Metabolic Resistance Research Articles

Long-term impact of exposure to Royal Guard, a pyriproxyfen-based bed net, on pyrethroid-resistant malaria vectors from Cameroon using DNA-based metabolic resistance markers.

Escalating pyrethroid resistance in malaria vectors highlights the urgency of implementing new control tools incorporating non-pyrethroid molecules. Here, using DNA-based metabolic resistance markers, we assessed the efficacy of the dual active ingredients net Royal Guard against pyrethroids-resistant malaria vectors in Cameroon, establishing its long-term impact on mosquitoes' life traits after exposure. Cone assays revealed low efficacy of Royal Guard against field Anopheles populations. However, analysis of the survival curves revealed that unexposed mosquitoes lived longer (11.4 ± 0.4 days) than those exposed to Royal Guard (7.9 ± 0.2 days) (χ2 = 6; P = 0.05), indicating that despite the lower immediate mortality observed against resistant mosquitoes, there is a long-term effect on Anopheles funestus longevity. High blood-feeding inhibition rate was observed (44-80% versus 11-41%), indicating that this net has a negative impact on blood meal intake. Additionally, female mosquitoes exposed to this net exhibited a 25% reduction in oviposition, 18.30% reduction in fecundity, 8.10% reduction in offspring, and a 74.74% infertility rate compared to the control. Genotyping of key resistance markers revealed that, metabolic markers and L1014F-Kdrw are associated with the reduced efficacy observed, with homozygote-resistant mosquitoes significantly more able to survive and live longer after exposure than homozygote-susceptible mosquitoes (odds ratio = 15.79; confidence interval = 5.35-43.27; P < 0.0001). This study revealed that although pyrethroid-resistant mosquitoes have higher ability to survive and live longer after exposure to Royal Guard, this net significantly affects their lifespan, blood-feeding ability and interestingly reduces their fecundity/fertility. © 2025 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Evaluating the potential of Kalanchoe pinnata, Piper amalago amalago, and other botanicals as economical insecticidal synergists against Anopheles gambiae

BackgroundSynergists reduce insecticide metabolism in mosquitoes by competing with insecticides for the active sites of metabolic enzymes, such as cytochrome P450s (CYPs). This increases the availability of the insecticide at its specific target site. The combination of both insecticides and synergists increases the toxicity of the mixture. Given the demonstrated resistance to the classical insecticides in numerous Anopheles spp., the use of synergists is becoming increasingly pertinent. Tropical plants synthesize diverse phytochemicals, presenting a repository of potential synergists.MethodsExtracts prepared from medicinal plants found in Jamaica were screened against recombinant Anopheles gambiae CYP6M2 and CYP6P3, and Anopheles funestus CYP6P9a, CYPs associated with anopheline resistance to pyrethroids and several other insecticide classes. The toxicity of these extracts alone or as synergists, was evaluated using bottle bioassays with the insecticide permethrin. RNA sequencing and in silico modelling were used to determine the mode of action of the extracts.ResultsAqueous extracts of Piper amalago var. amalago inhibited CYP6P9a, CYP6M2, and CYP6P3 with IC50s of 2.61 ± 0.17, 4.3 ± 0.42, and 5.84 ± 0.42 μg/ml, respectively, while extracts of Kalanchoe pinnata, inhibited CYP6M2 with an IC50 of 3.52 ± 0.68 μg/ml. Ethanol extracts of P. amalago var. amalago and K. pinnata displayed dose-dependent insecticidal activity against An. gambiae, with LD50s of 368.42 and 282.37 ng/mosquito, respectively. Additionally, An. gambiae pretreated with K. pinnata (dose: 1.43 μg/mosquito) demonstrated increased susceptibility (83.19 ± 6.14%) to permethrin in a bottle bioassay at 30 min compared to the permethrin only treatment (0% mortality). RNA sequencing demonstrated gene modulation for CYP genes in anopheline mosquitoes exposed to 715 ng of ethanolic plant extract at 24 h. In silico modelling showed good binding affinity between CYPs and the plants’ secondary metabolites.ConclusionThis study demonstrates that extracts from P. amalago var. amalago and K. pinnata, with inhibitory properties, IC50 < 6.95 μg/ml, against recombinant anopheline CYPs may be developed as natural synergists against anopheline mosquitoes. Novel synergists can help to overcome metabolic resistance to insecticides, which is increasingly reported in malaria vectors.Graphical

Relation of Insulin Resistance to Brain Glucose Metabolism in Fasting and Hyperinsulinemic States: A Systematic Review and Meta-analysis.

