Different Modes Of Action Research Articles

Binding, Neutralization and Internalization of the Interleukin-13 Antibody, Lebrikizumab.

IL-13 is the primary upregulated cytokine in atopic dermatitis (AD) skin and is the pathogenic mediator driving AD pathophysiology. Lebrikizumab, tralokinumab and cendakimab are therapeutic monoclonal antibodies (mAb) that target IL-13. We undertook studies to compare in vitro binding affinities and cell-based functional activities of lebrikizumab, tralokinumab and cendakimab. Lebrikizumab bound IL-13 with higher affinity (as determined using surface plasma resonance) and slower off-rate. It was more potent in neutralizing IL-13-induced effects in STAT6 reporter and primary dermal fibroblast periostin secretion assays than either tralokinumab or cendakimab. Live imaging confocal microscopy was employed to determine the mAb effects on IL-13 internalization into cells via the decoy receptor IL-13Rα2, using A375 and HaCaT cells. The results showed that only the IL-13/lebrikizumab complex was internalized and co-localized with lysosomes, whereas IL-13/tralokinumab or IL-13/cendakimab complexes did not internalize. Lebrikizumab is a potent, neutralizing high-affinity antibody with a slow disassociation rate from IL-13. Additionally, lebrikizumab does not interfere with IL-13 clearance. Lebrikizumab has a different mode of action to both tralokinumab and cendakimab, possibly contributing to the clinical efficacy observed by lebrikizumab in Ph2b/3 AD studies.

Sensitivity of Puccinia triticina f. sp. tritici from China to Triadimefon and Resistance Risk Assessment.

Wheat leaf rust, caused by Puccinia triticina f. sp. tritici (Pt), is distributed widely in wheat-producing areas and results in serious yield losses worldwide. In China, leaf rust has been largely controlled with a demethylation inhibitor (DMI) fungicide, triadimefon. Although high levels of fungicide resistance in pathogens have been reported, no field failure of wheat leaf rust to DMI fungicides has been reported in China. A resistance risk assessment of triadimefon to Pt was investigated in the present study. The sensitivity of 197 Pt isolates across the country to triadimefon was determined, and the density distribution of EC50 values (concentration at which mycelial growth is inhibited by 50%) showed a continuous multimodal curve because of the extensive use of this fungicide in wheat production, with a mean value of 0.46 μg/ml. The majority of the tested Pt isolates were sensitive to triadimefon, whereas 10.2% developed varying degrees of resistance. Characterization of parasitic fitness revealed that the triadimefon-resistant isolates exhibited strong adaptive traits in urediniospore germination rate, latent period, sporulation intensity, and lesion expansion rate. No correlation was observed between triadimefon and tebuconazole and hexaconazole, which have the similar mode of action, or pyraclostrobin and flubeneteram, which have different modes of action. Overexpression of the target gene Cyp51 led to the triadimefon resistance of Pt. The risk of resistance to triadimefon in Pt may be low to moderate. This study provided important data for fungicide resistance risk management against wheat leaf rust.

The inhibitory activity of a new scorpion venom-derived antimicrobial peptide Hp1470 against Gram-positive bacteria

Antimicrobial peptides (AMPs) are a new type of antibiotic and target a variety of microbes, including antibiotic-resistant strains; thus, AMPs have attracted widespread interest. Scorpion venoms contain many bioactive peptides, including AMPs, and have become an important natural resource of peptide-based drugs. Here, the antibacterial peptide gene Hp1470 from the venom of the scorpion Heterometrus petersii was characterized, and its antibacterial activity was determined. The cDNA sequence of Hp1470 is 300 nt in length and contains an open reading frame (ORF) of 207 nt. The ORF was shown to encode 68 amino acid residues, including a signal peptide (23 aa), a mature peptide (13 aa), a C-terminal posttranslational processing signal (3 aa), and a propeptide (29 aa). Multiple sequence alignment results indicated that Hp1470 is an antibacterial peptide. The mature peptide Hp1470, which has a molecular mass of 1564.09 Da, was further chemically synthesized with a purity of greater than 95%. Antimicrobial assays showed that the synthesized Hp1470 exerted an inhibitory effect on Gram-positive bacteria and clinical drug-resistant strains, including PRSA and MRSA, but not Gram-negative bacteria. Hp1470 was further found to protect mice from MRSA infection, suggesting its potential application as an in vivo antimicrobial agent. Interestingly, Hp1470 only inhibited bacterial growth but did not kill bacteria, which was consistent with scanning electron microscopy results showing that Hp1470 did not lyse the cell membrane of Staphylococcus aureus. Our work provides a new direction for developing antibacterial agents with different modes of action from natural scorpion venoms.

