Meanwhile, protein levels of the mammalian target of rapamycin (mTOR) and the 70-kDa ribosomal protein, S6 kinase1 (p70S6K), were also up-regulated in FTY720-treated animals, and the nonspecific SphK inhibitor, N,N-dimethylsphingosine (DMS), was found to cause a reverse effect. Our results indicate that modulation of the S1P signaling pathway by FTY720 could effectively decrease neuronal autophagy through the mTOR/p70S6K pathway and attenuate ischemic brain injury in mice. [ABSTRACT FROM AUTHOR]

Microglia become activated during cerebral ischemia and exert pro-inflammatory or anti-inflammatory role dependent of microglial polarization. NADPH oxidase ( NOX)-dependent reactive oxygen species ( ROS) production in microglia plays an important role in neuronal damage after ischemic stroke. Recently, NOX and ROS are consistently reported to participate in the microglial activation and polarization; NOX2 inhibition or suppression of ROS production are shown to shift the microglial polarization from M1 toward M2 state after stroke. The voltage-gated proton channel, Hv1, is selectively expressed in microglia and is required for NOX-dependent ROS generation in the brain. However, the effect of Hv1 proton channel on microglial M1/M2 polarization state after cerebral ischemia remains unknown. In this study, we investigated the role of microglial Hv1 proton channel in modulating microglial M1/M2 polarization during the pathogenesis of ischemic cerebral injury using a mouse model of photothrombosis. Following photothrombotic ischemic stroke, wild-type mice presented obvious brain infarct, neuronal damage, and impaired motor coordination. However, mice lacking Hv1 (Hv1−/−) were partially protected from brain damage and motor deficits compared to wild-type mice. These rescued phenotypes in Hv1−/− mice in ischemic stroke is accompanied by reduced ROS production, shifted the microglial polarization from M1 to M2 state. Hv1 deficiency was also found to shift the M1/M2 polarization in primary cultured microglia. Our study suggests that the microglial Hv1 proton channel is a unique target for modulation of microglial M1/M2 polarization in the pathogenesis of ischemic stroke. [ABSTRACT FROM AUTHOR]

Browning of white adipocyte tissue (WAT) has received considerable attention due to its potential implication in preventing obesity and related comorbidities. Ginsenoside Rb1 is reported to improve glycolipid metabolism and reduce body weight in obese animals. However whether the body reducing effect mediates by browning effect remains unclear. For this purpose, 3T3-L1 adipocytes were used to study the effect of ginsenoside Rb1 on browning adipocytes specific genes and oxygen consumptions. The results demonstrate that 10 μM of ginsenoside Rb1 increases basal glucose uptake and promoted browning evidenced by significant increases in mRNA expressions of UCP-1, PGC-1α and PRDM16 in 3T3-L1 mature adipocytes. Further, ginsenoside Rb1 also increases PPARγ activity. And the browning effect is abrogated by GW9692, a PPARγ antagonist. In addition, ginsenoside Rb1 increases basal respiration rate, ATP production and uncoupling capacity in 3T3-L1 adipocytes. Those effects are also blunted by GW9692. The results suggest that ginsenoside Rb1 promote browning of 3T3-L1 adipocytes through induction of PPARγ. Our finding offer a new source to discover browning agonists and also useful to understand and extend the applications of ginseng and its constituents. [ABSTRACT FROM AUTHOR]

