Resistance Management Research Articles

Exploring Mechanisms and Management of Drug Tolerance and Resistance in Schizophrenia

Schizophrenia is a multifaceted mental disorder affecting approximately 1% of the global population, significantly disrupting cognitive function, emotion, and behaviour. Antipsychotic medications are the primary treatment, targeting neurotransmitter regulation to alleviate symptoms. However, long-term use often leads to drug tolerance and resistance, diminishing treatment effectiveness and potentially exacerbating the patient's condition. This article examines the mechanisms and contributing factors associated with drug tolerance and resistance in schizophrenia, focusing on adaptive changes in neurotransmitter systems, alterations in drug metabolism, and neural remodeling. It explores the interplay of biological, environmental, and treatment-related influences on therapeutic outcomes and identifies common patterns in tolerance and resistance manifestations. Furthermore, the article proposes practical management strategies, including drug rotation, dosage adjustments, combination therapies, and the utilization of next-generation antipsychotics. By providing clinicians with insights into tailoring treatment approaches to individual patient needs, this study aims to improve the overall management of schizophrenia. A deeper understanding of drug tolerance and resistance is essential for optimizing treatment efficacy and enhancing the quality of life for affected individuals. Future research directions are also suggested to better elucidate the genetic underpinnings of these phenomena, paving the way for personalized treatment strategies.

Adoption of Hygienic Meat Production and Handling Practices among Value Chain Stakeholders of Chevon and Carabeef in Kerala, India

This study investigated the adoption of hygienic practices in Kerala's chevon and carabeef value chain, focusing on production and handling methods. Using a stratified multistage sampling approach, the research examined three stakeholder groups: farmers (producers), traders, and retailers. For farmers, the assessment covered hygiene practices in feeding, environmental management, livestock health, and biosecurity. For traders and retailers, evaluation parameters included animal welfare standards, handling protocols, transportation compliance, regulatory adherence, traceability systems, slaughter hygiene, packaging methods, and waste management practices. Demographic analysis revealed that participants were predominantly middle-aged males with secondary education and substantial industry experience. The findings indicated moderate adoption of hygiene practices across all stakeholder categories. The domain-specific analysis highlighted critical areas requiring improvement: antimicrobial resistance management, residue monitoring, biosecurity protocols, and general hygiene practices throughout the value chain. For meat traders and retailers specifically, the study identified regulatory compliance, product traceability, personal and environmental hygiene, and waste management as key areas needing enhancement. These findings underscore the necessity for targeted interventions to improve hygiene standards across Kerala's red meat value chain.

Susceptibility to organophosphate insecticides in Aedes aegypti (Diptera: Culicidae) from northern Colombia and associated resistance mechanisms

BackgroundAedes aegypti is the primary vector of dengue, chikungunya, and Zika viruses in Colombia. Various insecticides, including pyrethroid, organophosphate, and carbamate insecticides; growth regulators; and biological insecticides, such as Bacillus thuringiensis var. israelensis, have been used to control Ae. aegypti populations. However, organophosphates such as malathion, pirimiphos-methyl, and temephos have been used over the last decade owing to the high resistance to pyrethroids.MethodsThis study assessed the susceptibility to organophosphates in 14 Ae. aegypti populations from the Córdoba department in northern Colombia. Moreover, possible resistance mechanisms were investigated by determining the activity levels of α-esterases, β-esterases, mixed function oxidases (MFOs), glutathione S-transferases (GSTs), and insensitive acetylcholinesterase (iAChE). Additionally, the Ace-1 gene was sequenced to identify mutations at the target site of action.ResultsThe populations were susceptible to temephos and malathion but resistant to fenitrothion, and in three of them, to pirimiphos-methyl. Alterations in the enzyme activity levels of α-esterases and β-esterases, GST, and iAChE were observed among the populations, with high enzyme activity levels of α and β esterases associated with resistance to fenitrothion. No mutations were identified in the Ace-1 gene.ConclusionsThese findings are highly relevant for vector control programs in the region, as they allow for adjustments in resistance management strategies and improve the effectiveness of interventions against these arboviruses.Graphical

Cross-resistance between Pseudomonas chlororaphis strain AFS009 metabolites (Howler EVO) and fludioxonil in Botrytis cinerea.

