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Human relaxin-2 reduces hepatic fibrosis in mice. However, the effects of relaxin-2 on hepatic steatosis and fibrosis in animals with non-alcoholic fatty liver disease (NAFLD) remain to be elucidated. C57BL/6 mice fed a high-fat diet (HFD) or methionine-choline-deficient (MCD) diet were randomly assigned to receive recombinant human relaxin-2 (25 or 75 μg/kg/day) or vehicle for 4 weeks. In HFD-fed mice, relaxin-2 decreased systemic insulin resistance and reduced body weight, epididymal fat mass and serum leptin and insulin concentrations. In livers of HFD-fed mice, relaxin-2 attenuated steatosis and increased phosphorylation of insulin receptor substrate-1, Akt and endothelial nitric oxide synthase (eNOS), and activated genes that regulate fatty acid oxidation and suppressed acetyl-CoA carboxylase. Relaxin-2 had no direct anti-steatotic effect on primary mouse hepatocytes, but S-nitroso-N-acetylpenicillamine attenuated palmitic acid-induced steatosis and activated genes regulating fatty acid oxidation in hepatocytes. In mice fed an MCD diet, relaxin-2 attenuated steatosis, inflammation and fibrosis. Relaxin-2 increased eNOS and Akt phosphorylation and transcript levels of cytochrome P450-4a10 and decreased acetyl-CoA carboxylase in MCD-fed mouse livers. Moreover, expression levels of Kupffer cell activation, hepatic stellate cell activation and hepatocyte apoptosis were decreased in MCD diet-fed mice receiving relaxin-2. In conclusion, relaxin-2 reduces hepatic steatosis by activating intrahepatic eNOS in HFD-fed mice and further attenuates liver fibrosis in MCD diet-fed mice. Therefore, human relaxin-2 is a potential therapeutic treatment for NAFLD.

Background/aims: To investigate the prevalence of abnormal central and peripheral ultra-wide-field (UWF) angiography findings, and their association with clinical features in acute Vogt-Koyanagi-Harada (VKH) disease., Methods: This retrospective, observational study included 26 eyes of 13 treatment-naïve patients with acute VKH disease who underwent UWF fluorescein angiography (FA). Sixteen eyes of eight patients also underwent UWF indocyanine green angiography (ICGA). A circle simulating the central 75° field was used to divide the acquired image into the central fundus area (CFA) and peripheral fundus area (PFA), in which the presence of six previously reported abnormal angiographic findings were analysed. Correlations between abnormal angiography findings in FA and clinical features were also investigated., Results: All eyes demonstrated more than one abnormal angiographic finding in both the CFA and PFA. UWF FA revealed three abnormal findings in the CFA versus the PFA: focal leakage (92.3% vs 76.9%); pooling with a dark rim (84.6% vs 53.8%); and retinal vascular leakage (0% vs 46.2%). UWF ICGA revealed three abnormal findings in the CFA versus the PFA: hypofluorescent dark dots (100% vs 100%); diffusely leaking fuzzy choroidal vessels (93.8% vs 75.0%); and late hypofluorescent patches (81.3% vs 31.3%). Pooling with a dark rim and retinal vascular leakage in the PFA were significantly associated with low initial visual acuity (p=0.03) and subfoveal choroidal thickness change ratio (p=0.04), respectively., Conclusion: Abnormal UWF angiography findings were frequently detected in the CFA and PFA. Such findings may be useful in evaluation and monitoring of VKH disease., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

To evaluate the impact of DCAcAm on zebrafish gill, we measure the responses of antioxidant enzyme (superoxide dismutase, SOD), lipid peroxidation (malondialdehyde, MDA), ATPase (Na + /K + -ATPase and Ca 2+ /Mg 2+ -ATP) and histopathological changes of gill in adult zebrafish, after exposed to different concentrations of DCAcAm (0, 1, 10, 100, and 1000 μg L -1 ) for 30 days. Results indicated that DCAcAm first increased and then decreased SOD activity, and DCAcAm also lowered the activities of Na + /K + -ATPase and Ca 2+ /Mg 2+ -ATPase. These results indicated that high affinity of DCAcAm probably be a main factor, which can damage the structures of enzymes, thereby inhibiting the SOD and ATPase activities. Besides, histopathological investigation results also manifested that chronic exposure to DCAcAm can damage the gill tissues, disrupting the normal function of gills. We conclude that chronic exposure to DCAcAm was harmful to organisms, not only influence gill function, but also further cause damage on the gill tissues., (© 2019 Wiley Periodicals, Inc.)

The relation between visual working memory (VWM) capacity and attention has attracted much interest. In this study, we investigated the correlation between the participants' VWM capacity and their ability to voluntarily trade off the precision and number of items remembered. The two-phase resource allocation model proposed by Ye et al. (2017) suggests that for a given set size, it takes a certain amount of consolidation time for an individual to control attention to adjust the VWM resources to trade off the precision and number. To verify whether trade-off ability varies across VWM capacity, we measured each individual's VWM capacity and then conducted a colour recall task to examine their trade-off ability. By manipulating the task requirement, participants were instructed to memorise either more colours in a low-precision way or fewer colours in a high-precision way. We conducted two experiments by adjusting stimulus duration to be longer than predicted critical value (Experiment 1) and duration shorter than predicted critical value (Experiment 2). While the results of Experiment 1 showed a positive correlation between the VWM capacity and trade-off ability, the results of Experiment 2 showed a lack of such correlation. These results are consistent with the prediction from the two-phase model.

With the rapid development of global perinatal medicine and neonatal medicine, the survival rate of high-risk neonates (premature, and those who suffer neurologic lesion during or shortly after birth, et al.) improved significantly, however the incidence of cerebral visual impairment (CVI) also rose, which has become the most common cause of visual impairment in children in developed countries. Studies found that visual abnormalities of patients with CVI can be various. Since children's cognition and motor development are inseparable from visual functions, children with CVI are usually characterized by abnormalities in sensory perception, cognition and even movement, other than visual impairment itself. Due to the characteristics of CVI, such as early onset, complex etiology, difficulty in diagnosis and treatment, and involvement with ophthalmology, pediatrics, rehabilitation medicine, genetic epidemiology and other multi-disciplinary content, current domestic research on CVI is limited. From the perspective of ophthalmologist, this paper reviews the progress of ophthalmology diagnosis and treatment in children with CVI in recent years, aiming to have better early recognition and individualized intervention, so as to help pediatrician and rehabilitation physicians to improve survival skills for CVI children and their quality of life. (Chin J Ophthalmol, 2019, 55:469-474) .

Vascular calcification (VC) is a critical feature of chronic kidney disease (CKD), diabetes, hypertension, and atherosclerosis. Death-associated protein kinase 3 (DAPK3) is involved in vascular remodeling in hypertension. However, it remains to be clarified whether DAPK3 controls vascular smooth muscle cell (VSMC) phenotypic transition into an osteogenic cell phenotype, which is an important process for VC. In vivo VC was induced in rats by vitamin D3 and nicotine. VSMCs were incubated with calcifying media containing β-glycerophosphate and Ca 2+ to induce VC in vitro. Herein, we demonstrated increased expression of DAPK3 in the aortas of VC rats and VSMCs cultured in calcifying media. Knockdown of DAPK3 significantly inhibited calcifying media-induced VSMC mineralization and retarded the phenotypic transformation of VSMCs into osteogenic cells. Silencing of DAPK3 suppressed endoplasmic reticulum stress (ERS) related protein expressions, but upregulated the phosphorylation level of AMP-activated protein kinase (AMPK) in calcified VSMCs. Moreover, pretreatment with AMPK inhibitor Compound C abolished DAPK3 shRNA-mediated inhibition of ERS in VSMCs. In vivo, DAPK inhibitor significantly prevented calcium deposition in the aortas of VC rats. The present results revealed that DAPK3 modulated VSMC calcification through AMPK-mediated ERS signaling., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Bell peppers are valued for their plentiful vitamin C and nutritional content. Pepper fruits are susceptible to cold storage, which leads to chilling injury (CI); however, the crucial metabolic product and molecular basis response to cold stress have not been elucidated definitely yet. To comprehensively understand the gene regulation network and CI mechanisms in response to cold stress on a molecular level, we performed high-throughput RNA-Seq analysis to investigate genome-wide expression profiles in bell peppers at different storage temperatures (4 °C and 10 °C). A total of 61.55 Gb of clean data were produced; 3863 differentially expressed genes (DEGs) including 1669 up-regulated and 2194 down-regulated were annotated and classified between the CI group and control. Together, a total of 41 cold-induced transcription factor families comprising 250 transcription factors (TFs) were identified. Notably, numerous DEGs involved in biomembrane stability, dehydration and osmoregulation, and plant hormone signal transduction processes were discovered. The transcriptional level of 20 DEGs was verified by reverse transcription quantitative polymerase chain reaction (RT-qPCR). Our results present transcriptome profiles of bell peppers in response to cold stress; the data obtained may be useful for the identification of key candidate genes and elucidation of the mechanisms underlying membrane damage during chilling injury., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

