The role of purinergic signaling in acupuncture-mediated relief of neuropathic and inflammatory pain.

Acupuncture is a traditional medicinal practice in China that has been increasingly recognized in other countries in recent decades. Notably, several reports have demonstrated that acupuncture can effectively aid in pain management. However, the analgesic mechanisms through which acupuncture provides such benefits remain poorly understood. Purinergic signaling, which is mediated by purine nucleotides and purinergic receptors, has been proposed to play a central role in acupuncture analgesia. On the one hand, acupuncture affects the transmission of nociception by increasing adenosine triphosphate dephosphorylation and thereby decreasing downstream P2X3, P2X4, and P2X7 receptors signaling activity, regulating the levels of inflammatory factors, neurotrophic factors, and synapsin I. On the other hand, acupuncture exerts analgesic effects by promoting the production of adenosine, enhancing the expression of downstream adenosine A1 and A2A receptors, and regulating downstream inflammatory factors or synaptic plasticity. Together, this systematic overview of the field provides a sound, evidence-based foundation for future research focused on the application of acupuncture as a means of relieving pain.

Effects of co-supplementation of chromium and magnesium on metabolic profiles, inflammation, and oxidative stress in impaired glucose tolerance.

PURPOSE: To evaluate the effects of chromium (Cr) and magnesium (Mg) ions on metabolic profiles, inflammation, and oxidative stress with impaired glucose tolerance (IGT) and insulin resistance (IR). METHODS: 120 individuals with IGT and IR were randomly divided into four groups treated with (1) chromium, (2) magnesium, (3) chromium and magnesium or (4) placebo. Metabolic and inflammatory indicators were measured at baseline and after 3 months intervention. RESULTS: Comparison among groups showed that fasting plasma glucose (FPG), 2 h post glucose (2hPPG), fasting insulin (FINS) and homeostatic model assessment for insulin resistance (HOMA-IR) in Cr + Mg group were significantly decreased compared with the other three groups (p < .05), and high density lipoprotein (HDL-c) levels were higher. 8-iso prostaglandin F2 alpha (8-iso-PGF2a) decreased in Cr, Mg, and Cr + Mg groups compared with placebo (p < .05), and 8-iso-PGF2a decreased in Cr + Mg groups compared with Cr group and Mg groups (p > .05). Intra-group comparison showed that the levels of FPG, 2hPPG and FINS in Cr + Mg group were significantly decreased after intervention (p < .05), and FINS in Mg group was significantly decreased (p < .01). The levels of HDL-c and triacylglycerol (TG) in Cr + Mg group were significantly improved (p < .05). The level of HDL-c in Mg group was significantly improved compared with baseline (p < .05). Compared with baseline, high-sensitivity C-reactive protein (hsCRP) levels in Cr + Mg group and Mg group were significantly decreased (p < .05). CONCLUSIONS: The co-supplementation of Cr and Mg improves glycemic and lipid levels and reduces the inflammatory response and oxidative stress profiles of individuals with impaired glucose tolerance and insulin resistance.

Mechanisms of acupuncture-electroacupuncture on inflammatory pain.

Acupuncture, as a traditional treatment, has been extensively used in China for thousands of years. According to the World Health Organization (WHO), acupuncture is recommended for the treatment of 77 diseases. And 16 of these diseases are related to inflammatory pain. As a combination of traditional acupuncture and modern electrotherapy, electroacupuncture (EA) has satisfactory analgesic effects on various acute and chronic pain. Because of its good analgesic effects and no side effects, acupuncture has been widely accepted all over the world. Despite the increase in the number of studies, the mechanisms via which acupuncture exerts its analgesic effects have not been conclusively established. A literature review of related research is of great significance to elaborate on its mechanisms and to inform on further research directions. We elucidated on its mechanisms of action on inflammatory pain from two levels: peripheral and central. It includes the mechanisms of acupuncture in the periphery (immune cells and neurons, purinergic pathway, nociceptive ion channel, cannabinoid receptor and endogenous opioid peptide system) and central nervous system (TPRV1, glutamate and its receptors, glial cells, GABAergic interneurons and signaling molecules). In this review, we collected relevant recent studies to systematically explain the mechanisms of acupuncture in treating inflammatory pain, with a view to providing direction for future applications of acupuncture in inflammatory pain and promoting clinical development.

