Association between body roundness index and overactive bladder: results from the NHANES 2005-2018.

BACKGROUND AND AIM: An increasing amount of research has indicated obesity greatly affects individuals with overactive bladder (OAB). However, traditional anthropometric methods present challenges in accurately assessing the likelihood of OAB. Hence, this study's objective was to identify the correlation between the body roundness index (BRI) and OAB. METHODS: The research included 12,401 individuals who participated in the National Health and Nutrition Examination Survey spanning 2005-2018. The correlation between BRI and OAB was explored by using weighted multiple logistic regression and weighted restricted cubic spline (RCS). Subgroup analyses showed the associations based on different population types. The study also analyzed the predictive capability of various anthropometric indices, including BRI, body mass index, waist circumference, and weight, in assessing the likelihood of OAB through Receiver-operating characteristic (ROC) curves. RESULTS: An independent positive correlation between OAB and BRI was identified after adjusting for potential confounders in weighted multivariate logistic models[odds ratio (OR) = 1.15, 95% confidence interval (CI), 1.12-1.17]. Weighted RCS analysis found a positive dose-response correlation between OAB and BRI. The effect size of BRI on OAB remained stable across all prespecified subgroups (all P for interactions > 0.05). In ROC analysis, BRI showed better discriminatory ability for OAB compared with other anthropometric measures for both genders (all P < 0.01). The best BRI cutoff for predicting OAB was lower for men (5.151) than for women (5.383), suggesting that men were more susceptible to changes in BRI than women. CONCLUSIONS: This study demonstrated that a raised BRI is correlated with a higher likelihood of OAB. Due to the effectiveness and non-invasiveness of BRI in predicting OAB, it is expected to become the preferred method for early detection and management strategies.

PxRdl2 dsRNA increased the insecticidal activities of GABAR-targeting compounds against Plutella xylostella.

The utilization of RNA interference (RNAi) for pest management has garnered global interest. The bioassay results suggested the knockout of the PxRdl2 gene significantly increased the insecticidal activities of the γ-aminobutyric acid receptor (GABAR)-targeting compounds (fipronil, two pyrazoloquinazolines, and two isoxazolines), thereby presenting a viable target gene for RNAi-mediated pest control. Consequently, we suggest enhancing the insecticidal activities of GABAR-targeting compounds by knockdown the transcript level of PxRdl2. Furthermore, PxRdl2 dsRNA was expressed in HT115 Escherichia coli to reduce costs and protect dsRNA against degradation. In comparison to in vitro synthesized dsRNA, the recombinant bacteria (ds-B) exhibited superior interference efficiency and greater stability when exposed to UV irradiation. Collectively, our results provide a strategy for insecticide spray that combines synergistically with insecticidal activities by suppressing PxRdl2 using ds-B and may be beneficial for reducing the usage of insecticide and slowing pest resistance.

Structural optimization based on 4,5-dihydropyrazolo[1,5-a]quinazoline scaffold for improved insecticidal activities.

The long-term and irrational application of insecticides has increased the rate of development of pest resistance and caused numerous environmental issues. To address these problems, our previous work reported that 4,5-dihydropyrazolo[1,5-a]quinazoline (DPQ) is a class of gelled heterocyclic compounds that act on insect γ-aminobutyric acid receptors (GABAR). DPQ scaffold has no cross-resistance to existing insecticides, so the development of this scaffold is an interesting task for integrated pest management. In the present study, a novel series of 4,5-dihydropyrazolo[1,5-a]quinazolines (DPQs) were designed and synthesized based on pyraquinil, a highly insecticidal compound discovered in our previous work. Insecticidal activities of the target compounds against diamondback moth (Plutella xylostella), beet armyworm (Spodoptera exigua), fall armyworm (Spodoptera frugiperda), and red imported fire ant (Solenopsis invicta Buren) were evaluated. Compounds 6 and 12 showed the best insecticidal activity against Plutella xylostella (P. xylostella) (LC50 = 1.49 and 0.97 mg/L), better than pyraquinil (LC50 = 1.76 mg/L), indoxacarb and fipronil (LC50 = 1.80 mg/L). Meanwhile, compound 12 showed slow toxicity to Solenopsis invicta Buren (S. invicta), with a 5 d mortality rate of 98.89% at 0.5 mg/L that is similar to fipronil. Moreover, Electrophysiological studies against the PxRDL1 GABAR heterologously expressed in Xenopus oocytes indicated that compound 12 could act as a potent GABA receptor antagonist (2 µΜ, inhibition rate, 68.25%). Molecular docking results showed that Ser285 (chain A) and Thr289 (chain D) of P. xylostella GABAR participated in hydrogen bonding interactions with compound 12, and density functional theory (DFT) calculations suggested the importance of pyrazolo[1,5-a]quinazoline core in potency. This systematic study provides valuable clues for the development of DPQ scaffold in the field of agrochemicals, and compound 12 can be further developed as an insecticide and bait candidate.

