Sertraline as a new potential anthelmintic against Haemonchus contortus: toxicity, efficacy, and biotransformation

Haemonchus contortus is a parasitic nematode of ruminants which causes significant losses to many farmers worldwide. Since the drugs currently in use for the treatment of haemonchosis are losing their effectiveness due to the drug-resistance of this nematode, a new or repurposed drug is highly needed. As the antipsychotic drug sertraline (SRT) has been shown to be effective against the parasitic nematodes Trichuris muris, Ancylostoma caninum and Schistosoma mansoni, the aim of the present study was to evaluate the possible effect of SRT on H. contortus. The potential hepatotoxicity of SRT was tested in sheep, a common H. contortus host. In addition, the main metabolic pathways of SRT in H. contortus and the ovine liver were identified. While no effect of SRT on H. contortus egg hatching was observed, SRT was found to significantly decrease the viability of H. contortus adults in drug-sensitive and resistant strains, with its effect comparable to the commonly used anthelmintics levamisole and monepantel. Moreover, SRT in anthelmintically active concentrations showed no toxicity to the ovine liver. Biotransformation of SRT in H. contortus was weak, with most of the drug remaining unmetabolized. Production of the main metabolite hydroxy-SRT did not differ significantly between strains. Other minor metabolites such as SRT-O-glucoside, dihydroxy-SRT, and SRT-ketone were also identified in H. contorts adults. Compared to H. contortus, the ovine liver metabolized SRT more extensively, mainly via desmethylation and glucuronidation. In conclusion, the potency of SRT against H. contortus was proven, and it should be tested further toward possible repurposing.

Morphospecies Abundance of Above-Ground Invertebrates in Agricultural Systems under Glyphosate and Microplastics in South-Eastern Mexico

Soil invertebrates are important for diverse soil ecosystem services, which are jeopardized by pesticides and microplastics. In the present study, we aimed to assess above-ground invertebrates’ morphospecies abundance in the presence of glyphosate (GLY), its main metabolite aminomethylphosphonic acid (AMPA), and microplastics (MPs). Three land-use systems were analyzed: agricultural systems with and without plastic mulch and pesticides (AwPM, AwoPM) and natural unmanaged farming systems (UF). Soil GLY, AMPA, MP concentrations and above-ground invertebrates were quantified. GLY concentrations were also assessed inside invertebrate tissues. GLY, AMPA and the highest concentration of GLY in invertebrates’ tissue were found only in AwoPM at 0.14–0.45 mg kg−1, 0.12–0.94 mg kg−1 and 0.03–0.26 mg kg−1, respectively. MPs were present as follows: AwPM system (100%, 400–2000 particles kg−1) > AwoPM (70.8%, 200–1000 particles kg−1) > UF (37.5%, 200–400 particles kg−1). No significant correlations were found between soil MPs, GLY and AMPA. There was a significant correlation between MPs and morphospecies from the order Entomobrymorpha (Collembola, R = 0.61, p < 0.05). Limnophila, Mesogastropoda (Gastropoda) and Siphonaptera morphospecies were only present in the UF system. GLY in invertebrate tissue was inversely correlated with soil GLY (R = −0.73, p < 0.05) and AMPA (R = −0.59, p < 0.05). Further investigations are required to understand these phenomena.

Atrazine Induces the Cytotoxicity of Ovarian Granulosa Cells via Inhibition of Nrf2-Mediated Defense Response

Atrazine (ATR) is a commercial herbicide, which is widely used worldwide. Diaminochlorotriazine (DACT) is the main metabolite of ATR, which poses potential risks to ecosystem and health. However, the mechanism of ATR and DACT on ovarian granulocyte cells (GCs) is still not clear. To investigate the toxic effect of ATR and DACT in quail ovarian GCs. We established primary ovarian GCs as models. GCs were cultured with ATR (20, 100, and 250 µM) and DACT (20, 100 and 200 µM). Which showed normal morphology and uniform size in GCs of the control group, ovarian GCs are specifically identified, in which cell purity was above 90%. The half-inhibitory concentrations (IC50) of ATR and DACT were 261.20 µM and 214.17 µM, respectively. High doses of ATR and DACT caused changes in the ultrastructure of mitochondria, leading to oxidative stressand changes in apoptosis-related indicators, ATR and DACT activated Nrf2-mediated defense system-related factors. Our research showed that ATR and DACT are cytotoxic to GCs. ATR induced oxidative stress in ovarian GCs and activated Nrf2-mediated antioxidant signaling pathway to alleviate the toxicity of ATR. These results suggested useful evidence to investigate the female reproductive toxicity of ATR and DACT.

