Intramolecular Ni-catalyzed reductive coupling enables enantiodivergent synthesis of linoxepin.

A nickel-catalyzed reductive tandem cyclization of the elaborated ß-bromo acetal with a dibenzoxepin scaffold was invented to strategically construct the remaining two rings in linoxepin. The generated diasterodivergent intermediates could be easily converted to both enantiomers of this unique cyclolignan molecule via facile oxidations, thus realizing enantiodivergent total synthesis of linoxepin for the first time.

A Highly Stretchable Force Sensitive and Temperature Sensitive Sensor Material with the Sandwich Structure of PDMS + PDMS/GaInSn + PDMS.

Flexible conductive sensor materials have received great attention for their sensitive electrical response to external conditions and their promising applications in flexible wearable and robotic applications. In this work, a highly stretchable force sensitive and temperature sensitive sensor material with a sandwich structure was prepared from the polydimethylsiloxane (PDMS) and the liquid metal (LM) gallium-indium-tin alloy (GaInSn). The sandwich structure (PDMS + PDMS/GaInSn + PDMS) was proven to prevent the "leakage" of LM. The preparation method of the sensing material was simple and time-saving (less than 1.5 h) and can be used for industrial production. The electrical performance analysis results confirmed that the resistance (R) of the material was sensitive to the external force, such as repeated stretching, compressing, bending, and impacting. The ΔR/R changed periodically and stably with the repeated stretching, when the GaInSn/Part A ≥ 0.4, the cyclic tensile strain ≤ 50%, and the cyclic tensile rate ≤ 2.5 mm/min. The R of the sensor materials was also responsive to the temperature, such as hot air and liquid nitrogen. In conclusion, this work provides a method for preparing sensing materials with the sandwich structure, which was confirmed to be sensitive to force and temperature without leaking LM, and it produced different types of R signals under different deformations and different temperatures.

The dual impacts of specialized agricultural services on pesticide application intensity: Evidence from China.

BACKGROUND: Specialized agricultural services are a new trend in agricultural production around the world, especially in developing countries. However, the growing impacts of specialized agricultural services on pesticide application intensity are unclear. In regions facing pesticide overuse, do specialized agricultural services exacerbate or mitigate the problem? RESULTS: Based on province-level panel data from China from 2004 to 2018, this study examines the impact of specialized agricultural services on pesticide application intensity, considering both direct and indirect (i.e. spatial spillover) effects. The dual impacts of specialized agricultural services on pesticide application intensity in China are identified. First, specialized agricultural services directly increase pesticide application intensity, likely due to increased cultivation and specialized management of land that was previously abandoned or marginally managed. Second, there is a negative indirect or spatial spillover effect of specialized agricultural services on pesticide application intensity, likely due to technology and efficiency diffusion enabled by the cross-regional provision of specialized agricultural services. The net impact of specialized agricultural services on pesticide application intensity is negative. CONCLUSION: Crop protection services are regarded as the core force to promote the reduction of pesticide application intensity. Steps should be taken to promote the research and development, demonstration, and promotion of new technologies and equipment for crop protection services, particularly the development of crop protection by drones. © 2022 Society of Chemical Industry.

Protective Effects of Combined Utilization of Quercetin and Florfenicol on Acute Hepatopancreatic Necrosis Syndrome Infected Litopenaeus vannamei.

This study aimed to determine the immunity, survival rate, and disease resistance of Litopenaeus vannamei treated using quercetin and florfenicol alone or in combination, after infection with acute hepatopancreatic necrosis syndrome caused by Vibrio parahaemolyticus (VPAHPND). After infection with VPAHPND, different types of feed were given to the shrimp for 5 days, including a control diet (drug-free), florfenicol only diet (15 mg/kg), quercetin only diet (400 mg/kg), a low-dose florfenicol/quercetin combined diet (200 mg/kg quercetin + 7.0 mg/kg florfenicol), a moderate-dose florfenicol/quercetin combined diet (400 mg/kg quercetin + 15 mg/kg florfenicol), and a high-dose florfenicol/quercetin combined diet (800 mg/kg quercetin + 30 mg/kg florfenicol). The cumulative mortality of shrimp was significantly reduced in the drug combination groups compared with either drug used alone (p < 0.05). The density of Vibrio was significantly lower and the immune parameters were significantly increased in the drug combination groups compared with either drug used alone (p < 0.05). Moreover, in the drug combination groups, the hepatopancreas tubules showed better integrity and structure compared with those when either drug was used alone. Therefore, compared with single drug treatment, the florfenicol and quercetin combination enhanced disease resistance, survival, and immune activity of VPAHPND-infected shrimp. When the combination treatment is used, the dosage of florfenicol can be reduced and a better therapeutic effect is obtained.

