High-throughput screening unveils nitazoxanide as a potent PRRSV inhibitor by targeting NMRAL1.

Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) poses a major threat to the global swine industry, yet effective prevention and control measures remain elusive. This study unveils Nitazoxanide (NTZ) as a potent inhibitor of PRRSV both in vitro and in vivo. Through High-Throughput Screening techniques, 16 potential anti-PRRSV compounds are identified from a library comprising FDA-approved and pharmacopeial drugs. We show that NTZ displays strong efficacy in reducing PRRSV proliferation and transmission in a swine model, alleviating viremia and lung damage. Additionally, Tizoxanide (TIZ), the primary metabolite of NTZ, has been identified as a facilitator of NMRAL1 dimerization. This finding potentially sheds light on the underlying mechanism contributing to TIZ's role in augmenting the sensitivity of the IFN-ß pathway. These results indicate the promising potential of NTZ as a repurposed therapeutic agent for Porcine Reproductive and Respiratory Syndrome (PRRS). Additionally, they provide valuable insights into the antiviral mechanisms underlying NTZ's effectiveness.

The anticancer potential of the CLK kinases inhibitors 1C8 and GPS167 revealed by their impact on the epithelial-mesenchymal transition and the antiviral immune response.

The diheteroarylamide-based compound 1C8 and the aminothiazole carboxamide-related compound GPS167 inhibit the CLK kinases, and affect the proliferation of a broad range of cancer cell lines. A chemogenomic screen previously performed with GPS167 revealed that the depletion of components associated with mitotic spindle assembly altered sensitivity to GPS167. Here, a similar screen performed with 1C8 also established the impact of components involved in mitotic spindle assembly. Accordingly, transcriptome analyses of cells treated with 1C8 and GPS167 indicated that the expression and RNA splicing of transcripts encoding mitotic spindle assembly components were affected. The functional relevance of the microtubule connection was confirmed by showing that subtoxic concentrations of drugs affecting mitotic spindle assembly increased sensitivity to GPS167. 1C8 and GPS167 impacted the expression and splicing of transcripts in pathways relevant to tumor progression, including MYC targets and the epithelial mesenchymal transition (EMT). Finally, 1C8 and GPS167 altered the expression and alternative splicing of transcripts involved in the antiviral immune response. Consistent with this observation, depleting the double-stranded RNA sensor DHX33 suppressed GPS167-mediated cytotoxicity on HCT116 cells. Our study uncovered molecular mechanisms through which 1C8 and GPS167 affect cancer cell proliferation as well as processes critical for metastasis.

Xa inhibitor edoxaban ameliorates hepatic ischemia-reperfusion injury via PAR-2-ERK 1/2 pathway.

Hepatic ischemia-reperfusion injury causes liver damage during surgery. In hepatic ischemia-reperfusion injury, the blood coagulation cascade is activated, causing microcirculatory incompetence and cellular injury. Coagulation factor Xa (FXa)- protease-activated receptor (PAR)-2 signaling activates inflammatory reactions and the cytoprotective effect of FXa inhibitor in several organs. However, no studies have elucidated the significance of FXa inhibition on hepatic ischemia-reperfusion injury. The present study elucidated the treatment effect of an FXa inhibitor, edoxaban, on hepatic ischemia-reperfusion injury, focusing on FXa-PAR-2 signaling. A 60 min hepatic partial-warm ischemia-reperfusion injury mouse model and a hypoxia-reoxygenation model of hepatic sinusoidal endothelial cells were used. Ischemia-reperfusion injury mice and hepatic sinusoidal endothelial cells were treated and pretreated, respectively with or without edoxaban. They were incubated during hypoxia/reoxygenation in vitro. Cell signaling was evaluated using the PAR-2 knockdown model. In ischemia-reperfusion injury mice, edoxaban treatment significantly attenuated fibrin deposition in the sinusoids and liver histological damage and resulted in both anti-inflammatory and antiapoptotic effects. Hepatic ischemia-reperfusion injury upregulated PAR-2 generation and enhanced extracellular signal-regulated kinase 1/2 (ERK 1/2) activation; however, edoxaban treatment reduced PAR-2 generation and suppressed ERK 1/2 activation in vivo. In the hypoxia/reoxygenation model of sinusoidal endothelial cells, hypoxia/reoxygenation stress increased FXa generation and induced cytotoxic effects. Edoxaban protected sinusoidal endothelial cells from hypoxia/reoxygenation stress and reduced ERK 1/2 activation. PAR-2 knockdown in the sinusoidal endothelial cells ameliorated hypoxia/reoxygenation stress-induced cytotoxicity and suppressed ERK 1/2 phosphorylation. Thus, edoxaban ameliorated hepatic ischemia-reperfusion injury in mice by protecting against micro-thrombosis in sinusoids and suppressing FXa-PAR-2-induced inflammation in the sinusoidal endothelial cells.

