Design, synthesis, biological evaluation and molecular docking studies of quinoline-anthranilic acid hybrids as potent anti-inflammatory drugs.

Despite the high global prevalence, rheumatoid arthritis lacks a satisfactory treatment. Hence, the present study is undertaken to design and synthesize novel anti-inflammatory compounds. For this, quinoline and anthranilic acid, two medicinally-privileged moieties, were linked by pharmacophore hybridization, and following their computational assessments, three hybrids 5a-c were synthesized in good over all yields. The in vitro and in vivo anti-inflammatory potential of these hybrids was determined by anti-denaturation and anti-proteinase, and carrageenan-induced paw edema models. The computational studies of these hybrids revealed their drug-likeness, optimum pharmacokinetics, and less toxicity. Moreover, they demonstrated high binding affinity (-9.4 to -10.6 kcal mol-1) and suitable binding interactions for TNF-α, FLAP, and COX-II. A three-step synthetic route resulted in the hybrids 5a-c with 83-86% yield of final step. At 50 µg mL-1, the antiprotease and anti-denaturation activity of compound 5b was significantly higher than 5a and 5c. Furthermore, 5b significantly reduced the edema in the right paw of the rats that received carrageenan. The results of this study indicate the medicinal worth of the novel hybrids in treating inflammatory disorders such as rheumatoid arthritis.

The combination of Butyricicoccus pullicaecorum and 3-hydroxyanthranilic acid prevents postmenopausal osteoporosis by modulating gut microbiota and Th17/Treg.

BACKGROUND: Postmenopausal osteoporosis (PMO) is a chronic condition characterized by decreased bone strength. This study aims to investigate the effects and mechanisms of the combination of Butyricicoccus pullicaecorum (Bp) and 3-hydroxyanthranilic acid (3-HAA) on PMO. METHODS: The effects of Bp and 3-HAA on PMO were evaluated in ovariectomized (OVX) rats by assessing stereological parameters, femur microstructure, and autophagy levels. The T helper (Th) 17/Regulatory T (Treg) cells of rats were detected using flow cytometric analysis. Furthermore, the impact of Bp and 3-HAA on the gut microbiota of rats was assessed using 16S rRNA gene sequencing. The correlation between the gut microbiota of rats and Th17/Treg immune factors, as well as femoral stereo parameters, was separately assessed using Spearman rank correlation analysis. RESULTS: Bp and 3-HAA treatments protected OVX rats by promoting osteogenesis and inhibiting autophagy. Compared to the Sham group, OVX rats showed an increase in Th17 cells and a decrease in Treg cells. Bp and 3-HAA reversed these changes. Enterorhabdus and Pseudomonas were significantly enriched in OVX rats. Bp and 3-HAA regulated the gut microbiota of OVX rats, enriching pathways related to nutrient metabolism and immune function. There was a correlation between the gut microbiota and the Th17/Treg, as well as femoral stereo parameters. The concurrent administration of Bp and 3-HAA medication facilitated the enrichment of gut microbiota associated with the improvement of PMO. CONCLUSION: The combination therapy of Bp and 3-HAA can prevent PMO by modulating the gut microbiota and restoring Th17/Treg immune homeostasis.

Sphingomonas bacteria could serve as an early bioindicator for the development of chlorantraniliprole resistance in Spodoptera frugiperda.

