Capsaicin combined with stem cells improved mitochondrial dysfunction in PIG3V cells, an immortalized human vitiligo melanocyte cell line, by inhibiting the HSP70/TLR4/mTOR/FAK signaling axis.

BACKGROUND: Vitiligo is a common autoimmune skin disease. Capsaicin has been found to exert a positive effect on vitiligo treatment, and mesenchymal stem cells (MSCs) are also confirmed to be an ideal cell type. This study aimed to explore the influence of capsaicin combined with stem cells on the treatment of vitiligo and to confirm the molecular mechanism of capsaicin combined with stem cells in treating vitiligo. METHODS AND RESULTS: PIG3V cell proliferation and apoptosis were detected using CCK-8 and TUNEL assays, MitoSOX Red fluorescence staining was used to measure the mitochondrial ROS level, and JC-1 staining was used to detect the mitochondrial membrane potential. The expression of related genes and proteins was detected using RT‒qPCR and Western blotting. Coimmunoprecipitation was used to analyze the protein interactions between HSP70 and TLR4 or between TLR4 and mTOR. The results showed higher expression of HSP70 in PIG3V cells than in PIG1 cells. The overexpression of HSP70 reduced the proliferation of PIG3V cells, promoted apoptosis, and aggravated mitochondrial dysfunction and autophagy abnormalities. The expression of HSP70 could be inhibited by capsaicin combined with MSCs, which increased the levels of Tyr, Tyrp1 and DCT, promoted the proliferation of PIG3V cells, inhibited apoptosis, activated autophagy, and improved mitochondrial dysfunction. In addition, capsaicin combined with MSCs regulated the expression of TLR4 through HSP70 and subsequently affected the mTOR/FAK signaling pathway CONCLUSIONS: Capsaicin combined with MSCs inhibits TLR4 through HSP70, and the mTOR/FAK signaling pathway is inhibited to alleviate mitochondrial dysfunction and autophagy abnormalities in PIG3V cells.

Combination of 308-nm excimer laser and piperine promotes melanocyte proliferation, migration, and melanin content production via the miR-328/SFRP1 axis.

OBJECTIVE: Both piperine and a 308-nm excimer laser have significant curative effects on vitiligo. This study mainly explored the molecular mechanism of a 308-nm excimer combined with piperine in regulating melanocyte proliferation. METHODS: Epidermal melanocytes were cultured in piperine solution, and the cells were irradiated by an XTRAC excimer laser treatment system at 308-nm output monochromatic light. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were for detecting the expression levels of genes or proteins. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and Transwell method was for assessing cell viability and migration capacity. The content of melanin was also detected. RESULTS: The combination of the 308-nm excimer laser and piperine enhanced the cell proliferation, migration, and melanin production of melanocytes and upregulated the level of miR-328, and restraint of miR-328 reversed the influence of the 308-nm excimer laser and piperine. Secreted frizzled-related protein 1 (SFRP1) is a direct target gene of miR-328, and miR-328 can inhibit the expression of SFRP1 and elevate the protein level of the Wnt/ß-catenin signaling pathway. CONCLUSION: The 308-nm excimer laser combined with piperine may be more efficient than piperine alone in the remedy of vitiligo, and the miR-328/SFRP1 and Wnt/ß-catenin pathways are participated in the proliferation, migration, and melanin synthesis of melanocytes.

A cross-trait study of lung cancer and its related respiratory diseases based on large-scale exome sequencing population.