Rational Design of Insecticidal Isoxazolines Containing Sulfonamide or Sulfinamide Structure as Antagonists of GABA Receptors with Reduced Toxicities to Honeybee and Zebrafish.

To develop highly effective, nontarget organism-friendly insecticides based on the isoxazoline scaffold, we rationally designed and synthesized 25 isoxazoline derivatives containing sulfonamides and sulfinamides. Their insecticidal activities against the diamondback moth (Plutella xylostella), fall armyworm (Spodoptera frugiperda), beet armyworm (Spodoptera exigua), and Spodoptera litura Fabricius (S. litura) were evaluated. The trifluoromethyl sulfinamide-containing compound 7w displayed excellent activities with LC50 values being 0.09, 0.84, 0.87, and 0.68 mg/L against P. xylostella, S. frugiperda, S. exigua, and S. litura, respectively, which were superior to fluxametamide (LC50 = 0.09, 1.24, 1.10, and 0.65 mg/L, respectively) and maintained at the same order of magnitude LC50 values as fluralaner (LC50 = 0.02, 0.17, 0.12, and 0.19 mg/L, respectively). Importantly, compound 7w showed a medium toxicity level of acute toxicity to honeybee (LD50 = 2.22 µg/adult), which is significantly lower than the fluralaner (high toxicity level, LD50 = 0.09 µg/adult). Acute toxicity experiments with zebrafish (Danio rerio) indicated that compound 7w was safe with the LC50 value being 42.4 mg/L (low toxicity level). Furthermore, electrophysiological experiments and molecular docking studies preliminarily verified that compound 7w acts on the insect GABA receptor, and the theoretical calculations explained that the sulfinamide structure may play an important role in exhibiting biological activities. The above results suggest that compound 7w could be employed as a potentially highly effective, environmentally friendly insecticide to control multiple agricultural pests.

Mode of Action of Novel Pyrazoloquinazoline on Diamondback Moth (Plutella xylostella) Ligand-Gated Chloride Channels.

In our previous study, a series of novel pyrazoloquinazolines were synthesized. Pyrazoloquinazoline 5a showed high insecticidal activity against the diamondback moth (Plutella xylostella) and no cross-resistance to fipronil. Patch clamp electrophysiology performed on P. xylostella pupae brains and two-electrode voltage clamp electrophysiology performed on Xenopus Laevis oocytes indicated that 5a might act on the ionotropic γ-aminobutyric acid (GABA) receptor (GABAR) and glutamate-gated chloride channel (GluCl). Moreover, 5a's potency on PxGluCl was about 15-fold higher than on fipronil, which may explain why there was no cross-resistance between 5a and fipronil. Downregulation of the PxGluCl transcription level significantly enhanced the insecticidal activity of 5a on P. xylostella. These findings shed light on the mode of action of 5a and provide important insights into the development of new insecticides for agricultural applications.

Design, synthesis, and biological activity of novel spiro-pyrazolo[1,5-a]quinazolines derivatives as potential insecticides.

BACKGROUND: Arylpyrazole insecticides display broad-spectrum insecticidal activity against insect pests. However, the high toxicity toward honeybees associated with fipronil prohibits its agronomic utility. To explore reducing the toxicity of aryl pyrazole analogs to bees, a series of new spiro-pyrazolo[1,5-a]quinazoline derivatives were designed and synthesized. RESULTS: Bioassay results showed that these compounds exhibited good insecticidal activity. In particular, the insecticidal activity of compound 5f against Plutella xylostella larvae (median lethal contentration, LC50  = 1.43 mg L-1 ) was equivalent to that of fipronil. Moreover, some compounds also showed good insecticidal activity against Solenopsis invicta. Importantly, the bee toxicity study confirmed that compound 5f had much lower acute oral toxicity, with a median lethal dose (LD50 ) = 1.15 µg bee-1 that was three to four orders of magnitude greater than that of fipronil (0.0012 µg bee-1 ). Electrophysiological studies were conducted using honeybee γ-aminobutyric acid receptor heterologously expressed in Xenopus oocytes to explain the reduced bee toxicity of compound 5f. The inhibitory effect of compound 5f (16.29 µmol L-1 ) was determined to be approximately 700-fold lower than that of fipronil (0.023 µmol L-1 ). CONCLUSION: These spiro-pyrazolo[1,5-a]quinazoline derivatives could be potential candidates and lead structures for the discovery of novel insecticides with low bee toxicity. © 2022 Society of Chemical Industry.