Howler EVO is a biological fungicide based on metabolites of the bacterium Pseudomonas chlororaphis strain AFS009. One of the metabolites, pyrrolnitrin (PRN), is a chemical analogue of the phenylpyrrole fludioxonil used to manage gray mold of fruit crops caused by Botrytis cinerea. Resistance to fludioxonil in B. cinerea is well documented and linked to mutations in the transcription factor mrr1, leading to overexpression of the ATP-Binding Cassette (ABC) transporter gene BcatrB. Moderately resistant isolates are designated MDR1 and MRD1h based on the specific variation of mutations in mrr1 and the level of BcatrB expression. This study investigated EC50 values of 54 B. cinerea isolates sensitive and with moderate resistance to fludioxonil for sensitivity to fludioxonil and Howler EVO. The Pearson correlation coefficient indicated a strong correlation between EC50 values of fludioxonil and Howler EVO. Isolates that were moderately resistant to fludioxonil and classified as MDR strains were also moderately resistant to Howler EVO. The effect of Howler EVO and fludioxonil on BcatrB gene expression was studied by qPCR. Both fungicides induced the BcatrB gene expression significantly up to 100-fold in sensitive B. cinerea isolates. Howler EVO significantly induced the BcatrB gene expression in all MDR1 isolate but not in the MDR1h isolate. In detached fruit assays on cherry, sensitive B. cinerea isolates were completely inhibited by formulated fludioxonil (Scholar) and significantly suppressed in growth by Howler EVO. However, MDR1 and MDR1h isolates produced disease in Scholar and Howler EVO treatments. Our results indicate cross-resistance between the synthetic fungicide fludioxonil and the biofungicide Howler EVO, indicating that, at least for some biofungicides, resistance management is necessary.

Comparative Proteomics of Resistant and Susceptible Strains of Frankliniella occidentalis to Abamectin.

Western flower thrips, Frankliniella occidentalis (Thysanoptera: Thripidae) is an invasive agricultural pest with developed resistance to abamectin in some strains due to frequent treatment with the pesticide. In this study, we examined differentially expressed proteins (DEPs) between abamectin-resistant (AbaR; under abamectin selective pressure) and susceptible strains (AbaS; without abamectin selective pressure) of F. occidentalis. Proteins were isolated from second instar larvae of both strains and separated via two-dimensional polyacrylamide gel electrophoresis. Nano-flow liquid chromatography-tandem mass spectrometry identified selected protein spot features. From 70 DEPs, 43 spot features were identified: A total of 23 showed an increase in abundance, and 20 were down-regulated in response to abamectin pressure. The enzymatic and structural proteins were classified into the functional groups of macromolecular metabolisms, signaling and cellular processes, immune system, genetic information processing, and exoskeleton-related proteins. The up-regulation of exoskeleton-related proteins may contribute to forming a thicker cuticle, potentially hindering abamectin penetration, which is an interesting finding that needs further investigation. Two novel proteins, triacylglycerol lipase and cuticle protein CPF 2, were only expressed in AbaR. This work provides insights into abamectin resistance mechanisms in F. occidentalis, which will provide important information for developing insecticide resistance management approaches for this pest.

Establishing best practices for insect resistance management: a new paradigm for genetically engineered toxins in cotton expressing Mpp51Aa2.

