A Systematic Review and Meta-Analysis of Efficacy and Safety of Cilostazol Prescription in Patients With Femoropopliteal Peripheral Artery Disease After Endovascular Therapy.

PURPOSE: The purpose of this study is to assess the efficacy and safety of cilostazol prescription in patients with femoropopliteal peripheral artery disease (PAD) after endovascular therapy (EVT). MATERIALS AND METHODS: We conducted a systematic review and meta-analysis of all studies reporting the outcomes of cilostazol after femoropopliteal EVT of PAD up to September 2022. Clinical outcomes of interest included primary patency, in-stent restenosis (ISR), vessel re-occlusion, freedom from target lesion revascularization (TLR), repeat revascularization, all-cause mortality, amputation, major adverse cardiovascular events (MACEs) and major adverse limb events (MALEs), and bleeding complication. RESULTS: A total of 4 randomized controlled trials (RCTs) and 8 observational studies containing a total of 4898 patients met the inclusion criteria and were included in this systematic review and meta-analysis. We found that the use of cilostazol was associated with higher primary patency after femoropopliteal artery EVT (odds ratio [OR]=1.67, 95% confidence interval [CI]=1.50-1.87, p<0.001, I2=33.2%), a lower risk of ISR (OR=0.43, 95% CI=0.29-0.63, p<0.001, I2=37.6%), repeat revascularization (OR=0.43, 95% CI=0.24-0.76, p<0.005, I2=27.4%), and vessel re-occlusion (OR=0.59, 95% CI=0.38-0.93, p<0.05, I2=0%). There was an increase in freedom from TLR rate (OR=2.19, 95% CI=1.58-3.05, p<0.001, I2=0%), as well as a reduction in the occurrence of MALEs (OR=0.50, 95% CI=0.29-0.85, p<0.05, I2=0%). However, there was no significant difference in amputation, MACEs, all-cause mortality, and major bleeding complications. Subgroup analysis showed that cilostazol treatment in patients with femoropopliteal drug-eluting stents (DES) implantation remained associated with higher primary patency and a lower risk of ISR. CONCLUSIONS: After EVT of femoropopliteal artery lesions, additional oral cilostazol enhances primary patency, reduces the occurrences of ISR and vessel re-occlusion, diminishes the risks associated with MALEs, lowers the need for repeat revascularization, and increases freedom from TLR rates. However, it does not impact amputation, MACEs, all-cause mortality, or major bleeding complications. These findings suggest cilostazol as a potentially safe and effective adjunct therapy in patients with femoropopliteal PAD after EVT. CLINICAL IMPACT: After undergoing endovascular therapy (EVT) for femoropopliteal artery lesions, the addition of cilostazol to antiplatelet therapy can significantly improve primary patency, reducing the incidence of in-stent restenosis, repeat revascularization, vessel re-occlusion, and major adverse limb events while increasing freedom from target lesion revascularization rate. The simultaneous use of drug-eluting stents in the femoropopliteal artery lesions, combined with cilostazol, potentially results in a synergistic anti-stenotic effect. This therapeutic approach does not appear to be associated with an increased risk of major bleeding events or all-cause mortality. These findings provide additional evidence supporting the treatment of anti-stenosis in patients with femoropopliteal artery lesions after EVT.

A Rule for Response Sensitivity of Structural-Color Photonic Colloids.

To mimic natural photonic crystals having color regulation capacities dynamically responsive to the surrounding environment, periodic assembly structures have been widely constructed with response materials. Beyond monocomponent materials with stimulus responses, binary and multiphase systems generally offer extended color space and complex functionality. Constructing a rule for predicting response sensitivity can provide great benefits for the tailored design of intelligently responsive photonic materials. Here, we elucidate mathematical relationships between the response sensitivity of dynamically structural-color changes and the location distances of photonic co-phases in three-dimensional Hansen space that can empirically express the strength of their interaction forces, including dispersion force, polarity force, and hydrogen bonding. Such an empirical rule is proven to be applicable for some typical alcohols, acetone, and acetic acid regardless of their molecular structures, as verified by angle resolution spectroscopy, in situ infrared spectroscopy, and molecular simulation. The theoretical method we demonstrate provides rational access to custom-designed responsive structural coloration.

Tandem Electrocatalytic Alkyne Semihydrogenation over Bicomponent Catalysts through Hydrogen Spillover.

