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Drosophila egg-derived tyrosine phosphatase (EDTP), a lipid phosphatase that removes 3-position phosphate at the inositol ring, has dual functions in oogenesis and muscle performance in adults. A mammalian homologous gene MTMR14, which encodes the myotubularin-related protein 14, negatively regulates autophagy. Mutation of EDTP/MTMR14, however, causes at least three deleterious consequences: (1) the lethality in early embryogenesis in Drosophila; (2) a “jumpy” phenotype with apparently impaired motor functions; and (3) an association with a rare genetic disorder called centronuclear myopathy. The potential benefit of EDTP/MTMR14 downregulation is likely masked by the lethality or severe muscle defects due to ubiquitous loss of this gene. Here we show that flies carrying a heterozygous EDTP mutation had increased survivorship to prolonged anoxia; tissue-specific downregulation of EDTP in non-muscle tissues, particularly motoneurons, extended lifespan and improved survivorship to beta-amyloid peptides (Aβ42) and polyglutamine protein aggregates. These data highlight the significance of selective downregulation of EDTP in non-muscles for beneficial consequences. MTMR14 expression was evident in the hippocampus and cortex in C57BL/6 J and APP/PS1 mice. Compared with C57BL/6 J mice, APP/PS1 mice had reduced MTMR14 in the cortex. Hippocampal expression of MTMR14 was increased and plateaued at 9–17 months compared with 2–6 months in C57BL/6 J mice. Additionally, MTMR14 was inducible by Aβ42 in the rat primarily hippocampal neurons and mouse Neuro2a neuroblasts. We demonstrate a novel approach of tissue-specific downregulation of the disease-associated gene EDTP/MTMR14 for extended lifespan and improved survivorship to cellular protein aggregates. This approach could be extended from insects to mammals.

Gasdermin E (GSDME), also called DFNA5, is a member of the gasdermin family. GSDME is involved in the regulation of apoptosis and necrosis. The N-terminal domain of GSDME displays an apoptosis-inducing activity while the C-terminal domain may serve as an apoptosis-inhibiting regulator by shielding the N-terminal domain. Besides its function in the regulation of apoptosis, GSDME was recently reported to be a substrate of caspase-3 and cleavage of GSDME by caspase-3 into necrotic N-terminal fragment leads to the induction of secondary necrosis. GSDME was first identified as a deafness gene because its mutation was associated with a specific form of autosomal dominant progressive sensorineural hearing loss. Furthermore, GSDME has been considered a tumor suppressor implicated in several types of cancer. This mini-review summarized recent reports relevant to the functions of GSDME in the regulation of apoptosis and necrosis as well as its clinical relevance.

Receptor-interacting protein kinase 1/3 (RIPK1/3) and mixed lineage kinase domain-like (MLKL)-mediated necroptosis contributes to brain injury after ischemic stroke. Ligustroflavone is an ingredient of common privet with activities of anti-inflammation and complement inhibition. This study aims to explore the effect of ligustroflavone on ischemic brain injury in stroke rat and the underlying mechanisms. A rat model of ischemic stroke was established by middle cerebral artery occlusion (MCAO), which showed ischemic injury (increase in neurological deficit score and infarct volume) and upregulation of necroptosis-associated proteins (RIPK1, RIPK3 and MLKL/p-MLKL). Administration of ligustroflavone (30 mg/kg, i.g.) 15 min before ischemia evidently improved neurological function, reduced infarct volume, and decreased the levels of necroptosis-associated proteins except the RIPK1. Consistently, hypoxia-cultured PC12 cells (O2/N2/CO2, 1:94:5, 8 h) caused cellular injury (LDH release and necroposis) concomitant with up-regulation of necroptosis-associated proteins, and these phenomena were blocked in the presence of ligustroflavone (25 μM) except the elevated RIPK1 levels. Using the Molecular Operating Environment (MOE) program, we identified RIPK1, RIPK3, and MLKL as potential targets of ligustroflavone. Further studies showed that the interaction between RIPK3 and RIPK1 or MLKL was significantly enhanced, which was blocked in the presence of ligustroflavone. Based on these observations, we conclude that ligustroflavone protects rat brain from ischemic injury, and its beneficial effect is related to the prevention of necroptosis through a mechanism involving targeting RIPK1, RIPK3, and/or MLKL.

Phenotypic transformation of vascular smooth muscle cells (VSMCs) contributes to vascular remodeling in hypertension. High mobility group box-1 (HMGB1) has been reported to be involved in several pathogenic processes including VSMC proliferation and migration. The present study was designed to determine the role of HMGB1 in VSMC phenotypic transformation in hypertension. First, we demonstrated that HMGB1 was elevated in a model of Ang II-induced VSMC phenotypic transformation, which showed down-regulation of contractile proteins and up-regulation of synthetic proteins. Knockdown of HMGB1 and losartan could block the phenotypic transformation. Next, we identified three potential miRNAs for upstream regulation of HMGB1 by bioinformatic analysis; only miR-181b-5p was significantly down-regulated in Ang II-treated cells. Co-treating the cells with miR-181b-5p mimics suppressed HMGB1 expression as well as the phenotypic transformation, migration, and proliferation. Furthermore, the luciferase reporter gene assay confirmed the direct interaction between miR-181b-5p and HMGB1. Finally, to extend these cell-based studies to clinical patients, we demonstrated that plasma miR-181b-5p levels were decreased, while Ang II and HMGB1 levels, as well as the intima-media thickness (IMT) were increased in hypertensive patients; these effects were reversed following the administration of angiotensin receptor blockers. Based on these observations, we conclude that the down-regulation of miR-181b-5p leads to the elevation of HMGB1 levels in hypertensive patients, which accounts, at least partially, for VSMCs phenotypic transformation and vascular remodeling. Our findings also highlight that the plasma levels of miR-181b-5p and HMGB1 may serve as novel biomarkers for vascular remodeling in the hypertensive patients.

