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Mitochondrial quality in skeletal muscle is crucial for maintaining energy homeostasis during metabolic stresses. However, how muscle mitochondrial quality is controlled and its physiological impacts remain unclear. Here, we demonstrate that mitoprotease LONP1 is essential for preserving muscle mitochondrial proteostasis and systemic metabolic homeostasis. Skeletal muscle–specific deletion of Lon protease homolog, mitochondrial (LONP1) impaired mitochondrial protein turnover, leading to muscle mitochondrial proteostasis stress. A benefit of this adaptive response was the complete resistance to diet-induced obesity. These favorable metabolic phenotypes were recapitulated in mice overexpressing LONP1 substrate ΔOTC in muscle mitochondria. Mechanistically, mitochondrial proteostasis imbalance elicits an unfolded protein response (UPRmt) in muscle that acts distally to modulate adipose tissue and liver metabolism. Unexpectedly, contrary to its previously proposed role, ATF4 is dispensable for the long-range protective response of skeletal muscle. Thus, these findings reveal a pivotal role of LONP1-dependent mitochondrial proteostasis in directing muscle UPRmtto regulate systemic metabolism.

Oxidative stress and endoplasmic reticulum (ER) stress are the key contributing factors for cataract progression. In our previous studies, we demonstrated that the nuclear factor erythroid 2-like-2 (Nrf-2)/heme oxygenase-1 (HO-1)/carbon monoxide (CO) axis protects lens epithelial cells (LECs) against oxidants and ER stress. In the present study, transgenic FVB/N mice overexpressing the negative dominant mutant HO-1 G143H (TgHO-1 G143H) were generated to evaluate the crosstalk among HO-1, oxidative stress and ER stress in maintaining lens transparency. Slit-lamp examination revealed that nuclear cataracts occurred at 4 months in the TgHO-1 G143H mice, which was 5 months earlier than that of the control mice. The lenses of the transgenic mice showed an accumulation of malondialdehyde and protein carbonyl with a decrease in glutathione and protein sulfhydryl levels. Elevated concentrations of ER stress biomarkers (Bip, PERK, ATF6, IRE1, CHOP, caspase-12 and caspase-3) in the lenses of the TgHO-1 G143H mice were identified by western blotting. Furthermore, we confirmed that overexpressed HO-1 G143H in LECs resulted in oxidative insult and apoptosis in vitro. All of these data suggested that HO-1 enzymatic activity loss induces early-onset nuclear cataracts by activating oxidative stress and ER stress.

Mitochondrial proteolysis is an evolutionarily conserved quality-control mechanism to maintain proper mitochondrial integrity and function. However, the physiological relevance of stress-induced impaired mitochondrial protein quality remains unclear. Here, we demonstrate that LONP1, a major mitochondrial protease resides in the matrix, plays a role in controlling mitochondrial function as well as skeletal muscle mass and strength in response to muscle disuse. In humans and mice, disuse-related muscle loss is associated with decreased mitochondrial LONP1 protein. Skeletal muscle-specific ablation of LONP1 in mice resulted in impaired mitochondrial protein turnover, leading to mitochondrial dysfunction. This caused reduced muscle fiber size and strength. Mechanistically, aberrant accumulation of mitochondrial-retained protein in muscle upon loss of LONP1 induces the activation of autophagy-lysosome degradation program of muscle loss. Overexpressing a mitochondrial-retained mutant ornithine transcarbamylase (ΔOTC), a known protein degraded by LONP1, in skeletal muscle induces mitochondrial dysfunction, autophagy activation, and cause muscle loss and weakness. Thus, these findings reveal a role of LONP1-dependent mitochondrial protein quality-control in safeguarding mitochondrial function and preserving skeletal muscle mass and strength, and unravel a link between mitochondrial protein quality and muscle mass maintenance during muscle disuse.

Metabolically beneficial beige adipocytes offer tremendous potential to combat metabolic diseases. The folliculin interacting protein 1 (FNIP1) is implicated in controlling cellular metabolism via AMPK and mTORC1. However, whether and how FNIP1 regulates adipocyte browning is unclear. Here, we demonstrate that FNIP1 plays a critical role in controlling adipocyte browning and systemic glucose homeostasis. Adipocyte-specific ablation of FNIP1 promotes a broad thermogenic remodeling of adipocytes, including increased UCP1 levels, high mitochondrial content, and augmented capacity for mitochondrial respiration. Mechanistically, FNIP1 binds to and promotes the activity of SERCA, a main Ca2+ pump responsible for cytosolic Ca2+ removal. Loss of FNIP1 resulted in enhanced intracellular Ca2+ signals and consequential activation of Ca2+-dependent thermogenic program in adipocytes. Furthermore, mice lacking adipocyte FNIP1 were protected against high-fat diet–induced insulin resistance and liver steatosis. Thus, these findings reveal a pivotal role of FNIP1 as a negative regulator of beige adipocyte thermogenesis and unravel an intriguing functional link between intracellular Ca2+ dynamics and adipocyte browning.

