Putative Mechanisms Of Action Research Articles

Celastrol: A Potential Natural Lead Molecule for New Drug Design, Development and Therapy for Memory Impairment.

Celastrol is a naturally occurring chemical isolated from Tripterygium wilfordii Hook. f., root extracts widely known for their neuroprotective properties. In this review, we focus on the efficacy of celastrol in mitigating memory impairment (MI) in both in vivo and in vitro models. Scopus, PubMed and Web of Science databases were utilised to locate pertinent literatures that explore the effects of celastrol in the brain, including its pharmacokinetics, bioavailability, behavioral effects and some of the putative mechanisms of action on memory in many MI models. To date, preclinical studies strongly suggest that celastrol is highly effective in enhancing the cognitive performance of MI animal models, particularly in the memory domain, including spatial, recognition, retention and reference memories, via reduction in oxidative stress and attenuation of neuro-inflammation, among others. This review also emphasised the challenges and potential associated enhancement of medication delivery for MI treatment. Additionally, the potential structural alterations and derivatives of celastrol in enhancing its physicochemical and drug-likeness qualities are examined. The current review demonstrated that celastrol can improve cognitive performance and mitigate MI in several preclinical investigations, highlighting its potential as a natural lead molecule for the design and development of a novel neuroprotective medication.

Excitatory synchronization of rat hippocampal interneurons during network activation in vitro.

Hippocampal interneurons (INs) are known to synchronize their electrical activity via mechanisms, which are poorly defined due to immense complexity of neural tissue but seem to depend on local cell interactions and intensity of network activity. Here, synchronization of INs was studied using paired patch-clamp recordings in a simplified culture model with intact glutamate transmission. The level of network activity was moderately elevated by field electric stimulation, which is probably an analogue of afferent processing in situ. Even in baseline conditions, ∼45% of spontaneous inhibitory postsynaptic currents (sIPSCs) resulting from firing of individual presynaptic INs coincided between cells within ±1 ms due to simple divergence of inhibitory axons. Brief network activation induced an appearance of 'hypersynchronous' (∼80%) population sIPSCs occurring in response to coherent discharges of several INs with jitter ±4 ms. Notably, population sIPSCs were preceded by transient inward currents (TICs). Those were excitatory events capable to synchronize firing of INs, in this respect being reminiscent of so-called fast prepotentials observed in studies on pyramidal neurons. TICs also had network properties consisting of heterogeneous components: glutamate currents, local axonal and dendritic spikelets, and coupling electrotonic currents likely via gap junctions; putative excitatory action of synaptic gamma-aminobutyric acid (GABA) was not involved. The appearance of population excitatory-inhibitory sequences could be initiated and reproduced by firing of a single excitatory cell reciprocally connected with one IN. Our data demonstrate that synchronization of INs is initiated and dominated by glutamatergic mechanisms, which recruit, in a whole-sale manner, into supporting action other excitatory means existing in a given neural system.

Soluble Klotho protects against glomerular injury through regulation of ER stress response

αKlotho (Klotho) has well established renoprotective effects; however, the molecular pathways mediating its glomerular protection remain incompletely understood. Recent studies have reported that Klotho is expressed in podocytes and protects glomeruli through auto- and paracrine effects. Here, we examined renal expression of Klotho in detail and explored its protective effects in podocyte-specific Klotho knockout mice, and by overexpressing human Klotho in podocytes and hepatocytes. We demonstrate that Klotho is not significantly expressed in podocytes, and transgenic mice with either a targeted deletion or overexpression of Klotho in podocytes lack a glomerular phenotype and have no altered susceptibility to glomerular injury. In contrast, mice with hepatocyte-specific overexpression of Klotho have high circulating levels of soluble Klotho, and when challenged with nephrotoxic serum have less albuminuria and less severe kidney injury compared to wildtype mice. RNA-seq analysis suggests an adaptive response to increased endoplasmic reticulum stress as a putative mechanism of action. To evaluate the clinical relevance of our findings, the results were validated in patients with diabetic nephropathy, and in precision cut kidney slices from human nephrectomies. Together, our data reveal that the glomeruloprotective effects of Klotho is mediated via endocrine actions, which increases its therapeutic potential for patients with glomerular diseases.