We have reported a high expression of IGF-I in pancreatic islet β-cells of transgenic mice under the metallothionein promoter. cDNA microarray analysis of the islets revealed that the expression of 82 genes was significantly altered compared to wild-type mice. Of these, 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1), which is responsible for the conversion of inert cortisone (11-dehydrocorticosterone, DHC in rodents) to active cortisol (corticosterone) in the liver and adipose tissues, has not been identified previously as an IGF-I target in pancreatic islets. We characterized the changes in its protein level, enzyme activity and glucose-stimulated insulin secretion. In freshly isolated islets, the level of 11β-HSD1 protein was significantly lower in MT-IGF mice. Using dual-labeled immunofluorescence, 11β-HSD1 was observed exclusively in glucagon-producing, islet α-cells but at a lower level in transgenic vs. wild-type animals. MT-IGF islets also exhibited reduced enzymatic activities. Dexamethasone (DEX) and DHC inhibited glucose-stimulated insulin secretion from freshly isolated islets of wild-type mice. In the islets of MT-IGF mice, 48-h pre-incubation of DEX caused a significant decrease in insulin release, while the effect of DHC was largely blunted consistent with diminished 11β-HSD1 activity. In order to establish the function of intracrine glucocorticoids, we overexpressed 11β-HSD1 cDNA in MIN6 insulinoma cells, which together with DHC caused apoptosis and a significant decrease in proliferation. Both effects were abolished with the treatment of an 11β-HSD1 inhibitor. Our results demonstrate an inhibitory effect of IGF-I on 11β-HSD1 expression and activity within the pancreatic islets, which may mediate part of the IGF-I effects on cell proliferation, survival and insulin secretion. [ABSTRACT FROM AUTHOR]

We have reported earlier that murine-regenerating gene mReg2 protects MIN6 mouse insulinoma cells from ER stress and caspase-mediated apoptosis. In apoptotic cells, DNA damage is induced by the nuclear translocation of mitochondrial apoptosis-inducing factor (AIF). Here we tested the hypothesis that mReg2 may regulate Scythe and/or hsp70 which influence the nuclear import of AIF. Treatment with thapsigargin (Tg) or doxorubicin induced an increase in nuclear AIF in MIN6 cells carrying the empty transfection vector (MIN6-VC) but not in cells overexpressing mReg2 (MIN6-mReg2). On one hand, nuclear Scythe was higher in the nucleus of MIN6-mReg2 compared with that in MIN6-VC cells. mReg2 did not alter the expression of AIF or Scythe. On the other hand, mReg2 induced the expression of hsp70 which is known to promote cytosolic retention of AIF. We conclude that mReg2 inhibits AIF-mediated apoptosis by promoting the nuclear presence of Scythe and inducing hsp70. [ABSTRACT FROM AUTHOR]

In addition to their extended lifespans, slow-aging growth hormone receptor/binding protein gene-disrupted (knockout) ( GHR- KO) mice are hypoinsulinemic and highly sensitive to the action of insulin. It has been proposed that this insulin sensitivity is important for their longevity and increased healthspan. We tested whether this insulin sensitivity of the GHR- KO mouse is necessary for its retarded aging by abrogating that sensitivity with a transgenic alteration that improves development and secretory function of pancreatic β-cells by expressing Igf-1 under the rat insulin promoter 1 ( RIP:: IGF-1). The RIP:: IGF-1 transgene increased circulating insulin content in GHR- KO mice, and thusly fully normalized their insulin sensitivity, without affecting the proliferation of any non-β-cell cell types. Multiple (nonsurvivorship) longevity-associated physiological and endocrinological characteristics of these mice (namely beneficial blood glucose regulatory control, altered metabolism, and preservation of memory capabilities) were partially or completely normalized, thus supporting the causal role of insulin sensitivity for the decelerated senescence of GHR- KO mice. We conclude that a delayed onset and/or decreased pace of aging can be hormonally regulated. [ABSTRACT FROM AUTHOR]

Highlights: [•] mReg2 inhibits ER stress-induced unfolded protein response in MIN6 cells. [•] mReg2 increases basal expression of GRP78 via Akt–mTORC1 signaling axis. [•] mReg2 attenuates ER stress-induced apoptosis. [•] si-RNA mediated knockdown of GRP78 blunts the protective effect of mReg2. [ABSTRACT FROM AUTHOR]