The fall armyworm (Spodoptera frugiperda) was found to have invaded China in December 2018, and in just one year, crops in 26 provinces were heavily affected. Currently, the most effective method for emergency control of fulminant pests is to use of chemical pesticides. Recently, most fall armyworm populations in China were begining to exhibite low level resistance to chlorantraniliprole. At present, it is not possible to sensitively reflect the low level resistance of S. frugiperda by detecting target mutation and detoxification enzyme activity. In this study we found that 12 successive generations of screening with chlorantraniliprole caused S. frugiperda to develop low level resistance to this insecticide, and this phenotype was not attribute to genetic mutations in S. frugiperda, but rather to a marked increase in the relative amount of the symbiotic bacteria Sphingomonas. Using FISH and qPCR assays, we determined the amount of Sphingomonas in the gut of S. frugiperda and found Sphingomonas accumulation to be highest in the 3rd-instar larvae. Additionally, Sphingomonas was observed to provide a protective effect to against chlorantraniliprole stress to S. frugiperda. With the increase of the resistance to chlorantraniliprole, the abundance of bacteria also increased, we propose Sphingomonas monitoring could be adapted into an early warning index for the development of chlorantraniliprole resistance in S. frugiperda populations, such that timely measures can be taken to delay or prevent the widespread propagation of resistance to this highly useful agricultural chemical in S. frugiperda field populations.

Comparative transcriptome profiling of two pesticides, Acephate and Chlorantraniliprole in non-targeted insect model, Drosophila melanogaster.

Acephate and chlorantraniliprole are two insecticides widely used in agricultural applications. Several studies were focused on the mode of action and related biological and cellular level expressions. However, the sub-lethal dose and related molecular expression level of acephate and chlorantraniliprole have not been evaluated or studied to the same degree. In this study, we investigated the sub-lethal toxicity of acephate and chlorantraniliprole in Drosophila melanogaster. The EC50 value was recorded with high difference, and is found to be 1.9 µg/ml and 0.029 µg/ml respectively for acephate and chlorantraniliprole, the difference is simply because of the different modes of action. The 1/5th EC50 concentration was selected for studying the pesticide induced transcriptomics in D. melanogaster. Both pesticides significantly altered the expression profile of several transcripts which are involved in proteolysis, detoxification, chromosome associated proteins and immune response genes and so on. The effect of both pesticides on D. melanogaster was further explored by screening the genes involved in toxicity, which were analyzed using, GO and KEGG pathways. The results revealed that the sub-lethal exposure of both pesticides caused significant changes in the global gene transcription profiles and each pesticide had their unique mode of alteration in the D. melanogaster.

Risk assessment, fitness cost and transcriptome analysis of cyantraniliprole resistance in Spodoptera frugiperda.

Spodoptera frugiperda is a notorious invasive pest causing substantial yield losses of crops and has developed resistance to various types of insecticides. In this study, a cyantraniliprole-resistant strain, SfCYAN-R, was obtained from a susceptible strain, SfCYAN-S, after 13 generations of selection with cyantraniliprole. The fitness cost in SfCYAN-R strain was evaluated, and the putative resistance-related genes were explored by RNA-seq analysis. The results showed that SfCYAN-R strain developed 23.97-fold resistance to cyantraniliprole with the realistic heritability of 0.127. The development time of eggs, larvae, prepupae and pupae in SfCYAN-R strain was significantly prolonged than that in SfCYAN-S strain, but no difference in pupation rate, emergence rate and female fecundity was observed between SfCYAN-R and SfCYAN-S strains. Comparative gene expression analysis between SfCYAN-R and SfCYAN-S strains identified 776 significant differentially expressed genes (DEGs), among which several DEGs associated with xenobiotic metabolism were upregulated in SfCYAN-R strain. These results provide insights into the resistance mechanisms of cyantraniliprole and would be helpful for resistance management of S. frugiperda.

Sublethal effects of chlorantraniliprole on immunity in Spodoptera frugiperda (Smith) (Lepidoptera: Noctuidae): Promote encapsulation by upregulating a heat shock protein 70 family gene SfHSP68.1.