The Impact of Health Risk Perception on Blockchain Traceable Fresh Fruits Purchase Intention in China.

This paper systematically investigates the impact of consumers' health risk perceptions on the purchase intention of blockchain traceable fresh fruits in China. It uses online-survey data collected from four pilot cities that are part of the food traceability system in China. The ordinary least squares (OLS) and the ordered probit model was applied to examine the posited relationships. The results show that consumers' health risk perception has a significant positive effect on the purchase intention of blockchain traceable fresh fruits. The stronger consumers' health risk perception, the stronger their purchase intention of blockchain traceable fresh fruits. Likewise, heterogeneity exists among gender, age, income, and education in their corresponding effect of consumers' health risk perception on blockchain traceable fresh fruit purchase intention. This suggests that male, high-aged, high-income and high-educated groups have a higher health risk perception, and therefore a higher purchase perception for blockchain traceable fresh fruits than female, low-aged, low-income and low-educated, respectively. Furthermore, family structure, consumers' traceability cognition and purchase experience of traceable products affect the purchase intention of blockchain traceable fresh fruits. The study has several insights on the broader promotion, acceptance and development of the food traceability system and provides practical cues for policy and practice.

Recent advancement in small molecules as HCV inhibitors.

Hepatitis C virus (HCV) has caused a considerable threat to human health. To date, no treatments are without side effects. The proteins and RNA associated with HCV have specific functions during the viral life cycle. The vulnerabilities to virus are associated with those proteins or RNA. Thus, targeting these proteins and RNA is an efficient strategy to develop anti-HCV therapeutics. The treatment for HCV-infected patients has been greatly improved after the approval of direct-acting antivirals (DAAs). However, the cost of DAAs is unusually high, which adds to the economic burden on patients with chronic liver diseases. So far, many efforts have been devoted to the development of small molecules as novel HCV inhibitors. Investigations on the inhibitory activities of these small molecules have involved the target identification and the mechanism of action. In this mini-review, these small molecules divided into four kinds were elaborated, which focused on their targets and structural features. Furthermore, we raised the current challenges and promising prospects. This mini-review may facilitate the development of small molecules with improved activities targeting HCV based on the chemical scaffolds of HCV inhibitors.

A coumarin-based fluorescent probe for NIR imaging-guided photodynamic therapy against S. aureus-induced infection in mouse models.

A coumarin-based viscosity-responsive fluorescent probe (HZAU800) was designed and synthesized. The probe, containing a strong electron-donating and rigid group on the 7-position of coumarin and a rhodamine derivative containing an oxonium ion on 3-position, could not only shift the emission wavelength to near-infrared region (NIR, λem = 800 nm) but also deliver a good PDT effect due to its high rigid planarity. The NIR fluorescence of HZAU800 can be lighted up in the S. aureus-infected region due to its high viscous environment. Under the laser's irradiation at 690 nm, the PDT effect was effectively triggered up, and the antibacterial evaluation in vitro and in vivo was successfully carried out. This study not only offers a new strategy for constructing coumarin-based phototherapy agents but also facilitates the exploration of the next generation of antibacterial materials based on coumarin architectures.

Quercetin ameliorates testosterone secretion disorder by inhibiting endoplasmic reticulum stress through the miR-1306-5p/HSD17B7 axis in diabetic rats.

