Search Results (23,256)

The emergence of SARS-CoV-2 variants highlights the urgent need for novel therapeutic strategies, particularly entry inhibitors that could efficiently prevent viral infection. Medicinal herbs and herbal combination formulas have long been recognized for their effects in treating infectious diseases and their antiviral properties, thus providing abundant resources for the discovery of antiviral candidates. While many candidates have been suggested to have antiviral activity against SARS-CoV-2 infection, few have been validated for their mechanisms, including possible effects on viral entry. This study aimed to identify SARS-CoV-2 entry inhibitors from medicinal herbs and herbal formulas that are known for heat-clearing and detoxifying properties and/or antiviral activities. A SARS-CoV-2 pseudoparticle (SARS-CoV-2pp) system was used to assess mechanism-specific entry inhibition. Our results showed that the methanol extract of Anemarrhena asphodeloides rhizome, as well as the water extracts of Cimicifuga foetida rhizome, Xiao Chai Hu Tang (XCHT), and Sheng Ma Ge Gen Tang (SMGGT), have substantial inhibitory effects on the entry of SARS-CoV-2pps into host cells. Given the observation that Cimicifuga foetida exhibited the most potent inhibition and is a constituent of SMGGT, we further investigated the major compounds of the herb and identified caffeic acid as a bioactive component for blocking SARS-CoV-2pp entry. Entry inhibition of Cimicifuga foetida and caffeic acid was validated on both wild-type and the currently dominant JN.1 strain SARS-CoV-2pp systems. Moreover, caffeic acid was able to both inactivate the pseudoparticles and prevent their entry into pretreated host cells. The results support the traditional use of these herbal medicines and underscore their potential as valuable resources for identifying active compounds and developing therapeutic entry inhibitors for the management of COVID-19. Full article

Macrophage-mediated inflammation is known to be involved in the epithelial–mesenchymal transition (EMT) of various types of cancer. This makes macrophage-derived inflammatory factors prime targets for the development of new treatments. This study uncovers the therapeutic potential and action mechanism of DAB-2-28, a small-molecule derived from para-aminobenzoic acid, in the treatment of breast cancer. The luminal MCF-7 and the triple-negative MDA-MB-231 cancer cell lines used in this study represent, respectively, breast cancers in which the differentiation states are related to the epithelial phenotype of the mammary gland and breast cancers expressing a highly aggressive mesenchymal phenotype. In MCF-7 cells, soluble factors from macrophage-conditioned media (CM-MØ) induce a characteristic morphology of mesenchymal cells with an upregulated expression of Snail1, a mesenchymal marker, as opposed to a decrease in the expression of E-cadherin, an epithelial marker. DAB-2-28 does not affect the differential expression of Snail1 and E-cadherin in response to CM-MØ, but negatively impacts other hallmarks of EMT by decreasing invasion and migration capacities, in addition to MMP9 expression and gelatinase activity, in both MCF-7 and MDA-MB-231 cells. Moreover, DAB-2-28 inhibits the phosphorylation of key pro-EMT transcriptional factors, such as NFκB, STAT3, SMAD2, CREB, and/or AKT proteins, in breast cancer cells exposed to different EMT inducers. Overall, our study provides evidence suggesting that inhibition of EMT initiation or maintenance is a key mechanism by which DAB-2-28 can exert anti-tumoral effects in breast cancer cells. Full article

The two-spotted spider mite, Tetranychus urticae, is one of the polyphagous pests of several crops and forestry, resistant to numerous conventional chemicals. Due to the negative side effects of harmful chemical pesticides, such as environmental pollution, and risks to human health, the introduction of effective and low-risk alternatives is essential. The promising pesticidal effects of essential oils (EOs) isolated from Artemisia annua have been documented in recent studies. In the present study, the acaricidal effects of an A. annua EO, along with its two dominant monoterpenoids, 1,8-cineole and camphor, were investigated against adults of T. urticae. Artemisia annua EO, 1,8-cineole, and camphor, with 24 h-LC₅₀ values of 0.289, 0.533, and 0.64 µL/L air, respectively, had significant toxicity by fumigation against T. urticae adults. Along with lethality, A. annua EO and monoterpenoids had significant inhibitory effects on the activity of detoxifying enzymes, including α- and β-esterases, glutathione S-transferases, and cytochrome P-450 monooxygenase. According to the findings of the present study, A. annua EO and its two dominant monoterpenoids, 1,8-cineole and camphor, with significant toxicity and inhibitory effects on detoxifying enzymes, can be introduced as available, effective, and eco-friendly acaricides in the management of T. urticae. Full article

