Action Potential Research Articles

Impaired excitability of fast-spiking neurons in a novel mouse model of KCNC1 epileptic encephalopathy.

The recurrent pathogenic variant KCNC1-p.Ala421Val (A421V) is a cause of developmental and epileptic encephalopathy characterized by moderate-to-severe developmental delay/intellectual disability, and infantile-onset treatment-resistant epilepsy with multiple seizure types including myoclonic seizures. Yet, the mechanistic basis of disease is unclear. KCNC1 encodes Kv3.1, a voltage-gated potassium channel subunit that is highly and selectively expressed in neurons capable of generating action potentials at high frequency, including parvalbumin-positive fast-spiking GABAergic inhibitory interneurons in cerebral cortex (PV-INs) known to be important for cognitive function and plasticity as well as control of network excitation to prevent seizures. In this study, we generate a novel transgenic mouse model with conditional expression of the Ala421Val pathogenic missense variant (Kcnc1-A421V/+ mice) to explore the physiological mechanisms of KCNC1 developmental and epileptic encephalopathy. Our results indicate that global heterozygous expression of the A421V variant leads to epilepsy and premature lethality. We observe decreased PV-IN cell surface expression of Kv3.1 via immunohistochemistry, decreased voltage-gated potassium current density in PV-INs using outside-out nucleated macropatch recordings in brain slice, and profound impairments in the intrinsic excitability of cerebral cortex PV-INs but not excitatory neurons in current-clamp electrophysiology. In vivo two-photon calcium imaging revealed hypersynchronous discharges correlated with brief paroxysmal movements, subsequently shown to be myoclonic seizures on electroencephalography. We found alterations in PV-IN-mediated inhibitory neurotransmission in young adult but not juvenile Kcnc1-A421V/+ mice relative to wild-type controls. Together, these results establish the impact of the recurrent Kv3.1-A421V variant on neuronal excitability and synaptic physiology across development to drive network dysfunction underlying KCNC1 epileptic encephalopathy.

An efficient approach for EMG controlled pattern recognition system based on MUAP identification and segregation

An Electromyography (EMG) based pattern recognition system constitutes various steps of signal processing and control engineering from signal acquisition to real-time control. Efficient control of external devices largely depends on the signal processing steps executed before the final output. This work presents a new approach to signal processing using Motor Unit Action Potential (MUAP) based signal decomposition and segmentation. An MUAP is a neurological response during muscle contraction. Due to the higher contact area of surface electrodes, MUAPs from multiple muscles are captured. An MUAP generated from a single muscle usually has identical waveshapes and similar discharging rates and usually lasts for 8–15 ms. These are known as primary MUAPs. The proposed algorithm identifies and uses the primary observed MUAPs for feature extraction and classification. Firstly, noise signals are eliminated by a determined noise margin, which also separates the active muscle movement signals. Next, a novel MUAP identification algorithm is implemented to detect the MUAP trains. Then, identified primary MUAPs are used to make segments with variable widths to extract feature vectors. Based on the correlation score of all the primary MUAPs, the segmentation is performed, which results in segmentation width varying from 110–200 ms. The achieved segmentation width is lesser than the conventional overlapping and non-overlapping methods — the proposed approach results in a 20 to 50% reduction in the segmentation width. Four different classifiers are tested during the machine learning stage to investigate the performance of the proposed approach. The obtained feature sets are then used to train the Linear Discriminant Analysis (LDA), K-Nearest Neighbor (kNN), Decision Tree (DT), and Random Forest (RF) classifiers. The classifiers are tested with precision, recall, F1 score, and accuracy. The kNN and DT classifiers performed better than the LDA and RF classifiers. The maximum precision and recall are 100% while the maximum achieved accuracy is 98.56%. The comparative results show higher accuracy even at lower segmentation widths than the conventional constant window scheme. The kNN and DT classifiers provide a 5% to 15% increment in accuracy compared to the constant window segmentation-based approach.

Modulatory Impact of Oxidative Stress on Action Potentials in Pathophysiological States: A Comprehensive Review.