Flexible needle-type Microbiosensor for real-time monitoring traditional acupuncture-mediated adenosine release In vivo.

Rapid adenosine (ADO) signaling, on the time frame of seconds, regulates physiological and pathological processes, including the therapeutic efficacy of acupuncture. Nevertheless, standard monitoring strategies are limited by poor temporal resolution. Herein, an implantable needle-type microsensor capable of monitoring ADO release in vivo in response to acupuncture in real time has been developed. Electrocatalytic Prussian Blue nanoparticles, an immobilized multienzyme system, and a permselective poly-o-phenylenediamine-based membrane were used for the sequential modification of the sensing region of the electrode. The resultant sensor can perform amperometric measurements of ADO levels in response to a very low level of applied potential (-0.05 V vs Ag/AgCl). This microsensor also functioned across a broad linear range (0-50 µM) and exhibited good sensitivity (1.1 nA/µM) with a rapid response time of under 5 s. Importantly, the sensor also exhibited good reproducibility and high selectivity. For in vivo animal studies, the microsensor was employed for the continuous assessment of instantaneous ADO release at the ST36 (Zusanli) acupoint when this acupoint was subjected to twirling-rotating acupuncture manipulation. Benefiting from superior sensor in vivo performance and stability, the positive correlation between the variability in acupuncture-induced ADO release and the stimulus intensity levels that affect the clinical benefit can be demonstrated for the first time. Overall, these results highlight a powerful approach to analyzing the in vivo physiological effects of acupuncture, expanding application realm of micro-nano sensor technology on a fast time scale.

The mechanistic basis for the effects of electroacupuncture on neuropathic pain within the central nervous system.

Nociceptive signaling responses to painful stimuli are transmitted to the central nervous system (CNS) from the afferent nerves of the periphery through a series of neurotransmitters and associated signaling mechanisms. Electroacupuncture (EA) is a pain management strategy that is widely used, with clinical evidence suggesting that a frequency of 2-10 Hz is better able to suppress neuropathic pain in comparison to higher frequencies such as 100 Hz. While EA is widely recognized as a viable approach to alleviating neuralgia, the mechanistic basis underlying such analgesic activity remains poorly understood. The present review offers an overview of current research pertaining to the mechanisms whereby EA can alleviate neuropathic pain in the CNS, with a particular focus on the serotonin/norepinephrine, endogenous opioid, endogenous cannabinoid, amino acid neurotransmitter, and purinergic pathways. Moreover, the corresponding neurotransmitters, neuromodulatory compounds, neuropeptides, and associated receptors that shape these responses are discussed. Together, this review seeks to provide a robust foundation for further studies of the EA-mediated alleviation of neuropathic pain.

Network pharmacology integrated with experimental validation to explore the therapeutic role and potential mechanism of Epimedium for spinal cord injury.

Objective: Epimedium (EPI) is a common Chinese herb with neuroprotective effects against a variety of central nervous system disorders, especially spinal cord injury (SCI). In this study, we performed network pharmacology and molecular docking analyses to reveal the mechanism underlying EPI treatment of SCI, then validated its efficacy using animal models. Methods: The active ingredients and targets of EPI were screened by Traditional Chinese Medicine Systems Pharmacology (TCMSP) and their targets annotated on the UniProt platform. SCI-related targets were searched from OMIM, TTD, and GeneCards databases. We employed the STRING platform to construct a protein-protein interaction (PPI) network then visualized the results using Cytoscape (3.8.2) software. We also subjected key EPI targets to ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, then docked the main active ingredients with the key targets. Finally, we established an SCI rat model to evaluate efficacy of EPI in treating SCI and validate the effects of different biofunctional modules predicted by network pharmacology. Results: A total of 133 EPI targets were associated with SCI. GO terms and KEGG pathway enrichment results showed that EPI's effect in treating SCI was significantly associated with inflammatory response, oxidative stress and the PI3K/AKT signaling pathway. Molecular docking results indicated that EPI's active ingredients have a high affinity for the key targets. Results from animal experiments revealed that EPI not only markedly improved Basso, Beattie, and Bresnahan scores in SCI rats, but also significantly improved p-PI3K/PI3K and p-AKT/AKT ratio. Moreover, EPI treatment not only mediated a significant decrease in malondialdehyde (MDA) but also increased both superoxide dismutase (SOD), and glutathione (GSH). However, this phenomenon was successfully reversed by LY294002, a PI3K inhibitor. Conclusion: EPI improves behavioral performance in SCI rats through anti-oxidative stress, which may be mediated by activation of the PI3K/AKT signaling pathway.