The cytoplasmic coat protein complex-II (COPII) is evolutionarily conserved machinery that is essential for efficient trafficking of protein and lipid cargos. How the COPII machinery is regulated to meet the metabolic demand in response to alterations of the nutritional state remains largely unexplored, however. Here, we show that dynamic changes of COPII vesicle trafficking parallel the activation of transcription factor X-box binding protein 1 (XBP1s), a critical transcription factor in handling cellular endoplasmic reticulum (ER) stress in both live cells and mouse livers upon physiological fluctuations of nutrient availability. Using live-cell imaging approaches, we demonstrate that XBP1s is sufficient to promote COPII-dependent trafficking, mediating the nutrient stimulatory effects. Chromatin immunoprecipitation (ChIP) coupled with high-throughput DNA sequencing (ChIP-seq) and RNA-sequencing analyses reveal that nutritional signals induce dynamic XBP1s occupancy of promoters of COPII traffic-related genes, thereby driving the COPII-mediated trafficking process. Liver-specific disruption of the inositol-requiring enzyme 1α (IRE1α)–XBP1s signaling branch results in diminished COPII vesicle trafficking. Reactivation of XBP1s in mice lacking hepatic IRE1α restores COPII-mediated lipoprotein secretion and reverses the fatty liver and hypolipidemia phenotypes. Thus, our results demonstrate a previously unappreciated mechanism in the metabolic control of liver protein and lipid trafficking: The IRE1α-XBP1s axis functions as a nutrient-sensing regulatory nexus that integrates nutritional states and the COPII vesicle trafficking.

IntroductionLinum usitatissimum seed or flax seed is known as a potential candidate as a remedy to treat various diseases in many traditional medicines around the world. In the current study, the antioxidant, cytotoxicity, and anti-human lung cancer properties of Linum usitatissimum seed were investigated in in vitro conditions.Material and methodsAntioxidant activity of the plant was analyzed using radical scavenging activity and ferrous ion chelating assay. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was used to evaluate anti-lung cancer properties of the plant.ResultsThe plant extract scavenged 2,2-diphenyl-1-picrylhydrazyl (DPPH) as a free radical with an IC50 of 34.2 ±0.9 µg/ml. The plant was also found to be rich in phenolic compounds with 294.8 ±2.3 mg GAE/g for total phenolic content. Cell viability of Linum usitatissimum seed was very low against lung poorly differentiated adenocarcinoma (PC-14), lung moderately differentiated adenocarcinoma (LC-2/ad), and lung well-differentiated bronchogenic adenocarcinoma (HLC-1) cell lines without any cytotoxicity towards the normal cell line. The best anti-human lung cancer properties of Linum usitatissimum seed against the above cell lines were observed in the case of the PC-14 cell line. According to the above findings, Linum usitatissimum seed may be administered for the treatment of several types of human lung cancer in humans. According to the results, the IC50 values of plant extract against lung poorly differentiated adenocarcinoma (PC-14), lung moderately differentiated adenocarcinoma (LC-2/ad), and lung well-differentiated bronchogenic adenocarcinoma (HLC-1) cell lines were found to be 392, 483, and 564 µg/ml, respectively.ConclusionsIt appears the recent formulation can be used as a novel chemotherapeutic supplement in humans.

Skeletal muscle depends on the precise orchestration of contractile and metabolic gene expression programs to direct fiber-type specification and to ensure muscle performance. Exactly how such fiber type-specific patterns of gene expression are established and maintained remains unclear, however. Here, we demonstrate that histone monomethyl transferase MLL4 (KMT2D), an enhancer regulator enriched in slow myofibers, plays a critical role in controlling muscle fiber identity as well as muscle performance. Skeletal muscle-specific ablation of MLL4 in mice resulted in downregulation of the slow oxidative myofiber gene program, decreased numbers of type I myofibers, and diminished mitochondrial respiration, which caused reductions in muscle fatty acid utilization and endurance capacity during exercise. Genome-wide ChIP-Seq and mRNA-Seq analyses revealed that MLL4 directly binds to enhancers and functions as a coactivator of the myocyte enhancer factor 2 (MEF2) to activate transcription of slow oxidative myofiber genes. Importantly, we also found that the MLL4 regulatory circuit is associated with muscle fiber-type remodeling in humans. Thus, our results uncover a pivotal role for MLL4 in specifying structural and metabolic identities of myofibers that govern muscle performance. These findings provide therapeutic opportunities for enhancing muscle fitness to combat a variety of metabolic and muscular diseases.

Background Uncontrolled hemorrhage (UH) remains the most common cause of death on the battlefield. This study examined the pathophysiological characteristics of UH in rats acutely exposed to high altitude. Material and methods Rats raised at sea level were randomly divided into two groups. Rats in the high-altitude group were exposed to hypobaric hypoxia in a hypobaric chamber (simulating 4000 m above sea level) for 2 d and then were performed a hemorrhagic shock protocol in the hypobaric chamber. Rats that underwent the same hemorrhage procedure at sea level were used as control. Anesthetized rats were bled to maintain their mean arterial pressure at 45 mmHg for 1 h. The distal quarter of the tail was amputated to allow free blood loss. After 1 h, the tail cut was ligated to induce hemostasis. mean arterial pressure, acid–base balance, blood loss, and survival were recorded. Rats were killed, and tissues were obtained for histological analysis. Results Rats in the high-altitude group suffered less uncontrolled blood loss, more severe acidosis (lower pH and base excess), and inferior tissue oxygen supply (lower oxygen saturation and higher arterial lactate concentration) during the hemorrhage periods compared with the control group. Survival rates were significantly lower in the high-altitude group than those in the control group (P Conclusions In this rat model of hemorrhagic shock, acute high-altitude exposure resulted in decreased UH but more serious hemorrhagic shock injuries than that at sea level.

