Identifying potential monkeypox virus inhibitors: an in silico study targeting the A42R protein.

Monkeypox (now Mpox), a zoonotic disease caused by the monkeypox virus (MPXV) is an emerging threat to global health. In the time span of only six months, from May to October 2022, the number of MPXV cases breached 80,000 and many of the outbreaks occurred in locations that had never previously reported MPXV. Currently there are no FDA-approved MPXV-specific vaccines or treatments, therefore, finding drugs to combat MPXV is of utmost importance. The A42R profilin-like protein of the MPXV is involved in cell development and motility making it a critical drug target. A42R protein is highly conserved across orthopoxviruses, thus A42R inhibitors may work for other family members. This study sought to identify potential A42R inhibitors for MPXV treatment using computational approaches. The energy minimized 3D structure of the A42R profilin-like protein (PDB ID: 4QWO) underwent virtual screening using a library of 36,366 compounds from Traditional Chinese Medicine (TCM), AfroDb, and PubChem databases as well as known inhibitor tecovirimat via AutoDock Vina. A total of seven compounds comprising PubChem CID: 11371962, ZINC000000899909, ZINC000001632866, ZINC000015151344, ZINC000013378519, ZINC000000086470, and ZINC000095486204, predicted to have favorable binding were shortlisted. Molecular docking suggested that all seven proposed compounds have higher binding affinities to A42R (-7.2 to -8.3 kcal/mol) than tecovirimat (-6.7 kcal/mol). This was corroborated by MM/PBSA calculations, with tecovirimat demonstrating the highest binding free energy of -68.694 kJ/mol (lowest binding affinity) compared to the seven shortlisted compounds that ranged from -73.252 to -97.140 kJ/mol. Furthermore, the 7 compounds in complex with A42R demonstrated higher stability than the A42R-tecovirimat complex when subjected to 100 ns molecular dynamics simulations. The protein-ligand interaction maps generated using LigPlot+ suggested that residues Met1, Glu3, Trp4, Ile7, Arg127, Val128, Thr131, and Asn133 are important for binding. These seven compounds were adequately profiled to be potential antivirals via PASS predictions and structural similarity searches. All seven potential lead compounds were scored Pa > Pi for antiviral activity while ZINC000001632866 and ZINC000015151344 were predicted as poxvirus inhibitors with Pa values of 0.315 and 0.215, and Pi values of 0.052 and 0.136, respectively. Further experimental validations of the identified lead compounds are required to corroborate their predicted activity. These seven identified compounds represent solid footing for development of antivirals against MPXV and other orthopoxviruses.

Screening of growth inhibitors for epithelial-mesenchymal transition-induced cells by TGF-ß from plant-based sources identified the active compound hydroxychavicol from Piper bitle.

Epithelial-mesenchymal transition (EMT) has recently been associated with cancer invasion, metastasis, and resistance. In our previous study, we discovered nanaomycin K, a natural growth inhibitor for EMT-induced Madin Darby canine kidney (MDCK) cells, from the cultured broth of actinomycetes. However, the screening method was undeveloped, because the activity of nanaomycin K was discovered accidentally. In this study, we established a screening method by analyzing the characteristics of nanaomycin K in MDCK cells. Nanaomycin K showed the characteristic growth inhibitory activity on MDCK cells cultured under four conditions: medium containing dimethyl sulfoxide, SB431542, TGF-ß, and a mixture of SB431542 and TGF-ß. The activity was stronger in TGF-ß-treated cells than in DMSO-treated cells. In the mixture of SB431542 and TGF-ß-treated cells, the activity of nanaomycin K was suppressed. The anti-cancer agents, mitomycin C, cisplatin, and staurosporine, lacked the characteristics as that of nanaomycin K for these four treatment conditions. Since these four conditions distinguish between the effects of nanaomycin K and other anti-cancer agents in EMT-induced cells, the screening method was established. Among the 13,427 plant extracts tested, Piper betle leaf extract displayed growth inhibitory activity against EMT-induced cells. Through the purification of the extract via bio-guided fractionation, hydroxychavicol was isolated as an active compound. The cytotoxic activity of hydroxychavicol was stronger in EMT-induced MDCK cells than in control cells. However, its cytotoxic activity was suppressed in EMT-inhibited cells. Furthermore, hydroxychavicol exhibited same activity against SAS cells (human squamous cell carcinoma of the tongue). Thus, we have successfully established a screening method for growth inhibitors of EMT-induced cells and have discovered an inhibitor from plant-based sources.