Purpose Pellino3, an ubiquitin E3 ligase, prevents the formation of the death-induced signaling complex in response to TNF-α via targeting receptor-interacting protein kinase 1 (RIPK1), and bioinformatics analysis predicts the interaction between Pellino3 and caspofungin, a common antifungal drug used in clinic. This study aims to explore the effect of caspofungin on brain injury in ischemic stroke and the underlying mechanisms. Methods The SD rat brains (or nerve cells) were subjected to 2h-ischemia (or 8h-hypoxia) plus 24h-reperfusion (or 24h-reoxygenation) to establish the I/R (or H/R) injury model. The cerebral injury was assessed by the methods of triphenyltetrazolium chloride (TTC) staining and Hematoxylin & eosin (H&E) staining. The correlations among caspofungin, Pellino3 and necroptosis in I/R-treated brain or H/R-treated nerve cells were evaluated by biochemistry, molecular and gene overexpression assays. Results The I/R-treated brain showed the injuries (increase in neurological deficit score and infarct volume), downregulation of Pellino3, decreased ubiquitination of RIPK1 and up-regulation of necroptosis-associated proteins [RIPK1, RIPK3, mixed lineage kinase domain-like protein (MLKL), p-RIPK1, p-RIPK3 and p-MLKL]. Caspofungin treatment improved neurological function, reduced infarct volume, up-regulated Pellino3, increased RIPK1 ubiquitination and down-regulated levels of RIPK1, p-RIPK1, p-RIPK3 and p-MLKL. In PC12 cells, H/R treatment caused cellular injury (LDH release and necroptosis), downregulation of Pellino3, decreased ubiquitination of RIPK1 and up-regulation of necroptosis-associated proteins, these phenomena were reversed by overexpression of Pellino3. Conclusion Pellino3 has an important role in counteracting necroptosis via ubiquitination of RIPK1 and caspofungin can suppress the brain cell necroptosis in ischemic stroke via upregulation of Pellino3.

Background. The occurrence and development of hepatocellular carcinoma (HCC) are closely related to immune function, as is the capacity of hepatoma cells to escape. Immunosurveillance is a key mechanism. Catgut implantation at acupoint (CIAA) is a promising acupuncture improvement method that can regulate immunity and has been widely used in the clinical treatment of a variety of diseases. The aim of this study is to observe the therapeutic effect of CIAA on HCC and to investigate the potential mechanism of immune escape. Materials and Methods. A total of 40 mice were randomly divided into three groups: the HCC model group (n = 15), the CIAA treatment group (n = 15), and the control group (n = 10). HCC was chemically induced in 30 mice by the combination of DEN, carbon tetrachloride, and ethanol for 150 days. Among them, 15 were selected for CIAA treatment to ascertain the therapeutic effect. The mRNA expression levels of AFP, IL-10, PD-1, and CTLA-4 in three groups were examined by using RT-PCR. AFP and AKT expressions were measured by using western blotting. PD1, CTLA-4, IL-10, CD4+, and CD8+ protein expression levels were evaluated by using IHC. The mortality rate, body weight, and psychological conditions of three groups were also compared. Results. The mRNA and protein expression levels of AFP, PD-1, CTLA-4, and IL-10 were significantly downregulated in the CIAA-treated mice in comparison with HCC mice. IHC assay shows that CD4+ and CD8+ expression levels were notably upregulated after CIAA treatment. Western blotting assay shows that AKT pathway was deactivated in CIAA-treated mice. CIAA notably reduced the mortality rate and inhibited weight loss caused by HCC and improved the overall psychological condition of the mice. Conclusions. Taken together, our data corroborate the effective potency of CIAA in the treatment of HCC by and inhibiting immune escape and deactivating the AKT pathway.

Overloading of ammonia and nitrite nitrogen in aquaculture can result in toxicity to aquatic animals. In order to eliminate the hazardous substances, a highly efficient denitrifying bacterium, Bacillus sp. SC16, was identified in a fishery pond and isolated subsequently. The strain SC16 could remove nitrate up to 97%, ammonia up to 36.6%, and nitrite up to 99.99% when incubated with nitrate at an initial concentration of 306.9 mg&middot, L&minus, 1 for 72 h, ammonia at 165.49 mg&middot, 1 for 48 h, and nitrite at 200 mg&middot, 1 for 24 h under aerobic conditions. The nitrite reductase gene was identified as the nirK gene. The transcriptional levels of the nirK gene in strain SC16 incubated with ammonia, nitrate, and nitrite showed similar expression patterns. When the strain SC16 was used to treat the aquaculture water, the concentration of ammonia decreased significantly, from 8.35 mg&middot, 1 to 4.56 mg&middot, 1, and there was almost no accumulation of nitrite by the end of experiment. Therefore, the results indicated that Bacillus sp. SC16 could be a promising candidate for aquaculture water treatment.

Necroptosis, ferroptosis and cyclophilin D (Cyp D)-dependent necrosis contribute to myocardial ischemia/reperfusion (I/R) injury, and ponatinib, deferoxamine and cyclosporine are reported to inhibit necroptosis, ferroptosis and Cyp D-dependent necrosis, respectively. This study aims to explore whether the any two combination between ponatinib, deferoxamine and cyclosporine exerts a better cardioprotective effect on I/R injury than single medicine does. The H9c2 cells were subjected to 10 h of hypoxia (H) plus 4 h of reoxygenation (R) to establish H/R injury model. The effects of any two combination between ponatinib, deferoxamine and cyclosporine on H/R injury were examined. On this basis, a I/R injury model in rat hearts was established to focus on the effect of ponatinib, deferoxamine and their combination on myocardial I/R injury and the underlying mechanisms. In H/R-treated H9c2 cells, all three medicines can attenuate H/R injury (decrease in LDH release and necrosis percent). However, only the combination of ponatinib with deferoxamine exerted synergistic effect on reducing H/R injury, showing simultaneous suppression of necroptosis and ferroptosis. Expectedly, administration of ponatinib or deferoxamine either before or after ischemia could suppress necroptosis or ferroptosis in the I/R-treated rat hearts as they did in vitro, concomitant with a decrease in myocardial infarct size and creatine kinase release, and the combination therapy is more efficient than single medication. Based on these observations, we conclude that the combination of ponatinib with deferoxamine reduces myocardial I/R injury via simultaneous inhibition of necroptosis and ferroptosis.