Identification of potential biological target for trypanocidal sesquiterpene lactones derivatives

Sesquiterpene lactones are natural products of the Asteraceae family that have shown trypanocidal activity against Trypanosoma cruzi, even exceeding the effectiveness of drugs used in the treatment of American trypanosomiasis. However, there is no agreement on their mechanism of action and their specificity to interact with parasite proteins. For this reason, we aimed to find biological targets that can interact with these compounds by reverse virtual screening with ligand pharmacophores and putative binding sites and the use of bioinformatic databases. Therefore, 41 possible biological targets were found, and four of them (with crystallized proteins), interfering directly or indirectly in the trypanosomatid redox system, were studied in detail. As a first approach, we focused on the study of trypanothione reductase, and protein-ligand interaction fingerprint analyses were performed to find binding site determinants that promote a possible inhibition of the enzyme. This study contributes to the understanding of one of the putative mechanisms of action of sesquiterpene lactones on one of the numerous suggested targets.Communicated by Ramaswamy H. Sarma

Molecular Signatures of the Eagle Effect Induced by the Artificial Siderophore Conjugate LP-600 in E. coli.

Achieving cellular uptake is a central challenge for novel antibiotics targeting Gram-negative bacterial pathogens. One strategy is to hijack the bacterial iron transport system by siderophore-antibiotic conjugates that are actively imported into the cell. This was realized with the MECAM-ampicillin conjugate LP-600 we recently reported that was highly active against E. coli. In the present study, we investigate a paradoxical regrowth of E. coli upon treatment of LP-600 at concentrations 16-32 times above the minimum inhibitory concentration (MIC). The phenomenon, coined "Eagle-effect" in other systems, was not due to resistance formation, and it occurred for the siderophore conjugate but not for free ampicillin. To investigate the molecular imprint of the Eagle effect, a combined transcriptome and untargeted metabolome analysis was conducted. LP-600 induced the expression of genes involved in iron acquisition, SOS response, and the e14 prophage upon regrowth conditions. The Eagle effect was diminished in the presence of sulbactam, which we ascribe to a putative synergistic antibiotic action but not to β-lactamase inhibition. The study highlights the relevance of the Eagle effect for siderophore conjugates. Through the first systematic -omics investigations, it also demonstrates that the Eagle effect manifests not only in a paradoxical growth but also in unique gene expression and metabolite profiles.

LC-ESI-MS phenolic contents assessment, antioxidant, and protective ability of Punica granatum root bark extract against ethanol-induced gastric ulcer in rats: in silico H+, K+-ATPase inhibitory pathway study.

The objectives of the current study were to evaluate the Punica granatum root bark extract's (PGE) antioxidant and gastroprotective activities against ethanol-induced gastric ulcers in Wistar rats and to elucidate the putative mechanism of action using in silico analysis. The PGE phytochemical study shows high levels of phenolics, flavonoids, tannins, and polysaccharides. In vitro, the PGE was more effective at scavenging hydroxyl radicals than quercetin and had lower ferric reducing activity than catechin. In vivo, it was revealed that pretreatment of ethanol-ulcerated rats with PGE at oral doses of 100, 200, and 400mg/kg b.w. offered a dose-dependent shield against ethanol-induced ulcers when compared to Omeprazole (20mg/kg b.w.) by preventing the development of deep ulcer lesions, lowering gastric juice output and pH rises, boosting gastric mucus production and antioxidant enzyme levels, and attenuating malondialdehyde and myeloperoxidase contents. Moreover, the liquid chromatography-mass spectrometry analysis of PGE identified 5 phenolic acids and 4 flavonoids, which revealed an in silico high oral bioavailability, drug-likenesses, and good binding affinities and thus inhibitory effects on the gastric H+, K+-ATPase enzyme. PGE may have synergistic antioxidant, anti-inflammatory, and H+, K+-proton pump inhibitory actions that contribute to its antiulcer efficacy.

Clofazimine for the treatment of tuberculosis.

