Residues of pesticides in milk may pose a threat to human health. This study aimed to develop a liquid-phase microextraction (LPME) method using hexafluoroisopropanol (HFIP)-based supramolecular solvent (SUPRAS) for the simultaneous extraction and purification of four pesticides (boscalid, novaluron, cypermethrin and bifenthrin) in milk. Pesticides were extracted using SUPRAS prepared with nonanol and HFIP, and the extraction efficiency was analyzed. Results showed satisfactory recoveries ranging from 80.8%-111.0%, with relative standard deviations (RSDs) of <6.4%. Additionally, satisfactory linearities were observed, with correlation coefficients >0.9952. The limits of quantification (LOQs) were in the range of 1.8 μg·L-1-14.0 μg·L-1. The established method demonstrated high extraction efficiency with a short operation time (15 mins) and low solvent consumption (2.7 mL). The HFIP-based SUPRAS LPME method offers a convenient and efficient approach for the extraction of pesticides from milk, presenting a promising alternative to conventional techniques.

TMEM16A, a member of the Transmembrane protein 16 family, serves as the molecular basis for calcium activated chloride channels (CaCCs). We use RT-PCR to demonstrate the expression of TMEM16A in the neurons of Helicoverpa armigera, and record the CaCCs current of acute isolated neurons of H. armigera for the first time using patch clamp technology. In order to screen effective inhibitors of calcium-activated chloride channels, the inhibitory effects of four chloride channel inhibitors, CaCCinh-A01, NPPB, DIDS, and SITS, on CaCCs were compared. The inhibitory effects of the four inhibitors on the outward current of CaCCs were CaCCinh-A01 (10 μM, 56.31 %), NPPB (200 μM, 43.69 %), SITS (1 mM, 12.41 %) and DIDS (1 mM, 13.29 %). Among these inhibitors, CaCCinh-A01 demonstrated the highest efficacy as a blocker. To further explore whether calcium channel proteins can serve as potential targets of pyrethroids, we compared the effects of (type I) tefluthrin and (type II) deltamethrin on CaCCs. 10 μM and 100 μM tefluthrin can stimulate a large tail current in CaCCs, prolonging their deactivation time by 10.44 ms and 31.49 ms, and the V0.5 shifted in the hyperpolarization by 2-8 mV. Then, deltamethrin had no obvious effect on the deactivation and activation of CaCCs. Therefore, CaCCs of H. armigera can be used as a potential target of pyrethroids, but type I and type II pyrethroids have different effects on CaCCs.

There is an unmet clinical need for effective anticoagulant therapies for the management of thromboembolic diseases that are not associated with a relevant risk of bleeding. Asundexian (BAY 2433334) is an oral, direct, small-molecule inhibitor of activated factor XI (FXIa). Phase I data from healthy Caucasian male participants indicated predictable pharmacokinetic (PK) and pharmacodynamic (PD) profiles and no clinically relevant bleeding-related adverse events (AEs). Reported here are data from two phase I, randomized, placebo-controlled, single- and multiple-dose escalation studies of asundexian conducted in 60 healthy men: 24 Japanese and 36 Chinese. Baseline characteristics were comparable between the treatment groups. All treatment-emergent AEs were mild, with no serious AEs or AEs of special interest reported. Systemic exposure to asundexian increased dose proportionally after single or multiple dosing, with relatively low accumulation following multiple once-daily dosing in both Chinese and Japanese volunteers. Asundexian induced dose-dependent prolongation of activated partial thromboplastin time and inhibition of FXIa activity, with no effects on prothrombin time or FXI concentration in Japanese participants. There were no clinically relevant interethnic differences in PK profile across the Japanese, Chinese, and Caucasian (data from the previous phase I study) participants and no clinically relevant difference in PD response between Japanese and Caucasian participants.