Background and objective It has been proven that circular RNAs (circRNAs) play an important role on the process of many types cancer and circUBAP2 was a cancer-promoting circRNA, however, the role and mechanism in lung cancer was not clear. The aim of this study is to investigate the effects of circUBAP2 on cell proliferation and invasion of human lung cancer A549 cells. Methods CCK-8 assay was employed to detect the effect of circUBAP2 sliencing on cell proliferation of A549 cells. Fow cytometry was applied to detect the impact of circUBAP2 sliencing on cell cycle and cell anoikis, and Transwell invasion assay was applied to determine cell invasion of A549 cells. We also employed Western blot and Real-time PCR to determine the expressions of CDK6, cyclin D1, p27 and c-IAP1, Bcl-2, Survivin, Bax, FAK, Rac1 and MMP2, and the activities of JNK and ERK1/2, luciferase report gene assay was used to detect the targets. Results CCK-8 assay showed that the inhibition of cell proliferation in the circUBAP2-siRNA group compared to untreated group and siRNA control group. Results of cell cycle detected by flow cytometry showed that cell cycle arrestd at G0/G1 after circUBAP2 silencing, cell apoptosis rate increased also. We also found that after circUBAP2 silencing, cell invasion of A549 cells was significantly inhibited. Western blot and Real-time PCR results showed that expression of CDK6, cyclin D1, c-IAP1, Bcl-2, Survivin, FAK, Rac1 and MMP2 were down-regulated, and the expression of p27 and Bax were up-regulated. Moreover, the activities of JNK and ERK1/2 were inhibited because of circUBAP2 silencing, the target genes were miR-339-5p, miR-96-3p and miR-135b-3p. Conclusion CircUBAP2 plays an important role in the proliferation and invasion of human lung cancer. Silencing of circUBAP2 might be a novel target for molecular targeted therapy of patients with lung cancer.

Background Oxidative stress induced by hemorrhagic shock (HS) is known to initiate a systemic inflammatory response, which leads to subsequent acute lung injury. This study is aimed to assess the efficacy of exendin-4 (Ex-4) in attenuating lung injury in a rat model of HS and resuscitation (HS/R). Methods HS was induced in sodium pentobarbital–anesthetized adult male Wistar rats by withdrawing blood to maintain a mean arterial pressure of 30-35 mm Hg for 50 min. Then, the animals received Ex-4 (5 μg/kg) or vehicle (saline) intravenously and were resuscitated with a volume of normal saline 1.5 times that of the shed blood volume. Mean arterial pressure was measured throughout the experiment, and acid-base status, oxidative stress, inflammation, and lung injury were evaluated at 2 h after resuscitation. Results Ex-4 infusion reduced the methemoglobin content, the malondialdehyde content, the myeloperoxidase activity, and the expression of tumor necrosis factor-α and interleukin-6 in the lungs. The histologic injury was also markedly decreased in the Ex-4 group compared with the vehicle group. Conclusions Ex-4 ameliorates the oxidative stress, inflammatory response, and subsequent acute lung injury occurring after HS/R. Although future studies are required to elucidate the underlying mechanism, our results indicate that Ex-4 infusion may be a promising strategy for improving lung injury in the treatment of HS.

Background: It is known that LINC00974 is an oncogenic long noncoding RNA in liver cancer. Results: The authors observed in this study that LINC00974 was upregulated in gastric cancer (GC) and positively correlated with CDK6. Survival analysis showed that high levels of LINC00974 and CDK6 predicted poor survival. In GC tissues, LINC00974 and CDK6 were positively correlated. In GC cells, LINC00974 overexpression led to upregulated, whereas LINC00974 siRNA silencing led to downregulated CDK6. Analysis of cell cycle progression and proliferation showed that LINC00974 and CDK6 overexpression promoted and siRNA silencing inhibited G1-S transition and cell proliferation. Conclusion: Therefore, LINC00974 upregulates CDK6 to promote cell cycle progression in GC.

Mitochondria are essential for maintaining skeletal muscle metabolic homeostasis during adaptive response to a myriad of physiologic or pathophysiological stresses. The mechanisms by which mitochondrial function and contractile fiber type are concordantly regulated to ensure muscle function remain poorly understood. Evidence is emerging that the Folliculin interacting protein 1 (Fnip1) is involved in skeletal muscle fiber type specification, function, and disease. In this study, Fnip1 was specifically expressed in skeletal muscle in Fnip1-transgenic (Fnip1Tg) mice. Fnip1Tg mice were crossed with Fnip1-knockout (Fnip1KO) mice to generate Fnip1TgKO mice expressing Fnip1 only in skeletal muscle but not in other tissues. Our results indicate that, in addition to the known role in type I fiber program, FNIP1 exerts control upon muscle mitochondrial oxidative program through AMPK signaling. Indeed, basal levels of FNIP1 are sufficient to inhibit AMPK but not mTORC1 activity in skeletal muscle cells. Gain-of-function and loss-of-function strategies in mice, together with assessment of primary muscle cells, demonstrated that skeletal muscle mitochondrial program is suppressed via the inhibitory actions of FNIP1 on AMPK. Surprisingly, the FNIP1 actions on type I fiber program is independent of AMPK and its downstream PGC-1α. These studies provide a vital framework for understanding the intrinsic role of FNIP1 as a crucial factor in the concerted regulation of mitochondrial function and muscle fiber type that determine muscle fitness., Author summary Mitochondria provide an essential source of energy to drive cellular processes and the function of mitochondria is particularly important in skeletal muscle, a metabolically demanding tissue that depends critically on mitochondria, accounting for ~40% of total body mass. In this study, we discovered an essential function of adaptor protein FNIP1 in the coordinated regulation of the mitochondrial and structural programs controlling muscle fitness. Using both gain-of-function and loss-of-function strategies in mice and muscle cells, we provide clear genetic data that demonstrate FNIP1-dependent signaling is crucial for muscle mitochondrial remodeling as well as type I muscle fiber specification. We also uncover that FNIP1 exerts control upon muscle mitochondrial program through AMPK but not mTORC1 signaling. Furthermore, we demonstrate that FNIP1 acts independently of PGC-1α to regulate fiber type specification. Hence, our study emphasizes FNIP1 as a dominant factor that coordinates mitochondrial and muscle fiber type programs that govern muscle fitness.

