Preparation and indoor virulence determination of a temperature-sensitive insecticide against Zeugodacus cucurbitae (Coquillett).

Zeugodacus cucurbitae (Coquillett) is an important fruit and vegetable pest, especially in high-temperature seasons. In our previous research, we developed a temperature-sensitive sustained-release attractant for Z. cucurbitae, that not only can control the release rate of cuelure according to the temperature change, but also shows an excellent trapping effect on Z. cucurbitae. To further enhance the killing effect of the temperature-sensitive attractant on Z. cucurbitae, this study proposed using it in combination with an insecticide to prepare a temperature-sensitive insecticide for Z. cucurbitae. Based on the controlled release technology of pesticides, a temperature-sensitive Z. cucurbitae insecticide was developed by using PNIPAM gel as a temperature-sensitive switch to carry both cuelure and insecticide at the same time. In addition, the lethal effect of different pesticides on Z. cucurbitae were tested by indoor toxicity test, and the best pesticide combination was screened out. The temperature-sensitive insecticide prepared in this study not only had excellent thermal response and controlled release ability, but also enhanced its toxicological effects on Z. cucurbitae because it contained insecticides. Among them, combining thiamethoxam and clothianidin with the temperature-sensitive attractants was the most effective, and their lethality reached more than 97% against Z. cucurbitae. This study is not only of great practical significance for the monitoring and controlling Z. cucurbitae, but also provides theoretical basis and reference value for the combination of temperature-sensitive attractant and insecticide.

Transcription Factors AhR and ARNT Regulate the Expression of CYP6SX1 and CYP3828A1 Involved in Insecticide Detoxification in Bradysia odoriphaga.

Aryl hydrocarbon receptor (AhR) and aryl hydrocarbon receptor nuclear translocator (ARNT) mediate the responses of adaptive metabolism to various xenobiotics. Here, we found that BoAhR and BoARNT are highly expressed in the midgut of Bradysia odoriphaga larvae. The expression of BoAhR and BoARNT was significantly increased after exposure to imidacloprid and phoxim. The knockdown of BoAhR and BoARNT significantly decreased the expression of CYP6SX1 and CYP3828A1 as well as P450 enzyme activity and caused a significant increase in the sensitivity of larvae to imidacloprid and phoxim. Exposure to ß-naphthoflavone (BNF) significantly increased the expression of BoAhR, BoARNT, CYP6SX1, and CYP3828A1 as well as P450 activity and decreased larval sensitivity to imidacloprid and phoxim. Furthermore, CYP6SX1 and CYP3828A1 were significantly induced by imidacloprid and phoxim, and the silencing of these two genes significantly reduced larval tolerance to imidacloprid and phoxim. Taken together, the BoAhR/BoARNT pathway plays key roles in larval tolerance to imidacloprid and phoxim by regulating the expression of CYP6SX1 and CYP3828A1.

Stereoselective and controllable C3-Amination or C1,C3-di-amination of 2-nitroglycals.

Precise and selective modification of carbohydrates is a critical strategy in producing diverse carbohydrate derivatives for exploiting their functions. We disclosed a simple, efficient, and highly regioselective and stereoselective protocol to controllable amination of 2-nitroglycals under mild conditions in 5 min. A range of 3-amino-carbohydrates including 3-arylamino-2-nitro-glycals and 1,3-di-amino-carbohydrate derivatives were obtained in good to excellent yield with excellent stereoselectivity. The produced 3-amino-2-nitro-glycals can be used as a precursor for further transformation.

Imidacloprid-induced lung injury in mice: Activation of the PI3K/AKT/NF-κB signaling pathway via TLR4 receptor engagement.