Can neonicotinoid and pyrrole insecticides manage malaria vector resistance in high pyrethroid resistance areas in Côte d'Ivoire?

BACKGROUND: Anopheles mosquito resistance to insecticide remains a serious threat to malaria vector control affecting several sub-Sahara African countries, including Côte d'Ivoire, where high pyrethroid, carbamate and organophosphate resistance have been reported. Since 2017, new insecticides, namely neonicotinoids (e.g.; clothianidin) and pyrroles (e.g.; chlorfenapyr) have been pre-qualified by the World Health Organization (WHO) for use in public health to manage insecticide resistance for disease vector control. METHODS: Clothianidin and chlorfenapyr were tested against the field-collected Anopheles gambiae populations from Gagnoa, Daloa and Abengourou using the WHO standard insecticide susceptibility biossays. Anopheles gambiae larvae were collected from several larval habitats, pooled and reared to adulthood in each site in July 2020. Non-blood-fed adult female mosquitoes aged 2 to 5 days were exposed to diagnostic concentration deltamethrin, permethrin, alpha-cypermethrin, bendiocarb, and pirimiphos-methyl. Clothianidin 2% treated papers were locally made and tested using WHO tube bioassay while chlorfenapyr (100 µg/bottle) was evaluated using WHO bottle assays. Furthermore, subsamples of exposed mosquitoes were identified to species and genotyped for insecticide resistance markers including the knock-down resistance (kdr) west and east, and acetylcholinesterase (Ace-1) using molecular techniques. RESULTS: High pyrethroid resistance was recorded with diagnostic dose in Abengourou (1.1 to 3.4% mortality), in Daloa (15.5 to 33.8%) and in Gagnoa (10.3 to 41.6%). With bendiocarb, mortality rates ranged from 49.5 to 62.3%. Complete mortality (100% mortality) was recorded with clothianidin in Gagnoa, 94.9% in Daloa and 96.6% in Abengourou, while susceptibility (mortality > 98%) to chlorfenapyr 100 µg/bottle was recorded at all sites and to pirimiphos-methyl in Gagnoa and Abengourou. Kdr-west mutation was present at high frequency (0.58 to 0.73) in the three sites and Kdr-east mutation frequency was recorded at a very low frequency of 0.02 in both Abengourou and Daloa samples and absent in Gagnoa. The Ace-1 mutation was present at frequencies between 0.19 and 0.29 in these areas. Anopheles coluzzii represented 100% of mosquitoes collected in Daloa and Gagnoa, and 72% in Abengourou. CONCLUSIONS: This study showed that clothianidin and chlorfenapyr insecticides induce high mortality in the natural and pyrethroid-resistant An. gambiae populations in Côte d'Ivoire. These results could support a resistance management plan by proposing an insecticide rotation strategy for vector control interventions.

Structure-Based Design of Novel Thiazolone[3,2-a]pyrimidine Derivatives as Potent RNase H Inhibitors for HIV Therapy.

Ribonuclease H (RNase H) was identified as an important target for HIV therapy. Currently, no RNase H inhibitors have reached clinical status. Herein, a series of novel thiazolone[3,2-a]pyrimidine-containing RNase H inhibitors were developed, based on the hit compound 10i, identified from screening our in-house compound library. Some of these derivatives exhibited low micromolar inhibitory activity. Among them, compound 12b was identified as the most potent inhibitor of RNase H (IC50 = 2.98 µM). The experiment of magnesium ion coordination was performed to verify that this ligand could coordinate with magnesium ions, indicating its binding ability to the catalytic site of RNase H. Docking studies revealed the main interactions of this ligand with RNase H. A quantitative structure activity relationship (QSAR) was also conducted to disclose several predictive mathematic models. A molecular dynamics simulation was also conducted to determine the stability of the complex. Taken together, thiazolone[3,2-a]pyrimidine can be regarded as a potential scaffold for the further development of RNase H inhibitors.

