[Characteristics and Source Apportionment of Volatile Organic Compounds (VOCs) in a Typical Industrial Area in Dongguan During Periods of Ozone and Non-ozone Pollution in Summer].

To investigate the characteristics and sources of atmospheric volatile organic compounds (VOCs) in a typical industrial zone in Dongguan, 56 VOCs species were continuously measured in Houjie Town of Dongguan in summer of 2020. In addition, mass concentrations of O3, NOx, and CO and meteorological data were synchronously collected. Then, characteristics of total VOCs and major species, the contributions of major VOCs species to ozone formation potential (OFP), and source apportionment of VOCs under the different ozone concentrations were discussed. The mean mixing ratio of VOCs was 53.1×10-9 including aromatics (24.7×10-9), alkanes (23.7×10-9), alkenes (3.9×10-9), and alkynes (0.7×10-9). The mean mixing ratios of aromatics, alkanes, alkenes, and alkynes increased approximately 10%, 43%, 38%, and 98% during the period of ozone pollution, respectively, compared with those during the period of non-ozone pollution. Aromatics contributed the most to OFP during the periods of both ozone pollution and non-ozone pollution, followed by alkanes, alkenes, and alkynes. Solvent sources, liquefied petroleum gas (LPG) leakage, fossil fuel combustion, and hydrocarbon volatilization were resolved using the PMF model, which accounted for 60%±20%, 16%±11%, 15%±11%, and 9%±6% of total VOCs, respectively. During the period of ozone pollution, the contribution of solvent sources to the total VOCs decreased to 44%, whereas that of LPG leakage and hydrocarbon volatilization increased to 21% and 16%, respectively.

Associations between serum uric acid and hepatobiliary-pancreatic cancer: A cohort study.

BACKGROUND: Uric acid is the end product of purine metabolism. Previous studies have found that serum uric acid (SUA) levels are associated with the total cancer risk. However, due to the dual effect of uric acid on cancer, the relationship between the SUA levels and most specific-site cancer remains unclear. AIM: To investigate the associations between the SUA levels and incidence of hepatobiliary-pancreatic cancer. METHODS: In this prospective cohort study, 444462 participants free of cancer from the UK Biobank were included. The SUA levels were measured at baseline, and the incidence of hepatobiliary-pancreatic cancer was determined by contacting the cancer registry. The hazard ratios (HRs) and 95% confidence intervals (CIs) between the SUA levels and hepatobiliary-pancreatic cancer were investigated using multiple adjusted Cox regression models adjusted for potential confounders. RESULTS: In total, 920 participants developed liver, gallbladder, biliary tract or pancreatic cancer during a median of 6.6 yrs of follow-up. We found that the HR of pancreatic cancer in the highest SUA group was 1.77 (95%CI: 1.29-2.42) compared with that in the lowest group. After stratifying by gender, we further found that SUA was associated with an increased risk of pancreatic cancer only among the females (highest quartile vs lowest quartile HR 2.04, 95%CI: 1.35-3.08). Among the males, the SUA levels were positively associated with the gallbladder cancer risk (highest quartile vs lowest quartile HR 3.09, 95%CI: 1.28-7.46), but a U-shaped association with the liver cancer risk was observed (P-nonlinear = 0.03). CONCLUSION: SUA is likely to have gender-specific effects on hepatobiliary-pancreatic cancer. High SUA levels are a risk factor for pancreatic cancer in females and gallbladder cancer in males. A U-shaped association with the liver cancer risk was identified.

Ubc9 Attenuates Myocardial Ischemic Injury Through Accelerating Autophagic Flux.

