ASD2023: towards the integrating landscapes of allosteric knowledgebase.

Allosteric regulation, induced by perturbations at an allosteric site topographically distinct from the orthosteric site, is one of the most direct and efficient ways to fine-tune macromolecular function. The Allosteric Database (ASD; accessible online at http://mdl.shsmu.edu.cn/ASD) has been systematically developed since 2009 to provide comprehensive information on allosteric regulation. In recent years, allostery has seen sustained growth and wide-ranging applications in life sciences, from basic research to new therapeutics development, while also elucidating emerging obstacles across allosteric research stages. To overcome these challenges and maintain high-quality data center services, novel features were curated in the ASD2023 update: (i) 66 589 potential allosteric sites, covering > 80% of the human proteome and constituting the human allosteric pocketome; (ii) 748 allosteric protein-protein interaction (PPI) modulators with clear mechanisms, aiding protein machine studies and PPI-targeted drug discovery; (iii) 'Allosteric Hit-to-Lead,' a pioneering dataset providing panoramic views from 87 well-defined allosteric hits to 6565 leads and (iv) 456 dualsteric modulators for exploring the simultaneous regulation of allosteric and orthosteric sites. Meanwhile, ASD2023 maintains a significant growth of foundational allosteric data. Based on these efforts, the allosteric knowledgebase is progressively evolving towards an integrated landscape, facilitating advancements in allosteric target identification, mechanistic exploration and drug discovery.

HDAC inhibitors as a potential therapy for chemotherapy-induced neuropathic pain.

Cancer, a chronic disease characterized by uncontrolled cell development, kills millions of people globally. The WHO reported over 10 million cancer deaths in 2020. Anticancer medications destroy healthy and malignant cells. Cancer treatment induces neuropathy. Anticancer drugs cause harm to spinal cord, brain, and peripheral nerve somatosensory neurons, causing chemotherapy-induced neuropathic pain. The chemotherapy-induced mechanisms underlying neuropathic pain are not fully understood. However, neuroinflammation has been identified as one of the various pathways associated with the onset of chemotherapy-induced neuropathic pain. The neuroinflammatory processes may exhibit varying characteristics based on the specific type of anticancer treatment delivered. Neuroinflammatory characteristics have been observed in the spinal cord, where microglia and astrocytes have a significant impact on the development of chemotherapy-induced peripheral neuropathy. The patient's quality of life might be affected by sensory deprivation, loss of consciousness, paralysis, and severe disability. High cancer rates and ineffective treatments are associated with this disease. Recently, histone deacetylases have become a novel treatment target for chemotherapy-induced neuropathic pain. Chemotherapy-induced neuropathic pain may be treated with histone deacetylase inhibitors. Histone deacetylase inhibitors may be a promising therapeutic treatment for chemotherapy-induced neuropathic pain. Common chemotherapeutic drugs, mechanisms, therapeutic treatments for neuropathic pain, and histone deacetylase and its inhibitors in chemotherapy-induced neuropathic pain are covered in this paper. We propose that histone deacetylase inhibitors may treat several aspects of chemotherapy-induced neuropathic pain, and identifying these inhibitors as potentially unique treatments is crucial to the development of various chemotherapeutic combination treatments.

Analgesic effect of nobiletin against neuropathic pain induced by the chronic constriction injury of the sciatic nerve in mice.

Neuropathic pain is chronic pain resulting from central or peripheral nerve damage that remains difficult to treat. Current evidence suggests that nobiletin, isolated from Citrus reticulata Blanco, possesses analgesic and neuroprotective effects. However, its effect on neuropathic pain has not been reported. This study evaluated the analgesic effect of nobiletin on neuropathic pain induced by chronic constriction injury (CCI) in mice. In vivo, mice were intragastrically administered with nobiletin (30, 60, 120 mg/kg) for eight consecutive days, respectively. Our study indicated that nobiletin ameliorated mechanical allodynia, cold allodynia and thermal hyperalgesia on CCI mice at doses that do not induce significant sedation. Moreover, nobiletin could ameliorate axonal and myelin injury of the sciatic nerve and further restore abnormal sciatic nerve electrical activity on CCI mice. In vitro studies indicated that nobiletin could suppress the proteins and mRNA expression of the IRF5/P2X4R/BDNF signalling pathway in fibronectin-induced BV2 cells. Overall, our results indicated that nobiletin might exert an analgesic effect on CCI-induced neuropathic pain in mice by inhibiting the IRF5/P2X4R/BDNF signalling pathway in spinal microglia. This study provided a novel potential therapeutic drug for neuropathic pain and new insights into the pharmacological action of nobiletin.

Glycosides for Peripheral Neuropathic Pain: A Potential Medicinal Components.