Background: Genome-wide association studies (GWASs) explain the genetic susceptibility between diseases and common variants. Nevertheless, with the appearance of large-scale sequencing profiles, we could explore the rare coding variants in disease pathogenesis. Methods: We estimated the genetic correlation of nine respiratory diseases and lung cancer in the UK Biobank (UKB) by linkage disequilibrium score regression (LDSC). Then, we performed exome-wide association studies at single-variant level and gene-level for lung cancer and lung cancer-related respiratory diseases using the whole-exome sequencing (WES) data of 427,934 European participants. Cross-trait meta-analysis was conducted by association analysis based on subsets (ASSET) to identify the pleiotropic variants, while in-silico functional analysis was performed to explore their function. Causal mediation analysis was used to explore whether these pleiotropic variants lead to lung cancer is mediated by affecting the chronic respiratory diseases. Results: Five respiratory diseases [emphysema, pneumonia, asthma, chronic obstructive pulmonary disease (COPD), and fibrosis] were genetically correlated with lung cancer. We identified 102 significant independent variants at single-variant levels for lung cancer and five lung cancer-related diseases. 15:78590583:G>A (missense variant in CHRNA5) was shared in lung cancer, emphysema, and COPD. Meanwhile, 14 significant genes and 87 suggestive genes were identified in gene-based association tests, including HSD3B7 (lung cancer), SRSF2 (pneumonia), TNXB (asthma), TERT (fibrosis), MOSPD3 (emphysema). Based on the cross-trait meta-analysis, we detected 145 independent pleiotropic variants. We further identified abundant pathways with significant enrichment effects, demonstrating that these pleiotropic genes were functional. Meanwhile, the proportion of mediation effects of these variants ranged from 6 to 23 (emphysema: 23%; COPD: 20%; pneumonia: 20%; fibrosis: 7%; asthma: 6%) through these five respiratory diseases to the incidence of lung cancer. Conclusions: The identified shared genetic variants, genes, biological pathways, and potential intermediate causal pathways provide a basis for further exploration of the relationship between lung cancer and respiratory diseases.

Proteome-wide Mendelian randomization identifies causal plasma proteins in lung cancer.

Plasma proteins are promising biomarkers and potential drug targets in lung cancer. To evaluate the causal association between plasma proteins and lung cancer, we performed proteome-wide Mendelian randomization meta-analysis (PW-MR-meta) based on lung cancer genome-wide association studies (GWASs), protein quantitative trait loci (pQTLs) of 4,719 plasma proteins in deCODE and 4,775 in Fenland. Further, causal-protein risk score (CPRS) was developed based on causal proteins and validated in the UK Biobank. 270 plasma proteins were identified using PW-MR meta-analysis, including 39 robust causal proteins (both FDR-q < 0.05) and 78 moderate causal proteins (FDR-q < 0.05 in one and p < 0.05 in another). The CPRS had satisfactory performance in risk stratification for lung cancer (top 10% CPRS:Hazard ratio (HR) (95%CI):4.33(2.65-7.06)). The CPRS [AUC (95%CI): 65.93 (62.91-68.78)] outperformed the traditional polygenic risk score (PRS) [AUC (95%CI): 55.71(52.67-58.59)]. Our findings offer further insight into the genetic architecture of plasma proteins for lung cancer susceptibility.

Cascade Cyclization of 1,5-Diynols and (RO)2P(O)SH to Construct Benzo[b]fluorenyl S-Alkyl Phosphorothioates under Catalyst-Free Conditions.

An efficient and practical cascade cyclization of 1,5-diynols with (RO)2P(O)SH as the acid promoter and nucleophile under mild conditions was developed. A variety of highly substituted benzo[b]fluorenyl-containing S-alkyl phosphorothioates were successfully constructed in moderate to excellent yields. Furthermore, this protocol exhibited good functional group tolerance, a broad substrate scope, and potential practical applications, with water as the only byproduct. The reaction proceeded with allenyl thiophosphate as a key intermediate, followed by a Schmittel-type cyclization process to produce the target product.

Osimertinib induces paraptosis and TRIP13 confers resistance in glioblastoma cells.