Abnormal brain glucose metabolism may cause cognitive disease in type 2 diabetes, yet the relation between insulin resistance and brain glucose metabolism has not been systematically described. We evaluated the impact of metabolic condition (fasting vs insulin stimulation, eg, from hyperinsulinemic clamp) on the association between insulin resistance of different etiologies and brain glucose metabolism. PubMed, Embase, Cochrane Library, and Web of Science were systematically searched from inception until February 2022. Of 656 unique records, we deemed 31 eligible. Criteria were studies assessing brain glucose metabolism (uptake or metabolic rate) by 18F-2-fluoro-2-deoxy-D-glucose-positron emission tomography in individuals characterized by measures of or clinical proxies for insulin resistance (eg, type 2 diabetes and obesity). Two independent investigators extracted data and assessed study quality. We applied random-effects models to pool Hedge's g standardized mean differences. Insulin resistance was associated with decreased brain glucose metabolism during fasting [-0.47 SD, 95% confidence interval (CI): -0.73 to -0.22, P < .001, I2 = 71%] and increased metabolism during insulin stimulation (1.44 SD, 95% CI 0.79 to 2.09, P = .002, I2 = 43%). Contrary to type 2 diabetes and other insulin resistance-related conditions, obesity was not associated with brain hypometabolism in fasting states (0.29 SD, 95% CI -.81 to 1.39). Metabolic conditions modify associations between insulin resistance and brain glucose metabolism; ie, most individuals with insulin resistance display hypometabolism during fasting and hypermetabolism during insulin stimulation.

Differentially spliced mitochondrial CYP419A1 contributes to ethiprole resistance in Nilaparvata lugens.

The brown planthopper Nilaparvata lugens is one of the most economically important pests of cultivated rice in Southeast Asia. Extensive use of insecticide treatments, such as imidacloprid, fipronil and ethiprole, has resulted in the emergence of multiple resistant strains of N. lugens. Previous investigation of the mechanisms of resistance to imidacloprid and ethiprole demonstrated that overexpression and qualitative changes in the cytochrome P450 gene CYP6ER1 lead to enhanced metabolic detoxification of these compounds. Here, we present the identification of a secondary mechanism enhancing ethiprole resistance mediated by differential splicing and overexpression of CYP419A1, a planthopper-specific, mitochondrial P450 gene. Although metabolic resistance to insecticides is usually mediated by overexpression of P450 genes belonging to either CYP 3 or 4 clades, we validate the protective effect of over-expression of CYP419A1, in vivo, using transgenic Drosophila melanogaster. Additionally, we report some unusual features of both the CYP419A1 gene locus and protein, which include, altered splicing associated with resistance, a non-canonical heme-binding motif and an extreme 5' end extension of the open reading frame. These results provide insight into the molecular mechanisms underpinning resistance to insecticides and have applied implications for the control of a highly damaging crop pest.

Fungi on the cuticle surface increase the resistance of Aedes albopictus to deltamethrin.

Aedes albopictus (Ae. albopictus) is widely distributed and can transmit many infectious diseases, and insecticide-based interventions play an important role in vector control. However, increased insecticide resistance has become a severe public health problem, and the clarification of its detailed mechanism is a matter of urgence. This study found that target-site resistance and metabolic resistance could not fully explain insecticide resistance in field Ae. albopictus, and there were likely other resistance mechanisms involved. The 16S and internal transcribed spacer sequencing revealed significant differences in the species compositions of the cuticle surface symbiotic bacteria and fungi between deltamethrin (DM)-resistant (DR) and DM-susceptible (DS) Ae. albopictus. Additionally, the abundances of Serratia spp. and Candida spp. significantly increased after DM treatment. Furthermore, 2 fungi (Rhodotorula mucilaginosa and Candida melibiosica) and 3 bacteria (Serratia marcescens, Klebsiella aerogenes, and Serratia sp.) isolated from DR Ae. albopictus can use DM as their sole carbon source. After reinoculation onto the cuticle surface of DS Ae. albopictus, R. mucilaginosa and C. melibiosica significantly enhanced the DM resistance of Ae. albopictus. Moreover, transcriptome sequencing of the surviving Ae. albopictus after DM exposure revealed that the gene expression of cytochrome P450 enzymes and glutathione-S-transferases increased, suggesting that besides the direct degradation, the candidate degrading microbes could also cause insecticide resistance via indirect enhancement of mosquito gene expression. In conclusion, we demonstrated that the cuticle surface symbiotic microbes were involved in the development of insecticide resistance in Ae. albopictus, providing novel and supplementary insights into insecticide resistance mechanisms.