Acetylcholinesterase inhibitors for autistic spectrum disorders.

Autism spectrum disorder (autism) is a neurodevelopmental condition characterised by impairments in social communication and interaction, plus restricted, repetitive patterns of behaviour and interests. Whilst some people embrace autism as part of their identity, others struggle with their difficulties, and some seek treatment. There are no current interventions that result in complete reduction of autism features. Acetylcholine is a neurotransmitter for the cholinergic system and has a role in attention, novelty seeking, and memory. Low levels of acetylcholine have been investigated as a potential contributor to autism symptomatology. Donepezil, galantamine, and rivastigmine (commonly referred to as acetylcholinesterase inhibitors) all inhibit acetylcholinesterase, and have slightly different modes of action and biological availability, so their effectiveness and side-effect profiles may vary. The effect of various acetylcholinesterase inhibitor on core autism features across the lifespan, and possible adverse effects, have not been thoroughly investigated. To evaluate the efficacy and harms of acetylcholinesterase inhibitors for people with the core features (social interaction, communication, and restrictive and repetitive behaviours) of autism. To assess the effects of acetylcholinesterase inhibitors on non-core features of autism. In November 2022, we searched CENTRAL, MEDLINE, Embase, eight other databases, and two trials registers. We also searched the reference lists of included studies and relevant reviews, and contacted authors of relevant studies. Randomised controlled trials (RCTs), comparing acetylcholinesterase inhibitors (e.g. galantamine, donepezil, or rivastigmine) of varying doses, delivered orally or via transdermal patch, either as monotherapy or adjunct therapy, with placebo. People of any age, with a clinical diagnosis of autism were eligible for inclusion. We used standard methodological procedures expected by Cochrane. Our primary outcomes were core features of autism and adverse effects. Secondary outcomes were language, irritability, hyperactivity, and general health and function. We used GRADE to assess certainty of evidence. We included two RCTs (74 participants). One study was conducted in Iran, the second in the USA, although exact location in the USA is unclear. Galantamine plus risperidone versus placebo plus risperidone One study compared the effects of galantamine plus risperidone to placebo plus risperidone (40 participants, aged 4 years to 12 years). Primary and secondary outcomes of interest were measured postintervention, using subscales of the Aberrant Behavior Checklist (score 0 to 3; higher scores = greater impairment). Very low-certainty evidence showed there was little to no difference between the two groups postintervention for social communication (mean difference (MD) -2.75, 95% confidence interval (CI) -5.88 to 0.38), and restricted and repetitive behaviour (MD -0.55, 95% CI -3.47 to 2.37). Overall autism features were not assessed. Adverse events may be higher in the galantamine plus risperidone group (75%) compared with the placebo plus risperidone group (35%): odds ratio 5.57, 95% CI 1.42 to 21.86, low-certainty evidence. No serious adverse events were reported. Low-certainty evidence showed a small difference in irritability (MD -3.50, 95% CI -6.39 to -0.61), with the galantamine plus risperidone group showing a greater decline on the irritability subscale than the placebo group postintervention. There was no evidence of a difference between the groups in hyperactivity postintervention (MD -5.20, 95% CI -10.51 to 0.11). General health and function were not assessed. Donepezil versus placebo One study compared donepezil to placebo (34 participants aged 8 years to 17 years). Primary outcomes of interest were measured postintervention, using subscales of the Modified Version of The Real Life Rating Scale (scored 0 to 3; higher scores = greater impairment). Very low-certainty evidence showed no evidence of group differences immediately postintervention in overall autism features (MD 0.07, 95% CI -0.19 to 0.33), or in the autism symptom domains of social communication (MD -0.02, 95% CI -0.34 to 0.30), and restricted and repetitive behaviours (MD 0.04, 95% CI -0.27 to 0.35). Significant adverse events leading to study withdrawal in at least one participant was implied in the data analysis section, but not explicitly reported. The evidence is very uncertain about the effect of donepezil, compared to placebo, on the secondary outcomes of interest, including irritability (MD 1.08, 95% CI -0.41 to 2.57), hyperactivity (MD 2.60, 95% CI 0.50 to 4.70), and general health and function (MD 0.03, 95% CI -0.48 to 0.54) postintervention. Across all analyses within this comparison, we judged the evidence to be very low-certainty due to high risk of bias, and very serious imprecision (results based on one small study with wide confidence intervals). The study narratively reported adverse events for the study as a whole, rather than by treatment group. Evidence about the effectiveness of acetylcholinesterase inhibitors as a medication to improve outcomes for autistic adults is lacking, and for autistic children is very uncertain. There is a need for more evidence of improvement in outcomes of relevance to clinical care, autistic people, and their families. There are a number of ongoing studies involving acetylcholinesterase inhibitors, and future updates of this review may add to the current evidence.