Significant impairment of pulmonary function has been demonstrated through long-term exposure to neonicotinoid insecticides, such as imidacloprid (IMI). However, the underlying mechanisms of lung injury induced by IMI remain unclear. In this study, a mouse model of IMI-induced pulmonary injury was established, and the toxicity and lung damage were assessed through mouse body weight, organ index, hematological parameters, and histopathological analysis of lung tissues. Furthermore, metabolomics and transcriptomics techniques were employed to explore the mechanistic aspects. Results from the toxicity assessments indicated that mouse body weight was significantly reduced by IMI, organ index was disturbed, and hematological parameters were disrupted, resulting in pulmonary injury. The mechanistic experimental results indicate that the differences in metabolites and gene expression in mouse lungs could be altered by IMI. Validation of the results through combined analysis of metabolomics and transcriptomics revealed that the mechanism by which IMI induces lung injury in mice might be associated with the activation of the TLR4 receptor, thereby activating the PI3K/AKT/NF-κB signaling pathway to induce inflammation in mouse lungs. This study provided valuable insights into the mechanisms underlying IMI-induced pulmonary damage, potentially contributing to the development of safer pest control strategies. The knowledge gained served as a robust scientific foundation for the prevention and treatment of IMI-related pulmonary injuries.

Regenerated SERS substrate based on Ag/AuNPs-TiO2-oxidized carbon cloth for detection of imidacloprid.

Imidacloprid (IMI) are widely used in modern tea industry for pest control, but IMI residues pose a great threat to human health. Herein, we propose a regeneration metal-semiconductor SERS substrate for IMI detection. We fabricated the SERS sensor through the in-situ growth of a nano-heterostructure incorporating a semiconductor (TiO2) and plasmonic metals (Au, Ag) on oxidized carbon cloth (OCC). Leveraging the high-density hot spots, the formed Ag/AuNPs-TiO2-OCC substrate exhibits higher enhancement factors (1.92 × 108) and uniformity (RSD = 7.68%). As for the detection of IMI on the substrate, the limit of detection was lowered to 4.1 × 10-6 µg/mL. With a hydrophobic structure, the Ag/AuNPs-TiO2-OCC possessed excellent self-cleaning performance addressing the limitation of single-use associated with traditional SERS substrates, as well as the degradation capability of the substrate under ultraviolet (UV) light. Accordingly, Ag/AuNPs-TiO2-OCC showcases outstanding SERS sensing and regenerating properties, making it poised for extensive application in the field of food safety assurance.

Neonicotinoid exposure increases Varroa destructor (Mesostigmata: Varroidae) mite parasitism severity in honey bee colonies and is not mitigated by increased colony genetic diversity.

Agrochemical exposure is a major contributor to ecological declines worldwide, including the loss of crucial pollinator species. In addition to direct toxicity, field-relevant doses of pesticides can increase species' vulnerabilities to other stressors, including parasites. Experimental field demonstrations of potential interactive effects of pesticides and additional stressors are rare, as are tests of mechanisms via which pollinators tolerate pesticides. Here, we controlled honey bee colony exposure to field-relevant concentrations of 2 neonicotinoid insecticides (clothianidin and thiamethoxam) in pollen and simultaneously manipulated intracolony genetic heterogeneity. We showed that exposure increased rates of Varroa destructor (Anderson and Trueman) parasitism and that while increased genetic heterogeneity overall improved survivability, it did not reduce the negative effect size of neonicotinoid exposure. This study is, to our knowledge, the first experimental field demonstration of how neonicotinoid exposure can increase V. destructor populations in honey bees and also demonstrates that colony genetic diversity cannot mitigate the effects of neonicotinoid pesticides.

Toxicity evaluation of neonicotinoids to earthworm (Eisenia fetida) behaviors by a novel locomotion tracking assay.