Background/Objectives: The diminished efficacy of azoles in treating fungal infections is attributed to the emergence of resistance among pathogenic fungi. Employing a synergistic approach with other compounds to enhance the antifungal activity of azoles has shown promise, yet the availability of clinically valuable adjuvants for azoles and allylamines remains limited. Studies have demonstrated that the human host environment provides multiple carbon sources, which can influence the susceptibility of C. albicans to antifungal agents. Therefore, a comprehensive investigation into the mechanisms by which carbon sources modulate the susceptibility of C. albicans to azoles may uncover a novel pathway for enhancing the antifungal efficacy of azoles. Methods: This study explored the impact of various carbon sources on the antifungal efficacy of azoles through methodologies including minimum inhibitory concentration (MIC) assessments, super-MIC growth (SMG) assays, disk diffusion tests, and spot assays. Additionally, the mechanism by which galactose augments the antifungal activity of azoles was investigated using a range of experimental approaches, such as gene knockout and overexpression techniques, quantitative real-time PCR (qRT-PCR), Western blot analysis, and cycloheximide (CHX) chase experiments. Results: This study observed that galactose enhances the efficacy of azoles against C. albicans by inhibiting the translation of Erg1. This results in the suppression of Erg1 protein levels and subsequent inhibition of ergosterol biosynthesis in C. albicans. Conclusions: In C. albicans, the translation of Erg1 is inhibited when galactose is utilized as a carbon source instead of glucose. This novel discovery of galactose’s inhibitory effect on Erg1 translation is expected to enhance the antifungal efficacy of azoles. Full article

Conessine is a steroidal alkaloid found in many plants. The pharmacological efficacies of conessine on various ailments, including antiviral effects against Zika, Herpes, and Coronavirus, were reported. However, the effect of conessine on the influenza virus was still unknown. In this study, conessine exhibited a strong inhibitory effect against influenza A virus (IAV) infection. We examined the effect of conessine on IAV using green fluorescent protein (GFP)-expressing Influenza A/PR8/34 and wild-type A/PR8/34. The fluorescence-activated cell sorting, fluorescence microscopy, cytopathic effect analysis, and plaque assay demonstrated that conessine significantly inhibits IAV infection. Consistently, immunofluorescence results showed that conessine strongly reduces the expression of IAV proteins. The time-of-drug-addition assay revealed that conessine could affect the viral attachment and entry into the cells upon IAV infection. Further, conessine eradicated the virus before binding to the cells in the early stage of viral infection. Our results suggest that conessine has strong anti-viral efficacy against IAV infection and could be developed as an anti-influenza viral agent. Full article

Background/Objectives: Perceptions of obesity critically influence people’s eating behaviors and responses to food stimuli. However, few studies have investigated the impact of negative body perception on behavioral and neural responses to food stimuli. This study investigates how elevated body dissatisfaction modulates food-related inhibitory control. Methods: Fifty-one participants comprising three cohorts—overweight/obese individuals (OO), normal-weight participants exhibiting high negative body image (HNN), and healthy controls—performed a food-specific inhibitory control task under EEG recording. Results: The results showed that the HNN cohort achieved superior no-go accuracy and enhanced inhibitory control compared to controls. An event-related potentials (ERPs) analysis revealed increased conflict detection (P200) for high-calorie foods and reduced conflict resolution (LPP) in the HNN group, similar to the overweight/obese group. A multivariate pattern analysis (MVPA) identified earlier neural discrimination in the HNN group, suggesting more efficient inhibitory processing. Conclusions: These findings underscore negative body perception as a critical modulator of food-related cognitive control mechanisms. Full article

