Positive Modulator Research Articles

Selective Potentiation of the (α4)3(β2)2 Nicotinic Acetylcholine Receptor Response by NS9283 Analogues.

NS9283, 3-(3-pyridyl)-5-(3-cyanophenyl)-1,2,4-oxadiazole, is a selective positive allosteric modulator of (α4)3(β2)2 nicotinic acetylcholine receptors (nAChRs). It has good subtype selective therapeutic potential afforded by its specific binding to the unique α4-α4 subunit interface present in the (α4)3(β2)2 nAChR. However, there is currently a lack of structure activity relationship (SAR) studies aimed at developing a class of congeners endowed with the same profile of activity that can help consolidate the druggability of the α4-α4 subunit interface. In this study, new NS9283 analogues were designed, synthesized, and characterized for their ability to selectively potentiate the ACh activity at heterologous (α4)3(β2)2 nAChRs vs nAChR subtypes (α4)2(β2)3, α5α4β2, and α7. With few exceptions, all the NS9283 analogues exerted positive modulation of the (α4)3(β2)2 nAChR ACh-evoked responses. Above all, those modified at the 3-cyanophenyl moiety by replacement with 3-nitrophenyl (4), 4-cyanophenyl (10), and N-formyl-4-piperidinyl (20) showed the same efficacy as NS9283, although with lower potency. Molecular dynamics simulations of NS9283 and some selected analogues highlighted consistency between potentiation activity and pose of the ligand inside the α4-α4 site with the main interaction being with the complementary (-) side and induction of a significant conformational change of the Trp156 residue in the principal (+) side.

Gene expression reprogramming of Pseudomonas alloputida in response to arginine through the transcriptional regulator ArgR.

Different bacteria change their life styles in response to specific amino acids. In Pseudomonas putida (now alloputida) KT2440, arginine acts both as an environmental and a metabolic indicator that modulates the turnover of the intracellular second messenger c-di-GMP, and expression of biofilm-related genes. The transcriptional regulator ArgR, belonging to the AraC/XylS family, is key for the physiological reprogramming in response to arginine, as it controls transport and metabolism of the amino acid. To further expand our knowledge on the roles of ArgR, a global transcriptomic analysis of KT2440 and a null argR mutant growing in the presence of arginine was carried out. Results indicate that this transcriptional regulator influences a variety of cellular functions beyond arginine metabolism and transport, thus widening its regulatory role. ArgR acts as positive or negative modulator of the expression of several metabolic routes and transport systems, respiratory chain and stress response elements, as well as biofilm-related functions. The partial overlap between the ArgR regulon and those corresponding to the global regulators RoxR and ANR is also discussed.

Foot-and-Mouth Disease Virus Capsid Protein VP1 Antagonizes Type I Interferon Signaling via Degradation of Histone Deacetylase 5.

Foot-and-mouth disease (FMD) is a highly contagious and economically important disease of cloven-hoofed animals that hampers trade and production. To ensure effective infection, the foot-and-mouth disease virus (FMDV) evades host antiviral pathways in different ways. Although the effect of histone deacetylase 5 (HDAC5) on the innate immune response has previously been documented, the precise molecular mechanism underlying HDAC5-mediated FMDV infection is not yet clearly understood. In this study, we found that silencing or knockout of HDAC5 promoted FMDV replication, whereas HDAC5 overexpression significantly inhibited FMDV propagation. IFN-β and IFN-stimulated response element (ISRE) activity was strongly activated through the overexpression of HDAC5. The silencing and knockout of HDAC5 led to an increase in viral replication, which was evident by decreased IFN-β, ISG15, and ISG56 production, as well as a noticeable reduction in IRF3 phosphorylation. Moreover, the results showed that the FMDV capsid protein VP1 targets HDAC5 and facilitates its degradation via the proteasomal pathway. In conclusion, this study highlights that HDAC5 acts as a positive modulator of IFN-β production during viral infection, while FMDV capsid protein VP1 antagonizes the HDAC5-mediated antiviral immune response by degrading HDAC5 to facilitate viral replication.