Electrocatalytic alkyne semihydrogenation under mild conditions is a more attractive approach for alkene production than industrial routes but suffers from either low production efficiency or high energy consumption. Here, we describe a tandem catalytic concept that overcomes these challenges. Component (i), which can trap hydrogen effectively, is partnered with component (ii), which can readily release hydrogen for hydrogenation, to enable efficient generation of active hydrogen on component (i) at low overpotentials and timely (i)-to-(ii) hydrogen spillover and facile desorptive hydrogenation on component (ii). We examine this concept over bicomponent palladium-copper catalysts for the production of representative 2-methyl-3-butene-2-ol (MBE) from 2-methyl-3-butyne-2-ol (MBY) and achieve a record high MBE production rate of 1.44 mmol h-1 cm-2 and a Faraday efficiency of ~88.8 % at a low energy consumption of 1.26 kWh kgMBE -1. With these catalysts, we further achieve 60 h continuous production of MBE with record high profit space.

Heteroatom Coordination Regulates Iron Single-Atom-Catalyst with Superior Oxygen Reduction Reaction Performance for Aqueous Zn-Air Battery.

Platinum group metal (PGM)-free M-N-C catalysts have exhibited dramatic electrocatalytic performance and are considered the most promising candidate of the Pt catalysts in oxygen reduction reaction (ORR). However, the electrocatalytic performance of the M-N-C catalysts is still limited by their inferior intrinsic activity and finite active site density. Regulating the coordination environment and increasing the pore structure of the catalyst is an effective strategy to enhance the electrocatalytic performance of the M-N-C catalysts. In this work, the coordination environment and pore structure exquisitely regulated Fe-N-C catalyst exhibit excellent ORR activity and durability. With the enhanced intrinsic activity and increased active site density, the optimized Fe-N/S-C catalyst shows impressive ORR activity (E1/2  = 0.904 V vs reversible hydrogen electrode (RHE)) and superior long-term durability in an alkaline medium. As the advanced physical characterization and theoretical chemistry methods illustrate, the S-modified Fe-Nx (Fe-N3 /S-C) moiety is confirmed as the improved active center for ORR, and the increased active site density further improved ORR efficiency. Based on the Fe-N/S-C cathode, a Zn-air battery is fabricated and shows superior power density (315.4 mW cm-2 ) and long-term discharge stability at 20 mA cm-2 . This work would open a new perspective to design atomically dispersed iron-metal site catalysts for advanced electro-catalysis.

Advances in Transition-Metal-Based Dual-Atom Oxygen Electrocatalysts.

Oxygen electrocatalysis has aroused considerable interest over the past years because of the new energy technologies boom in hydrogen energy and metal-air battery. However, due to the sluggish kinetic of the four-electron transfer process in oxygen reduction reaction and oxygen evolution reaction, the electro-catalysts are urgently needed to accelerate the oxygen electrocatalysis. Benefit from the high atom utilization efficiency, unprecedentedly high catalytic activity, and selectivity, single-atom catalysts (SACs) are considered the most promising candidate to replace the traditional Pt-group-metal catalysts. Compared with SACs, the dual-atom catalysts (DACs) are attracting more attraction including higher metal loading, more versatile active sites, and excellent catalytic activity. Therefore, it is essential to explore the new universal methods approaching to the preparation, characterization, and to elucidate the catalytic mechanisms of the DACs. In this review, several general synthetic strategies and structural characterization methods of DACs are introduced and the involved oxygen catalytic mechanisms are discussed. Moreover, the state-of-the-art electrocatalytic applications including fuel cells, metal-air batteries, and water splitting have been sorted out at present. The authors hope this review has given some insights and inspiration to the researches about DACs in electro-catalysis.

Defect-Rich Single Atom Catalyst Enhanced Polysulfide Conversion Kinetics to Upgrade Performance of Li-S Batteries.