An important question in neural correlate of consciousness (NCC) studies is whether event-related potential (ERP) component P3 reflects visual awareness or the confidence with which one reports a visual experience. In the present study, participants detected visual stimuli presented at threshold-level contrast, then rated their subjective confidence with respect to their response on a four-point scale (very confident, quite confident, slightly confident, and not confident at all). Because awareness responses in trials with rating of "not confident at all" were likely noise, we analyzed the data excluding those trials. The ERP results revealed a significant positive difference in P3 amplitude between "aware" and "unaware" trials. P3 amplitude was more positive in aware trials compared to unaware trials. Importantly, this pattern was observed for trials with combined confidence ratings of "very confident" and "quite confident," and for trials with confidence ratings of "slightly confident," suggesting that awareness alone can modulate P3. A significant interaction between awareness and confidence is reported, suggesting that confidence influences P3 as well. In addition, ERP results revealed that visual awareness negativity (VAN) was observed over posterior temporal and occipital electrodes and largely not influenced by confidence. This result indicated that VAN is an early neural correlate of visual awareness.

Inhibition of Return (IOR) refers to an individual's slowed localization or discrimination performance for targets that appear in previously cued versus uncued location after a relatively long delay after cue (∼300-500 ms). The current study adopted a cue-target paradigm and used behavioral and event-related potential (ERP) measures to investigate whether IOR would be modulated by emotional faces during an emotion recognition task. For reaction time measure, we found IOR effect and the magnitude of IOR effect were comparable for fearful face target and neutral face target. For ERP measures, valid cues were associated with smaller P1 and larger N1 waveform than that for invalid cues. Fearful faces were associated with a larger N170 than neutral faces. The onset latency of the stimulus-locked lateralised readiness potential (LRP) in the valid cue condition was longer than that in the invalid cue condition, while there was no significant difference on the onset latency of the response-locked LRP between the valid cue and invalid cue condition. These results support the notion that, regardless the emotion component of the stimulus, the inhibitory bias of attention to previous visited location before response contributes to the IOR.

With the strength of liquid nuclear magnetic resonance (NMR) to noninvasively and specifically realize the structural elucidation and quantitative analysis of small organic molecules, in principle, liquid in situ electrochemical-NMR (EC-NMR) possesses great advantages for detecting dissolved species during the electrochemical process. However, the intrinsic incompatibilities between the coupling techniques as well as the sophisticated setups modification still limit the applications toward a wide range. To overcome these bottlenecks, herein we propose an easy-to-construct design with good compatibility and presenting improved electrochemical and NMR performances. As proof of concept, model experiments of alcohol electrooxidation were performed to confirm the capacity of this device for liquid in situ EC-NMR study. The temporal evolution of both the product and the current distributions can be reliably recorded to aid mechanistic and kinetic understanding of electrocatalysis. The depiction of the selective electrooxidation reveals the surface structure-catalytic functionality. This work demonstrates the universality and effectivity of the proposed platform to develop the liquid in situ EC-NMR technique as a useful tool for the dynamic analysis of electrochemical processes at a molecular level.

Catalpol is an iridoid glycoside extracted from the root of Rehmannia glutinosa. It has been reported to have antioxidant stress effects. Adenosine 5' monophosphate-activated protein kinase( AMPK) plays an important role in inhibiting oxidative stress. This study was designed to investigate the protective effects of catalpol on TNF-α-exposed human aorta epithelial cells( HAECs) via inhibit oxidative stress,and the relationship between catalpol and AMPK was detected by RNA interference technique. Levels of superoxide dismutase( SOD),malonaldehyde( MDA),glutathione( GSH) and lactate dehydrogenase( LDH) were measured with a colorimetric assay kit. The level of ROS was measured with FACS calibur. Western blot was employed to detect the protein expression of AMPK,phosphorylated-AMPK and NOX4. Finally,RNA interference technique was used to investigate the role of AMPK in catalpol-induced protective effects. TNF-α treatment decreased the expression of phosphorylated-AMPK protein level,however,catalpol could reverse the decreased phosphorylated-AMPK level. Catalpol could inhibit NOX4 protein expression and decrease ROS overproduction. After using AMPK siRNA that effects of catalpol on ROS overproduction and NOX4 protein expression inhibition were attenuated. The above results suggest that catalpol inhibits oxidative stress in TNF-α-exposed HAECs by activating AMPK.

Uncontrolled proliferation and defective apoptosis are two major factors responsible for maintaining the malignant properties of melanoma cells. Our previous study demonstrated that induced expression of four reprogramming factors remodeled the phenotype of B16‑F10 mouse melanoma cells into melanoma stem cells. The present study was conducted to investigate the effect of the four Yamanaka reprogramming factors, namely Oct4, Sox2, Klf4 and c‑Myc (OSKM), on the proliferation and apoptosis of melanoma cells, and to identify the responsible molecular signals. The results identified that expression of the four reprogramming factors was highly induced by doxycycline treatment in the stable melanoma cell clone that was transfected with a plasmid expressing these factors, driven by the Tet‑On element. It was further confirmed that induced expression of these factors enhanced the proliferation and suppressed the apoptosis of the melanoma cells. In addition, induced OSKM expression increased cell proliferation, accelerated the progression of the cell cycle, and upregulated the mRNA expression levels of Janus kinase 2 (JAK2) and Cyclin‑B1. Induced expression of these factors also decreased the apoptosis, as well as upregulated B‑cell lymphoma 2 (BCL‑2) and downregulated BCL‑2‑associated X (BAX) mRNA expression levels. Taken together, the results suggested that upregulated JAK2 and Cyclin‑B1 may be responsible for the enhanced proliferation of melanoma cells, and that BCL‑2 upregulation and BAX downregulation may account for the suppressed apoptosis of these cells.

2,6-dichlorobenzoquinone (2,6-DCBQ), an emerging disinfection by-production, frequently occurs in reclaimed water and drinking water. However, limited information was available regarding its toxicity. To evaluate its impact, zebrafish at early life stage were exposed to 0, 10, 30, 60, 90, or 120 μg L -1 2,6-BDCQ for 72 h. Our results indicated that 2,6-BDCQ decreased zebrafish's survival rate to 65% and 44% at 90 and 120 μg L -1 treatments and increased its aberration rate to 11% and 26% at 90 μg L -1 and 120 μg L -1 treatments. Besides, 2,6-BDCQ had adverse effect on its oxidative stress (elevated superoxide dismutase activity), lipid peroxidation (increased malondialdehyde levels), DNA damage (increased 8-hydroxydeoxyguanosine contents) and apoptosis (increased caspase-3 activity). Although lower concentrations (≤60 μg L -1 ) of 2,6-BDCQ didn't exhibit significant effect on its survival development or lipid peroxidation of zebrafish, they induced obvious DNA damage and apoptosis occurrence. These results revealed 2,6-BDCQ caused genotoxicity and cytotoxicity to zebrafish. This study provides novel insight into 2,6-DCBQ-induced toxicity in zebrafish., (Copyright © 2018. Published by Elsevier Ltd.)

Neuroinflammation has been well recognized as a key pathological event in acute glaucoma. The medical therapy of acute glaucoma mainly focuses on lowering intraocular pressure (IOP), while there are still scarce anti-inflammatory agents in the clinical treatment of acute glaucoma. Here we reported that β,3α,5α-trihydroxy-androst-6-one (sterone), a novel synthetic polyhydric steroid, blocked neuroinflammation mediated by microglia/macrophages and alleviated the loss of retinal ganglion cells (RGCs) caused by acute intraocular hypertension (AIH). The results showed that sterone significantly inhibited the morphological changes, the up-regulation of inflammatory biomarker ionized calcium-binding adapter molecule 1 (Iba-1), and the mRNA increase of proinflammatory tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) induced by lipopolysaccharide (LPS) in BV2 microglia and RAW264.7 macrophages. Moreover, immunofluorescence and western blotting analysis revealed that sterone markedly abrogated the nuclear translocation and phosphorylation of nuclear factor-κB (NF-κB) p65 subunit. Furthermore, sterone significantly suppressed the inflammatory microglial activation and RGCs' reduction caused by retinal ischemia/reperfusion (I/R) injury in a rat AIH model. These results suggest sterone may be a potential candidate in the treatment of acute glaucoma caused by microglial activation-mediated neuroinflammatory injury.