Shorter (6-9months), fully oral regimens containing new and repurposed drugs are now the first-choice option for the treatment of drug-resistant tuberculosis (DR-TB). Clofazimine, long used in the treatment of leprosy, is one such repurposed drug that has become a cornerstone of DR-TB treatment and ongoing trials are exploring novel, shorter clofazimine-containing regimens for drug-resistant as well as drug-susceptible tuberculosis. Clofazimine's repurposing was informed by evidence of potent activity against DR-TB strains in vitro and in mice and a treatment-shortening effect in DR-TB patients as part of a multidrug regimen. Clofazimine entered clinical use in the 1950s without the rigorous safety and pharmacokinetic evaluation which is part of modern drug development and current dosing is not evidence-based. Recent studies have begun to characterize clofazimine's exposure-response relationship for safety and efficacy in populations with TB. Despite being better tolerated than some other second-line TB drugs, the extent and impact of adverse effects including skin discolouration and cardiotoxicity are not well understood and together with emergent resistance, may undermine clofazimine use in DR-TB programmes. Furthermore, clofazimine's precise mechanism of action is not well established, as is the genetic basis of clofazimine resistance. In this narrative review, we present an overview of the evidence base underpinning the use and limitations of clofazimine as an antituberculosis drug and discuss advances in the understanding of clofazimine pharmacokinetics, toxicity, and resistance. The unusual pharmacokinetic properties of clofazimine and how these relate to its putative mechanism of action, antituberculosis activity, dosing considerations and adverse effects are highlighted. Finally, we discuss the development of novel riminophenazine analogues as antituberculosis drugs.

Discovery and characterization of antidepressant mediated activation of 5-HT1E and 5-HT1F receptors.

Of the 13 serotonin (5-hydroxytryptamine, 5-HT) receptors in humans, the 5-HT1E and 5-HT1F subtypes (1E and 1F, respectively), are understudied G protein-coupled receptors with high sequence identity among themselves, and to a lesser degree, the other 5-HT1 receptor subtypes. While 1F is a validated target for anti-migraine drugs, the physiological function of 1E remains unknown due to a lack of rodent orthologs and selective compounds. To expand the repertoire of potential chemical scaffolds that could be used to generate 1E- and 1F-selective compounds, we screened a small library of medications and research compounds with known activities at various aminergic receptors. This screen led us to discover that a series of clinically-used drugs featuring a tetracyclic scaffold are high-affinity agonists at 1E and 1F, while they have generally been reported as pan-aminergic antagonists. Seeking to elucidate their mechanisms, we determined structures of 5-HT1E complexed with Gi1 and bound by two of these drugs at 3.31 and 3.28 Å. These structures reveal unambiguous binding poses that demonstrate key interactions with binding pocket residues that confer high affinity in a ligand-specific fashion, and lay the stage for the generation of 1E-specific agonists for physiological studies. Additionally, our functional work offers a putative mechanism of action for the reported anti-migraine activities of the medications characterized in this study.

Past and current drug repurposing clinical trials to treat cognition in methamphetamine use: a scoping review of pharmacotherapy candidates

Globally, methamphetamine is one of the most widely used illicit substances. Despite this, there are no Food and Drug Administration (FDA)-approved pharmacotherapies for treating methamphetamine use disorder. Accumulating evidence suggests consistent cognitive impairments in people with methamphetamine use disorder, which are also associated with neural dysfunction. Importantly, improving cognition may be highly beneficial in reducing methamphetamine use. Indeed, there are medications that have been or are currently being assessed in clinical trials as repurposing drugs to treat methamphetamine use disorder and associated cognitive deficits. Given the known safety profiles and bioavailability, as well as established manufacturing processes, drug repurposing can bypass some steps of conventional drug discovery. This shortens the timeline from bench to bedside translation with lower cost and less risk. Hence, drug repurposing to find pharmacotherapies to treat methamphetamine use disorder should be highly encouraged. The aim of the present review is to scope all repurposed medications in past and current clinical trials in people with methamphetamine use disorder that also assess cognitive function. Medications were selected from publicly available clinical trials registration databases. Based on human and animal literature, we will describe their putative mechanism of action, pharmacological properties, and their potential to improve cognitive functioning in people who use methamphetamine. We hope this scoping review will stimulate drug repurposing and promote rigorous neuroscience-based rationale in future clinical trials to treat methamphetamine use disorder.

Bioprospecting the American Alligator Peptidome for antiviral peptides against Venezuelan equine encephalitis virus.

The innate immune protection provided by cationic antimicrobial peptides (CAMPs) has been shown to extend to antiviral activity, with putative mechanisms of action including direct interaction with host cells or pathogen membranes. The lack of therapeutics available for the treatment of viruses such as Venezuelan equine encephalitis virus (VEEV) underscores the urgency of novel strategies for antiviral discovery. American alligator plasma has been shown to exhibit strong in vitro antibacterial activity, and functionalized hydrogel particles have been successfully employed for the identification of specific CAMPs from alligator plasma. Here, a novel bait strategy in which particles were encapsulated in membranes from either healthy or VEEV-infected cells was implemented to identify peptides preferentially targeting infected cells for subsequent evaluation of antiviral activity. Statistical analysis of peptide identification results was used to select five candidate peptides for testing, of which one exhibited a dose-dependent inhibition of VEEV and also significantly inhibited infectious titers. Results suggest our bioprospecting strategy provides a versatile platform that may be adapted for antiviral peptide identification from complex biological samples.

