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Avermectins are pharmaceutical drugs widely used mainly in livestock to combat both ectoparasites and endoparasites. Drugs belonging to this family include ivermectin, abamectin, doramectin, selamectin, eprinomectin, and emamectin benzoate, and they share similar chemical characteristics. When administered to livestock, between 80 and 98% of the drug is estimated to leave the body without being metabolized in feces, thus reaching the soil. For this reason, concern for avermectin contamination in soil is increasing, and researchers are focused on estimating the effects on non-target organisms, such as plants and soil invertebrates. This review aimed to compile and discuss updated data of avermectin toxicity on non-target organisms to better comprehend its effect on the environment. Effects on plants are scarcely studied, since they were not believed to absorb these drugs. However, recent studies suggest that plants can be negatively affected. Regarding soil invertebrates, negative effects such as increased mortality and reduced reproduction are best known to dung-beetles. Recently, some studies have also suggested that earthworms, springtails, and enchytraeids can be adversely affected by avermectin exposure. Since ivermectin was the first avermectin marketed, most of the data refers to this product. According to new data on scientific literature, avermectins can now be considered harmful to non-target organisms, and its prudent use is recommended in order to reduce negative effects on the environment. For future investigations, inclusion of avermectins other than ivermectin, as well as field and “omics” studies is suggested.

Purpose Doramectin (DRM) is a kind of avermectin drugs, and it has been shown that DRM has anti-cancer effects. However, the molecular mechanism of DRM in programmed cell death (PCD) aspects is still unclear. The objective of this study was to confirm whether DRM induced PCD in glioma cells. Methods In this experiment, the MTT assay and Ki-67 assay were used to detect in vitro cell viability and in vivo tumor proliferation. Then, the effect of DRM on PCD was analyzed by transcriptome comparison. Next, Endogenous apoptosis was detected by transmission electron microscopy (TEM), the DNA gel electrophoresis, JC-1 assay, western blotting and qRT-PCR. Meanwhile, necroptosis was detected by TEM, Hoechst 33342, FITC and PI staining assay, western blotting. Results We found DRM induced apoptosis through Bcl-2/Bax/Caspase-3 pathway. And, DRM induced ROS overproduction, then ROS caused necroptosis through RIPK1/RIPK3/MLKL pathway, Mitochondria acted as a bridge between the two pathways. Conclusion Our research provided new insight with the function of anti-cancer of DRM. These results demonstrated DRM may be used as potential therapeutic agents inducing apoptosis and necroptosis for cancer therapy.

Dengue virus (DENV) remains a significant global health challenge, infecting approximately 400 million individuals annually. This study utilizes molecular docking and molecular dynamics (MD) simulations to investigate the binding dynamics and stability of Avermectin and Doramectin with DENV Methyltransferase (MTase) and NS5 proteins. Root Mean Squared Deviation (RMSD) analysis revealed stable complexes, with values ranging from 2.5 to 3.2 Å. The radius of gyration (Rg) values stabilized around 20–23 Å, indicating compact structural integrity. Binding free energy calculations demonstrated that Doramectin exhibited stronger predicted binding and may offer improved inhibitory potential, with ΔG values of -13.9 ± 2.8 kcal/mol for MTase and − 23.8 ± 0.82 kcal/mol for NS5, compared to Avermectin (-5.8 ± 1.2 kcal/mol and − 4.8 ± 0.52 kcal/mol, respectively). Dynamic Cross-Correlation Matrix (DCCM) analysis identified critical correlated motions in key binding residues, such as Gly79 and Arg78 in MTase and Gly104 and Arg155 in NS5, emphasizing Doramectin’s role in stabilizing protein conformations. Key interactions through hydrogen bonding and residue mapping, involving Ser50, Gly52, and Asp141, played pivotal roles in inhibitor binding. This study highlights Doramectin as a promising candidate for further investigation in the treatment of Dengue.