Although numerous studies have indicated that chronic stress causes cognitive dysfunction with the impairment of synaptic structures and functions, the relationship between cognitive deficits induced by repeated restraint stress and the level of NMDA receptors in the subregion of the hippocampus has been relatively unknown until now. In this study, 3-week-old male Sprague-Dawley rats were exposed to repeated restraint stress for seven consecutive days, their cognitive functions were evaluated through behavioral tests, and then they were sacrificed for electrophysiological, morphological, and biochemical assays. Chronic repeated restraint stress led to cognitive and electrophysiological impairments, with a reduced density of dendritic spines. We also found that the protein level of NMDA receptors only increased in the hippocampal CA3 region. Nevertheless, repeated restraint stress-induced cognitive and synaptic dysfunction were effectively reversed by Ro25-6981, an inhibitor of the GluN2B receptor. These findings suggest that repeated restraint stress-induced synaptic and cognitive deficits are probably mediated through NMDA receptors.

Background Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), involves multiple organs. Testicular involvement is largely unknown. Objective To determine the pathological changes and whether SARS-CoV-2 can be detected in the testes of deceased COVID-19 patients. Design, setting, and participants Postmortem examination of the testes from 12 COVID-19 patients was performed using light and electron microscopy, and immunohistochemistry for lymphocytic and histiocytic markers. Reverse transcription-polymerase chain reaction (RT-PCR) was used to detect the virus in testicular tissue. Outcome measurements and statistical analysis Seminiferous tubular injury was assessed as none, mild, moderate, or severe according to the extent of tubular damage. Leydig cells in the interstitium were counted in ten 400× microscopy fields. Results and limitations Microscopically, Sertoli cells showed swelling, vacuolation and cytoplasmic rarefaction, detachment from tubular basement membranes, and loss and sloughing into lumens of the intratubular cell mass. Two, five, and four of 11 cases showed mild, moderate, and severe injury, respectively. The mean number of Leydig cells in COVID-19 testes was significantly lower than in the control group (2.2 vs 7.8, p, Take Home Message We found significant injury in the testes of coronavirus disease 2019 (COVID-19) patients. However, the virus was not detected in the testes in the majority of cases. These findings can provide evidence-based guidance for sperm donation and inform management strategies to mitigate the risk of testicular injury during the COVID-19 disease course.

Direct or indirect exposure to inorganic arsenic (iAs) in the forms of AsIII (arsenite) and AsV (arsenate) through consumption of As-contaminated food materials and drinking water leads to arsenic poisoning. Rice (Oryza sativa L.) plant potentially accumulates a high amount of iAs from paddy fields than any other cereal crops. This makes it to be a major source of iAs especially among the population that uses it as their dominant source of diet. The accumulation of As in human bodies poses a serious global health risk to the human population. Various conventional methods have been applied to reduce the arsenic accumulation in rice plant. However, the success rate of these techniques is low. Therefore, the development of efficient and effective methods aimed at lowering iAs toxicity is a very crucial public concern. With the current advancement in technology, new strategies aimed at addressing this concern are being developed and utilized in various parts of the world. In this review, we discuss the recent advances in the management of iAs in rice plants emphasizing the use of nanotechnology and biotechnology approaches. Also, the prospects and challenges facing these approaches are described.

Ferroptosis is an iron-dependent regulated necrosis. This study aims to evaluate the contribution of ferroptosis to ischemia or reperfusion injury, and lay a basis for precise therapy of myocardial infarction. The Sprague-Dawley (SD) rat hearts were subjected to ischemia for different duration or the hearts were treated with 1 h-ischemia plus different duration of reperfusion. The myocardial injury was assessed by biochemical assays and hematoxylin & eosin (HE) staining. The ferroptosis was evaluated with the levels of acyl-CoA synthetase long-chain family member 4 (ACSL4), glutathione peroxidase 4 (GPX4), iron, and malondialdehyde. Iron chelator (deferoxamine) was applied to verify the contribution of ferroptosis to ischemia and reperfusion injury. The results showed that ischemic injury (infarction and CK release) was getting worse with the extension of ischemia, but no significant changes in ferroptosis indexes (ACSL4, GPX4, iron, and malondialdehyde) in cardiac tissues were observed. Differently, the levels of ACSL4, iron, and malondialdehyde were gradually elevated with the extension of reperfusion concomitant with a decrease of GPX4 level. In the ischemia-treated rat hearts, no significant changes in myocardial injury were observed in the presence of deferoxamine, while in the ischemia/reperfusion-treated rat hearts, myocardial injury was markedly attenuated in the presence of deferoxamine concomitant with a reduction of ferroptosis. Based on these observations, we conclude that ferroptosis occurs mainly in the phase of myocardial reperfusion but not ischemia. Thus, intervention of ferroptosis exerts beneficial effects on reperfusion injury but not ischemic injury, laying a basis for precise therapy for patients with myocardial infarction.

Apoptosis, necrosis and autophagy-dependent cell death are the three major types of cell death. Traditionally, necrosis is thought as a passive and unregulated form of cell death. However, certain necrosis can also occur in a highly regulated manner, referring to regulated necrosis. Depending on the signaling pathways, regulated necrosis can be further classified as necroptosis, pyroptosis, ferroptosis, parthanatos and CypD-mediated necrosis. Numerous studies have reported that regulated necrosis contributes to the progression of multiple injury-relevant diseases. For example, necroptosis contributes to the development of myocardial infarction, atherosclerosis, heart failure and stroke; pyroptosis is involved in the progression of myocardial or cerebral infarction, atherosclerosis and diabetic cardiomyopathy; while ferroptosis, parthanatos and CypD-mediated necrosis participate in the pathological process of myocardial and/or cerebral ischemia/reperfusion injury. Thereby, targeting the pathways of regulated necrosis pharmacologically or genetically could be an efficient strategy for reducing cardio-cerebrovascular injury. Further study needs to focus on the crosstalk and interplay among different types of regulated necrosis. Pharmacological intervention of two or more types of regulated necrosis simultaneously may have advantages in clinic to treat injury-relevant diseases.

We use laser-induced plasma shock waves to remove Al nanoparticles from a smooth silicon substrate. Our experimental results show that the removal mechanism varies for different substrate regions. We examine the factors influencing particle removal by evaluating the shock-wave spatial distribution and the removal mechanisms. Further, we evaluate the influence of the gap between the laser focus and substrate on the removal results. The effects of the laser focus and substrate particle sizes are also investigated, and the optimum removal conditions are obtained. Our study can aid in better understanding the mechanisms of particle removal from surfaces.