AIMS: SUMOylation is a post-translational modification that plays a crucial role in the cellular stress response. We aimed to demonstrate whether and how the SUMO E2 conjugation enzyme Ubc9 affects acute myocardial ischemic (MI) injury. METHODS AND RESULTS: Adenovirus expressing Ubc9 was administrated by multipoint injection in the border zone of heart immediately after MI in C57BL/6 mice. Neonatal rat cardiomyocytes (NRCMs) were also infected, followed by oxygen and glucose deprivation (OGD). In vivo, Ubc9 adenovirus-injected mice showed decreased cardiomyocyte apoptosis, reduced myocardial fibrosis, and improved cardiac function post-MI. In vitro, overexpression of Ubc9 decreased cardiomyocyte apoptosis, whereas silence of Ubc9 showed the opposite results during OGD. We next found that Ubc9 significantly decreased the accumulation of autophagy marker p62/SQSTM, while the LC3 II level hardly changed. When in the presence of bafilomycin A1 (BAF), the Ubc9 adenovirus plus OGD group presented a higher level of LC3 II and GFP-LC3 puncta than the OGD group. Moreover, the Ubc9 adenovirus group displayed increased numbers of yellow plus red puncta and a rising ratio of red to yellow puncta on the mRFP-GFP-LC3 fluorescence assay, indicating that Ubc9 induces an acceleration of autophagic flux from activation to degradation. Mechanistically, Ubc9 upregulated SUMOylation of the core proteins Vps34 and Beclin1 in the class III phosphatidylinositol 3-kinase (PI3K-III) complexes and boosted the protein assembly of PI3K-III complex I and II under OGD. Moreover, the colocalization of Vps34 with autophagosome marker LC3 or lysosome marker Lamp1 was augmented after Ubc9 overexpression, indicating a positive effect of Ubc9-boosted protein assembly of the PI3K-III complexes on autophagic flux enhancement. CONCLUSIONS: We uncovered a novel role of Ubc9 in protecting cardiomyocytes from ischemic stress via Ubc9-induced SUMOylation, leading to increased PI3K-III complex assembly and autophagy-positioning. These findings may indicate a potential therapeutic target, Ubc9, for treatment of myocardial ischemia.

Inhibitory effect of α1D/1A antagonist 2-(1H-indol-3-yl)-N-[3-(4-(2-methoxyphenyl) piperazinyl) propyl] acetamide on estrogen/androgen-induced rat benign prostatic hyperplasia model in vivo.

Benign prostatic hyperplasia (BPH) is a common disorder of the urinary system in aging men. 2-(1H-indol-3-yl)-N-[3-(4-(2-methoxyphenyl) piperazinyl) propyl] acetamide (HJZ-3), which is derived from naftopidil, exhibited 97.7- and 64.6-fold greater inhibitory effects for a1D adrenoceptor than for a1B- and a1A-adrenoceptors in vitro, respectively. To investigate the therapeutic potential for treating BPH, we evaluated the pharmacological activity of HJZ-3. Specifically, we evaluated through estrogen/androgen-induced rat benign prostatic hyperplasia model in vivo. HJZ-3 effectively prevented the progression of rat prostatic hyperplasia by suppressing the increase in prostate index and reducing the quantitative analysis of the relative acinus volume, relative stroma, epithelial volume and epithelial thickness and expression of proliferating cell nuclear antigen and α-smooth muscle actin. HJZ-3 decreased α1A- and α1D-adrenoceptor protein expressions in prostate tissue. HJZ-3 is a good alternative for α1A- and α1D-adrenoceptor blocker. It may relax smooth muscle tone and relieve symptoms of BPH.

Piperazine-Derived α1D/1A Antagonist 1- Benzyl-N- (3-(4- (2-Methoxyphenyl) Piperazine-1-yl) Propyl) -1H- Indole-2- Carboxamide Induces Apoptosis in Benign Prostatic Hyperplasia Independently of α1-Adrenoceptor Blocking.