Debate over resistance management tactics for genetically engineered (GE) crops expressing insecticidal toxins is not new. For several decades, researchers, regulators, and agricultural industry scientists have developed strategies to limit the evolution of resistance in populations of lepidopteran and coleopteran pests. A key attribute of many of these events was insecticide resistance management (IRM) strategies designed around a presumed high-dose expression sufficient to kill 99.5% of exposed larvae for some of the main target pests in corn, Zea mays L. and cotton, Gossypium hirsutum L. In contrast, other target pests did not meet this high-dose criterion. Similarly, the recent release of ThryvOn cotton that expresses thysanopteran and hemipteran active Mpp51Aa2.834_16 toxin is not high dose, working on a combination of behavioral and sublethal effects to suppress populations. This unique mode of control has generated considerable uncertainty about what IRM strategies will be most effective to limit field-evolved resistance to this unique spectrum of pests. The goal of this manuscript is to present several knowledge gaps that exist in proposed Mpp51Aa2 IRM plans, focusing on its activity on thrips, Frankliniella spp. Addressing these gaps will be crucial to limit resistance and preserve the benefits that this technology may provide by alleviating reliance on conventional insecticides and seed treatments. Broadly, these considerations will be important for future GE events that are non-high dose but remain valuable components of a more holistic insect management programs that integrate multiple tactics to reduce conventional insecticide use for challenging pests.

Review and Improvement of Runway Friction and Aircraft Skid Resistance Regulation, Assessment and Management

Review and Improvement of Runway Friction and Aircraft Skid Resistance Regulation, Assessment and Management

Identification of hsa_circ_0076957 and miR-4512-targeted COL19A1 as Regulators in Clopidogrel Resistance among Stable Coronary Heart Disease Patients through Comprehensive circRNA and miRNA Analysis

BackgroundClopidogrel resistance (CR) increases the risk of atherothrombotic events. Emerging evidence suggests that circRNAs may influence pharmacodynamic responses to clopidogrel. MethodsA total of 25 CR and 25 non-clopidogrel resistance (NCR) patients were enrolled. To identify circRNAs and miRNAs associated with CR, a microarray analysis was performed on RNA samples from 5 CR and 5 NCR patients. Based on the 10 most dysregulated circRNAs, a circRNA-miRNA network was constructed to explore target interactions. Next, the expression of selected circRNAs and their targeted mRNAs was measured, and their diagnostic value for CR was evaluated. Through joint analysis, the candidate miRNAs were identified and verified by RT‒PCR. Finally, after THLE-2 cells were cultivated and transfected with plasmids, the interactions among circ_007695, miR-4512 and COL19A1 were detected. ResultsOur present study revealed circRNA and miRNA microarray expression profiles in CR and NCR patients and constructed a circRNA‒miRNA network. Moreover, in the CR group, hsa_circ_0076837, hsa_circ_0057714, and hsa_circ_0076957 were downregulated, and the mRNA expression of AOX1 and COL19A1 was also lower in these CR patients. ROC curve analysis indicated that hsa_circ_0057714 (targeting AOX1) and hsa_circ_0076957 (targeting COL19A1) may serve as reliable biomarkers for distinguishing CR. Furthermore, we revealed that the level of miR-4512 was greater in CR and circ-0076957 could regulate COL19A1 expression by targeting miR4512 in THLE-2 cells. ConclusionThese findings highlight hsa_circ_0057714 and hsa_circ_0076957 as novel biomarkers for CR and suggest that circ-0076957 may regulate COL19A1 expression by targeting miR-4512, providing insights that could improve management of clopidogrel resistance in CAD.

Overexpression of ace2 compensating for the acetylcholinesterase activity loss from ace1 mutations accelerated the development of eggs and early nymphs in Nilaparvata lugens.