Oxidative stress, characterized by an imbalance between the production of reactive oxygen species (ROS) and the body's antioxidant defenses, significantly affects cellular function and viability. It plays a pivotal role in modulating membrane potentials, particularly action potentials (APs), essential for properly functioning excitable cells such as neurons, smooth muscles, pancreatic beta cells, and myocytes. The interaction between oxidative stress and AP dynamics is crucial for understanding the pathophysiology of various conditions, including neurodegenerative diseases, cardiac arrhythmias, and ischemia-reperfusion injuries. This review explores how oxidative stress influences APs, focusing on alterations in ion channel biophysics, gap junction, calcium dynamics, mitochondria, and Interstitial Cells of Cajal functions. By integrating current research, we aim to elucidate how oxidative stress contributes to disease progression and discuss potential therapeutic interventions targeting this interaction.

The upregulation of K+ and HCN channels in developing spiral ganglion neurons is mediated by cochlear inner hair cells.

Spiral ganglion neurons (SGNs) are primary sensory afferent neurons that relay acoustic information from the cochlear inner hair cells (IHCs) to the brainstem. The response properties of different SGNs diverge to represent a wide range of sound intensities in an action-potential code. This biophysical heterogeneity is established during pre-hearing stages of development, a time when IHCs fire spontaneous Ca2+ action potentials that drive glutamate release from their ribbon synapses onto the SGN terminals. The role of spontaneous IHC activity in the refinement of SGN characteristics is still largely unknown. Using pre-hearing otoferlin knockout mice (Otof-/-), in which Ca2+-dependent exocytosis in IHCs is abolished, we found that developing SGNs fail to upregulate low-voltage-activated K+-channels and hyperpolarisation-activated cyclic-nucleotide-gated channels. This delayed maturation resulted in hyperexcitable SGNs with immature firing characteristics. We have also shown that SGNs that synapse with the pillar side of the IHCs selectively express a resurgent K+ current, highlighting a novel biophysical marker for these neurons. RNA-sequencing showed that several K+ channels are downregulated in Otof-/- mice, further supporting the electrophysiological recordings. Our data demonstrate that spontaneous Ca2+-dependent activity in pre-hearing IHCs regulates some of the key biophysical and molecular features of the developing SGNs. KEY POINTS: Ca2+-dependent exocytosis in inner hair cells (IHCs) is otoferlin-dependent as early as postnatal day 1. A lack of otoferlin in IHCs affects potassium channel expression in SGNs. The absence of otoferlin is associated with SGN hyperexcitability. We propose that type I spiral ganglion neuron functional maturation depends on IHC exocytosis.

Retina-Inspired Lightweight Spiking Convolutional Neural Network for Single-Image Dehazing.

Suspended particles in hazy medium absorb and scatter light, severely degrading imaging quality. Numerous single-image dehazing methods have been proposed to reconstruct clear images from hazy ones. However, most of them focus on increasing depth and width to improve dehazing performance, which incurs high computation and energy costs. To address this issue, we propose a lightweight spiking convolutional neural network (CNN) referred to as retina-inspired spiking CNN (RI-SCNN) for the reconstruction of hazy images. Unlike conventional dehazing techniques, first, our proposed network simulates the hierarchical structure and cellular function of the retina and devises five network modules to efficiently encode and extract image features through ON and OFF roads. Furthermore, the linear reconstruction mechanism is introduced to integrate the outputs from different roads, adaptively preserving regions with optimal details and constructing a comprehensive visual representation. Finally, by the transformed atmospheric scattering formula, our network can generate the dehazy image. Incorporating the microscale spiking mechanism of the brain, the entire network leverages discrete binary spike trains for information encoding and transmission, directly trained by spiking surrogate gradient learning on integrate-and-fire (IF) neurons. Experimental results demonstrate the superiority of the proposed RI-SCNN in terms of quantitative dehazing performance, qualitative visual effect, energy efficiency, and run speed. Considering its lightweight architecture with ultralow computation and energy costs, the network is encouraged to be deployed in the visual sensor hardware to improve overall performance.

Diosmin and Hesperidin Have a Protective Effect in Diabetic Neuropathy via the FGF21 and Galectin-3 Pathway.