Determination of enzalutamide long-term safety and efficacy for castration-resistant prostate cancer patients after combined anti-androgen blockade followed by alternative anti-androgen therapy: a multicenter prospective DELC study.

BACKGROUND: Alternative anti-androgen therapy has been widely used as a first-line treatment for castration-resistant prostate cancer, and it may affect treatment outcome of subsequent agents targeting the androgen receptor axis. We conducted the prospective observational DELC (Determination of Enzalutamide Long-term safety and efficacy for Castration-resistant prostate cancer patients after combined anti-androgen blockade followed by alternative anti-androgen therapy) study to evaluate the efficacy of enzalutamide in patients with castration-resistant prostate cancer who underwent prior combined androgen blockade with bicalutamide and then alternative anti-androgen therapy with flutamide. METHODS: The DELC study enrolled 163 Japanese patients with castration-resistant prostate cancer who underwent alternative anti-androgen therapy with flutamide following failure of initial combined androgen blockade with bicalutamide in multiple institutions between January 2016 and March 2019. Primary endpoint was overall survival. Administration of enzalutamide was started at 160 mg orally once daily in all patients. RESULTS: The rate of decline of prostate-specific antigen by 50% or more was 72.2%, and median overall survival was 42.05 months. Multivariate analysis revealed that higher pretreatment serum levels of prostate-specific antigen (≥11.3 ng/mL; P = 0.004), neuron-specific enolase (P = 0.014) and interleukin-6 (≥2.15 pg/mL; P = 0.004) were independent risk factors for overall survival. Fatigue (30.0%), constipation (19.6%) and appetite loss (17.8%) were the most common clinically relevant adverse events. The enzalutamide dose was not reduced in any patient under the age of 70, but adherence was decreased in those over 70. CONCLUSIONS: In the DELC study, the safety of enzalutamide was comparable to that in previous reports. Serum levels of neuron-specific enolase and interleukin-6 were suggested as prognostic factors for castration-resistant prostate cancer with potential clinical utility.

Seladelpar combined with complementary therapies improves fibrosis, inflammation, and liver injury in a mouse model of nonalcoholic steatohepatitis.

Seladelpar, a selective peroxisome proliferator-activated receptor δ (PPARδ) agonist, improves markers of hepatic injury in human liver diseases, but histological improvement of nonalcoholic steatohepatitis (NASH) and liver fibrosis has been challenging with any single agent. To discover how complementary agents could work with seladelpar to achieve optimal outcomes, this study evaluated a variety of therapeutics (alone and in combination) in a mouse model of NASH. Mice on a high-fat amylin liver NASH (AMLN) diet were treated for 12 wk with seladelpar, GLP-1-R (glucagon-like peptide-1 receptor) agonist liraglutide, apoptosis signal-regulating kinase 1 (ASK1) inhibitor selonsertib, farnesoid X receptor (FXR) agonist obeticholic acid, and with seladelpar in combination with liraglutide or selonsertib. Seladelpar treatment markedly improved plasma markers of liver function. Seladelpar alone or in combination resulted in stark reductions in liver fibrosis (hydroxyproline, new collagen synthesis rate, mRNA indices of fibrosis, and fibrosis staining) compared with vehicle and the other single agents. Robust reductions in liver steatosis were also observed. Seladelpar produced a reorganization of metabolic gene expression, particularly for those genes promoting peroxisomal and mitochondrial lipid oxidation. In summary, substantial improvements in NASH and NASH-induced fibrosis were observed with seladelpar alone and in combination with liraglutide in this model. Broad gene expression analysis suggests seladelpar should be effective in concert with diverse mechanisms of action.NEW & NOTEWORTHY NASH is a chronic, progressive, and increasingly problematic liver disease that has been resistant to treatment with individual therapeutics. In this study using a diet-induced mouse model of NASH, we found that the PPARδ agonist seladelpar reduced fibrosis and NASH pathology alone and in combinations with a GLP-1-R agonist (liraglutide) or an ASK1 inhibitor (selonsertib). Liver transcriptome analysis comparing each agent and coadministration suggests seladelpar should be effective in combination with a variety of therapeutics.

Cost-effectiveness of alternative NTRK testing strategies in cancer patients followed by histology-independent therapy with entrectinib: an analysis of three European countries.