As an agricultural pest, the fall armyworm (FAW), Spodoptera frugiperda, poses a severe threat to agriculture in China. Chlorantraniliprole has been widely used to control this pest. In our previous studies, we discovered that LD10, LD20, and LD30 chlorantraniliprole promoted encapsulation in the 4th instar larvae of the FAW, with LD30 chlorantraniliprole having the most significant effect. To further investigate the molecular mechanism underlying the sublethal effects of chlorantraniliprole on encapsulation in the FAW, this study conducted the effects of encapsulation in 4th instar larvae of the FAW exposed to LD30 chlorantraniliprole. Then, we analyzed the transcriptome of the FAW hemolymph treated with LD30 chlorantraniliprole and identified genes related to encapsulation using RNAi. Our results showed that the encapsulation in the FAW was enhanced at 6, 12, 18, 24, and 48 h after exposure to LD30 chlorantraniliprole. Additionally, LD30 chlorantraniliprole significantly affected the expression of certain immune-related genes, with the heat shock protein 70 family gene SfHSP68.1 showing the most significant upregulation. Subsequent interference with SfHSP68.1 resulted in a significant inhibition of encapsulation in FAW. These findings suggested that LD30 chlorantraniliprole can promote encapsulation in the FAW by upregulating SfHSP68.1 expression. This study provides valuable insights into the sublethal effects of chlorantraniliprole on encapsulation in the FAW and the interaction between encapsulation and heat shock proteins (HSPs).

Biophoton emission-based approach of the effects of systemic insecticides on the survival of Eurydema ventralis Kolenati, 1846 (Hemiptera: Pentatomidae) and on the photosynthetic activity of oilseed rape.

The choice of effective crop protection technologies is a key factors in the economical production of oilseed rape. Insecticides belonging to the group of active substances butenolides and diamides are active substances available as seed treatments in oilseed rape and promising control tools in the crop protection technologies. Our laboratory experiment demonstrated that the experimental insecticides flupyradifurone and cyantraniliprole are both effective against Eurydema ventralis (Hemiptera: Pentatomidae) when used as a seed and in-crop treatments, but there is a fundamental difference in their insect mortality inducing effects. Flupyradifurone was found to have a total mortality 96 h after application based on basipetal translocation. In the case of cyantraniliprole, the insecticidal effect of the same treatment was 27% less. The experiment showed that the acropetal translocation of the tested active substances after seed treatment did not induce efficacy comparable to that of the basipetal translocation. The study of the biophoton emission of the plants demonstrated a verifiable correlation between the different application methods of the insecticides and the photon emission intensity per unit plant surface area. In conclusion, the systematic insecticides tested, in addition to having the expected insecticidal effect, interfere with plant life processes by enhancing photosynthetic activity.

Monitoring the susceptibility of Bemisia tabaci Middle East-Asia Minor 1 (Hemiptera: Aleyrodidae) to afidopyropen, cyantraniliprole, dinotefuran, and flupyradifurone in south Florida vegetable fields.

Bemisia tabaci Middle East-Asia Minor 1 (MEAM1) is a significant pest that damages a wide range of high-value vegetable crops in south Florida. This pest has demonstrated the ability to develop resistance to various insecticide groups worldwide. Monitoring the resistance levels of MEAM1 populations and maintaining baseline susceptibility data are crucial for the long-term effectiveness of insecticide management strategies. We conducted serial dilution bioassays on 15 field populations of MEAM1 collected in south Florida to assess their resistance to 4 key insecticides: afidopyropen, cyantraniliprole, dinotefuran, and flupyradifurone. To quantify resistance levels, resistance ratios (RR) were generated by comparing the LC50 values of field populations to those of a known susceptible MEAM1 colony reared in the laboratory. Our findings reveal that all field-collected populations were susceptible to dinotefuran (RR 1-8) and flupyradifurone (RR 2-8). While over 80% of the populations tested were susceptible to afidopyropen (RR 1-9), 2 populations exhibited low (RR 38) and moderate resistance (RR 51), respectively. In contrast, most of the populations (57%) showed low to moderate resistance to cyantraniliprole (RR 21-78), and the remaining populations were susceptible (RR 3-10). The 2 populations with resistance to afidopyropen also exhibited moderate resistance to cyantraniliprole. Further research in this direction can aid in refining insecticide resistance management programs in Florida and other regions where B. tabaci MEAM1 is a major pest. Exploring the implications of these findings will be essential for insecticide use and integrated pest management strategies in south Florida.