Lithium-sulfur (Li-S) batteries have attracted considerable attention owing to their extremely high energy densities. However, the application of Li-S batteries has been limited by low sulfur utilization, poor cycle stability, and low rate capability. Accelerating the rapid transformation of polysulfides is an effective approach for addressing these obstacles. In this study, a defect-rich single-atom catalytic material (Fe-N4/DCS) is designed. The abundantly defective environment is favorable for the uniform dispersion and stable existence of single-atom Fe, which not only improves the utilization of single-atom Fe but also efficiently adsorbs polysulfides and catalyzes the rapid transformation of polysulfides. To fully exploit the catalytic activity, catalytic materials are used to modify the routine separator (Fe-N4 /DCS/PP). Density functional theory and in situ Raman spectroscopy are used to demonstrate that Fe-N4 /DCS can effectively inhibit the shuttling of polysulfides and accelerate the redox reaction. Consequently, the Li-S battery with the modified separator achieves an ultralong cycle life (a capacity decay rate of only 0.03% per cycle at a current of 2 C after 800 cycles), and an excellent rate capability (894 mAh g-1 at 3 C). Even at a high sulfur loading of 5.51 mg cm-2 at 0.2 C, the reversible areal capacity still reaches 5.4 mAh cm-2 .

The consideration of surgery on primary lesion of advanced non-small cell lung cancer.

BACKGROUND: Numerous reports have shown that medical treatment confers excellent survival benefits to patients with advanced stage IV non-small cell lung cancer (NSCLC). However, the implications of surgery for primary lesions as palliative treatment remain inconclusive. METHODS: We retrospectively extracted clinical data from the Surveillance, Epidemiology, and End Results Program (SEER) database and selected patients with stage IV NSCLC. Patients were classified into non-surgery and surgery groups, and propensity score matching (PSM) analysis was performed to balance the baseline information. Patients in the surgery group, whose overall survival (OS) was longer than the median survival time of those in the non-surgery group, were deemed to benefit from surgery. We evaluated the efficacy of three surgical techniques, namely, local destruction, sub-lobectomy, and lobectomy, on the primary site in the beneficial population. RESULTS: The results of Cox regression analyses revealed that surgery was an independent risk factor for both OS (hazard ratio [HR]: 0.441; confidence interval [CI]: 0.426-0.456; P < 0.001) and cancer-specific survival (CSS) (HR: 0397; CI: 0.380-0.414; P < 0.001). Notably, patients who underwent surgery had a better prognosis than those who did not (OS: P < 0.001; CSS: P < 0.001). Moreover, local destruction and sub-lobectomy significantly compromised survival compared to lobectomy in the beneficial group (P < 0.001). After PSM, patients with stage IV disease who underwent lobectomy needed routine mediastinal lymph node clearing (OS: P = 0.0038; CSS: P = 0.039). CONCLUSION: Based on these findings, we recommend that patients with stage IV NSCLC undergo palliative surgery for the primary site and that lobectomy plus lymph node resection should be conventionally performed on those who can tolerate the surgery.

Urban-rural difference in the lagged effects of PM2.5 and PM10 on COPD mortality in Chongqing, China.

BACKGROUND: It is true that Chronic obstructive pulmonary disease (COPD) will increase social burden, especially in developing countries. Urban-rural differences in the lagged effects of PM2.5 and PM10 on COPD mortality remain unclear, in Chongqing, China. METHODS: In this study, a distributed lag non-linear model (DLNMs) was established to describe the urban-rural differences in the lagged effects of PM2.5, PM10 and COPD mortality in Chongqing, using 312,917 deaths between 2015 and 2020. RESULTS: According to the DLNMs results, COPD mortality in Chongqing increases with increasing PM2.5 and PM10 concentrations, and the relative risk (RR) of the overall 7-day cumulative effect is higher in rural areas than in urban areas. High values of RR in urban areas occurred at the beginning of exposure (Lag 0 ~ Lag 1). High values of RR in rural areas occur mainly during Lag 1 to Lag 2 and Lag 6 to Lag 7. CONCLUSION: Exposure to PM2.5 and PM10 is associated with an increased risk of COPD mortality in Chongqing, China. COPD mortality in urban areas has a high risk of increase in the initial phase of PM2.5 and PM10 exposure. There is a stronger lagging effect at high concentrations of PM2.5 and PM10 exposure in rural areas, which may further exacerbate inequalities in levels of health and urbanization.

Spatial association between green space and COPD mortality: a township-level ecological study in Chongqing, China.