Development of novel N-aryl-2,4-bithiazole-2-amine-based CYP1B1 degraders for reversing drug resistance.

Extrahepatic cytochrome P450 1B1 (CYP1B1), which is highly expressed in non-small cell lung cancer, is an attractive target for cancer prevention, therapy, and overcoming drug resistance. Historically, CYP1B1 inhibition has been the primary therapeutic approach for treating CYP1B1-related malignancies, but its success has been limited. This study introduced CYP1B1 degradation as an alternative strategy to counter drug resistance and metastasis in CYP1B1-overexpressing non-small cell lung cancer A549/Taxol cells via a PROTAC strategy. Our investigation revealed that the identification of the potent CYP1B1 degrader PV2, achieving DC50 values of 1.0 nM and inducing >90 % CYP1B1 degradation at concentrations as low as 10 nM in A549/Taxol cells. Importantly, PV2 enhanced the sensitivity of the A549/Taxol subline to Taxol, possibly due to its stronger inhibitory effects on P-gp through CYP1B1 degradation. Additionally, compared to the CYP1B1 inhibitor A1, PV2 effectively suppressed the migration and invasion of A549/Taxol cells by inhibiting the FAK/SRC and EMT pathways. These findings hold promise for a novel therapy targeting advanced CYP1B1+ non-small cell lung cancer.

Ziprasidone triggers inflammasome signaling via PI3K-Akt-mTOR pathway to promote atrial fibrillation.

BACKGROUND: Second-generation antipsychotics increase the risk of atrial fibrillation. This study explores whether the atypical antipsychotic ziprasidone triggers inflammasome signaling, leading to atrial arrhythmia. METHODS: Electromechanical and pharmacological assessments were conducted on the rabbit left atria (LA). The patch-clamp technique was used to measure ionic channel currents in single cardiomyocytes. Detection of cytosolic reactive oxygen species production was performed in atrial cardiomyocytes. RESULTS: The duration of action potentials at 50 % and 90 % repolarization was dose-dependently shortened in ziprasidone-treated LA. Diastolic tension in LA increased after ziprasidone treatment. Ziprasidone-treated LA showed rapid atrial pacing (RAP) triggered activity. PI3K inhibitor, Akt inhibitor and mTOR inhibitor abolished the triggered activity elicited by ziprasidone in LA. The NLRP3 inhibitor MCC950 suppressed the ziprasidone-induced post-RAP-triggered activity. MCC950 treatment reduced the reverse-mode Na+/Ca2+ exchanger current in ziprasidone-treated myocytes. Cytosolic reactive oxygen species production decreased in ziprasidone-treated atrial myocytes after MCC950 treatment. Protein levels of inflammasomes and proinflammatory cytokines, including NLRP3, caspase-1, IL-1ß, IL-18, and IL-6 were observed to be upregulated in myocytes treated with ziprasidone. CONCLUSIONS: Our findings suggest ziprasidone induces atrial arrhythmia, potentially through upregulation of the NLRP3 inflammasome and enhancement of reactive oxygen species production via the PI3K/Akt/mTOR pathway.

Fungicidal Activity of New Pyrrolo[2,3-d]thiazoles and Their Potential Action on the Tryptophan Metabolic Pathway and Wax Biosynthesis.