Gradually increased oxygen administration (GIOA) seems promising in hemorrhagic shock. However, the effects of GIOA on survival remain unclear, and details of GIOA are to be identified. After the induction of hemorrhagic shock, the rats were randomized into five groups ( n = 9): normoxic group (Normo), hyperoxic group (Hypero), normoxic to hyperoxic group (GIOA1), long-time hypoxemic to hyperoxic group (GIOA2), and short-time hypoxemic to hyperoxic group (GIOA3). Survival was recorded for 96 h, plasma alanine transaminase, oxidative stress, hemodynamics, and blood gas were measured. The mean survival time of the GIOA3 was significantly longer than that of the Normo, Hypero, and GIOA2. Plasma alanine transaminase levels were significantly lower in the Normo, GIOA1, and GIOA3 compared to the Hypero and GIOA2 at 2 h post-resuscitation (PR). Plasma 3-nitrotyrosine levels at 2 h PR were significantly lower in the GIOA2 and GIOA3 compared to the Normo and Hypero. Central venous oxygen saturation at 2 h PR in the GIOA3 was significantly higher than the Normo; however, no significant difference was observed between GIOA1 and Normo. Besides, at 2 h PR, mean arterial pressure in the GIOA3 was significantly higher than the GIOA2; however, no significant difference was observed between GIOA1 and GIOA2. (1) GIOA could significantly prolong survival time compared to normoxemic resuscitation and hyperoxic resuscitation; (2) early moments of GIOA are critical to the benefits; and (3) hypoxemia at onset of resuscitation may be imperative, more works are needed to determine the optimal initial oxygen concentration of GIOA.

It has been proven that circular RNAs (circRNAs) play an important role on the process of many types cancer and circUBAP2 was a cancer-promoting circRNA, however, the role and mechanism in lung cancer was not clear. The aim of this study is to investigate the effects of circUBAP2 on cell proliferation and invasion of human lung cancer A549 cells.CCK-8 assay was employed to detect the effect of circUBAP2 sliencing on cell proliferation of A549 cells. Fow cytometry was applied to detect the impact of circUBAP2 sliencing on cell cycle and cell anoikis, and Transwell invasion assay was applied to determine cell invasion of A549 cells. We also employed Western blot and Real-time PCR to determine the expressions of CDK6, cyclin D1, p27 and c-IAP1, Bcl-2, Survivin, Bax, FAK, Rac1 and MMP2, and the activities of JNK and ERK1/2, luciferase report gene assay was used to detect the targets.CCK-8 assay showed that the inhibition of cell proliferation in the circUBAP2-siRNA group compared to untreated group and siRNA control group. Results of cell cycle detected by flow cytometry showed that cell cycle arrestd at G0/G1 after circUBAP2 silencing, cell apoptosis rate increased also. We also found that after circUBAP2 silencing, cell invasion of A549 cells was significantly inhibited. Western blot and Real-time PCR results showed that expression of CDK6, cyclin D1, c-IAP1, Bcl-2, Survivin, FAK, Rac1 and MMP2 were down-regulated, and the expression of p27 and Bax were up-regulated. Moreover, the activities of JNK and ERK1/2 were inhibited because of circUBAP2 silencing, the target genes were miR-339-5p, miR-96-3p and miR-135b-3p.CircUBAP2 plays an important role in the proliferation and invasion of human lung cancer. Silencing of circUBAP2 might be a novel target for molecular targeted therapy of patients with lung cancer. .背景与目的 已有的研究证明环状RNA（circular RNAs, circRNAs）在多种肿瘤发生发展中起重要作用，circUBAP2是一种促癌的circRNA，但是其在肺癌中的作用和机制尚不明确。本研究旨在探讨circular RNA UBAP2（circUBAP2）对人肺癌A549细胞体外增殖和侵袭能力的影响并初步探讨其机制。方法 应用CCK-8法检测circUBAP2表达沉默对A549细胞生长的抑制作用，采用流式细胞仪技术检测circUBAP2表达沉默对A549细胞周期和细胞失巢凋亡的影响，Transwell实验检测circUBAP2表达沉默对A549细胞侵袭能力的影响，Western blot和Real-time PCR检测CDK6、cyclin D1、p27、c-IAP1、Bcl-2、Survivin、Bax、FAK、Rac1、MMP2的表达变化以及JNK和ERK1/2的活性，荧光素酶报告技术检测circUBAP2直接靶基因。结果 CCK-8实验结果显示circUBAP2表达沉默后，A549细胞株增殖能力受抑制；流式细胞结果显示，circUBAP2表达沉默后，细胞周期停滞在G0期/G1期，且细胞凋亡率显著增加；Transwell实验结果显示，细胞体外侵袭能力明显受到抑制。Western blot和Real-time PCR结果显示，circUBAP2表达沉默后，CDK6、cyclin D1、c-IAP1、Bcl-2、Survivin、FAK、Rac1、MMP2等基因的表达水平显著下降，而p27和Bax的表达显著上升，而且JNK、ERK1/2的活性也受到明显的抑制，circUBAP2直接靶基因为miR-339-5p、miR-96-3p和miR-135b-3p。结论 circUBAP2在肺癌的体外增殖和侵袭中发挥重要的作用，抑制其表达，有望成为肺癌分子靶向治疗的新靶点。.

