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Peripheral nerve injury causes neuropathic pain and microglia activation. P2Y12 receptors on microglia are thought to be a key player in the surveillance of the local environment, but whether or how these receptors are engaged in the cross-talk between microglia and neurons of the dorsal horn remain ambiguous. Using a rodent model of nerve injury-induced pain, we investigated the roles of P2Y12 in microglia activation, excitatory synaptic transmission, and nociceptive allodynia. We found that spinal nerve ligation (SNL) significantly increased the level of P2Y12 receptors specifically in the microglia of the ipsilateral dorsal horn. Injections of P2Y12 antagonists (MRS2395 or clopidogrel) attenuated microglia activation and increased the paw withdrawal latency in response to thermal stimuli on the ipsilateral side without affecting the basal threshold on the contralateral side. These effects on pain behaviors were replicated in P2Y12 knockout mice. Patch-clamp recordings further revealed that partial sciatic nerve ligation (PSNL)-induced excessive miniature excitatory postsynaptic currents (mEPSCs) were significantly attenuated in P2Y12 knockout mice. Moreover, we found that SNL activates the GTP-RhoA/ROCK2 signaling pathway and elevates the level of phosphorylated p38 mitogen-activated protein kinase (MAPK), which was inhibited by the P2Y12 antagonist. The phosphorylation of p38 MAPK was inhibited by a ROCK inhibitor, but not vice versa, suggesting that p38 MAPK is downstream of ROCK activation. Our findings suggest that nerve injury engages the P2Y12 receptor-dependent GTP-RhoA/ROCK2 signaling pathway to upregulate excitatory synaptic transmission in the dorsal horn. This cross-talk ultimately participates in the manifestation of nociceptive allodynia, implicating P2Y12 receptor as a potential target for alleviating neuropathic pain.

New drug discovery has been acknowledged as a complicated, expensive, time-consuming, and challenging project. It has been estimated that around 12 years and 2.7 billion USD, on average, are demanded for a new drug discovery traditional drug development pipeline. How to reduce the research cost and speed up the development process of new drug discovery has become a challenging, urgent question for the pharmaceutical industry. Computer-aided drug discovery (CADD) has emerged as a powerful, and promising technology for faster, cheaper, and more effective drug design. Recently, the rapid growth of computational tools for drug discovery, including anticancer therapies, has exhibited a significant and outstanding impact on anticancer drug design, and has also provided fruitful insights into the area of cancer therapy. In this work, we discussed the different subareas of the computer-aided drug discovery process with a focus on anticancer drugs.

Predicting protein-ligand binding free energy rapidly and accurately remains a challenging question in modern drug discovery. Molecular mechanics/Poisson-Boltzmann (Generalized Born) surface area (MM/PB(GB)SA) has emerged as an essential tool for accelerating cost-efficient binding free energy calculation. This study presents benchmarks with three membrane-bound protein systems and six soluble protein systems. Different parameters were sampled for different benchmarks to explore the highest accuracy. These include ligand charges, protein force fields, extra points, GB models, nonpolar optimization methods, internal dielectric constants and membrane dielectric constants. Comparisons of accuracy were made between MM/PB(GB)SA, docking and free energy perturbation (FEP). The results reveal a competitive performance between MM/PB(GB)SA and FEP. In summary, MM/PB(GB)SA is a powerful approach to predict ligand binding free energy rapidly and accurately. Parameters of MM/PB(GB)SA calculations, such as the GB models and membrane dielectric constants, need to be optimized for different systems. This method can be served as a powerful tool for drug design.

Central nervous system (CNS) diseases can lead to motor, sensory, speech, cognitive dysfunction, and sometimes even death. These diseases are recognized to cause a substantial socio-economic impact on a global scale. Tetramethylpyrazine (TMP) is one of the main active ingredients extracted from the Chinese herbal medicine Ligusticum striatum DC . (Chuan Xiong). Many in vivo and in vitro studies have demonstrated that TMP has a certain role in the treatment of CNS diseases through inhibiting calcium ion overload and glutamate excitotoxicity, anti-oxidative/nitrification stress, mitigating inflammatory response, anti-apoptosis, protecting the integrity of the blood-brain barrier (BBB) and facilitating synaptic plasticity. In this review, we summarize the roles and mechanisms of action of TMP on ischemic cerebrovascular disease, spinal cord injury, Parkinson’s disease, Alzheimer’s disease, cognitive impairments, migraine, and depression. Our review will provide new insights into the clinical applications of TMP and the development of novel therapeutics.

Icariside II, an active flavonoid, is extracted from the traditional Chinese medicinal herb Epimedii . It possesses multiple biological and pharmacological properties, including anti-inflammatory, anticancer, and anti-osteoporotic properties. In recent years, apoptosis has become the hot spot in anticancer therapies. Icariside II exerts positive effects on inducing apoptosis and inhibiting proliferation in various cancers. The antitumorigenic activity of Icariside II was also proven through cell cycle arrest, triggering autophagy, reducing cellular metabolism, and inhibiting cancer metastasis and tumor-associated angiogenesis. Additionally, Icariside II, as a natural product, contributed to a synergistic effect alongside chemotherapeutic drugs. Due to its poor aqueous solubility and permeability, more strategies were developed to improve its therapeutic effects. This review aimed to summarize the chemopreventive properties of Icariside II in solid tumors and reveal its underlying molecular mechanisms.