Arterial hypertension remains to be a serious problem with considerable morbidity and mortality worldwide in the present age. Hypertension is a major risk factor for cardiovascular diseases such as stroke, myocardial infarction, renal failure, and heart failure. Hypertensive nephropathy is the second leading cause of death in chronic kidney disease (CKD) around the world. Long-time hypertension loading results in renal interstitial fibrosis, which is associated with aberrant activation of renal fibroblasts and excessive generation of extracellular matrix (ECM) proteins. Increasing evidence supported that proteinuria, tubular hypertrophy, oxidative stress, activation of renin-aldosterone-angiotensin system (RAAS), collagen turnover, chronic inflammation, and vasoactive substances synergistically contributed to the pathogenesis of hypertensive renal fibrosis. However, the mechanisms involving the pathogenesis of hypertensive renal fibrosis are complex and not fully understood. Also, the effective clinical therapy to halt or even reverse renal fibrosis in hypertension is still limited. In this chapter, we aimed to provide an overview of the main pathophysiologic and mechanistic features of renal fibrosis under hypertensive state. The completion of the studies in these directions would improve our understanding of renal fibrosis in hypertension and also help us better screen treatment strategies for preventing renal destruction associated with hypertension.

Purpose: Thyroid-stimulating hormone (TSH) suppression is widely used to treat well-differentiated thyroid cancer, whereas its role in poorly differentiated thyroid cancer (PDTC) is undetermined. Besides thyrocytes, TSH also binds to stromal cells, comprising tumor microenvironments. This study aimed to investigate the effects of TSH on tumor microenvironments in PDTC., Experimental Design: An ectopic tumor model using PDTC cells (BHP10-3SCp and FRO), which exhibit TSH/cAMP-independent cell growth, was treated with TSH. IHC was performed using tissue microarrays from 13 PDTCs., Results: TSH treatment significantly enhanced tumor growth of PDTCs with increased vascularity but not that of breast cancer cells, suggesting this effect is unique to thyroid cancer cells, not stromal cells. TSH significantly upregulated VEGF-A and CXCL8 expressions in BHP10-3SCp cells via AKT and ERK signaling, resulting in higher concentrations of VEGF-A and CXCL8 in conditioned medium of TSH-treated BHP10-3SCp cells (TSH-CM) compared with controls. TSH-CM treatment enhanced tube formation potentials of endothelial cells, and blocking VEGF and/or CXCL8 reduced them. Blocking VEGF and/or CXCL8 also reduced TSH-dependent tumor growth with reduced tumor vasculature in vivo . TSH-treated tumors showed increased macrophage densities, and macrophage inhibition reduced TSH-dependent tumor growth in vivo . In human PDTCs, preoperative TSH levels were positively associated with VEGF-A and tumor size, and the expression of VEGF-A was positively correlated with CD31, CD163, and CXCL8, and their clinical poor prognosis., Conclusions: Aberrant TSH receptor signaling modulates tumor angiogenesis by stimulating VEGF-A and CXCL8 secretion from PDTC cells and enhances tumor growth; thus, TSH suppression is beneficial for treating PDTCs., (©2018 American Association for Cancer Research.)

Objective: To observe the effect of proximal humerus internal locking system (PHILOS) plate in the treatment of Neer 2 and 3 part fractures of proximal humerus through tuberosity approach., Methods: From July 2015 to January 2018, 15 cases of proximal humerus Neer 2 and 3 fractures were treated with PHILOS plate through intertubercular sulcus approach. There were 7 males and 8 females. The age ranged from 23 to 67 years old, with an average of 46 years old. There were 5 cases on the left side and 10 cases on the right side (including 7 cases of Neer 2 partial fracture and 8 cases of Neer 3 partial fracture). X-ray films and CT were taken before and after operation to assess fracture location and fracture healing. Clinical evaluation included Constant-Murley shoulder function score and operative complications. All 15 patients were treated with the PHILOS. Constant-Murley score was used to evaluate shoulder function after operation., Results: All the 15 cases were followed up, and the duration ranged from 14 to 36 months. All the fractures healed and the healing time ranged from 14 to 26 weeks, averaged 19.1 weeks. There were no complications such as humeral head necrosis, axillary nerve injury and fracture nonunion after operation. At the 3rd month after operation, the shoulder function score of Constant-Murley ranged from 72 to 94 points, with an average of 81 points; 2 cases got an excellent result and 13 good., Conclusions: The PHILOS plate for the treatment of proximal humerus fractures has the advantages of simple operation, small injury and quick recovery of shoulder joint function., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© 2018 by the China Journal of Orthopaedics and Traumatology Press.)

Objective: To apply Nutritional Risk Screening-2002(NRS-2002) to perform nutritional status score for the patients with thoracic esophageal squamous cell carcinoma (ESCC) receiving surgery, and to explore the prognostic impact of long-term survival. Methods: A total of 117 patients who were diagnosed with ESCC from 2010 to 2012 were retrospectively analyzed. They recieved standard curative esophagectomy in the Yangzhou University Affiliated Taixing People's Hospital. The nutritional status and risk score for recruited patients were assessed according to the standard of NRS-2002 tool prior to surgery, and these patients were grouped for further analysis according to the median values of NRS-2002 score. Finally, the relationship between NRS-2002 score and prognosis was analyzed. Results: Patients were classified into two groups, with 45 in the NRS-2002<2.0 group, and 72 cases in the NRS-2002≥2.0, respectively. In the NRS-2002<2.0 group, the 1-, 3-, and 5-year progression-free survival (PFS) rates were 75.6%, 44.4% and 40.0% separately, while in the NRS-2002≥2.0 group, the PFS rates were 61.1%, 6.9% and 4.2% respectively, and the differences were statistically significant ( P <0.001). Correspondingly, in the NRS-2002< 2.0 group, the 1-, 3-, and 5-year overall survival (OS) rates were 97.8%, 66.7% and 57.8% separately, while in the NRS-2002≥2.0 group, the OS rates were 91.7%, 33.3% and 16.7% respectively, and the differences were also statistically significant ( P <0.001). Univariate analysis showed that N stage, TNM stage and NRS-2002 score were closely related to PFS and OS ( P <0.05), and T stage was only associated with OS in patients with thoracic esophageal squamous cell carcinoma ( P <0.05). Furthermore, multivariate Cox regression analysis showed that N stage ( RR =1.640, 95% CI 1.049-2.565, P =0.030) and NRS-2002 ( RR =3.154, 95% CI 1.946-5.113, P <0.001) were independent prognostic factors for PFS in patients with ESCC after surgery. Additionally, pathological differentiation ( RR =1.556, 95% CI 1.004-2.440, P =0.041), N stage ( RR =1.624, 95% CI 1.017-2.593, P =0.042) and NRS-2002 ( RR =3.906, 95% CI 2.245-6.795, P <0.001) were independent prognostic factors for OS in ESCC patients following surgery. Conclusion: Preoperative nutritional risk screening NRS-2002 score is an independent prognostic factor in patients with ESCC receiving surgery and could be used as a tool for primary screening for nutritional risk.