Construction of cuproptosis-related genes risk model predicts the prognosis of Uterine Corpus Endometrial Carcinoma

Cuproptosis, a recently discovered form of cell death, has emerged as a crucial player in tumor development, although its role in uterine corpus endometrial carcinoma (UCEC) remains inadequately explored. This study aims to identify prognostically relevant cuproptosis-related genes in endometrial cancer. Cuproptosis-related genes were sourced from previously published studies and the FerrDb database. UCEC gene expression profiles and clinical data were obtained from the TCGA database. Differential gene expression was determined using LIMMA analysis, and functional enrichment analysis was conducted on identified cuproptosis-related genes. A prognostic model for UCEC was developed using LASSO Cox regression analysis and a Nomogram, integrating survival data, status, and gene signatures. TIMER analysis assessed the impact of crucial cuproptosis-related genes on immune cell infiltration in UCEC. Validation of the selected genes, CDKN2A, GLS, and PPAT, was performed at both mRNA and protein levels. A total of 27 cuproptosis-related genes were identified, with 19 upregulated and 6 downregulated in UCEC. These genes were associated with key signaling pathways, including the TCA cycle, Pyruvate metabolism, Glycolysis/Gluconeogenesis, and Platinum drug resistance. The LASSO regression and Nomogram models demonstrated robust predictive performance for UCEC prognosis, identifying CDKN2A, GLS, and PPAT as critical prognostic genes. Furthermore, these genes played essential roles in immune cell infiltration in UCEC, confirming their significance. Validation at both mRNA and protein levels solidified the role of CDKN2A, GLS, and PPAT. The identified signature of CDKN2A, GLS, and PPAT demonstrates significant predictive value for UCEC prognosis, suggesting their potential as therapeutic targets, including their application in immunotherapy strategies.

MTHFD2 Enhances cMYC O-GlcNAcylation to Promote Sunitinib Resistance in Renal Cell Carcinoma.

Sunitinib is a first-line targeted therapy for patients with renal cell carcinoma (RCC), but resistance represents a significant obstacle to the treatment of advanced and metastatic RCC. Metabolic reprogramming is a characteristic of RCC, and changes in metabolic processes might contribute to resistance to sunitinib. Here, we identified MTHFD2, a mitochondrial enzyme involved in one-carbon metabolism, as a critical mediator of sunitinib resistance in RCC. MTHFD2 was elevated in sunitinib resistant RCC cells, and loss of MTHDF2 conferred sensitivity to sunitinib. In patients, MTHFD2 was highly expressed in RCC and was associated with poor outcomes. Mechanistically, MTHFD2 stimulated UDP-GlcNAc biosynthesis and promoted cMYC O-GlcNAcylation by driving the folate cycle. O-GlcNAcylation enhanced cMYC stability and promoted MTHFD2 and CCND1 transcription. Targeting MTHFD2 or cyclin D1 sensitized tumor cells to sunitinib in vitro and in vivo. Consistently, development of a peptide drug capable of efficiently degrading MTHFD2 enabled reversal of sunitinib resistance in RCC. These findings identify a noncanonical metabolic function of MTHFD2 in cell signaling and response to therapy and reveal the interplay between one-carbon metabolism and sunitinib resistance in RCC. Targeting MTHFD2 could be an effective approach to overcome sunitinib resistance.

Overexpression of multiple cytochrome P450 genes with and without knockdown resistance mutations confers high resistance to deltamethrin in Culex quinquefasciatus