Key role of the ryanodine receptor I4790K mutation in mediating diamide resistance in Plutella xylostella.

The diamondback moth Plutella xylostella, a global insect pest of cruciferous vegetables, has evolved resistance to many classes of insecticides including diamides. Three point mutations (I4790M, I4790K, and G4946E) in the ryanodine receptor of P. xylostella (PxRyR) have been identified to associate with varying levels of resistance. In this study, we generated a knockin strain (I4790K-KI) of P. xylostella, using CRISPR/Cas9 to introduce the I4790K mutation into PxRyR of the susceptible IPP-S strain. Compared to IPP-S, the edited I4790K-KI strain exhibited high levels of resistance to both anthranilic diamides (chlorantraniliprole 1857-fold, cyantraniliprole 1433-fold) and the phthalic acid diamide flubendiamide (>2272-fold). Resistance to chlorantraniliprole in the I4790K-KI strain was inherited in an autosomal and recessive mode, and genetically linked with the I4790K knockin mutation. Computational modeling suggests the I4790K mutation reduces the binding of diamides to PxRyR by disrupting key hydrogen bonding interactions within the binding cavity. The approximate frequencies of the 4790M, 4790K, and 4946E alleles were assessed in ten geographical field populations of P. xylostella collected in China in 2021. The levels of chlorantraniliprole resistance (2.3- to 1444-fold) in these populations were significantly correlated with the frequencies (0.017-0.917) of the 4790K allele, but not with either 4790M (0-0.183) or 4946E (0.017-0.450) alleles. This demonstrates that the PxRyR I4790K mutation is currently the major contributing factor to chlorantraniliprole resistance in P. xylostella field populations within China. Our findings provide in vivo functional evidence for the causality of the I4790K mutation in PxRyR with high levels of diamide resistance in P. xylostella, and suggest that tracking the frequency of the I4790K allele is crucial for optimizing the monitoring and management of diamide resistance in this crop pest.

Discovery of Trisubstituted N-Phenylpyrazole Containing Diamides with Improved Insecticidal Activity.

To increase the structural diversity of insecticides and meet the needs of effective integrated insect management, the structure of chlorantraniliprole was modified based on a previously established three-dimensional quantitative structure-activity relationship (3D-QSAR) model. The pyridinyl moiety in the structure of chlorantraniliprole was replaced with a 4-fluorophenyl group. Further modifications of this 4-fluorophenyl group by introducing a halogen atom at position 2 and an electron-withdrawing group (e.g., iodine, cyano, and trifluoromethyl) at position 5 led to 34 compounds with good insecticidal efficacy against Mythimna separata, Plutella xylostella, and Spodoptera frugiperda. Among them, compound IV f against M. separata showed potency comparable to that of chlorantraniliprole. IV p against P. xylostella displayed a 4.5 times higher potency than chlorantraniliprole. In addition, IV d and chlorantraniliprole exhibited comparable potencies against S. frugiperda. Transcriptome analysis showed that the molecular target of compound IV f is the ryanodine receptor. Molecular docking was further performed to verify the mode of action and insecticidal activity against resistant P. xylostella.

Methyl N,N-dimethylanthranilate and ethyl propionate: repellents effective against spotted wing drosophila, Drosophila suzukii.