One major challenge in cellular neuroscience is to elucidate how the accurate alignment of presynaptic release sites with postsynaptic densely clustered ligand-gated ion channels at chemical synapses is achieved upon synapse assembly. The clustering of neurotransmitter receptors at postsynaptic sites is a key moment of synaptogenesis and determinant for effective synaptic transmission. The number of the ionotropic neurotransmitter receptors at these postsynaptic sites of both excitatory and inhibitory synapses is variable and is regulated by different mechanisms, thus allowing the modulation of synaptic strength, which is essential to tune neuronal network activity. Several well-regulated processes seem to be involved, including lateral diffusion within the plasma membrane and local anchoring as well as receptor endocytosis and recycling. The molecular mechanisms implicated are numerous and were reviewed recently in great detail. The role of pre-synaptically released neurotransmitters within the complex regulatory apparatus organizing the postsynaptic site underneath presynaptic terminals is not completely understood, even less for inhibitory synapses. In this mini review article, we focus on this aspect of synapse formation, summarizing and contrasting findings on the functional role of the neurotransmitters glycine and γ-aminobutyric acid (GABA) for initiation of postsynaptic receptor clustering and regulation of Cl⁻ channel receptor numbers at inhibitory synapses gathered over the last two decades. Full article

L-type Ca²⁺ channels, particularly Ca_V1.2, play a crucial role in cardiac excitation-contraction coupling and are known to exhibit mechanosensitivity. However, the mechanisms regulating their response to mechanical stress remain poorly understood. To investigate the mechanosensitivity and nitric oxide (NO)-dependent regulation of L-type Ca²⁺ channels in rat ventricular cardiomyocytes, we used RNA sequencing to assess isoform expression and whole-cell patch-clamp recordings to measure L-type Ca²⁺ current (I_Ca,L) under controlled mechanical and pharmacological conditions. RNA sequencing revealed predominant expression of Ca_V1.2 (TPM: 0.1170 ± 0.0075) compared to Ca_V1.3 (0.0021 ± 0.0002) and Ca_V1.1 (0.0002 ± 0.0002). Local axial stretch (6–10 μm) consistently reduced I_Ca,L in proportion to stretch magnitude. The NO donor SNAP (200 μM) had variable effects on basal I_Ca,L in unstretched cells (stimulatory, inhibitory, or biphasic) but consistently restored stretch-reduced I_Ca,L to control levels. Ascorbic acid (10 μM), which reduces S-nitrosylation, increased basal I_Ca,L and partially restored the reduction caused by stretch, implicating S-nitrosylation in channel regulation. The sGC inhibitor ODQ (5 μM) decreased I_Ca,L in both stretched and unstretched cells, indicating involvement of the NO–cGMP pathway. Mechanical stress modulates L-type Ca²⁺ channels through a complex interplay between S-nitrosylation and NO–cGMP signaling, with S-nitrosylation playing a predominant role in stretch-induced effects. This mechanism may represent a key component of cardiac mechanotransduction and could be relevant for therapeutic targeting in cardiac pathologies involving mechanically induced dysfunction. Full article

Since the onset of industrialization, the safety of arable land has become a pressing global concern, with soil salinization emerging as a critical threat to agricultural productivity and food security. To address this challenge, the cultivation of economically valuable salt-tolerant plants has been proposed as a viable strategy. In the study, we investigated the physiological and molecular responses of Lycium ruthenicum Murr. to varying NaCl concentrations. Results revealed a concentration-dependent dual effect: low NaCl levels significantly promoted seed germination, while high concentrations exerted strong inhibitory effects. To elucidate the mechanisms underlying these divergent responses, a combined analysis of metabolomics and transcriptomics was applied to identify key metabolic pathways and genes. Notably, salt stress enhanced photosynthetic efficiency through coordinated modulation of ribulose 5-phosphate and erythrose-4-phosphate levels, coupled with the upregulation of critical genes encoding RPIA (Ribose 5-phosphate isomerase A) and RuBisCO (Ribulose-1,5-bisphosphate carboxylase/oxygenase). Under low salt stress, L. ruthenicum maintained intact cellular membrane structures and minimized oxidative damage, thereby supporting germination and early growth. In contrast, high salinity severely disrupted PS I (Photosynthesis system I) functionality, blocking energy flow into this pathway while simultaneously inducing membrane lipid peroxidation and triggering pronounced cellular degradation. This ultimately suppressed seed germination rates and impaired root elongation. These findings suggested a mechanistic framework for understanding L. ruthenicum adaptation under salt stress and pointed out a new way for breeding salt-tolerant crops and understanding the mechanism. Full article