Acetylcholinesterase (AChE) guarantees the acetylcholine signal in insect central nervous system, and is the target of organophosphorus and carbamate insecticides, towards which resistance was often reported due to AChE mutations. In Nilaparvata lugens, a major pest on rice, two mutations (G119S and F331C) were detected in AChE1 in a chlorpyrifos-resistant (CHL) strain. The double mutations in AChE1 reduced total AChE activity in metabolizing acetylcholine, such as low protein stability, substrate affinity and catalytic efficiency, which needed compensation in a special way. In CHL strain, the transcriptional level of ace2 encoding AChE2 was systematically elevated, such as over 30-fold overexpression in brain. The ace2 overexpression not only compensated for AChE activity loss in brain due to AChE1 mutations, but also accelerated the development of eggs and early nymphs in CHL strain. When performing ace2 RNAi in CHL eggs, the egg and early nymph duration were recovered. In CHL eggs, the transcriptional levels of three basic helix-loop-helix transcription factors (Ase2, Ato1 and SCL), which were closely related to neural development, were significantly upregulated. Their respective RNAi in CHL strain also significantly recovered the egg duration, as RNAi towards ace2, which partially explained the reason for the accelerated development of eggs and early nymphs. The results revealed AChE2 non-canonical function in insect embryonic development, and uncovered a physiological effect caused by ace2 overexpression as a compensation action for resistance mechanism due to AChE1 mutations, providing a base for insecticide resistance management in insects.

Zumba Exercise Training in the Management of Body Composition and Insulin Resistance in Sedentary Obese Women

Obesity is a pathophysiologic component of type 2 diabetes (T2D) and is typically linked to insulin resistance (IR). However, incorporating regular physical exercise into one’s daily schedule is an effective approach to managing IR, blood sugar levels, and general health. The study’s goal is to assess the feasibility of the Zumba fitness program and its effects on body composition and IR indicators. It is a quasi-experimental design for a single-group pre- and post-Zumba dancing intervention at a fitness center in Al-Ahsa Governorate, Saudi Arabia. Sixty-two sedentary obese women (body mass index [BMI]: 37.55 ± 3.99 kg/m2) 32.5± 0.56 years, completed a 16-week intervention attending moderate to vigorous Zumba dancing sessions 5 d/week, 60 min/class. Study instruments were structured by anthropometric measurements, body composition analysis, and some biochemical markers. After implementing the Zumba exercise program, the results show a substantial improvement in BMI, body fat composition, and IR when compared to before the program. According to body fat position, the reduction in fat composition ranged from 3.7 to 9.71%, while BMI decreased on average by around 6.31%. Significant variations have also been noted in fasting blood glucose levels of 28.04%, in leptin levels of 13.75%, in insulin levels of 28.27%, and IR levels of 8.83%. Further, decrease in total cholesterol, triglycerides, very-low-density lipoprotein cholesterol, and low-density lipoprotein cholesterol were between 2.18% and 4.91%, and the increase in high-density lipoprotein was 5.22%. Total bilirubin, total protein, and total albumin did not vary significantly between the pre- and post-program periods, though aspartate aminotransferase, alkaline transaminase, and alkaline phosphatase did. In conclusion, the program demonstrated strong feasibility and adherence, and it had a favorable impact on body weight, BMI, body fat composition, lipid profiles, and IR parameters, which can improve insulin sensitivity and stop women from developing T2D in the future.

Leveraging RNA interference technology for selective and sustainable crop protection.

Double-stranded RNA (dsRNA) has emerged as key player in gene silencing for the past two decades. Tailor-made dsRNA is now recognized a versatile raw material, suitable for a wide range of applications in biopesticide formulations, including insect control to pesticide resistance management. The mechanism of RNA interference (RNAi) acts at the messenger RNA (mRNA) level, utilizing a sequence-dependent approach that makes it unique in term of effectiveness and specificity compared to conventional agrochemicals. Two primary categories of small RNAs, known as short interfering RNAs (siRNAs) and microRNAs (miRNAs), function in both somatic and germline lineages in a broad range of eukaryotic species to regulate endogenous genes and to defend the genome from invasive nucleic acids. Furthermore, the application of RNAi in crop protection can be achieved by employing plant-incorporated protectants through plant transformation, but also by non-transformative strategies such as the use of formulations of sprayable RNAs as direct control agents, resistance factor repressors or developmental disruptors. This review explores the agricultural applications of RNAi, delving into its successes in pest-insect control and considering its broader potential for managing plant pathogens, nematodes, and pests. Additionally, the use of RNAi as a tool for addressing pesticide-resistant weeds and insects is reviewed, along with an evaluation of production costs and environmental implications.