Neuropathic pain is a refractory disease that occurs across the world and pharmacotherapy has limited efficacy and/or safety. This disease imposes a significant burden on both the somatic and mental health of patients; indeed, some patients have referred to neuropathic pain as being 'worse than death'. The pharmacological agents that are used to treat neuropathic pain at present can produce mild effects in certain patients, and induce many adverse reactions, such as sedation, dizziness, vomiting, and peripheral oedema. Therefore, there is an urgent need to discover novel drugs that are safer and more effective. Natural compounds from medical plants have become potential sources of analgesics, and evidence has shown that glycosides alleviated neuropathic pain via regulating oxidative stress, transcriptional regulation, ion channels, membrane receptors and so on. In this review, we summarize the epidemiology of neuropathic pain and the existing therapeutic drugs used for disease prevention and treatment. We also demonstrate how glycosides exhibit an antinociceptive effect on neuropathic pain in laboratory research and describe the antinociceptive mechanisms involved to facilitate the discovery of new drugs to improve the quality of life of patients experiencing neuropathic pain.

Identification of Matrine as a Kirsten rats Arcomaviral oncogene homolog inhibitor alleviating chemotherapy-induced neuropathic pain.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) represents a prevailing and severe clinical concern, characterized by limited availability of clinically effective treatment strategies. Current evidence endorses matrine's potential as a neuroprotective and analgesic agent for CIPN. Nevertheless, the precise targets and mechanisms of action of matrine remain insufficiently explored, impeding comprehensive pharmacological investigation and clinical application. OBJECTIVE: This study endeavors to elucidate the analgesic and neuroprotective effects of matrine in mice with vincristine-induced neuropathic pain. A focal point is the identification of matrine's specific target and the underlying molecular mechanisms governing its analgesic and neuroprotective actions. METHODS: To discern matrine's analgesic effects in CIPN mice, we conducted behavioral experiments encompassing the Von Frey filament test and Hargreaves Test. Furthermore, we conducted electrophysiological and histopathological assessments involving HE staining, Nissl staining, and Fluoro-Jade B staining to evaluate matrine's effects on neuroprotection within dorsal root ganglia and the spinal cord of CIPN mice. Sequentially, thermal shift assay, GTP hydrolysis assay, and nucleotide exchange assay were executed to validate matrine's inhibitory effects on KRAS. Molecular docking and site-directed mutagenesis experiments were implemented to identify the precise binding pocket of matrine on KRAS. Lastly, matrine's inhibitory effects on downstream signaling pathways of KRAS were confirmed through experiments conducted at animal model. RESULTS: Matrine exhibited a notable increase in mechanical withdrawal threshold and thermal withdrawal latency in vincristine-treated mice. This compound substantially ameliorated the neurofunctional blockade associated with sensory and motor functions induced by vincristine. Moreover, matrine mitigated pathological damage within DRG and the L4-L5 spinal cord regions. The study's MST experiments indicated matrine's substantial elevation of KRAS's melting temperature. The GTP hydrolysis and nucleotide exchange assays revealed concentration-dependent inhibition of KRAS activity by matrine. Molecular docking provided insight into the binding mode of matrine with KRAS, while site-directed mutagenesis verified the specific binding site of matrine on KRAS. Lastly, matrine's inhibition of downstream Raf/Erk1/2 and PI3K/Akt/mTOR signaling pathways of KRAS was confirmed in VCR mice. CONCLUSION: Compared to previous studies, our research has identified matrine as a natural inhibitor of the elusive protein KRAS, often considered "undruggable." Furthermore, this study has revealed that matrine exerts its therapeutic effects on chemotherapy-induced peripheral neuropathy (CIPN) by inhibiting KRAS activation, subsequently suppressing downstream signaling pathways such as Raf/Erk1/2 and PI3K/Akt/mTOR. This investigation signifies the discovery of a novel target for matrine, thus expanding the potential scope of its involvement in KRAS-related biological functions and diseases. These findings hold the promise of providing a crucial experimental foundation for forthcoming drug development initiatives centered around matrine, thereby advancing the field of pharmaceutical research.

Targeting the chemokine ligand 2-chemokine receptor 2 axis provides the possibility of immunotherapy in chronic pain.

Chronic pain affects patients' physical and psychological health and quality of life, entailing a tremendous public health challenge. Currently, drugs for chronic pain are usually associated with a large number of side effects and poor efficacy. Chemokines in the neuroimmune interface combine with their receptors to regulate inflammation or mediate neuroinflammation in the peripheral and central nervous system. Targeting chemokines and their receptor-mediated neuroinflammation is an effective means to treat chronic pain. In recent years, growing evidence has shown that the expression of chemokine ligand 2 (CCL2) and its main chemokine receptor 2 (CCR2) is involved in its occurrence, development and maintenance of chronic pain. This paper summarises the relationship between the chemokine system, CCL2/CCR2 axis, and chronic pain, and the CCL2/CCR2 axis changes under different chronic pain conditions. Targeting chemokine CCL2 and its chemokine receptor CCR2 through siRNA, blocking antibodies, or small molecule antagonists may provide new therapeutic possibilities for managing chronic pain.