The Role of MaWRKY70 in Regulating Lipoxygenase Gene Transcription during Chilling Injury Development in Banana Fruit.

Banana is a typical cold-sensitive fruit; it is prone to chilling injury (CI), resulting in a quality deterioration and commodity reduction. However, the molecular mechanism underlying CI development is unclear. In this study, cold storage (7 °C for 5 days) was used to induce CI symptoms in bananas. As compared with the control storage (22 °C for 5 days), cold storage increased the CI index and cell membrane permeability. Moreover, we found that the expression levels of the WRKY transcription factor MaWRKY70 were increased consistently with the progression of CI development. A subcellular localization assay revealed that MaWRKY70 was localized in the nucleus. Transcriptional activation analyses showed that MaWRKY70 processed a transactivation ability. Further, an electrophoretic mobility shift assay (EMSA) and dual-luciferase reporter (DLR) assays showed that MaWRKY70 was directly bound to the W-box motifs in the promoters of four lipoxygenase (LOX) genes associated with membrane lipid degradation and activated their transcription. Collectively, these findings demonstrate that MaWRKY70 activates the transcription of MaLOXs, thereby acting as a possible positive modulator of postharvest CI development in banana fruit.

Arthrospira platensis prevents contractile reactivity damage in obese rats fed a hypercaloric diet by positive modulating the Rho-A/Rho-kinase pathway, inflammation and oxidative stress

Obesity is characterized by excess fat, which favors the development of intestinal diseases. Arthrospira platensis (AP) has been the subject of several studies. However, few studies involve its effects on intestinal reactivity and associated mechanisms of action. The effects of AP and the mechanisms by which the seaweed prevents damage to contractile reactivity in the ileum were evaluated. Rats were fed on standard diet (SD), hypercaloric diet (HCD), or HCD supplemented with AP at a dose of 25 mg/kg (HCD + AP25). The preventive effects of seaweed were associated with positive modulation of the Rho kinase complex (ROCK), nitric oxide (NO), contractile prostanoids, superoxide dismutase (SOD) and reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase signaling pathways, which may be associated with the presence of gamma linolenic acid (GLA), as the main component of AP. Therefore, AP appears as an adjunct in the prevention of obesity and intestinal diseases.

Melatonin delayed senescence by modulating the contents of plant signalling molecules in postharvest okras.

Okra has been widely cultivated worldwide. Consumers appreciate its nutritional value and delicious taste. However, okra is very perishable after harvest because of rapid senescence and high susceptibility to mechanical injuries, which limits its storage life and reduces consumer acceptance. This study examined the influence of melatonin treatment on senescence process and endogenous plant signalling molecules in postharvest okras. The results indicated that melatonin treatment delayed senescence by increasing the endogenous melatonin content through upregulation of its biosynthetic genes. In addition, the treatment increased the contents of indole-3-acetic acid (IAA) and gibberellin (GA) due to the positive modulation of their metabolic and signalling genes. Furthermore, treated okras exhibited higher levels of γ-aminobutyric acid (GABA) but lower abscisic acid (ABA) content, contributing to the delayed senescence process compared to control. Overall, the findings suggested that melatonin postponed senescence in okras fruit by positively regulating endogenous signalling molecules such as melatonin, IAA, GABA, GA, and ABA.

Positive modulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors differentially alters spatial learning and memory in juvenile rats younger and older than three weeks.

Remarkable performance improvements occur at the end of the third postnatal week in rodents tested in various tasks that require navigation according to spatial context. While alterations in hippocampal function at least partially subserve this cognitive advancement, physiological explanations remain incomplete. Previously, we discovered that developmental modifications to hippocampal glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in juvenile rats was related to more mature spontaneous alternation behavior in a symmetrical Y-maze. Moreover, a positive allosteric modulator of AMPA receptors enabled immature rats to alternate at rates seen in older animals, suggesting an excitatory synaptic limitation to hippocampal maturation. We then validated the Barnes maze for juvenile rats in order to test the effects of positive AMPA receptor modulation on a goal-directed spatial memory task. Here we report the effects of the AMPA receptor modulator, CX614, on spatial learning and memory in the Barnes maze. Similar to our prior report, animals just over 3 weeks of age display substantial improvements in learning and memory performance parameters compared to animals just under 3 weeks of age. A moderate dose of CX614 enabled immature animals to move more directly to the goal location, but only after 1 day of training. This performance improvement was observed on the second day of training with drug delivery or during a memory probe trial performed without drug delivery after the second day of training. Higher doses created more search errors, especially in more mature animals. Overall, CX614 provided modest performance benefits for immature rats in a goal-directed spatial memory task.