BACKGROUND: Spotted wing drosophila, Drosophila suzukii (Matsumura) (Diptera: Drosophilidae), is an economically important pest of soft and stone fruit crops. The aim of this study was to identify repellents, formulated in dispensers, which could protect crops from D. suzukii. Fourteen potential repellents were screened against summer- and winter-morph D. suzukii through electroantennography and behavioural bioassays. Repellents effective in the laboratory were tested in polytunnels to determine their efficacy in reducing catches in fruit-baited traps. Further trials of three potential repellents were conducted to determine the distances over which repellent dispensers could reduce D. suzukii emergence in a strawberry crop. RESULTS: All 14 chemicals screened were detected by the antennae of both D. suzukii morphs. Hexyl acetate and geosmin both elicited a significantly greater corrected EAG response in summer morphs than winter morphs. Summer-morph D. suzukii were repelled by butyl acetate, ethyl propionate, methyl N,N-dimethyl anthranilate, geosmin, methyl salicylate, DEET and benzaldehyde at one or more doses test in laboratory bioassays. Winter morphs were repelled by ethyl propionate, methyl anthranilate, methyl N,N-dimethyl anthranilate, DEET, benzaldehyde and butyl anthranilate at one or more of the doses tested in the laboratory. Ethyl propionate, methyl N,N-dimethylanthranilate and benzaldehyde repelled both morphs from fruit-baited traps in polytunnel trapping trials. Ethyl propionate and methyl N,N-dimethylanthranilate reduced emergence of D. suzukii in a strawberry crop over 3-5 m. CONCLUSIONS: Ethyl propionate and methyl N,N-dimethylanthranilate may protect strawberry crops against D. suzukii. Future work should test these repellents in combination with attractants in a 'push-pull' strategy. © 2024 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Design and discovery of anthranilamide derivatives as a potential treatment for neurodegenerative disorders via targeting cholinesterases and monoamine oxidases.

Neurodegenerative diseases with progressive cellular loss of the central nervous system and elusive disease etiology provide a continuous impetus to explore drug discovery programmes aiming at identifying robust and effective inhibitors of cholinesterase and monoamine oxidase enzymes. We herein present a concise library of anthranilamide derivatives involving a palladium-catalyzed Suzuki-Miyaura cross-coupling reaction to install the diverse structural diversity required for the desired biological action. Using Ellman's method, cholinesterase inhibitory activity was performed against AChE and BuChE enzymes. In vitro assay results demonstrated that anthranilamides are potent inhibitors with remarkable potency. Compound 6k emerged as the lead candidate and dual inhibitor of both enzymes with IC50 values of 0.12 ± 0.01 and 0.49 ± 0.02 µM against AChE and BuChE, respectively. Several other compounds were found as highly potent and selective inhibitors. Anthranilamide derivatives were also tested against monoamine oxidase (A and B) enzymes using fluorometric method. In vitro data revealed compound 6h as the most potent inhibitor against MAO-A, showing an IC50 value of 0.44 ± 0.02 µM, whereas, compound 6k emerged as the top inhibitor of MAO-B with an IC50 value of 0.06 ± 0.01 µM. All the lead inhibitors were analyzed for the identification of their mechanism of action using Michaelis-Menten kinetics experiments. Compound 6k and 6h depicted a competitive mode of action against AChE and MAO-A, whereas, a non-competitive and mixed-type of inhibition was observed against BuChE and MAO-B by compounds 6k. Molecular docking analysis revealed remarkable binding affinities of the potent inhibitors with specific residues inside the active site of receptors. Furthermore, molecular dynamics simulations were performed to explore the ability of potent compounds to form energetically stable complexes with the target protein. Finally, in silico ADME calculations also demonstrated that the potent compounds exhibit promising pharmacokinetic profile, satisfying the essential criteria for drug-likeness. Altogether, the findings reported in the current work clearly suggest that the identified anthranilamide derivatives have the potential to serve as effective drug candidates for future investigations.

Uninheritable but Widespread Bacterial Symbiont Enterococcus casseliflavus Mediates Detoxification of the Insecticide Chlorantraniliprole in the Agricultural Invasive Pest Spodoptera frugiperda.