Aim: To explore variations in the cost-effectiveness of entrectinib across different testing strategies and settings. Methods: Four testing strategies where adult cancer patients received entrectinib if they tested positive for NTRK gene fusions compared with 'no testing' and standard of care (SoC) for all patients were evaluated. Results: Immunohistochemistry for all patients followed by RNA-based next-generation sequencing after a positive result was the optimal strategy in all included countries. However, the incremental net monetary benefit compared with SoC was negative in all countries, ranging between international euros (int€) -206 and -404. In a subgroup analysis with only NTRK-positive patients, the incremental net monetary benefit was int€ 8405 in England, int€ -53,088 in Hungary and int€ 54,372 in The Netherlands. Conclusion: Using the cost-effectiveness thresholds recommended by national guidelines, none of the testing strategies were cost-effective compared with no testing. The implementation of entrectinib is unlikely to become cost-effective in Hungary, due to the large cost difference between the entrectinib and SoC arms, while there might be more potential in England and The Netherlands.

Histology-independent pharmaceuticals are a new phenomenon in cancer care. Most chemotherapies are prescribed based on the tumor's (primary) location, while histology-independent therapies are prescribed based on genetic markers in the tumor DNA. In this study, the added value of the histology-independent treatment entrectinib, which is aimed at cancer patients with so-called NTRK gene fusions, was investigated. Because these patients must be identified before they can be given entrectinib, various strategies for diagnostic testing were considered. An economic model was programmed to gain insight into the costs and health outcomes associated with the different testing strategies. The same analysis was done for three different countries (England, Hungary and The Netherlands) using local data. In all three countries, the health gains from receiving entrectinib may be large for patients with NTRK gene fusions. However, treatment with entrectinib was also much more expensive than standard-care treatment, especially in Hungary. In each of the three countries, all evaluated testing strategies were found to offer a negative net benefit to society (i.e., a net loss). This may be partially explained by the fact that NTRK gene fusions are rare, meaning that a large group of cancer patients has to receive (costly) testing while, subsequently, only a few patients enjoy the benefit of switching to a treatment that is more effective for them (i.e., entrectinib). Nonetheless, in England and Hungary, even if the most accurate test was provided for free, the net benefit to society of implementing entrectinib remained negative. Further changes, such as a reduction in the price of entrectinib, may therefore be needed.

Pharmacokinetics of Herb-Drug Interactions of Plumbagin and Tazemetostat in Rats by UPLC-MS/MS.

Objective: A sensitive and rapid UPLC-MS/MS method for determination of tazemetostat in rat plasma was developed, and the pharmacokinetics of herb-drug interactions (HDIs) of plumbagin (PLB) and tazemetostat was investigated. Methods: After the rat plasma samples were precipitated by acetonitrile, tazemetostat and verubecestat (ISTD) were detected. Gradient elution was performed with 0.1% formic acid and acetonitrile as mobile phases. The multi-reaction monitoring was used with ESI+ source, and the ion pairs for tazemetostat and ISTD were m/z 573.12→135.99 and m/z 410.10→124.00, respectively. 12 SD rats were randomly divided into the control group and the experimental group, 6 rats in each group. The rats in the experimental group were given PLB 100 mg/kg by gavage once a day for 7 consecutive days. The rats in the control group were given the same amount of 0.1% sodium carboxymethyl cellulose solution by gavage once a day for 7 consecutive days. At the seventh day, tazemetostat (80 mg/kg) was given and the blood was collected at different time points. The main parameters of pharmacokinetics were calculated and the herb-drug interactions (HDIs) were evaluated. Results: In the calibrated range of 1-1000 ng/mL, tazemetostat had a good linearity. The extraction recovery was more than 84%, and the RSD of intra-batch and inter-batch precision were both less than 15%. The Cmax of tazemetostat in the experimental group was 32.48% higher than that in the control group, and the AUC(0-t) and AUC(0-∞) of tazemetostat in the experimental group were 46.24% and 46.67% higher than that in the control group, respectively, and the t1/2 was prolonged from 10.56 h to 11.73 h. Conclusion: A simple, rapid and sensitive UPLC-MS/MS method for the determination of tazemetostat in rat plasma was established. PLB can inhibit the metabolism of tazemetostat and increase the plasma exposure of tazemetostat in rats.