Decoding low-frequency climate variations: A case study on ENSO and ocean surface warming

Current perspectives on lower frequency variations and secular warming have predominantly been shaped by traditional anomalies that assume an annual cycle (AC) with a time-invariant amplitude. However, this anomaly framework falls short in capturing the complexity of multiple periodic modes with intricate waveforms and time dependent amplitude—the traits, in general, shared by externally forced responses of complex dynamical systems. By allowing interannual amplitude modulation of ACs, we show that the monotonic amplitude increases of the first AC of Sea Surface Temperature (SST) are manifested as the basin-wide secular warming of the ocean surface. Notably, the first SST-AC exhibits significant interannual variances and the largest linear warming rates in the Pacific Warm Pool. While the linear warming pattern mirrors that of a long-term mean SST, it depicts an entirely different warming pattern on the surface of the tropical Pacific Ocean compared to those reported so far. Moreover, all interannual warm (El Niño) and cold (La Niña) events in tropical Pacific regions are abnormal interannual modulations in the third and fourth ACs of SST, respectively. Specifically, a strong El Niño event occurs when a positive amplitude modulation leads to the overlap of two consecutive positive phases of the third AC of SST. Conversely, the absence of such overlaps during negative amplitude modulations significantly contributes to the positive skewness of SST anomalies. No systematic decadal changes in the zonal propagation characteristics of SST in the eastern Pacific (EP) and central Pacific (CP) regions were detected. These findings underscore that the secular warming and low-frequency events in EP and CP are intrinsic to three distinct ACs.

AMBRA1 promotes intestinal inflammation by antagonizing PP4R1/PP4c mediated IKK dephosphorylation in an autophagy-independent manner.

IκB kinase (IKK) complex is central regulators of the NF-κB pathway, and dysregulation of IKK phosphorylation leads to hyperactivation of proinflammatory response in various chronic inflammatory diseases, including inflammatory bowel disease (IBD). However, the dynamic modulation of IKK phosphorylation and dephosphorylation in intestinal inflammation remains uncharacterized. Here, we found that autophagy/beclin-1 regulator 1 (AMBRA1) was highly expressed in inflamed colons in a colitis mouse model and in clinical IBD samples. Importantly, AMBRA1 deletion significantly decreased proinflammatory cytokine expression and enhanced the therapeutic effect of infliximab on intestinal inflammation. Mechanistically, the N-term F1 domain of AMBRA1 was required for AMBRA1 to competitively interact with protein phosphatase 4 regulatory subunit 1 (PP4R1) and catalytic protein phosphatase 4 (PP4c) to suppress their interactions with IKK, promote the dissociation of the PP4R1/PP4c complex, and antagonize the dephosphorylation activity of this complex towards the IKK complex. In response to TNF-α stimulation, IKKα phosphorylates AMBRA1 at S1043 to stabilize AMBRA1 expression by impairing its binding to Cullin4A (CUL4A) to decrease its CUL4A-mediated K48-linked ubiquitination. Overall, our study identifies an autophagy-independent function of AMBRA1 as a positive modulator of IKK phosphorylation to promote intestinal inflammation, thus providing a new targeted therapeutic strategy for patients with refractory IBD.

Impact of Waste Cooking Oils Addition on Thermophilic Dry Co-Digestion of Wheat Straw and Horse Manure for Renewable Energy Production in Two Stages.