Host-symbiont interaction plays a crucial role in determining the host's fitness under toxic stress, as observed in numerous insect species. However, the mechanism of the symbionts involved in the detoxification of insecticides remains poorly known. In this study, through microbiome, proteomic, and genomic analysis, we identified a prevalent symbiont, Enterococcus casseliflavus EMBL-3, in a major invasive insect pest,Spodoptera frugiperda. This symbiont enhances the host's insecticide resistance to chlorantraniliprole by breaking amide bonds and dehalogenating insecticides. Complying with the increase in exposure risk of chlorantraniliprole, the E. casseliflavus isolates of insects' symbionts but not those from mammals or environmental strains showed a significant enrichment of potential chlorantraniliprole degradation genes. EMBL-3 is popular in field population insects with efficient horizontal transmission ability through cross-diet and cannibalism. This study provides a new therapeutic target for agricultural pests based on symbiont-targeted insect control for global crop protection.

Unlocking the potential of tranilast: Targeting fibrotic signaling pathways for therapeutic benefit.

Fibrosis is the excessive deposition of extracellular matrix in an organ or tissue that results from an impaired tissue repair in response to tissue injury or chronic inflammation. The progressive nature of fibrotic diseases and limited treatment options represent significant healthcare challenges. Despite the substantial progress in understanding the mechanisms of fibrosis, a gap persists translating this knowledge into effective therapeutics. Here, we discuss the critical mediators involved in fibrosis and the role of tranilast as a potential antifibrotic drug to treat fibrotic conditions. Tranilast, an antiallergy drug, is a derivative of tryptophan and has been studied for its role in various fibrotic diseases. These include scleroderma, keloid and hypertrophic scars, liver fibrosis, renal fibrosis, cardiac fibrosis, pulmonary fibrosis, and uterine fibroids. Tranilast exerts antifibrotic effects by suppressing fibrotic pathways, including TGF-ß, and MPAK. Because it disrupts fibrotic pathways and has demonstrated beneficial effects against keloid and hypertrophic scars, tranilast could be used to treat other conditions characterized by fibrosis.

Chlorantraniliprole Resistance in Spodoptera frugiperda: Resistance Monitoring, Resistance Risk, and Resistance Mechanisms.

Spodoptera frugiperda is a significant global pest, and chlorantraniliprole (CAP) is extensively used in China for its control. Understanding CAP resistance in S. frugiperda is crucial for effective management of this pest. Field populations exhibited varying degrees of resistance to CAP (RR = 1.74-5.60-fold). After 10 generations of selection, the CAP-resistant strain developed over 10-fold resistance, with a realized heritability (h2) of 0.10. Genetic analysis reveals inheritance patterns as autosomal, incomplete recessive, and monofactorial. The CAP-resistant strain showed limited cross-resistance to lufenuron and tetrachlorantraniliprole, negative cross-resistance to spinetoram, and no observed cross-resistance to other insecticides. Biochemical analysis suggested that P450-mediated detoxification is the primary resistance mechanism, with 26 genes overexpressed in the CAP-resistant strain. Additionally, the knockdown of CYP4L13, CYP6B39, CYP6B40, and CYP4G74 significantly increased the sensitivity of the resistant larvae to CAP. These findings highlight the resistance risk of CAP in S. frugiperda and emphasize the crucial role of P450 enzymes in resistance.

Tranilast alleviates visceral hypersensitivity and colonic hyperpermeability by suppressing NLRP3 inflammasome activation in irritable bowel syndrome rat models.

