Endothelial basement membranes constitute barriers to extravasating leukocytes during inflammation, a process where laminin isoforms define sites of leukocyte exit; however, how this occurs is poorly understood. In addition to a direct effect on leukocyte transmigration, we show that laminin 511 affects endothelial barrier function by stabilizing VE-cadherin at junctions and downregulating expression of CD99L2, correlating with reduced neutrophil extravasation. Binding of endothelial cells to laminin 511, but not laminin 411 or non-endothelial laminin 111, enhanced transendothelial cell electrical resistance (TEER) and inhibited neutrophil transmigration. Data suggest that endothelial adhesion to laminin 511 via β1 and β3 integrins mediates RhoA-induced VE-cadherin localization to cell-cell borders, and while CD99L2 downregulation requires integrin β1, it is RhoA-independent. Our data demonstrate that molecular information provided by basement membrane laminin 511 affects leukocyte extravasation both directly and indirectly by modulating endothelial barrier properties.

The -1237T/C polymorphism of the Toll-like receptor 9 (TLR9) gene has been implicated in the susceptibility of inflammatory bowel diseases (IBDs), but the results remain conflicting. We further investigated this association via meta-analysis.

The pandemic tendency of obesity and its strong association with serious co-morbidities have elicited interest in the underlying mechanisms of these pathologies. Lipid homeostasis, closely involved in obesity, has been reported to be regulated by multiple pathways. mTORC1 is emerging as a critical regulator of lipid metabolism. Here, we describe that the consumption of soy isoflavones, with a structural similarity to that of estradiol, could mitigate obesity through an AKT/mTORC1 pathway. Fed with soy isoflavones, the diet-induced obesity (DIO) male rats exhibited decreased body weight, accompanied with suppressed lipogenesis and adipogenesis, as well as enhanced lipolysis and β‑oxidation. The phosphorylation of AKT and S6 were decreased after soy isoflavone treatment in vivo and in vitro, suggesting an inhibition effect of soy isoflavones on mTORC1 activity. Our study reveals a potential mechanism of soy isoflavones regulating lipid homeostasis, which will be important for obesity treatment.

Under fierce market competition and the demand for low-carbon economy, cold chain logistics companies have to pay attention to customer satisfaction and carbon emissions for better development. In order to simultaneously consider cost, customer satisfaction, and carbon emissions in the cold chain logistics path optimization problem, based on the idea of cost⁻benefit, this paper proposes a comprehensive cold chain vehicle routing problem optimization model with the objective function of minimizing the cost of unit satisfied customer. For customer satisfaction, this paper uses the punctuality of delivery as the evaluation standard. For carbon emissions, this paper introduces the carbon trading mechanism to calculate carbon emissions costs. An actual case data is used with a cycle evolutionary genetic algorithm to carry out computational experiments in the model. First, the effectiveness of the algorithm and model were verified by a numerical comparison experiment. The optimization results of the model show that increasing the total cost by a small amount can greatly improve average customer satisfaction, thereby obtaining a highly cost-effective solution. Second, the impact of carbon price on total costs, carbon emissions, and average customer satisfaction have also been numerically analyzed. The experimental results show that as carbon price increases, there are two opposite trends in total costs, depending on whether carbon quota is sufficient. Increasing carbon price within a certain range can effectively reduce carbon emissions, but at the same time it will reduce average customer satisfaction to a certain extent; there is a trade-off between carbon emissions and customer satisfaction. This model enriches the optimization research of cold chain logistics distribution, and the study results complement the impact research of carbon price on carbon emissions and customer satisfaction. Finally, some practical managerial implications for enterprises and government are offered.

We conducted a systematic review and meta-analysis of observational case-control studies to evaluate markers of oxidative stress in seminal plasma of patients with male infertility.

Pain and inflammation are associated with many diseases in humans and animals. Galla Chinensis, a traditional Chinese medicine, has a variety of pharmacological properties. The purpose of this study was to evaluate analgesic and anti-inflammatory activities of Galla Chinensis through different animal models.

In this study, the optimal naphthoquinones-enriched ethanol extract from the roots of Onosma hookeri Clarke. var. longiforum Duthie (OHC-LD) was obtained under an optimal condition (69% ethanol, material to solution ratio of 27:1 at 60℃ for 59 min) by the ultrasound-assisted extraction, according to four-variable three-level Box-Behnken design-response surface methodology. The experimental yield of ethanol extract was 42.08 ± 0.65%, and the contents of naphthoquinones reached to 1.07 ± 0.004%. The optimal extract exhibited similar scavenging activity against ABTS (2,2'-azino-bis-3-ethylbenzthiazoline-6-sulfonic acid) radical as BHT(butylated hydroxytoluene) at 1,250 µg/ml, and better DPPH (2,2-diphenyl-1-picrylhydrazyl) scavenging activity than BHT at 250 µg/ml. However, the optimal ethanol extract was not sensitive to MCF-7 cell line ( IC50 of 321.849 µg/ml). The results revealed the naphthoquinones-enriched ethanol extract from the roots of OHC-LD had could be used as a potential natural antioxidant.

