Chemical Composition of Essential Oil from Citrus reticulata Blanco cv. Chachiensis (Chachi) and Its Anti-Mosquito Activity against Pyrethroid-Resistant Aedes albopictus.

The overuse of synthetic insecticides has led to various negative consequences, including insecticide resistance, environmental pollution, and harm to public health. This may be ameliorated by using insecticides derived from botanical sources. The primary objective of this study was to evaluate the anti-mosquito activity of the essential oil (EO) of Citrus reticulata Blanco cv. Chachiensis (Chachi) (referred to as CRB) at immature, semi-mature, and mature stages. The chemical compositions of the CRB EO were analyzed using GC-MS. The main components were identified to be D-limonene and γ-terpinene. The contents of D-limonene at the immature, semi-mature, and mature stages were 62.35%, 76.72%, and 73.15%, respectively; the corresponding contents of γ-terpinene were 14.26%, 11.04%, and 11.27%, respectively. In addition, the corresponding contents of a characteristic component, methyl 2-aminobenzoate, were 4.95%, 1.93%, and 2.15%, respectively. CRB EO exhibited significant larvicidal activity against Aedes albopictus (Ae. albopictus, Diptera: Culicidae), with the 50% lethal doses being 65.32, 61.47, and 65.91 mg/L for immature, semi-mature, and mature CRB EO, respectively. CRB EO was able to inhibit acetylcholinesterase and three detoxification enzymes, significantly reduce the diversity of internal microbiota in mosquitoes, and decrease the relative abundance of core species within the microbiota. The present results may provide novel insights into the utilization of plant-derived essential oils in anti-mosquitoes.

A sonographic endometrial thickness <7 mm in women undergoing in vitro fertilization increases the risk of placenta accreta spectrum.

BACKGROUND: The prevalence of placenta accreta spectrum, a potentially life-threatening condition, has exhibited a significant global rise in recent decades. Effective screening methods and early identification strategies for placenta accreta spectrum could enable early treatment and improved outcomes. Endometrial thickness plays a crucial role in successful embryo implantation and favorable pregnancy outcomes. Extensive research has been conducted on the impact of endometrial thickness on assisted reproductive technology cycles, specifically in terms of pregnancy rates, live birth rates, and pregnancy loss rates. However, limited knowledge exists regarding the influence of endometrial thickness on placenta accreta spectrum. OBJECTIVE: This study aimed to evaluate the association between preimplantation endometrial thickness and the occurrence of placenta accreta spectrum in women undergoing assisted reproductive technology cycles. STUDY DESIGN: A total of 4637 women who had not undergone previous cesarean delivery and who conceived by in vitro fertilization or intracytoplasmic sperm injection-embryo transfer treatment and subsequently delivered at the Third Affiliated Hospital of Guangzhou Medical University between January 2008 and December 2020 were included in this study. To explore the relationship between endometrial thickness and placenta accreta spectrum, we used smooth curve fitting, threshold effect, and saturation effect analysis. Multivariate logistic regression analysis was performed to evaluate the independent association between endometrial thickness and placenta accreta spectrum while adjusting for potential confounding factors. Propensity score matching was performed to reduce the influence of bias and unmeasured confounders. Furthermore, we used causal mediation effect analysis to investigate the mediating role of endometrial thickness in the relationship between gravidity and ovarian stimulation protocol and the occurrence of placenta accreta spectrum. RESULTS: Among the 4637 women included in this study, pregnancies with placenta accreta spectrum (159; 3.4%) had significantly thinner endometrial thickness (non-placenta accreta spectrum, 10.08±2.04 mm vs placenta accreta spectrum, 8.88±2.21 mm; P<.001) during the last ultrasound before embryo transfer. By using smooth curve fitting, it was found that changes in endometrial thickness had a significant effect on the incidence of placenta accreta spectrum up to a thickness of 10.9 mm, beyond which the effect plateaued. Then, the endometrial thickness was divided into the following 4 groups: ≤7, >7 to ≤10.9, >10.9 to ≤13, and >13 mm. The absolute rates of placenta accreta spectrum in each group were 11.91%, 3.73%, 1.35%, and 2.54%, respectively. Compared with women with an endometrial thickness from 10.9 to 13 mm, the odds of placenta accreta spectrum increased from an adjusted odds ratio of 2.27 (95% confidence interval, 1.33-3.86) for endometrial thickness from 7 to 10.9 mm to an adjusted odds ratio of 7.15 (95% confidence interval, 3.73-13.71) for endometrial thickness <7 mm after adjusting for potential confounding factors. Placenta previa remained as an independent risk factor for placenta accreta spectrum (adjusted odds ratio, 11.80; 95% confidence interval, 7.65-18.19). Moreover, endometrial thickness <7 mm was still an independent risk factor for placenta accreta spectrum (adjusted odds ratio, 3.91; 95% confidence interval, 1.57-9.73) in the matched cohort after PSM. Causal mediation analysis revealed that approximately 63.9% of the total effect of gravidity and 18.6% of the total effect of ovarian stimulation protocol on placenta accreta spectrum were mediated by endometrial thickness. CONCLUSION: The findings of our study indicate that thin endometrial thickness is an independent risk factor for placenta accreta spectrum in women without previous cesarean delivery undergoing assisted reproductive technology treatment. The clinical significance of this risk factor is slightly lower than that of placenta previa. Furthermore, our results demonstrate that endometrial thickness plays a significant mediating role in the relationship between gravidity or ovarian stimulation protocol and placenta accreta spectrum.