The efficacy of osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor, has been evaluated in glioblastoma (GBM) through preclinical and clinical trials. However, the underlying mechanism of osimertinib-induced GBM cell death and the underlying resistance mechanism to osimertinib remains unclear. Here, we demonstrate that Osimertinib induces paraptosis in GBM cells, as evidenced by the formation of cytoplasmic vacuoles, accumulation of ubiquitinated proteins, and upregulation of endoplasmic reticulum (ER) stress markers like CHOP. Additionally, neither apoptosis nor autophagy was involved in the osimertinib-induced cell death. RNAseq analysis revealed ER stress was the most significantly downregulated pathway upon exposure to osimertinib. Consistently, pharmacologically targeting the PERK-eIF2α axis impaired osimertinib-induced paraptosis. Notably, we show that the expression of thyroid receptor-interacting protein 13 (TRIP13), an AAA+ATPase, alleviated osimertinib-triggered paraptosis, thus conferring resistance. Intriguingly, MK-2206, an AKT inhibitor, downregulated TRIP13 levels and synergized with Osimertinib to suppress TRIP13-induced high GBM cell growth in vitro and in vivo. Together, our findings reveal a novel mechanism of action associated with the anti-GBM effects of osimertinib involving ER stress-regulated paraptosis. Furthermore, we identify a TRIP13-driven resistance mechanism against Osimertinib in GBM and offer a combination strategy using MK-2206 to overcome such resistance.

A Large-Scale Exome-Wide Association Study Identifies Novel Germline Mutations in Lung Cancer.

Rationale: Genome-wide association studies have identified common variants of lung cancer. However, the contribution of rare exome-wide variants, especially protein-coding variants, to cancers remains largely unexplored. Objectives: To evaluate the role of human exomes in genetic predisposition to lung cancer. Methods: We performed exome-wide association studies to detect the association of exomes with lung cancer in 30,312 patients and 652,902 control subjects. A scalable and accurate implementation of a generalized mixed model was used to detect the association signals for loss-of-function, missense, and synonymous variants and gene-level sets. Furthermore, we performed association and Bayesian colocalization analyses to evaluate their relationships with intermediate exposures. Measurements and Main Results: We systematically analyzed 216,739 single-nucleotide variants in the human exome. The loss-of-function variants exhibited the most notable effects on lung cancer risk. We identified four novel variants, including two missense variants (rs202197044TET3 [Pmeta (P values of meta-analysis) = 3.60 × 10-8] and rs202187871POT1 [Pmeta = 2.21 × 10-8]) and two synonymous variants (rs7447927TMEM173 [Pmeta = 1.32 × 10-9] and rs140624366ATRN [Pmeta = 2.97 × 10-9]). rs202197044TET3 was significantly associated with emphysema (odds ratio, 3.55; Pfdr = 0.015), whereas rs7447927POT1 was strongly associated with telomere length (ß = 1.08; Pfdr (FDR corrected P value) = 3.76 × 10-53). Functional evidence of expression of quantitative trait loci, splicing quantitative trait loci, and isoform expression was found for the four novel genes. Gene-level association tests identified several novel genes, including POT1 (protection of telomeres 1), RTEL1, BSG, and ZNF232. Conclusions: Our findings provide insights into the genetic architecture of human exomes and their role in lung cancer predisposition.

Exploring boron applications in modern agriculture: Antifungal activities and mechanisms of phenylboronic acid derivatives.

BACKGROUND: The unreasonable use of chemical fungicides causes common adverse consequences that not only affect the environment, but also cause resistance and resurgence problems of plant pathogens, which are extremely harmful to human health, the economy, and the environment. Based on the rich biological activities of boron-based compounds, 82 phenylboronic acid derivatives were selected and their antifungal activities against six agricultural plant pathogens were determined. Combined with transcriptomics tools, the mechanism of action of compound A49 (2-chloro-5-trifluoromethoxybenzeneboronic acid) against Botrytis cinerea Pers (B. cinerea) was studied. RESULTS: The EC50 values of compounds A24, A25, A30, A31, A36, A41, A49 and B23 against all six fungi were under 10 µg/mL. Compound A49 displayed significant activity against B. cinerea (EC50 = 0.39 µg/mL), which was better than that of commercial fungicide boscalid (EC50 = 0.55 µg/mL). A49 not only inhibited the germination of B. cinerea spores, but also caused abnormal cell morphology, loss of cell membrane integrity, enhanced cell membrane permeability, and accumulation of intracellular reactive oxygen species. Further findings showed that A49 reduced cellular antioxidant activity, and peroxidase and catalase activities. Transcriptomic results indicated that A49 could degrade intracellular redox processes and alter the metabolism of some amino acids. Meanwhile, A49 showed obvious activity in vivo and low cytotoxicity to mammal cells. CONCLUSION: The boron-containing small molecule compounds had high efficiency and broad-spectrum antifungal activities against six plant pathogens, and are expected to be candidate compounds for a new class of antifungal drugs. © 2023 Society of Chemical Industry.