Recent developments in the synthesis of the isoquinoline-1,3(2H,4H)-dione by radical cascade reaction.

In recent years, isoquinoline-1,3(2H,4H)-dione compounds have attracted extensive attention from synthetic chemists, with the aim of finding simple, mild, green and efficient synthetic methods. In this review, we summarize the diverse range of synthetic methods employing acryloyl benzamides as key substrates to furnish isoquinoline-1,3-diones using different radical precursors, such as those containing carbon, sulphur, phosphorus, nitrogen, silicon and bromine. This will stimulate the interest of readers to engage in research in this field.

Sarco/endoplasmic reticulum Ca2+ ATPase (SERCA)-mediated ER stress crosstalk with autophagy is involved in tris(2-chloroethyl) phosphate stress-induced cardiac fibrosis.

Excessive organophosphate flame retardant (OPFR) use in consumer products has been reported to increase human disease susceptibility. However, the adverse effects of tris(2-chloroethyl) phosphate (TCEP) (a chlorinated alkyl OPFR) on the heart remain unknown. In this study, we tested whether cardiac fibrosis occurred in animal models of TCEP (10 mg/kg b.w./day) administered continuously by gavage for 30 days and evaluated the specific role of sarco/endoplasmic reticulum Ca2+ ATPase (SERCA). First, we confirmed that TCEP could trigger cardiac fibrosis by histopathological observation and cardiac fibrosis markers. We further verified that cardiac fibrosis occurred in animal models of TCEP exposure accompanied by SERCA2a, SERCA2b and SERCA2c downregulation. Notably, inductively coupled plasma-mass spectrometry (ICP-MS) analysis revealed that the cardiac concentrations of Ca2+ increased by 45.3% after TCEP exposure. Using 4-Isopropoxy-N-(2-methylquinolin-8-yl)benzamide (CDN1163, a small molecule SERCA activator), we observed that Ca2+ overload and subsequent cardiac fibrosis caused by TCEP were both alleviated. Simultaneously, the protein levels of endoplasmic reticulum (ER) markers (protein kinase R-like endoplasmic reticulum kinase (PERK), inositol requiring protein 1α (IRE1α), eukaryotic initiation factor 2 α (eIF2α)) were upregulated by TCEP, which could be abrogated by CDN1163 pretreatment. Furthermore, we observed that CDN1163 supplementation prevented overactive autophagy induced by TCEP in the heart. Mechanistically, TCEP could lead to Ca2+ overload by inhibiting the expression of SERCA, thereby triggering ER stress and overactive autophagy, eventually resulting in cardiac fibrosis. Together, our results suggest that the Ca2+ overload/ER stress/autophagy axis can act as a driver of cardiotoxicity induced by TCEP.

[Systematic review and pharmacoeconomic evaluation of Qizhi Weitong Granules in treatment of functional dyspepsia].

This study aims to investigate the efficacy, safety, and cost-effecctiveness of Qizhi Weitong Granules in the treatment of functional dyspepsia. Specifically, two commonly used clinical protocols for the treatment of functional dyspepsia were selected: Qizhi Weitong Granules+Mosapride vs Mosapride alone(control). Meta-analysis of previous clinical studies was performed to examine the efficacy and safety, and pharmacoeconomic evaluation was carried out according to the results of the Meta-analysis. The cost-effectiveness analysis was carried out to elucidated the incremental cost-effectiveness ratio(ICER), and the sensitivity was analyzed with tornado dia-gram and Monte Carlo simulation. The willingness-to-pay threshold of patients for functional dyspepsia was investigated and compared with the ICER to evaluate whether Qizhi Weitong Granules was cost-effective. The result showed that the effective rate of Qizhi Weitong Granules combined with Mosapride in the treatment of functional dyspepsia was 95.49%, which was higher than that of Mosapride alone(73.30%)(OR=8.52, 95%CI[4.36, 16.64])(P<0.000 1). The two groups showed no significant difference in safety. The price of Qizhi Weitong Granules+Mosapride was higher than that of Mosapride alone. The ICER was 640.29 CNY, 1 506.67 CNY lower than the willingness-to-pay threshold. The sensitivity analysis showed that the analysis results were relatively stable. Thus, Qizhi Weitong Granules+Mosapride is safe, effective, and economical in the treatment of functional dyspepsia, which should be further promoted in clinical settings.