The main challenge in the development of agrochemicals is the lack of new leads and/or targets. It is critical to discover new molecular targets and their corresponding ligands. YZK-C22, which contains a 1,2,3-thiadiazol-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole skeleton, is a fungicide lead compound with broad-spectrum fungicidal activity. Previous studies suggested that the [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole scaffold exhibited good antifungal activity. Inspired by this, a series of pyrrolo[2,3-d]thiazole derivatives were designed and synthesized through a bioisosteric strategy. Compounds C1, C9, and C20 were found to be more active against Rhizoctonia solani than the positive control YZK-C22. More than half of the target compounds provided favorable activity against Botrytis cinerea, where the EC50 values of compounds C4, C6, C8, C10, and C20 varied from 1.17 to 1.77 µg/mL. Surface plasmon resonance and molecular docking suggested that in vitro potent compounds C9 and C20 have a new mode of action instead of acting as pyruvate kinase inhibitors. Transcriptome analysis revealed that compound C20 can impact the tryptophan metabolic pathway, cutin, suberin, and wax biosynthesis of B. cinerea. Overall, pyrrolo[2,3-d]thiazole is discovered as a new fungicidal lead structure with a potential new mode of action for further exploration.

Anticancer Potential of Indole Phytoalexins and Their Analogues.

Indole phytoalexins, found in economically significant Cruciferae family plants, are synthesized in response to pathogen attacks or stress, serving as crucial components of plant defense mechanisms against bacterial and fungal infections. Furthermore, recent research indicates that these compounds hold promise for improving human health, particularly in terms of potential anticancer effects that have been observed in various studies. Since our last comprehensive overview in 2016 focusing on the antiproliferative effects of these substances, brassinin and camalexin have been the most extensively studied. This review analyses the multifaceted pharmacological effects of brassinin and camalexin, highlighting their anticancer potential. In this article, we also provide an overview of the antiproliferative activity of new synthetic analogs of indole phytoalexins, which were synthesized and tested at our university with the aim of enhancing efficacy compared to the parent compound.

Activation of PPARδ in bone marrow endothelial progenitor cells improves their hematopoiesis-supporting ability after myelosuppressive injury.

Dysfunctional bone marrow (BM) endothelial progenitor cells (EPCs) with high levels of reactive oxygen species (ROS) are responsible for defective hematopoiesis in poor graft function (PGF) patients with acute leukemia or myelodysplastic neoplasms post-allotransplant. However, the underlying mechanism by which BM EPCs regulate their intracellular ROS levels and the capacity to support hematopoiesis have not been well clarified. Herein, we demonstrated decreased levels of peroxisome proliferator-activated receptor delta (PPARδ), a lipid-activated nuclear receptor, in BM EPCs of PGF patients compared with those with good graft function (GGF). In vitro assays further identified that PPARδ knockdown contributed to reduced and dysfunctional BM EPCs, characterized by the impaired ability to support hematopoiesis, which were restored by PPARδ overexpression. Moreover, GW501516, an agonist of PPARδ, repaired the damaged BM EPCs triggered by 5-fluorouracil (5FU) in vitro and in vivo. Clinically, activation of PPARδ by GW501516 benefited the damaged BM EPCs from PGF patients or acute leukemia patients in complete remission (CR) post-chemotherapy. Mechanistically, we found that increased expression of NADPH oxidases (NOXs), the main ROS-generating enzymes, may lead to elevated ROS level in BM EPCs, and insufficient PPARδ may trigger BM EPC damage via ROS/p53 pathway. Collectively, we found that defective PPARδ contributes to BM EPC dysfunction, whereas activation of PPARδ in BM EPCs improves their hematopoiesis-supporting ability after myelosuppressive therapy, which may provide a potential therapeutic target not only for patients with leukemia but also for those with other cancers.

Unique aminothiazolyl coumarins as potential DNA and membrane disruptors towards Enterococcus faecalis.

Aminothiazolyl coumarins as potentially new antimicrobial agents were designed and synthesized in an effort to overcome drug resistance. Biological activity assay revealed that some target compounds exhibited significantly inhibitory efficiencies toward bacteria and fungi including drug-resistant pathogens. Especially, aminothiazolyl 7-propyl coumarin 8b and 4-dichlorobenzyl derivative 11b exhibited bactericidal potential (MBC/MIC = 2) toward clinically drug-resistant Enterococcus faecalis with low cytotoxicity to human lung adenocarcinoma A549 cells, rapidly bactericidal effects and no obvious bacterial resistance development against E. faecalis. The preliminary antibacterial action mechanism studies suggested that compound 11b was able to disturb E. faecalis membrane effectively, and interact with bacterial DNA isolated from resistant E. faecalis through noncovalent bonds to cleave DNA, thus inhibiting the growth of E. faecalis strain. Further molecular modeling indicated that compounds 8b and 11b could bind with SER-1084 and ASP-1083 residues of gyrase-DNA complex through hydrogen bonds and hydrophobic interactions. Moreover, compound 11b showed low hemolysis and in vivo toxicity. These findings of aminothiazolyl coumarins as unique structural scaffolds might hold a large promise for the treatments of drug-resistant bacterial infection.