Pesticides are substances used for controlling, preventing, and repelling pests in agriculture. Among them, neonicotinoids have become the fastest-growing class of insecticides because of their efficiency in targeting pests. They work by strongly binding to nicotinic acetylcholine receptors (nAChRs) in the central nervous system of insects, leading to receptor blockage, paralysis, and death. Despite their selectivity for insects, these substances may be hazardous to non-target creatures, including earthworms. Although earthworms may be invasive in some regions like north America, they contribute to the development of soil structure, water management, nutrient cycling, pollution remediation, and cultural services, positively impacting the environment, particularly in the soil ecosystem. Thus, this study aimed to develop a novel earthworm behavior assay since behavior is a sensitive marker for toxicity assay, and demonstrated its application in evaluating the toxicity of various neonicotinoids. Here, we exposed Eisenia fetida to 1 and 10 ppb of eight neonicotinoids (acetamiprid, clothianidin, dinotefuran, imidacloprid, nitenpyram pestanal, thiacloprid, thiametoxam, and sulfoxaflor) for 3 days to observe their behavior toxicities. Overall, all of the neonicotinoids decreased their locomotion, showed by a reduction of average speed by 24.94-68.63% and increment in freezing time movement ratio by 1.51-4.25 times, and altered their movement orientation and complexity, indicated by the decrement in the fractal dimension value by 24-70%. Moreover, some of the neonicotinoids, which were acetamiprid, dinotefuran, imidacloprid, nitenpyram, and sulfoxaflor, could even alter their exploratory behaviors, which was shown by the increment in the time spent in the center area value by 6.94-12.99 times. Furthermore, based on the PCA and heatmap clustering results, thiametoxam was found as the neonicotinoid that possessed the least pronounced behavior toxicity effects among the tested pesticides since these neonicotinoid-treated groups in both concentrations were grouped in the same major cluster with the control group. Finally, molecular docking was also conducted to examine neonicotinoids' possible binding mechanism to Acetylcholine Binding Protein (AChBP), which is responsible for neurotransmission. The molecular docking result confirmed that each of the neonicotinoids has a relatively high binding energy with AChBP, with the lowest binding energy was possessed by thiametoxam, which consistent with its relatively low behavior toxicities. Thus, these molecular docking results might hint at the possible mechanism behind the observed behavior alterations. To sum up, the present study demonstrated that all of the neonicotinoids altered the earthworm behaviors which might be due to their ability to bind with some specific neurotransmitters and the current findings give insights into the toxicities of neonicotinoids to the environment, especially animals in a soil ecosystem.

Ecological implications and drivers of emerging contaminants in Dongting Lake of Yangtze River Basin, China: A multi-substance risk analysis.

Emerging contaminants (ECs) are increasingly recognized as a global threat to biodiversity and ecosystem health. However, the cumulative risks posed by ECs to aquatic organisms and ecosystems, as well as the influence of anthropogenic activities and natural factors on these risks, remain poorly understood. This study assessed the mixed risks of ECs in Dongting Lake, a Ramsar Convention-classified Typically Changing Wetland, to elucidate the major EC classes, key risk drivers, and magnitude of anthropogenic and natural impacts. Results revealed that ECs pose non-negligible acute (30% probability) and chronic (70% probability) mixed risks to aquatic organisms in the freshwater lake ecosystem, with imidacloprid identified as the primary pollutant stressor. Redundancy analysis (RDA) and structural equation modeling (SEM) indicated that cropland and precipitation were major drivers of EC contamination levels and ecological risk. Cropland was positively associated with EC concentrations, while precipitation exhibited a dilution effect. These findings provide critical insights into the ecological risk status and key risk drivers in a typical freshwater lake ecosystem, offering data-driven support for the control and management of ECs in China.

Metabolic perturbations in zebrafish (Danio rerio) larvae exposed to sulfentrazone and imidacloprid.