Direct Synthesis of Benzo[b]fluorenyl Thiophosphates via Tandem Cyclization of Diynols with (RO)2P(O)SH.

A general and metal-free protocol for the construction of benzo[b]fluorenyl thiophosphates was developed through the cascade cyclization of easily prepared diynols and (RO)2P(O)SH, with water as the only byproduct. The novel transformation involved the allenyl thiophosphate as the key intermediate, followed by Schmittel-type cyclization to achieve the desired products. Notably, (RO)2P(O)SH acted not only as a nucleophile but also as an acid-promoter to initiate the reaction.

SUFU suppresses ferroptosis sensitivity in breast cancer cells via Hippo/YAP pathway.

Ferroptosis is a new kind of regulated cell death that is characterized by highly iron-dependent lipid peroxidation. Cancer cells differ in their sensitivity to ferroptosis. Here we showed that the Suppressor of fused homolog (SUFU), a critical component in Hedgehog signaling, regulates ferroptosis sensitivity of breast cancer cells. Ectopic SUFU expression suppressed, whereas depletion of SUFU enhanced the sensitivity of breast cancer cells to RSL3-triggered ferroptosis through deregulation of ACSL4. Moreover, SUFU depletion promoted the activation of Yes-associated protein (YAP), thereby increasing the expression of ACSL4. Mechanistically, SUFU is associated with LATS1. Deletion of a region comprising residues 174-385 in SUFU disrupted SUFU binding to LATS1, thus abrogating SUFU-mediated downregulation of the YAP-ACSL4 axis and sensitivity to ferroptosis. Noteworthy, we showed that vincristine downregulated SUFU, thus increasing breast cancer cell sensitivity to RSL3 in vitro and in vivo. Together, our findings uncover SUFU as a novel regulator in ferroptosis sensitivity.

Dahuang Zhechong pills inhibit liver cancer growth in a mouse model by reversing Treg/Th1 balance.

The infiltration of immune cells into the hepatocellular carcinoma microenvironment is the main reason why hepatocellular carcinoma patients are prone to carcinoma recurrence and the disease are incurable. Notably, the infiltration of Treg cells is the main trigger. Dahuang Zhechong pill (DHZCP) is a traditional Chinese herbal compound successful in the treatment of hepatitis and hepatocellular carcinoma. DHZCP can heal and nourish while slowing the onset of the disease, thereby strengthening the body's immune function. It can localize tumors and ultimately achieve the goal of eliminating tumors. In this study, an orthotopic liver cancer model of mice was used to explore the mechanism of DHZCP enhancing anti-tumor immunity, which showed more Th1 cells in the peripheral blood and spleen after DHZCP treatment, while more IFN-γ was secreted to activate CD8+ T cells and Treg cell production was inhibited, thereby suppressing the growth of HCC. Finally, we also analyzed the potential components of DHZCP from the perspective of modern targets using network pharmacology methods and experimental results.

Design, Synthesis, and Antimicrobial Activity of Quindoline Derivatives Inspired by the Cryptolepine Alkaloid.

Based on the structural characteristics of the cryptolepine alkaloid, a series of new quindoline derivatives bearing various substituents were prepared and evaluated for their fungicidal and antibacterial activities. Bioassay results showed that compound D7 displayed superior in vitro fungicidal activities against Sclerotinia sclerotiorum, Botrytis cinerea, Fusarium graminearum, and Rhizoctonia solani with EC50 values of 0.780, 3.62, 1.59, and 2.85 µg/mL, respectively. Compound A7 showed apparent antibacterial activities toward Xanthomonas oryzae pv. oryzae with a minimum inhibitory concentration (MIC) value of 3.12 µg/mL. Significantly, in vivo antifungal activity suggested that the curative effect (98.3%) of compound D7 was comparable to that of the positive control azoxystrobin (96.7%) at 100 µg/mL. Preliminary mechanistic studies showed that compound D7 might cause mycelial abnormality of S. sclerotiorum, cell membrane breakage, accumulation of reactive oxygen species (ROS), and inhibition of sclerotia formation. Therefore, compound D7 could be a novel broad-spectrum fungicidal candidate against plant fungal diseases.