Objective: To observe the effect of electroacupuncture (EA)on mechanical pain transition and content of protein kinase C epsilon(PKCε)in dorsal root ganglia (DRG) in inflammatory articular pain rats，so as to explore its peripheral mechanism underlying relieving transition from acute to chronic pain., Methods: 1)In the first part of the present study，male SD rats were equally randomized into blank control，sham hyperalgesic priming(HP), and real HP groups( n ＝6 in each). The HP model was established by subcutaneous injection of 1% carrageenan (100 µL) into the left hind paw (the first injection)，followed by injection of PGE 2 (100 ng/25 µL, the second injection) into the dorsum pedis of the same hind paw 7 days after the first injection. The mechanical withdrawal threshold (MWT) of the ipsilateral paw was detected before and 4, 24, 48, 72 h, and 7 d after the first injection，and 1, 4, 24 and 48 h after the second injection. 2) In the second part，SD rats were randomly divided into sham-HP，real HP，sham-EA and EA groups( n ＝6 in each). The sham-HP and HP models were made in the same way as those in the first part. Bilateral "Zusanli"(ST 36)and "Kunlun"(BL 60)were punctured with filiform needles and also stimulated with electrical current：2 Hz/100 Hz，0.5－1.5 mA(0.5 mA increase per 10 min)for 30 min，1 time/d from the 1 st carrageenan injection on till the end of the experiments. PKCε protein expression in the L 4－L 6 DRGs was assayed by Western blot 48 h after the second injection., Results: 1)In the first part of the study，compared with the sham-HP group，the MWT at 4, 24、48 h after carrageenan injection and 4, 24 and 48 h after PGE 2 injection were significantly decreased in the HP model group( P <0.01). 2)In the second part，compared with the HP group，the MWT at 24、48 and 72 h after carrageenan injection, and 24 and 48 h after PGE 2 injection were significantly up-regulated in the EA group( P <0.05， P <0.01). 3)The relative content of PKCε in the DRGs(L 4－L 6)was significantly higher in the HP group than in the sham-HP group( P <0.01)，but considerably lower in the EA group than in the HP group ( P <0.01)．., Conclusion: EA has a good effect on pain conversion in inflammatory joint pain rats，which may be related to its effect in down-regulating the PKCε level in the ipsilateral lumbar DRGs.

Background: Evidence has shown that the greater the accumulation of risk factors for stroke, the greater the risk of stroke. Early intervention in the accumulation of risk factors for stroke can effectively reduce the incidence of stroke. The study aimed to investigate the distribution of the number of certain risk factors for stroke (hypertension, hyperlipidemia, overweight and obesity, and diabetes) and to explore the cause of the accumulation of certain stroke risk factors. Methods: A total of 4,052 participants aged 40 years or older were selected by the multistage stratified cluster sampling method in Dehui City in Jilin province, China. Descriptive data analyses were conducted. Multiple regression analyses were used to explore the adjusted association between the accumulation of key stroke risk factors and subjects' lifestyle and demographic characteristics. Results: Overall, 84.1% of the participants in this study had one or more of the four certain risk factors for stroke. The odds ratios (ORs) and 95% confidence intervals (CIs) of having ≥1, ≥2, and ≥3 key stroke risk factors were 1.627 (1.258, 2.103), 1.446 (1.209, 1.728), and 1.394 (1.164, 1.670), respectively, for males compared to females. Similarly, the ORs and 95% CIs of having ≥1, ≥2, and ≥3 key stroke risk factors were 1.227 (1.009, 1.492), 1.256 (1.096, 1.442), and 1.450 (1.262, 1.667), respectively, for partially salty diets compared to normal diets. Compared to people who did not exercise regularly, the ORs and 95% CIs of having ≥1, ≥2, and ≥3 key stroke risk factors were 0.693 (0.544, 0.883), 0.800 (0.679, 0.944), and 0.775 (0.659, 0.913), respectively, for people who regularly exercised. Compared to people who without a family history of cerebrovascular diseases, the ORs and 95% CIs were 1.418 (1.162, 1.732), 1.327 (1.154, 1.525), and 1.209 (1.050, 1.393), for people who with it. Conclusions: Male, partially salty diets, and family history of cerebrovascular diseases were risk factors for the accumulation of certain stroke risk factors while regular physical exercise was a protective factor.

Low concentrations of arsenic (As) contamination in aquatic environment is a worldwide issue, which is of great concern. To evaluate the impact of low concentrations of As on zebrafish, we measured the growth, antioxidant enzymes including superoxide dismutase (SOD) and catalase (CAT), oxidative damage (malondialdehyde, MDA) and apoptosis-related genes (nrf2, p53 and c-jun) of adult zebrafish after exposing to different AsIII concentrations (0, 10, 50, 100 or 150 μg L -1 ) for 28 d. Results indicated that exposure to low AsIII concentrations decreased the zebrafish weight by 14%, increased the activities of SOD and CAT by 23-41% and 31-59%, decreased the contents of MDA by 29-54%, and modulated transcription of apoptosis related genes. Our study showed that chronic exposure to AsIII concentrations <150 μg L -1 generated oxidative stress and damage on zebrafish, and altered apoptosis-related genes in zebrafish., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Coracoid approach brachial plexus block (CABPB) is safe and effective for clinical anesthesia and analgesia. Dual stimulation can enhance the block effect of CABPB when using nerve stimulator. Dexmedetomidine is a highly selective α-adrenoceptor agonist and it can prolong the duration of anesthesia when it is added into local anesthetics. The aim of this study was to assess the effects of dexmedetomidine on the duration of anesthesia and the effective postoperative analgesia time when it was mixed with ropivacaine for CABPB under dual stimulation., Methods: A total of 60 patients were randomly assigned into 2 groups (groups D and C), 30 patients in each group. CABPB were guided by nerve stimulator under dual stimulation. Each patient received 40 mL of 0.375% ropivacaine (group C), or 40 mL of 0.375% ropivacaine mixed with 1 μg/kg dexmedetomidine (group D). The duration of anesthesia, the effective postoperative analgesia time, sensory and motor block onset time, visual analog scale (VAS), and the cumulative dose of rescue tramadol were recorded., Results: Twenty-eight patients in each group were analyzed. The duration of anesthesia was longer in group D as compared with group C (759 vs 634 minutes, P < .05) and the effective postoperative analgesia time was longer in group D as compared with group C (986 vs 789 minutes, P < .05) too. The onset time of sensory and motor blocks were not significantly different between the 2 groups (P > .05). The VAS was similar in the 2 groups at 6 and 12 hours after block (P > .05), but it was lower in group D at 24 hours after block as compared to group C (P < .05). The cumulative dose of rescue tramadol during the first 48 hours postoperative period was significantly lower in group D as compared to group C (P < .05). No significant changes were observed in vital signs in either group., Conclusion: The addition of 1 μg/kg dexmedetomidine to ropivacaine extends the duration of anesthesia and the effective postoperative analgesia time for CABPB under dual stimulation. The VAS at 24 hours after block and the demand for rescue tramadol during the first 48 hours postoperative period are lower as well without side effects in the study group.(Registered in ClinicalTrials.gov id. NCT02961361).

With the purpose of identifying novel selective κ opioid receptor (KOR) antagonists as potential antidepressants from nepenthone analogues, starting from N-nor-N-cyclopropylmethyl-nepenthone (SLL-020ACP), a highly selective and potent KOR agonist, a series of 7β-methyl-nepenthone analogues was conceived, synthesized and assayed on opioid receptors based on the concept of hybridization. According to the pharmacological results, the functional reversal observed in orvinol analogues by introduction of 7β-methyl substituent could not be reproduced in nepenthone analogues. Alternatively, introduction of 7β-methyl substituent was associated with substantial loss of both subtype selectivity and potency but not efficacy for nepenthone analogues, which was not found in 7β-methyl orvinol analogues. Surprisingly, SLL-603, a 7β-methyl analogue of SLL-020ACP, was identified to be a KOR full agonist. The possible molecular mechanism for the heterogeneity in activity cliff was also investigated. In conclusion, 7β-methyl substituent was a structural locus associated with activity cliff and demonstrated as a pharmacological heterogeneity between nepenthone and orvinol analogues that warrants further investigations., (Copyright © 2018. Published by Elsevier Ltd.)