Testicular damage and testosterone secretion disorder are associated with diabetes mellitus. Quercetin,  a common flavonoid, has antioxidant, anti-cancer,  and blood sugar lowering effects. Therefore, this study aims to investigate the effect of quercetin on the reproductive system of male rats with diabetes in vivo and in vitro and elucidate its mechanism. Streptozotocin (STZ)  induction was used to establish a diabetes model in forty male Sprague Dawley (SD) rats, which were subsequently administered with 20 or 50 mg/kg of quercetin. Leydig cells of rat testes were treated by high glucose (HG) followed by 5 or 10 µM quercetin. Two doses of quercetin increased rat body weight and testicular weight, decreased blood glucose,and inhibited oxidative stress. RT-qPCR and Western blotting revealed that quercetin alleviated STZ-induced testicular damage and promoted testosterone synthesis. Both doses of quercetin reduced ROS and MDA levels, and increased SOD level in HG-treated cells. Both, in vivo and in vitro results confirmed that a high dose of quercetin was more effective. MiR-1306-5p was upregulated in testicular tissue of diabetic rats and HG-treated cells. 17ß-hydroxysteroid dehydrogenase (HSD17B7) was a target of miR-1306-5p and HSD17B7 was downregulated in STZ-induced rat tissues and HG-treated cells. HSD17B7 overexpression reversed the increase of C/EBP homologous protein (CHOP) and glucose-regulated protein 78 (Grp78) protein levels as well as eIF2α phosphorylation level and promotion of cell apoptosis caused by miR-1306-5p overexpression. Moreover, overexpression of HSD17B7 activated the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) axis in HG-treated cells. In conclusion, quercetin inhibits ER stress and improves testosterone secretion disorder through the miR-1306-5p/HSD17B7 axis in diabetic rats.

Magnetic solid-phase extraction based on carbon nanotubes for determination of sulfamethoxazole, acetyl sulfamethoxazole and aditoprim residues in edible swine tissues with liquid chromatography tandem mass spectrometry.

Sulphonamides (SAs) are widely used in animal husbandry. In our work, based on multi-walled carbon nanotubes, a novel residue method was developed for highly sensitive and determination trace levels of sulfamethoxazole, acetyl sulfamethoxazole and aditoprim in edible swine tissues by LC-MS/MS with magnetic solid-phase extraction. The samples were extracted using 2% ammoniated acetonitrile and purified by magnetic solid phase extraction (MSPE). Under the optimal conditions, good linearity was obtained ranging from 5 to 160 µg kg-1. The limits of detection (LOD) and quantification (LOQ) were 2 µg kg-1 and 5 µg kg-1 respectively. The average recoveries were 73.9-94.8% at different spiking levels. The inter-day RSDs were 6.2-10.7% and the intra-day RSDs were 2.4-5.4%. MSPE based on multi-walled carbon nanotubes was a simple and efficient method to enrich and separate the analyses and could be successfully applied for extraction of sulfamethoxazole, acetyl sulfamethoxazole and aditoprim residues in swine tissues.

A highly selective switch-on fluorescence sensor targeting telomeric dimeric G-quadruplex.

The fluorescence probes with high selectivity and sensitivity for telomeric multimeric G-quadruplexes have attracted much attention. Nevertheless, few small molecules have exhibited telomeric multimeric G-quadruplexes recognition specificity. Thus, there is an urgent demand to develop specific fluorescence probes for telomeric multimeric G-quadruplexes. We reported herein the specific sensing of telomeric dimeric G-quadruplex TTA45 via a fluorescence light-up response using a commercially available triazine derivative HPTA-1 as a probe. HPTA-1 could discriminate the telomeric dimeric G-quadruplex TTA45 against other types of DNA structures accompanied by a drastic enhancement of the emission intensity without compromising the conformation and stability. Compared with most multimeric G-quadruplex recognition ligands, HPTA-1 had much simpler structure and lower molecular weight. The binding mechanism studies suggested that the distinct fluorescence response was caused by electrostatic and π-π stacking interactions of HPTA-1 with the pocket between two G-quadruplex units of telomeric dimeric G-quadruplex TTA45..

Recent advances in the development of small molecules targeting RNA G-quadruplexes for drug discovery.

Extensive evidence indicates that RNA G-quadruplexes have associated with some important cellular events. Investigation of RNA G-quadruplexes is thus vital to revealing their biofunctions. Several small molecules have been developed to target RNA G-quadruplexes to date. Some of the small molecules showed significantly light-up fluorescence signals upon binding to RNA G-quadruplexes, while some of them regulated the biofunctions of RNA G-quadruplexes. In this mini-review, the small molecules divided into four kinds are expounded which focused mainly on their structural features and biological activities. Moreover, we raised the current challenges and promising prospects. This mini-review might contribute to exploiting more sophisticated small molecules targeting RNA G-quadruplexes with high specificity based on the reported chemical structural features.