Anaerobic co-digestion of waste wheat straw and horse manure in two steps was revealed as a promising option for renewable energy production in the form of hydrogen and methane. Addition of waste cooking oils, disposal of which could cause damage to health or the environment, as a third substrate for digestion, is suggested as an approach not only to help handle the increasing volume of food waste worldwide but also to improve process performance. In the present study, waste cooking oil, in a concentration of 5%, appeared to be a positive modulator of anaerobic digestion with the production of hydrogen and did not lead to inhibition of the hydrolysis phase. The overall efficiency of the two-stage anaerobic digestion of the mixture, which contains mainly lignocellulose waste, is positively dependent on thermochemical pretreatment with the alkali reagent (Ca(OH)2), but elevated temperature (55 °C) and cooking oil addition revealed the opportunity to omit the pre-treatment step. Nevertheless, the overall energy production was lower due to the methane production step. However, the addition of waste cooking oils to the process in which lig-nocellulose is not pretreated (V3) led to an increase in the methane production and energy yield compared to V1. The anaerobic digestion of lignocellulosic waste is a complex process and comprises successive degradation pathways and syntrophic microbial associations' activities, so the division in two reactors ensured suitable conditions for the microorganisms residing in each of them. In this study, along with the production of hydrogen and methane and the separation of the hydrolysis and methanogenesis stages, utilization of agriculture- and kitchen-generated wastes was realized in the context of waste-to-energy sustainable production methods.

The NMDA receptor modulator zelquistinel durably relieves behavioral deficits in three mouse models of autism spectrum disorder

Autism spectrum disorders (ASD) are complex neurodevelopmental disorders characterized by deficient social communication and interaction together with restricted, stereotyped behaviors. Currently approved treatments relieve comorbidities rather than core symptoms. Since excitation/inhibition balance and synaptic plasticity are disrupted in ASD, molecules targeting excitatory synaptic transmission appear as highly promising candidates to treat this pathology. Among glutamatergic receptors, the NMDA receptor has received particular attention through the last decade to develop novel allosteric modulators. Here, we show that positive NMDA receptor modulation by zelquistinel, a spirocyclic β-lactam platform chemical, relieves core symptoms in two genetic and one environmental mouse models of ASD. A single oral dose of zelquistinel rescued, in a dose-response manner, social deficits and stereotypic behavior in Shank3Δex13-16−/− mice while chronic intraperitoneal administration promoted a long-lasting relief of such autistic-like features in these mice. Subchronic oral mid-dose zelquistinel treatment demonstrated durable effects in Shank3Δex13-16−/−, Fmr1−/− and in utero valproate-exposed mice. Carry-over effects were best maintained in the Fmr1 null mouse model, with social parameters being still fully recovered two weeks after treatment withdrawal. Among recently developed NMDA receptor subunit modulators, zelquistinel displays a promising therapeutic potential to relieve core symptoms in ASD patients, with oral bioavailability and long-lasting effects boding well for clinical applications. Efficacy in three mouse models with different etiologies supports high translational value. Further, this compound represents an innovative pharmacological tool to investigate plasticity mechanisms underlying behavioral deficits in animal models of ASD.

Inhibition and potentiation of the exercise pressor reflex by pharmacological modulation of TRPC6 in male rats.