BACKGROUND: There are regional differences in the effect of green space on mortality of Chronic obstructive pulmonary disease (COPD). We conduct an ecological study, using the administrative divisions of Chongqing townships in China as the basic unit, to investigate the association between COPD mortality and green space based on data of 313,013 COPD deaths in Chongqing from 2012 to 2020. Green space is defined by Fractional vegetation cover (FVC), which is further calculated based on the normalised vegetation index (NDVI) from satellite remote sensing imagery maps. METHODS: After processing the data, the non-linear relationship between green space and COPD mortality is revealed by generalised additive models; the spatial differences between green space and COPD mortality is described by geographically weighted regression models; and finally, the interpretive power and interaction of each factor on the spatial distribution of COPD mortality is examined by a geographic probe. RESULTS: The results show that the FVC local regression coefficients ranged from - 0.0397 to 0.0478, 63.0% of the regions in Chongqing have a positive correlation between green space and COPD mortality while 37.0% of the regions mainly in the northeast and west have a negative correlation. The interpretive power of the FVC factor on the spatial distribution of COPD mortality is 0.08. CONCLUSIONS: Green space may be a potential risk factor for increased COPD mortality in some regions of Chongqing. This study is the first to reveal the relationship between COPD mortality and green space in Chongqing at the township scale, providing a basis for public health policy formulation in Chongqing.

Diverse associations between adiposity and blood pressure among 80,000 multi-ethnic Chinese adults.

BACKGROUND: Adiposity is widely recognized as one of the risk factors for high blood pressure (BP) and increasing adiposity is associated with elevated BP. However, which measures of adiposity could be most strongly associated with BP in multi-ethnic population remains uncertain, giving rise to implications that population-based adiposity measures could be necessary. METHODS: 80,000 multi-ethnic adults recruited from 5 provinces across Southwest China during 2018 ~ 2019 were studied. Multiple linear regression was applied to investigate the associations of systolic blood pressure (SBP) with: (1) two measures of general adiposity, body mass index (BMI) and height-adjusted weight; and (2) three measures of central adiposity, waist circumference (WC), hip circumference (HC) and waist hip ratio (WHR). RESULTS: Two distinct population-specific patterns were identified, as "BMI to SBP" and "WC to SBP". 90% of the participants fall into "BMI to SBP" pattern, in which the associations of SBP with BMI were independent of WC, and SBP-WC associations were considerably decreased by adjustment for BMI. And in this pattern, 10 kg/m2 greater BMI was associated with 11.9 mm Hg higher SBP on average. As for the rest population (Han males in Yunnan and Tibetans in Lhasa), they are suited for "WC to SBP" pattern, 10 cm wider WC was associated with 3.4 mm Hg higher SBP. CONCLUSION: Our results indicated that when selecting proper predictors for BP, population-specific adiposity measures are needed, considering ethnicity, sex and residing regions. A better understanding of adiposity and BP may better contribute to the potential clinical practices and developing precision application strategies.

NLRP3 inflammasome-mediated choroid plexus hypersecretion contributes to hydrocephalus after intraventricular hemorrhage via phosphorylated NKCC1 channels.

BACKGROUND: Hydrocephalus is a severe complication of intracerebral hemorrhage with ventricular extension (ICH-IVH) and causes cerebrospinal fluid (CSF) accumulation. The choroid plexus epithelium plays an important role in CSF secretion and constitutes the blood-CSF barrier within the brain-immune system interface. Although the NLRP3 inflammasome, as a key component of the innate immune system, promotes neuroinflammation, its role in the pathogenesis of hydrocephalus after hemorrhage has not been investigated. Therefore, this study aimed to investigate the potential mechanism of NLRP3 in hydrocephalus to discover a potential marker for targeted therapy. METHODS: A rat model of hydrocephalus after ICH-IVH was developed through autologous blood infusion in wild-type and Nlrp3-/- rats. By studying the features and processes of the model, we investigated the relationship between the NLRP3 inflammasome and CSF hypersecretion in the choroid plexus. RESULTS: The ICH-IVH model rats showed ventricular dilation accompanied by CSF hypersecretion for 3 days. Based on the choroid plexus RNA-seq and proteomics results, we found that an inflammatory response was activated. The NLRP3 inflammasome was investigated, and the expression levels of NLRP3 inflammasome components reached a peak at 3 days after ICH-IVH. Inhibition of NLRP3 by an MCC950 inflammasome inhibitor or Nlrp3 knockout decreased CSF secretion and ventricular dilation and attenuated neurological deficits after ICH-IVH. The mechanism underlying the neuroprotective effects of NLRP3 inhibition involved decreased phosphorylation of NKCC1, which is a major protein that regulates CSF secretion by altering Na+- and K+-coupled water transport, via MCC950 or Nlrp3 knockout. In combination with the in vitro experiments, this experiment confirmed the involvement of the NLRP3/p-NKCC1 pathway and Na+ and K+ flux. CONCLUSIONS: This study demonstrates that NKCC1 phosphorylation in the choroid plexus epithelium promotes NLRP3 inflammasome-mediated CSF hypersecretion and that NLRP3 plays an important role in the pathogenesis of hydrocephalus after hemorrhage. These findings provide a new therapeutic strategy for treating hydrocephalus.