Pyrrolizine/indolizine-bearing (un)substituted isoindole moiety: design, synthesis, antiproliferative and MDR reversal activities, and in silico studies.

Two new series of pyrrolizine/indolizine derivative-bearing (un)substituted isoindole moiety were designed and synthesized. The anticancer potential of the new compounds was evaluated against hepatocellular carcinoma (HepG-2), colorectal carcinoma, colon cancer (HCT-116), and breast cancer (MCF-7) cell lines. Compounds 6d and 6o were the most potent derivatives with IC50 values ranging from 6.02 to 13.87 μM against HePG-2, HCT-116, and MCF-7 cell lines. Moreover, methyl analog of the fluoro-substituted indolizine derivative 6m revealed significant antiproliferative activity against HePG-2, HCT-116, and MCF-7 cancer cell lines with IC50 values of 11.97, 28.37, and 19.87 μM, respectively. The most active anticancer analogs, 6d, 6m, and 6o, were inspected for their putative mechanism of action by estimating their epidermal growth factor receptor (EGFR) and cyclin-dependent kinase (CDK 2) inhibitory activities. Thus, compound 6o displayed the most inhibitory activity against EGFR and CDK 2 with IC50 values of 62 and 118 nM, respectively. Additionally, the quantitative real-time PCR analysis for the P-glycoprotein effect of compounds 6d, 6m, and 6o was performed, in which compound 6o illustrated significant down-regulation of P-gp against the HepG-2 cell line by 0.2732 fold. Mechanistic studies for the most active compounds involving the reversal doxorubicin (DOX) effect of compounds 6d, 6m, and 6o were performed, which illustrated cytotoxic activity with IC50 22.27, 3.88, and 8.79 μM, respectively. Moreover, the apoptotic activity of the most active derivative 6o on HCT-116 cancer cells showed accumulation in the G1 and S phases of the cell cycle.

The antimalarial artemisinin is a non-electrophilic agonist of the transient receptor potential ankyrin type 1 receptor-channel

Artemisinin and its derivatives are the main therapeutic drugs against Plasmodium protists, the causative agents of malaria. While several putative mechanisms of action have been proposed, the precise molecular targets of these compounds have not been fully elucidated. In addition to their antimalarial properties, artemisinins have been reported to act as anti-tumour agents and certain antinociceptive effects have also been proposed. We investigated the effect of the parent compound, artemisinin, on a number of temperature-gated Transient Receptor Potential ion channels (so called thermoTRPs), given their demonstrated roles in pain-sensing and cancer. We report that artemisinin acts as an agonist of the Transient Receptor Potential Ankyrin type 1 (TRPA1) receptor channel. Artemisinin was able to evoke calcium transients in HEK293T cells expressing recombinant human TRPA1, as well as in a subpopulation of mouse dorsal root ganglion (DRG) neurons which also responded to the selective TRPA1 agonist allyl isothiocyanate (AITC) and these responses were reversibly abolished by the selective TRPA1 antagonist A967079. Artemisinin also triggered whole-cell currents in HEK293T cells transiently transfected with human TRPA1, as well as in TRPA1-expressing DRG neurons, and these currents were inhibited by A967079. Interestingly, using human TRPA1 mutants, we demonstrate that artemisinin acts as a non-electrophilic agonist of TRPA1, activating the channel in a similar manner to carvacrol and menthol. These results may provide a better understanding of the biological actions of the very important antimalarial and anti-tumour agent artemisinin.