In our previous study, a new compound, octadecanoic acid-3, 4-tetrahydrofuran diester, possessing potent acaricidal activity was obtained from neem oil. This study performed RNA-seq transcriptomics and iTRAQ proteomics to uncover the acaricidal mechanism of the compound against Sarcoptes scabiei var. cuniculi. The results of transcriptomics indicated that after treatment with octadecanoic acid-3, 4-tetrahydrofuran diester, genes related to "Energy metabolism" were significantly up-/down-regulated, including citrate cycle, oxidative phosphorylation pathway and fatty acid metabolism. Proteomics analysis showed accordant changes of proteins related to oxidative phosphorylation pathway. The target proteins of the compound were NADH dehydrogenase, Ubiquinol-cytochrome c reductase, Cytochrome c oxidase, ATP synthase, enolase and superoxide dismutase. In transcriptomics-proteomics correlation analysis, the concordance rate between protein abundances and their corresponding mRNAs was 57%, while others (43%) were discordant changes, suggesting divergent regulating effects of octadecanoic acid-3, 4-tetrahydrofuran diester. These results suggested that the acaricidal mechanism of octadecanoic acid-3, 4-tetrahydrofuran diester attributed to interference with energy metabolism, especially oxidative phosphorylation pathway.

The high recurrence frequency of gliomas but deficiency of effective treatment and prevalent chemoresistance have elicited interests in exploring and developing new agents. Paris polyphyllins are monomers extracted from rhizome of Paris polyphylla var. yunnanensis. Here, we first reported that polyphyllin VII (PP7) exhibited cytotoxic effect on glioma cells. PP7 significantly suppressed the viability and induced cell death of U87-MG and U251 cells after 24 h, with the IC50 values 4.24 ± 0.87 μM and 2.17 ± 0.14 μM, respectively. Both apoptotic and autophagic processes were involved in the cytotoxic effect of PP7, as PP7 activated the Bcl2/Bax pathway and the inhibition of autophagy partly rescued the toxicity of PP7 in glioma cells. In addition, an inhibition of AKT/mTORC1 activity was found after PP7 administration, and it seemed that the overproduction of reactive oxygen species (ROS) was responsible for this effect. Namely, the removal of ROS by NAC treatment mitigated PP7-induced cell death, autophagy, and its effect on the AKT/mTORC1 signaling. Additionally, a combination assay of PP7 with temozolomide (TMZ), the most used chemotherapy for glioma patients, was performed resulting in synergism, while PP7 reduced TMZ resistance through inhibition of MGMT expression. Thus, our study reports PP7 as a potential agent for glioma treatment and reveals its underlying mechanisms of action.

Obesity is a common metabolic disorder that increases the risk of many diseases, such as type II diabetes, hypertension, cardiovascular disease. Hypothalamus plays a very important role in the progression of obesity, and many studies reveal that hypothalamic injures are implicated in obesity processes. Here, we describe that the consumption of soy isoflavones, with a structural similarity to that of estradiol, could mitigate obesity through improving the hypothalamic inflammation and apoptosis, which are induced by oxidative stress. Also, our in vitro studies demonstrate that daidzein and genistein, common ingredients of soy isoflavones, could protect hypothalamic N42 cells against palmitic acid induced oxidative stress and apoptosis. Moreover, the transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator 1 alpha (PGC1-alpha), which plays a role in oxidative defense, is increased after soy isoflavone treatment in vivo and in vitro, suggesting an improved effect of soy isoflavones on hypothalamic antioxidant defense is mediated by PGC-1α. Our study reveals a potential mechanism of soy isoflavones regulating oxidative stress induced hypothalamic inflammation and cellular apoptosis, which will be important for obesity treatment.

Resveratrol (Res) is a natural compound that possesses anti-inflammatory properties. However, the protective molecular mechanisms of Res against lipopolysaccharide (LPS)-induced inflammation have not been fully studied. In the present study, RAW264.7 cells were stimulated with LPS in the presence or absence of Res, and the subsequent modifications to the LPS-induced signaling pathways caused by Res treatment were examined. It was identified that Res decreased the mRNA levels of Toll-like receptor 4 (TLR4), myeloid differentiation primary response protein MyD88, TIR domain-containing adapter molecule 2, which suggested that Res may inhibit the activation of the TLR4 signaling pathway. It suppressed the expression levels of total and phosphorylated TLR4, NF-κB inhibitor, p38 mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase, extracellular signal-regulated kinase 1/2 and interferon (IFN) regulatory factor 3 (IRF3) proteins. Following treatment with Res or specific inhibitors, the production of pro-inflammatory mediators including tumor necrosis factor-α, interleukin (IL)-6, IL-8 and IFN-β were decreased and the expression of anti-inflammatory mediator IL-10 was increased. These results suggested that Res may inhibit the signaling cascades of NF-κB, MAPKs and IRF3, which modulate pro-inflammatory cytokines. In conclusion, Res exhibited a therapeutic effect on LPS-induced inflammation through suppression of the TLR4-NF-κB/MAPKs/IRF3 signaling cascades.