The intensive and widespread application of pesticides in agroecosystems can lead to the simultaneous exposure of non-target aquatic organisms to insecticides and herbicides. However, the underlying mechanisms through which aquatic organisms undergo metabolic reprogramming to withstand the combined effects of the insecticide imidacloprid (IMI) and herbicide sulfentrazone (SUL) remain poorly elucidated. This study employs metabolomics to investigate the effects of individual and combined exposures to IMI and SUL on zebrafish (Danio rerio), aiming to simulate complex environmental conditions. Metabolomics analysis revealed extensive metabolic reprogramming in larvae induced by the selected agrochemicals. Both individual and combined exposures disrupted nucleotide metabolism, inhibited glycolysis, and led to the accumulation of acetylcholine through the shared modulation of differential metabolites. Notably, individual exposure exhibited a unique mode of action. Larvae exposed to IMI alone showed mitochondrial dysfunction, potentially stemming from interference with the electron transport chain, while SUL-induced disruptions were associated with glycerophospholipid accumulation, marking it as a critical target. Additionally, calculations of the metabolic effect level index indicated antagonistic interactions between SUL and IMI mixtures at an overall metabolic level. The results obtained through investigating the lethal and sub-lethal effects also revealed that the simultaneous application of SUL and IMI may have the potential to diminish acute and developmental toxicity in zebrafish. This study underscores the significance of metabolomics as a valuable and effective strategy for deciphering the toxicity and interactions of agrochemical mixtures.

Aptamer-based biosensors for the detection of neonicotinoid insecticides in environmental samples: A systematic review.

Neonicotinoids, sometimes abbreviated as neonics, represent a class of neuro-active insecticides with chemical similarities to nicotine. Neonicotinoids are the most widely adopted group of insecticides globally since their discovery in the late 1980s. Their physiochemical properties surpass those of previously established insecticides, contributing to their popularity in various sectors such as agriculture and wood treatment. The environmental impact of neonicotinoids, often overlooked, underscores the urgency to develop tools for their detection and understanding of their behavior. Conventional methods for pesticide detection have limitations. Chromatographic techniques are sensitive but expensive, generate waste, and require complex sample preparation. Bioassays lack specificity and accuracy, making them suitable as preliminary tests in conjunction with instrumental methods. Aptamer-based biosensor is recognized as an advantageous tool for neonicotinoids detection due to its rapid response, user-friendly nature, cost-effectiveness, and suitability for on-site detection. This comprehensive review represents the inaugural in-depth analysis of advancements in aptamer-based biosensors targeting neonicotinoids such as imidacloprid, thiamethoxam, clothianidin, acetamiprid, thiacloprid, nitenpyram, and dinotefuran. Additionally, the review offers valuable insights into the critical challenges requiring prompt attention for the successful transition from research to practical field applications.

Risk analysis for groundwater intakes based on the example of neonicotinoids.

Neonicotinoids are a class of broad-spectrum insecticides that are dominant in the world market. They are widely distributed in the environment. Understanding the sources, distribution, and fate of these contaminants is critical to mitigating their effects and maintaining the health of aquatic ecosystems. Contamination of surface and groundwater by neonicotinoids has become a widespread problem worldwide, requiring comprehensive action to accurately determine the mechanisms behind the migration of these pesticides, their properties, and their adverse effects on the environment. A new approach to risk analysis for groundwater intake contamination with emerging contaminants was proposed. It was conducted on the example of four neonicotinoids (acetamiprid, clothianidin, thiamethoxam, and imidacloprid) in relation to groundwater accessed by a hypothetical groundwater intake, based on data obtained in laboratory tests using a dynamic method (column experiments). The results of the risk analysis conducted have shown that in this case study the use of acetamiprid and thiamethoxam for agricultural purposes poses an acceptable risk, and does not pose a risk to the quality of groundwater extracted from the intake for food purposes. Consequently, it does not pose a risk to the health and life of humans and other organisms depending on that water. The opposite situation is observed for clothianidin and imidacloprid, which pose a higher risk of groundwater contamination. For higher maximum concentration of neonicotinoids used in the risk analysis, the concentration of clothianidin and imidacloprid in the groundwater intake significantly (from several to several hundred thousand times) exceeds the maximum permissible levels for drinking water (<0.1 µg/L). This risk exists even if the insecticides containing these pesticides are used according to the information sheet provided by the manufacturer (lower maximum concentration), which results in exceeding the maximum permissible levels for drinking water from several to several hundred times.