Anticancer Potential of Rhychosia beddomei: An In vitro and In silico Study

Rhychosia beddomei is widely distributed in tropical and subtropical regions around the world. Traditionally this plant has been used as a medicine for multiple ailments including cancer. The present study addresses the evaluation of In vitro anticancer activity by using MTT Assay of methanolic extracts of whole plant of Rhychosia beddomei in Human Hepatocellular Carcinoma (HepG2) cell line in comparison with standard drug doxorubicin as well as In silico analysis. Doxorubicin acts in the cancer cell by intercalation into DNA and disruption of topoisomerase-II-mediated DNA repair and generation of free radicals and their damage to cellular membranes, DNA and proteins. Cytotoxicity studies have indicated that the phytoconstituents of Rhychosia beddomei have the ability to selectively target cancer, whereas minimal or negligible cytotoxic effects were observed on normal cells. The molecular docking approach was employed to check binding conformations of phytochemicals against human cyclin-dependent kinase 2, CDK-2 and Topoisomerase-2, Topo-II proteins (Protein Data bank-ID: 1DI8 and 1ZXM) through Mcule online molecular modelling tool. The docking revealed an encouraging binding score with a maximum score of -11.5 and -10.4 kCal/mol with CDK-2 and Topo-II respectively and all the selected ligands indicate promising anticancer activity. Molecular docking studies using the phytoconstituents were performed in order to gain a better understanding of the putative mechanisms of action leading to the development of improved and affordable therapies. This study paves a way to better understand the integration of molecular docking and in vitro studies can accelerate cancer drug discovery showing a good consistency of anticancer therapeutic drug potentials of Rhychosia beddomei by In vitro and In silico approaches.

Phytochemistry, Pharmacology and Molecular Mechanisms of Herbal Bioactive Compounds for Sickness Behaviour.

The host's response to acute infections or tissue injury is a sophisticated and coordinated adaptive modification called sickness behaviour. Many herbs have been studied for their ability to protect animals against experimentally induced sickness behaviour. However, there is a lack of knowledge and experimental evidence on the use of herbal bioactive compounds (HBACs) in the management of sick behaviour. The goal of this review is to provide a concise summary of the protective benefits and putative mechanisms of action of phytochemicals on the reduction of lipopolysaccharide (LPS)-induced sickness behaviour. Relevant studies were gathered from the search engines Scopus, ScienceDirect, PubMed, Google Scholar, and other scientific databases (between 2000 and to date). The keywords used for the search included "Lipopolysaccharide" OR "LPS" OR "Sickness behaviour" OR "Sickness" AND "Bioactive compounds" OR "Herbal medicine" OR "Herbal drug" OR "Natural products" OR "Isolated compounds". A total of 41 published articles that represented data on the effect of HBACs in LPS-induced sickness behaviour were reviewed and summarised systemically. There were 33 studies that were conducted in mice and 8 studies in rats. A total of 34 HBACs have had their effects against LPS-induced changes in behaviour and biochemistry investigated. In this review, we examined 34 herbal bioactive components that have been tested in animal models to see if they can fight LPS-induced sickness behaviour. Future research should concentrate on the efficacy, safety, and dosage needed to protect against illness behaviour in humans, because there is a critical shortage of data in this area.

Analysis of the chemotactic response of ram spermatozoa to steroid hormones

Some substances in follicular fluid may be acting as sperm attractants, and steroid hormones progesterone (P4) and estradiol (E2), both secreted by the cumulus cells, are possible candidates. We have previously observed a chemotactic effect of the ewe follicular fluid in ram spermatozoa (data not published). The presence of progesterone and estrogen receptors in ram spermatozoa suggests the involvement of these hormones in the sperm functionality, including guided movement towards the oocyte. P4 acts as a chemoattractant in human and rabbit sperm, but there is no information on its effect, or E2 effect, on ram spermatozoa. The objective of this work was to study the putative chemotactic action of P4 and E2 on ram spermatozoa, analyzing the influence of the sperm capacitation state. Swim-up selected spermatozoa from nine Rasa Aragonesa rams were incubated without (cap-TALP) or with cAMP-elevating agents (cap-Cocktail) to induce in vitro capacitation. After evaluating the sperm quality parameters in non- capacitated and incubated samples (motility, viability, capacitation state), IBIDI® µ-Slide Chemotaxis chamber (Ibidi GmbH) was loaded with swim-up, cap-TALP or cap-Cocktail sperm samples according to the manufacturer’s instructions. P4 or E2 were added to the chambers at 100 pM or 1 µM concentration each. Medium with 0.01% dimethyl sulfoxide (DMSO) was used as control treatment. After 5 min of equilibration, 200 fps videos were recorded for 3 sec with a video camera mounted on a microscope. Sperm trajectories and chemotaxis were analyzed with the OpenCASA software (Alquezar-Baeta et al., PLoS Comput Biol, 15(1), 2019), which calculates a chemotaxis index. Differences were analysed by χ² test, except for the chemotaxis index (ANOVA) using GraphPad PRISM® (versión 8.0.1). A chemotactic response was only observed in capacitated spermatozoa, as we previously described in presence of follicular fluid. P4 at both concentrations had a chemotactic effect on capacitated ram spermatozoa. However, E2 had no effect on any of the studied samples. These results reveal, for the first time, the chemotactic effect of P4 in ram spermatozoa. Grants: AGL-2017-83799-R and DGA A07-17R. S.M.-J. has a predoctoral contract from the Diputación General de Aragón (DGA).