Epidemiological Characteristics of COVID-19 under Government-Mandated Control Measures during January-February 2020 in Inner Mongolia, China.

The coronavirus disease 2019 (COVID-19) pandemic has had severe health impacts worldwide. We aim to provide suggestions to the government for managing serious infectious disease outbreaks in remote regions having relatively poor medical resources. Basic reproduction number (R0), incubation period, time from symptom onset to confirmation, and duration of hospitalization were analyzed. We compared the compositions of imported and local secondary cases and cases with mild/common and severe/critical illnesses according to age, sex, and clinical symptoms. From January 23 to February 19, 2020 (less than one month), 75 local COVID-19 cases were confirmed in Inner Mongolia. Among these, the median age was 45.0 years, and 33 (44.0%) were imported cases. More than 80.0% cases had mild/common illness. The case fatality rate was 1.3%, and R0 was estimated to be 2.3. The median incubation period was 8.5 days. There was a significant difference in the incubation period between imported and local secondary cases (P < 0.001). Early and mandatory control strategies implemented by the government were associated with a rapid reduction in COVID-19 incidence in Inner Mongolia.

Joint effects of self-reported sleep and modifiable physical activity on risk of dyslipidaemia in women aged 45-55 years: a cross-sectional study.

OBJECTIVES: Modifiable physical activity (PA) plays an important role in dyslipidaemia risk in middle-aged women with sleep problems, especially perimenopausal women. We aimed to explore the joint effects of sleep and PA on the risk of dyslipidaemia in women aged 45-55 years, and the extent to which PA moderated the effect of sleep on the risk of dyslipidaemia. DESIGN: A cross-sectional study. SETTING: This study was based on the survey of Chronic Disease and Nutrition Monitoring in Adults in Inner Mongolia in 2015. PARTICIPANTS: 721 women aged 45-55 years were included. OUTCOME MEASUREMENT: PA was measured by the Global Physical Activity Questionnaire. Sleep was measured by questionnaire formulated by the Chinese Center for Disease Control and Prevention. Multivariate logistic regression analyses were performed to determine the joint effects of sleep and PA on dyslipidaemia risk. OR and 95% CI were reported. RESULTS: Among all participants, 60.6% had sleep problems, 29.0% had low PA and 41.1% had dyslipidaemia. Women with sleep problems had higher dyslipidaemia risk than women without sleep problems, irrespective of low, moderate or high PA, with OR (95% CI) of 4.24 (2.40 to 7.49), 3.14 (1.80 to 5.49) and 2.04 (1.20 to 3.48), respectively. PA could not completely attenuate the negative association between sleep and dyslipidaemia risk. With PA increased from low to high, the OR of dyslipidaemia decreased by 2.20. Women with sleep problems and low PA had higher risks of high total cholesterol, high triglyceride, low high-density lipoprotein cholesterol and high low-density lipoprotein cholesterol than women without sleep problems and high PA, with OR (95% CI) of 2.51 (1.18 to 5.35), 2.42 (1.23 to 4.74), 2.88 (1.44 to 5.74) and 2.52 (1.12 to 5.70), respectively. CONCLUSIONS: Among women aged 45-55 years, the joint effects of self-reported sleep and PA on dyslipidaemia risk were more marked for sleep than for PA. Modifiable PA is a widely accessible and effective intervention to reduce the dyslipidaemia risk in women with sleep problems, particularly among perimenopausal women.

Design, synthesis and biological evaluation of novel evodiamine and rutaecarpine derivatives against phytopathogenic fungi.