Previous studies have indicated that α1D/1A antagonist naftopidil (NAF) suppresses prostate growth by decreasing cell proliferation without affecting apoptosis and prostate volume in benign prostatic hyperplasia (BPH). A NAF-derived α1D/1A antagonist 1- benzyl-N-(3-(4-(2-methoxyphenyl) piperazine-1-yl) propyl)-1H-indole-2- carboxamide (HJZ-12) has been reported from our laboratory, which exhibits high subtype-selectivity to both α1D- and α1A- AR (47.9- and 19.1- fold, respectively) with respect to a1B-AR in vitro. However, no further study was conducted. In the present study, a pharmacological evaluation of HJZ-12 in BPH was performed on an estrogen/androgen-induced rat BPH model and human BPH-1 cell line. In vivo, HJZ-12 exhibited better performance than NAF in preventing the progression of rat prostatic hyperplasia by not only decreasing prostate weight and proliferation (similar to NAF) but also, shrinking prostate volume and inducing prostate apoptosis (different from NAF). In vitro, HJZ-12 exhibited significant cell viability inhibition and apoptotic induction in BPH-1 cell line, without presenting cell anti-proliferation properties. Intriguingly, the role of HJZ-12 on cell viability and apoptosis was an α1-independent action. Furthermore, RNA-Seq analysis was applied to screen out six anti-apoptotic genes (Bcl-3, B-lymphoma Mo-MLV insertion region 1 [Bmi-1], ITGA2, FGFR3, RRS1, and SGK1). Amongst them, Bmi-1 was involved in the apoptotic induction of HJZ-12 in BPH-1. Overall, HJZ-12 played a remarkable role in preventing the progression of prostatic hyperplasia through α1-independent apoptotic induction, indicating that it will be a multi-target effective candidate for BPH treatment.

HIF­1α promotes NLRP3 inflammasome activation in bleomycin­induced acute lung injury.

The inflammatory response is one of the most important factors in the occurrence and development of acute lung injury (ALI). Hypoxia­inducible factor­1α (HIF­1α) and the NOD­like receptor 3 (NLRP3) inflammasome have been demonstrated to serve an important role in the pathogenesis of ALI. The objective of the present study was to investigate whether HIF­1α could regulate activation of the NLRP3 inflammasome and its potential function and specific mechanism in bleomycin (BLM)­induced ALI. Activation of the NLRP3 inflammasome and secretion of IL­1ß were detected following silencing of HIF­1α or NF­κB, respectively, in BLM­treated A549 and RLE­6TN cells. The results demonstrated that the NLRP3 inflammasome could be activated after BLM treatment. HIF­1α and NF­κB expression significantly increased in the BLM group. The levels of NF­κB­ and NLRP3 inflammasome­associated proteins, including NLRP3, apoptosis­associated speck­like protein containing CARD and caspase­1, markedly decreased after treating A549 and RLE­6TN cells with HIF­1α small interfering RNA. Activation of the NLRP3 inflammasome was also inhibited after silencing NF­κB. Furthermore, the levels of IL­1ß markedly decreased in the cellular culture supernatants following inhibition of HIF­1α and NF­κB. Therefore, the present study indicated that HIF­1α could modulate the activation of the NLRP3 inflammasome and the secretion of IL­1ß through NF­κB signaling in BLM­induced ALI. The current results improve understanding of the mechanism of ALI and may provide new ideas for identifying therapeutic targets of ALI.

(1-aryloxy-2-hydroxypropyl)-phenylpiperazine derivatives suppress Candida albicans virulence by interfering with morphological transition.

Clinical treatment of Candida albicans infections has become more difficult due to the limited development of antifungal agents and the rapid emergence of drug resistance. In this study, we demonstrate the synthesis of a series of piperazine derivatives and the evaluation of their inhibitory activity against C. albicans virulence. Thirty-four (1-aryloxy-2-hydroxypropyl)-phenylpiperazine derivatives, including 25 new compounds, were synthesized and assessed for their efficacy against the physiology and pathogenesis of C. albicans. Several compounds strongly inhibited the morphological transition and virulence of C. albicans cells, although they did not influence the growth rate of the fungal pathogen. A leading novel compound, (1-(4-ethoxyphenyl)-4-(1-biphenylol-2-hydroxypropyl)-piperazine), significantly attenuated C. albicans virulence by interfering with the process of hyphal development, but it showed no cytotoxicity against human cells at a micromolar level. These findings suggest that (1-aryloxy-2-hydroxypropyl)-phenylpiperazine derivatives could potentially be developed as novel therapeutic agents for the clinical treatment of C. albicans infections by interfering with morphological transition and virulence.

Novel naftopidil derivatives containing methyl phenylacetate and their blocking effects on α1D/1A-adrenoreceptor subtypes.