The potential ecological risk of per- and polyfluorinated alkyl substances (PFASs) in phytoremediation has raised social concerns, promoting a need to better understand their distribution and risks in the recovery process of aquatic plants. Herein, we aim to fill this knowledge gap by investigating the distribution and ecotoxicological effects of PFASs on the structure and function of water-macrophyte-sediment microcosm systems. Among the entire system, 63.0 %-73.1 % PFOA was found in sediments and submerged plants, however, 52.5 %-53.0 % of PFPeA and 47.0 %-47.5 % of PFBS remained in the water under different treatments. PFOA was more bioavailable than the other substances, as demonstrated by the bioaccumulation factors (BAF) with ranges exposed to PFPeA and PFBS. Bioaccumulation PFASs induced plant oxidative stress which generates enzymes to suppress superoxide, and disturbed the processes of lysine biosynthesis, in which allysine, meso-2,6-diaminoheptanedioate, and Nsuccinyl-2-amino-6-ketopimelate were downregulated. PFASs were detected in the propagator (turions) of an ecological restoration species, where short-chain PFASs (70.1 % and 45.7 % for 2 or 20 μg/L PFAS exposure, respectively) were found to spread further into new individuals and profoundly influence ecological processes shaping populations. PFASs significantly enhanced the number of microbial species in the sediment, but the degree of differentiation in the microbial community structure was not significantly different. This study enhances our understanding of the ecological mechanisms of PFASs in the water-macrophyte-sediment systems and potential threats to the recovery process of macrophytes.

Enzymes capable of assimilating fluorinated feedstocks are scarce. This situation poses a challenge for the biosynthesis of fluorinated compounds used in pharmaceuticals, agrochemicals, and materials. We developed a photoenzymatic hydrofluoroalkylation that integrates fluorinated motifs into olefins. The photoinduced promiscuity of flavin-dependent ene-reductases enables the generation of carbon-centered radicals from iodinated fluoroalkanes, which are directed by the photoenzyme to engage enantioselectively with olefins. This approach facilitates stereocontrol through interaction between a singular fluorinated unit and the enzyme, securing high enantioselectivity at β, γ, or δ positions of fluorinated groups through enzymatic hydrogen atom transfer-a process that is notably challenging with conventional chemocatalysis. This work advances enzymatic strategies for integrating fluorinated chemical feedstocks and opens avenues for asymmetric synthesis of fluorinated compounds.

Oxathiapiprolin (OXA), which targets the oxysterol-binding protein (OSBP), is an outstanding piperidinyl thiazole isoxazoline (PTI) fungicide that can be used to control oomycetes diseases. In this study, starting from the structure of OXA, a series of novel OSBP inhibitors were designed and synthesized by introducing an indole moiety to replace the pyrazole in OXA. Finally, compound b24 was found to exhibit the highest control effect (82%) against cucumber downy mildew (CDM) in the greenhouse at a very low dosage of 0.069 mg/L, which was comparable to that of OXA (88%). Furthermore, it showed better activity against potato late blight (PLB) than other derivatives of indole. The computational results showed that the R-conformation of b24 should be the dominant conformation binding to PcOSBP. The results of the present work indicate that the 3-fluorine-indole ring is a favorable fragment to increasing the electronic energy when binding with PcOSBP. Furthermore, compound b24 could be used as a lead compound for the discovery of new OSBP inhibitors.

In our continuing effort devoted at developing agents targeting the EphA2 receptor by means of protein-protein interaction (PPI) inhibitors, we report here the design and synthesis of a new class of l-β-homotryptophan conjugates of 3-β-hydroxy-Δ5-cholenic acid bearing a set of arylsulfonyl substituents at the indole nitrogen atom. An extensive structure-activity relationship (SAR) analysis indicates that the presence of a bulky lipophilic moiety at the indole nitrogen is fundamental for improving potency on the EphA2 receptor, while abrogating activity on the EphB1-EphB3 receptor subtypes. A rational exploration, guided by the combined application of an experimental design on σp and π physicochemical descriptors and docking simulations, led to the discovery of UniPR1454, a 1-(4-(trifluoromethyl)phenyl)sulfonyl derivative acting as potent and competitive EphA2 antagonist able to inhibit ephrin-A1 dependent signals and to reduce proliferation of glioblastoma (U251) cell line at micromolar concentration.