Jiedu Sangen Decoction Reverses Epithelial-to-mesenchymal Transition and Inhibits Invasion and Metastasis of Colon Cancer via AKT/GSK-3ß Signaling Pathway.

Ethnopharmacology relevance: Jiedu Sangen Decoction (JSD), an empirical prescription of Traditional Chinese Medicine (TCM), has been reported to inhibit invasion and metastasis of colon cancer in our previous study. The aim of this study was to investigate the mechanism of JSD-triggered inhibition of invasion and metastasis in colon cancer. Methods: In vitro, AKT1 knockdown (si-AKT1) or overexpression (oe-AKT1) cells were successfully constructed both in SW480 and SW620 cell lines. Si-AKT1 and oe-AKT1 cells were then treated with or without JSD. Cell invasion, metastasis potential and expression of epithelial-mesenchymal transformation (EMT)-related and AKT1/GSK-3ß proteins were then observed by wound healing, transwell, and western blot assays. In vivo, liver metastasis model mice were developed by inoculating SW480 cells. After JSD diet intervention, living fluorescence imaging and weight measurements were carried out to investigate JSD induced inhibition effects on liver metastasis of colon cancer. Immunohistochemistry and western blot assays were performed to observe tissue features and detect protein expression. Results: Invasion and metastasis potential, as well as EMT of colon cancer, can be markedly inhibited by JSD treatment or AKT1 knockdown, while enhanced by AKT1 overexpression. JSD-induced inhibition effects were significantly weakened when AKT1 was knocked down, while clearly enhanced when AKT1 was overexpressed. Additionally, JSD could lead to an increase in expression of E-cadherin, and a decrease in expression of N-cadherin, Vimentin, p-AKT1, AKT1, p- GSK-3ß, Snail, Slug, and Twist in colon cancer cells. Conclusion: JSD reverses EMT and inhibits invasion and metastasis of colon cancer through the AKT/GSK-3ß signaling pathway.

Jiedu Sangen Decoction Inhibits the Invasion and Metastasis of Colorectal Cancer Cells by Regulating EMT through the Hippo Signaling Pathway.

Colorectal cancer (CRC) is one of the most common malignant tumors affecting the digestive tract. Moreover, the invasion and metastasis of CRC are the main reason therapy is usually inefficient. Decreased intercellular adhesion and enhanced cell motility induced by epithelial-mesenchymal transition (EMT) provide the basic conditions for the invasion and metastasis of the epithelial tumor cells of CRC. The Jiedu Sangen Decoction (JSD) is a prescription that has been used for more than 50 years in the treatment of CRC in the Zhejiang Hospital of Traditional Chinese Medicine. The aim of this study was to investigate the mechanism of JSD-triggered inhibition of invasion and metastasis in colon cancer. In vitro, the EMT model of the SW480 cells was induced by using epithelial growth factor (50 ng/mL). In vivo, the murine model of liver metastasis was constructed by inoculating mice with the SW480 cells. The effects of JSD on cell migration, invasion, and proliferation were determined using the transwell assay and CCK-8 assay. Moreover, the proteins related to the EMT process and the Hippo signaling pathway in the cancerous tissues and cell lines were determined by western blotting and immunostaining. JSD could significantly inhibit the proliferation, migration, and invasion of CRC cells and reverse their EMT status (all, P < 0.05). Moreover, after intervention with JSD, the levels of E-Cadherin (E-cad) increased, whereas the expression levels of N-Cadherin (N-cad), Yes-associated protein (YAP), and the transcriptional coactivator with the PDZ-binding motif (TAZ) decreased in both the SW480 cells and the tumor tissues. In summary, JSD reversed EMT and inhibited the invasion and metastasis of CRC cells through the Hippo signaling pathway.