In vitro insecticide resistance patterns in field strains of the sheep blowfly, Lucilia cuprina.

The control of the sheep blowfly relies on the use of insecticides. There have been several reports of in vitro and in vivo resistance to the most widely-used flystrike control chemical, dicyclanil. A recent report also described in vitro resistance to imidacloprid in a strain collected from a single property over three consecutive seasons that also showed resistance to dicyclanil. The present study aimed to use in vitro assays to examine five field-collected blowfly strains to determine if this co-occurrence of resistance to dicyclanil and imidacloprid was present more widely in field strains and to also measure resistance patterns to the other currently-used flystrike control chemicals. Each of the strains showed significant levels of resistance to both dicyclanil and imidacloprid: resistance factors at the IC50 of 9.1-23.8 for dicyclanil, and 8.7-14.1 for imidacloprid. Resistance factors at the IC95 ranged from 16.5 to 53.7, and 14.6-24.3 for dicyclanil and imidacloprid, respectively. Resistance factors were up to 8.5 for cyromazine at the IC95. Resistance to dicyclanil and imidacloprid was suppressed by co-treatment with the cytochrome P450 inhibitor, aminobenzotriazole, implicating this enzyme system in the observed resistances. We discuss the implications of the co-occurrence of resistance to dicyclanil and imidacloprid on insecticide rotation strategies for blowfly control. We also discuss the roles of insecticide resistance, environmental factors (e.g. rainfall), operational factors (e.g. insecticide application technique) and other animal health issues (e.g. scouring / diarrhoea) that together will impact on the likelihood of flystrike occurring at an earlier time point than expected after insecticide application.

Imidacloprid reduces the mating success of males in bumblebees.

Bumblebees play a vital role in both natural and agricultural environments, but there has been a noticeable decline in their populations. Pesticides, particularly neonicotinoids, are widely regarded as a substantial contributing factor to the decline in bumblebee populations, as evidenced by the detrimental impacts documented across many stages of their life cycle. Mating is vital for the population maintenance of bumblebees. Nevertheless, there is a scarcity of research conducted on the effects of pesticides on the mating process. In this study, we individually examined the impact of imidacloprid on the mating behavior of bumblebee males and queens. A competitive mating experiment was conducted to evaluate the effect on the competitive prowess of male individuals and the mate selection behavior of female individuals. The study revealed that the mating rate of bumblebees exposed to a concentration of 10 ppb of imidacloprid was 3 %. This finding demonstrated a statistically significant impact when compared to the control group, which exhibited a mating rate of 58 % in the normal mating experiment. Furthermore, in the competitive mating experiment, we found that the competitive mating success rate of treated males (1 %) was significantly lower than that of untreated males (35 %). Hence, it provides evidence that neonicotinoid imidacloprid negatively affects bumblebee mating success and cautions us to protect bumblebees from pesticide exposure to prevent a severe impact on their populations.

Combined pesticides in field doses weaken honey bee (Apis cerana F.) flight ability and analyses of transcriptomics and metabolomics.

Imidacloprid, chlorpyrifos, and glyphosate rank among the most extensively employed pesticides worldwide. The effects of these pesticides and their combined on the flight capability of Apis cerana, and the potential underlying mechanisms remain uncertain. To investigate these effects, we carried out flight mill, transcriptome, and metabolome experiments. Our findings reveal that individual acute oral treatments with pesticides, specifically 20 µL of 10 ng/g imidacloprid (0.2 ng per bee), 30 ng/g chlorpyrifos (0.6 ng per bee), and 60 ng/g glyphosate (1.2 ng per bee), did not impact the flight capability of the bees. However, when bees were exposed to a combination of two or three pesticides, a notable reduction in flight duration and distance was observed. In the transcriptomic and metabolomic analyses, we identified 307 transcripts and 17 metabolites that exhibited differential expression following exposure to combined pesticides, primarily associated with metabolic pathways involved in energy regulation. Our results illuminate the intricate effects and potential hazards posed by combined pesticide exposures on bee behavior. These findings offer valuable insights into the synergistic potential of pesticide combinations and their capacity to impair bee behavior. Understanding these complex interactions is essential for comprehending the broader consequences of pesticide formulations on honey bee populations.