Background and Objectives: This study aimed to investigate the protective effect of diosmin and hesperidin in diabetic neuropathy using a rat model, focusing on their impact on nerve regeneration through the fibroblast growth factor 21 (FGF21) and galectin-3 (gal3) pathway. Materials and Methods: Forty adult male Wistar rats were used in this study. Diabetes was induced using streptozotocin (STZ), and the rats were divided into control, diabetes and saline-treated, diabetes and diosmin + hesperidin (150 mg/kg) treated, and diabetes and diosmin + hesperidin (300 mg/kg) treated groups. Electromyography (EMG) and inclined plane testing were performed to assess nerve function and motor performance. Sciatic nerve sections were examined histopathologically. Plasma levels of FGF21, galectin-3, and malondialdehyde (MDA) were measured as markers of oxidative stress and inflammation. Results: Diabetic rats treated with saline displayed reduced nerve conduction parameters and impaired motor performance compared to controls. Treatment with diosmin and hesperidin significantly improved compound muscle action potential (CMAP) amplitude, distal latency, and motor performance in a dose-dependent manner. Histopathological examination revealed decreased perineural thickness in treated groups. Additionally, treatment with diosmin and hesperidin resulted in increased plasma FGF21 levels and reduced plasma levels of galectin-3 and MDA, indicating decreased oxidative stress and inflammation. Conclusions: Diosmin and hesperidin exhibited protective effects in diabetic neuropathy by promoting nerve regeneration, enhancing nerve conduction, and improving motor performance. These effects were associated with modulation of the FGF21 and galectin-3 pathway. These findings suggest that diosmin and hesperidin may hold potential as adjunctive therapies for diabetic neuropathy.

A Brief Review on Neuropharmacological Evaluation of Different Phytochemicals and Medicinal Plants in The Management of Stress and Depression.

Numerous neuropsychiatric and neurodegenerative problems, such as anxiety, cerebrovascular problems, depression, seizures, Parkinson’s disease, and others. are currently dominating the scene as a result of their high-stress lifestyle. Treatment of these issues with postponed association of produced drugs will provoke serious coincidental impacts. In recent years, researchers have stood out sufficiently to be noticed in their investigation of phytochemicals as potential treatments for neurological issues. The unique phytochemicals found in various plants, such as alkaloids, steroids, terpenoids, saponins, phenolics, and flavonoids, contribute to the neuroprotective effects of nootropic flavors. Phytocompounds from restorative plants have a significant impact on maintaining the mind’s compound equilibrium by following up on the capability of receptors for the major inhibitory synapses. recovering plants, for example, Valeriana officinalis, Nardostachys jatamansi, Withania somnifera, Bacopa monniera, Ginkgo biloba and Panax ginseng have been utilized broadly in various standard frameworks of treatment considering their adaptogenic, psychotropic and neuroprotective properties. The significance of phytochemicals’ system of action and beneficial potential in relation to neuroprotective capacity and other issues is the subject of this study.

Epidural Spinal Cord Recordings (ESRs): sources of neural-appearing artifact in stimulation evoked compound action potentials.

Evoked compound action potentials (ECAPs) measured during epidural spinal cord stimulation (SCS) can help elucidate fundamental mechanisms for the treatment of pain and inform closed-loop control of SCS. Previous studies have used ECAPs to characterize neural responses to various neuromodulation therapies and have demonstrated that ECAPs are highly prone to multiple sources of artifact, including post-stimulus pulse capacitive artifact, electromyography (EMG) bleed-through, and motion artifact. However, a thorough characterization has yet to be performed for how these sources of artifact may contaminate recordings within the temporal window commonly used to determine activation of A-beta fibers in a large animal model.
We characterized sources of artifacts that can contaminate the recording of ECAPs in an epidural SCS swine model using the Abbott Octrode™ lead. Spinal ECAP recordings can be contaminated by capacitive artifact, short latency EMG from nearby muscles of the back, and motion artifact. The capacitive artifact can appear nearly identical in duration and waveshape to evoked A-beta responses. EMG bleed-through can have phase shifts across the electrode array, similar to the phase shift anticipated by propagation of an evoked A-beta fiber response. The short latency EMG is often evident at currents similar to those needed to activate A-beta fibers associated with the treatment of pain. Changes in CSF between the cord and dura, and motion induced during breathing created a cyclic oscillation in all evoked components of recorded ECAPs. 
Controls must be implemented to separate neural signal from sources of artifact in SCS ECAPs. We suggest experimental procedures and reporting requirements necessary to disambiguate underlying neural response from these confounds. These data are important to better understand the framework for recorded ESRs, with components such as ECAPs, EMG, and artifacts, and have important implications for closed-loop control algorithms to account for transient motion such as postural changes and cough.