Comparative Review of Fusarium graminearum Infection in Maize and Wheat: Similarities in Resistance Mechanisms and Future Directions.

Fusarium graminearum is one of the most important plant-pathogenic fungi that causes disease on wheat and maize, as it decreases yield in both crops and produces mycotoxins that pose a risk to human and animal health. Resistance to Fusarium head blight (FHB) in wheat is well studied and documented. However, resistance to Gibberella ear rot (GER) in maize is less understood, despite several similarities with FHB. In this review, we synthesize existing literature on the colonization strategies, toxin accumulation, genetic architecture and potential mechanisms of resistance to GER in maize and compare it to what is known regarding FHB in wheat. There are several similarities in the infection and colonization strategies of F. graminearum in maize and wheat. We describe multiple types of GER resistance in maize and identify distinct genetic regions for each resistance type. We discuss the potential of phenylpropanoids for biochemical resistance to F. graminearum. Phenylpropanoids are well characterized, and there are many similarities in their functional roles for resistance between wheat and maize. These insights can be utilized to improve maize germplasm for GER resistance and are also useful for FHB resistance breeding and management.

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.

Performance of a broth microdilution assay for routine minimum inhibitory concentration determination of 14 anti-tuberculous drugs against the Mycobacterium tuberculosis complex based on the EUCAST reference protocol.

This comparative study aimed at qualifying a broth microdilution (BMD) assay for phenotypic drug susceptibility testing (pDST) of Mycobacterium tuberculosis complex (MTBC) strains for implementation in a routine DST workflow. The assay was developed based on the EUCAST (European Committee on Antimicrobial Susceptibility Testing) reference protocol for determination of the minimum inhibitory concentration (MIC) of 14 anti-tuberculous drugs (isoniazid [INH], rifampicin [RIF], ethambutol [EMB], amikacin [AMI], moxifloxacin [MFX], levofloxacin [LFX], bedaquiline [BDQ], clofazimine [CFZ], delamanid [DLM], pretomanid [PA], para-aminosalicylic acid [PAS], linezolid [LZD], ethionamide [ETH], and cycloserine [CS]). Forty MTBC strains with various drug resistance profiles were tested to determine the agreement between MIC results and genotypic drug susceptibility testing (gDST) results derived from whole-genome sequencing (WGS). The agreement between the BMD and gDST results was solid for the majority of the drugs (average agreement 98%, range 90%-100%), including key drugs such as INH, RIF, MFX, LFX, BDQ, DLM, and PA. Ten discrepancies were identified (corresponding to 1.8% of the total number of MIC determinations) and most (8/10) were characterized by MICs equal or close to the potential critical concentration (pCC) applied in the BMD assay. Importantly, the assay can be adjusted to new drug recommendations and concentrations, tailored to local needs. We conclude that the BMD assay provides reliable results, and its implementation in our MTBC routine workflow will produce valuable data that improve our understanding and management of MTBC drug resistance.

Exploring the Potential of Epigallocatechin Gallate in Combating Insulin Resistance and Diabetes.