Combined and sequential therapies with anabolic and antiresorptive drugs in the management of patients with postmenopausal osteoporosis

The aim of osteoporosis therapy is to reduce the increased fracture risk associated with osteoporosis-related bone fragility. Prevention of fragility fracture relies on balanced nutrition, weight-bearing and balance-improving physical exercises, and pharmacological therapies. Among the latter, the antiresorptive drugs are the most widely used. Bone formation stimulators (anabolics) are second line-therapy with reversible effects once discontinued. For patients at very high risk or imminent risk of fracture, the question arises of whether combining drugs with different modes of action, or using sequential regimens with these agents, could achieve early, higher-magnitude antifracture efficacy than is obtained with usual antiresorptives, and sustained antifracture efficacy. As regards combination therapies, until we have clear evidence that using drugs together provides greater fracture risk reduction than monotherapy, these therapies are not recommended. Anabolic treatments like teriparatide, the amino-terminal fragment of parathyroid hormone, abaloparatide, an analog of parathyroid hormone related protein, and romosozumab, the monoclonal antibody against sclerostin, decrease vertebral and non-vertebral fracture risk and are more efficacious in fracture risk reduction than antiresorptives, as shown in head-to-head trials. However, an anabolic agent should be followed by an antiresorptive drug to maintain and even further increase its antifracture efficacy, which is otherwise rapidly reversible. Because of their early, high-magnitude and sustained antifracture efficacy, such sequential regimens should become the standard of care for patients at very high or imminent risk of fracture.

Natural therapeutics for cancer treatment: success, challenges, and prospect

Cancer is a terrifying disease that has become one of the world’s most challenging health concerns, necessitating a proactive approach to its treatment. Nature is a rich source of new chemical entities and a promising avenue for cancer research. Because of their different modes of action on target events in many ways, nature-derived chemicals are considered good possibilities for anticancer drug development. The current review article highlights recent breakthroughs in cancer therapeutics, including natural therapeutic molecules and their mechanisms of action against cancer treatment, as well as their limits, challenges, and prospect. For the review, article data have been collected from previously studied and published research reports, clinical evaluations, case studies, and clinical statistical data generated by scientific research organizations of repute. The chemical structures have been drawn using computational software (chemsketch). The development of promising candidates that can prevent or reduce the proliferation of cancer cells without causing adverse effects from these therapeutics is now underway. Further, nature-derived products are a game-changer because they are simple, safer, environmentally friendly, low-cost, quick, and less toxic than traditional treatment techniques. However, many bioactive chemicals and their analogs have been discovered as possible anticancer treatment options. In the review, the potent therapeutics phytochemicals derived from nature with their tremendous anticancer effects with limitations and prospects have been studied and analyzed based on previously published articles and reports.