Inhibition of KIF5b-mediated Nav1.8 transport by ropivacaine contributes to axonal regeneration following sciatic nerve injury in rats

Peripheral nerve injury (PNI), typically caused by traumatic accidents or medical events, is currently one of the most common diseases that leads to limb disability. After PNI, tetrodotoxin-resistant voltage-gated sodium channel Nav1.8 is upregulated at the lesion site. Our earlier study suggested that ropivacaine promotes axon regrowth by regulating Nav1.8-mediated macrophage signaling. Nevertheless, the mechanism of ropivacaine in regulation of Nav1.8 expression remains incompletely understood. Kinesin family 5b (KIF5b) was reported to mediate the Nav1.8 axonal transport from dorsal root ganglia (DRGs) to lesion site. Herein, we investigated whether ropivacaine promotes axon regeneration through inhibition of KIF5b-mediated Nav1.8 transport. Reduced levels of KIF5b and Nav1.8 in DRGs coincide with their increase at the lesion site. Nav1.8 mRNA was significantly increased at the lesion site but not in DRGs. Surprisingly, ropivacaine reversed the alterations of Nav1.8 and KIF5b protein expression without affecting Nav1.8 mRNA level. Due to KIF5b overexpression in DRGs, Nav1.8 protein level was significantly decreased in DRGs and increased at the lesion site. We also found KIF5b overexpression significantly impaired behavioral functions, reduced the recovery index of compound muscle action potential (CMAP) amplitude, inhibited axonal regrowth, slowed M1 macrophage infiltration and shift to M2 phenotype, and delayed myelin debris clearance. Notably, all aforementioned results caused by KIF5b overexpression were alleviated by ropivacaine. Furthermore, we demonstrated that inhibition of Nav1.8 transport by A-803467 produced mitigating effects on the impairment of regenerative capacity induced by KIF5b overexpression similar to ropivacaine. These results suggest that ropivacaine promotes axonal regeneration at least partially by inhibiting KIF5b-mediated Nav1.8 forward transport.

The long-term impact of rehabilitation in upper limb plexopathies

The main objective of the research consists in providing evidence that a long-term rehabilitation protocol is favorable for the patient. In adult brachial plexus (BP) palsies, after several surgical attempts, the lack of results in the upper limb’s functionality leads to less compliance to rehabilitation therapy. The upper limb’s functionality of 22 patients with posttraumatic operated chronic BP paresis (either on the right or left, regardless the dominant limb) was assessed retrospectively. The patients were evaluated regarding MRC scaling, dynamometric tests and electroneuromyographic examination. All patients have gone through at least one rehabilitation interval (10 days) after an initial evaluation, and were evaluated again, by same methods, at a second session, at least 6 months later, but no more than one year.. Mild and inconstant improvements were obtained in a total of 9 patients, especially in better dynamometric results and improved amplitudes of motor and sensory action potentials. The electrodiagnosis correlates with dynamometric parameters (muscle strength) and slight amelioration of the motor deficit. Given the small sample size as a limitation, as well as no standardized therapeutic protocol, it should be noted that the 9 patients were the only ones who either attended more than one interval or did more procedures as frequency in time (more often meaning 3 times weekly for 6 months, in 6 patients). Although the most frequent procedures were neuromuscular electrical stimulation (NMES) and proprioceptive neuromuscular facilitation (PNF), the results suggest that regardless of the techniques, the more active patients had better results. Proving the need for long-term rehabilitation, even contrary to the less visible results, can be the trigger point for future research and therapy strategies, as the results suggest central mechanisms involved, adding the cortical ongoing plasticity into the equation.