Impact of selenium on the intestinal microbiome-eCBome axis in the context of diet-related metabolic health in mice.

Dietary micronutrients act at the intestinal level, thereby influencing microbial communities, the host endocannabinoidome, and immune and anti-oxidative response. Selenium (Se) is a trace element with several health benefits. Indeed, Se plays an important role in the regulation of enzymes with antioxidative and anti-inflammatory activity as well as indicators of the level of oxidative stress, which, together with chronic low-grade inflammation, is associated to obesity. To understand how Se variations affect diet-related metabolic health, we fed female and male mice for 28 days with Se-depleted or Se-enriched diets combined with low- and high-fat/sucrose diets. We quantified the plasma and intestinal endocannabinoidome, profiled the gut microbiota, and measured intestinal gene expression related to the immune and the antioxidant responses in the intestinal microenvironment. Overall, we show that intestinal segment-specific microbiota alterations occur following high-fat or low-fat diets enriched or depleted in Se, concomitantly with modifications of circulating endocannabinoidome mediators and changes in cytokine and antioxidant enzyme expression. Specifically, Se enrichment was associated with increased circulating plasma levels of 2-docosahexaenoyl-glycerol (2-DHG), a mediator with putative beneficial actions on metabolism and inflammation. Others eCBome mediators also responded to the diets. Concomitantly, changes in gut microbiota were observed in Se-enriched diets following a high-fat diet, including an increase in the relative abundance of Peptostreptococcaceae and Lactobacillaceae. With respect to the intestinal immune response and anti-oxidative gene expression, we observed a decrease in the expression of proinflammatory genes Il1β and Tnfα in high-fat Se-enriched diets in caecum, while in ileum an increase in the expression levels of the antioxidant gene Gpx4 was observed following Se depletion. The sex of the animal influenced the response to the diet of both the gut microbiota and endocannabinoid mediators. These results identify Se as a regulator of the gut microbiome and endocannabinoidome in conjunction with high-fat diet, and might be relevant to the development of new nutritional strategies to improve metabolic health and chronic low-grade inflammation associated to metabolic disorders.

A review about the putative mechanisms of action of electroconvulsive therapy in schizophrenia in human research

Electroconvulsive therapy (ECT) has multiple uses in psychiatry, but its mechanisms of action (MA) in patients with schizophrenia (PS) are poorly understood. We synthesize and discuss the available evidence in this regard. We conducted a search for primary human studies and systematic reviews searching MA of ECT in PS published in PubMed/Medline, SciELO, PsycInfo, and the Cochrane Library, including 24 articles. Genetic findings are scarce and inconsistent. At the molecular level, the dopaminergic and GABAergic role stands out. The increase in brain derived neurotrophic factor (BDNF) after ECT, is a predictor of positive clinical outcomes, while the change in N-acetyl aspartate levels would demonstrate a neuroprotective role for ECT. This intervention would improve inflammatory and oxidative parameters, thereby resulting in a symptomatic improvement. ECT is associated with an increase in functional connectivity in the thalamus, right putamen, prefrontal cortex and left precuneus, structures that play a role in the neural default mode network. A decrease in connectivity between the thalamus and the sensory cortex and an enhanced functional connectivity of the right thalamus to right putamen along with a clinical improvement have been reported after ECT. Moreover a volumetric increase in hippocampus and insula has been reported after ECT. These changes could be associated with the biochemical pathophysiology of schizophrenia. Most of the included studies are observational or quasi-experimental, with small sample sizes. However, they show simultaneous changes at different neurobiological levels, with a pathophysiological and clinical correlation. We propose that the research on ECT should be carried out from neurobiological dimensions, but with a clinical perspective.