We determined the role played by the transient receptor potential canonical 6 (TRPC6) channel in evoking the mechanical component of the exercise pressor reflex in male decerebrated Sprague-Dawley rats. TRPC6 channels were identified by quadruple-labelled (DiI, TRPC6, neurofilament-200 and peripherin) immunohistochemistry in dorsal root ganglion (DRG) cells innervating the triceps surae muscles (n=12). The exercise pressor reflex was evoked by statically contracting the triceps surae muscles before and after injection of the TRPC6 antagonist BI-749327 (n=11; 12μgkg-1 ) or SAR7334 (n=11; 7μgkg-1 ) or the TRPC6 positive modulator C20 (n=11; 18μgkg-1 ). Similar experiments were conducted while the muscles were passively stretched (n=8-12), a manoeuvre that isolated the mechanical component of the reflex. Blood pressure, tension, renal sympathetic nerve activity (RSNA) and blood flow were recorded. Of the DRG cells innervating the triceps surae muscles, 85% stained positive for the TRPC6 antigen, and 45% of those cells co-expressed neurofilament-200. Both TRPC6 antagonists decreased the reflex pressor responses to static contraction (-32 to -42%; P < 0.05) and to passive stretch (-35 to -52%; P < 0.05), whereas C20 increased these responses (55-65%; P < 0.05). In addition, BI-749327 decreased the peak and integrated RSNA responses to both static contraction (-39 to -43%; P < 0.05) and passive stretch (-56 to -62%; P < 0.05), whereas C20 increased the RSNA to passive stretch only. The onset latency of the decrease or increase in RSNA occurred within 2s of the onset of the manoeuvres (P < 0.05). Collectively, our results show that TRPC6 plays a key role in evoking the mechanical component of the exercise pressor reflex. KEY POINTS: The exercise pressor reflex plays a key role in the sympathetic and haemodynamic responses to exercise. This reflex is composed of two components, namely the mechanoreflex and the metaboreflex. The receptors responsible for evoking the mechanoreflex are poorly documented. A good candidate for this function is the transient receptor potential canonical 6 (TRPC6) channel, which is activated by mechanical stimuli and expressed in dorsal root ganglia of rats. Using two TRPC6 antagonists and one positive modulator, we investigated the role played by TRPC6 in evoking the mechanoreflex in decerebrated rats. Blocking TRPC6 decreased the renal sympathetic and the pressor responses to both contraction and stretch, the latter being a manoeuvre that isolates the mechanoreflex. In contrast, the positive modulator increased the pressor reflex to contraction and stretch, in addition to the sympathetic response to stretch. Our results provide strong support for a role played by the TRPC6 channel in evoking the mechanoreflex.

ATH-1105, a small-molecule positive modulator of the neurotrophic HGF system, is neuroprotective, preserves neuromotor function, and extends survival in preclinical models of ALS.

Amyotrophic lateral sclerosis (ALS), a progressive and fatal neurodegenerative disorder, primarily affects the motor neurons of the brain and spinal cord. Like other neurodegenerative conditions, ongoing pathological processes such as increased inflammation, excitotoxicity, and protein accumulation contribute to neuronal death. Hepatocyte growth factor (HGF) signaling through the MET receptor promotes pro-survival, anti-apoptotic, and anti-inflammatory effects in multiple cell types, including the neurons and support cells of the nervous system. This pleiotropic system is therefore a potential therapeutic target for treatment of neurodegenerative disorders such as ALS. Here, we test the effects of ATH-1105, a small-molecule positive modulator of the HGF signaling system, in preclinical models of ALS. In vitro, the impact of ATH-1105 on HGF-mediated signaling was assessed via phosphorylation assays for MET, extracellular signal-regulated kinase (ERK), and protein kinase B (AKT). Neuroprotective effects of ATH-1105 were evaluated in rat primary neuron models including spinal motor neurons, motor neuron-astrocyte cocultures, and motor neuron-human muscle cocultures. The anti-inflammatory effects of ATH-1105 were evaluated in microglia- and macrophage-like cell systems exposed to lipopolysaccharide (LPS). In vivo, the impact of daily oral treatment with ATH-1105 was evaluated in Prp-TDP43A315T hemizygous transgenic ALS mice. In vitro, ATH-1105 augmented phosphorylation of MET, ERK, and AKT. ATH-1105 attenuated glutamate-mediated excitotoxicity in primary motor neurons and motor neuron- astrocyte cocultures, and had protective effects on motor neurons and neuromuscular junctions in motor neuron-muscle cocultures. ATH-1105 mitigated LPS-induced inflammation in microglia- and macrophage-like cell systems. In vivo, ATH-1105 treatment resulted in improved motor and nerve function, sciatic nerve axon and myelin integrity, and survival in ALS mice. Treatment with ATH-1105 also led to reductions in levels of plasma biomarkers of inflammation and neurodegeneration, along with decreased pathological protein accumulation (phospho-TDP-43) in the sciatic nerve. Additionally, both early intervention (treatment initiation at 1 month of age) and delayed intervention (treatment initiation at 2 months of age) with ATH-1105 produced benefits in this preclinical model of ALS. The consistent neuroprotective and anti-inflammatory effects demonstrated by ATH-1105 preclinically provide a compelling rationale for therapeutic interventions that leverage the positive modulation of the HGF pathway as a treatment for ALS.