Magnetic Detection of Neural Activity by Nanocoil Transducers.

Electrophysiological recordings from brain cells are performed routinely using implanted electrodes, but they traditionally require a wired connection to the outside of the brain. A completely passive, wireless device that does not require on-board power for active transmission but that still facilitates remote detection could open the door for mass-scale direct recording of action potentials and transform the way we acquire brain signals. We present a nanofabricated coil that forms a neuroelectromagnetic junction, yielding a highly enhanced magnetic field transduction of electrophysiology. We show that this micrometer-scale device enables remote magnetic detection of neuronal fields from the center of the coil using room temperature superconducting quantum interference device (SQUID) microscopy. Further, time-locked stimulation in conjunction with magnetometry demonstrates thresholding behavior that affirms the viability of the technology for detection with no requirement for wires or on-board power. This strategy may permit unprecedented detection of electrophysiology using magnetoencephalography and magnetic resonance imaging.

ChiSCAT: Unsupervised Learning of Recurrent Cellular Micromotion Patterns from a Chaotic Speckle Pattern.

There is considerable evidence that action potentials are accompanied by "intrinsic optical signals", such as a nanometer-scale motion of the cell membrane. Here we present ChiSCAT, a technically simple imaging scheme that detects such signals with interferometric sensitivity. ChiSCAT combines illumination by a chaotic speckle pattern and interferometric scattering microscopy (iSCAT) to sensitively detect motion in any direction. The technique features reflective high-NA illumination, common-path suppression of vibrations, and a large field of view. This approach maximizes sensitivity to motion, but does not produce a visually interpretable image. We show that unsupervised learning based on matched filtering and motif discovery can recover underlying motion patterns and detect action potentials. We demonstrate these claims in an experiment on blebbistatin-paralyzed cardiomyocytes. ChiSCAT opens the door to action potential measurement in scattering tissue, including a living brain.

Psychedelics as novel therapeutic agents for chronic pain: mechanisms and future perspectives

Chronic neuropathic pain is a significant public health issue affecting an estimated 1.5 billion individuals worldwide. The mechanisms underlying chronic pain are multifaceted and not fully understood. Chronic pain amplifies specific neural pathways through peripheral and central sensitization triggered by repeated exposure to noxious stimuli, ultimately resulting in physical and emotional pain. Traditional treatment options targeting these mechanisms, such as opioid and non-opioid analgesics, are associated with adverse effects, addiction, and suboptimal pain relief. Using psychedelics to treat chronic pain is an area of growing interest. While psychedelic substances, such as psilocybin, lysergic acid diethylamide, mescaline, and 3,4-methylenedioxymethamphetamine are primarily associated with recreational use or spiritual practices, emerging evidence suggests their potential therapeutic benefits for various mental health disorders, including chronic pain. Psychedelics alter pain perception by directly activating serotonin receptors, exerting anti-inflammatory effects, enhancing descending inhibition, opening a window of neuroplasticity, and facilitating synaptic remodeling. This review mainly elucidates the ongoing research regarding the psychedelic mechanisms of action, pharmacology, clinical applications, and therapeutic potential in treating neuropathic pain.

Statistical Inference for Networks of High-Dimensional Point Processes

Fueled in part by recent applications in neuroscience, the multivariate Hawkes process has become a popular tool for modeling the network of interactions among high-dimensional point process data. While evaluating the uncertainty of the network estimates is critical in scientific applications, existing methodological and theoretical work has primarily addressed estimation. To bridge this gap, we develop a new statistical inference procedure for high-dimensional Hawkes processes. The key ingredient for the inference procedure is a new concentration inequality on the first- and second-order statistics for integrated stochastic processes, which summarize the entire history of the process. Combining recent martingale central limit theorem with the new concentration inequality, we then characterize the convergence rate of the test statistics in a continuous time domain. Finally, to account for potential non-stationarity of the process in practice, we extend our statistical inference procedure to a flexible class of Hawkes processes with time-varying background intensities and unknown transition functions. The finite sample validity of the inferential tools is illustrated via extensive simulations and further applied to a neuron spike train dataset. Supplementary materials for this article are available online, including a standardized description of the materials available for reproducing the work.