Specific recognition of telomeric multimeric G-quadruplexes by a simple-structure quinoline derivative.

The development of highly sensitive fluorescence probes for telomeric multimeric G-quadruplexes has attracted extensive attention. However, few probes reported have exhibited selectivity for telomeric multimeric G-quadruplexes. Thus, it is challenging to design fluorescence probes with high specificity and selectivity for telomeric multimeric G-quadruplexes. This study employed a commercially available quinoline derivative BEPQ-1 as an effective switch-on sensor for telomeric multimeric G-quadruplexes. The fluorescence intensity enhanced more than 20 folds upon the addition of telomeric multimeric G-quadruplexes. This probe exhibited good selectivity and sensitivity for telomeric multimeric G-quadruplexes. And the detection limit of BEPQ-1 for the telomeric multimeric G-quadruplex TTA45 was calculated to be 0.11 µM. The distinctive feature of BEPQ-1 is the simple structure and small size. In the light of binding mode, BEPQ-1 could even simultaneously bind to the end two G-quartets of the two adjacent G-quadruplex units in telomeric multimeric G-quadruplex by π-π stacking. To our knowledge, this is the first simple-structure fluorescence probe for telomeric multimeric G-quadruplex. This finding might provide a strategy to design specific probes for telomeric multimeric G-quadruplexes and contribute to understand the structures and functions of G-quadruplexes in the telomere region.

Recent advances in the development of ligands specifically targeting telomeric multimeric G-quadruplexes.

Long human telomeric DNA sequence could form higher-order G-quadruplex structures, namely telomeric multimeric G-quadruplexes. The formation of telomeric multimeric G-quadruplexes has been demonstrated. Several efforts have been devoted to the development of ligands targeting telomeric multimeric G-quadruplexes in recent years. The reported ligands specifically targeting telomeric multimeric G-quadruplexes exhibited either high anticancer activity with effective stabilization ability or distinct fluorescence responses to telomeric multimeric G-quadruplexes. In this review, the ligands including three types of small molecules are discussed which focus on their structural features and binding modes. Furthermore, we put forward the promising prospects and current challenges. This presented review might provide new strategies to exploit more sophisticated ligands targeting telomeric multimeric G-quadruplexes.

Selective recognition of c-MYC Pu22 G-quadruplex by a fluorescent probe.

Nucleic acid mimics of fluorescent proteins can be valuable tools to locate and image functional biomolecules in cells. Stacking between the internal G-quartet, formed in the mimics, and the exogenous fluorophore probes constitutes the basis for fluorescence emission. The precision of recognition depends upon probes selectively targeting the specific G-quadruplex in the mimics. However, the design of probes recognizing a G-quadruplex with high selectivity in vitro and in vivo remains a challenge. Through structure-based screening and optimization, we identified a light-up fluorescent probe, 9CI that selectively recognizes c-MYC Pu22 G-quadruplex both in vitro and ex vivo. Upon binding, the biocompatible probe emits both blue and green fluorescence with the excitation at 405 nm. With 9CI and c-MYC Pu22 G-quadruplex complex as the fluorescent response core, a DNA mimic of fluorescent proteins was constructed, which succeeded in locating a functional aptamer on the cellular periphery. The recognition mechanism analysis suggested the high selectivity and strong fluorescence response was attributed to the entire recognition process consisting of the kinetic match, dynamic interaction, and the final stacking. This study implies both the single stacking state and the dynamic recognition process are crucial for designing fluorescent probes or ligands with high selectivity for a specific G-quadruplex structure.

Effectiveness of traditional Chinese herbal medicine, San-Huang-San, in combination with enrofloxacin to treat AHPND-causing strain of Vibrio parahaemolyticus infection in Litopenaeus vannamei.