α1-Adrenoceptor (α1-AR) antagonists are considered to be the most effective monotherapy agents for lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH). In this study, we synthesized compounds 2-17, which are novel piperazine derivatives that contain methyl phenylacetate. We then evaluated the vasodilatory activities of these compounds. Among them, we found that compounds 2, 7, 12, which contain 2-OCH3, 2-CH3 or 2, 5-CH3, respectively, exhibited potent α1-blocking activity similar to protype drug naftopidil (1). The antagonistic effects of 2, 7, and 12 on the (-)-noradrenaline-induced contractile response of isolated rat prostatic vas deferens (α1A), spleen (α1B) and thoracic aorta (α1D) were further characterized to assess the sub receptor selectivity. Compared with naftopidil (1) and terazosin, compound 12 showed the most desirable α1D/1A subtype selectivity, especially improved α1A subtype selectivity, and the ratios pA2 (α1D)/pA2 (α1B) and pA2 (α1A)/pA2 (α1B) were 17.0- and 19.5-fold, respectively, indicating less cardiovascular side effects when used to treat LUTS/BPH. Finally, we investigated the chiral pharmacology of 12. We found, however, that the activity of enantiomers (R)-12 and (S)-12 are not significantly different from that of rac-12.

[Effect and mechanism of total flavone of epimedium on primary callus formation in ovariectomized rats with fractures].

OBJECTIVE: To explore the effects and related mechanisms of total flavone of epimedium treatment(TFE)on primary callus for mation in ovariectomized rats. METHODS: Forty male SD rats weighted from 209 to 246 g and aged 6 to 8 weeks were selected. Six weeks after ovariectomy a femur fracture model with middiaphyseal segment fracture was established, estimated and randomly divided into TFE group (150 mg·kg⁻¹·d⁻¹) and control group(received saline). HE staining was used to evaluate the morphologic difference of primary callus during the bone callus healing between these two groups. The relative expression of Runt-related transcription factor 2(Runx2) mRNA in the callus was identified by real-time polymerase chain reaction. Immunohistochemical technique was used to observe the Casein kinase 2-interacting protein 1(CKIP-1) protein level in the callus of the two groups. Maximum fracture load was tested by three point bend test. RESULTS: The BMD, primary callus volume, trabecular member(Tb.N) and trabecular thickness(Tb.Th) were higher in TFE group than that in control group(P<0.001). The Tb.N and Tb.Th of primary callus were higher in TFE group than control group (P=0.001). The volume and bone volume/tissue volume of primary callus were in TFE group than control group(P<0.01). The trabecular separation(Tb.Sp) of primary callus were in control group higher than TFE group(P<0.01). The HE staining of the 6 week slices showed that the degree of cartilage ossification in callus of the TFE group was significantly higher than that in control group under high magnification. Real-time PCR revealed that the comparative expression of Runx2 mRNA in control group was higher than that in TFE group(P<0.001); the positive number of CKIP-1 was less in TFE group than that in control group (P<0.001). TFE could increase the maximum load of the primary callus (P<0.001). CONCLUSIONS: TFE can promote the cartiage ossification of callus in ovariectomized rats, enhancing the bone strength and bone quality in the process of fracture healing via the CKIP-1/Runx2 pathway.

Human UDP-Glucuronosyltransferase 2B4 and 2B7 Are Responsible for Naftopidil Glucuronidation in Vitro.