Monitoring surgical nociception using multisensor physiological models

Monitoring nociception, the flow of information associated with harmful stimuli through the nervous system even during unconsciousness, is critical for proper anesthesia care during surgery. Currently, this is done by tracking heart rate and blood pressure by eye. Monitoring objectively a patient's nociceptive state remains a challenge, causing drugs to often be over- or underdosed intraoperatively. Inefficient management of surgical nociception may lead to more complex postoperative pain management and side effects such as postoperative cognitive dysfunction, particularly in elderly patients. We collected a comprehensive and multisensor prospective observational dataset focused on surgical nociception (101 surgeries, 18,582 min, and 49,878 nociceptive stimuli), including annotations of all nociceptive stimuli occurring during surgery and medications administered. Using this dataset, we developed indices of autonomic nervous system activity based on physiologically and statistically rigorous point process representations of cardiac action potentials and sweat gland activity. Next, we constructed highly interpretable supervised and unsupervised models with appropriate inductive biases that quantify surgical nociception throughout surgery. Our models track nociceptive stimuli more accurately than existing nociception monitors. We also demonstrate that the characterizing signature of nociception learned by our models resembles the known physiology of the response to pain. Our work represents an important step toward objective multisensor physiology-based markers of surgical nociception. These markers are derived from an in-depth characterization of nociception as measured during surgery itself rather than using other experimental models as surrogates for surgical nociception.

P300/CBP KATs Are Critical for Maturation and Differentiation of Adult Neural Progenitors.

Epigenetic modifications play a pivotal role in the process of neurogenesis. Among these modifications, reversible acetylation fine-tunes gene expression for both embryonic and adult neurogenesis. The CBP/KAT3A and its paralogue p300/KAT3B are well-known lysine acetyltransferases with transcriptional coactivation ability that engage in neural plasticity and memory. The exclusive role of their KAT activity in neurogenesis and memory could not be addressed due to the absence of a p300/CBP modulator, which can cross the blood-brain barrier. Previous work from our laboratory has shown that a small molecule activator, TTK21, specific to CBP/p300, when conjugated to glucose-derived carbon nanospheres (CSP), is efficiently delivered to the mouse brain and could induce dendritic branching and extend long-term memory. However, the molecular mechanisms of p300 acetyltransferase activity-dependent enhanced dendritogenesis are yet to be understood. Here, we report that CSP-TTK21 treatment to primary neuronal culture derived from mouse embryo enhances the expression of five critical genes: Neurod1 (central nervous system development), Tubb3 (immature neural marker), Camk2a (synaptic plasticity and LTP), Snap25 (spine morphogenesis plasticity), and Scn2a (propagation of the action potential). Activation of these genes by inducing the p300/CBP KAT activity presumably promotes the maturation and differentiation of adult neuronal progenitors and thereby the formation of long and highly branched doublecortin-positive functional neurons in the subgranular zone of the dentate gyrus.

Haptic Perception and Its Relation to Action.

Haptic perception uses signals from touch receptors to detect, locate, and mentally represent objects and surfaces. Research from behavioral science, neuroscience, and computational modeling advances understanding of these essential functions. Haptic perception is grounded in neural circuitry that transmits external contact to the brain via increasingly abstracted representations. Computational models of mechanical interactions at the skin predict peripheral neural firing rates that initiate the processing chain. Behavioral phenomena and associated neural processes illustrate the reciprocal relationship by which perception supports action and action gates experience. The interaction of sensation and action is evident in how features of surfaces and objects such as softness and curvature are encoded. By incorporating touch sensations in conjunction with motor control, biologically embedded prosthetics enhance user capabilities and may elicit feelings of ownership. Efforts to create virtual haptic experience with advanced technologies underscore the complexity of this fundamental perceptual channel and its relation to action.