Differences in intravaginal ejaculation latency reflect normal biological variation, but the causes are poorly understood. Here, we investigated whether variation in ejaculation latency in an experimental rat model is related to altered sympathetic nervous system (SNS) activity and expression of N-methyl-D-aspartic acid (NMDA) receptors in the paraventricular nucleus of the hypothalamus (PVN). Male rats were classified as "sluggish," "normal," and "rapid" ejaculators on the basis of ejaculation frequency during copulatory behavioral testing. The lumbar splanchnic nerve activity baselines in these groups were not significantly different at 1460 ± 480 mV, 1660 ± 600 mV, and 1680 ± 490 mV, respectively (P = 0.71). However, SNS sensitivity was remarkably different between the groups (P < 0.01), being 28.9% ± 8.1% in "sluggish," 48.4% ± 7.5% in "normal," and 88.7% ± 7.4% in "rapid" groups. Compared with "normal" ejaculators, the percentage of neurons expressing NMDA receptors in the PVN of "rapid" ejaculators was significantly higher, whereas it was significantly lower in "sluggish" ejaculators (P = 0.01). In addition, there was a positive correlation between the expression of NMDA receptors in the PVN and SNS sensitivity (r = 0.876, P = 0.02). This study shows that intravaginal ejaculatory latency is associated with SNS activity and is mediated by NMDA receptors in the PVN., Competing Interests: All authors declared no competing interests

The main goal of our study was to characterize the population pharmacokinetics of vancomycin in critically ill Chinese neonates to develop a pharmacokinetic model and investigate factors that have significant influences on the pharmacokinetics of vancomycin in this population. The study population consisted of 80 neonates in the neonatal intensive care unit (ICU) from which 165 trough and peak concentrations of vancomycin were obtained. Nonlinear mixed effect modeling was used to develop a population pharmacokinetic model for vancomycin. The stability and predictive ability of the final model were evaluated based on diagnostic plots, normalized prediction distribution errors and the bootstrap method. Serum creatinine (Scr) and body weight were significant covariates on the clearance of vancomycin. The average clearance was 0.309 L/h for a neonate with Scr of 23.3 μmol/L and body weight of 2.9 kg. No obvious ethnic differences in the clearance of vancomycin were found relative to the earlier studies of Caucasian neonates. Moreover, the established model indicated that in patients with a greater renal clearance status, especially Scr < 15 μmol/L, current guideline recommendations would likely not achieve therapeutic area under the concentration-time curve over 24 h/minimum inhibitory concentration (AUC 24h /MIC) ≥ 400. The exceptions to this are British National Formulary (2016-2017), Blue Book (2016) and Neofax (2017). Recommended dose regimens for neonates with different Scr levels and postmenstrual ages were estimated based on Monte Carlo simulations and the established model. These findings will be valuable for developing individualized dosage regimens in the neonatal ICU setting.

The dedifferentiation, proliferation and migration of vascular smooth muscle cells (VSMCs) are essential in the progression of hypertension, atherosclerosis and intimal hyperplasia. Nesfatin-1 is a potential modulator in cardiovascular functions. However, the role of nesfatin-1 in VSMC biology has not been explored. The present study was designed to determine the regulatory role of nesfatin-1 in VSMC proliferation, migration and intimal hyperplasia after vascular injury. Herein, we demonstrated that nesfatin-1 promoted VSMC phenotype switch from a contractile to a synthetic state, stimulated VSMC proliferation and migration in vitro. At the molecular level, nesfatin-1 upregulated the protein and mRNA levels, as well as the promoter activities of matrix metalloproteinase 2 (MMP-2) and MMP-9, but downregulated peroxisome proliferator-activated receptor γ (PPARγ) levels and promoter activity in VSMCs. Blockade of MMP-2/9 or activation of PPARγ prevented the nesfatin-1-induced VSMC proliferation and migration. In vivo, knockdown of nesfatin-1 ameliorated neointima formation following rat carotid injury. Taken together, our results indicated that nesfatin-1 stimulated VSMC proliferation, migration and neointimal hyperplasia by elevating MMP2/MMP-9 levels and inhibiting PPARγ gene expression., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Purpose: To establish three-dimensional models of upper airway pre- and post-orthognathic surgery in patients with skeletal Class Ⅲ malocclusion, and to compare the effects of different modes of orthognathic surgery on the cross-sectional areas and volumes of upper airway., Methods: Twenty-eight patients with skeletal Class Ⅲ malocclusion were divided into 2 groups. Group A (12 patients) underwent bilateral sagittal split ramus osteotomy(BSSRO) for mandibular setback, named single jaw surgery group; group B (16 patients) underwent BSSRO + Le Fort I osteotomy for mandibular setback and maxillary advancement, named bimaxillary surgery group. All patients received CT scanning before (T1) and 3 months after surgery (T2). The three-dimensional models of the upper airway containing velopharynx, glossopharynx and laryngopharynx were established by using Dolphin Imaging 11.7 software. The changes of sagittal diameters, coronal diameters, cross-sectional areas and volumes of the upper airway were measured and compared between the two groups pre- and post- surgery (T1, T2) using SPSS 16.0 software package, respectively., Results: In velopharynx, the values of group A were decreased after surgery, while the other values of group B were increased except the value of coronal diameter. There was a significant difference between the two groups (P<0.05). In glossopharynx and laryngopharynx, the values of group A and group B were both decreased after surgery. The reduction of the cross-sectional areas and volumes in group A were more obvious than group B (P<0.05)., Conclusions: The amount of narrowing of the upper airway is smaller in patients undergoing bimaxillary surgery than in patients undergoing mandibular setback surgery.

The phenotypic transformation from differentiated to dedifferentiated vascular smooth muscle cells (VSMCs) plays a crucial role in VSMC proliferation and vascular remodeling in many cardiovascular diseases including hypertension. Nesfatin-1, a multifunctional adipocytokine, is critically involved in the regulation of blood pressure. However, it is still largely unexplored whether nesfatin-1 is a potential candidate in VSMC phenotypic switch and proliferation in hypertension. Experiments were carried out in Wistar-Kyoto rats (WKY), spontaneously hypertensive rats (SHR), human VSMCs and primary rat aortic VSMCs. We showed that the expression of nesfatin-1 was upregulated in media layer of the aorta in SHR and SHR-derived VSMCs. Nesfatin-1 promoted VSMC phenotypic transformation, accelerated cell cycle progression and proliferation. Knockdown of nesfatin-1 inhibited the VSMC phenotype switch from a contractile to a synthetic state, attenuated cell cycle progression and retarded VSMC proliferation in SHR-derived VSMCs. Moreover, nesfatin-1-activated PI3K/Akt/mTOR signaling was abolished by JAK/STAT inhibitor WP1066, and the increased phosphorylation levels of JAK2/STAT3 in response to nesfatin-1 were suppressed by inhibition of PI3K/Akt/mTOR in VSMCs. Pharmacological blockade of the forming feedback loop between PI3K/Akt/mTOR and JAK2/STAT3 prevented the proliferation of nesfatin-1-incubated VSMCs and primary VSMCs from SHR. Chronic intraperitoneal injection of nesfatin-1 caused severe hypertension and cardiovascular remodeling in normal rats. In contrast, silencing of nesfatin-1 gene ameliorated hypertension, phenotype switching, and vascular remodeling in the aorta of SHR. Therefore, our data identified nesfatin-1 as a key modulator in hypertension and vascular remodeling by facilitating VSMC phenotypic switching and proliferation., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: To investigate the influence of condylar fractures on the growth of condylars after conservative treatments by three-dimensional measurement. Methods: Twenty three children with unilateral condylar fracture followed-up for at least 1 year in Shanghai Ninth People's Hospital were included from June 2016 to March 2017. CT scans were performed for each patient. Three-dimensional virtual skulls were reconstructed and measuring points were defined with Simplant 11.04 software. The depth of glenoid fossa, height of articular eminence, width, height and depth of condylar, deviation of pogonion were measured. Statistical analyses were conducted to assess difference between the bifid group and the normal group. Results: No difference was observed in the vertical position of crest of the articular eminence between two groups ( P =0.110). The vertical position of roof of the glenoid fossa in bifid side was significantly superior than the one in normal side ( P =0.010). Bifid side had a shorter ( P =0.002) and wider( P =0.002) condylar than normal side did. No difference was observed in the depth of condylar between two groups ( P =0.071). The average deviation of pogonion was (0.69±1.75) mm ( P =0.072) from sagittal plan. Conclusions: This short-termed study indicates that children's growth potential of condylar is under average after conservative treatments. Because the bone hyperosteogeny of glenoid fossa compensates the hypotrophy of condylar, no deviation of pogonion is detected.

Objectives: This study sought to compare surgical outcomes after the removal of submandibular gland (SMG) stones via 2 different surgical methods., Materials and Methods: From June 2015 to July 2016, a total of 40 patients with SMG stones were selected from the Department of Oral and Maxillofacial Surgery, School of Stomatology, China Medical University (Shenyang, China), and were randomly assigned to 2 groups. Twenty patients underwent sialendoscopy-assisted stone removal via extraoral incision with preservation of the SMG, and 20 patients underwent traditional SMG resection. The outcomes of the 2 surgical procedures were assessed., Results: The operation time and hospital stay were shorter in the SMG preservation group than the SMG resection group. There were no significant differences in stone size or location between the groups. The mean visual analog scale (VAS) score was lower in the SMG preservation group than the SMG resection group. All patients in the SMG resection group exhibited varying degrees of scarring and concave deformity on the face and neck, whereas all patients in the SMG preservation group retained intact facial morphology., Conclusions: Sialendoscopy-assisted stone removal with preservation of the SMG exhibited many advantages relative to traditional SMG resection., (Copyright © 2018. Published by Elsevier Inc.)