Activation of the α7 Nicotinic Acetylcholine Receptor Prevents against Microglial-Induced Inflammation and Insulin Resistance in Hypothalamic Neuronal Cells.

Neuronal hypothalamic insulin resistance is implicated in energy balance dysregulation and contributes to the pathogenesis of several neurodegenerative diseases. Its development has been intimately associated with a neuroinflammatory process mainly orchestrated by activated microglial cells. In this regard, our study aimed to investigate a target that is highly expressed in the hypothalamus and involved in the regulation of the inflammatory process, but still poorly investigated within the context of neuronal insulin resistance: the α7 nicotinic acetylcholine receptor (α7nAchR). Herein, we show that mHypoA-2/29 neurons exposed to pro-inflammatory microglial conditioned medium (MCM) showed higher expression of the pro-inflammatory cytokines IL-6, IL-1ß, and TNF-α, in addition to developing insulin resistance. Activation of α7nAchR with the selective agonist PNU-282987 prevented microglial-induced inflammation by inhibiting NF-κB nuclear translocation and increasing IL-10 and tristetraprolin (TTP) gene expression. The anti-inflammatory role of α7nAchR was also accompanied by an improvement in insulin sensitivity and lower activation of neurodegeneration-related markers, such as GSK3 and tau. In conclusion, we show that activation of α7nAchR anti-inflammatory signaling in hypothalamic neurons exerts neuroprotective effects and prevents the development of insulin resistance induced by pro-inflammatory mediators secreted by microglial cells.

Dissipation and risk assessment of fluopyram and trifloxystrobin on onion by GC-MS/MS.

The dissipation and risk assessment studies on fluopyram, trifloxystrobin and their metabolites were carried out on onion under field conditions after two treatments of fluopyram 250 g/L + trifloxystrobin 250 g/L SC @ 150 and 300 g a.i. ha-1. The onion bulb samples were collected at 0, 3, 7, 14, and 21 days after second spray to study the pattern of dissipation using QuEChERS methodology for processing and analysis on GC-MS/MS. The total initial residues of fluopyram (fluopyram + fluopyram benzamide) in immature onion bulb were 2.14 and 4.93 mg kg-1, at single and double dose, respectively. The residues of 0.02 and 0.06 mg kg-1 persisted in the mature onion bulb collected at the harvest (30 days after treatment). The total initial residues of trifloxystrobin (trifloxystrobin + CGA 321113) in immature onion bulb were 0.65 and 1.97 mg kg-1, at single and double dose, respectively, which reached < LOQ and 0.06 mg kg-1 at the respective doses at the harvest time. Dissipation of fluopyram followed second-order kinetics with DT50 values of 1.83 and 1.74 days, whereas trifloxystrobin followed first-order kinetics with DT50 values of 4.73 and 4.78 days, at single and double dose respectively. Risk assessment in terms of hazard quotient was done to estimate the risk that can occur due to application of this combination pesticide. It was observed that even the spray at the double recommended dose could not have dietary risks on the consumers.

URB597 and Andrographolide Improve Brain Microvascular Endothelial Cell Permeability and Apoptosis by Reducing Oxidative Stress and Inflammation Associated with Activation of Nrf2 Signaling in Oxygen-Glucose Deprivation.

Ischemic stroke, a cerebrovascular disease worldwide, triggers a cascade of pathophysiological events, including blood-brain barrier (BBB) breakdown. Brain microvascular endothelial cells (BMECs) play a vital role in maintaining BBB function. The injury of BMECs may worsen neurovascular dysfunction and patients' prognosis. Therefore, uncover the principal molecular mechanisms involved in BBB disruption in stroke becomes pressing. The endocannabinoid system (ECS) has been implicated in increasingly physiological functions, both in neurometabolism and cerebrovascular regulation. Modulating its activities by the fatty acid amide hydrolase (FAAH) shows anti-inflammatory characteristics. Andrographolide (AG), one Chinese herbal ingredient, has also attracted attention for its role in immunomodulatory and as a therapeutic target in BBB disorders. Recently, the FAAH inhibitor URB597 and AG have important regulatory effects on neuronal and vascular cells in ischemia. However, the effects of URB597 and AG on BMEC permeability and apoptosis in oxygen-glucose deprivation (OGD) and the underlying mechanisms remain unclear. To address these issues, cultured BMECs (bEnd.3 cells) were exposed to OGD. The cell viability, permeability, tube formation, and apoptosis were assessed following treatment with URB597, AG, and cotreatment. Mitochondrial membrane potential (MMP), reactive oxygen species (ROS), superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), proinflammatory factors, tight junction (TJ) proteins, and oxidative stress-mediated Nrf2 signaling were also investigated. Results revealed that OGD broke the endothelial barrier, cell viability, MMP, and tube formation, which was reversed by URB597 and AG. OGD-induced enhancement of ROS, MDA, and apoptosis was reduced after drug interventions. URB597 and AG exhibited antioxidant/anti-inflammatory and mitochondrial protective effects by activating Nrf2 signaling. These findings indicated that URB597 and AG protect BMECs against OGD-induced endothelial permeability impairment and apoptosis by reducing mitochondrial oxidative stress and inflammation associated with activation of Nrf2 signaling. URB597 and AG showing the vascular protection may have therapeutic potential for the BBB damage in ischemic cerebrovascular diseases.