In this study, the potential effects are evaluated of epigallocatechin gallate (EGCG) on the prognosis of diabetes and insulin resistance. In an experiment, 35 male Wistar albino rats were used and in the streptozotocin (STZ)-induced diabetic rats, the effects were examined of different doses (50 mg/kg, 100 mg/kg, 200 mg/kg) of EGCG on metabolic parameters associated with diabetes and insulin resistance. The findings show favorable effects of EGCG on fasting blood glucose levels, insulin secretion, insulin resistance, and beta cell function. In this study, it was observed that EGCG was able to significantly lower fasting blood glucose levels, especially at high doses (200 mg/kg), providing the most significant improvement. Furthermore, EGCG has been found to reduce insulin resistance and improve insulin sensitivity by increasing insulin secretion. When the biochemical parameters of increased insulin secretion are evaluated, it is also observed that it creates clinically significant changes. At doses of 100 mg/kg and 200 mg/kg, EGCG has the potential to help control diabetes by most effectively improving insulin resistance and beta cell function. The study results suggest that EGCG, especially at high doses, is an effective component in the treatment of diabetes and the management of insulin resistance. The inclusion of EGCG as a natural flavonoid in medical nutrition therapy may contribute to glycemic control and improve insulin sensitivity in individuals with diabetes. These findings suggest that EGCG may be used as an alternative option in the treatment of diabetes and future studies may further clarify the potential benefits in this area.

Genome-wide association studies unveil major genetic loci driving insecticide resistance in Anopheles funestus in four eco-geographical settings across Cameroon

BackgroundInsecticide resistance is jeopardising malaria control efforts in Africa. Deciphering the evolutionary dynamics of mosquito populations country-wide is essential for designing effective and sustainable national and subnational tailored strategies to accelerate malaria elimination efforts. Here, we employed genome-wide association studies through pooled template sequencing to compare four eco-geographically different populations of the major vector, Anopheles funestus, across a South North transect in Cameroon, aiming to identify genomic signatures of adaptive responses to insecticides.ResultsOur analysis revealed limited population structure within Northern and Central regions (FST<0.02), suggesting extensive gene flow, while populations from the Littoral/Coastal region exhibited more distinct genetic patterns (FST>0.049). Greater genetic differentiation was observed at known resistance-associated loci, resistance-to-pyrethroids 1 (rp1) (2R chromosome) and CYP9 (X chromosome), with varying signatures of positive selection across populations. Allelic variation between variants underscores the pervasive impact of selection pressures, with rp1 variants more prevalent in Central and Northern populations (FST>0.3), and the CYP9 associated variants more pronounced in the Littoral/Coastal region (FST =0.29). Evidence of selective sweeps was supported by negative Tajima’s D and reduced genetic diversity in all populations, particularly in Central (Elende) and Northern (Tibati) regions. Genomic variant analysis identified novel missense mutations and signatures of complex genomic alterations such as duplications, deletions, transposable element (TE) insertions, and chromosomal inversions, all associated with selective sweeps. A 4.3 kb TE insertion was fixed in all populations with Njombe Littoral/Coastal population, showing higher frequency of CYP9K1 (G454A), a known resistance allele and TE upstream compared to elsewhere.ConclusionOur study uncovered regional variations in insecticide resistance candidate variants, emphasizing the need for a streamlined DNA-based diagnostic assay for genomic surveillance across Africa. These findings will contribute to the development of tailored resistance management strategies crucial for addressing the dynamic challenges of malaria control in Cameroon.

Real-world studies of crizotinib in patients with ROS1-positive non-small-cell lung cancer: experience from China.

The treatment of non-small-cell lung cancer (NSCLC) has progressed from histology-oriented cytotoxic therapy to the era of molecular biology-oriented targeted therapy and immunotherapy. As the first tyrosine kinase inhibitor (TKI) targeting the ROS1 pathway, crizotinib is widely used as a first-line regimen for ROS1-rearranged NSCLC. However, due to the paucity of solid data from randomized, controlled phase III clinical studies, clinicians often require more systematic, real-world data-based guidance for its optimal clinical use. As one of the leading countries of real-world research on crizotinib, China has contributed significantly to data on standardization of the therapeutic use of crizotinib, including its clinical treatment patterns, the timing and duration of treatment and drug resistance monitoring and management.

Diuretic strategies in acute decompensated heart failure.