Design and synthesis of novel thiazole-derivatives as potent ALK5 inhibitors.

TGF-ß is an immunosuppressive cytokine and plays a key role in progression of cancer by inducing immunosuppression in tumor microenvironment. Therefore, inhibition of TGF-ß signaling pathway may provide a potential therapeutic intervention in treating cancers. Herein, we report the discovery of a series of novel thiazole derivatives as potent inhibitors of ALK5, a serine-threonine kinase which is responsible for TGF-ß signal transduction. Compound 29b was identified as a potent inhibitor of ALK5 with an IC50 value of 3.7 nM with an excellent kinase selectivity.

Design, synthesis and biological evaluation of Thiazolo[3, 2-a]Pyrimidine derivatives as novel RNase H inhibitors.

Targeting Ribonuclease H (RNase H) has been considered a viable strategy for HIV therapy. In this study, a series of novel thiazolo[3, 2-a]pyrimidine derivatives were firstly designed and synthesized as potential inhibitors of HIV-1 RNase H. Among these compounds, A28 exhibited the most potent inhibition against HIV-1 RNase H with an IC50 value of 4.14 µM, which was about 5-fold increase in potency than the hit compound A1 (IC50 = 21.49 µM). To gain deeper insights into the structure-activity relationship (SAR), a CoMFA model was constructed to yield reasonable statistical results (q2 = 0.658 and R2 = 0.969). Results from magnesium ion chelation experiments and molecular docking studies revealed that these thiazolopyrimidine inhibitors may exert their inhibitory activity by binding to an allosteric site on RNase H at the interface between subunits p51 and p66. Furthermore, this analog demonstrated favorable physicochemical properties. Our findings provide valuable groundwork for further development of allosteric inhibitors targeting HIV-1 RNase H.

Activation and inhibition of the sweet taste receptor TAS1R2-TAS1R3 differentially affect glucose tolerance in humans.

The sweet taste receptor, TAS1R2-TAS1R3, is expressed in taste bud cells, where it conveys sweetness, and also in intestinal enteroendocrine cells, where it may facilitate glucose absorption and assimilation. In the present study, our objective was to determine whether TAS1R2-TAS1R3 influences glucose metabolism bidirectionally via hyperactivation with 5 mM sucralose (n = 12) and inhibition with 2 mM sodium lactisole (n = 10) in mixture with 75 g glucose loads during oral glucose tolerance tests (OGTTs) in healthy humans. Plasma glucose, insulin, and glucagon were measured before, during, and after OGTTs up to 120 minutes post-prandially. We also assessed individual participants' sweet taste responses to sucralose and their sensitivities to lactisole sweetness inhibition. The addition of sucralose to glucose elevated plasma insulin responses to the OGTT (F(1, 11) = 4.55, p = 0.056). Sucralose sweetness ratings were correlated with early increases in plasma glucose (R2 = 0.41, p<0.05), as well as increases in plasma insulin (R2 = 0.38, p<0.05) when sucralose was added to the OGTT (15 minute AUC). Sensitivity to lactisole sweetness inhibition was correlated with decreased plasma glucose (R2 = 0.84, p<0.01) when lactisole was added to the OGTT over the whole test (120 minute AUC). In summary, stimulation and inhibition of the TAS1R2-TAS1R3 receptor demonstrates that TAS1R2-TAS1R3 helps regulate glucose metabolism in humans and may have translational implications for metabolic disease risk.

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.

Design, synthesis and molecular modeling of novel D-ring substituted steroidal 4,5-dihydropyrazole thiazolinone derivatives as anti-inflammatory agents by inhibition of COX-2/iNOS production and down-regulation of NF-κB/MAPKs in LPS-induced RAW264.7 macrophage cells.