Evodiamine and rutaecarpine are two alkaloids isolated from traditional Chinese herbal medicine Evodia rutaecarpa, which have been reported to have various biological activities in past decades. To explore the potential applications for evodiamine and rutaecarpine alkaloids and their derivatives, various kinds of evodiamine and rutaecarpine derivatives were designed and synthesized. Their antifungal profile against six phytopathogenic fungi Rhizoctonia solani, Botrytis cinerea, Fusarium graminearum, Fusarium oxysporum, Sclerotinia sclerotiorum, and Magnaporthe oryzae were evaluated for the first time. Furthermore, a series of modified imidazole derivatives of rutaecarpine were synthesized to investigate the structure-activity relationship. The results of antifungal activities in vitro showed that imidazole derivative of rutaecarpine A1 exhibited broad-spectrum inhibitory activities against R. solani, B. cinerea, F. oxysporum, S. sclerotiorum, M. oryzae and F. graminearum with EC50 values of 1.97, 5.97, 12.72, 2.87 and 16.58 µg/mL, respectively. Preliminary mechanistic studies showed that compound A1 might cause mycelial abnormalities of S. sclerotiorum, mitochondrial distortion and swelling, and inhibition of sclerotia formation and germination. Moreover, the curative effects of compound A1 were 94.7%, 81.5%, 80.8%, 65.0% at 400, 200, 100, 50 µg/mL in vivo experiments, which was far more effective than the positive control azoxystrobin. Significantly, no phytotoxicity of compound A1 on oilseed rape leaves was observed obviously even at a high concentration of 400 µg/mL. Therefore, compound A1 is expected to be a novel leading structure for the development of new antifungal agents.

Socioeconomic Determinants of Diet Quality on Overweight and Obesity in Adults Aged 40-59 Years in Inner Mongolia: A Cross-Sectional Study.

Objectives: This study investigated the relationship of socioeconomic status (SES), diet quality and overweight and obesity in adults aged 40-59 years in Inner Mongolia. Methods: This cross-sectional study was based on the survey of Chronic Disease and Nutrition Monitoring in Adults in Inner Mongolia in 2015. Diet quality was evaluated by the Alternate Mediterranean Diet score (aMeds). SES was measured by household annual income. Generalized estimating equations and path analysis were performed to determine the association of SES, diet quality and overweight and obesity. Results: Among participants, 63.0% had overweight and obesity. In high SES group, 66.4% had overweight and obesity. Higher SES was associated with a higher risk of overweight and obesity (OR = 1.352, 95%CI: 1.020-1.793). And higher aMeds was associated with a lower risk of overweight and obesity (OR = 0.597, 95%CI: 0.419-0.851). There was a positive correlation between SES and the intake of red and processed meat (r = 0.132, p < 0.05). Higher intake of red and processed meat was associated with lower diet quality (ß = -0.34). And lower diet quality was associated with a higher risk of overweight and obesity (ß = -0.10). Conclusion: In Inner Mongolia, during the period of economic transition, people aged 40-59 years in high SES had poor diet quality, which was related to a higher risk of overweight and obesity.

Design, Synthesis, and Antifungal Evaluation of Luotonin A Derivatives against Phytopathogenic Fungi.

Crop diseases caused by fungi threaten food security and exacerbate the food crisis. Inspired by the application of fungicide candidates from natural products in agrochemical discovery, a series of luotonin A derivatives were designed, synthesized, and evaluated for their antifungal activities against five plant fungi. Most of these compounds exhibited significant fungicidal activity against Botrytis cinerea in vitro with EC50 values less than 1 µg/mL. Among them, compounds w7, w8, w12, and w15 showed superior antifungal activity against B. cinerea with EC50 values of 0.036, 0.050, 0.042, and 0.048 µg/mL, respectively, which were more potent than boscalid (EC50 = 1.790 µg/mL). Preliminary mechanism studies revealed that compound w7 might pursue its antifungal activity by disrupting the fungal cell membrane and cell wall. Moreover, in vivo bioassay also indicated that compound w7 could be effective for the control of B. cinerea. The above results evidenced the potential of luotonin A derivatives as novel and promising candidate fungicides.

Antifungal Activity and Action Mechanism Study of Coumarins from Cnidium monnieri Fruit and Structurally Related Compounds.