The organization of consciousness is described through increasingly rich theoretical models. We review evidence that working memory capacity—essential to generating consciousness in the cerebral cortex—is supported by dual limbic memory systems. These dorsal (Papez) and ventral (Yakovlev) limbic networks provide the basis for mnemonic processing and prediction in the dorsal and ventral divisions of the human neocortex. Empirical evidence suggests that the dorsal limbic division is (i) regulated preferentially by excitatory feedforward control, (ii) consolidated by REM sleep, and (iii) controlled in waking by phasic arousal through lemnothalamic projections from the pontine brainstem reticular activating system. The ventral limbic division and striatum, (i) organizes the inhibitory neurophysiology of NREM to (ii) consolidate explicit memory in sleep, (iii) operating in waking cognition under the same inhibitory feedback control supported by collothalamic tonic activation from the midbrain. We propose that (i) these dual (excitatory and inhibitory) systems alternate in the stages of sleep, and (ii) in waking they must be balanced—at criticality—to optimize the active inference that generates conscious experiences. Optimal Bayesian belief updating rests on balanced feedforward (excitatory predictive) and feedback (inhibitory corrective) control biases that play the role of prior and likelihood (i.e., sensory) precision. Because the excitatory (E) phasic arousal and inhibitory (I) tonic activation systems that regulate these dual limbic divisions have distinct affective properties, varying levels of elation for phasic arousal (E) and anxiety for tonic activation (I), the dual control systems regulate sleep and consciousness in ways that are adaptively balanced—around the entropic nadir of E–I criticality—for optimal self-regulation of consciousness and psychological health. Because they are emotive as well as motive control systems, these dual systems have unique qualities of feeling that may be registered as subjective experience. Full article

The escalating global challenges of antimicrobial resistance (AMR) and cancer necessitate innovative therapeutic solutions from natural sources. This study investigated the multifaceted therapeutic potential of pigment-enriched plant extracts. We screened diverse plant extracts for antimicrobial and antibiofilm activity against multidrug-resistant bacteria and fungi. Hibiscus sabdariffa emerged as the most promising, demonstrating potent broad-spectrum antimicrobial and significant antibiofilm activity. Sub-inhibitory concentrations of H. sabdariffa robustly downregulated essential bacterial virulence genes and suppressed aflatoxin gene expression. Comprehensive chemical profiling via HPLC identified major anthocyanin glucosides, while GC-MS revealed diverse non-pigment bioactive compounds, including fatty acids and alcohols. Molecular docking suggested favorable interactions of key identified compounds (Cyanidin-3-O-glucoside and 1-Deoxy-d-arabitol) with E. coli outer membrane protein A (OmpA), indicating potential antiadhesive and antimicrobial mechanisms. Furthermore, H. sabdariffa exhibited selective cytotoxicity against MCF-7 breast cancer cells. These findings establish H. sabdariffa pigment-enriched extract as a highly promising, multi-functional source of novel therapeutics, highlighting its potential for simultaneously addressing drug resistance and cancer challenges through an integrated chemical, biological, and computational approach. Full article

The ability of the neuropeptide oxytocin to affect glial cell function is receiving increasing attention. We previously reported that oxytocin at a low nanomolar concentration could inhibit both astrocytic Ca²⁺ signals and glutamate release. Here, we investigate the ability of oxytocin receptors to couple both inhibitory and stimulatory pathways in astrocytes, as already reported in neurons. We assessed the effects of oxytocin at concentrations ranging from low to high in the nanomolar range on intracellular Ca²⁺ signals and on the glutamate release in astrocyte processes freshly prepared from the striatum of adult rats. Our main findings are as follows: oxytocin could induce dual responses in astrocyte processes, namely the inhibition and facilitation of both Ca²⁺ signals and glutamate release; the inhibitory and the facilitatory response appeared dependent on activation of the G_i and the G_q pathway, respectively; both inhibitory and facilitatory responses were evoked at the same nanomolar oxytocin concentrations; and the biased agonists atosiban and carbetocin could duplicate oxytocin’s inhibitory and facilitatory response, respectively. In conclusion, due to the coupling of striatal astrocytic oxytocin receptors to different transduction pathways and the dual effects on Ca²⁺ signals and glutamate release, oxytocin could also play a crucial role in neuron–astrocyte bi-directional communication through a subtle regulation of striatal glutamatergic synapses. Therefore, astrocytic oxytocin receptors may offer pharmacological targets to regulate glutamatergic striatal transmission, which is potentially useful in neuropsychiatric disorders and in neurodegenerative diseases. Full article