Exogenous salicylic acid alleviates fomesafen toxicity by improving photosynthetic characteristics and antioxidant defense system in sugar beet.

Fomesafen herbicide application has become major pollution in the growth and production of crops. Spraying fomesafen on the target crops may drift out to non-target crops. In northeast China, sugar beets are always planted adjacent to soybeans. Salicylic acid (SA) plays an important role in crop growth and alleviating abiotic stress, however, the role of SA in relieving fomesafen stress in sugar beet growth has rarely been investigated. Therefore, a pot study was conducted to elucidate the effects of different concentrations (0.025, 0.25, 0.5, 1, 5, and 10 mM) of SA on morphological parameters, photosynthetic performance, and antioxidant defense system in sugar beet seedlings under fomesafen (22.5 g a.i. ha-1) stress. The results showed that fomesafen stress inhibited the growth of sugar beet seedlings, and photosynthetic performance, while increased membrane lipid peroxidation and oxidative stress. However, exogenous SA alleviated the fomesafen stress and increased plant height, biomass, photosynthetic pigment contents, net photosynthetic rate (Pn), and photochemical efficiency of PSⅡ (Fv/Fm) in sugar beet leaves. Meanwhile, exogenous SA maintained the cell membrane integrity by reducing the content of malondialdehyde (MDA) and electrolyte permeability and regulating the activities of antioxidant enzymes including superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), and polyphenol (PPO). Therefore, it is concluded that exogenous SA ameliorated the adverse effects of fomesafen on the growth of sugar beet seedlings, with a pronounced effect at 1 mM SA. The present study results may have useful implications in managing other plants that are poisoned by herbicides.

Tetravalent Spiroselenurane Catalysts: Intramolecular Se···N Chalcogen Bond-Driven Catalytic Disproportionation of H2O2 to H2O and O2 and Activation of I2 and NBS.

Chalcogen-bonding interactions have recently gained considerable attention in the field of synthetic chemistry, structure, and bonding. Here, three organo-spiroselenuranes, having a Se(IV) center with a strong intramolecular Se···N chalcogen-bonded interaction, have been isolated by the oxidation of the respective bis(2-benzamide) selenides derived from an 8-aminoquinoline ligand. Further, the synthesized spiroselenuranes, when assayed for their antioxidant activity, show disproportionation of hydrogen peroxide into H2O and O2 with first-order kinetics with respect to H2O2 for the first time by any organoselenium molecules as monitored by 1H NMR spectroscopy. Electron-donating 5-methylthio-benzamide ring-substituted spiroselenurane disproportionates hydrogen peroxide at a high rate of 15.6 ± 0.4 × 103 µM min-1 with a rate constant of 8.57 ± 0.50 × 10-3 s-1, whereas 5-methoxy and unsubstituted-benzamide spiroselenuranes catalyzed the disproportionation of H2O2 at rates of 7.9 ± 0.3 × 103 and 2.9 ± 0.3 × 103 µM min-1 with rate constants of 1.16 ± 0.02 × 10-3 and 0.325 ± 0.025 × 10-3 s-1, respectively. The evolved oxygen gas from the spiroselenurane-catalyzed disproportion of H2O2 has also been confirmed by a gas chromatograph-thermal conductivity detector (GCTCD) and a portable digital polarographic dissolved O2 probe. Additionally, the synthesized spiroselenuranes exhibit thiol peroxidase antioxidant activities for the reduction of H2O2 by a benzenethiol co-reductant monitored by UV-visible spectroscopy. Next, the Se···N bonded spiroselenuranes have been explored as catalysts in synthetic oxidation iodolactonization and bromination of arenes. The synthesized spiroselenurane has activated I2 toward the iodolactonization of alkenoic acids under base-free conditions. Similarly, efficient chemo- and regioselective monobromination of various arenes with NBS catalyzed by chalcogen-bonded synthesized spiroselenuranes has been achieved. Mechanistic insight into the spiroselenuranes in oxidation reactions has been gained by 77Se NMR, mass spectrometry, UV-visible spectroscopy, single-crystal X-ray structure, and theoretical (DFT, NBO, and AIM) studies. It seems that the highly electrophilic nature of the selenium center is attributed to the presence of an intramolecular Se···N interaction and a vacant coordination site in spiroselenuranes is crucial for the activation of H2O2, I2, and NBS. The reaction of H2O2, I2, and NBS with tetravalent spiroselenurane would lead to an octahedral-Se(VI) intermediate, which is reduced back to Se(IV) due to thermodynamic instability of selenium in its highest oxidation state and the presence of a strong intramolecular N-donor atom.