Antinociceptive and neuroprotective effect of echinacoside on peripheral neuropathic pain in mice through inhibiting P2X7R/FKN/CX3CR1 pathway.

Clinically, neuropathic pain treatment remains a challenging issue because the major therapy, centred around pharmacological intervention, is not satisfactory enough to patient by reason of low effectiveness and more adverse reaction. Therefore, it is still necessary to find more effective and safe therapy to ameliorate neuropathic pain. The purpose of this study was to explore the antinociceptive effect of Echinacoside (ECH), an active compound of Cistanche deserticola Ma, on peripheral neuropathic pain induced by chronic constriction injury (CCI) in mice, and to demonstrate its potential mechanism in vivo and vitro. In the present study, results showed that intraperitoneal administration of ECH (50, 100, and 200 mg/kg) could alleviate mechanical allodynia, cold allodynia and thermal hyperalgesia via behavioural test. Moreover, the structure and function of injured sciatic nerve by CCI were taken a turn for the better to a certain extent after ECH treatment using histopathological and electrophysiological test. Furthermore, ECH repressed the expression of the P2X7R and FKN and reduced the expression and release of the IL-1ß, IL-6 and TNF-α. Besides, ECH could decrease Ca2+ influx and Cats efflux and inhibit phosphorylation of p38MAPK. To sum up, the present study illustrated that ECH could alleviate peripheral neuropathic pain by inhibiting microglia overactivation and inflammation through P2X7R/FKN/CX3CR1 signalling pathway in spinal cord. This study would provide a new perspective and strategy for the pharmacological treatment on neuropathic pain.

Effects of alkaloids on peripheral neuropathic pain: a review.

Neuropathic pain is a debilitating pathological pain condition with a great therapeutic challenge in clinical practice. Currently used analgesics produce deleterious side effects. Therefore, it is necessary to investigate alternative medicines for neuropathic pain. Chinese herbal medicines have been widely used in treating intractable pain. Compelling evidence revealed that the bioactive alkaloids of Chinese herbal medicines stand out in developing novel drugs for neuropathic pain due to multiple targets and satisfactory efficacy. In this review, we summarize the recent progress in the research of analgesic effects of 20 alkaloids components for peripheral neuropathic pain and highlight the potential underlying molecular mechanisms. We also point out the opportunities and challenges of the current studies and shed light on further in-depth pharmacological and toxicological studies of these bioactive alkaloids. In conclusion, the alkaloids hold broad prospects and have the potentials to be novel drugs for treating neuropathic pain. This review provides a theoretical basis for further applying some alkaloids in clinical trials and developing new drugs of neuropathic pain.

Antinociceptive effect of isoorientin against neuropathic pain induced by the chronic constriction injury of the sciatic nerve in mice.

Neuropathic pain is a widespread and debilitating chronic pain and the treatment remains a clinical challenge. Isoorientin (3',4',5,7-tetrahydroxy-6-C-glucopyranosyl flavone) is a natural flavonoid-like compound that exhibits antioxidant and anti-inflammatory activities; however, its effect on neuropathic pain remains unclear. Our study aimed to evaluate the antinociceptive effect of isoorientin in neuropathic pain mouse models induced by chronic constriction injury (CCI). In our study, the mice with CCI were administered with 7.5, 15, and, 30 mg/kg isoorientin for 8 consecutive days. Behavioral parameters were assayed on days 0, 7, 8, 10, 12, and 14 post-CCI surgery. Electrophysiological, histopathological, and biochemical indices were analyzed on day 14. Immunofluorescence was utilized to examine matrix metalloproteinase-9 (MMP-9) and glial cell activation, and proinflammatory cytokine expression levels were detected via Western blot. It is obvious that the treatment of Isoorientin remarkably ameliorated hyperalgesia and allodynia, increased sensory nerve conduction velocities, and restored CCI-induced sciatic nerve damage in mice. Isoorientin treatment significantly increased the total antioxidant capacity (T-AOC), total superoxide dismutase (T-SOD) and catalase (CAT) levels, and decreased the malondialdehyde (MDA) concentrations. Isoorientin also suppressed MMP-9 and glial cell activation, and downregulated tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1ß (IL-1ß) expression levels. Therefore, this study provided a novel approach for neuropathic pain treatment and new insights into the pharmacological action of isoorientin.