Distinct roles of two RDL GABA receptors in fipronil action in the diamondback moth (Plutella xylostella).

The phenylpyrazole insecticide fipronil blocks resistance to dieldrin (RDL) γ-aminobutyric acid (GABA) receptors in insects, thereby impairing inhibitory neurotransmission. Some insect species, such as the diamondback moth (Plutella xylostella), possess more than one Rdl gene. The involvement of multiple Rdls in fipronil toxicity and resistance remains largely unknown. In this study, we investigated the roles of two Rdl genes, PxRdl1 and PxRdl2, in P. xylostella fipronil action. In Xenopus oocytes, PxRDL2 receptors were 40 times less sensitive to fipronil than PxRDL1. PxRDL2 receptors were also less sensitive to GABA compared with PxRDL1. Knockout of the fipronil-sensitive PxRdl1 reduced the fipronil potency 10-fold, whereas knockout of the fipronil-resistant PxRdl2 enhanced the fipronil potency 4.4-fold. Furthermore, in two fipronil-resistant diamondback moth field populations, PxRdl2 expression was elevated 3.7- and 4.1-fold compared with a susceptible strain, whereas PxRdl1 expression was comparable among the resistant and susceptible strains. Collectively, our results indicate antagonistic effects of PxRDL1 and PxRDL2 on fipronil action in vivo and suggest that enhanced expression of fipronil-resistant PxRdl2 is potentially a new mechanism of fipronil resistance in insects.

Antitumor Activity and Mechanism of Robustic Acid from Dalbergia benthami Prain via Computational Target Fishing.

Dalbergia benthami Prain (D.benthami) is an important legume species of the Dalbergia family, due to the use of its trunk and root heart in traditional Chinese medicine (TCM). In the present study, we reported the isolation, characterization and pharmacological activities of robustic acid (RA) from the ethyl acetate extract of D. benthami Prain. The SwissADME prediction showed that the RA satisfied the Lipinski's rule of five (molecule weight (MW): 380.39 g/mol, lipid-water partition coefficient (log P): 3.72, hydrogen bond donors (Hdon): 1, hydrogen bond acceptors (Hacc): 6, rotatable bonds (Rbon): 3. Other chemical and pharmacological properties of this RA were also evaluated, including topological polar surface area (TPSA) = 78.13 Šand solubility (Log S) = -4.8. The probability values of the antineoplastic, anti-free radical activities and topoisomerase I (TopoⅠ) inhibitory activity were found to be 0.784, 0.644 and 0.379, respectively. The molecular docking experiment using the Surflex-Dock showed that the Total Score and C Score of RNA binding with the human DNA-Topo I complex were 7.80 and 4. The MTS assay experiment showed that the inhibitory rates of RA on HL-60, MT4, Hela, HepG2, SK-OV-3 and MCF-7 cells were 37.37%, 97.41%, 81.22%, 34.4%, 32.68% and 51.4%, respectively. In addition, RA exhibited an inhibitory effect on the angiogenesis of zebrafish embryo, a good TopoⅠ inhibitory activity at a 10 mM concentration and in a dose-dependent manner, excellent radical scavenging in the DPPH and ABTS assays, and the free radical scavenging rate was close to the positive control (BHT) at different concentrations (0.5-2.0 mg/mL). Furthermore, 18 potential targets were found for this RA by PharmMapper, including ANXA3, SRC, FGFR2, GSK3B, CSNK2B, YARS, LCK, EPHA2, MAPK14, RORA, CRABP2, PPP1CC, METAP2, MME, TTR, MET and KDR. The GO and KEGG pathway analysis revealed that the "protein tyrosine kinase activity", "rap1 signaling pathway" and "PI3K-Akt signaling pathway" were significantly enriched by the RA target genes. Our results will provide new insights into the pharmaceutical use of this species. More importantly, our data will expand our understanding of the molecular mechanisms of RA functions.