Phytotoxicity response of sugar beet (Beta vulgaris L.) seedlings to herbicide fomesafen in soil.

Fomesafen is the most widely used herbicide in the soybean field. However, there are urgent practical challenges with the long-term persistence of fomesafen in soil and its effects on the subsequent crops in agricultural production. Therefore, pot experiments were conducted to study the effects of fomesafen residues (0-0.05 mg kg-1) on growth, photosynthetic characteristics, and the antioxidant defense system of sugar beet seedlings. The results showed that with the increase of fomesafen residues, the phytotoxicity index increased, while the plant height, leaf area, root length, root volume, and dry weight of sugar beet decreased. Photosynthetic pigment content, net photosynthetic rate (Pn), maximum photosynthetic efficiency (Fv/Fm), and actual photosynthetic efficiency (Y(II)) declined with a dose-dependent manner of fomesafen, but the intercellular CO2 concentration (Ci) and non-photochemical quenching coefficient (NPQ) increased under fomesafen. On the other hand, the residues of fomesafen increased the content of malondialdehyde (MDA) and membrane permeability by aggravating oxidative stress and triggering the activities of superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), and polyphenol oxidase (PPO). In addition, sugar beet seedlings were significantly sensitive to fomesafen as the concentration of fomesafen in the soil was up to 0.025 mg kg-1. In conclusion, the present study showed that fomesafen residues in the soil could affect the morphophysiology and photosynthetic performance of sugar beet. This study is beneficial for understanding the effects of the herbicide fomesafen residues on non-target crops.

Chidamide stacked in magnetic polypyrrole nano-composites counter thermotolerance and metastasis for visualized cancer photothermal therapy.

Photothermal therapy (PTT) has become one of the most promising therapies in cancer treatment as its noninvasiveness, high selectivity, and favorable compliance in clinic. However, tumor thermotolerance and distal metastasis reduce its efficacy, becoming the bottleneck of applying PTT in clinic. In this study, a chidamide-loaded magnetic polypyrrole nanocomposite (CMPP) has been fabricated as a visualized cancer photothermal agent (PTA) to counter tumor thermotolerance and metastasis. The efficacy of CMPP was characterized by in vitro and in vivo assays. As a result, this kind of magnetic polypyrrole nanocomposites were black spherical nanoparticles, possessing a favorable photothermal effect and the suitable particle size of 176.97 ± 1.45 nm with a chidamide loading rate of 12.92 ± 0.45%. Besides, comparing with PTT, CMPP exhibited significantly higher cytotoxicity and cellular apoptosis rate in two tumor cell lines (B16-F10 and HepG2). In vivo study, the mice showed obvious near-infrared (NIR) and magnetic resonance imaging (MRI) dual-modal imaging at tumor sites and sentinel lymph nodes (SLNs); on the other hand, magnetic targeting guided CMPP achieved a cure level on melanoma-bearing mice through preventing metastasis and thermotolerance. Overall, with high loading efficiency of chidamide and strong magnetic targeting to tumor sites and SLNs, CMPP could significantly raise efficiency of PTT by targeting tumor thermotolerance and metastasis, and this strategy may be exploited therapeutically to upgrade PTT with MPP as one of appropriate carriers for histone deacetylase inhibitors (HDACis).