Inhibiting RhoA-subfamily GTPases by C3 transferase is widely recognized as a prospective strategy to enhance axonal regeneration. When C3 transferase is administered for treating the injured peripheral nerves, Schwann cells (SCs, important glial cells in peripheral nerve) are inevitably impacted and therefore SC bioeffects on nerve regeneration might be influenced. However, the potential role of C3 transferase on SCs remains elusive. Assessed by cell counting, EdU and water-soluble tetrazolium salt-1 (WST-1) assays as well as western blotting with PCNA antibody, herein we first found that CT04 (a cell permeable C3 transferase) treatment could significantly suppress SC proliferation. Unexpectedly, using Y27632 to inhibit ROCK (the well-accepted downstream signal molecule of RhoA subfamily) did not impact SC proliferation. Further studies indicated that CT04 could inactivate AKT pathway by altering the expression levels of phosphorylated AKT (p-AKT), PI3K and PTEN, while activating AKT pathway by IGF-1 or SC79 could reverse the inhibitory effect of CT04 on SC proliferation. Based on present data, we concluded that inhibition of RhoA-subfamily GTPases could suppress SC proliferation, and this effect is independent of conventional ROCK pathway but involves inactivation of AKT pathway.

To investigate the association between gamma-glutamyl transferase (GGT) and type 2 diabetes mellitus (T2DM) risk.

Wallerian degeneration, the progressive disintegration of distal axons and myelin that occurs after peripheral nerve injury, is essential for creating a permissive microenvironment for nerve regeneration, and involves cytoskeletal reconstruction. However, it is unclear whether microtubule dynamics play a role in this process. To address this, we treated cultured sciatic nerve explants, an in vitro model of Wallerian degeneration, with the microtubule-targeting agents paclitaxel and nocodazole. We found that paclitaxel-induced microtubule stabilization promoted axon and myelin degeneration and Schwann cell dedifferentiation, whereas nocodazole-induced microtubule destabilization inhibited these processes. Evaluation of an in vivo model of peripheral nerve injury showed that treatment with paclitaxel or nocodazole accelerated or attenuated axonal regeneration, as well as functional recovery of nerve conduction and target muscle and motor behavior, respectively. These results suggest that microtubule dynamics participate in peripheral nerve regeneration after injury by affecting Wallerian degeneration. This study was approved by the Animal Care and Use Committee of Southern Medical University, China (approval No. SMU-L2015081) on October 15, 2015.

Despite the multiple diagnostic and therapeutic strategies implemented in clinical practice, the mortality rate of patients with pulmonary arterial hypertension (PAH) remains high. Understanding the mechanisms and key genes involved could provide insight into the drivers of the pathogenesis of PAH. In this research, we aimed to examine the mechanisms underlying PAH and identify key genes with potential usefulness as clinical biomarkers of PAH and thereby establish therapeutic targets for PAH. The datasets GSE117261, GSE113439, and GSE53408 were downloaded from the Gene Expression Omnibus (GEOs) database. We used weighted gene coexpression network analysis (WGCNA) to identify networks and the most relevant modules in PAH. Functional enrichment analysis was performed for the selected clinically relevant modules. The least absolute shrinkage and selection operator (LASSO) was applied to identify key genes in lung samples from patients with PAH. The genes were validated in a monocrotaline-induced PAH rat model. Three clinically relevant modules were identified through average linkage hierarchical clustering. The genes in the clinically relevant modules were related to endothelial cell differentiation, inflammation, and autoimmunity. Seven genes were screened as key genes significantly associated with PAH. Interferon-induced protein 44-like (IFI44L) and signal transducer and activator of transcription 1 (STAT1) were expressed at higher levels in the lung tissues of the PAH rat model than in those of the controls. Our findings reveal the novel pathological mechanisms underlying PAH and indicate that STAT1 and IFI44L may represent potential therapeutic targets in PAH.