Epidemiological surveys show that 70–80% of patients with Alzheimer’s disease (AD) have type 2 diabetes mellitus (T2DM) or show an abnormality of blood glucose levels. Therefore, an increasing number of evidence has suggested that diabetic hyperglycemia is tightly linked with the pathogenesis and progression of AD. In the present study, we replicated T2DM animal model via subcutaneous injection of newborn Sprague-Dawley (SD) rats with monosodium glutamate (MSG) during the neonatal period to investigate the effects and underlying mechanisms of hyperglycemia on cognitive ability. We found that neonatal MSG exposure induced hyperglycemia as well as Alzheimer-like learning and memory deficits with decreased dendritic spine density and hippocampal synaptic-related protein expression and increased phosphorylated tau levels in ∼3-month-old SD rats. Our results suggested that hyperglycemia probably causes cognitive impairment and Alzheimer-like neuropathological changes, which provide the experimental data connecting T2DM and AD.

Despite the severity of osteoarthritis (OA), current medical therapy strategies for OA aim at symptom control and pain reduction, as there is no ideal drug for effective OA treatment. OA rat model was used to explore the therapeutic function of quercetin on remission of OA, by determining the reactive oxygen species (ROS) levels, mitochondrial function and extracellular matrix integrity. Quercetin could attenuate ROS generation and augment the glutathione (GSH) and glutathione peroxidase (GPx) expression levels in OA rat. Quercetin not only enhanced mitochondrial membrane potential, oxygen consumption, adenosine triphosphate (ATP) levels in mitochondria, but also increased the mitochondrial copy number. Furthermore, the interlukin (IL)-1β-induced accumulation of nitric oxide (NO), matrixmetalloproteinase (MMP)-3) and MMP-13 could be suppressed by quercetin. Finally, we confirmed that the therapeutic properties of quercetin on OA might function through the adenosine monophosphate-activated protein kinase/sirtuin 1 (AMPK/SIRT1) signaling pathway. In summary, quercetin could alleviate OA through attenuating the ROS levels, reversing the mitochondrial dysfunction and keeping the integrality of extracellular matrix of joint cartilage. The underlying mechanism might involve the regulation of AMPK/SIRT1 signaling pathway.

Assessment of crop health status in real time could provide reliable and useful information for making effective and efficient management decisions regarding the appropriate time and method to control crop diseases and insect damage. In this study, hyperspectral reflectance of symptomatic and asymptomatic rice leaves infected by Pyricularia grisea Sacc, Bipolaris oryzae Shoem, Aphelenchoides besseyi Christie and Cnaphalocrocis medinalis Guen was measured in a laboratory within the 350–2 500 nm spectral region. Principal component analysis was performed to obtain the principal component spectra (PCs) of different transformations of the original spectra, including original (R), common logarithm of reciprocal (lg (1/R)), and the first derivative of original and common logarithm of reciprocal spectra (R′ and (lg (1/R))′). A probabilistic neural network classifier was applied to discriminate the symptomatic rice leaves from asymptomatic ones with the front PCs. For identifying symptomatic and asymptomatic rice leaves, the mean overall discrimination accuracies for R, lg (1/R), R′ and (lg (1/R))′ were 91.3, 93.1, 92.3 and 92%, and the mean Kappa coefficients were 0.771, 0.835, 0.829 and 0.82, respectively. To discriminate between disease and insect damage, the overall accuracies for R, lg (1/R), R′ and (lg (1/R))′ were 97.7, 98.1, 100 and 100%, and the Kappa coefficients were 0.962, 0.97, 1 and 1, respectively. These results demonstrated that hyperspectral remote sensing can discriminate between multiple diseases and the insect damage of rice leaves under laboratory conditions.

In this paper, we consider stochastic second-order-cone complementarity problems (SSOCCP). We first use the so-called second-order-cone complementarity function to present an expected residual minimization (ERM) model for giving reasonable solutions of SSOCCP. Then, we introduce a smoothing function, by which we obtain a smoothing approximate ERM model. We further show that the global solution sequence and weak stationary point sequence of this smoothing approximate ERM model converge to the global solution and the weak stationary point of the original ERM model as the smoothing parameter tends to zero respectively. Moreover, since the ERM formulation contains an expectation, we employ a sample average approximate method for solving the smoothing ERM model. As the convergence analysis, we first show that the global optimal solution of this smoothing sample average approximate problem converges to the global optimal solution of the ERM problem with probability one. Subsequently, we consider the weak stationary points’ convergence results of this smoothing sample average approximate problem of ERM model. Finally, some numerical examples are given to explain that the proposed methods are feasible.

Fasudil is a potent Rho-kinase (ROCK) inhibitor and can relax smooth muscle or cardiac muscle contraction through decreasing the phosphorylation level of myosin regulatory light chain (p-MLC20 or p-MLC2v), while p-MLC2v can function as a transcription factor to promote the NADPH oxidase 2 (NOX2) expression in rat hearts subjected to ischemia/reperfusion (I/R). This study aims to explore whether fasudil can protect the rat hearts against I/R oxidative injury through suppressing NOX2 expression via reduction of p-MLC2v level. The SD rat hearts were subjected to 1h-ischemia plus 3h-reperfusion, which showed myocardial injuries (myocardial fiber loss and disarray, increase of creatine kinase release and myocardial infarction/apoptosis), increase in ROCK activity and nuclear p-MLC2v level concomitant with up-regulation of NOX2 and H2O2 production; these phenomena were attenuated by fasudil in a dose-dependent manner. Next, we verified the cardioprotective effect of fasudil and the underlying mechanisms in hypoxia-reoxygenation (H/R) -treated H9c2 cells. Consistent with the results in vivo, the H/R-treated H9c2 cells showed cellular injury (increase in apoptotic ratio), elevation in ROCK activity and nuclear p-MLC2v level, accompanied by up-regulation of NOX2 and H2O2 production; these effects were blocked in the presence of fasudil in a dose-dependent way. Based on these observations, we conclude that beneficial effect of fasudil against myocardial I/R or H/R oxidative injury is related to the suppression of NOX2 expression through decrease of the p-MLC2v level. Our findings also highlight that intervention of MLC2v phosphorylation by drugs may provide a novel strategy to protect heart from I/R oxidative injury.