Naftopidil (NAF) is widely used for the treatment of benign prostatic hyperplasia and prevention of prostate cancer in elderly men. These patients receive a combination of drugs, which involves high risk for drug-drug interaction. NAF exhibits superior efficacy but must be administered at a much higher dosage than other therapeutic drugs. We previously showed that extensive glucuronidation of NAF enantiomers caused poor bioavailability. However, the metabolic pathway and mechanism of action of NAF enantiomer remain to be elucidated. The present study was performed to identify the human UDP-glucuronosyltransferases (UGTs) responsible for the glucuronidation of NAF enantiomers and to investigate the potential inhibition of UGT activity by NAF. The major metabolic sites examined were liver and kidney, which were compared with intestine. Screening of 12 recombinant UGTs showed that UGT2B7 primarily contributed to the metabolism of both enantiomers. Moreover, enzyme kinetics for R(+)-NAF, UGT2B7 (mean Km, 21 µM; mean Vmax, 1043 pmol/min/mg) showed significantly higher activity than observed for UGT2B4 and UGT1A9. UGT2B4 (mean Km, 55 µM; mean Vmax, 1976 pmol/min/mg) and UGT2B7 (mean Km, 38 µM; mean Vmax, 1331 pmol/min/mg) showed significantly higher catalysis of glucuronidation of S(-)-NAF than UGT1A9. In human liver microsomes, R(+)-NAF and S(-)-NAF also inhibited UGT1A9: mean Ki values for R(+)-NAF and S(-)-NAF were 10.0 µM and 11.5 µM, respectively. These data indicate that UGT2B7 was the principal enzyme mediating glucuronidation of R(+)-NAF and S(-)-NAF. UGT2B4 plays the key role in the stereoselective metabolism of NAF enantiomers. R(+)-NAF and S(-)-NAF may inhibit UGT1A9. Understanding the metabolism of NAF enantiomers, especially their interactions with metabolic enzymes, will help to elucidate potential drug-drug interactions and to optimize the administration of this medicine.

Observation of the clinical efficacy of Yiqi Yangxue Qufeng therapy in the treatment of recurrent patients with herpes simplex keratitis / 国际眼科杂志(Guoji Yanke Zazhi)

·AIM: To observe the clinical efficacy of Yiqi Yangxue Qufeng therapy ( Heijing Tuiyi Decoction ) in current patients with herpes simplex keratitis.· METHODS: Totally 58 cases with recurrent herpes simplex keratitis patients were selected, then randomly divided into treatment group and control group. Patients in the control group were be treated with recombinant human interferon α - 2b eye drop and ganciclovir ophthalmic gel, patients with iridocyclitis and corneal endothelitis were treated with compound tropicamide eye drops for mydriasis. Fluorometholone eye drops was used to treat eye diseases according to the circumstances, while patients in the treatment group were treated by Heijing Tuiyi Decoction on the basis of the control group. All patients were be treated for 4wk, observed the clinical therapeutic effect and recurrence rate of the disease within 6mo.· RESULTS: There was significant difference in the clinical curative effect and the recurrence rate between the 2 groups (P<0. 05). Compared with before treatment, the CD4+ ratio and CD4+/CD8+ ratio significantly increased after treatment, and significantly higher than that of the control group ( P < 0. 01 ); CD8 + of treatment group significantly decreased and was significantly lower than the control group (P<0. 01).· CONCLUSION: Yiqi Yangxue Qufeng method of traditional Chinese medicine Heijing Tuiyi Decoction combined with conventional antiviral medicine treatment, is better for patients with herpes simplex keratitis, prevent its recurrence, improve clinical efficacy, thereby improves the life quality of patients.

Pharmaceutical evaluation of naftopidil enantiomers: Rat functional assays in vitro and estrogen/androgen induced rat benign prostatic hyperplasia model in vivo.

Naftopidil (NAF) is a α1D/1A adrenoceptor selective drug used for the treatment of both benign prostatic hyperplasia and lower urinary tract symptoms (BPH/LUTS). However, NAF is used as a racemate in clinic. To compare the differences and similarities among two enantiomers and racemate, pharmacological activities were evaluated through rat functional assays in vitro and estrogen/androgen (E/T) induced rat BPH model in vivo. NAF and the two enantiomers showed similar blocking activity on α1 receptor. S-NAF exhibited more α1D/1A adrenoceptor subtype selectivity than R-NAF and the racemate. The selectivity ratios pA2 (α1D)/pA2 (α1B) and pA2 (α1A)/pA2 (α1B) were 40.7- and 16.2-fold, respectively. NAF and its enantiomers effectively prevented the development of rat prostatic hyperplasia via suppressing the increase of the prostatic wet weight, visually. The quantitative analysis of the relative acinus volume, relative stroma volume, relative epithelial volume, epithelial height and expression of proliferating cell nuclear antigen (PCNA) and α-smooth muscle actin (α-SMA) were carried out. S-NAF showed an advantage on the effect of inhibiting prostate wet weight and stroma volume over R-NAF and racemate NAF (P<0.05). Nevertheless, no other significant difference was observed between these two enantiomers. In conclusion, both R-NAF and S-NAF not only relax prostate muscle but also inhibit the prostate growth, thus relieve BPH.