This study evaluated the inhibitory efficacy of sulphur dioxide, hydrogen peroxide, copper sulphate pentahydrate, chlorine-based formulations, a chlorine-free formulation, ethanol, and acetic acid against Cladosporium cladosporioides, Aspergillus niger, and Penicillium expansum. An in vitro inhibition test was employed to investigate the inhibitory properties. The results demonstrated different sensitivities of filamentous fungi to the inhibitors. All tested substances displayed fungicidal properties. Sulphur dioxide (40% NH₄HSO₃ solution) inhibited growth at a 4% v/v concentration. No minimum effective concentration was established for H₂O₂; only a 30% w/v solution inhibited P. expansum. CuSO₄·5H₂O completely inhibited fungal growth at 5% w/v solution, with 2.5% w/v also proving effective. For the chlorine-based product, 40% w/v solution (48 g∙L⁻¹ active chlorine) had the most substantial effect, though it only slowed growth, and NaClO solution completely inhibited growth at 2.35 g NaClO per 100 g of product (50% w/v solution). FungiSAN demonstrated fungicidal effects; however, the recommended dose was insufficient for complete inhibition. Ethanol exhibited the lowest efficacy, while the inhibitory threshold for CH₃COOH was found to be a 5% v/v solution. The findings of this study may serve as a basis for informed decision-making when selecting the most suitable product, depending on specific application conditions. Full article

Among the new strategies for managing diseases in agricultural crops is the application of metallic nanoparticles due to their ability to inhibit the development of phytopathogenic microorganisms and to induce plant defense responses. Therefore, this research evaluated the effects of silver (AgNPs), zinc oxide (ZnONPs), and silicon dioxide (SiO₂NPs) nanoparticles on symptom progression and physiological parameters in two pathosystems: Pseudomonas syringae pv. tomato (Psto) in tomato (pathosystem one, culturable pathogen) and Candidatus Liberibacter solanacearum (CaLso) in pepper plants (pathosystem two, non-culturable pathogen). For in vitro pathosystem one assays, SiO₂NPs did not inhibit Psto growth. The minimum inhibitory concentration (MIC) was 31.67 ppm for AgNPs and 194.3 ppm for ZnONPs. Furthermore, the minimum lethal concentration (MLC) for AgNPs was 100 ppm, while for ZnONPs, it was 1000 ppm. For in planta assays, ZnONPs, AgNPs, and SiO₂NPs reduced the number of lesions per leaf, but only ZnONPs significantly decreased the severity. Regarding pathosystem two, AgNPs, ZnONPs, and SiO₂NPs application delayed symptom progression. However, only AgNPs significantly reduced severity percentage. Moreover, treatments with AgNPs and SiO₂NPs increased the plant height and dry weight compared to the results for the control. Full article

Background: Antibacterial resistance (ABR) poses a major challenge to global health, with methicillin-resistant Staphylococcus aureus (MRSA) being one of the prominent multidrug-resistant strains. MRSA has developed resistance through the expression of Penicillin-Binding Protein 2a (PBP2a), a key transpeptidase enzyme involved in bacterial cell wall biosynthesis. Objectives: The objective was to design and characterize a novel small-molecule inhibitor targeting PBP2a as a strategy to combat MRSA. Methods: We synthesized a new indole triazole conjugate (ITC) using eco-friendly and click chemistry approaches. In vitro antibacterial tests were performed against a panel of strains to evaluate the ITC antibacterial potential. Further, a series of in silico evaluations like molecular docking, MD simulations, free energy landscape (FEL), and principal component analysis (PCA) using the crystal structure of PBP2a (PDB ID: 4CJN), in order to predict the mechanism of action, binding mode, structural stability, and energetic profile of the 4CJN-ITC complex. Results: The compound ITC exhibited noteworthy antibacterial activity, which effectively inhibited the selected strains. Binding score and energy calculations demonstrated high affinity of ITC for the allosteric site of PBP2a and significant interactions responsible for complex stability during MD simulations. Further, FEL and PCA provided insights into the conformational behavior of ITC. These results gave the structural clues for the inhibitory action of ITC on the PBP2a. Conclusions: The integrated in vitro and in silico studies corroborate the potential of ITC as a promising developmental lead targeting PBP2a in MRSA. This study demonstrates the potential usage of rational drug design approaches in addressing therapeutic needs related to ABR. Full article