Statins are reported to exert benefits on endothelial function through a mechanism involving in prevention of endothelial senescence. This study aims to explore whether atorvastatin exerts inhibitory effect on endothelial senescence in hyperlipidemic rats or ox-LDL-treated HUVECs through a mechanism involving suppress of miR-21-5p/203a-3p expression and their downstream pathway. The rats were fed with high-fat diet to establish a hyperlipidemic model, which showed an increase in plasma lipids and endothelial senescence, accompanied by the elevation in plasma levels of miR-21-5p/203a-3p, down-regulation of Drp1 and up-regulation of p53 in the aorta of hyperlipidemic rats; these phenomena were reversed by atorvastatin. Next, HUVECs were incubated with ox-LDL to establish a senescent model in vitro. Consistent with the finding in vivo, atorvastatin treatment decreased the level of miR-21-5p and miR-203a-3p in the ox-LDL-treated HUVECs, restored Drp1 expression and mitochondrial function, as well as suppressed p53 and p16 expression and endothelial senescence. Based on these observations, we conclude that atorvastatin exerts inhibitory effect on endothelial senescence in hyperlipidemic rats through a mechanism involving down-regulation of miR-21-5p/203a-3p, which leads to the restoration of Drp1 level and recovery of mitochondrial function. Our findings highlight a novel non-lipid effect for atorvastatin besides its function in modulation of lipids.

Allopurinol, a xanthine oxidase (XO) inhibitor, is reported to alleviate myocardial ischemia/reperfusion (I/R) injury by reducing the production of reactive oxygen species (ROS). As an XO-derived product, H2O2 can act as a substrate of vascular peroxidase 1 (VPO1) to induce the generation of hypochlorous acid (HOCl), a potent oxidant. This study aims to explore whether the XO/VPO1 pathway is involved in the anti-oxidative effects of allopurinol on the myocardial I/R injury. In a rat heart model of I/R, allopurinol alleviated I/R oxidative injury accompanied by decreased XO activity, XO-derived products (H2O2 and uric acid), and VPO1 expression (mRNA and protein). In a cardiac cell model of hypoxia/reoxygenation (H/R), allopurinol or XO siRNA reduced H/R injury concomitant with decreased XO activity, VPO1 expression as well as the XO and VPO1-derived products (H2O2, uric acid, and HOCl). Although knockdown of VPO1 could also exert a beneficial effect on H/R injury, it did not affect XO activity, XO expression, and XO-derived products. Based on these observations, we conclude that the novel pathway of XO/VPO1 is responsible for, at least partly, myocardial I/R-induced oxidative injury, and allopurinol exerted the cardioprotective effects on myocardial I/R injury via inhibiting the XO/VPO1 pathway.

The presence of genetically modified (GM) protein in the endosperm is important information for the public when considering the biological safety of transgenic rice. To limit the expression of GM proteins to rice green tissues, we developed a modified Cre-lox gene switch using two cassettes named KEY and LOCK. KEY contains a nuclear-localized Cre recombinase driven by the green-tissue-specific promoter rbcS. LOCK contains a Nos terminator (NosT), which is used to block the expression of the gene of interest (GOI), bounded by two loxP sites. When KEY and LOCK are pyramided into hybrid rice, a complete gene switch system is formed. The Cre recombinase from KEY excises loxP-NosT in LOCK and unlocks the GOI in green tissues but keeps it locked in the endosperm. This regulatory effect was demonstrated by eYFP and Bt expression assays. The presence of eYFP and Cre were confirmed in the leaf, sheath, stem, and glume but not in the root, anther or seed of the gene-switch-controlled eYFP hybrids. Meanwhile, gene switch-controlled Bt hybrid rice not only confined the expression of Bt protein to the green tissues but also showed high resistance to striped stem borers and leaffolders.

We present a new method for solving the box-constrained stochastic linear variational inequality problem with three special types of uncertainty sets. Most previous methods, such as the expected value and expected residual minimization, need the probability distribution information of the stochastic variables. In contrast, we give the robust reformulation and reformulate the problem as a quadratically constrained quadratic program or convex program with a conic quadratic inequality quadratic program, which is tractable in optimization theory.

The preparation and characterizations of soluble copolymers poly (p-phenylene terephthamide-co-furandicarboxylic p-Phenylenediamine)(PPTA-co-PPF) by direct polycondensation was described. The chemical structure of polyamides was investigated by 1H NMR and FT-IR. The good solubility of copolymers in organic solvents was certified at room temperature. Their thermal stability and mechanical properties were observed by TGA and tensile testing and then compared with that of traditional high performance aromatic polyamides (PPTA and PMIA, for example, with trademarks of Kevlar® and Nomex®). The furan ring incorporated polyamide was expected to form thermal reversible cross-linked polymer network through D-A reaction.

In this paper, we consider the stochastic second-order cone complementarity problems (SSOCCP). We first formulate the SSOCCP contained expectation as an optimization problem using the so-called second-order cone complementarity function. We then use sample average approximation method and smoothing technique to obtain the approximation problems for solving this reformulation. In theory, we show that any accumulation point of the global optimal solutions or stationary points of the approximation problems are global optimal solution or stationary point of the original problem under suitable conditions. Finally, some numerical examples are given to explain that the proposed methods are feasible.

NADPH oxidases (NOXs) are a group of enzymes for superoxide anion (O2·- ) generation through transferring electrons from NADPH to molecular oxygen, which is rapidly converted into hydrogen peroxide (H2O2). There are seven members in NOX family, including NOX1 to NOX5, dual oxidase1, and dual oxidase 2. Recent studies have demonstrated that NOX subtypes may have different functions in different types of pulmonary arterial hypertension (PAH). The NOX-derived reactive oxygen species (ROS) are key factors that are involved in promoting the processes of pulmonary vascular remodeling, such as endothelial dysfunction, proliferation of pulmonary arterial smooth muscle cells (PASMCs), and cellular trans-differentiation, which are the basic pathologic characteristics of PAH. Inhibition of NOX shows beneficial effect on prevention of PAH development. Thus, NOX might be a potential target for PAH therapy. The main purpose of this review is to summarize recent findings on the role of NOX, particularly the NOX subtypes, in promotion of PAH development and to list recent progress regarding the NOX-based intervention for PAH.