Physicochemical properties of pressure moisture treated (PMT) and heat moisture treated (HMT) starches

Physicochemical properties of pressure moisture treated (PMT, 550 MPa, 10 min) and heat moisture treated (HMT, 100 °C, 10 h) starches were investigated. Effects of PMT and HMT were different depending on starch type. PMT starches showed dramatic changes in moisture sorption isotherm, pasting properties, thermal characteristics, solubility and swelling power (at 90 °C), and in vitro digestibility. The most dramatic difference between PMT and HMT starches was amylopectin melting transition, i.e., broadening in PMT and shift to high temperature in HMT starches. Moreover, B- and C-type starches revealed the more increase in amylopectin melting enthalpy than A-type starch. Both PMT and HMT did not increase the crystallinity but reorganized the amorphous area to compact, resulting in lower rapidly digestible starch and higher slowly digestible starch than those of native starches. Consequently, PMT changed the digestibility and physicochemical properties of starches with different modes of action compared with HMT.

Recombinant glutathione transferases from flufenacet-resistant black-grass (Alopecurus myosuroides Huds.) form different flufenacet metabolites and differ in their interaction with pre- and post-emergence herbicides.

Black-grass (Alopecurus myosuroides Huds.) has become a problematic weed in cereals in Europe. Besides resistance to post-emergent herbicides becoming increasingly widespread, enhanced metabolism of inhibitors of the synthesis of very-long-chain fatty acids (VLCFAs), such as flufenacet, is evolving. Yet, cross-resistance patterns and evolution of this resistance remains poorly understood. The cDNA sequences of five glutathione transferases (GSTs) upregulated in flufenacet resistant black-grass were identified and used for recombinant protein expression. Moderate to slow detoxification of flufenacet was verified for all candidate GSTs expressed in E. coli, and the most active protein produced flufenacet-alcohol instead of a glutathione conjugate, in the presence of reduced glutathione (GSH). Moreover, cross-resistance to other VLCFA-inhibitors e.g., acetochlor and pyroxasulfone and the ACCase inhibitor fenoxaprop was verified in vitro. Various other herbicides of different modes of action including VLCFA-inhibitors were not detoxified by the candidate GSTs. As several in planta upregulated GSTs detoxified flufenacet in vitro, the shift in sensitivity observed in black-grass populations, is likely a result of an additive effect. The polygenic character and the relatively low turnover rate of the individual GSTs may explain the slow evolution of flufenacet resistance. In addition, flufenacet resistance was accompanied by cross-resistance with some, but not all, herbicides of the same mode of action, and furthermore to the ACCase inhibitor fenoxaprop-ethyl. Hence, not only the rotation of herbicide modes of action, but also of individual active ingredients is important for resistance management. © 2023 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Endophytic actinobacteria from wild medicinal plants are a natural source of insecticide to control the African cotton leafworm (Spodoptera littoralis)

Insecticide resistance in agricultural pests has prompted the need to discover novel compounds with new modes of action. We investigated the potency of secondary metabolites from seventy endophytic actinobacteria against laboratory and field strains of Spodoptera littoralis (fourth instar), comparable to the bioinsecticide spinetoram (Radiant SC 12%). Endophytes from Artemisia herba-alba and A. judaica were highly effective. Chemical profiling of the most potent metabolite of the strain Streptomyces sp. ES2 was investigated using LC-QTOF-MS-MS technique, and the activity was validated through molecular docking studies. Metabolic extracts from actinobacteria belonging to Streptomyces, Nocardioides, and Pseudonocardia showed immediate and latent death to the Spodoptera littoralis fourth instar larvae. The metabolite from strain ES2 has shown the most promising and significant histopathological and inhibitory effects on the fourth instar larvae. ES2 metabolite caused lesions in the body wall cuticle, indicating a different mode of action than that of Radiant. Chemical profiling of ES2 showed the presence of cyromazine (molt inhibitor), 4-nitrophenol, and diazinon as key constituents. In conclusion, these findings suggest that secondary metabolites from endophytic actinobacteria inhabiting wild medicinal plants can be a sustainable source for promising natural biocontrol agents. This is the first illustration of the insecticidal activity of Artemisia spp. microbiome, and natural cyromazine synthesis by actinobacteria.

Axons will not be silenced! A balancing act of attractive receptors

Axons crossing the CNS midline regulate their responsiveness to both attractive and repulsive cues. In this issue, Dailey-Krempel etal. find different modes of action for DCC isoforms and uncover evidence against the silencing model of axon guidance.