Efficacy and Skin Microbiome Modulation Effects of a Fixed-Concentration Combination of Benzoyl Peroxide 4% Plus Niacinamide 4% in a Film-Forming Cream in Subjects with Mild-to-Moderate Acne: A Non-Sponsored, Prospective, Assessor-Blinded, Pilot Trial

Benzoyl peroxide (BPO) and niacinamide (Niac) are commonly used alone or in combination with other molecules in the treatment of acne. BPO and Niac in the same product could exert complementary and synergistic effects improving efficacy in acne. Furthermore, Niac could reduce some side effects of BPO, such as skin irritation and erythema. A film-forming cream product containing BPO 4% and Niac 4%, vehiculated in a mixture of polyvinyl alcohol (PVA) and perfluoropolyether (PFPE) has been recently developed (B-N cream). A 28-day, assessor-blinded pilot trial was conducted to evaluate the clinical efficacy, skin tolerability, sebum production, skin redness, and skin microbiome modulation of B-N cream in subjects with mild to moderate acne of the face. Twenty-two adult men and women with mild-to-moderate acne of the face participated in this trial, after their written informed consent. B-N cream was applied once daily in the evening. The use of B-N cream was associated with a statistically significant decrease in acne lesions after treatment in comparison with baseline (non-inflammatory lesions: −40%; inflammatory lesions: −43% and total lesions: −41%). The use of the cream was not associated with a skin barrier function alteration. The skin redness score (−11%) and the sebum production (−42%) were significantly reduced after treatment. The use of B-N cream determined a reduction in the relative abundance of the Actinobacteria phylum (Corynebacterium and Propionibacterium, from 56% to 47%) and a significant increase in the abundance of Bacteroidetes phylum (from 3% to 5.2%). In addition, the product was well tolerated. In conclusion, this film-forming, medical device cream was effective in subjects with mild-to-moderate acne, reducing acne lesions and sebum production without altering skin barrier function, offering good skin tolerability. Furthermore, this product exerts positive skin microbiome modulation effects.

Brain-derived neurotrophic factor and stroke: perspectives on exercise as a health care strategy

PurposeStroke is the second most common cause of mortality worldwide and the third most common cause of motor disability. From another perspective, brain-derived neurotrophic factor (BDNF) is a metabolite that plays several neuroprotective roles. While cardiometabolic diseases are the leading cause of stroke, BDNF represents a target factor in the prevention and/or recovery from stroke. Aim: In this narrative review, I have summarised the clinical evidence of BDNF participation in the recovery from a stroke and discuss the potential use of exercise as a rehabilitation tool.MethodsMultiple combinations of the terms ‘brain infarction’, ‘cerebral infarction’, ‘hemorrhagic stroke’, ‘ischemic stroke’, ‘embolic stroke’ or ‘thrombotic stroke’ AND ‘BDNF’ or ‘pro-BDNF’ were used in PubMed databases. Studies not available in the English language or addressing animal experiments were excluded.Results and prospectsSeventeen clinical studies published up to June 30th of 2023 were included in this review. Changes in the patients circulating BDNF levels represent their capability of recovery from the stroke outcomes. A subtle, but consistent, negative influence of the presence of the 66Met-allele in BDNF on motor and cognitive competencies is seen in patients recovering from a stroke throughout the studies – an effect that is not reportedly detectable in other neuropathological conditions. Exercise exerts a positive modulation on BDNF levels that accompanies improvements in stroke recovery and might exert a preventive role against the severity of stroke outcomes.