This paper considers a class of stochastic second-order-cone complementarity problems (SSOCCP), which are generalizations of the noticeable stochastic complementarity problems and can be regarded as the Karush–Kuhn–Tucker conditions of some stochastic second-order-cone programming problems. Due to the existence of random variables, the SSOCCP may not have a common solution for almost every realization . In this paper, motivated by the works on stochastic complementarity problems, we present a deterministic formulation called the expected residual minimization formulation for SSOCCP. We present an approximation method based on the Monte Carlo approximation techniques and investigate some properties related to existence of solutions of the ERM formulation. Furthermore, we experiment some practical applications, which include a stochastic natural gas transmission problem and a stochastic optimal power flow problem in radial network.

The cadmium (Cd) and lead (Pb) content in both white and wholemeal flour milled from 110 leading rice cultivars was assessed. The white flour Cd content ranged from

NADPH oxidases (NOX) - derived reactive oxygen species (ROS) contribute to oxidative injury in hypoxia-induced pulmonary arterial hypertension. This study aims to evaluate the status of NOX in endothelial progenitor cells (EPCs) under hypoxic condition and to determine whether NOX inhibitors could attenuate hypoxia-induced dysfunctions of EPCs. EPCs were isolated from peripheral blood of SD rats and subjected to hypoxia (O2/N2/CO2, 1/94/5) for 24 h. The cells were collected for β-galactosidase or Hoechst staining, or for functional analysis (migration, adhesion and tube formation). The NOX expression, activity and H2O2 content in EPCs were measured. The results showed that hypoxia treatment promoted EPC senescence and apoptosis, accompanied by the deteriorated functions of EPCs (the reduced abilities in adhesion, migration and tube formation), as well as an increase in NOX2 and NOX4 expression, NOX activity and H2O2 production, these phenomena were attenuated by NOX inhibitors. Furthermore, administration of catalase could also improve the functions of hypoxia-treated EPCs. Based on these observations, we conclude that NOX-derived ROS contributes to the dysfunctions of EPCs under hypoxic condition. Thus, suppression of NOX may provide a novel strategy to improve endothelial functions in hypoxia-relevant diseases.

Mitochondrial dysfunctions contribute to brain injury in ischemic stroke while disturbance of mitochondrial dynamics results in mitochondrial dysfunction. Mitochondrial E3 ubiquitin ligase 1 (Mul1) involves in regulation of mitochondrial fission and fusion. This study aims to explore whether Mul1 contributes to brain injury in ischemic stroke and the underlying mechanisms. First, a rat ischemic stroke model was established by middle cerebral artery occlusion (MCAO), which showed ischemic injuries (increase in neurological deficit score and infarct volume) and upregulation of Mul1 in brain tissues. Next, Mul1 siRNAs were injected intracerebroventricularly to knockdown Mul1 expression, which evidently attenuated brain injuries (decrease in neurological deficit score, infarct volume and caspase-3 activity), restored mitochondrial dynamics and functions (decreases in mitochondrial fission and cytochrome c release while increase in ATP production), and restored protein levels of dynamin-related protein 1 (Drp1, a mitochondrial fission protein) and mitofusin2 (Mfn2, a mitochondrial fusion protein) through suppressing their sumoylation and ubiquitination, respectively. Finally, PC12 cells were cultured under hypoxic condition to mimic the ischemic stroke. Consistently, knockdown of Mul1 significantly reduced hypoxic injuries (decrease in apoptosis and LDH release), restored protein levels of Drp1 and Mfn2, recovered mitochondrial dynamics and functions (decreases in mitochondrial fission, mitochondrial membrane potential, reactive oxygen species production and cytochrome c release while increase in ATP production). Based on these observations, we conclude that upregulation of Mul1 contributes to brain injury in ischemic stroke rats and disturbs mitochondrial dynamics through sumoylation of Drp1 and ubiquitination of Mfn2.

Right ventricle (RV) remodeling is a major pathological feature in pulmonary arterial hypertension (PAH). Magnesium lithospermate B (MLB) is a compound isolated from the roots of Salvia miltiorrhiza and it possesses multiple pharmacological activities such as anti-inflammation and antioxidation. This study aims to investigate whether MLB is able to prevent RV remodeling in PAH and the underlying mechanisms. In vivo, SD rats were exposed to 10% O2 for 21 d to induce RV remodeling, which showed hypertrophic features (increases in the ratio of RV weight to tibia length, cellular size, and hypertrophic marker expression), accompanied by upregulation in expression of NADPH oxidases (NOX2 and NOX4) and vascular peroxidase 1 (VPO1), increases in hydrogen peroxide (H2O2) and hypochlorous acid (HOCl) production and elevation in phosphorylation levels of ERK; these changes were attenuated by treating rats with MLB. In vitro, the cultured H9c2 cells were exposed to 3% O2 for 24 h to induce hypertrophy, which showed hypertrophic features (increases in cellular size and hypertrophic marker expression). Administration of MLB or VAS2870 (a positive control for NOX inhibitor) could prevent cardiomyocyte hypertrophy concomitant with decreases in NOX (NOX2 and NOX4) and VPO1 expression, H2O2 and HOCl production, and ERK phosphorylation. Based on these observations, we conclude that MLB is able to prevent RV remodeling in hypoxic PAH rats through a mechanism involving a suppression of NOX/VPO1 pathway as well as ERK signaling pathway. MLB may possess the potential clinical value for PAH therapy.

Necroptosis is an important form of cell death following myocardial ischemia/reperfusion (I/R) and phosphoglycerate mutase 5 (PGAM5) functions as the convergent point for multiple necrosis pathways. This study aims to investigate whether inhibition of PGAM5 could reduce I/R-induced myocardial necroptosis and the underlying mechanisms.The SD rat hearts (or H9c2 cells) were subjected to 1-h ischemia (or 10-h hypoxia) plus 3-h reperfusion (or 4-h reoxygenation) to establish the I/R (or H/R) injury model. The myocardial injury was assessed by the methods of biochemistry, HE (hematoxylin and eosin), and PI/DAPI (propidium iodide/4',6-diamidino-2-phenylindole) staining, respectively. Drug interventions or gene knockdown was used to verify the role of PGAM5 in I/R (or H/R)-induced myocardial necroptosis and possible mechanisms.The I/R-treated heart showed the injuries (increase in infarct size and creatine kinase release), upregulation of PGAM5, dynamin-related protein 1 (Drp1), p-Drp1-S616, and necroptosis-relevant proteins (RIPK1/RIPK3, receptor-interacting protein kinase 1/3; MLKL, mixed lineage kinase domain-like); these phenomena were attenuated by inhibition of PGAM5 or RIPK1. In H9c2 cells, H/R treatment elevated the levels of PGAM5, RIPK1, RIPK3, MLKL, Drp1, and p-Drp1-S616 and induced mitochondrial dysfunctions (elevation in mitochondrial membrane potential and ROS level) and cellular necrosis (increase in LDH release and the ratio of PIInhibition of PGAM5 can reduce necroptosis in I/R-treated rat hearts through suppression of Drp1; there is a positive feedback between RIPK1 and PGAM5, and PGAM5 might serve as a novel therapeutic target for prevention of myocardial I/R injury.