X-ray Crystallography, DFT Calculations and Molecular Docking of Indole-Arylpiperazine Derivatives as α1A-Adrenoceptor Antagonists.

Indole-arylpiperazine derivatives have exhibited good selectivity for the α1A-adrenoceptor, but the structure-activity-binding mechanism relationship remains unclear. In the current study, three compounds (1, 2 and 3) were investigated through single-crystal X-ray diffraction analysis, density functional theory (DFT) calculations and molecular docking using a homology model of the α1A receptor. Compounds 1 and 3 form H-bonds networks to stabilize their three-dimensional structures, while C-H···π interactions play a significant role in the packing of 2. Based on DFT-optimized conformations, the HOMO-LUMO energy gaps and molecular electrostatic potential (MEP) were theoretically calculated at the B3LYP/6-311G (d, p) level of theory. Chemical reactivity increases in the order of 3 < 2 < 1, and the maximum positive region of the MEP maps is mainly localized over the NH group. The binding mechanisms of ligand-α1A-adrenoceptor complexes were illustrated by molecular docking. Binding to Gln177 of the second extracellular loop region via hydrogen bonds is likely to be essential for α1A-selective antagonists. The present work sheds light on the studies of structure-activity-binding mechanism and aids in the design of α1A antagonists with high selectivity.

Expression patterns of two Arabidopsis endo-beta-1,4-glucanase genes (At3g43860, At4g39000) in reproductive development.

Endo-beta-1,4-D-glucanases (EGases) are a widespread and vital group of glycosyl hydrolases that generally break the beta-1,4-glucosyl linkages. Studies of plant EGases have mainly been concentrated on vegetative growth, while little is currently known about their role in reproductive processes. Using the GUS reporter aided analysis of promoter activities, we identified the expression patterns of two putative Arabidopsis EGases genes (At3g43860 and At4g39000) whose promoters conferred specific localization of the GUS activity in reproductive organs. We found that At3g43860, which is similar to KOR in its protein structural organization, is expressed in mature pollen and the pollen tube, implying that it may have a role in pollen and pollen tube growth. At4g39000 was found to be activated in the developing ovules and seeds, especially at the micropylar end of the inner integuments and nucellus in a proximal-distal pattern. Our results suggested that the two EGases play specific roles in Arabidopsis sexual reproduction.

[Clinical study of prevention of epidural scar and adhesion with polylactic acid membrane].

OBJECTIVE: To investigate the clinical effect of polylactic acid membrane in prevention of epidural scar and adhesion. METHODS: From July 1998 to April 2000, 62 patients with lumbar disc herniation were randomly assigned into two groups. All were treated surgically with discectomy by fenestration or laminectomy. One group were placed with a thin of polylactic acid membrane covering the interlaminar space(n = 32). The thickness of the film was 0.1 mm. The other group was blank control(n = 30). After 2 weeks of operation, we observed the local and systemic reactions. After 6 months clinical symptoms were revaluated and the degrees of epidural scar and adhesion were determined by CT scans. RESULTS: After 2 weeks, we found no adverse systemic reactions in all patients. Wound healing was excellent. No abnormalities of hepatic and renal functions as well as blood for routine were found. Temperature after operation was normal. After 6 months, the curative effects were as follows in experimental group and in control group: excellent in 27 patients and in 24 patients, good in 4 patients and in 4 patients, fair in 1 patient and in 1 patient, and poor in 0 patient and in 1 patient, respectively. There are no significant difference between two groups. The CT scans showed no adhesion between the epidural scar and the dural sac in all patients of experimental group. There existed various extents of adhesion in control group. CONCLUSION: The results demonstrate that the polylactic acid membrane can effectively prevent the epidural scar adhesion with a good biocompatibility and no toxity. Its clinical application was promising.