Hospitalization for ADHF is linked to poor outcomes, with residual congestion at discharge significantly increasing the risk of HF readmissions and mortality. Diuretic resistance is a major contributor to inadequate decongestion during ADHF treatment. In this review, we discuss various decongestive strategies, emphasizing the management of diuretic resistance. Additionally, we examine the limitations of current decongestion trials and highlight key priorities for future research.

Impact of field evolved resistance on biological parameters of non-targeted Aedes aegypti populations.

The yellow fever mosquito, Aedes aegypti L., known for transmitting viruses causing yellow fever, dengue, chikungunya, and Zika fever, presents a substantial risk to global human health. The development of insecticide resistance in disease vectors has become a significant problem in Ae. aegypti. Monitoring insecticide resistance is essential for resistance management in Ae. aegypti. This study involved the collection of Ae. aegypti populations from four important cotton-growing regions in southern Punjab, Pakistan, for resistance monitoring over a two-year period (2021-2022). This study also assessed the impact of insecticide resistance on biological parameters of Ae. aegypti. Moderate-to-high levels of resistance were observed against all the tested insecticides viz., chlorpyrifos, chlorfenapyr, deltamethrin, flonicamid, spirotetramat, and spinetoram. However, compared to the Lab-susceptible population, higher levels of resistance to buprofezin (59.03-84.40) and imidacloprid (68.49-100.01) were found in all populations. This high resistance can be attributed to increased use of these two insecticides in cotton fields, as compared to other insecticides. In the lab-susceptible population, higher values for the intrinsic rate of increase (r) and the net reproductive rate (R0) i.e., 0.20 per day and 23.24 offspring/female were observed, respectively. This was also validated by population projection data where more than 2.5-fold adults (1,020,361.80 individuals) were calculated in the Lab-susceptible population as compared to the most resistant populations. Sublethal exposure to insecticides may induce physiological or biochemical changes in organisms, subsequently influencing the biological traits. Resistance monitoring provides essential guidance before launching a successful chemical-based vector management program.

Bile acids as a key target: traditional Chinese medicine for precision management of insulin resistance in type 2 diabetes mellitus through the gut microbiota-bile acids axis.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease caused by insulin resistance (IR) and insufficient insulin secretion. Its characteristic pathophysiological processes involve the interaction of multiple mechanisms. In recent years, globally, the prevalence of T2DM has shown a sharp rise due to profound changes in socio-economic structure, the persistent influence of environmental factors, and the complex role of genetic background. It is worth noting that most T2DM patients show significant IR, which further exacerbates the difficulty of disease progression and prevention. In the process of extensively exploring the pathogenesis of T2DM, the dynamic equilibrium of gut microbes and its diverse metabolic activities have increasingly emphasized its central role in the pathophysiological process of T2DM. Bile acids (BAs) metabolism, as a crucial link between gut microbes and the development of T2DM, not only precisely regulates lipid absorption and metabolism but also profoundly influences glucose homeostasis and energy balance through intricate signaling pathways, thus playing a pivotal role in IR progression in T2DM. This review aims to delve into the specific mechanism through which BAs contribute to the development of IR in T2DM, especially emphasizing how gut microbes mediate the metabolic transformation of BAs based on current traditional Chinese medicine research. Ultimately, it seeks to offer new insights into the prevention and treatment of T2DM. Diet, genetics, and the environment intricately sculpt the gut microbiota and BAs metabolism, influencing T2DM-IR. The research has illuminated the significant impact of single herbal medicine, TCM formulae, and external therapeutic methods such as electroacupuncture on the BAs pool through perturbations in gut microbiota structure. This interaction affects glucose and lipid metabolism as well as insulin sensitivity. Additionally, multiple pathways including BA-FXR-SHP, BA-FXR-FGFR15/19, BA-FXR-NLRP3, BA-TGR5-GLP-1, BAs-TGR5/FXR signaling pathways have been identified through which the BAs pool significantly alter blood glucose levels and improve IR. These findings offer novel approaches for enhancing IR and managing metabolic disorders among patients with T2DM.