Ichthyophthirius multifiliis, a ciliated parasite, results in “white spot disease” of freshwater fish. The outbreak of this disease causes a significant economic loss in the aquaculture industry. The present study aimed to screen the plants mixture with high antiparasitic efficacy against I. multifiliis and assess the toxicity of plants mixture to grass carp. The screening study indicated that ethanol extracts of Cynanchum atratum, Psoralea corylifolia, Zingiber officinale, Sophora flavescens, Homalomena occulta, Curcuma longa, and Morus alba showed antiparasitic efficacy against I. multifiliis. Twenty-one combinations composed of every two of the seven plants were prepared to investigate their additive, synergistic, and antagonistic effects as well as indifference using the checkerboard arrays method. Nine combinations with synergistic and additive effects were screened for the further in vitro, in vivo, and acute toxicity experiments. Finally, combination 4 (Com 4) containing C. atratum and S. flavescens showed high efficacy in treating grass carp infected with I. multifiliis. Com 4 at a concentration of 6 mg/L with a continuous usage for 10 days cured the infected grass carp. The 96 h median lethal concentration (LC50) of Com 4 to grass carp was 173.4 mg/L with a safe concentration (SC) of 47.4 mg/L. Thus, Com 4 has a low toxicity potential candidate to prevent and control I. multifiliis in grass carp.

Numerous studies demonstrate that reactive aldehydes are highly toxic and aldehyde dehydrogenase 2 (ALDH2)-mediated detoxification of reactive aldehydes is thought as an endogenous protective mechanism against reactive aldehydes-induced cell injury. This study aims to explore whether lipoic acid, a potential ALDH2 activator, is able to protect gastric mucosa from ethanol-induced injury through a mechanism involving clearance of reactive aldehydes. The rats received 60% of acidified ethanol through intragastric administration and held for 1 h to establish a mucosal injury model. Lipoic acid (10 or 30 mg/kg) or Alda-1 (a positive control, 10 mg/kg) was given 45 min before the ethanol treatment. The gastric tissues were collected for analysis of gastric ulcer index, cellular apoptosis, 4-hydroxy-2-nonenal (4-HNE) and malondialdehyde (MDA) contents, and ALDH2 activity. The results showed that acute administration of ethanol led to an increase in gastric ulcer index, cellular apoptosis, 4-HNE and MDA contents concomitant with a decrease in ALDH2 activity; these phenomena were reversed by lipoic acid or Alda-1. The gastric protection of lipoic acid was attenuated in the presence of ALDH2 inhibitor. Based on these observations, we conclude that lipoic acid exerts the beneficial effects on ethanol-induced injury through a mechanism involving, at least in part, ALDH2 activation. As a dietary supplement or a medicine already in some countries, lipoic acid can be used to treat the ethanol - induced gastric mucosal injury.

Model constructing was conducted with 3D Studio Max modeling technology for hardwood minute structure in three steps. In the first step, the single-cell models were built according to the true form and shape of various kinds of cells, including vessel elements, wood-fiber cells, longitudinal parenchyma cells and ray cells. In the second step, the single-tissue models for all the four kinds of wood tissues (vessel, wood-fiber, longitudinal parenchyma and wood ray) were constructed by setting the same kind of single-cell models together according to the cell grouping ways inside true wood. In the third step, according to the distributing and arranging ways of the four kinds of wood tissues inside true wood, the whole model of wood block in minute structure was constructed by assembling the four kind of single-tissue models in a block. After that, the virtual model in computer was materialized by means of modern 3D printing technology, and finally the solid model in minute structure of Ficus microcarpa wood was constructed.

Suppression of dimethylarginine dimethylaminohydrolase (DDAH) activation is related to endothelial dysfunction in hyperlipidemia, and nonmuscle myosin regulatory light chain (nmMLC20) has been show to exert transcriptional function in regulation of gene expression. This study aims to explore whether the suppression of DDAH activation promotes endothelial injury under the condition of hyperlipidemia and whether nmMLC20 can regulate DDAH expression in a phosphorylation-dependent manner. The rats were fed with high-fat diet for 8 weeks to establish a hyperlipidemic model, which showed an increase in plasma lipids and endothelial injury, accompanied by an elevation in myosin light chain kinase (MLCK) activity, phosphorylated nmMLC20 (p-nmMLC20) level, and asymmetric dimethylarginine (ADMA) content as well as a reduction in DDAH2 expression, DDAH activity, and nitric oxide (NO) content. Next, human umbilical vein endothelial cells (HUVECs) were incubated with oxidized low-density lipoprotein (ox-LDL; 100 μg/mL) for 24 hours to establish a cellular injury model in vitro. Consistent with the finding in vivo, ox-LDL induced HUVECs injury (apoptosis and necrosis) concomitant with an increase in MLCK activity, p-nmMLC20 level (in total or nuclear proteins), and ADMA content as well as a reduction in DDAH2 expression, DDAH activity, and NO content; these phenomena were attenuated by MLCK inhibitor. Either in hyperlipidemic rats or in ox-LDL-treated HUVECs, there was not significant change in DDAH1 expression. Based on these observations, we conclude that the suppression of DDAH2 expression might account for, at least partially, the vascular endothelial dysfunction in hyperlipidemia, and nmMLC20 plays a role in suppression of DDAH2 expression in a phosphorylation-dependent manner.