Visceral hypersensitivity resulting from compromised gut barrier with activated immune system is a key feature of irritable bowel syndrome (IBS). Corticotropin-releasing factor (CRF) and Toll-like receptor 4 (TLR4) activate proinflammatory cytokine signaling to induce these changes, which is one of the mechanisms of IBS. As activation of the NLRP3 inflammasome by lipopolysaccharide (LPS) or TLR4 leads to release interleukin (IL)-1ß, the NLRP3 inflammasome may be involved in the pathophysiology of IBS. Tranilast, an anti-allergic drug has been demonstrated to inhibit the NLRP3 inflammasome, and we evaluated the impact of tranilast on visceral hypersensitivity and colonic hyperpermeability induced by LPS or CRF (IBS rat model). Visceral pain threshold caused by colonic balloon distention was measured by monitoring abdominal muscle contractions electrophysiologically. Colonic permeability was determined by quantifying the absorbed Evans blue within the colonic tissue. Colonic protein levels of NLRP3 and IL-1ß were assessed by immunoblot or ELISA. Intragastric administration of tranilast (20-200 mg/kg) for 3 days inhibited LPS (1 mg/kg)-induced visceral hypersensitivity and colonic hyperpermeability in a dose-dependent manner. Simultaneously, tranilast also abolished these alterations induced by CRF (50 µg/kg). LPS increased colonic protein levels of NLRP3 and IL-1ß, and tranilast inhibited these changes. ß-hydroxy butyrate, an NLRP3 inhibitor, also abolished visceral hypersensitivity and colonic hyperpermeability caused by LPS. In contrast, IL-1ß induced similar GI alterations to LPS, which were not modified by tranilast. In conclusion, tranilast improved visceral pain and colonic barrier by suppression of the NLRP3 inflammasome in IBS rat models. Tranilast may be useful for IBS treating.

Design, synthesis, molecular modeling, in vitro and in vivo biological evaluation of potent anthranilamide derivatives as dual P-glycoprotein and CYP3A4 inhibitors.

Paclitaxel (PTX) is considered the blockbuster chemotherapy treatment for cancer. Paclitaxel's (PTX) oral administration has proven to be extremely difficult, mostly because of its susceptibility to intestinal P-glycoprotein (P-gp) and cytochrome P450 (CYP3A4). The concurrent local inhibition of intestinal P-gp and CYP3A4 is a promising approach to improve the oral bioavailability of paclitaxel while avoiding potential unfavorable side effects of their systemic inhibition. Herein, we report the rational design and evaluation of novel dual potent inhibitors of P-gp and CYP3A4 using an anthranilamide derivative tariquidar as a starting point for their structural optimizations. Compound 14f, bearing N-imidazolylbenzyl side chain, was found to have potent and selective P-gp (EC50 = 28 nM) and CYP3A4 (IC50 = 223 nM) inhibitory activities with low absorption potential (Papp (A-to-B) <0.06). In vivo, inhibitor 14f improved the oral absorption of paclitaxel by 6 times in mice and by 30 times in rats as compared to vehicle, while 14f itself remained poorly absorbed. Compound 14f, possessing dual P-gp and CYP3A4 inhibitory activities, offered additional enhancement in paclitaxel oral absorption compared to tariquidar in mice. Evaluating the CYP effect of 14f on oral absorption of paclitaxel requires considering the variations in CYP expression between animal species. This study provides further medicinal chemistry advice on strategies for resolving concerns with the oral administration of chemotherapeutic agents.

Tranilast Inhibits TRPV2 and Suppresses Fibrosis Progression and Weight Gain in a NASH Model Mouse.