Within-Season Shift in Fungicide Sensitivity Profiles of Pseudoperonospora cubensis Populations in Response to Chemical Control.

Cucurbit downy mildew, caused by Pseudoperonospora cubensis, is an important disease affecting cucurbits worldwide. Chemical control is an effective method for disease control but P. cubensis has a high risk for developing resistance to fungicides. Alternating fungicides with different modes of action is recommended to avoid an increase of resistant subpopulations. Thus, this study was conducted to establish shifts in the sensitivity profiles of P. cubensis isolates during the growing season, wherein chlorothalonil was applied in alternation with either cymoxanil, fluopicolide, or propamocarb in field experiments conducted from 2018 to 2020 at Rocky Mount, NC and in 2018 and 2020 at Charleston, SC. The sensitivity of baseline isolates sampled early in the season or exposed isolates sampled late in the season to these single-site fungicides was determined using a detached-leaf assay, where tested isolates were classified as sensitive or resistant based on the relative disease severity. Based on the Kruskal-Wallis test, the distribution profile of relative disease severity among baseline and exposed isolates was significantly different where chlorothalonil was alternated with fluopicolide (χ2 = 10.82; P = 0.001) but not with cymoxanil (χ2 = 1.39; P = 0.238) or propamocarb (χ2 = 2.37; P = 0.412). Although there was a directional selection toward resistance for isolates sampled from plots that were treated with fluopicolide or propamocarb alternated with chlorothalonil during a growing season, a significant shift in fungicide sensitivity distribution based on combined data were observed for fluopicolide (χ2 = 8.25; P = 0.004) but not propamocarb (χ2 = 1.05; P = 0.461). Baseline and exposed isolates sampled from the cymoxanil-treated plots were all resistant to this fungicide and there was no significant shift in their fungicide sensitivity profile during a growing season (χ2 = 0.06; P = 1.000). These results indicate that a shift toward reduced sensitivity in P. cubensis can occur during a growing season and the efficacy of fluopicolide is likely to decrease as the frequency of the less sensitive subpopulations increases during a production season. The resultant effect on disease severity and selection of an insensitive subpopulation may accelerate the development of resistance to propamocarb in the southeastern United States.

Identification, expression profiles and involvement in insecticides tolerance and detoxification of carboxylesterase genes in Bactrocera dorsalis

Carboxylesterases (CarEs) are a multifunctional superfamily of enzymes and play an important role in detoxification of various insecticides in insects. The oriental fruit fly, Bactrocera dorsalis, is one of the most destructive agricultural pests and has developed different degrees of resistance to organophosphates in field. However, the involvement of BdCarEs in tolerance or resistance to other alternative insecticides are still unclear. In the present study, 33 BdCarEs genes were identified based on the genome database of B. dorsalis. Phylogenetic analysis demonstrated that they were classified into nine clades, with abundance of α-esterases. Meanwhile, the sequence characterization and the chromosome distribution were also analyzed. The spatiotemporal expression analysis of BdCarEs genes suggested that the diversity of potential function in different physiological processes. With the exception of BdCarE21, all BdCarEs genes responded to at least one insecticide exposure, and BdCarE20 was found to be up-regulated after exposure to all five tested insecticides individually. Eight BdCarEs genes were overexpressed in MR strain when compared to that in SS strain. Subsequently, knockdown the expression of representative BdCarEs genes significantly increased the susceptibility of the oriental fruit fly to corresponding insecticides, which indicated that the tested BdCarEs genes contributed to one or multiple insecticide detoxification. These findings provide valuable insights into the potential role in respond to tolerance or resistance to insecticides with different mode of action, and will facilitate development of efficiency management strategy for B. dorsalis.

PROTACs in the Management of Prostate Cancer.