It has been reported that 4,5-dihydropyrazole and thiazole derivatives have many biological functions, especially in the aspect of anti-inflammation. According to the strategy of pharmacophore combination, we introduced thiazolinone and dihydropyrazole moiety into steroid skeleton to design and synthesize a novel series of D-ring substituted steroidal 4,5-dihydropyrazole thiazolinone derivatives, and assessed their in vitro anti-inflammatory profiles against Lipopolysaccharide (LPS)-induced inflammation in RAW 264.7 macrophage cells. The anti-inflammatory activities assay demonstrated that compound 12e was considered as the most effective anti-inflammatory drug, which suppressed the expression of pro-inflammatory mediators including nitric oxide (NO), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), it also dose-dependently inhibited the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in LPS-induced RAW 264.7 macrophage cells. Furthermore, the results of the Western blot analysis showed a correlation between the inhibition of the Nuclear factor-kappa B (NF-κB) and Mitogen-activated protein kinases (MAPKs) signaling pathways and the suppressive effects of compound 12e on pro-inflammatory cytokines. Molecular docking studies of compound 12e into the COX-2 protein receptor (PDB ID: 5IKQ) active site was performed to rationalize their COX-2 inhibitory potency. The results were found to be in line with the biological findings as they exerted more favorable interactions compared to that of dexamethasone (DXM), explaining their remarkable COX-2 inhibitory activity. The findings revealed that these candidates could be identified as potent anti-inflammatory agents, compound 12e could be a promising drug for the treatment of inflammatory diseases.

In Silico Analysis of the Ga3+/Fe3+ Competition for Binding the Iron-Scavenging Siderophores of P. aeruginosa-Implementation of Three Gallium-Based Complexes in the "Trojan Horse" Antibacterial Strategy.

The emergence of multidrug-resistant (MDR) microorganisms combined with the ever-draining antibiotic pipeline poses a disturbing and immensely growing public health challenge that requires a multidisciplinary approach and the application of novel therapies aimed at unconventional targets and/or applying innovative drug formulations. Hence, bacterial iron acquisition systems and bacterial Fe2+/3+-containing enzymes have been identified as a plausible target of great potential. The intriguing "Trojan horse" approach deprives microorganisms from the essential iron. Recently, gallium's potential in medicine as an iron mimicry species has attracted vast attention. Different Ga3+ formulations exhibit diverse effects upon entering the cell and thus supposedly have multiple targets. The aim of the current study is to specifically distinguish characteristics of great significance in regard to the initial gallium-based complex, allowing the alien cation to effectively compete with the native ferric ion for binding the siderophores pyochelin and pyoverdine secreted by the bacterium P. aeruginosa. Therefore, three gallium-based formulations were taken into consideration: the first-generation gallium nitrate, Ga(NO3)3, metabolized to Ga3+-hydrated forms, the second-generation gallium maltolate (tris(3-hydroxy-2-methyl-4-pyronato)gallium), and the experimentally proven Ga carrier in the bloodstream-the protein transferrin. We employed a reliable in silico approach based on DFT computations in order to understand the underlying biochemical processes that govern the Ga3+/Fe3+ rivalry for binding the two bacterial siderophores.

Did the prolonged residual efficacy of clothianidin products lead to a greater reduction in vector populations and subsequent malaria transmission compared to the shorter residual efficacy of pirimiphos-methyl?