PARP-1 modulates the expression of miR-223 through histone acetylation to involve in the hydroquinone-induced carcinogenesis of TK6 cells.

The upstream regulators of microRNAs were rarely reported. Hydroquinone (HQ) is the main metabolite of benzene, one of the important environmental factors contributing to leukemia and lymphoma. In HQ-induced malignant transformed TK6 (TK6-HT) cells, the expression of PARP-1 and miR-223 were upregulated. When in PARP-1 silencing TK6-HT cells, miR-223 was downregulated and the apoptotic cell number correspondingly increased. In TK6 cells treated with HQ for different terms, the expression of miR-223 and PARP-1 were dynamically observed and found to be decreased and increased, respectively. Trichostatin A could increase the expression of miR-223, then the expression of HDAC1-2 and nuclear factor kappa B were found to be increased, but that of mH2A was decreased. PARP-1 silencing inhibited the protein expression of H3Ac, mH2A, and H3K27ac. By co-immunoprecipitation experiment, PARP-1 and HDAC2 were found to form a regulatory complex. In conclusion, we demonstrated that the upregulation of PARP-1 mediated activation of acetylation to promote the transcription of miR-223 possibly via coregulating with HDAC2, an epigenetic regulation mechanism involved in cell malignant transformation resulting from long-term exposure to HQ, in which course, H3K27ac might be a specific marker for the activation of histone H3, which also gives hints for benzene exposure research.

Comparison of Velocity and Percentage-based Training on Maximal Strength: Meta-analysis.

The purpose was to analyze the comparison of velocity-based resistance training and one-repetition maximum (%1RM) percentage-based training in maximal strength improvement by meta-analyzing and to find the reasons for the controversial findings of different studies. Ten studies were included in the systematic review and seven were subjected to meta-analysis. A total of 139 subjects were selected from the included articles after exclusion, including athletes of different specialties (N=93) and non-athletes mainly from fitness groups (N=46). The overall effect size was SMD=0.26 (95%CL 0.03 to 0.49, P=0.03, I²=0). As for the comparison of the analysis of different intervention objects as subgroups, the effect size of athletes as the subgroup was 0.35 (95%CI 0.06 to 0.64, p=0.02, I²=0), indicating that in the RCT with athletes as the intervention target, the effect of VBRT in improving the maximal strength was significantly different from that of PBT. Velocity-based resistance training might be more effective than percentage-based training in maximal strength improvement, in which velocity-based resistance training is more suitable for athletes in season, while percentage-based training is more suitable for the general sports population. More high-quality researches should deal with the effect of other athletic performance with velocity-based resistance training in the future.

Regulation of ARHGAP19 in the endometrial epithelium: a possible role in the establishment of uterine receptivity.

BACKGROUND: The establishment of uterine receptivity is essential for embryo implantation initiation and involves a significant morphological transformation in the endometrial epithelial cells (EECs). The remodeling of junctional complexes and membrane-associated cytoskeleton is crucial for epithelial transformation. However, little is known about how this process is regulated in EECs during the receptive phase. ARHGAP19 is a Rho GTPase-activating protein that participates in various cytoskeletal-related events, including epithelial morphogenesis. Here, we investigated the role of ARHGAP19 in endometrial epithelial transformation during the establishment of uterine receptivity. The upstream regulator of ARHGAP19 was also investigated. METHODS: ARHGAP19 expression was examined in mouse uteri during early pregnancy and in human EEC lines. The role of ARHGAP19 was investigated by manipulating its expression in EECs. The effect of ARHGAP19 on junctional proteins in EECs was examined by western blotting and immunofluorescence. The effect of ARHGAP19 on microvilli was examined by scanning electron microscopy. The upstream microRNA (miRNA) was predicted using online databases and validated by the dual-luciferase assay. The in vivo and in vitro effect of miRNA on endogenous ARHGAP19 was examined by uterine injection of miRNA agomirs and transfection of miRNA mimics or inhibitors. RESULTS: ARHGAP19 was upregulated in the receptive mouse uteri and human EECs. Overexpression of ARHGAP19 in non-receptive EECs downregulated the expression of junctional proteins and resulted in their redistribution. Meanwhile, upregulating ARHGAP19 reorganized the cytoskeletal structure of EECs, leading to a decline of microvilli and changes in cell configuration. These changes weakened epithelial cell polarity and promoted the transition of non-receptive EECs to a receptive phenotype. Besides, miR-192-5p, a miRNA that plays a key role in maintaining epithelial properties, was validated as an upstream regulator of ARHGAP19. CONCLUSION: These results suggested that ARHGAP19 may contribute to the transition of EECs from a non-receptive to a receptive state by regulating the remodeling of junctional proteins and membrane-associated cytoskeleton.