Cancer treatments with targeted therapy have gained immense interest due to their low levels of toxicity and high selectivity. Proteolysis-Targeting Chimeras (PROTACs) have drawn special attention in the development of cancer therapeutics owing to their unique mechanism of action, their ability to target undruggable proteins, and their focused target engagement. PROTACs selectively degrade the target protein through the ubiquitin-proteasome system, which describes a different mode of action compared to conventional small-molecule inhibitors or even antibodies. Among different cancer types, prostate cancer (PC) is the most prevalent non-cutaneous cancer in men. Genetic alterations and the overexpression of several genes, such as FOXA1, AR, PTEN, RB1, TP53, etc., suppress the immune response, resulting in drug resistance to conventional drugs in prostate cancer. Since the progression of ARV-110 (PROTAC for PC) into clinical phases, the focus of research has quickly shifted to protein degraders targeting prostate cancer. The present review highlights an overview of PROTACs in prostate cancer and their superiority over conventional inhibitors. We also delve into the underlying pathophysiology of the disease and explain the structural design and linkerology strategies for PROTAC molecules. Additionally, we touch on the various targets for PROTAC in prostate cancer, including the androgen receptor (AR) and other critical oncoproteins, and discuss the future prospects and challenges in this field.

Potential Effects of Geraniol on Cancer and Inflammation-Related Diseases: A Review of the Recent Research Findings.

Geraniol (GNL), a natural monoterpene, is found in many essential oils of fruits, vegetables, and herbs, including lavender, citronella, lemongrass, and other medicinal and aromatic plants. GNL is commonly used by the cosmetic and food industries and has shown a wide spectrum of pharmacological activities including anti-inflammatory, anticancer, antimicrobial, antioxidant, and neuroprotective activities. It represents a potential anti-inflammatory agent and a promising cancer chemopreventive agent, as it has been found to be effective against a broad range of cancers, including colon, prostate, breast, lung, skin, kidney, liver, and pancreatic cancer. Moreover, GNL scavenges free radicals and preserves the activity of antioxidant enzymes. In addition, GNL induces apoptosis and cell cycle arrest, modulates multiple molecular targets, including p53 and STAT3, activates caspases, and modulates inflammation via transcriptional regulation. In the present study, different modes of action are described for GNL's activity against cancer and inflammatory diseases. This compound protects various antioxidant enzymes, such as catalase, glutathione-S-transferase, and glutathione peroxidase. Experiments using allergic encephalomyelitis, diabetes, asthma, and carcinogenesis models showed that GNL treatment had beneficial effects with low toxicity. GNL has been shown to be effective in animal models and tumor cell lines, but there have not been any clinical studies carried out for it. The aim of the present review is to provide updated data on the potential effects of GNL on cancer and inflammation, and to enhance our understanding of molecular targets, involved pathways, and the possible use of GNL for clinical studies and therapeutic purposes in the treatment of cancer and inflammation-related diseases.

Evaluating the Sublethal Effects of Origanum vulgare Essential Oil and Carvacrol on the Biological Characteristics of Culex pipiens biotype molestus (Diptera: Culicidae).

Culex pipiens is a mosquito species complex spread worldwide that poses a serious threat to human health as the primary vector of West Nile virus. Its control is mainly based on larvicidal applications with synthetic insecticides on mosquito breeding sites. However, the excessive use of synthetic larvicides may provoke mosquito resistance issues and negative side effects to the aquatic environment and human health. Plant-derived essential oils, including those from the Lamiaceae family, can be eco-friendly alternative larvicidal agents causing acute larval toxicity and/or growth inhibitory effects on the developmental stages of mosquitoes through different modes of action. In the current laboratory study, we evaluated the sublethal effects of carvacrol-rich oregano essential oil and pure carvacrol on Cx. pipiens biotype molestus, the autogenous member of the Cx. pipiens species complex, after the exposure of 3rd-4th instar larvae to LC50 concentrations. The short-term (24 h) larvicidal treatment with the sublethal concentrations of both tested materials exhibited an acute lethal effect on the exposed larvae as well as significant delayed mortality for surviving larvae and pupae. Larvicidal treatment with carvacrol reduced the longevity of the emerged males. In addition, the morphological abnormalities that were observed at the larval and pupal stage along with failed adult emergence indicate the potential growth inhibitory properties of the tested bioinsecticides. Our findings suggest that carvacrol and carvacrol-rich oregano oil are effective plant-based larvicides at doses lower than the acute lethal ones, thus promoting an environmentally friendly and more affordable perspective for their use against the WNV vector Cx. pipiens biotype molestus.