BACKGROUND/AIM: This study aimed to investigate the role of transient receptor potential vanilloid 2 (TRPV2) in a mouse model with non-alcoholic steatohepatitis (NASH) and to examine the effects of tranilast on TRPV2 and fibrosis-related cytokines. MATERIALS AND METHODS: C57BL/6N mice were fed a Gubra-Amylin NASH (GAN) diet for 20 weeks to induce NASH. The tranilast groups received oral administration of tranilast at doses of 300, 400 and 500 mg/kg/day, five days per week for 20 weeks, in addition to the GAN diet. The effects of tranilast were assessed based on the dosage of food intake, changes in body weight, liver weight, blood biochemical parameters, histopathological examination, and expression of TRPV2 and inflammatory cytokines. RESULTS: Hepatic expression of TRPV2 was observed in the GAN-fed NASH mouse model. The tranilast groups showed significantly suppressed increases in body and liver weights. The development of intrahepatic fat deposition and liver fibrosis, assessed histopathologically, was inhibited. Tranilast administration improved the expression of TRPV2 and inflammatory cytokines in the liver. Additionally, blood tests indicated a reduction in elevated liver enzyme levels. CONCLUSION: In GAN diet NASH models, TRPV2 was up-regulated in the liver and tranilast inhibited TRPV2 and suppressed fibrosis. Therefore, it might prevent the incidence of hepatocellular carcinoma associated with NASH.

Potential of natural repellents methylanthranilate and anthraquinone applied on maize seeds and seedlings against house sparrow (Passer domesticus) in captivity / Potencial de repelentes naturais, metilantranilato e antraquinona aplicados em sementes de milho e mudas contra o pardal (Passer domesticus) em cativeiro

Abstract Various bird pests caused severe economic losses to valuable crops and fruit orchards all over the world. Among the birds, house sparrow is also considered to cause heavy plunder, not only to seeds of crops but also seedlings especially in organic farming. In present study two bird repellents, methylanthranilate and anthraquinone tested against house sparrows on maize seeds and seedlings in aviary conditions. Trial group in aviary-I, the treated maize seeds and seedlings with different doses of both bird repellents, control group in aviary-II, untreated seeds and seedlings were provided for three hours in the early morning. In each aviary, two closed circuit cameras were also installed to monitor the behavioral responses against different concentrations of both chemical repellents. Statistical analysis showed that there existed highly significant (P<0.01) variations among the trial and control groups for seeds and seedlings. By comparing both repellents, significant (P<0.05) differences were detected and anthraquinone showed better efficacy when compared to methylanthranilate, but in maize seedlings both repellents equal repellent properties. Non-significant (P>0.05) differences were observed in different grading of both natural chemical repellents for maize seeds while significant (P<0.05) variations were noticed for maize seedlings when provided to sparrows. By videotaped behavior sparrows presented manifest head juddering and feather upsetting activities by consumption of treated seeds and seedlings with higher concentrations of both natural bird repellents.

Resumo Várias pragas de aves causaram graves perdas econômicas para cultivos valiosos e pomares de frutas em todo o mundo. Entre os pássaros, o pardal da casa também é considerado um grande saqueo, não só para as sementes das culturas, mas também para as mudas, especialmente na agricultura orgânica. No presente estudo, dois repelentes de aves, metilantranilato e antraquinona testados contra pardais de casa em sementes de milho e mudas em condições de aviário. O grupo de ensaio em aviary-I, as sementes de milho tratadas e as mudas com diferentes doses de repelentes de aves, grupo de controle em aviary-II, sementes não tratadas e mudas foram fornecidas por três horas no início da manhã. Em cada aviário, duas câmeras de circuito fechado também foram instaladas para monitorar as respostas comportamentais contra diferentes concentrações de ambos os repelentes químicos. A análise estatística mostrou que existiam variações altamente significativas (P<0,01) entre os grupos de teste e controle para sementes e mudas. Ao comparar os dois repelentes, detectaram-se diferenças significativas (P<0,05) e a antraquinona apresentou maior eficácia quando comparada ao metilantranilato, mas em mudas de milho, ambos os repelentes são iguais às propriedades repelentes. As diferenças não significantes (P>0,05) foram observadas em diferentes classificações de repelentes químicos naturais para sementes de milho, enquanto as variações significativas (P<0,05) foram observadas para as mudas de milho quando fornecidas aos pardais. Por um comportamento gravado em video, os pardais apresentaram manifestações de cabeça e vibrações de penas por consumo de sementes tratadas e mudas com maiores concentrações de repelentes de aves naturais.