The DNMT1-associated lncRNA UCA1 was upregulated in TK6 cells transformed by long-term exposure to hydroquinone and benzene-exposed workers via DNA hypomethylation.

Exposure to benzene or its metabolite hydroquinone (HQ) is a risk factor for a series of myeloid malignancies, and long noncoding RNAs play an important role in the process of pathogenesis. Urothelial cancer-associated 1 (UCA1) functions as an oncogene in the development of acute myeloid leukemia. However, the association between DNMT1 and UCA1 with benzene or HQ exposure has not been explored. We characterized UCA1 expression in cells briefly exposed to HQ (HQ-ST cells) and HQ-induced malignantly transformed (TK6-HT cells) treated with 5-aza-2'-deoxycytidine (5-AzaC) or trichostatin A (TSA). Compared to that in control cells, UCA1 expression was increased, whereas DNMT1 was decreased in HQ-ST cells and TK6-HT cells treated with 5-AzaC or TSA. Moreover, UCA1 expression was also upregulated and positively correlated with benzene exposure time in benzene-exposed workers. Furthermore, the expression of UCA1 was negatively associated with the DNA methylation level of its promoter in benzene-exposed workers. DNMT1 rather than DNMT3b knockout in TK6-HT cells activated the expression of UCA1 by inducing its promoter hypomethylation. These results suggest that benzene or HQ exposure leads to UCA1 upregulation via DNA hypomethylation in the UCA1 promoter, which is mediated by DNMT1.

The Influence of Exercise Training on Endothelial Function, Serum Irisin and Inflammatory Markers in the Elderly with Metabolic Syndrome.

BACKGROUND: Although exercise has beneficial effects on metabolic syndrome (Mets), the effects of exercise training on endothelial function and irisin level in the elderly with MetS remain controversial. The aim of this study is to evaluate the influence of exercise training on endothelial function and serum irisin level in the elderly with MetS. METHODS: Volunteers with MetS were recruited (n = 30). After 8 consecutive weeks of exercise training, flow-mediated dilation (FMD), colony-forming units (CFU) of endothelial progenitor cell (EPC), and serum irisin level were determined. Body mass index (BMI), Homeostasis Model of Assessment of Insulin Resistance (HOMA-IR), and inflammatory markers were detected. RESULTS: Exercise training program improved endothelial function, increased EPC-CFU, decreased HOMA-IR and inflammatory markers in patients with metabolic syndrome. However, exercise training had no influence on the serum irisin level. Multivariate linear regression analysis showed that change of EPC-CFU and HOMA-IR were independent prognostic risk factors for change of FMD. CONCLUSIONS: Exercise training improved endothelial function, alleviated insulin resistance and inflammation in the elderly with MetS. The findings suggest that exercise training program is an effective means for the treatment of MetS in the elderly.

Diffusion tensor imaging and electrophysiology as robust assays to evaluate the severity of acute spinal cord injury in rats.