Brassica oleracea displays remarkable morphological variations. It intrigued researchers to study the underlying cause of the enormous diversification of this organism. However, genomic variations in complex heading traits are less known in B. oleracea. Herein, we performed a comparative population genomics analysis to explore structural variations (SVs) responsible for heading trait formation in B. oleracea. Synteny analysis showed that chromosomes C1 and C2 of B. oleracea (CC) shared strong collinearity with A01 and A02 of B. rapa (AA), respectively. Two historical events, whole genome triplication (WGT) of Brassica species and differentiation time between AA and CC genomes, were observed clearly by phylogenetic and Ks analysis. By comparing heading and non-heading populations of B. oleracea genomes, we found extensive SVs during the diversification of the B. oleracea genome. We identified 1205 SVs that have an impact on 545 genes and might be associated with the heading trait of cabbage. Overlapping the genes affected by SVs and the differentially expressed genes identified by RNA-seq analysis, we identified six vital candidate genes that may be related to heading trait formation in cabbage. Further, qRT-PCR experiments also verified that six genes were differentially expressed between heading leaves and non-heading leaves, respectively. Collectively, we used available genomes to conduct a comparison population genome analysis and identify candidate genes for the heading trait of cabbage, which provides insight into the underlying reason for heading trait formation in B. oleracea.

Our previous results showed that icariin (ICA) could inhibit apoptosis and provide neuroprotection against hypoxic-ischemic brain damage (HIBD) in neonatal mice, but the specific mechanism of its neuroprotective effect remains unknown. This study aims at exploring whether ICA plays a neuroprotective role in apoptosis inhibition by regulating autophagy through the estrogen receptor α (ERα)/estrogen receptor β (ERβ) pathway in neonatal mice with HIBD.

Haemophilus parasuis, a symbiotic bacteria of upper respiratory tract of swine, is the etiological agent of Glässer's disease, which is characterized by fibrinous polyserositis. Emodin, exhibits antibacterial activity against H. parasuis, yet the action mode has not been fully understood. In present study, isobaric tag for relative and absolute quantification (iTRAQ) method was applied to analyze the global protein alteration of H. parasuis in response to 16μg/mL Emodin. In total, 338 proteins exhibiting significant differential expressions were identified. It was speculated that, through application of bioinformatics analysis to theses differentially expressed proteins, Emodin mainly inhibited some key proteins expression of ABC transport system, carbohydrate metabolism pathway and bacterial cell division by inhibiting the ribosome synthesis, resulting in the growth inhibition of H. parasuis. Remarkably, nine virulence-associated proteins were detected differently expressed, further experiments revealed that after treatment with Emodin, H. parasuis could be inhibited to adhere to and invade into porcine kidney epithelial cells (PK-15 line) and exhibited increased sensitivity to serum complement in a concentration-dependent manner. Phagocytosis assay showed Emodin also could enhance phagocytic activity of porcine alveolar macrophages PAM to H. parasuis. These results indicated that Emodin also can attenuate virulence of H. parasuis and reduce infection.

Accumulating evidences suggest that peripheral nerve injury (PNI) may initiate astrocytic responses in the central nervous system (CNS). However, the response of astrocytes in the spinal ventral horn and its potential role in nerve regeneration after PNI remain unclear. Herein, we firstly illustrated that astrocytes in the spinal ventral horn were dramatically activated in the early stage following sciatic nerve injury, and these profiles were eliminated in the chronic stage. Additionally, we found that the expression of neurotrophins, including brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and neurotrophin-3 (NT-3), also accompanied with astrocyte activation. In comparison with the irreversible transected subjects, astrocyte activation and the neurotrophic upregulation in the early stage were more drastic in case the transected nerve was rebridged immediately after injury. Furthermore, administering fluorocitrate to inhibit astrocyte activation resulted in decreased neurotrophin expression in the spinal ventral horn and delayed axonal regeneration in the nerve as well as motor function recovery. Overall, the present study indicates that peripheral nerve injury can initiate astrocyte activation accompanied with neurotrophin upregulation in the spinal ventral horn. The above responses mainly occur in the early stage of PNI and may contribute to nerve regeneration and motor function recovery.

Sijunzi Decoction (SJZD) is a formula used for the treatment of spleen deficiency and gastrointestinal diseases in Traditional Chinese Medicine. Polysaccharides are reported to be the main components of SJZD responsible for its bio-functions. However, highly purified and clearly characterized polysaccharides from SJZD are not well described. Here we obtained a purified polysaccharide (SJZDP-II-I) from SJZD using ion exchange chromatography and gel filtration. Structure analysis by FT-IR and NMR identified SJZDP-II-I as a typical pectic polysaccharide with homogalacturonan and rhamnogalacturonan type I regions and arabinogalactan type I and II as side chains. In vitro studies indicated that SJZDP-II-I treatment could significantly enhance the total antioxidant capacity of SW480 cells, resulting from the promoted expressions of antioxidant enzymes and their master regulator PGC-1α, which would be valuable for further research and applications.