The effects of oral administration of enrofloxacin (ENR) and San-Huang-San (SHS), singly or in combination, on the survival performance, disease resistance, and immunity of Litopenaeus vannamei were investigated. After challenge with an AHPND-causing strain of Vibrio parahaemolyticus (VPAHPND), shrimp were immediately fed a drug-free diet, diets containing only ENR (20 mg·kg-1) or SHS (500 mg·kg-1) or diets containing low-dose (10 mg·kg-1 ENR + 250 mg ·kg-1 SHS), medium-dose (20 mg·kg-1 ENR + 500 mg ·kg-1 SHS), and high-dose (40 mg·kg-1 ENR + 1000 mg ·kg-1 SHS) drug combinations for 5 days. The cumulative shrimp mortality over 5 days after injection of VPAHPND in the ENR + SHS combination groups was significantly lower than that in the ENR or SHS alone groups (p < 0.05). Immune parameters, including the vibrio density, total hemocyte counts (THCs), hemocyanin (HEM) concentration, antibacterial activity, activity levels of lysozyme (LZM), acid phosphatase (ACP), alkaline phosphatase (AKP), and phenoloxidase (PO) in cell-free hemolymph, and the expression levels of the immune-related genes anti-lipopolysaccharide factor (ALF), cathepsin B (catB), crustin, lectin (Lec), lysozyme (LZM), and Toll-like receptor (TLR) in hemocytes were determined in the shrimp. The results showed that the shrimp in drug combination groups cleared more VPAHPND than that in the ENR or SHS group in the same time. The values for other immune parameters in the drug combination groups were higher than those in the ENR or SHS group (p < 0.05). Finally, in the histological examinations, the histological structural alignment and integrity of the hepatopancreatic tubules in the drug combination groups were better than that in the ENR and SHS groups. Under the experimental conditions, compared with ENR or SHS used alone, the combination use of ENR and SHS could improve immunity and disease resistance in shrimp after VPAHPND infection, and could reduce the use of ENR when the better therapeutic effect was achieved.

Comparison of florfenicol pharmacokinetics in Exopalaemon carinicauda at different temperatures and administration routes.

Florfenicol is a broad-spectrum antibacterial drug. Exopalaemon carinicauda is important in the prawn aquaculture industry in China. Florfenicol pharmacokinetics in E. carinicauda were studied at different temperatures and via different routes of administration to provide a scientific basis for the rational use of drugs for E. carinicauda production. At water temperatures of 22 ± 0.4°C and 28 ± 0.3°C, after intramuscular (IM) injection and oral (per ora (PO)) administration of florfenicol at 10 mg/kg body weight (BW) and 30 mg/kg BW, respectively, the florfenicol concentration in the plasma, hepatopancreas, gills, muscles, and carapace of E. carinicauda was determined by high-performance liquid chromatography. After IM injection at different temperatures, the metabolism of florfenicol in E. carinicauda conformed to a two-compartment open model with zero-order absorption. After PO administration, the metabolism of florfenicol in E. carinicauda was consistent with a two-compartment open model with first-order absorption. Using an identical administration route but different water temperatures, the metabolism of florfenicol in E. carinicauda was quite different. Overall, florfenicol was absorbed rapidly and distributed widely in E. carinicauda, but elimination was slow and the bioavailability was not high. A low temperature and PO administration resulted in a low elimination rate.

Evaluation of combination effects of Astragalus polysaccharides and florfenicol against acute hepatopancreatic necrosis disease-causing strain of Vibrio parahaemolyticus in Litopenaeus vannamei.