Glutathione S-transferase directly metabolizes imidacloprid in the whitefly, Bemisia tabaci.

The whitefly Bemisia tabaci poses a significant threat to various crops and ornamental plants and causes severe damage to the agricultural industry. Over the past few decades, B. tabaci has developed resistance to several pesticides, including imidacloprid. Therefore, elucidating the mechanism that leads to insecticide detoxification is very important for controlling B. tabaci and managing whitefly resistance to neonicotinoid insecticides. Among insect detoxification enzymes, glutathione S-transferase (GST) is an important phase II detoxification enzyme that helps detoxify exogenous toxic substances. In this study, we cloned the BtGSTz1 gene and observed that its expression level was greater in imidacloprid-resistant populations than sensitive populations of B. tabaci. By silencing BtGSTz1 via RNA interference, we found a significant increase in the mortality of imidacloprid-resistant B. tabaci. Additionally, prokaryotic expression and in vitro metabolism studies revealed that the recombinant BtGSTz1 protein could metabolize 36.36% of the total imidacloprid, providing direct evidence that BtGSTz1 plays a crucial role in the detoxification of imidacloprid. Overall, our study elucidated the role of GSTs in physiological activities related to insecticide resistance, which helps clarify the resistance mechanisms conferred by GSTs and provides useful insights for sustainable integrated pest management.

[The effect of deep neuromuscular block combined with low pneumoperitoneum pressure on postoperative pain in patients undergoing laparoscopic radical colorectal surgery].

Objective: To investigate the effect of deep neuromuscular blockade (DNMB) combined with low pneumoperitoneum pressure anesthesia strategy on postoperative pain in patients undergoing laparoscopic colorectal surgery. Methods: This study was a randomized controlled trial. One hundred and twenty patients who underwent laparoscopic colorectal surgery at Cancer Hospital of Chinese Academy of Medical Sciences from December 1, 2022 to May 31, 2023 were selected and randomly divided into two groups by random number table method. Moderate neuromuscular blockade [train of four stimulations count (TOFC)=1-2] was maintained in patients of the control group (group C, n=60) and pneumoperitoneum pressure level was set at 15 mmHg(1 mmHg=0.133 kPa). DNMB [post-tonic stimulation count (PTC)=1-2] was maintained in patients of the DNMB combined with low pneumoperitoneum pressuregroup (group D, n=60) and pneumoperitoneum pressure level was set at 10 mmHg. The primary measurement was incidence of moderate to severe pain at 1 h after surgery. The secondary measurements the included incidence of moderate to severe pain at 1, 2, 3, 5 d and 3 months after surgery, the incidence of rescue analgesic drug use, the doses of sufentanil in analgesic pumps, surgical rating scale (SRS) score, the incidence of postoperative residual neuromuscular block, postoperative recovery [evaluated with length of post anesthesia care unit (PACU) stay, time of first exhaust and defecation after surgery and length of hospital stay] and postoperative inflammation conditions [evaluated with serum concentration of interleukin (IL)-1ß and IL-6 at 1 d and 3 d after surgery]. Results: The incidence of moderate to severe pain in group D 1 h after surgery was 13.3% (8/60), lower than 30.0% (18/60) of group C (P<0.05). The incidence of rescue analgesia in group D at 1 h and 1 d after surgery were 13.3% (8/60) and 4.2% (5/120), respectively, lower than 30.0% (18/60) and 12.5% (15/120) of group C (both P<0.05). The IL-1ß level in group D was (4.1±1.8)ng/L at 1 d after surgery, which was lower than (4.9±2.6) ng/L of group C (P=0.048). The IL-6 level in group D was (2.0±0.7)ng/L at 3 d after surgery, which was lower than (2.4±1.1) ng/L of group C (P=0.018). There was no significant difference in the doses of sufentanil in analgesic pumps, intraoperative SRS score, incidence of neuromuscular block residue, time spent in PACU, time of first exhaust and defecation after surgery, incidence of nausea and vomiting, and length of hospitalization between the two groups (all P>0.05). Conclusion: DNMB combined with low pneumoperitoneum pressure anesthesia strategy alleviates the early-stage pain in patients after laparoscopic colorectal surgery.