Organic photoredox catalysts: tuning the operating mechanisms in the degradation of pollutants

Abstract Photocatalysis is an emerging area of chemistry that takes advantage of light as the primary source of energy to carry out chemical transformations. In this context, organic photocatalysts appear as an alternative that has proven to be efficient in treating polluted effluents. Although organic photocatalysts are not able to generate hydroxyl radical, their photoactivated excited states generated using visible light can act as strong oxidants in most cases. In fact, pollutant photooxidation can be produced from an initial electron transfer between an excited state of an organic photocatalyst and the contaminant, generating their respective radical anion and cation (Type I mechanism). However, as most of the organic photocatalysts are able to generate singlet oxygen, pollutant degradation can also be initiated from this oxidative species (Type II mechanism). Moreover, the heterogenization of the photocatalysts seems the straightforward step to boost photostability and facilitate recovery after the reaction. In the present review, we chronicle our research progress and how interestingly, it cannot be assumed that the main reaction pathways of a photocatalyst are the same under homogeneous conditions as in heterogeneous media. Herein we have selected Rose Bengal (RB), Riboflavin (RF), and a perylene diimide derivative (PDI) to illustrate the different modes of action of these organic photocatalysts under homogeneous/heterogeneous conditions.

Clinically relevant glioblastoma patient-derived xenograft models to guide drug development and identify molecular signatures.

Glioblastoma (GBM) heterogeneity, aggressiveness and infiltrative growth drastically limit success of current standard of care drugs and efficacy of various new therapeutic approaches. There is a need for new therapies and models reflecting the complex biology of these tumors to analyze the molecular mechanisms of tumor formation and resistance, as well as to identify new therapeutic targets. We established and screened a panel of 26 patient-derived subcutaneous (s.c.) xenograft (PDX) GBM models on immunodeficient mice, of which 15 were also established as orthotopic models. Sensitivity toward a drug panel, selected for their different modes of action, was determined. Best treatment responses were observed for standard of care temozolomide, irinotecan and bevacizumab. Matching orthotopic models frequently show reduced sensitivity, as the blood-brain barrier limits crossing of the drugs to the GBM. Molecular characterization of 23 PDX identified all of them as IDH-wt (R132) with frequent mutations in EGFR, TP53, FAT1, and within the PI3K/Akt/mTOR pathway. Their expression profiles resemble proposed molecular GBM subtypes mesenchymal, proneural and classical, with pronounced clustering for gene sets related to angiogenesis and MAPK signaling. Subsequent gene set enrichment analysis identified hallmark gene sets of hypoxia and mTORC1 signaling as enriched in temozolomide resistant PDX. In models sensitive for mTOR inhibitor everolimus, hypoxia-related gene sets reactive oxygen species pathway and angiogenesis were enriched. Our results highlight how our platform of s.c. GBM PDX can reflect the complex, heterogeneous biology of GBM. Combined with transcriptome analyses, it is a valuable tool in identification of molecular signatures correlating with monitored responses. Available matching orthotopic PDX models can be used to assess the impact of the tumor microenvironment and blood-brain barrier on efficacy. Our GBM PDX panel therefore represents a valuable platform for screening regarding molecular markers and pharmacologically active drugs, as well as optimizing delivery of active drugs to the tumor.

Herbicidal ionic liquids containing double or triple anions as a new potential tool for weed control including herbicide-resistant biotypes

Herbicides are commonly used in modern agriculture for the control of unwanted plants. Contemporary expectations regarding agrochemicals emphasize the need to ensure high effectiveness and reduce side effects. Multicomponent herbicidal ionic liquids possess these features. In planning the syntheses of herbicidal ionic liquids (HILs), we took into account ensuring high activity against weeds using reduced doses of active substances and the problem of controlling herbicide-resistant weeds.Eight new double-anion and eight new triple-anion HILs were synthesized. All obtained HILs contained methyl dodecylbetainate cation and herbicidal anions belonging to both sulfonylurea and auxin-like groups of active substances in a single compound. The new HILs were tested under greenhouse and field conditions and they showed excellent efficacy against target dicotyledonous weeds. Some compounds showed very good surface properties, which are desirable for foliar application to plants. Moreover, HILs with three herbicidal anions (iodosulfuron or metsulfuron + 2,4-D + clopyralid) were very effective against cornflower biotype resistant to acetolactate synthase inhibitors.Our research indicate that herbicidal ionic liquids containing a cation of natural origin and herbicidal anions characterized by a different mode of action in a single compound are a potential new tool for weed management. The use of multicomponent herbicidal ionic liquids enables effective weed control with lower doses of the active ingredient.