Stereoselective Synthesis of 24-Fluoro-25-Hydroxyvitamin D3 Analogues and Their Stability to hCYP24A1-Dependent Catabolism

Two 24-fluoro-25-hydroxyvitamin D3 analogues (3,4) were synthesized in a convergent manner. The introduction of a stereocenter to the vitamin D3 side-chain C24 position was achieved via Sharpless dihydroxylation, and a deoxyfluorination reaction was utilized for the fluorination step. Comparison between (24R)- and (24S)-24-fluoro-25-hydroxyvitamin D3 revealed that the C24-R-configuration isomer 4 was more resistant to CYP24A1-dependent metabolism than its 24S-isomer 3. The new synthetic route of the CYP24A1 main metabolite (24R)-24,25-dihydroxyvitamin D3 (6) and its 24S-isomer (5) was also studied using synthetic intermediates (30,31) in parallel.

Berberine and Its Main Metabolite Berberrubine Inhibit Platelet Activation Through Suppressing the Class I PI3Kβ/Rasa3/Rap1 Pathway

Background: Berberine (BBR), a natural product, was reported to inhibit platelet aggregation; however, the molecular mechanisms remain unclear. This study aims to investigate the effects and mechanisms of BBR in inhibiting platelet activation and thrombus formation.Methods: Flow cytometry, immunofluorescence, and Western blot were used to determine the inhibitory effects and mechanisms of BBR and its main metabolite berberrubine (M2) on platelet activation in vitro and ex vivo. Purified integrin αIIbβ3, class I PI3K kit, and molecular docking were used to identify the possible targets of BBR and M2. A carrageenan-induced mouse thrombosis model was used to evaluate the effects of BBR on thrombus formation in vivo.Results:In vitro, BBR and M2 significantly inhibited ADP-induced integrin αIIbβ3 activation, reduced the level of P-selectin on the platelet membrane, and suppressed the binding of fibrinogen to the platelets. In this process, BBR and M2 greatly suppressed the PI3K/Akt pathway and inhibited Rasa3 membrane translocation and Rap1 activation. Furthermore, BBR and M2 selectively inhibited class I PI3Kβ, perhaps through binding to its active site. The activities of BBR were stronger than those of M2. After oral administration, BBR significantly inhibited the PI3K/Akt pathway and Rap1 activation and suppressed ADP-induced platelet activation and carrageenan-induced thrombosis in mice without prolonging bleeding time.Conclusions: We reveal for the first time the possible targets and mechanisms of BBR and M2 in inhibiting platelet activation. Our research may support the future clinical application of BBR as an antiplatelet drug in the prevention or treatment of thrombotic diseases.

Istaroxime metabolite PST3093 selectively stimulates SERCA2a and reverses disease-induced changes in cardiac function

Background: Heart failure (HF) therapeutic toolkit would strongly benefit from the availability of ino-lusitropic agents with a favorable pharmacodynamics and safety profile. PST3093 is the main metabolite of istaroxime, an agent combining Na+/K+ pump inhibition and SERCA2a stimulation, shown by phase 2 trials to be promising in the acute setting. PST3093 half-life is substantially longer than that of istaroxime; therefore, if it retained the effects of the parent compound, it would allow to exploit istaroxime pharmacodynamics in chronic treatment. Methods and Results: We studied PST3093 for its effects on SERCA2a and Na+/K+ ATPase activities, Ca2+ dynamics in isolated myocytes and hemodynamic effects in an in-vivo rat model of diabetic (streptozotocin (STZ)-induced) cardiomyopathy. At variance with its parent compound, PST3093 is a "selective" (i.e. devoid of Na+/K+ pump inhibition) SERCA2a activator. In in-vivo echocardiographic assessment, PST3093 improved overall cardiac performance (e.g. stroke volume) without decreasing heart rate, and reversed most STZ-induced abnormalities. Modulation of both systolic and diastolic indexes contributed to the improvement. For i.v. administration, PST3093 toxicity was considerably lower than that of istaroxime and its evaluation against 50 targets commonly involved in cardiac and extracardiac side-effects, failed to reveal significant interactions. Conclusions: PST3093 is a "selective" SERCA2a activator, the prototype of a novel pharmacodynamic category with a potential in the ino-lusitropic approach to HF, particularly with prevailing diastolic dysfunction. While PST3093 may actually contribute to the proven clinical efficacy of istaroxime, its pharmacodynamics are peculiar and its pharmacokinetics are suitable for chronic administration.