BackgroundThe cytochrome P450s-mediated metabolic resistance and the target site insensitivity caused by the knockdown resistance (kdr) mutation in the voltage-gated sodium channel (vgsc) gene were the main mechanisms conferring resistance to deltamethrin in Culex quinquefasciatus from Thailand. This study aimed to investigate the expression levels of cytochrome P450 genes and detect mutations of the vgsc gene in deltamethrin-resistant Cx. quinquefasciatus populations in Thailand.MethodsTwo field-collected strains of Cx. quinquefasciatus, Cq_SP and Cq_NiH, were selected with deltamethrin to generate the resistant strains Cq_SP-R and Cq_NiH-R, respectively. Bioassays were tested on larvae and adults of each strain according to WHO methods. Eight cytochrome P450 genes were analyzed for the expression level using quantitative real time-PCR. The cDNA of mosquitoes was amplified and sequenced for four fragments of vgsc gene. The kdr L1014F mutation and the haplotype of the CYP9M10 gene were detected in survivor and dead mosquitoes after exposure to the deltamethrin WHO test paper. Statistical analyses were performed using Fisher’s exaction test.ResultsBioassay tests revealed a significantly higher resistance level in Cq_SP-R than in Cq_NiH-R strains in both larvae and adults. All eight cytochrome P450 genes were significantly overexpressed in larvae of Cq_NiH-R strain compared to the parent and susceptible Cq_Sus strains. The CYP6AA7 and CYP9J34 genes had the highest expression ratios, exceeding 24-fold in Cq_NiH-R larvae. In Cq_SP-R strain, the CYP4H34 and CYP9J34 genes were overexpressed in both stages. The kdr L1014F mutation was found in Cq_SP-R and its parent Cq_SP strains with a significantly higher mutant allele frequency in the survivor mosquitoes than in dead mosquitoes (P < 0.0001). The V240M and novel L925F mutations were found only in Cq_SP-R strain. Heterozygous genotype for the D-Cu( +)/Cu(–) of CYP9M10 gene was detected in Cq_NiH and Cq_NiH-R strains but other strains were mostly homozygous for the Cu(–)/Cu(–).ConclusionsOverexpression of multiple cytochrome P450 genes alone has a relatively minor impact on resistance. The combined mechanisms of cytochrome P450- and kdr-mediated resistance result in significantly higher resistance to deltamethrin in Cx. quinquefasciatus. This study supports sustainable public health initiatives in Thailand to address the evolving challenges of insecticide resistance.

The Interactive Effects of Fruit Intake Frequency and Serum miR-484 Levels as Biomarkers for Incident Type 2 Diabetes in a Prospective Cohort of the Spanish Adult Population: The Di@bet.es Study.

Background/Objectives: Although evidence suggests that miR-484 and several fruit components are involved in glucose metabolism and insulin resistance metabolic pathways, the relationship between serum miR-484 levels and fruit consumption in relation to the risk of Type 2 diabetes (T2DM) remains elusive. The aim of this study was to evaluate the possible association between serum miR-484 levels and fruit intake frequency with the risk of T2DM in the Spanish adult population. Methods: 2234 subjects from the Di@bet.es cohort study without T2DM at baseline were studied. Socio-demographic, anthropometric and clinical data were recorded, as well as responses to a questionnaire on habits, including frequency of fruit consumption (daily vs. occasional). T2DM was diagnosed at baseline and after 7.5 years of follow-up. Baseline serum miR-484 levels were measured using real-time qPCR and categorized based on the 25th percentile. Association analyses were performed using logistic regression models adjusted for potential confounders. Interaction effects were evaluated on the multiplicative and additive scales. Results: There was no association between miR-484 levels and fruit intake frequency. Categorized miR-484 levels and fruit consumption were inversely and independently associated with the likelihood of incident T2DM. Analysis of the interaction effect suggests the presence of both positive multiplicative and additive interactions between miR-484 categories and fruit consumption frequency. Conclusions: Our study demonstrates a protective effect of daily fruit intake and high miR-484 levels regarding the risk of T2DM and supports the nutritional recommendations advocating daily fruit consumption. This study also suggests that the combined effect of low miR-484 levels and occasional fruit intake may increase the risk of T2DM beyond their independent effects.

Application of a dynamic colonic gastrointestinal digestion model to red wines: a study of flavanol metabolism by the gut microbiota and the cardioprotective activity of microbial metabolites.

Over the last decade, research has emphasized the role of the microbiome in regulating cardiovascular physiology and disease progression. Understanding the interplay between wine polyphenols, the gut microbiota, and cardiovascular health could provide valuable insights for uncovering novel therapeutic strategies aimed at preventing and managing cardiovascular disease. In this study, two commercial red wines were subjected to in vitro dynamic gastrointestinal digestion (GIS) to monitor the flavanol-microbiota interaction by evaluating the resulting microbial metabolites. Furthermore, the cardiovascular protective activity of wine flavanol microbial metabolites was investigated, integrating their effects on antihypertensive activity, cholesterol metabolism and insulin resistance into human endothelial (EA.hy926) and hepatic (HepG2) cell lines. A significant production of microbial flavanol metabolites, with a prevalence of phenylpropionic and phenylacetic acids, valerolactones and short chain fatty acids such as butyric acid, was observed, particularly in the transverse and descending colon sections. Incubating HAECs and HepG2 cells with the colon improved cardioprotective parameters. Specifically, an increase in the vasodilator NO, an improvement in the LDL receptors and the HMGCoA enzyme, with positive effects on cholesterol metabolism, and the reduction of glycogen levels improving insulin resistance were observed.