BACKGROUND: Diffusion tensor imaging (DTI) is an effective method to identify subtle changes to normal-appearing white matter (WM). Here we analyzed the DTI data with other examinations, including motor evoked potentials (MEPs), histopathological images, and behavioral results, to reflect the lesion development in different degrees of spinal cord injury (SCI) in acute and subacute stages. METHOD: Except for 2 Sprague -Dawley rats which died from the anesthesia accident, the rest 42 female rats were randomized into 3 groups: control group (n = 6), moderate group (n = 18), and severe group (n = 18). Moderate (a 50-g aneurysm clip with 0.4-mm thickness spacer) or severe (a 50-g aneurysm clip with no spacer) contusion SCI at T8 vertebrae was induced. Then the electrophysiological assessments via MEPs, behavioral deterioration via the Basso, Beattie, and Bresnaha (BBB) scores, DTI data, and histopathology examination were analyzed. RESULTS: In this study, we found that the damage of WM myelin, MEPs amplitude, BBB scores and the decreases in the values of fractional anisotropy (FA) and axial diffusivity (AD) were more obvious in the severe injury group than those of the moderate group. Additionally, the FA and AD values could identify the extent of SCI in subacute and early acute SCI respectively, which was reflected in a robust correlations with MEPs and BBB scores. While the values of radial diffusivity (RD) showed no significant changes. CONCLUSIONS: Our data confirmed that DTI was a valuable in ex vivo imaging tool to identify damaged white matter tracts after graded SCI in rat, which may provide useful information for the early identification of the severity of SCI.

Development of indazole mineralocorticoid receptor antagonists and investigation into their selective late-stage functionalization.

The derivatization of pharmaceuticals is a core activity in the discovery and development of new medicines. Late-stage functionalization via modern CH functionalization chemistry has emerged as a powerful technique with which to diversify advanced pharmaceutical intermediates. We report herein a case study in late-stage functionalization towards the development of a new class of indazole-based mineralocorticoid receptor antagonists (MRA). An effort to modify the electronics of the core indazole heterocycle inspired the use of modern CH borylation chemistry. New reactivity patterns were revealed and studied computationally. Ultimately, a de novo synthesis delivered a key 6-fluoroindazole compound 26, a potent MRA with excellent metabolic stability.

E4F1 silencing inhibits the cell growth through cell-cycle arrest in malignant transformed cells induced by hydroquinone.

Hydroquinone (HQ), one of the most significant metabolic activation products of benzene in an organism, can cause hematological toxicity, such as acute myeloid leukemia. It is a clear carcinogen that can cause changes in the disorder of cell cycle and cell growth. However, its molecular mechanisms remain unclear. E4 transcription factor 1 (E4F1), an important transcription factor, participating in the regulation of cell cycle may be related to the occurrence of tumor. Here, we examined the HQ-induced malignant transformed TK6 cells (TK6-HT) to illustrate the role of E4F1 in carcinogenesis. The present study showed that both the expressions of E4F1 messenger RNA and protein increased obviously in TK6-HT, preliminarily indicating that E4F1 is associated with HQ-induced carcinogenesis. To further explore the role of E4F1, we established E4F1 silencing TK6-HT (pLVX-shE4F1) and its control cells (pLVX-shNC) using lentiviral short hairpin RNA (shRNA) interference expression plasmid vector pLVX-shRNA. Flow cytometry and cell counting kit-8 assay were used to determine the effects of E4F1 silencing on cell cycle and cell growth, respectively. E4F1 silencing inhibited cell growth in TK6-HT. The results from flow cytometry indicated that the inhibitory effect on cell growth may be the results of the E4F1 silencing-induced accumulation in G2/M compared with TK6-HT-shNC. Meanwhile, levels of DNA damage (γ-H2AX), proteins of Rb and phosphorylated Rb, and reactive oxygen species were increased in TK6-HT-shRNA2 cells, which is the critical reason of cell-cycle arrest. In conclusion, E4F1 silencing inhibits the cell growth through cell-cycle arrest in malignant transformed cells induced by HQ.

Using Functionalized Graphene Oxide as Carrier for Immobilization of Glutaryl-7-Aminocephalosporanic Acid Acylase.

Graphene oxide has been widely used in biological applications because of good biocompatibility. In the present work, graphene oxide was synthesized successfully and was employed to immobilize glutaryl-7-aminocephalosporanic acid acylase (GLA). The immobilization conditions like pH, temperature, immobilization time, and enzyme/carrier ratio were investigated. Under the optimal immobilization conditions, the immobilization yield and efficiency were 86% and 52%, respectively. The characterization of the immobilized GLA was performed and compared with the free enzyme. The results indicated that the stability of the immobilized GLA was 1.7-folds than that of the free enzyme, and the kinetic parameters were also calculated. All these results show the potential industrial applications of the immobilized GLA in the production of 7-aminocephalosporinal acid (7-ACA).