We have studied the magnetic and electrical transport properties of epitaxial NiAs-type CrTe thin films grown on SrTiO 3 (111) substrates. Unlike rectangle hysteresis loops obtained from magnetic measurements, we have identified intriguing extra bump/dip features from anomalous Hall experiments on the films with thicknesses less than 12 nm. This observed Hall anomaly is phenomenologically consistent with the occurrence of a topological Hall effect(THE) in chiral magnets with a skyrmion phase. Furthermore, the THE contribution can be tuned by the film thickness, showing the key contribution of asymmetric interfaces in stabilizing Néel-type skyrmions. Our work demonstrates that a CrTe thin film on SrTiO 3 (111) substrates is a good material candidate for studying real-space topological transport.

A research model combining a disease and syndrome can provide new ideas for the treatment of ischemic stroke. In the field of traditional Chinese medicine, blood stasis and toxin (BST) syndrome is considered an important syndrome seen in patients with ischemic stroke (IS). However, the biological basis of IS-BST syndrome is currently not well understood. Therefore, this study aimed to explore the biological mechanism of IS-BST syndrome. This study is divided into two parts: (1) establishment of an animal model of ischemic stroke disease and an animal model of BST syndrome in ischemic stroke; (2) use of omics methods to identify differentially expressed genes and metabolites in the models. We used middle cerebral artery occlusion (MCAO) surgery to establish the disease model, and utilized carrageenan combined with active dry yeast and MCAO surgery to construct the IS-BST syndrome model. Next, we used transcriptomics and metabolomics methods to explore the differential genes and metabolites in the disease model and IS-BST syndrome model. It is found that the IS-BST syndrome model exhibited more prominent characteristics of IS disease and syndrome features. Both the disease model and the IS-BST syndrome model share some common biological processes, such as thrombus formation, inflammatory response, purine metabolism, sphingolipid metabolism, and so on. Results of the “gene–metabolite” network revealed that the IS-BST syndrome model exhibited more pronounced features of complement-coagulation cascade reactions and amino acid metabolism disorders. Additionally, the “F2 (thrombin)–NMDAR/glutamate” pathway was coupled with the formation process of the blood stasis and toxin syndrome. This study reveals the intricate mechanism of IS-BST syndrome, offering a successful model for investigating the combination of disease and syndrome.

To quantitatively measure the volume of white matter hyperintensities (WMHs) in different parts of the brain in patients with different types of cognitive function and analyze the relationship between WMH volume and cognitive function to obtain a threshold WMH volume for the early detection and clinical assessment of cognitive dysfunction. The clinical data and magnetic resonance imaging (MRI) data of patients with WMHs indicated by cranial MR in the Department of General Medicine of Shandong Provincial Third Hospital were collected. The FLAIR sequence images of the patients were subsequently analyzed with computer automated detection technology. Through deep learning-based 3D reconstruction, the specific volumes of the patients’ WMHs were obtained. Patients were divided into three groups according to the Fazekas scale score: Fazekas score 1, Fazekas score 2, and Fazekas score 3. The WMH volumes within each group were subsequently compared, and the correlations between the WMH volumes of the patients in each group and their Montreal Cognitive Assessment (MoCA) scores, Trail Making Test A (TMT-A) scores, Trail Making Test B (TMT-B) scores, age, duration of hypertension, duration of diabetes, basic information, etc., were analyzed. The patients were subsequently divided into a normal group (MoCA > 25) and a mild cognitive impairment group (18 < MoCA ≤ 25) on the basis of their MoCA scores. The WMH volumes in each group were then calculated separately. The cutoff values of the WMH volume for differentiating between the normal group and mild cognitive impairment group were obtained through receiver operating characteristic (ROC) curve analysis. The MoCA scores significantly differed among the three Fazekas score groups (r = − 0.5716, P  < 0.0001). There were also statistically significant differences in the total volume of WMHs among the three groups (r = 0.7527, P  < 0.0001). WMH volume was positively correlated with the TMT-A and TMT-B scores (r = 0.2345,   P < 0.05; r = 0.2404, P  < 0.05) but negatively correlated with the MoCA score (r = − 0.4789, P  < 0.0001). Moreover, WMH volume was positively associated with the duration of hypertension (F = 4.743, P  < 0.05) but not with the duration of diabetes (F = 1.431, P  = 0.2456). The cutoff value of WMH volume between the normal group and mild cognitive impairment group was 15.474900; at this value, the sensitivity of the WMH volume in discriminating the two groups was 0.808, and the specificity was 0.556. Automated detection technology can successfully be used to obtain the volume of WMHs in different parts of patients’ brains. Since WMH volume is correlated with cognitive function scores, we can use MRI to identify and assess individuals who show potential early signs of cognitive dysfunction and administer early interventions. These findings provide potential preventive and therapeutic targets for the clinical diagnosis and treatment of cognitive dysfunction.