Comparative efficacy of Vector Guard® to Olyset® Plus insecticide-treated nets against strongly pyrethroid-resistant Anopheles arabiensis in experimental huts in Tanzania

IntroductionThe resistance of malaria vectors to pyrethroids has compromised the efficacy of pyrethroid insecticide-treated nets (ITNs). In response, ITNs with pyrethroids and piperonyl butoxide (PBO) synergists were developed to overcome metabolic pyrethroid resistance mechanisms. One such net is Vector Guard®. To demonstrate its potential efficacy for public health use, a comparative efficacy study was conducted to evaluate Vector Guard® relative to Olyset® Plus (a pyrethroid–PBO ITN proven to reduce malaria transmission more effectively than pyrethroid ITNs) and Royal® Sentry 2.0 (a pyrethroid-only ITN included to demonstrate the added benefit of PBO) in experimental huts in Tanzania.MethodsAn experimental hut trial using two blocks of a 7 × 7 Latin square design was conducted over seven rounds (49 experimental nights). Treatments were rotated at the end of each round, and volunteers were rotated nightly within one block. Both unwashed and 20× washed nets of each type were evaluated, alongside an untreated net used as a negative control. The primary endpoint was the proportion of Anopheles arabiensis that died within 24 h, and the secondary endpoint was the proportion of blood feeding. Data were analyzed using binomial logistic regression with fixed effects using a 7% non-inferiority margin.ResultsThe pooled results showed that Vector Guard® was non-inferior and was superior to Olyset® Plus, with higher mortality for Vector Guard® [28% vs. 18%; odds ratio (OR) = 1.93, 95%CI = 1.81–2.06]. Both pyrethroid–PBO nets were superior to Royal Sentry® 2.0 (p &amp;lt; 0.001) in terms of mosquito mortality. For the secondary blood feeding endpoint, Vector Guard® was also found to be non-inferior to Olyset® Plus (0.6% vs. 0.2%; OR = 2.37, 95%CI = 1.77–3.17). Vector Guard® showed similar efficacy to Royal Sentry® 2.0 in reducing the proportion of mosquito blood feeding (0.6% vs. 0.6%; OR = 0.85, 95%CI = 0.68–1.07, p = 0.161).ConclusionVector Guard® demonstrated superior mosquito mortality compared with both Olyset® Plus and Royal Sentry® 2.0, indicating that Vector Guard® is another promising pyrethroid–PBO ITN for the control of resistant malaria vectors. The addition of Vector Guard® to the class of pyrethroid–PBO ITNs will enable malaria control programs to select cost-effective ITNs, improving access to effective protection from malaria transmitted by resistant vectors.

Pyrethroid-resistant malaria vector Anopheles gambiae restored susceptibility after pre-exposure to piperonyl-butoxide: results from country-wide insecticide resistance monitoring in Tanzania, 2023

BackgroundEffective vector control interventions, notably insecticide-treated nets (ITNs) and indoor residual spraying (IRS) are indispensable for malaria control in Tanzania and elsewhere. However, the emergence of widespread insecticide resistance threatens the efficacy of these interventions. Monitoring of insecticide resistance is, therefore, critical for the selection and assessment of the programmatic impact of insecticide-based interventions.MethodsThe study was conducted country-wide across 22 sentinel districts of Tanzania between May and July 2023 using standard World Health Organization susceptibility test with 1×, 5×, and 10× of deltamethrin, permethrin, and alpha-cypermethrin and discriminating concentrations of 0.25% pirimiphos-methyl. Synergist assays were conducted to explore the underlying mechanisms of the observed phenotypic pyrethroid-resistant mosquitoes. Three- to five-day-old wild adult females in the first filiar generation of Anopheles gambiae sensu lato (s.l.) were used for the susceptibility bioassays.ResultsAnopheles gambiae s.l. were resistant to all pyrethroids at the discriminating dose in most sentinel districts except in Rorya, which remains fully susceptible, and Ushetu, which remains susceptible to deltamethrin but not permethrin. In 5 sites (Bukombe, Ukerewe, Kilwa, Kibondo, and Kakonko), the An. gambiae s.l. species exhibited strong resistance to pyrethroids surviving the 10 X concentrations (mortality rate < 98%). However, they remained fully susceptible to pirimiphos-methyl in almost all the sites except in Kibondo and Shinyanga. Likewise, there was full restoration to susceptibility to pyrethroid following pre-exposure of An. gambiae s.l. to piperonyl-butoxide (PBO) in 13 out of 16 sites. The 3 sites that exhibited partial restoration include Kakonko, Tandahimba, and Newala.ConclusionThe evidence of widespread pyrethroid resistance of the major malaria vector justifies the decision made by the Tanzania National Malaria Control Programme to transition to PBO-based ITNs. Without this switch, the gains achieved in malaria control could be compromised. Equally important, the lack of full restoration to susceptibility observed in three sentinel districts upon pre-exposure to PBO merits close monitoring, as there could be other underlying resistance mechanisms besides oxidase metabolic resistance.