Abstract: Poly(ADP-ribose) polymerase (Parp) 1 is a key regulator of cell death, its inhibition prevented streptozotocin-induced diabetes and attenuated caerulein-induced acute pancreatitis. Reg family proteins are significantly induced by Parp1 inhibitor, experimental diabetes and/or acute pancreatitis. We propose that Reg proteins are involved in the protection of pancreatic cells by Parp1 inhibition. To test this possibility, Parp1−/− and wild-type mice were injected with streptozotocin to induce diabetes. Separately, acute pancreatitis was induced with repeated injections of caerulein. Upon streptozotocin administration, Parp1−/− mice displayed much decreased hyperglycemia and preserved serum insulin level. The treatment induced similar levels of Reg1, -2, -3α and -3β genes in the pancreas of both wild-type and Parp1−/− mice, suggesting that the upregulation of Reg family genes during streptozotocin-induced diabetes was independent of Parp1 ablation. In caerulein-induced pancreatitis, unlike being reported, Parp1 knockout caused no relief on the severity of pancreatitis; the upregulation of pancreatic Reg1, -2, -3α and -3β genes upon caerulein was unaffected by Parp1 deletion. Our results reconfirmed the protective effect of Parp1 gene deletion on islet β-cells but questioned its effect on the acinar cells. In either case, the significant induction of Reg family genes seemed independent of Parp1-mediated cell death. [Copyright &y& Elsevier]

Abstract: In recent years, quite many studies on polymer emulsions with unique core–shell structure have emerged at the frontier between material chemistry and many other fields because of their singular morphology, properties and wide range of potential applications. Organic substance as a coating material onto either inorganic or organic internal core materials promises an unparalleled opportunity for enhancement of final functions through rational designs. This contribution provides a brief overview of recent progress in the synthesis, characterization, and applications of both inorganic–organic and organic–organic polymer emulsions with core–shell structure. In addition, future research trends in polymer composites with core–shell structure are also discussed in this review. [Copyright &y& Elsevier]

Purpose: In view of the numerous clinical observations and laboratory studies that suggest a critical role for the spleen in immune thrombocytopenia (ITP) pathophysiology, we aimed to characterize Th1-associated chemokine receptors CXCR3 and CCR5 and Th2-associated chemokine receptor CCR3 in spleens of ITP patients and assess the significance of their differential expression in the clinical setting. Methods: The histopathology of spleens was observed using hematoxylin-eosin staining (HE), and the positive rate of CXCR3, CCR5 and CCR3 expression in spleens of 24 ITP patients and 12 patients with traumatic splenic rupture as normal controls was detected by immunohistochemistry using the SP method. CXCR3, CCR5 and CCR3 protein expression was analyzed by Western blot and mRNA levels were investigated by real-time polymerase chain reaction (RT-PCR). Results: Reactive hyperplasia could be seen in follicles of the white pulp, the germinal central zone was enlarged and the marginal zone was thickened, the central arteries were thickened and fibrotic, and the density of the capillary vessel was increased in ITP patients. ITP group displayed a higher rate of expression of Th1-associated chemokine receptors CXCR3 and CCR5 (83.3 % vs. 75 %, 100 % vs. 83.3 %) but lower rate of expression of Th2-associated chemokine receptor CCR3 (50 % vs. 66.7 %) compared with the controls ( P < 0.05, respectively). Western blot analysis revealed that CXCR3 and CCR5 protein expression was significantly increased in ITP patients while CCR3 was significantly reduced ( P < 0.05, respectively). Meanwhile, ITP patients displayed increased mRNA levels of CXCR3 and CCR5 but decreased gene expression of CCR3 ( P < 0.05, respectively). Conclusion: The data suggested that the abnormal expression of Th1/Th2 chemokine receptors may participate in splenic immune disorder in patients with ITP. Using corresponding inhibitors may inhibit Th1-dominant expression and mitigate the progress of the disease. [ABSTRACT FROM AUTHOR]