SYNOPTIC ABSTRACTIn this study, we consider stochastic generalized Nash equilibrium problems (SGNEP). They have a wide range of application and have drawn significant attention of researchers recently. First, we use the first order optimality conditions of SGNEP and the nonlinear complementary function to present an expected residual minimization (ERM) model for the case in which the involved function is not continuously differentiable. But this ERM model might have many solutions. It is not enough to find just an arbitrary solution, because other solutions could also provide reasonable outcomes of SGNEP. To this end, we introduce a restricted ERM model of SGNEP in which some additional conditions are imposed on the Lagrange multipliers for the dependent constraints. Then, we will employ a smoothing function to the restricted ERM model to deal with the noncontinuously differentiable case. We further show that the solutions of this smoothing restricted ERM converge to the true problem. Because the restrict...

We consider a stochastic non-smooth programming problem with equality, inequality and abstract constraints, which is a generalization of the problem studied by Xu and Zhang (Math Program 119:371---401, 2009) where only an abstract constraint is considered. We employ a smoothing technique to deal with the non-smoothness and use the sample average approximation techniques to cope with the mathematical expectations. Then, we investigate the convergence properties of the approximation problems. We further apply the approach to solve the stochastic mathematical programs with equilibrium constraints. In addition, we give an illustrative example in economics to show the applicability of proposed approach.

Objective Circulating microRNAs have been recognized as promising biomarkers for various diseases. The aim of the present study was to explore the potential role of circulating miR-107, miR-128b and miR-153 as non-invasive biomarkers in the diagnosis of ischemia stroke. Methods One hundred and fourteen ischemic stroke patients (61±11.3 years old) and 58 healthy volunteers (56±3.9 years old) matched for age and sex were enrolled in this study. Total RNA was isolated from plasma with TRIzol reagent. The circulating microRNAs levels were measured by quantitative real-time polymerase chain reaction. Results The circulating levels of miR-107, miR-128b and miR-153 significantly increased 2.78-, 2.13- and 1.83-fold in ischemia stroke patients in comparison to the healthy volunteers, respectively. Receiver operating characteristic (ROC) curves were analyzed using the SPSS software program and revealed the areas under the curve for circulating miR-107, miR-128b and miR-153 to be 0.97, 0.903 and 0.893 in ischemia stroke patients in comparison to healthy volunteers, respectively. The levels of circulating miR-107, miR-128b and miR-153 therefore positively correlated with the severity of stroke as defined by NIHSS classes. Conclusion Our results suggest that circulating miR-107, miR-128b and miR-153 might be used as potential novel non-invasive biomarkers for the diagnosis of ischemia stroke. However, future prospective trials in large-sized patient cohorts are needed before drawing any definitive conclusions.

NADPH oxidase (NOX)-derived reactive oxygen species (ROS) is involved in endothelial dysfunction of hyperlipidemia, and non-muscle myosin regulatory light chain (nmMLC20) is reported to have a transcriptional function in regulation of gene expression. The purposes of this study are to determine whether NOX-derived ROS can promote endothelial progenitor cell (EPC) senescence and whether nmMLC20 can regulate NOX expression through a phosphorylation-dependent manner. The rats were subjected to 8 weeks of high-fat diet feeding to establish a hyperlipidemic model, which showed an increase in plasma lipids and the accelerated senescence and reduced number of circulating EPCs, accompanied by an increase in myosin light chain kinase (MLCK) and NOX activities, p-nmMLC20 level, NOX (NOX2, NOX4) expression, and H2O2 content. Next, EPCs isolated from normal rats were incubated with ox-LDL (100 μg/mL) for 24 h to establish a senescent model in vitro. Consistent with our in vivo findings, ox-LDL treatment increased the senescence of EPCs concomitant with an increase in MLCK and NOX activities, p-nmMLC20 level (in total or nuclear proteins), NOX expression, and H2O2 content; these phenomena were reversed by MLCK inhibitor. NOX inhibitor achieved similar results to that of MLCK inhibitor except that there is no effect on MLCK activity and p-nmMLC20 level. Furthermore, knockdown of nmMLC20, NOX2, or NOX4 led to a down-regulation in NOX and a reduction in ox-LDL-induced EPC senescence. These results suggest that NOX-derived ROS promotes the senescence of circulating EPCs in hyperlipidemia and nmMLC20 may play a transcriptional role in the upregulation of NOX through a phosphorylation-dependent manner.

Micro/nanoparticles contamination is one of the key factors affecting the quality of precision manufacturing, and the traditional cleaning methods cannot function effectively. The laser plasma has high temperature and pressure, which can be used as a new and potential method to implement the removal of micro/nanoparticle, and it has become the focus of attention. This paper aims to analyze the particles removal process under the action of repetitively pulsed laser plasma, which is mainly composed of the changes in particle morphologies, the ultimate removal results, as well as the corresponding academic analysis based on the thermodynamic effects. Investigation results show that the particles removal characteristics depend heavily on the number of pulsed plasma, micrometer-size particles can be removed at the beginning, and then particles with the size about several hundred nanometers in the following stages. Analyzed from the morphological properties of particles, the refinement can be found, more specifically, the particle can be broken up into more smaller ones under the action of laser plasma with high pressure and temperature. The particles refinement will deepen the difficulty on removal efficiency, and when the particles ultimately convert into ultrasmall nanoparticles with several nanometers, which will attach to substrate presenting as flocculent aggregate, and cannot be completely wiped out.

Initiation of necroptosis has been considered as a promising strategy for anticancer therapies, especially for eradicating apoptosis-resistant malignant cells. Jujubisode B is a natural saponins extracted from the seeds of Zizyphi Spinosi Semen, and possesses multiple pharmacological activities, including antianxiety, anti-inflammation, antiplatelet aggregation and induction of apoptosis. This study aims to explore the effect of jujuboside B on acute leukemic cells and the underlying mechanisms. Our results showed that jujuboside B inhibited leukemia cell growth in a dose-dependent manner and attenuated the clonogenic ability of U937 cells, concomitant with activation of RIPK1/RIPK3/MLKL pathway; these phenomena were evidently blocked by necroptosis inhibitor (Nec-1). With the help of Molecular Operating Environment (MOE) program, we identified that RIPK1, RIPK3 and MLKL are potential targets of jujuboside B. To the best of our knowledge, this is the first study to provide evidence that jujuboside B possesses antileukemic activity via a mechanism involving activation of RIPK1/RIPK3/MLKL pathway.