In this study, graphene oxides with different functionalization degrees were prepared by a facile one-step hydrothermal reflux method at various reaction temperatures using graphene oxide (GO) as starting material and p -phenylenediamine (PPD) as the modifier. The effects of reaction temperature on structure, appearance and bonding type of the obtained materials were investigated by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), X-ray photoelectron spectroscopy (XPS), and scanning electron microscopy (SEM). The results showed that when the reaction temperature was 10⁻70 &deg;C, the GO reacted with PPD through non-covalent ionic bonds (⁻COO &minus; H₃⁺N⁻R) and hydrogen bonds (C⁻OH&hellip;H₂N⁻X). When the reaction temperature reached 90 &deg;C, the GO was functionalized with PPD through covalent bonds of C⁻N. The crystal structure of products became more ordered and regular, and the interlayer spacing ( d value) and surface roughness increased as the temperature increased. Furthermore, the results suggested that PPD was grafted on the surface of GO through covalent bonding by first attacking the carboxyl groups and then the epoxy groups of GO.

Phenotypic switch of vascular smooth muscle cells (VSMCs) is characterized by increased expressions of VSMC synthetic markers and decreased levels of VSMC contractile markers, which is an important step for VSMC proliferation and migration during the development and progression of cardiovascular diseases including atherosclerosis. Chicoric acid (CA) is identified to exert powerful cardiovascular protective effects. However, little is known about the effects of CA on VSMC biology. Herein, in cultured VSMCs, we showed that pretreatment with CA dose-dependently suppressed platelet-derived growth factor type BB (PDGF-BB)-induced VSMC phenotypic alteration, proliferation and migration. Mechanistically, PDGF-BB-treated VSMCs exhibited higher mammalian target of rapamycin (mTOR) and P70S6K phosphorylation, which was attenuated by CA pretreatment, diphenyleneiodonium chloride (DPI), reactive oxygen species (ROS) scavenger N-acetyl-l-cysteine (NAC) and nuclear factor-κB (NFκB) inhibitor Bay117082. PDGF-BB-triggered ROS production and p65-NFκB activation were inhibited by CA. In addition, both NAC and DPI abolished PDGF-BB-evoked p65-NFκB nuclear translocation, phosphorylation and degradation of Inhibitor κBα (IκBα). Of note, blockade of ROS/NFκB/mTOR/P70S6K signaling cascade prevented PDGF-BB-evoked VSMC phenotypic transformation, proliferation and migration. CA treatment prevented intimal hyperplasia and vascular remodeling in rat models of carotid artery ligation in vivo. These results suggest that CA impedes PDGF-BB-induced VSMC phenotypic switching, proliferation, migration and neointima formation via inhibition of ROS/NFκB/mTOR/P70S6K signaling cascade., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Chronic kidney disease causes uremia-related endothelial cell dysfunction associated with high risk for cardiovascular diseases. The vascular endothelium is permanently exposed to uraemic toxins including indoxyl sulfate, which provokes endothelial damage in subjects with end-stage renal disease. Pterostilbene (PT) is identified to be homologous derivative of resveratrol and exerts antioxidant and anti-inflammatory actions. However, the effects of PT on uraemic serum-induced endothelial cell damage have not been elucidated. In this study, we investigated the effects and mechanisms of PT on uraemic serum (US)-mediated injury in human umbilical vein endothelial cells (HUVECs). Treatment of US obviously reduced cell viability, inhibited superoxide dismutase activity and catalase activity, suppressed phosphorylated endothelial nitric oxide synthase (eNOS) protein level and eNOS activity, whereas promoted lactate dehydrogenase leakage, increased malondialdehyde, hydrogen peroxide, superoxide anions levels and NAD(P)H activity accompanied with increased nitrative stress and inflammatory response in HUVECs, and these changes were reversed after PT treatment. Under US environment, PT downregulated Kelch-like ECH-associated protein 1 (Keap1) and upregulated nuclear factor erythroid-2-related factor 2 (Nrf2) and its downstream target heme oxygenase-1 (HO-1) protein levels. Of note, the level of HO-1 was decreased after the transfection of cells with Nrf2-siRNA, and HO-1 inhibitor Snpp abolished the protective effects of PT on HUVECs in response to US. Collectively, our study demonstrated that PT is effective in reducing US-evoked endothelial cell dysfunction via suppression of oxidative/nitrative stress and inflammatory response, which at least partly depended on Keap1/Nrf2/HO-1 signaling pathway.

Purpose: To evaluate preoperative factors influencing the visual outcome and postoperative factors associated with the changes in visual acuity, after reattachment surgery to treat macula-off rhegmatogenous retinal detachment., Methods: A total of 180 eyes of 180 patients who underwent reattachment surgery to treat macula-off rhegmatogenous retinal detachment, and who were followed up for more than 12 months, were reviewed retrospectively. Preoperative and postoperative characteristics, including optical coherence tomography findings, were comprehensively analyzed using univariate and multivariate models to evaluate preoperative factors influencing best-corrected visual acuity 12 months after macula-off rhegmatogenous retinal detachment surgery and postoperative factors associated with changes in best-corrected visual acuity after surgery., Results: Preoperatively, the extent of detachment (P = 0.037), macula-off duration (P < 0.001), and integrity of the external limiting membrane (β = 0.163; P = 0.002) were significantly associated with postoperative visual prognosis. Six factors were associated with changes in visual acuity after surgery: disruption of ellipsoid zone integrity (β = 0.167; P < 0.001), the Henle's fiber layer and the outer nuclear layer (HFL + ONL)/photoreceptor layer ratio (β = 0.199; P < 0.001), the photoreceptor outer segment length (β = -0.020; P < 0.001), the photoreceptor inner segment length/photoreceptor outer segment length ratio (β = 0.047; P = 0.005), the ratio of photoreceptor layer thickness between the RD eye and fellow eye (β = -0.126; P = 0.018), and the photoreceptor outer segment length ratio between the RD eye and fellow eye (β = -0.425; P < 0.001)., Conclusion: Preoperative factors associated with the visual outcome after macula-off rhegmatogenous retinal detachment surgery were the extent of detachment, macula-off duration, and external limiting membrane integrity. Postoperatively, predictive factors were the outer retinal microstructures, particularly the photoreceptor outer segment layer.