Neuropathic pain is mainly triggered after nerve injury and associated with plasticity of the nociceptive pathway in primary sensory neurons. Currently, the treatment remains a challenge. In order to identify specific therapeutic targets, it is necessary to clarify the underlying mechanisms of neuropathic pain. It is well established that primary sensory neuron sensitization (peripheral sensitization) is one of the main components of neuropathic pain. Calcium channels act as key mediators in peripheral sensitization. As the target of gabapentin, the calcium channel subunit α2δ1 (Cavα2δ1) is a potential entry point in neuropathic pain research. Numerous studies have demonstrated that the upstream and downstream targets of Cavα2δ1 of the peripheral primary neurons, including thrombospondins, N -methyl- D -aspartate receptors, transient receptor potential ankyrin 1 (TRPA1), transient receptor potential vanilloid family 1 (TRPV1), and protein kinase C (PKC), are involved in neuropathic pain. Thus, we reviewed and discussed the role of Cavα2δ1 and the associated signaling axis in neuropathic pain conditions.

IntroductionStaphylococcus epidermidis is a significant cause of hospital bloodstream infections, often transmitted through medical devices. Methicillin-resistant Staphylococcus epidermidis (MRSE) exhibits multidrug resistance, challenging clinical treatment. Current options are limited, with vancomycin as the primary choice despite its negative effects. Traditional Chinese Medicine (TCM) is a valuable resource for novel antibiotics; Our research showed Patrinia scabiosifolia has potent anti-MRSE activity. TCM’s efficacy stems from active components, but active components and mechanisms of Patrinia scabiosifolia are unclear. Arginine deiminase (AD) directly promotes bacterial growth by participating in protein synthesis, energy metabolism, and intermediate product formation, serving as a key substance for bacterial adaptation and survival. Our preliminary results demonstrated that Patrinia scabiosifolia can effectively inhibit the expression of AD in MRSE. Thus, we propose that AD serves as the antibacterial target of Patrinia scabiosifolia against MRSE. TCM's efficacy stems from active components, but active components and mechanisms of Patrinia scabiosifolia are unclear. Consequently, it has emerged as a potential target for combating bacterial and drug-resistant infections. Therefore, this study is designed to screen active components of Patrinia scabiosifolia targeting AD and further investigate the underlying antibacterial mechanisms.MethodsTo validate the hypothesis, we constructed an arcA deletion strain ( ΔarcA ), in which the arcA gene encoding the AD protein was deleted via homologous recombination. Antimicrobial experiments in vitro and in vivo confirmed it as one target of Patrinia scabiosifolia . Furthermore, the active components of Patrinia scabiosifolia with anti-MRSE activity were screened by molecular docking and molecular dynamics (MD) simulations, using AD as the molecular target. In addition, the in vitro and in vivo antibacterial activities of the active components from Patrinia scabiosifolia were investigated. At last, the regulatory effect of the active components of Patrinia scabiosifolia on AD was determined by measuring the expression of the metabolite arcA gene and ornithine; Meanwhile, the binding effect of the active components of Patrinia scabiosifolia on AD was confirmed via determining the binding of AD to these components by microscale thermophoresis (MST), as well as identifying the binding sites through molecular simulation. Finally, nitric oxide (NO) and catalase (CAT) were determined, which further illustrates the antibacterial mechanism of the active components of Patrinia scabiosifolia targeting AD.ResultsThis study successfully constructed an MRSE arcA-deletion strain ( ΔarcA ), whose arcA gene encodes the AD protein, confirming that the deletion strain exhibited no growth defects. The minimum inhibitory concentration (MIC) of Patrinia scabiosifolia against MRSE was 5 mg/mL, whereas its MIC against ΔarcA was 10 mg/mL. Through MD simulations, 21 active components with anti-MRSE activity were screened from Patrinia scabiosifolia , among which hexadecanal demonstrated high antibacterial activity—showing a MIC of 7.81 μg/mL and a minimum bactericidal concentration (MBC) of 125 μg/mL against MRSE, and a MIC of 31.25 μg/mL against ΔarcA with no detectable MBC. Measurements of arcA gene expression and ornithine levels in MRSE treated with or without hexadecanal indicated that hexadecanal significantly downregulated arcA gene expression and reduced ornithine levels. MST and molecular simulation experiments further confirmed that hexadecanal binds to AD with high affinity, and identified Phe148 as its key binding site. In-depth studies revealed that hexadecanal targets AD, leading to marked reductions in NO and CAT levels.ConclusionsThis study elucidates that hexadecanal serves as the active components of Patrinia scabiosifolia targeting AD, and clarifies its antibacterial mechanism via binding to AD to regulate AD function and subsequently initiates oxidative stress.