Exploring the Mechanism of Action of Lycium barbarum in Treating Allergic Rhinitis Using Network Pharmacology and Molecular Docking

Objective: Approximately 10%-40% of the global population is affected by allergic rhinitis, and Lycium barbarum has a long history of dual use as a herbal medicine and also as a food. This study utilized network pharmacology and molecular docking to explore the mechanism of action of Lycium barbarum in treating allergic rhinitis. Methods: We screened active ingredients and potential action targets of Lycium barbarum using the TCMSP database. Relevant targets for allergic rhinitis diseases were accessed through the GeneCards and OMIM databases. GO function enrichment and KEGG pathway enrichment analyses of key targets were conducted using the DAVID database. Molecular docking validation was performed using Autodock Vina software to confirm the affinity between the core protein targets and the key active ingredients. Results: Network pharmacological analysis identified 35 major active ingredients of Lycium barbarum, 87 drug targets, and 2200 disease targets. GO functional analysis and KEGG pathway enrichment analysis revealed that the mechanism of action of Lycium barbarum in treating allergic rhinitis involves multiple pathways, including the HIF-1 signaling pathway, IL-17 signaling pathway, and TNF signaling pathway. Molecular docking results demonstrated good binding activity between the main active ingredients and the core protein target. Conclusion: Lycium barbarum exhibits multi-component, multi-target, and multi-pathway actions in treating allergic rhinitis by regulating relevant pathways and targets.

Evaluation of inhibition effect and interaction mechanism of antiviral drugs on main protease of novel coronavirus: Molecular docking and molecular dynamics studies

The outbreak of pneumonia caused by the novel coronavirus (SARS-CoV-2) has presented a challenge to public health. The identification and development of effective antiviral drugs is essential. The main protease (3CLpro) plays an important role in the viral replication of SARS-CoV-2 and is considered to be an effective therapeutic target. In this study, according to the principle of drug repurposing, a variety of antiviral drugs commonly used were studied by molecular docking and molecular dynamics (MD) simulations to obtain potential inhibitors of main proteases. 24 antiviral drugs were docked with 5 potential action sites of 3CLpro, and the drugs with high binding strength were further simulated by MD and the molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) binding free energy calculations. The results showed that the drugs with high flexibility could bind to 3CLpro better than those with low flexibility. The interaction mechanism between antiviral drugs and main protease was analyzed in detail by calculating the root mean square displacement (RMSD), root mean square fluctuation (RMSF) and interaction residues properties. The results showed that the six drugs with high flexibility (Remdesivir, Simnotrelvir, Sofosbuvir, Ledipasvir, Indinavir and Raltegravir) had strong binding strength with 3CLpro, and the last four antiviral drugs can be used as potential candidates for main protease inhibitors.

14K prolactin derived 14-mer antiangiogenic peptide targets bradykinin-/nitric oxide-cGMP-dependent angiogenesis.

Over the past few decades, VEGF-targeted antiangiogenic therapy for cancers has gained increasing attention. Nevertheless, there are still several limitations such as the potential resistance mechanisms arising in cancer cells against these therapies and their potential adverse effects. These limitations highlight the need for novel anti-angiogenesis molecules and better understanding of the mechanisms of tumor angiogenesis. In the present study, we investigated the antiangiogenic properties of a novel 14-mer antiangiogenic peptide (14-MAP) derived from N-terminal 14 kDa buffalo prolactin and characterized its mode of action. 14-MAP at the picomolar concentration inhibited VEGF- and bradykinin (an autacoid peptide expressed in vascular tissues in pathophysiology, BK)-stimulated endothelial nitric oxide (eNO) production, cell migration, and proliferation in endothelial cells and vessel development in the chick embryo. Although this peptide inhibited both VEGF- and BK-dependent angiogenic processes, its action was more pronounced in the latter. Moreover, the interference of 14-MAP with the eNO synthase (eNOS)-cyclic GMP pathway was also identified. A combination of a low dose of Avastin, a widely used drug targeting VEGF-dependent angiogenesis, and 14-MAP significantly reduced tumor size in an in vivo model of human colon cancer. Taken together, our results suggest that 14-MAP, a BK- and eNOS-dependent antiangiogenic peptide, might be useful for overcoming the limitation of VEGF-targeted antiangiogenic therapy in cancer patients. However, further studies will be required to further characterize its mode of action and therapeutic potential.