IGF-1 Signaling Modulates Oxidative Metabolism and Stress Resistance in ARPE-19 Cells Through PKM2 Function

The retinal pigment epithelium (RPE) contributes to retinal homeostasis, and its metabolic dysfunction is implied in the development of retinal degenerative disease. The isoform M2 of pyruvate kinase (PKM2) is a key factor in cell metabolism, and its function may be affected by insulin-like growth factor 1 (IGF-1). This study aims to investigate the effect of IGF-1 on PKM2 modulation of RPE cells and whether co-treatment with klotho may preserve it. ARPE-19 cells, an ex vivo model of human pigmented epithelium, were exposed to IGF-1. Then, we evaluated PKM2 expression, dimerization and subcellular localization, energy metabolism, and redox balance, and whether pre-treatment with Klotho may antagonize the effects of IGF-1. The results show that IGF-1 favors PKM2 dimerization, thus reducing the activity of PKM2 and leading to an altered cellular energy status coupled with reduced oxidative stress. In conclusion, PKM2 plays a pivotal role in the modulation of RPE metabolism and redox balance and could explain the mechanisms through which IGF-1 participates in the pathogenesis of some retinal diseases. Klotho may exert protective effects by mitigating the IGF-1 signal and its effect on mitochondrial function.

Therapeutic potential of the flavonoid compound Licochalcone D in metabolic dysfunction-associated steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic liver disease associated with type 2 diabetes, which doubles the risk of developing this condition. Various flavonoid compounds have a positive effect on lipid metabolism, inflammation, and insulin resistance and can contribute to slowing down the progression of MASLD. In the current study, we investigated the biological effects of Licochalcone D (Lico D), a flavonoid, in a metabolic disease model. Oil Red O staining, quantitative real-time polymerase chain reaction, and western blotting were performed. For in vivo experiments, we used high-fat diet (60%) plus low-dose streptozotocin (30mg/kg; 5 days; intraperitoneal)-induced metabolic disease mouse model and evaluated lipid metabolism. We observed that Lico D reduced lipid accumulation and increased lipid metabolism both in vitro and in vivo. Additionally, we identified that the AMP-activated protein kinase and Sirtuin 1 pathways were activated in the mouse liver and hepatic steatosis cell model. In silico analysis revealed that Lico D passes the "Lipinski Rule of Five," which indicates drug-likeness properties. In conclusion, our findings highlight the role of Lico D in improving metabolic dysfunction-associated steatotic liver disease.

Plasticity in Gene Expression Patterns and CYPSF Gene Possibly Involved in the Etofenprox-Resistant Population of White-Backed Planthopper, Sogatella furcifera.

The white-backed planthopper (WBPH) poses a significant threat to rice crops globally. A bioassay was conducted on three WBPH populations collected from Korean rice fields to assess the effectiveness of five insecticides, including etofenprox and fenobucarb. The results showed a mortality rate of over 97% at the recommended concentration for carbamate and organophosphate insecticides. However, etofenprox exhibited a mortality rate of less than 40% in all tested populations with the Jindo population showing the highest resistance. No mutations were identified in the voltage-sensitive sodium channel, the target site of etofenprox, suggesting an alternative resistance mechanism. To explore this, RNA-seq analysis was performed on the Jindo population to identify genes potentially associated with etofenprox resistance. Gene expression was assessed after treatment with two sublethal doses of etofenprox using the Jindo population. The analysis revealed that the CYPSF gene, part of the CYP6 family, was consistently overexpressed in both treated and untreated samples. This observation aligns with the bioassay results, where mortality increased significantly after treatment with the cytochrome P450 inhibitor PBO, indicating that CYPSF may play a key role in etofenprox resistance. Additionally, distinct gene expression patterns at different etofenprox concentrations suggest that metabolic resistance mechanisms may be involved.