Multi-shape VO2 nanoparticle stacking structure film with positive luminous modulation for smart window

Vanadium dioxide (VO2)-based thermochromic smart window show excellent promise for energy-saving and have been extensively researched. However, the performance of smart windows is restrained by the VO2 film negative modulation with luminous transmittance. Unfortunately, there has been no breakthrough in exploring negative modulation mechanism for VO2 thin nanofilm until now. In this work, we propose a novel structure design consisting of densely packed VO2 nanostructure over glass based on rectangular and circular nanoparticles array structure. The preparation process involves the magnetron sputtering and low-pressure annealing technique, which is well-suited for the glass substrate. According to optical measurements, the luminous transmittance modulation (ΔTlum = 1.86 %) was significantly increased compared to the continuous vanadium oxide film. Simultaneously, leading to the solar modulation (ΔTsol = 8.35 %) and luminous transmittance (Tlum = 57.18 %@30 °C) also were improved, which can be ascribed to the absorption between lager and small nanoparticles in the luminous when VO2 is in rutile state. The mechanisms are investigated by localized surface plasmon resonance theoretical analyses and numerical simulations. Our novel approach offers a promising solution for constructing energy-efficient VO2-based smart windows.

Chronic Treatment with Nigella sativa Oil Exerts Antimanic Properties and Reduces Brain Inflammation in Rats.

Nigella sativa (NS) is a native herb consumed habitually in several countries worldwide, possessing manifold therapeutic properties. Among them, anti-inflammatory features have been reported, presumably relating to mechanisms involved in the nuclear factor kappa-B pathway, among others. Given the observed association between neuroimmune factors and mental illness, the primary aim of the present study was to examine the effects of chronic NS use on manic-like behavior in rats, as well as analyze levels of brain inflammatory mediators following NS intake. Using male and female rats, baseline tests were performed; thereafter, rats were fed either regular food (control) or NS-containing food (treatment) for four weeks. Following intervention, behavioral tests were induced (an open field test, sucrose consumption test, three-chamber sociality test, and amphetamine-induced hyperactivity test). Subsequently, brain samples were extracted, and inflammatory mediators were evaluated, including interleukin-6, leukotriene B4, prostaglandin E2, tumor necrosis factor-α, and nuclear phosphorylated-p65. Our findings show NS to result in a marked antimanic-like effect, in tandem with a positive modulation of select inflammatory mediators among male and female rats. The findings reinforce the proposed therapeutic advantages relating to NS ingestion.

Wnt signalling pathways as mediators of neuroprotective mechanisms: therapeutic implications in stroke.

A stroke is a complicated neurological illness that occurs when there is a disruption in the blood flow to the brain. This disruption results in the damage of neurons, which then leads to functional abnormalities. The Wnt signalling pathway, which is already well-known for its important function in development and tissue homeostasis, has recently been recognised as a critical factor in the pathophysiology of stroke. Recent studies have shown the Wnt pathway's roles in stroke-related events. The complex-interactions between the Wnt pathway and stroke emphasising the pathway's contributions to neuro-protection and synaptic plasticity. The Wnt pathway's influence on neuro-genesis and synaptic plasticity underscores its potential for driving stroke recovery and rehabilitation strategies. The current review discusses about the Wnt signalling pathway in brain pathophysiology and stroke with special emphasis on the various pathways involved in the positive and negative modulation of Wnt pathway namely Phosphoinositide 3-kinase (PI3-K), Glycogen synthase kinase-3β (GSK-3β), Mitogen-activated protein kinase (MAPK) and nuclear factor erythroid 2-related factor 2 (Nrf2) pathway.

Exploring the binding site and mechanism of action of NS309, a superagonistic positive gating modulator for the calcium-activated potassium channel KCa3.1

Exploring the binding site and mechanism of action of NS309, a superagonistic positive gating modulator for the calcium-activated potassium channel KCa3.1

Defining Relations for Minimal Unitary Quantum Affine W-Algebras

We prove that any unitary highest weight module over a universal minimal quantum affine W-algebra at non-critical level descends to its simple quotient. We find the defining relations of the unitary simple minimal quantum affine W-algebras and the list of all their irreducible positive energy modules. We also classify all irreducible highest weight modules for the simple affine vertex algebras in the cases when the associated simple minimal W-algebra is unitary.