We investigated the reversal effect of afatinib (AFT) on activity of adriamycin (ADR) in A549T cells and clarified the related molecular mechanisms. A549T cells overexpressing P-glycoprotein (P-gp) were resistant to anticancer drug ADR. AFT significantly increased the antitumor activity of ADR in A549T cells. AFT increased the intracellular concentration of ADR by inhibiting the function and expression of P-gp at mRNA and protein levels in A549T cells. Additionally, the reversal effect of AFT on P-gp mediated multidrug resistance (MDR) might be related to the inhibition of PI3K/Akt pathway. Cotreatment with AFT and ADR could enhance ADR-induced apoptosis and autophagy in A549T cells. Meanwhile, the co-treatment significantly induced cell apoptosis and autophagy accompanied by increased expression of cleaved caspase-3, PARP, LC3B-II, and beclin 1. Apoptosis inhibitors had no significant effect on cell activity, while autophagy inhibitors decreased cell viability, suggesting that autophagy may be a self protective mechanism of cell survival in the absence of chemotherapy drugs. Interestingly, when combined with AFT and ADR, inhibition of apoptosis and/or autophagy could enhance cell viability. These results indicated that in addition to inhibit P-gp, ADR-induced apoptosis, and autophagy promoted by AFT contributed to the antiproliferation effect of combined AFT and ADR on A549T cells. These findings provide evidence that AFT combined ADR may achieve a better therapeutic effect to lung cancer in clinic. J. Cell. Biochem. 119: 414-423, 2018. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Cryptoendolithic lichens and cyanobacteria living in porous sandstone in the high-elevation McMurdo Dry Valleys are purported to be among the slowest growing organisms on Earth with cycles of death and regrowth on the order of 10 3 -10 4  years. Here, organic biomarker and radiocarbon analysis were used to better constrain ages and carbon sources of cryptoendoliths in University Valley (UV; 1,800 m.a.s.l) and neighboring Farnell Valley (FV; 1,700 m.a.s.l). Δ 14 C was measured for membrane component phospholipid fatty acids (PLFA) and glycolipid fatty acids, as well as for total organic carbon (TOC). PLFA concentrations indicated viable cells comprised a minor (<0.5%) component of TOC. TOC Δ 14 C values ranged from -272‰ to -185‰ equivalent to calibrated ages of 1,100-2,550 years old. These ages may be the result of fractional preservation of biogenic carbon and/or sudden large-scale community death and extended period(s) of inactivity prior to slow recolonization and incorporation of 14 C-depleted fossil material. PLFA Δ 14 C values were generally more modern than the corresponding TOC and varied widely between sites; the FV PLFA Δ 14 C value (+40‰) was consistent with modern atmospheric CO 2 , while UV values ranged from -199‰ to -79‰ (calibrated ages of 1,665-610 years). The observed variability in PLFA Δ 14 C depletions is hypothesized to reflect variations in the extent of fixation of modern atmospheric CO 2 and the preservation and recycling of older organic carbon by the community in various stages of sandstone recolonization. PLFA profiles and microbial community compositions as determined by molecular genetic characterizations and microscopy differed between the two valleys (e.g., predominance of biomarker 18:2 [>50%] in FV compared to UV), representing microbial communities that may reflect distinct stages of sandstone recolonization and/or environmental conditions. It is thus proposed that Dry Valley cryptoendolithic microbial communities are faster growing than previously estimated., (© 2017 John Wiley & Sons Ltd.)

This study was conducted to explore the hypothesis that the endogenous superoxide anions (O₂ - ) and nitric oxide (NO) system of the paraventricular nucleus (PVN) regulates the cardiac sympathetic afferent reflex (CSAR) contributing to sympathoexcitation in obese rats induced by a high-fat diet (42% kcal as fat) for 12 weeks. CSAR was evaluated by monitoring the changes of renal sympathetic nerve activity (RSNA) and the mean arterial pressure (MAP) responses to the epicardial application of capsaicin (CAP) in anaesthetized rats. In obese rats with hypertension (OH group) or without hypertension (OB group), the levels of PVN O₂ - , angiotensinII (Ang II), Ang II type 1 receptor (AT1R), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase were elevated, whereas neural NO synthase (nNOS) and NO were significantly reduced. Moreover, CSAR was markedly enhanced, which promoted the elevation of plasma norepinephrine levels. The enhanced CSAR was attenuated by PVN application of the superoxide scavenger polyethylene glycol-superoxide dismutase (PEG-SOD) and the NO donor sodium nitroprusside (SNP), and was strengthened by the superoxide dismutase inhibitor diethyldithiocarbamic acid (DETC) and the nNOS inhibitor N(ω)-propyl-l-arginine hydrochloride (PLA); conversely, there was a smaller CSAR response to PLA or SNP in rats that received a low-fat (12% kcal) diet. Furthermore, PVN pretreatment with the AT1R antagonist losartan or with PEG-SOD, but not SNP, abolished Ang II-induced CSAR enhancement. These findings suggest that obesity alters the PVN O₂ - and NO system that modulates CSAR and promotes sympathoexcitation., Competing Interests: The authors declare no conflict of interest.

The present study aimed to identify potential dysregulated pathways to further reveal the molecular mechanisms of postmenopausal osteoporosis (PMOP) based on pathway‑interaction network (PIN) analysis, which considers crosstalk between pathways. Protein‑protein interaction (PPI) data and pathway information were derived from STRING and Reactome Pathway databases, respectively. According to the gene expression profiles, pathway data and PPI information, a PIN was constructed with each node representing a biological pathway. Principal component analysis was used to compute the pathway activity for each pathway, and the seed pathway was selected. Subsequently, dysregulated pathways were extracted from the PIN based on the seed pathway and the increased classification accuracy, which was measured using the area under the curve (AUC) index according to 5‑fold cross validation. A PIN comprising 2,725 interactions was constructed, which was used to detect dysregulated pathways. Notably, the 'mitotic prometaphase' pathway was selected and defined as a seed pathway. Starting with the seed pathway, network‑based analysis successfully identified one pathway set for PMOP comprising eight dysregulated pathways (such as mitotic prometaphase, resolution of sister chromatid cohesion, mRNA splicing and mRNA splicing‑major) with an AUC score of 0.85, which may provide potential biomarkers for targeted therapy for PMOP.

Arsenic contamination in drinking water is a worldwide issue, posing threat to human health. Arsenic is an endocrine system disruptor, however, limited information is available regarding its long-term effects on thyroid endocrine system at low exposure. In this study, we assessed the thyroid toxicity of arsenate (AsV) and arsenite (AsIII) at 10-100 μg L -1 in juvenile mice after 8-week of exposure via drinking water. After 1-2 week, AsV and AsIII had little influence on thyroxine (T4) level (56.3-64.7 μg L -1 ) in mouse blood compared to control mice at 57.3-60.7 μg L -1 . However, after 4-8 weeks, 10 μg L -1 AsIII or AsV increased T4 levels to 83.8-88.8 μg L -1 compared to control treatment at 77.2-80.0 μg L -1 , while 100 μg L -1 AsV or AsIII decreased T4 levels except for 100 μg L -1 AsIII for 8 weeks. Based on transmission electron microscopy, exposure to 100 μg L -1 AsIII or AsV for 8 weeks caused thyroid gland damage. In addition, exposure to AsV or AsIII at 10 or 100 μg L -1 impacted gene transcription of hypothalamic-pituitary-thyroid axis including thyroid stimulating hormone and iodothyronine deiodinases. Our data demonstrated that exposing to low levels of AsIII or AsV disrupted T4 homeostasis, influenced the related gene transcription and damaged the thyroid glands in juvenile mice., (Published by Elsevier Ltd.)

Cardiovascular diseases are major causes of people death associated with high mortality and disability. Exosomes are nanosized extracellular vesicles containing protein, lipid, transcription factors, mRNAs, non-coding RNA (ncRNA) and nucleic acid contents, which are critical players of intercellular communication via long-range signals or cell-to-cell contact. The emergence of exosomes provides favorable strategies for the diagnosis and treatment of cardiovascular diseases. Exosomes-based molecular mechanisms are important for developing novel therapeutic approaches for cardiovascular events. In this review, we will (1) provide insights into the detrimental and beneficial effects of exosomes on cardiovascular physiology, (2) summarize the underlying biological mechanisms of the exosome in cardiovascular events, (3) investigate the therapeutic value of exosomes for cardiovascular disorders.

Angiogenesis is a complex physiological process involving the growth of new capillaries. The impaired angiogenesis plays important roles in chronic wounds and ischaemic heart disease. Fibroblast growth factor 2 (FGF-2) exerts pro-angiogenic actions via activation of fibroblast growth factor receptor 1 (FGFR-1). We have identified that vaccarin increased the angiogenic activity of endothelial cells. In this study, we investigated whether FGF-2-mediated FGFR1 signaling pathway participated in vaccarin-mediated neovascularization formation. Human microvascular endothelial cells (HMEC)-1 were incubated with various doses of vaccarin. Our results showed that vaccarin dose-dependently up-regulated FGF-2 levels and phosphorylation of FGFR-1. Neutralization of FGF-2 with anti-FGF-2 antibody also abolished the proliferation, migration and tube formation of HMEC-1 cells induced by vaccarin. Both FGFR-1 inhibitor SU5402 and FGFR-1 siRNA blocked vaccarin-induced cell cycle progression and angiogenesis. The mouse Matrigel model study further unveiled that vaccarin stimulated the neovascularization and microvessel density in vivo, which was prevented by FGFR-1 inhibitor SU5402. Taken together, our results demonstrated for the first time that vaccarin was a novel inducer for FGF-2 expression, followed by phosphorylation of FGFR-1 and subsequent angiogenic behaviors in endothelial cells. Vaccarin may be a promising candidate of angiogenesis activator for neurovascular repair or therapy., (Copyright © 2017. Published by Elsevier Masson SAS.)