Synthesis of green benzamide-decorated UiO-66-NH2 for biomedical applications.

Metal-organic frameworks (MOFs) biocompatible systems can host enzymes/bacteria/viruses. Herein we synthesized a series of fatty acid amide hydrolase (FAAH)-decorated UiO-66-NH2 based on Citrus tangerine leaf extract for drug delivery and biosensor applications. Five chemically manipulated FAAH-like benzamides were localized on the UiO-66-NH2 surface with physical interactions. Comprehensive cellular and molecular analyses were conducted on HEK-293, HeLa, HepG2, PC12, MCF-7, and HT-29 cell lines (cytotoxicity assessment after 24 and 48 h). MTT results proved above 95 and 50% relative cell viability in the absence and presence of the drug, respectively. A complete targeted drug-releasing capability of nanocarriers was demonstrated after capping with leaf extract from Citrus tangerine, with a stimuli-responsive effect in acidic media. Targeted delivery was complete to the nucleus and cytoplasm of HT-29 cell, but merely to the cytoplasm of HeLa cell lines. Nanocarrier could be targeted for drug delivery to the cytoplasm of the HeLa cell line and to both the nucleus and cytoplasm of HT-29 cell lines. MOF-based nanocarriers proved authentic in vivo towards kidney and liver tissues with targeted cancerous cells efficiently. Besides, FAAH-like molecules revealed optical biosensor potential with high selectivity (even ˂5 nM LOD) towards ssDNA, sgRNA, and Anti-cas9 proteins.

[Effect of electroacupuncture combined with mosapride on gastric motility in diabetic gastroparesis rats].

OBJECTIVE: To observe the effect of electroacupuncture (EA) at "Zusanli" (ST 36) combined with mosapride on gastric emptying rate and gastric motility in the rats with diabetic gastroparesis. METHODS: Using random number table method, 68 male SD rats were divided into a blank group (12 rats) and a model establishment group (56 rats). In the model establishment group, the models of diabetic gastroparesis were established with intraperitoneal injection of streptozotocin combined with high-fat and high-sugar diet. Six weeks later, the successful rat models in the model establishment group were randomized into a model group, an EA group, a mosapride group and a combined treatment group, 12 rats in each one. In the EA group, EA was exerted at "Zusanli" (ST 36) (disperse-dense wave, 2 Hz/15 Hz in frequency, 2 mA in intensity) for 20 min. In the mosapride group, mosapride was intervened with intragastric administration (2 mg/kg). In the combined treatment group, electroacupuncture at "Zusanli" (ST 36) was combined with intragastric administration of mosapride. The intervention was given once daily in each group. There was 1 day at interval after 6-day intervention, consecutively for 5 weeks. At the end of intervention, the random blood glucose, gastric emptying rate and the data of gastric motility (average intra-gastric pressure, amplitude and frequency of gastric motility) were detected. RESULTS: Compared with the blank group, blood glucose was increased in the model group (P<0.001). Blood glucose was reduced in the EA group, the mosapride group and the combined treatment group as compared with the model group separately (P<0.001, P<0.01), whereas, compared with the mosapride group, blood glucose was decreased in the combined treatment group (P<0.05). In comparison with the blank group, the gastric emptying rate, the average intra-gastric pressure and the amplitude of gastric motility were all decreased in the model group (P<0.001) and the frequency of gastric motility was increased (P<0.001). Gastric emptying rate, the average intra-gastric pressure and the amplitude of gastric motility were increased in the EA group, the mosapride group and the combined treatment group (P<0.01, P<0.05, P<0.001) and the frequency of gastric motility was decreased (P<0.001) as compared with the model group respectively. Compared with the EA group, the average intra-gastric pressure and the amplitude of gastric motility were increased in the combined treatment group (P<0.001). In comparison with the mosapride group, the gastric emptying rate, the average intra-gastric pressure, the amplitude and frequency of gastric motility in the combined treatment group, as well as the frequency of gastric motility in the EA group were all increased (P<0.05, P<0.001, P<0.01). CONCLUSION: Electroacupuncture at "Zusanli" (ST 36) combined with intragastric administration of mosapride could regulate blood glucose and improve the gastric motility in the rats with diabetic gastroparesis. The effect is better than either simple electroacupuncture or mosapride.