The poultry red mite (PRM), Dermanyssus gallinae, is one of the most detrimental ectoparasite on poultry farms worldwide. The blood fed on birds provides the mites with nutrition and energy for their activities, development and reproduction. In the evaluation of the efficacy of novel drugs or vaccines against PRMs, their effects on blood digestion are generally used as a key parameter. The blood digestion of haematophagous arthropods (including D. gallinae) is usually assessed by weighing; however, this method shows some limitations. The main objective of the present study was to develop a scoring method that can quickly and visually evaluate the blood digestion status of PRMs. A 0–4 point scoring criterion was established to describe the blood digestion status of D. gallinae based on the changes in appearance in the intestinal tract of PRMs during the blood digestion process. There was a good consistency between the results obtained by the blood digestion scoring and the weighing, indicating the reliability of this new method. The results obtained from volunteers were consistent with the results from researchers with low coefficient of variation, indicating that the scoring method has good practicability. The applicability of the scoring method was confirmed in an efficacy study, where it was found that doramectin could significantly inhibit the blood digestion of PRMs, lowering the blood digestion score.

Cholangiocarcinoma is a malignant tumor that emerges in the intrahepatic or extrahepatic bile ducts. Doramectin (DOR), a third-generation derivative of avermectins (AVMs), is renowned for its low toxicity and high efficiency. However, no research has hitherto focused on the anti-cholangiocarcinoma effects of these drugs. In this study, we undertook a preliminary exploration of the mechanism through which DOR inhibits the viability of human cholangiocarcinoma cells (Mz-ChA-1) via transcriptome analysis and molecular validation at the cellular level. The results indicated that DOR could suppress the growth and proliferation of Mz-ChA-1 cells in a dose-dependent manner. Moreover, it significantly diminished their migration and invasion abilities. Cell cycle analysis disclosed arrest in the G1 phase, accompanied by an increase in p21 expression and a decrease in the levels of the cyclin E1 and CDK2 proteins. Additionally, DOR induced apoptosis via the ROS-triggered mitochondrial pathway. This was attested by an elevation in the BAX/BCL-2 ratio, the activation of caspase 3/7 and the cleavage of PARP1. These mechanistic insights underscore DOR’s potential as a therapeutic agent against cholangiocarcinoma

Doramectin, an essential animal anthelmintic, is synthesized through the fermentation process of Streptomyces avermitilis . This study delves into the transcriptomic profiles of two strains, namely the doramectin-producing wild-type S. avermitilis N72 and its highly doramectin-producing mutant counterpart, S. avermitilis XY-62. Comparative analysis revealed 860 up-regulated genes and 762 down-regulated genes in the mutant strain, notably impacting the expression of key genes pivotal in doramectin biosynthesis, including ave A1, ave A2, ave A3, ave A4, ave E, and ave BI. These findings shed light on the molecular mechanisms underpinning the heightened doramectin production in S. avermitilis XY-62, presenting promising avenues for optimizing doramectin production processes. Graphical Abstract

Phytotherapy represents a promising field for developing new therapeutic strategies, either by acting as antiparasitic agents themselves or by enhancing the efficacy of synthetic drugs. The present study evaluated the in vivo pharmacokinetic and pharmacodynamic interactions following the administration of doramectin, either alone or in combination with cinnamaldehyde and pink grapefruit essential oil (CNM–PGF). Additionally, ex vivo P-glycoprotein-mediated interactions were assessed at the intestinal level. Higher efficacy against Haemonchus contortus was observed with the combined treatment of doramectin plus phytochemicals or loperamide. Although phytochemicals and loperamide reduced the ex vivo efflux of rhodamine 123, no pharmacokinetic interactions were detected in vivo. The enhanced efficacy is most likely attributable to localized drug–drug interactions and increased drug availability at the parasite interface. Based on the results obtained, the best treatment would be the combination of DRM with phytochemicals such as CNM–PGF and loperamide. However, a pharmaceutical formulation that allows sustained in vivo interaction between these compounds is needed.

Zika virus (ZIKV), belonging to the Flavivirus family and mainly transmitted by mosquitoes, causes a variety of adverse outcomes, including Guillain-Barré syndrome, microcephaly, and meningoencephalitis. However, there are no approved vaccines or drugs available for ZIKV. The discovery and research on drugs for ZIKV are still essential. In this study, we identified doramectin, an approved veterinary antiparasitic drug, as a novel anti-ZIKV agent (EC50 value from 0.85 μM to 3.00 μM) with low cytotoxicity (CC50 > 50 μM) in multiple cellular models. The expression of ZIKV proteins also decreased significantly under the treatment of doramectin. Further study showed that doramectin directly interacted with the key enzyme for ZIKV genome replication, RNA-dependent RNA polymerase (RdRp), with a stronger affinity (Kd = 16.9 μM), which may be related to the effect on ZIKV replication. These results suggested that doramectin might serve as a promising drug candidate for anti-ZIKV.