Sulfuric acid treated corn fiber hydrolysate (SACFH) inhibited cell growth and the production of butanol (4.7±0.2g/L) by Clostridium beijerinckii IB4 in P2 medium. Optimal medium components were determined using fractional factorial design. NH4HCO3, FeSO4·7H2O and CaCO3 were demonstrated to be significant components in the production of butanol. The Box–Behnken design and a corresponding quadratic model were used to predict medium components (NH4HCO3 1.96g/L, FeSO4·7H2O 0.26g/L and CaCO3 3.15g/L) and butanol yield (9.5g/L). The confirmation experiment, under the predicted optimal conditions, yielded a butanol level of 9.5±0.1g/L. This study indicates that the Box–Behnken design is an effective approach for screening the optimal medium components required for the production of butanol. It also demonstrates that SACFH, which has high levels of inhibitors such as furan and phenolic compounds, may be used as a renewable carbon source in the production of biofuels. [ABSTRACT FROM AUTHOR]

Abstract: Reg family proteins are expressed in the pancreas and involved in pancreatitis and islet β-cell growth. In order to explore transcriptional control, we transfected luciferase reporter genes driven by Reg promoters into acinar AR42J and islet MIN6 cells. Dexamethasone (DEX) significantly increased the promoter expression of Reg2 and Reg3β genes and the levels of endogenous Reg3β mRNA and protein in AR42J cells. DEX-induced promoter activation was inhibited by the inhibitor of poly(ADP-ribose) polymerase, nicotinamide. In MIN6 cells, DEX moderately stimulated the transcription of Reg3β but not Reg2 promoter. While IL-6 alone had no effect, coculture with DEX produced a remarkable synergism on Reg3β gene transcription, which was abolished by nicotinamide. Our results demonstrated a significant and direct stimulation of Reg2 and Reg3β genes by glucocorticoids, all three were activated in response to inflammation such as in pancreatitis. Prominent stimulation of specific Reg genes by glucocorticoids may constitute a functional synergism. [Copyright &y& Elsevier]

A new type of tissue-engineered bone was constructed by seeding hVEGF165 gene-modified endothelial progenitor cells into the nanohydroxyapatite/collagen/poly(L-lactic acid) scaffolds. These were implanted into the segmental femoral defects of rats to explore the promotion of angiogenesis and osteogenesis. The bone marrow of Sprague Dawley rats was cultured and proliferated, and the endothelial progenitor cells were transfected with Ad5–hVEGF165–EGFP. The gene-modified endothelial progenitor cells were seeded into the nanohydroxyapatite/collagen/poly(L-lactic acid) scaffolds; the growth was observed by scanning electron microscope, and the proliferation was evaluated by methyl thiazolyl tetrazolium assay. In vivo, 80 Sprague Dawley rats were divided randomly into four groups; segmental femoral defects (5 mm) were made and allografted: group A with hVEGF165/endothelial progenitor cells–nanohydroxyapatite/collagen/poly(L-lactic acid), group B with mock endothelial progenitor cells–nanohydroxyapatite/collagen/poly(L-lactic acid), group C with endothelial progenitor cells–nanohydroxyapatite/collagen/poly(L-lactic acid), and group D with scaffolds only. Radiographic, histological, and microvessel density tests were performed to evaluate the angiogenic and osteogenic ability. Reverse transcription polymerase chain reaction and western blot results showed that the target gene was expressed by endothelial progenitor cells. The scanning electron microscope findings and methyl thiazolyl tetrazolium assay revealed that endothelial progenitor cells were attached and proliferated within the nanohydroxyapatite/collagen/poly(L-lactic acid) scaffolds. The average radiographic score and capillary density were the highest in group A, and those in groups B and C were higher than that of group D. The histology showed osteogenesis and scaffold degradation in group A, with less in groups B and C and little in group D. The hVEGF165 gene-modified endothelial progenitor cells, which promoted angiogenesis and osteogenesis in bone-defected areas and the hVEGF165/endothelial progenitor cells–nanohydroxyapatite/collagen/poly(L-lactic acid) composites, may have potential application in repair of segmental bone defects. [ABSTRACT FROM PUBLISHER]