BACKGROUND: The residual activity of a clothianidin + deltamethrin mixture and clothianidin alone in IRS covered more than the period of malaria transmission in northern Benin. The aim of this study was to show whether the prolonged residual efficacy of clothianidin-based products resulted in a greater reduction in vector populations and subsequent malaria transmission compared with the shorter residual efficacy of pirimiphos-methyl. METHODS: Human bait mosquito collections by local volunteers and pyrethrum spray collections were used in 6 communes under IRS monitoring and evaluation from 2019 to 2021. ELISA/CSP and species PCR tests were performed on Anopheles gambiae sensu lato (s.l.) to determine the infectivity rate and subspecies by commune and year. The decrease in biting rate, entomological inoculation rate, incidence, inhibition of blood feeding, resting density of An. gambiae s.l. were studied and compared between insecticides per commune. RESULTS: The An. gambiae complex was the major vector throughout the study area, acounting for 98.71% (19,660/19,917) of all Anopheles mosquitoes collected. Anopheles gambiae s.l. collected was lower inside treated houses (45.19%: 4,630/10,245) than outside (54.73%: 5,607/10,245) after IRS (p < 0.001). A significant decrease (p < 0.001) in the biting rate was observed after IRS in all departments except Donga in 2021 after IRS with clothianidin 50 WG. The impact of insecticides on EIR reduction was most noticeable with pirimiphos-methyl 300 CS, followed by the clothianidin + deltamethrin mixture and finally clothianidin 50 WG. A reduction in new cases of malaria was observed in 2020, the year of mass distribution of LLINs and IRS, as well as individual and collective protection measures linked to COVID-19. Anopheles gambiae s.l. blood-feeding rates and parous were high and similar for all insecticides in treated houses. CONCLUSION: To achieve the goal of zero malaria, the optimal choice of vector control tools plays an important role. Compared with pirimiphos-methyl, clothianidin-based insecticides induced a lower reductions in entomological indicators of malaria transmission.

Discovery and Mechanistic Studies of Dual-Target Hits for Carbonic Anhydrase IX and VEGFR-2 as Potential Agents for Solid Tumors: X-ray, In Vitro, In Vivo, and In Silico Investigations of Coumarin-Based Thiazoles.

A dual-targeting approach is predicted to yield better cancer therapy outcomes. Consequently, a series of coumarin-based thiazoles (5a-h, 6, and 7a-e) were designed and constructed as potential carbonic anhydrase (CA) and VEGFR-2 suppressors. The inhibitory actions of the target compounds were assessed against CA isoforms IX and VEGFR-2. The assay results showed that coumarin-based thiazoles 5a, 5d, and 5e can effectively inhibit both targets. 5a, 5d, and 5e cytotoxic effects were tested on pancreatic, breast, and prostate cancer cells (PANC1, MCF7, and PC3). Further mechanistic investigation disclosed the ability of 5e to interrupt the PANC1 cell progression in the S stage by triggering the apoptotic cascade, as seen by increased levels of caspases 3, 9, and BAX, alongside the Bcl-2 decline. Moreover, the in vivo efficacy of compound 5e as an antitumor agent was evaluated. Also, molecular docking and dynamics displayed distinctive interactions between 5e and CA IX and VEGFR-2 binding pockets.

The small conductance Ca2+-activated K+ channel activator GW542573X impairs hippocampal memory in C57BL/6J mice.

Small conductance Ca2+-activated K+ (SK) channels, expressed throughout the CNS, are comprised of SK1, SK2 and SK3 subunits, assembled as homotetrameric or heterotetrameric proteins. SK channels expressed somatically modulate the excitability of neurons by mediating the medium component of the afterhyperpolarization. Synaptic SK channels shape excitatory postsynaptic potentials and synaptic plasticity. Such SK-mediated effects on neuronal excitability and activity-dependent synaptic strength likely underlie the modulatory influence of SK channels on memory encoding. Converging evidence indicates that several forms of long-term memory are facilitated by administration of the SK channel blocker, apamin, and impaired by administration of the pan-SK channel activator, 1-EBIO, or by overexpression of the SK2 subunit. The selective knockdown of dendritic SK2 subunits facilitates memory to a similar extent as that observed after systemic apamin. SK1 subunits co-assemble with SK2; yet the functional significance of SK1 has not been clearly defined. Here, we examined the effects of GW542573X, a drug that activates SK1 containing SK channels, as well as SK2/3, on several forms of long-term memory in male C57BL/6J mice. Our results indicate that pre-training, but not post-training, systemic GW542573X impaired object memory and fear memory in mice tested 24 h after training. Pre-training direct bilateral infusion of GW542573X into the CA1 of hippocampus impaired object memory encoding. These data suggest that systemic GW542573X impairs long-term memory. These results add to growing evidence that SK2 subunit-, and SK1 subunit-, containing SK channels can regulate behaviorally triggered synaptic plasticity necessary for encoding hippocampal-dependent memory.