The increasing resistance of plant diseases caused by phytopathogenic fungi highlights the need for highly effective and environmentally benign agents. The antifungal activities of Cnidium monnieri fruit extracts and five isolated compounds as well as structurally related coumarins against five plant pathogenic fungi were evaluated. The acetone extract, which contained the highest amount of five coumarins, showed strongest antifungal activity. Among the coumarin compounds, we found that 4-methoxycoumarin exhibited stronger and broader antifungal activity against five phytopathogenic fungi, and was more potent than osthol. Especially, it could significantly inhibit the growth of Rhizoctonia solani mycelium with an EC50 value of 21 µg mL-1 . Further studies showed that 4-methoxycoumarin affected the structure and function of peroxisomes, inhibited the ß-oxidation of fatty acids, decreased the production of ATP and acetyl coenzyme A, and then accumulated ROS by damaging MMP and the mitochondrial function to cause the cell death of R. solani mycelia. 4-Methoxycoumarin presented antifungal efficacy in a concentration- dependent manner in vivo and could be used to prevent the potato black scurf. This study laid the foundation for the future development of 4-methoxycournamin as an alternative and friendly biofungicide.

Antifungal Exploration of Quinoline Derivatives against Phytopathogenic Fungi Inspired by Quinine Alkaloids.

Enlightened from our previous work of structural simplification of quinine and innovative application of natural products against phytopathogenic fungi, lead structure 2,8-bis(trifluoromethyl)-4-quinolinol (3) was selected to be a candidate and its diversified design, synthesis, and antifungal evaluation were carried out. All of the synthesized compounds Aa1-Db1 were evaluated for their antifungal activity against four agriculturally important fungi, Botrytis cinerea, Fusarium graminearum, Rhizoctonia solani, and Sclerotinia sclerotiorum. Results showed that compounds Ac3, Ac4, Ac7, Ac9, Ac12, Bb1, Bb10, Bb11, Bb13, Cb1. and Cb3 exhibited a good antifungal effect, especially Ac12 had the most potent activity with EC50 values of 0.52 and 0.50 µg/mL against S. sclerotiorum and B. cinerea, respectively, which were more potent than those of the lead compound 3 (1.72 and 1.89 µg/mL) and commercial fungicides azoxystrobin (both >30 µg/mL) and 8-hydroxyquinoline (2.12 and 5.28 µg/mL). Moreover, compound Ac12 displayed excellent in vivo antifungal activity, which was comparable in activity to the commercial fungicide boscalid. The preliminary mechanism revealed that compound Ac12 might cause an abnormal morphology of cell membranes, an increase in membrane permeability, and release of cellular contents. These results indicated that compound Ac12 displayed superior in vitro and in vivo fungicidal activities and could be a potential fungicidal candidate against plant fungal diseases.

The Antifungal Mechanism of Isoxanthohumol from Humulus lupulus Linn.

Humulus lupulus Linn. is a traditional medicinal and edible plant with several biological properties. The aims of this work were: (1) to evaluate the in vitro antifungal activity of H. lupulus ethanolic extract; (2) to study the in vitro and in vivo antifungal activity of isoxanthohumol, an isoprene flavonoid from H. lupulus, against Botrytis cinerea; and (3) to explore the antifungal mechanism of isoxanthohumol on B. cinerea. The present data revealed that the ethanolic extract of H. lupulus exhibited moderate antifungal activity against the five tested phytopathogenic fungi in vitro, and isoxanthohumol showed highly significant antifungal activity against B. cinerea, with an EC50 value of 4.32 µg/mL. Meanwhile, it exhibited moderate to excellent protective and curative efficacies in vivo. The results of morphologic observation, RNA-seq, and physiological indicators revealed that the antifungal mechanism of isoxanthohumol is mainly related to metabolism; it affected the carbohydrate metabolic process, destroyed the tricarboxylic acid (TCA) cycle, and hindered the generation of ATP by inhibiting respiration. Further studies indicated that isoxanthohumol caused membrane lipid peroxidation, thus accelerating the death of B. cinerea. This study demonstrates that isoxanthohumol can be used as a potential botanical fungicide for the management of phytopathogenic fungi.