The effects of oral administration of Astragalus polysaccharides (APS) and florfenicol (FFC), singly or in combination, on the survival performance, disease resistance, and immunity of Litopenaeus vannamei were investigated. After challenge with an AHPND-causing strain of Vibrio parahaemolyticus (VPAHPND), shrimp were immediately fed a drug-free diet, diets containing only APS (200 mg·kg-1) or FFC (15 mg·kg-1), or diets containing low-dose (7.5 mg·kg-1 FFC + 100 mg·kg-1 APS), medium-dose (15 mg·kg-1 FFC + 200 mg·kg-1 APS), and high-dose (30 mg·kg-1 FFC+400 mg·kg-1 APS) drug combinations for 5 days. The cumulative shrimp mortality over 5 days after injection of VPAHPND in the APS + FFC combination groups was significantly lower than that in the APS or FFC alone groups (p < 0.05). Immune parameters, including the total hemocyte counts (THCs), hemocyanin (HEM) concentration, antibacterial activity, activity levels of lysozyme (LZM), and levels of acid phosphatase (ACP), alkaline phosphatase (AKP), and phenoloxidase (PO) in cell-free hemolymph, and the expression levels of the immune-related genes anti-lipopolysaccharide factor (ALF), cathepsin B (catB), crustin, lectin (Lec), lysozyme (LZM), and Toll-like receptor (TLR) in hemocytes and hepatopancreas were determined in the shrimp. The values for these immune parameters in the drug combination groups were higher than those in the APS or FFC group (p < 0.05). Finally, in the histological examinations, the histological structural alignment and integrity of the hepatopancreatic tubules in the drug combination groups was better than that in the APS and FFC groups. Under the experimental conditions, dietary APS and FFC had a synergistic effect on immunity and disease resistance among shrimp after VPAHPND infection.

Pharmacokinetic profiles of florfenicol in spotted halibut, Verasper variegatus, at two water temperatures.

The pharmacokinetic profiles of florfenicol in the spotted halibut (Verasper variegatus) were investigated at 15 and 20°C water temperatures, respectively. Florfenicol content in plasma samples was analyzed using an HPLC method. Drug concentration versus time data were best fitted to a three-compartment model after a single intravenous administration (15 mg/kg BW), and fitted to a two-compartment model after an oral administration (30 mg/kg BW) at 15 and 20°C. The florfenicol concentration in the blood increased slowly during the 12 hr following an oral administration at 15°C, with a peak concentration (Cmax ) of 9.1 mg/L, and then declined gradually. The half-lives of absorption, distribution, and elimination phase were 2.18, 5.66 and 14.25 hr, respectively. The bioavailability (F) was calculated to be 24.14%. After an oral administration at 20°C, shorter half-lives of absorption (1.33 hr), distribution (2.51 hr) and elimination (9.71 hr), a higher Cmax (12.2 mg/L), and a similar F (23.98%) were found. Based on the pharmacokinetics and pharmacodynamics, an oral dose of 30 mg/kg BW was suggested to be efficacious for bacterial disease control in spotted halibut farming.

Cyanidin-3-O-glucoside ameliorates diabetic nephropathy through regulation of glutathione pool.

Diabetic nephropathy (DN) is a common complication of diabetes and the major cause of chronic kidney disease. Cyanidin 3-glucoside (C3G) is the most widespread anthocyanin in nature. In the present study, we aimed to investigate the possible effects of C3G on DN in db/db mice. We found that body weights and high levels of fasting blood glucose, serum insulin, C-peptide, glycosylated hemoglobin A1c, and systolic blood pressure in diabetic mice were significantly reduced by C3G. C3G also reduced the ratio of kidney to body weight and the levels of blood urea nitrogen (BUN), serum creatinine, urinary albumin content and albumin/creatinine ratio (ACR), ameliorated the pathological changes of kidneys, reduced the surface area of Bowman's capsule, glomerular tuft, Bowman's space, and decreased renal expression of collagen IV, fibronectin, transforming growth factor ß 1 (TGFß1), matrix metalloprotein 9 (MMP9) and α-smooth muscle actin (α-SMA) in db/db mice. The Lee's index, perirenal white adipose tissue weight, and high levels of blood and renal triglyceride and cholesterol were decreased by C3G. Moreover, C3G reduced systemic levels and renal expression of tumor necrosis factor ɑ (TNFɑ), IL-1ɑ, and monocyte chemotactic protein-1 (MCP-1), indicating the inhibition of inflammation. Furthermore, C3G increased glutathione (GSH) level and decreased GSSG level in kidneys of diabetic mice. The renal mRNA expression of glutamate-cysteine ligase catalytic subunit (GCLC) and glutamate-cysteine ligase modifier subunit (GCLM) was increased by C3G in diabetic mice. Buthionine sulphoximine (BSO), an inhibitor of GSH synthesis, inhibited the effects of C3G on glucose metabolic dysfunction and DN. The data demonstrates that enhancement of GSH pool is involved in the renal-protective effects of C3G. Overall, C3G could be a promising therapeutic option for attenuation of diabetes and DN.