Discovery of novel cannabidiol derivatives with augmented antibacterial agents against methicillin-resistant Staphylococcus aureus.

Drug-resistant bacterium infections are a severe threat to public health and novel antimicrobial agents combating drug-resistant bacteria are an unmet medical need. Although cannabidiol (CBD) has been reported to show antibacterial effects, whether its antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) can be improved remains unclear. Herein, a series of novel CBD derivatives were designed and synthesized using various chemical approaches including amidation, Friedel-Crafts alkylation, and Negishi cross-coupling reaction for the modifications at the C-7, C-2', C-4', and C-6' positions of CBD skeleton. Derivative 21f showed augmented antibacterial activity against MRSA with a minimum inhibitory concentration of 4 µM without cytotoxic effect in microglia BV2 cells. Further mechanistic studies suggested that 21f inhibited the formation of biofilms, induced excess reactive oxygen species, and reduced bacterial metabolism, which collectively led to the acceleration of bacterial death. Findings from this study expand the understanding of CBD derivatives as promising antibacterial agents, which provides useful information for the development of cannabinoid-based antibacterial agents.

Novel Sophoridine Derivatives as Potential Larvicidal Agents against Aedes albopictus: Synthesis, Biological Evaluation, Acetylcholinesterase Inhibition, and Morphological Study.

Two series of novel sophoridine derivatives were designed, synthesized, and evaluated for their anti-mosquito activity. SOP-2g, SOP-2q, and SOP-2r exhibited potential larvicidal activity against Aedes albopictus larva with LC50 values of 330.98, 430.53, and 411.09 ppm, respectively. Analysis of structure-activity relationships indicated that the oxime ester group was beneficial for improving the larvicidal biological activity, whereas the long-chain aliphatic group and fused-ring group were introduced. Furthermore, the larvicidal mechanism was also investigated based on the inhibition assay of acetylcholinesterase (AChE) and the morphological observation of dead larva treated with derivatives. Results indicated that the AChE inhibitory activity of the preferred three derivatives were 63.16%, 46.67%, and 35.11%, respectively, at 250 ppm concentration. Additionally, morphological evidence demonstrated that SOP-2q and SOP-2r induced changes in the larva's intestinal cavity, caudal gill, and tail, thereby displaying larvicidal action against Ae. albopictus together with AChE inhibition. Therefore, this study implied that sophoridine and its novel derivatives could be used to control the population of mosquito larva, which may also be effective alkaloids to reduce the mosquito population density.

Novel Matrine Derivatives as Potential Larvicidal Agents against Aedes albopictus: Synthesis, Biological Evaluation, and Mechanistic Analysis.