Continuous growth in fluoroarene production has led to environmental pollution and health concerns owing to their persistence, which is attributed to the stable C-F bond in their structures. Herein, we investigated fluoroarene decomposition via hydrodefluorination using a rhodium-based catalyst, focusing on the effects of the chemical structure and functional group on the defluorination yield. Most compounds, except (pentafluoroethyl)benzene, exhibited full or partial reduction with pseudo-first-order rate constants in the range of 0.002-0.396 min-1 and defluorination yields of 0%-100%. Fluoroarenes with hydroxyl, methyl, and carboxylate groups were selected to elucidate how hydrocarbon and oxygen-containing functional groups influence the reaction rate and defluorination. Inhibition of the reaction rate and defluorination yield based on functional groups increased in the order of hydroxyl < methyl < carboxylate, which was identical to the order of the electron-withdrawing effect. Fluoroarenes with polyfluoro groups were also assessed; polyfluoro groups demonstrated a different influence on catalyst activity than non-fluorine functional groups because of fluorine atoms in the substituents undergoing defluorination. The reaction kinetics of (difluoromethyl)fluorobenzenes and their intermediates suggested that hydrogenation and defluorination occurred during degradation. Finally, the effects of the type and position of functional groups on the reaction rate and defluorination yield were investigated via multivariable linear regression analysis. Notably, the electron-withdrawing nature of functional groups appeared to have a greater impact on the defluorination yield of fluoroarenes than the calculated C-F bond dissociation energy.

BACKGROUND: The SCHUMANN study evaluated the efficacy and safety of the selective P2 × 3 antagonist eliapixant in patients with endometriosis-associated pelvic pain (EAPP).
METHODS: SCHUMANN was a randomized, placebo- and active comparator-controlled, double-blind to placebo and open-label to comparator, parallel-group, multicenter, dose-finding phase 2b study. The participants were women with surgically diagnosed endometriosis who fulfilled defined EAPP criteria. Participants were randomized 1:1:1:1 to twice daily (BID) 25 mg, 75 mg, or 150 mg oral eliapixant or a placebo for 12 weeks. An exploratory once-daily elagolix 150 mg treatment group was also included. The primary endpoint was the absolute change in mean worst EAPP from baseline to the end of intervention (EOI).
RESULTS: Overall, 215 participants were randomized for treatment (44 to eliapixant 25 mg, 44 to eliapixant 75 mg, 43 to eliapixant 150 mg, 43 to a placebo, and 41 to elagolix 150 mg). For safety reasons, the study was terminated early; both treatment and enrollment stopped immediately, producing less than 50% of the planned number of completers. The study found no significant differences in EAPP reduction from baseline between groups and no significant dose-response model. The elagolix 150 mg group showed better pain reduction than any of the other groups. No new safety signals were observed, relative to the previously known safety profile of eliapixant, which was generally well tolerated. However, one case of moderate and probably drug-induced liver injury in a participant receiving eliapixant 150 mg BID supported the association between eliapixant and a potential increase in liver function values, defined before the start of the phase 2 program.
CONCLUSIONS: This study did not meet its primary objective as no statistically significant or clinically relevant differences in changes of mean worst EAPP from baseline were observed between treatment groups. The single observed case of moderate, probably drug-induced liver injury was the second case in the eliapixant phase 2 program conducted in the following indications: refractory or unexplained chronic cough, diabetic neuropathic pain, overactive bladder, and EAPP. Due to this, the benefit-risk ratio for the study was no longer considered to be positive.
BACKGROUND: ClinicalTrials.gov identifier NCT04614246; registered November 3, 2020.