In this paper, we have synthesized 9H-pyrrolo[1,2-a]indol-9-ones and the isomeric indeno[2,1-b]pyrrol-8-ones. The interactions of human serum albumin with series of isomeric derivatives have been studied by spectrophotometric methods. Results show the intrinsic fluorescence is quenched by the derivatives with a static quenching procedure. The thermodynamics parameters indicate that van der Waals forces and hydrogen bonds play a major role in the interactions. The results of synchronous fluorescence spectra demonstrate that the microenvironments of Trp residue of human serum albumin are disturbed by most derivatives. Thermodynamic results showed that the 9H-pyrrolo[1,2-a]indol-9-ones are stronger quenchers and bind to human serum albumin with the higher affinity than isomeric indeno[2,1-b]pyrrol-8-ones. The influence of molecular structure on the binding aspects has been investigated.

The ability to restore heart function by replacement of diseased myocardium is one of the great challenges in biomaterials and regenerative medicine. Brown adipose derived stem cells (BADSCs) present a new source of cardiomyocytes to regenerate the myocardium after infarction. In this study, we explored an injectable tissue engineering strategy to repair damaged myocardium, in which chitosan hydrogels were investigated as a carrier for BADSCs. In vitro, the effect and mechanism of chitosan components on the cardiac differentiation of BADSCs were investigated. In vivo, BADSCs carrying double-fusion reporter gene (firefly luciferase and monomeric red fluorescent protein (fluc-mRFP)) were transplanted into infarcted rat hearts with or without chitosan hydrogel. Multi-techniques were used to assess the effects of treatments. We observed that chitosan components significantly enhanced cardiac differentiation of BADSCs, which was assessed by percentages of cTnT(+) cells and expression of cardiac-specific markers, including GATA-4, Nkx2.5, Myl7, Myh6, cTnI, and Cacna1a. Treatment with collagen synthesis inhibitors, cis-4-hydroxy-D-proline (CIS), significantly inhibited the chitosan-enhanced cardiac differentiation, indicating that the enhanced collagen synthesis by chitosan accounts for its promotive role in cardiac differentiation of BADSCs. Longitudinal in vivo bioluminescence imaging and histological staining revealed that chitosan enhanced the survival of engrafted BADSCs and significantly increased the differentiation rate of BADSCs into cardiomyocytes in vivo. Furthermore, BADSCs delivered by chitosan hydrogel prevented adverse matrix remodeling, increased angiogenesis, and preserved heart function. These results suggested that the injectable cardiac tissue engineering based on chitosan hydrogel and BADSCs is a useful strategy for myocardium regeneration.

Transfusion of red blood cells (RBCs) is an effective therapy in surgery and critical care. Comparing to fresh RBCs, the therapeutic effect of stored RBCs is greatly limited because of its loss of NO during storage, which leads to vasodilatation dysfunction upon transfusion. So far, there is no effective solution to this problem. Here, we summarize the protective effects of Haptoglobin (Hp) in RBCs storage and transfusion, by using data extracted from literature review. Because Free Hemoglobin (FHb) is the major factor responsible for rapid NO loss during storage, addition of FHb-sequestering protein Haptoglobin will prevent the loss of NO and improve the quality of stored RBCs.

The interaction between bovine hemoglobin and analogs of Biphenyldicarboxylate was investigated by fluorescence, synchronous fluorescence, ultraviolet–vis absorbance, resonance light-scattering spectra and three-dimensional fluorescence spectra at pH 7.40. The quenching mechanism and binding constants were determined by the quenching of bovine hemoglobin fluorescence in presence of analogs. Results showed that the nature of the quenching was of static type. Both the van der Waals and hydrogen bonding played a major role in stabilizing the complex. The distance between donor and acceptors was obtained to be 2.11–2.25 nm according to Forster's theory. The influence of analogs on the conformation of bovine hemoglobin was investigated.

The interaction between ovalbumin (OVA) and three purine alkaloids (caffeine, theophylline and diprophylline) was investigated by the aid of intrinsic and synchronous fluorescence, ultraviolet-vis absorbance, resonance light-scattering spectra and three-dimensional fluorescence spectra techniques. Results showed that the formation of complexes gave rise to the fluorescence quenching of OVA by caffeine, theophylline, and diprophylline. Static quenching was confirmed to results in the fluorescence quenching. The binding site number n, apparent binding constant KA and corresponding thermodynamic parameters were measured at different temperatures. The binding process was spontaneous molecular interaction procedures in which both enthalpy and Gibbs free energy decreased. Van der Waals forces and hydrogen bond played a major role in stabilizing the complex. The comparison between caffeine, theophylline, and diprophylline was made, and thermodynamic results showed that diprophylline was the strongest quencher and bound to OVA with the highest affinity among three compounds. The influence of molecular structure on the binding aspects was reported.