Assessment of toxic effects of imidacloprid on freshwater zooplankton: An experimental test for 27 species.

The neonicotinoid pesticide imidacloprid has been used worldwide since 1992. As one of the most important chemicals used in pest control, there have been concerns that its run-off into rivers and lakes could adversely affect aquatic ecosystems, where zooplankton play a central role in the energy flow from primary to higher trophic levels. However, studies assessing the effects of pesticides at the species level have relied on a Daphnia-centric approach, and no studies have been conducted using species-level assessments on a broad range of zooplankton taxa. In the present study, we therefore investigated the acute toxicity of imidacloprid on 27 freshwater crustacean zooplankton (18 cladocerans, 3 calanoid copepods and 6 cyclopoid copepods). The experiment showed that a majority of calanoid copepods and cladocerans were not affected at all by imidacloprid, with the exception of one species each of Ceriodaphnia and Diaphasoma, while all six cyclopoid copepods showed high mortality rates, even at concentrations of imidacloprid typically found in nature. In addition, we found a remarkable intra-taxonomic variation in susceptibility to this chemical. As many cyclopoid copepods are omnivorous, they act as predators as well as competitors with other zooplankton. Accordingly, their susceptibility to imidacloprid is likely to cause different responses at the community level through changes in predation pressure as well as changes in competitive interactions. The present results demonstrate the need for species-level assessments of various zooplankton taxa to understand the complex responses of aquatic communities to pesticide disturbance.

CC Chemokine Family Members' Modulation as a Novel Approach for Treating Central Nervous System and Peripheral Nervous System Injury-A Review of Clinical and Experimental Findings.

Despite significant progress in modern medicine and pharmacology, damage to the nervous system with various etiologies still poses a challenge to doctors and scientists. Injuries lead to neuroimmunological changes in the central nervous system (CNS), which may result in both secondary damage and the development of tactile and thermal hypersensitivity. In our review, based on the analysis of many experimental and clinical studies, we indicate that the mechanisms occurring both at the level of the brain after direct damage and at the level of the spinal cord after peripheral nerve damage have a common immunological basis. This suggests that there are opportunities for similar pharmacological therapeutic interventions in the damage of various etiologies. Experimental data indicate that after CNS/PNS damage, the levels of 16 among the 28 CC-family chemokines, i.e., CCL1, CCL2, CCL3, CCL4, CCL5, CCL6, CCL7, CCL8, CCL9, CCL11, CCL12, CCL17, CCL19, CCL20, CCL21, and CCL22, increase in the brain and/or spinal cord and have strong proinflammatory and/or pronociceptive effects. According to the available literature data, further investigation is still needed for understanding the role of the remaining chemokines, especially six of them which were found in humans but not in mice/rats, i.e., CCL13, CCL14, CCL15, CCL16, CCL18, and CCL23. Over the past several years, the results of studies in which available pharmacological tools were used indicated that blocking individual receptors, e.g., CCR1 (J113863 and BX513), CCR2 (RS504393, CCX872, INCB3344, and AZ889), CCR3 (SB328437), CCR4 (C021 and AZD-2098), and CCR5 (maraviroc, AZD-5672, and TAK-220), has beneficial effects after damage to both the CNS and PNS. Recently, experimental data have proved that blockades exerted by double antagonists CCR1/3 (UCB 35625) and CCR2/5 (cenicriviroc) have very good anti-inflammatory and antinociceptive effects. In addition, both single (J113863, RS504393, SB328437, C021, and maraviroc) and dual (cenicriviroc) chemokine receptor antagonists enhanced the analgesic effect of opioid drugs. This review will display the evidence that a multidirectional strategy based on the modulation of neuronal-glial-immune interactions can significantly improve the health of patients after CNS and PNS damage by changing the activity of chemokines belonging to the CC family. Moreover, in the case of pain, the combined administration of such antagonists with opioid drugs could reduce therapeutic doses and minimize the risk of complications.