The status of insecticide resistance of Anopheles coluzzii on the islands of São Tomé and Príncipe, after 20 years of malaria vector control

BackgroundInsecticide-based malaria vector control has been implemented on the islands of São Tomé and Príncipe (STP) for more than 20 years. During this period malaria incidence was significantly reduced to pre-elimination levels. While cases remained low since 2015, these have significantly increased in the last year, challenging the commitment of the country to achieve malaria elimination by 2025. To better understand the reasons for increasing malaria cases, levels and underlying mechanisms of insecticide resistance in the local Anopheles coluzzii populations were characterized.MethodsMosquito larval collections were performed in the rainy and dry seasons, between 2022 and 2024, in two localities of São Tomé and one locality in Príncipe. Susceptibility to permethrin, α-cypermethrin, pirimiphos-methyl and DDT was assessed using WHO bioassays and protocols. Intensity of resistance and reversal by PBO pre-exposure were determined for pyrethroid insecticides. The kdr locus was genotyped by PCR assays in subsamples of the mosquitoes tested.ResultsAnopheles coluzzii populations were fully susceptible to pirimiphos-methyl, but high levels of resistance to pyrethroids and DDT were detected, particularly in São Tomé rainy season collections. Increasing the pyrethroid and DDT dosages to 5 × and 10 × did not restore full susceptibility in all populations. Pre-exposure to PBO resulted into partial reversal of the resistance phenotype suggesting the presence of cytochrome P450 oxidases-mediated metabolic resistance. The L1014F knockdown resistance mutation was present in An. coluzzii on both islands but at much higher frequency in São Tomé where it was associated with the resistant phenotype.ConclusionsFuture vector control interventions should consider the use of non-pyrethroid insecticides or combination with synergists to overcome the high levels of pyrethroid resistance. Alternative control methods not dependent on the use of insecticides should be additionally implemented to achieve malaria elimination in STP.

Two highly selected mutations in the tandemly duplicated CYP6P4a and CYP6P4b genes drive pyrethroid resistance in Anopheles funestus in West Africa

BackgroundGaining a comprehensive understanding of the genetic mechanisms underlying insecticide resistance in malaria vectors is crucial for optimising the effectiveness of insecticide-based vector control methods and developing diagnostic tools for resistance management. Considering the heterogeneity of metabolic resistance in major malaria vectors, the implementation of tailored resistance management strategies is essential for successful vector control. Here, we provide evidence demonstrating that two highly selected mutations in CYP6P4a and CYP6P4b are driving pyrethroid insecticide resistance in the major malaria vector Anopheles funestus, in West Africa.ResultsContinent-wide polymorphism survey revealed escalated signatures of directional selection of both genes between 2014 and 2021. In vitro insecticide metabolism assays with recombinant enzymes from both genes showed that mutant alleles under selection exhibit higher metabolic efficiency than their wild-type counterparts. Using the GAL4-UAS expression system, transgenic Drosophila flies overexpressing mutant alleles exhibited increased resistance to pyrethroids. These findings were consistent with in silico predictions which highlighted changes in enzyme active site architecture that enhance the affinity of mutant alleles for type I and II pyrethroids. Furthermore, we designed two DNA-based assays for the detection of CYP6P4a-M220I and CYP6P4b-D284E mutations, showing their current confinement to West Africa. Genotype/phenotype correlation analyses revealed that these markers are strongly associated with resistance to types I and II pyrethroids and combine to drastically reduce killing effects of pyrethroid bed nets.ConclusionsOverall, this study demonstrated that CYP6P4a and CYP6P4b contribute to pyrethroid resistance in An. funestus and provided two additional insecticide resistance molecular diagnostic tools that would contribute to monitoring and better management of resistance.

Independent Genetic Mapping Experiments Identify Diverse Molecular Determinants of Host Adaptation in a Generalist Herbivore.

Interactions between plants and herbivores promote evolutionary change. Studying the evolution of herbivore mechanisms aimed to cope with different host plant species is a critical intersection between evolutionary biology and sustainable pest management. Generalist herbivores are of particular interest, as hybridization between genetically distinct populations can increase the standing genetic variation and therefore the adaptive potential of the species. Tetranychus urticae is a generalist arthropod known for its adaptive potential, evidenced in its immense host range and ability to develop metabolic resistance to xenobiotics. However, the molecular underpinnings associated with the potential of host adaptation and the consequences of host adaptation in this, and many other pests remain elusive. Here, we use two independent, empirical approaches to identify and map the genetic basis of host plant performance and adaptation in genetically distinct populations of T. urticae. In the first approach, we subject a genetically diverse mite population to tomato selection and map genomic regions linked to the phenotypic evolution of increased reproductive performance. In the second approach, we map genomic regions responsible for performance on tomato by comparing the genomes of pooled individuals from an F2 backcross between populations with high and low reproductive performance. Both approaches revealed specific and shared genomic regions associated with host plant performance and adaptation and key candidate genes were identified. Our findings highlight the power of spider mite genetic approaches to identify the complex genetic basis of host adaptation in generalist herbivores.