Oxidative stress induced by hemorrhagic shock (HS) initiates a systemic inflammatory response, which leads to subsequent kidney injury. This study assessed the efficacy of c-type natriuretic peptide (CNP) in attenuating kidney injury in a rat model of hemorrhagic shock and resuscitation (HS/R). Sodium pentobarbital-anesthetized adult male Wistar rats underwent HS induced by the withdrawal of blood to a mean arterial pressure of 30–35 mmHg for 50 min. Then, the animals received CNP (25 μg/kg) or vehicle (saline) intravenously, followed byresuscitation with 1.5 times the shed blood volume in the form of normal saline. Mean arterial pressure was measured throughout the experiment, and acid–base status, oxidative stress, inflammation, tissue injury and kidney function were evaluated after resuscitation. CNP infusion reduced the malondialdehyde content, lowered the myeloperoxidase activity and decreased the expression of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β in the kidney. The histologic injury score and the plasma creatinine concentration were also significantly decreased after CNP treatment compared to the vehicle group. CNP treatment ameliorates oxidative stress, the inflammatory response, and consequently acute kidney injury after HS/R. Thus, CNP may represent a promising strategy to improve resuscitation for the treatment of HS and deserves further investigation.

RBCs undergo numerous changes during storage and stored RBCs may induce adverse effects, ultimately resulting in organ injury in transfusion recipients. We tested the hypothesis that the addition of SP to stored RBCs would improve the quality of the stored RBCs and mitigate liver injury after transfusion in a murine model. RBCs were harvested from C57BL/6J mice and stored for 14 days in CPDA-1 containing either a solution of SP in saline or saline alone. Haemolysis, the 24-hour posttransfusion recovery, the oxygen-carrying capacity, and the SOD activity of stored RBCs were evaluated. The plasma biochemistry, hepatic MDA level, MPO activity, IL-6, TNF-αconcentrations, and histopathology were measured two hours after the transfusion of stored RBCs. Compared with RBCs stored in CPDA-1 and saline, the addition of SP to stored RBCs restored their oxygen-carrying capacity and SOD activity, reduced the AST activity, BUN concentrations, and LDH activity in the plasma, and decreased the MDA level, MPO activity, and concentrations of IL-6 and TNF-αin the liver. These data indicate that the addition of SP to RBCs during storage has a beneficial effect on storage lesionsin vitroand subsequently alleviates liver injury after the transfusion of stored RBCsin vivo.

This paper addresses the issue of image segmentation by clustering in the domain of image processing. The clustering algorithm taken account here is the Fuzzy C-Means which is widely adopted in this field. Bacterial Foraging Optimization Algorithm is an optimal algorithm inspired by the foraging behavior of E.coli. For the purpose to reinforce the global search capability of FCM, the Bacterial Foraging Algorithm was employed to optimize the objective criterion function which is interrelated to centroids in FCM. To evaluate the validation of the composite algorithm, cluster validation indexes were used to obtain numerical results and guide the possible best solution found by BF-FCM. Several experiments were conducted on three UCI data sets. For image segmentation, BF-FCM successfully segmented 8 typical grey scale images, and most of them obtained the desired effects. All the experiment results show that BF-FCM has better performance than that of standard FCM.

Background The optimal oxygen administration strategy during resuscitation from hemorrhagic shock (HS) is still controversial. Improving oxygenation and mitigating oxidative stress simultaneously seem to be contradictory goals. To maximize oxygen delivery while minimizing oxidative damage, the authors proposed the notion of gradually increased oxygen administration (GIOA), which entails making the arterial blood hypoxemic early in resuscitation and subsequently gradually increasing to hyperoxic, and compared its effects with normoxic resuscitation, hyperoxic resuscitation, and hypoxemic resuscitation in severe HS. Methods Rats were subjected to HS, and on resuscitation, the rats were randomly assigned to four groups (n = 8): the normoxic, the hyperoxic, the hypoxemic, and the GIOA groups. Rats were observed for an additional 1 h. Hemodynamics, acid–base status, oxygenation, and oxidative injury were observed and evaluated. Results Central venous oxygen saturation promptly recovered only in the hyperoxic and the GIOA groups, and the liver tissue partial pressure of oxygen was highest in the GIOA group after resuscitation. Oxidative stress in GIOA group was significantly reduced compared with the hyperoxic group as indicated by the reduced malondialdehyde content, increased catalase activity, and the lower histologic injury scores in the liver. In addition, the tumor necrosis factor-α and interleukin-6 expressions in the liver were markedly decreased in the GIOA group than in the hyperoxic and normoxic groups as shown by the immunohistochemical staining. Conclusions GIOA improved systemic/tissue oxygenation and mitigated oxidative stress simultaneously after resuscitation from severe HS. GIOA may be a promising strategy to improve resuscitation from HS and deserves further investigation.

Endothelial activation elicited by inflammatory agents is regarded as a key event in the pathogenesis of several vascular inflammatory diseases. In the present study, the inhibitory effects and underlying mechanism of C-type natriuretic peptide (CNP) on LPS-induced endothelial activation were examined in human umbilical vein endothelial cells (HUVECs). The effect of CNP on adhesion molecule expression was assessed using quantitative real-time RT-PCR and western blotting analyses. The nuclear factor-κB (NF-κB), MAPK, and PI3K/Akt signaling pathways in LPS-stimulated HUVECs were investigated using western blotting analyses, and the production of intracellular reactive oxygen species (ROS) was measured using a fluorescence method. Pretreatment with CNP inhibited LPS-induced expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, and P-selectin in a concentration-dependent manner. CNP suppressed the phosphorylation of p65 and NF-κB activation in LPS-stimulated cells. Moreover, CNP reduced ERK1/2 and p38 phosphorylation induced by LPS but not JNK. Furthermore, CNP induced Akt phosphorylation and activation of hemeoxygenase-1 (HO-1) expression. CNP significantly inhibited the production of intracellular ROS. These results suggest that CNP effectively attenuated LPS-induced endothelial activation by inhibiting the NF-κB and p38 signaling pathways, eliminating LPS-induced intracellular ROS production, and activating the PI3K/Akt/HO-1 pathway in HUVECs; thereby, demonstrating that CNP may be a potential therapeutic target for the treatment of sepsis and inflammatory vascular diseases.