Background Gastrointestinal nematodes pose a significant health risk to grazing livestock and cause economic losses, which are further increased by anthelmintic resistance. This study examined the gastrointestinal parasite fauna of Old World Camels (OWCs) in Germany and evaluated the efficacy of anthelmintic treatment. Methods In total, nine German OWC-keeping farms that dewormed their stock in spring 2023 were examined. The farms with their veterinarians independently selected the drug for treatment. The number of strongyle eggs per gram (EPG) feces was determined in 107 OWCs, Camelus bactrianus (86.0%), Camelus dromedarius (6.5%), and hybrids (7.5%), using the FLOTAC method (multiplication factor = 1) before and 14 days after treatment (paired sample size: 100 OWCs). The fecal egg count reduction (FECR) was calculated using bayescount and eggCounts software. For the identification and relative quantification of strongyle species, deep amplicon sequencing (nemabiome analysis) was used. Results Farms differed widely regarding egg shedding intensities and prevalence. On most farms, the weight of the animals was only estimated. Evaluation of the anthelmintic efficacy revealed FECRs of 26.6–90.8% after treatment with albendazole, fenbendazole, ivermectin, moxidectin, or doramectin, while only on one farm treatment with monepantel resulted in > 99% FECR. The strongyle species diversity, as determined using the nemabiome approach, was low. With Trichostrongylus colubriformis , Haemonchus contortus , Trichostrongylus axei , and Cooperia oncophora abundant strongyles of German domestic ruminants dominated, while Camelostrongylus mentulatus also occurred. After deworming, strongyle communities almost completely consisted of T. colubriformis and H. contortus . In contrast, C. mentulatus and C. oncophora were consistently eliminated by treatments. Conclusions This study shows the insufficient efficacy of standard treatments chosen by farmers/veterinarians for OWCs in Germany. Since treatment eliminated some species but did not eliminate others, not underdosing but resistant nematode species presumably led to treatment failure. However, owing to the small sample size, assessment of animal weight only by visual estimation, and no drugs licensed for OWCs in Europe, the term resistance should be used with care. The species T. colubriformis and H. contortus that survived after anthelmintic treatment are also frequently resistant in ruminants in Germany. Graphical Abstract

Mange in sheep is still results in serious economic problems the most one is losses of hid and wool. This requires not only treatment of primary disease but also rapid repairing of skin and wool. The most effective trace element helps the regeneration of skin and wool is zinc. The present study aimed to evaluate the efficacy of nano−zinc supplementation in reducing the time required to recovery and complete skin repair and wool regrowth during treatment of Psoroptic mange in sheep. Forty male Rahmani sheep were divided into four groups each one contained ten sheep. The first group was clinically healthy (CH) and the other three groups were clinically suffered from mange and divided according to treatment into nano-zinc (NZ) group which received doramectin injection plus nano-zinc orally, mineral mixture (MM) group which received doramectin injection plus mineral mixture orally, and DM group which injected by doramectin only. All animals were subjected to keen clinical and confirmative examination and criteria of recovery were routinely assessed day after day. Assessment of skin and wool repair as well as the serum samples were collected for analyses before treatment; at 0 day then at 15th and 30th days after treatment. The clinical examination revealed gradual recovery of clinical signs, and 3 days after treatment the signs of pruritis decreased and disappeared after 1 week. The lesions reduced in size toward the center with regrowth of wool from repaired peripheries of lesions. The assessment of skin and wool repair and biochemical constituents revealed rapid repaired lesions at the 15th day of treatment in NZ group, while MM and DM groups started to be recovered at the 30th day of treatment. Serum biochemical analyses revealed significant decrease in serum zinc, hyperproteinemia, hypoalbuminemia, and hyperglobulinemia and significantly decreased of ALP, AST, γ-GT, and LDH activities with significantly increased serum creatinine in NZ, MM, and DM groups before treatment. Most of these serum changes showed non-significant changes at the 15th day of treatment in NZ group compared to CH group. However, MM group began to improve after 15th day of treatment and in some parameters extended to the 30th day of treatment, while DM group restored majority of estimated parameters at the 30th day of treatment when compared to CH group. In conclusion, nano-zinc supplementation during treatment of Psoroptic mange in sheep provides more effective and rapid regeneration and repair of skin tissues and wool rather than doramectin injection alone or with zinc oxide supplementation.