A large number of studies have shown that matrine (MA) possesses various pharmacological activities and is one of the few natural, plant-derived pesticides with the highest prospects for promotion and application. Fifty-eight MA derivatives were prepared, including 10 intermediates and 48 target compounds in 3 series, to develop novel mosquitocidal agents. Compounds 4b, 4e, 4f, 4m, 4n, 6e, 6k, 6m, and 6o showed good larvicidal activity against Aedes albopictus, which is both a highly aggressive mosquito and an important viral vector that can transmit a wide range of pathogens. Dipping methods and a bottle bioassay were used for insecticidal activity evaluation. The LC50 values of 4e, 4m, and 6m reached 147.65, 140.08, and 205.79 µg/mL, respectively, whereas the LC50 value of MA was 659.34 µg/mL. Structure-activity relationship analysis demonstrated that larvicidal activity could be improved by the unsaturated heterocyclic groups introduced into the carboxyl group after opening the D ring. The MA derivatives with oxidized N-1 lost their mosquitocidal activities, indicating that the bareness of N-1 is crucial to maintain their anti-mosquito activity. However, the activity was not greatly influenced by introducing a cyan group at C-6 or a benzene sulfonyl group at N-16. Additionally, compounds 4e and 4m exhibited good inhibitory activities against acetylcholinesterase with inhibitory rates of 59.12% and 54.30%, respectively, at a concentration of 250 µg/mL, whereas the inhibitory rate of MA was 9.88%. Therefore, the structural modification and mosquitocidal activity of MA and its derivatives obtained here pave the way for those seeking strong mosquitocidal agents of plant origin.

Synthesis and Biological Evaluation of Novel Fusidic Acid Derivatives as Two-in-One Agent with Potent Antibacterial and Anti-Inflammatory Activity.

Fusidic acid (FA), a narrow-spectrum antibiotics, is highly sensitive to various Gram-positive cocci associated with skin infections. It has outstanding antibacterial effects against certain Gram-positive bacteria whilst no cross-resistance with other antibiotics. Two series of FA derivatives were synthesized and their antibacterial activities were tested. A new aromatic side-chain analog, FA-15 exhibited good antibacterial activity with MIC values in the range of 0.781-1.563 µM against three strains of Staphylococcus spp. Furthermore, through the assessment by the kinetic assay, similar characteristics of bacteriostasis by FA and its aromatic derivatives were observed. In addition, anti-inflammatory activities of FA and its aromatic derivatives were evaluated by using a 12-O-tetradecanoylphorbol-13-acetate (TPA) induced mouse ear edema model. The results also indicated that FA and its aromatic derivatives effectively reduced TPA-induced ear edema in a dose-dependent manner. Following, multiform computerized simulation, including homology modeling, molecular docking, molecular dynamic simulation and QSAR was conducted to clarify the mechanism and regularity of activities. Overall, the present work gave vital clues about structural modifications and has profound significance in deeply scouting for bioactive potentials of FA and its derivatives.

Ligand and structure-based approaches for the exploration of structure-activity relationships of fusidic acid derivatives as antibacterial agents.

Introduction: Fusidic acid (FA) has been widely applied in the clinical prevention and treatment of bacterial infections. Nonetheless, its clinical application has been limited due to its narrow antimicrobial spectrum and some side effects. Purpose: Therefore, it is necessary to explore the structure-activity relationships of FA derivatives as antibacterial agents to develop novel ones possessing a broad antimicrobial spectrum. Methods and result: First, a pharmacophore model was established on the nineteen FA derivatives with remarkable antibacterial activities reported in previous studies. The common structural characteristics of the pharmacophore emerging from the FA derivatives were determined as those of six hydrophobic centers, two atom centers of the hydrogen bond acceptor, and a negative electron center around the C-21 field. Then, seven FA derivatives have been designed according to the reported structure-activity relationships and the pharmacophore characteristics. The designed FA derivatives were mapped on the pharmacophore model, and the Qfit values of all FA derivatives were over 50 and FA-8 possessed the highest value of 82.66. The molecular docking studies of the partial target compounds were conducted with the elongation factor G (EF-G) of S. aureus. Furthermore, the designed FA derivatives have been prepared and their antibacterial activities were evaluated by the inhibition zone test and the minimum inhibitory concentration (MIC) test. The derivative FA-7 with a chlorine group as the substituent group at C-25 of FA displayed the best antibacterial property with an MIC of 3.125 µM. Subsequently, 3D-QSAR was carried on all the derivatives by using the CoMSIA mode of SYBYL-X 2.0. Conclusion: Hence, a computer-aided drug design model was developed for FA, which can be further used to optimize FA derivatives as highly potent antibacterial agents.