Integration of transcriptome, gut microbiota, and physiology reveals toxic responses of the red claw crayfish (Cherax quadricarinatus) to imidacloprid.

Imidacloprid enters the water environment through rainfall and causes harm to aquatic crustaceans. However, the potential chronic toxicity mechanism of imidacloprid in crayfish has not been comprehensively studied. In this study, red claw crayfish (Cherax quadricarinatus) were exposed to 11.76, 35.27, or 88.17 µg/L imidacloprid for 30 days, and changes in the physiology and biochemistry, gut microbiota, and transcriptome of C. quadricarinatus and the interaction between imidacloprid, gut microbiota, and genes were studied. Imidacloprid induced oxidative stress and decreased growth performance in crayfish. Imidacloprid exposure caused hepatopancreas damage and decreased serum immune enzyme activity. Hepatopancreatic and plasma acetylcholine decreased significantly in the 88.17 µg/L group. Imidacloprid reduced the diversity of the intestinal flora, increased the abundance of harmful flora, and disrupted the microbiota function. Transcriptomic analysis showed that the number of up-and-down-regulated differentially expressed genes (DEGs) increased significantly with increasing concentrations of imidacloprid. DEG enrichment analyses indicated that imidacloprid inhibits neurotransmitter transduction and immune responses and disrupts energy metabolic processes. Crayfish could alleviate imidacloprid stress by regulating antioxidant and detoxification-related genes. A high correlation was revealed between GST, HSPA1s, and HSP90 and the composition of gut microorganisms in crayfish under imidacloprid stress. This study highlights the negative effects and provides detailed sequencing data from transcriptome and gut microbiota to enhance our understanding of the molecular toxicity of imidacloprid in crustaceans.

Comparative evaluation of neonicotinoids and their metabolites-induced oxidative stress in carp primary leukocytes and CLC cells.

Neonicotinoids (NEOs) have been designed to act selectively on insect nicotinic acetylcholine receptors (nAChRs). However, nAChRs are also expressed in vertebrate immune cells, so NEOs may interfere with the immune system in exposed non-target animals. The present study shows that NEOs: imidacloprid and thiacloprid, and their main metabolites: desnitro-imidacloprid and thiacloprid amide, at sub-micromolar concentrations ranging from 2.25 to 20 µM, affect the immune cells of fish. This was found both in primary cultures of leukocytes isolated from the carp head kidney and in the continuous adherent carp monocyte/macrophage cell line. Moreover, the results revealed that the studied pesticides and metabolites generate oxidative stress in carp immune cells and that this is one of the most important mechanisms of neonicotinoid immunotoxicity. Significant increases were observed in the formation of ROS and malondialdehyde (MDA). The antioxidant status alteration was linked with decrease in antioxidant enzyme activity: superoxide dismutase (SOD), catalase (CAT), and non-enzymatic antioxidant glutathione (GSH). Importantly, the metabolites: desnitro-imidacloprid and thiacloprid amide showed significantly higher cytotoxicity towards fish leukocytes than their parent compounds, imidacloprid and thiacloprid, which emphasizes the importance of including intermediate metabolites in toxicology studies.