Perinatal exposure to the fungicide ketoconazole alters hypothalamic control of puberty in female rats.

Estrogenic endocrine disrupting chemicals (EDCs) such as diethylstilbestrol (DES) are known to alter the timing of puberty onset and reproductive function in females. Accumulating evidence suggests that steroid synthesis inhibitors such as ketoconazole (KTZ) or phthalates may also affect female reproductive health, however their mode of action is poorly understood. Because hypothalamic activity is very sensitive to sex steroids, we aimed at determining whether and how EDCs with different mode of action can alter the hypothalamic transcriptome and GnRH release in female rats. Female rats were exposed to KTZ or DES during perinatal (DES 3-6-12μg/kg.d; KTZ 3-6-12mg/kg.d), pubertal or adult periods (DES 3-12-48μg/kg.d; KTZ 3-12-48mg/kg.d). Ex vivo study of GnRH pulsatility revealed that perinatal exposure to the highest doses of KTZ and DES delayed maturation of GnRH secretion before puberty, whereas pubertal or adult exposure had no effect on GnRH pulsatility. Hypothalamic transcriptome, studied by RNAsequencing in the preoptic area and in the mediobasal hypothalamus, was found to be very sensitive to perinatal exposure to all doses of KTZ before puberty with effects persisting until adulthood. Bioinformatic analysis with Ingenuity Pathway Analysis predicted "Creb signaling in Neurons" and "IGF-1 signaling" among the most downregulated pathways by all doses of KTZ and DES before puberty, and "PPARg" as a common upstream regulator driving gene expression changes. Deeper screening ofRNAseq datasets indicated that a high number of genes regulating the activity of the extrinsic GnRH pulse generator were consistently affected by all the doses of DES and KTZ before puberty. Several, including MKRN3, DNMT3 or Cbx7, showed similar alterations in expression at adulthood. nRH secretion and the hypothalamic transcriptome are highly sensitive to perinatal exposure to both DES and KTZ. The identified pathways should be exploredfurther to identify biomarkers for future testing strategies for EDC identification and when enhancing the current standard information requirements in regulation.

Efficacy of Selected Insecticides in Combination with Economic Thresholds in Managing Fall Armyworm (Lepidoptera: Noctuidae) Larvae in Maize Grown in Mexico

Abstract In Mexico, conventional insecticides are the main tools used to manage the fall armyworm, Spodoptera frugiperda (J.E. Smith) (Lepidoptera: Noctuidae), in maize, Zea mays L. This scenario results in the need to continually assess the biological efficacy of insecticides used to combat this pest. In this study, we evaluated the efficacy of insecticides with different modes of action in diverse locations under different levels of S. frugiperda larval infestation. The insecticides evaluated decreased larval density per plant to levels below the recommended economic threshold (ET) of 2.0 larvae per 10 plants (0.2/plant), resulting in decreased levels of damage to the plant whorl. When applied at infestation levels below the ET, larval numbers remained below the ET for at least 7–14 d after application. In contrast, when applied with infestation levels above the recommended ET, the performance of some insecticides in terms of effectively reducing larval density decreased. We, however, found that Coragen® (chlorantraniliprole; FMC Agroquímica de México), Clavis® (thiodicarb + triflumuron; Bayer de México), and Pleo® 50 EC (pyridalyl; Valent de México) can be used under these conditions to provide adequate protection up to 21 d after application. The information obtained in our experiments confirms the need to adjust the current ET depending on the type of compound to be used, since the insecticides used performed more efficiently and for a long time at densities lower than 2.0 larvae per 10 plants.