Characteristics of airway microbiome co-occurrence network in patients with type 2 and non-type 2 asthma

Objective: To study the characteristics of the airway microbiome co-occurrence network in patients with type 2 and non-type 2 asthma. Methods: In a prospective study based on a cohort of asthma patients, respiratory induced sputum samples were collected from 55 asthma patients [25 males and 30 females, with a median age of 47.7 years (age range 34.3-63.0 years)] admitted to the Department of Respiratory and Critical Care, Beijing Chaoyang Hospital, Capital Medical University and 12 healthy controls from the Physical Examination Centre of Beijing Chaoyang Hospital, Capital Medical University, from May 2021 to May 2022. According to the level of exhaled breath nitric oxide (FeNO), the asthma patients were divided into 22 cases in the high FeNO group (FeNO≥40 ppb, i.e., type 2 asthma group) and 33 cases in the low FeNO group (FeNO<40 ppb, i.e., non-type 2 asthma group). All induced sputum samples were subjected to second-generation macrogenomic sequencing and bioinformatic analyses of microbial community diversity, compositional characteristics, symbiotic network characteristics and metabolic function prediction. The Kruskal-Wallis rank sum test was used for between-group comparisons, and the linear discriminant analysis (LEfSe) method was used to compare the differences in flora composition between groups. The R language was used for microbial network analysis. In addition, PICRUSt was used to predict the metabolic-functional characteristics of the microbial communities. Results: The microbial communities in the healthy control group had a lower proportion of p_Firmicutes and p_Proteobacteria than asthma patients, 29% and 21%, respectively; 37% and 33% in the low FeNO group and 42% and 26% in the high FeNO group. The microbial network in the low FeNO group had 64 pairs of edges forming 16 communities, and about 75% of the nodes had eigenvector centrality values between 0 and 0.05, and 25% of the nodes had eigenvector centrality values between 0.10 and 0.45. There were four layers of κ-nucleosynthesis, and about 42% of the vertices were in the centre of the two layers. The microbial network of the high-FeNO group had 80 pairs of edges forming 18 clusters, and 81% of the nodes had eigenvector centrality values between 0 and 0.05, and 19% of the nodes had eigenvector centrality values between 0.10 and 0.35. The κ-nucleus decomposition had eight layers, and 21% of the vertices were located in the centre's two layers. The main functional differences between the low and high FeNO groups were shown in metabolic pathways (including sugar, lipid, amino acid, and energy metabolism), drug resistance, biofilm transport, signalling, intercellular communication, and cellular repair. Conclusions: Compared with non-type 2 asthmatics, type 2 asthmatics had a higher alpha diversity of respiratory microbiota, lower levels of microorganisms in the p_Proteobacteria, and a more aggregated microbial network. There was a significant difference in the predicted metabolic function of the two endotypes of asthmatics.

Regulation of the Cilia as a Potential Treatment for Senescence and Tumors: A Review.

Millions of people worldwide die from malignant tumors every year, and the current clinical treatment is still based on radiotherapy and chemotherapy. Immunotherapy-adjuvant chemotherapy is widely applied, yet resistance to various factors persists in the management of advanced malignancies. Recently researchers have gradually discovered that the integrity of primary cilia is closely related to many diseases. The phenotypic changes in primary cilia are found in some cases of progeria, tumorigenesis, and drug resistance. Primary cilia seem to mediate signaling during these diseases. Hedgehog inhibitors have emerged in recent years to treat tumors by controlling signaling proteins on primary cilia. There is evidence for the use of anti-tumor drugs to treat senescence-related disease. Considering the close relationship between aging and obesity, as well as the obesity is the phenotype of many ciliopathies. Therefore, we speculate that some anti-tumor or anti-aging drugs can treat ciliopathies. Additionally, there is evidence suggesting that anti-aging drugs for tumor treatment, in which the process may be mediated by cilia. This review elucidates for the first time that cilia may be involved in the regulation of senescence, metabolic, tumorigenesis, and tumor resistance and hypothesizes that cilia can be regulated to treat these diseases in the future.