Antifungal activity of natamycin against kiwifruit soft rot caused by Botryosphaeria dothidea and potential mechanisms

Soft rot caused by Botryosphaeria dothidea leads to massive economic losses in the kiwifruit industry. Natamycin is a natural antimicrobial preservative that effectively prevents postharvest decay and preserves fruit quality. However, the ability to control kiwifruit soft rot and potential antifungal mechanisms have not been explored. In this study, the inhibitory impact of natamycin against soft rot caused by B. dothidea, as well as its putative action mechanisms were investigated. The results indicated that 2 mg L−1 natamycin effectively inhibited mycelial growth and spore germination of B. dothidea in vitro. Natamycin caused B. dothidea hypha to shrink and deform, along with vacuolation and plasmolysis in hypha cells, as observed by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Likewise, natamycin stimulated the accumulation of reactive oxygen species (ROS) in the hypha. The inhibition effect of natamycin on B. dothidea inoculated in kiwifruit was dose-dependent, with 500 mg L−1 natamycin significantly decreasing the incidence of soft rot to 35%. Furthermore, natamycin induced disease resistance in kiwifruit tissue by activating the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT), increasing the antioxidant compound total phenol, maintaining a low level of malondialdehyde (MDA), and repressing the activity of four cell wall degrading enzymes, as well as gene expression of β-galactosidase (β-Gal) and polygalacturonase (PG). Further field research revealed that pre-harvest treatment combined with the postharvest natamycin application significantly reduced the natural decay incidence of kiwifruit while having no negative effect on soft-ripe quality. In conclusion, our findings proved that natamycin has an antifungal effect on B. dothidea and may be applied as a safe preservative to reduce soft rot.

Tachykinin-related peptides modulate immune-gene expression in the mealworm beetle Tenebrio molitor L.

Tachykinins (TKs) are a group of conserved neuropeptides. In insects, tachykinin-related peptides (TRPs) are important modulators of several functions such as nociception and lipid metabolism. Recently, it has become clear that TRPs also play a role in regulating the insect immune system. Here, we report a transcriptomic analysis of changes in the expression levels of immune-related genes in the storage pest Tenebrio molitor after treatment with Tenmo-TRP-7. We tested two concentrations (10–8 and 10–6 M) at two time points, 6 and 24 h post-injection. We found significant changes in the transcript levels of a wide spectrum of immune-related genes. Some changes were observed 6 h after the injection of Tenmo-TRP-7, especially in relation to its putative anti-apoptotic action. Interestingly, 24 h after the injection of 10–8 M Tenmo-TRP-7, most changes were related to the regulation of the cellular response. Applying 10–6 M Tenmo-TRP-7 resulted in the downregulation of genes associated with humoral responses. Injecting Tenmo-TRP-7 did not affect beetle survival but led to a reduction in haemolymph lysozyme-like antibacterial activity, consistent with the transcriptomic data. The results confirmed the immunomodulatory role of TRP and shed new light on the functional homology between TRPs and TKs.

Unravelling Potential Health-Beneficial Properties of Corema album Phenolic Compounds: A Systematic Review.

Corema (C.) album belongs to the family Ericaceae and can be found in the Iberian Peninsula, especially on the coastal areas facing the Atlantic coast. C. album berries have been used for centuries in traditional medicine. Recent studies have revealed that not only the berries but also the leaves have relevant antioxidant, antiproliferative, and anti-inflammatory properties, bringing this plant to the forefront of discussion. A systematic review of the literature was carried out to summarize the phenolic compounds and bioactive properties identified in C. album berries and leaves and to search for research gaps on this topic. The search was conducted in three electronic databases (PubMed, SCOPUS, and Web of Science) using PRISMA methodology. The inclusion criteria were the chemical compositions of the berries, leaves, or their extracts and their bioactive properties. The exclusion criteria were agronomic and archaeological research. The number of studies concerning phenolic compounds’ composition and the bioactive properties of C. album berries and leaves is still limited (11 articles). However, the variety of polyphenolic compounds identified make it possible to infer new insights into their putative mechanism of action towards the suppression of NF-kB transcription factor activation, the modulation of inflammatory mediators/enzymes, the induction of apoptosis, the modulation of mitogen activated protein kinase, cell cycle arrest, and the reduction of oxidative stress. These factors can be of major relevance concerning the future use of C. album as nutraceuticals, food supplements, or medicines. Nevertheless, more scientific evidence concerning C. album’s bioactivity is required.