Reactive oxygen species (ROS), which were largely generated after myocardial ischemia, severely impaired the adhesion and survival of transplanted stem cells. In this study, we aimed to determine whether Exendin-4 pretreatment could improve the adhesion and therapeutic efficacy of transplanted adipose derived stem cells (ADSCs) in ischemic myocardium. In vitro, H2O2 was used to provide ROS environments, in which ADSCs pretreated with Exendin-4 were incubated. ADSCs without pretreatment were used as control. Then, cell adhesion and viability were analyzed with time. Compared with control ADSCs, Exendin-4 treatment significantly increased the adhesion of ADSCs in ROS environment, while reduced intracellular ROS and cell injury as determined by dihydroethidium (DHE) staining live/Dead staining, lactate dehydrogenase-release assay and MTT assay. Western Blotting demonstrated that ROS significantly decreased the expression of adhesion-related integrins and integrin-related focal adhesion proteins, which were significantly reversed by Exendin-4 pretreatment and followed by decreases in caspase-3, indicating that Exendin-4 may facilitate cell survival through enhanced adhesion. In vivo, myocardial infarction (MI) was induced by the left anterior descending artery ligation in SD rats. Autologous ADSCs with or without Exendin-4 pretreatment were injected into the border area of infarcted hearts, respectively. Multi-techniques were used to assess the beneficial effects after transplantation. Longitudinal bioluminescence imaging and histological staining revealed that Exendin-4 pretreatment enhanced the survival and differentiation of engrafted ADSCs in ischemic myocardium, accompanied with significant benefits in cardiac function, matrix remodeling, and angiogenesis compared with non-pretreated ADSCs 4 weeks post-transplantation. In conclusion, transplantation of Exendin-4 pretreated ADSCs significantly improved cardiac performance and can be an innovative approach in the clinical perspective.

To investigate the potential effects of variation of HO-1 activity on hemorheology, this study compared the hemorheological properties between transgenic HO-1G143H mutant mice and wild-type (WT) control mice. Fresh blood samples were obtained from mice via the ocular venous sinus. The whole blood viscosity was measured using a cone-plate viscometer. Erythrocyte deformability and aggregation was measured using ektacytometry. The elongation index was significantly reduced in the HO-1G143H mutant mice compared to the WT mice at the shear rates of 600, 800, and 1,000 s(-1). The integrated elongation index was decreased in the HO-1G143H mutant mice compared to the WT mice. There was no statistically significant difference between the HO-1G143H mutant mice and the WT mice in terms of whole blood viscosity, aggregation index, amplitude of aggregation, and aggregation half time. The present study demonstrated that a reduction in HO-1 activity results in an impaired erythrocyte deformability. Although the mechanism underlying this effect remains unclear, our study brings to light the participation of HO-1 in the variations of hemorheology.

This paper addresses the issue of image segmentation by clustering in the domain of image processing. The clustering algorithm taken account here is the Fuzzy C-Means which is widely adopted in this field. Bacterial Foraging Optimization Algorithm is an optimal algorithm inspired by the foraging behavior of E.coli. For the purpose to reinforce the global search capability of FCM, the Bacterial Foraging Algorithm was employed to optimize the objective criterion function which is interrelated to centroids in FCM. To evaluate the validation of the composite algorithm, cluster validation indexes were used to obtain numerical results and guide the possible best solution found by BF-FCM. Several experiments were conducted on three UCI data sets. For image segmentation, BF-FCM successfully segmented 8 typical grey scale images, and most of them obtained the desired effects. All the experiment results show that BF-FCM has better performance than that of standard FCM.

Heme oxygenase-1 (HO-1) is both beneficial and detrimental to the host in some viral infections by catalyzing the conversion of heme to biliverdin, iron, and carbon monoxide. Simian Virus 40 (SV40) early promoter plays an important role in transforming many cells as it can drive the transcription of large T antigen, which is a potent oncogene. In order to determine the effect of HO-1 on the SV40 early promoter, tumor cells overexpressing HO-1 and HO-1 dominant-negative mutant (glycine143 mutated to histidine) (HO-1G143H) were used. Western blot and HO activity for HO-1/HO-1G143H expression, cell growth, and luciferase activity driven by SV40 promoter were detected in this study. The luciferase activity was suppressed notably in BGC-823 cells transiently overexpressing HO-1, but significantly increased in BGC-823 cells transiently overexpressing HO-1G143H, compared with the mock, respectively. HO-1 overexpression in BGC-823 cells caused the cells containing Blasticidin-resistant gene driven by SV40 promoter to grow slowly under Blasticidin screening, compared with control groups. The luciferase activities were also suppressed in BGC-823, A549, and HepG2 cells stably overexpressing HO-1, and increased in these cell lines stably overexpressing HO-1G143H, compared with the mock, respectively. The results demonstrated that overexpression of HO-1 suppressed transcription driven by SV40 promoter in tumor cells and that HO-1 catalysates might play a major role in the process. Our preliminary results suggested that HO-1 might possess promising counteraction in cell transformation by suppressing SV40 large T-antigen expression, potentially applicable to therapeutic interventions in some virus diseases.