Hand-to-mouth activity is an important pathway for children's exposure to contaminated soils, which is often co-contaminated by Pb and As in mining and smelting sites. To reduce soil Pb risk to humans by oral exposure, phosphate amendments have been used to reduce Pb relative bioavailability (RBA), but its efficiency has not been investigated using validated in vitro assays nor its influence on As-RBA. Here, 5 contaminated soils (A-E) were amended with 0.5% phosphoric acid (PA) to study its effect on Pb- and As- RBA using a newly-developed mouse kidney model and bioaccessibility using 4 in vitro assays including UBM, SBRC, IVG, and PBET. Based on the mouse kidney model, Pb-RBA in PA-amended soils decreased from 14.2-62.5% to 10.1-29.8%. In contrast, As-RBA decreased from 26.5% to 15.9% in soil B but increased from 27.5 to 41.2% in soil D, with changes being insignificant in 3 other soils (35.8-58.8 to 28.1-61.1%). When assessing Pb bioaccessibility in PA-amended soils, decreased bioaccessibility were found using PBET and SBRC. For As, its bioaccessibility increased in PA-amended soils, inconsistent with in vivo data. Our results shed light on the importance of method selection to assess risk in Pb- and As-contaminated soils amended with phosphate., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Inflammation is involved in pathogenesis of hypertension. NLRP3 inflammasome activation is a powerful mediator of inflammatory response via caspase-1 activation. The present study was designed to determine the roles and mechanisms of NLRP3 inflammasome in phenotypic modulation and proliferation of vascular smooth muscle cells (VSMCs) in hypertension. Experiments were conducted in spontaneously hypertensive rats (SHR) and primary aortic VSMCs. NLRP3 inflammasome activation was observed in the media of aorta in SHR and in the VSMCs from SHR. Knockdown of NLRP3 inhibited inflammasome activation, VSMC phenotypic transformation and proliferation in SHR-derived VSMCs. Increased NFκB activation, histone acetylation and histone acetyltransferase expression were observed in SHR-derived VSMCs and in media of aorta in SHR. Chromatin immunoprecipitation analysis revealed the increased histone acetylation, p65-NFκB and Pol II occupancy at the NLRP3 promoter in vivo and in vitro. Inhibition of NFκB with BAY11-7082 or inhibition of histone acetyltransferase with curcumin prevented the NLRP3 inflammasome activation, VSMC phenotype switching and proliferation in VSMCs from SHR. Moreover, curcumin repressed NFκB activation. Silencing of NLRP3 gene ameliorated hypertension, vascular remodeling, NLRP3 inflammasome activation and phenotype switching in the aorta of SHR. These results indicate that NLRP3 inflammasome activation response to histone acetylation and NFκB activation contributes to VSMC phenotype switching and proliferation and vascular remodeling in hypertension.

The blood glycoprotein von Willebrand factor (vWF) is involved in coagulopathy and inflammation; however, its role in the pathogenesis of acute liver failure, as suggested by its higher expression levels in such patients, remains unknown. In this study, vWF-knockout (KO) mice showed more severe carbon tetrachloride (CCl 4 )-induced liver injury than wild-type mice. Patients with acute liver injury also showed elevated vWF protein activity and expression in liver tissues, as compared to healthy individuals. Using the mouse model and cultured human umbilical vein endothelial cells (HUVECs), CCl 4 was found to directly increase vWF protein expression through interaction with the highly expressed vWF receptor, GPIbα. Microarray analysis revealed that the genes showing the most differential expression in response to CCl 4 -induced liver injury and vWF deficiency were related to the MAPK signaling pathway. Subsequent inhibition of vWF protein activity in HUVECs led to activation of the MAPK signal pathway and elevated production of FGL2, and treatment with a phospho-p38 inhibitor suppressed the CCl 4 -induced production of FGL2. Exposure of liver sinusoidal endothelial cells isolated from the vWF-KO acute liver injury model mice to phospho-p38 inhibitor also decreased FGL2 expression. The vWF/GPIbα axis plays a protective role against development of acute liver injury by attenuating FGL2 production through the MAPK signaling pathway. Collectively, these data provide insight into the pathogenesis of acute liver injury and a potential novel strategy for its treatment.

Mou and McNamara have suggested that object locations are represented according to intrinsic reference frames. In three experiments, we investigated the limitations of intrinsic reference frames as a mean to represent object locations in spatial memory. Participants learned the locations of seven or eight common objects in a rectangular room and then made judgments of relative direction based on their memory of the layout. The results of all experiments showed that when all objects were positioned regularly, judgments of relative direction were faster or more accurate for novel headings that were aligned with the primary intrinsic structure than for other novel headings; however, when one irregularly positioned object was added to the layout, this advantage was eliminated. The experiments further indicated that with a single view at study, participants could represent the layout from either an egocentric orientation or a different orientation, according to experimental instructions. Together, these results suggest that environmental reference frames and intrinsic axes can influence performance for novel headings, but their role in spatial memory depends on egocentric experience, layout regularity, and instructions.

Purpose: To compare the responses of intravitreal injections of bevacizumab, ranibizumab, or aflibercept for the treatment of neovascular age-related macular degeneration (nAMD)., Methods: This retrospective study examined 232 eyes of 232 patients who received intravitreal anti-vascular endothelial growth factor (VEGF) injections due to treatment-naïve nAMD. All patients, who were followed-up for at least 1 year, were treated with intravitreal injections monthly until 3 months, and then as needed. We evaluated the effects of intravitreal injections for treatment of nAMD using the central macular thickness (CMT), subretinal fluid (SRF), pigment epithelial detachment (PED) size, and best-corrected visual acuity (BCVA)., Results: CMT, SRF, PED size, and BCVA (LogMAR) were significantly decreased after treatment with all three anti-VEGF agents. Overall, the bevacizumab, ranibizumab, and aflibercept treatments showed no significant differences in their responses. However, the aflibercept injections decreased PED size more quickly than bevacizumab injections (P = 0.034)., Conclusions: Bevacizumab, ranibizumab, and aflibercept injections are effective treatments for nAMD and have similar responses, although the number of injections of aflibercept was fewer than other anti-VEGF agents. In addition, aflibercept injections may be a better choice than other anti-VEGF agents for cases of severe increases in PED height.

Repeated visual context induces higher search efficiency, revealing a contextual cueing effect, which depends on the association between the target and its visual context. In this study, participants performed a visual search task where search items were presented with depth information defined by binocular disparity. When the 3-dimensional (3D) configurations were repeated over blocks, the contextual cueing effect was obtained (Experiment 1). When depth information was in chaos over repeated configurations, visual search was not facilitated and the contextual cueing effect largely crippled (Experiment 2). However, when we made the search items within a tiny random displacement in the 2-dimentional (2D) plane but maintained the depth information constant, the contextual cueing was preserved (Experiment 3). We concluded that the contextual cueing effect was robust in the context provided by 3D space with stereoscopic information, and more importantly, the visual system prioritized stereoscopic information in learning of spatial information when depth information was available.

Oxidized low-density lipoprotein (ox-LDL) is well known to disrupt normal functionality of endothelium, which plays a prominent role in endothelial dysfunction in many cardiovascular diseases. CO-releasing molecule 2 (CORM-2) is a promising candidate for treatment of cardiovascular diseases. However, it has not been defined whether CORM-2 might improve endothelial injury induced by ox-LDL. The present study was undertaken to determine the regulatory role of CORM-2 in cell injury of ox-LDL-treated human umbilical vein endothelial cells (HUVECs). Our results showed that ox-LDL inhibited the cell proliferation, but promoted apoptosis and release of cytochrome c (cytc) from mitochondrion into cytoplasm, stimulated the cleavage of caspase-3 and mitochondrial permeability transition pore (MPTP) opening. In addition, ox-LDL-incubated HUVECs exhibited excessive reactive oxygen species (ROS), increased protein levels of NADPH oxidase subunits p22 phox , p47 phox , NOX-2 and activation of Wnt/β-catenin signaling pathway. However, pretreatment with CORM-2 significantly reduced cell apoptosis, release of cytc from mitochondrion into cytoplasm, MPTP opening and cleavage of caspase-3, suppressed the superoxide anion generation and Wnt/β-catenin pathway activation in HUVECs response to ox-LDL. Collectively, we provide the evidence that CORM-2 attenuated ox-LDL-mediated endothelial apoptosis and oxidative stress by recovering the mitochondrial function and blocking Wnt/β-catenin pathway., (Copyright © 2017 Elsevier Inc. All rights reserved.)