Heme oxygenase-1 (HO-1) potently influences tumor growth and metastasis. To date, no study has been performed on HO-1 expression pattern and its clinicopathological significance in human gastric cancer (GC) cases. In this study, the expression of HO-1 in human GC tissues ( n = 74) and matched non-tumoral adjacent parenchyma ( n = 46) was investigated by immunohistochemistry. The correlation of HO-1 with the clinicopathological characteristics was analyzed. Results showed that HO-1 was expressed in 62 GC tissues from 74 cases (83.8%), which is significantly higher than non-tumoral adjacent parenchyma (20/46, 43.8%, P < 0.05). A high HO-1 expression rate showed a close association with well/moderate histological differentiation and negative lymph node metastasis ( P < 0.05). The expression of matrix metallopeptidase 9 (MMP9) and vascular endothelial growth factor A (VEGF-A) as well as chemosensitivity to cisplatin of MKN-45 cell lines with genetically altered HO-1 status were then determined by realtime polymerase chain reaction and 3-(4,5 dimethyl thiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), respectively. Whether the induction or inhibition of HO-1 by cobalt-protoporphyrin-IX (CoPP) or zinc-protoporphyrin-IX (ZnPP) could affect the sensitivity of MKN-45 cells to cisplatin was also studied. Results showed that the expression of MMP9 and VEGF-A were up-regulated in MKN-45 cells overexpressing HO-1, and down-regulated in HO-1 interfered cells. HO-1 overexpression could lead to an increased resistance to cisplatin, whereas down-regulation of HO-1 expression by siRNA or chemical inhibition of HO-1 could lead to increased chemosensitivity to cisplatin in MKN-45 cells. HO-1 may have multiple effects on protection against carcinogenesis and progression in GC.

PID controller is one of the most widely used strategies in the field of control engineering, but it is difficult to achieve the effect that people expect by the conventional PID controllers. For a long time, researchers are working on the parameter tuning of PID technology, and propose a lot of algorithms. In this paper, we have studied an intelligent algorithm inspired by nature — the Bacterial Foraging Algorithm. Four benchmark functions are used to test this algorithm, and an analysis of the global search capability of this algorithm is made. Then,we apply this algorithm to a high-speed and high-precision servo system of fourth order model of PID parameter tuning. The tuning results compared with that of the standard genetic algorithm show that Bacterial Foraging Algorithm is effective in the problem of PID optimization and can be more precision.

The chemical regeneration method of human enamel was improved for the probable clinical application: an oral medical device was designed to significantly reduce the necessary amount of remineralization liquid; the reactive liquid phase system was redesigned, thus the solution could be stored for long time.

Dental appearance is a significant concern given that the general public is dissatisfied with their tooth colour (Alkhatib et al., J. Dent., 2004, 32, 561–566). The existing products for tooth-whitening, such as peroxide, can cause damage to the teeth and the whitening effect tends not to last long. In this study a new method was developed to whiten teeth by constructing fluorapatite crystals in polyethylene oxide solution on the natural tooth surface. By adding polyacrylamide to solidify the whole system, a layer of well compacted fluorapatite film was successfully precipitated onto the natural enamel surface. The reconstructed layer is analogous to the natural enamel's chemical components, micro-architectural structure and mechanical properties, and efficiently whitens teeth. The mechanism of how these structures were formed and how the whitening effect was achieved are also proposed.

Regenerating the microstructure of human tooth enamel under near-physiological conditions (pH 6.0, 37 degrees C, 1 atm) using a simple chemical approach demonstrates a potential application to repair enamel damage in dental clinics.

Background Plasma expanders are commonly used in the management of critically ill patients, which may exhibit altered hemorheology. We evaluated the effects of various synthetic colloids and Lactated Ringer’s (LR) solution on hemorheological parameters in vitro and in a rodent hemorrhagic shock model. Methods For the in vitro experiments, rat blood was incubated with hydroxyethyl starch (HES) 130/0.4, HES 200/0.5, succinylated gelatine (GEL), or LR at various ratios. The control consisted of blood without dilution. The hemorheological parameters were measured after a 15-min incubation. For the in vivo study, rats were subjected to a severe volume-controlled hemorrhage and were resuscitated using a colloid solution (HES 130/0.4, HES 200/0.5, or GEL) or LR. The hemorheological parameters were measured 2 h after resuscitation. Results The GEL significantly elevated the plasma viscosity compared to the other groups. In the in vitro study, GEL and LR accelerated the erythrocyte aggregation. There was no significant difference between HES 130/0.4, HES 200/0.5, and control groups regarding the aggregation amplitude and index. In the in vivo study, the aggregation amplitude increased significantly in the GEL group compared to the HES 130/0.4, HES 200/0.5, LR, and sham groups. There was no significant difference between the groups with respect to the elongation index in vivo. Conclusions Hydroxyethyl starch did not change the erythrocyte aggregation compared to the control. GEL significantly accelerates the erythrocyte aggregation and elevates the plasma viscosity compared to hydroxyethyl starch. The in vitro hemorheological measurements most likely provide hints for the in vivo study.