Catheter ablation for lone atrial fibrillation in individuals aged under 35 years.

BACKGROUND: To assess the effectiveness of radiofrequency catheter ablation for lone atrial fibrillation in young adults. METHODS: This single-centre, retrospective, observational study enrolled 75 consecutive patients (86.7% men) under 35 (median, 30) years old with lone atrial fibrillation (68% paroxysmal, 26.7% persistent, and 5.3% long-standing persistent) without other cardiopulmonary diseases who underwent catheter ablation between April 2009 and May 2017. Procedural endpoints were circumferential pulmonary vein ablation for atrial fibrillation with pulmonary vein trigger, and target ablation or bidirectional block of lines and disappearance of complex fractionated atrial electrograms for atrial fibrillation with clear and unclear non-pulmonary vein triggers, respectively. RESULTS: Main study outcome was rate of survival free from atrial tachyarrhythmia recurrence, which at median 61 (range, 5-102) months follow-up was 62.7% (64.7 and 58.3% for paroxysmal and non-paroxysmal atrial fibrillation, respectively) after single ablation, and 69.3% (68.6 and 70.8% for paroxysmal and non-paroxysmal atrial fibrillation, respectively) after mean 1.2 ablations (two and three ablations in 11 and 2 patients, respectively). In multivariate analysis, non-pulmonary vein trigger was a significant independent predictor of recurrent atrial tachyarrhythmia (OR, 10.60 [95%CI, 2.25-49.96]; p = 0.003). There were no major periprocedural adverse events. CONCLUSIONS: In patients under 35 years old with lone atrial fibrillation, radiofrequency catheter ablation appeared effective particularly for atrial fibrillation with pulmonary vein trigger and regardless of left atrial size or atrial fibrillation duration or type. Atrial tachyarrhythmia recurrence after multiple ablations warrants further study.

Jiedu Sangen Decoction Inhibits Migration and Invasion of Colon Cancer SW480 Cells via Suppressing Epithelial Mesenchymal Transition.

Jiedu Sangen Decoction (JSD), a traditional Chinese medicine (TCM) formula, has been widely used in China to treat gastrointestinal cancer, especially as an adjuvant therapy in colorectal cancer (CRC) patients. This study aimed to evaluate the efficacy of JSD and Jiedu Sangen aqueous extract (JSAE) in colon cancer cells and explored the underlining mechanisms by cytotoxicity assay, scratch assay, transwell migration assay, matrigel invasion assay, confocal laser scanning microscopy, and western blot analysis. We demonstrated that JSAE inhibited the growth of colon cancer SW480 cells in a dose-dependent manner and JSAE repressed cancer cell migration and invasion. Furthermore, epithelial mesenchymal transition (EMT) was reversed by JSAE via enhancing E-cadherin expression and attenuating protein levels of EMT promoting factors such as N-cadherin, Slug, and ZEB1. These findings provided the first experimental evidence confirming the efficacy of JSAE in repressing invasion and metastasis of CRC and paving a way for the broader use of JSD in clinic.

Elevated Neurosteroids in the Lateral Thalamus Relieve Neuropathic Pain in Rats with Spared Nerve Injury.

Neurosteroids are synthesized in the nervous system from cholesterol or steroidal precursors imported from peripheral sources. These compounds are important allosteric modulators of γ-aminobutyric acid A receptors (GABAARs), which play a vital role in pain modulation in the lateral thalamus, a main gate where somatosensory information enters the cerebral cortex. Using high-performance liquid chromatography/tandem mass spectrometry, we found increased levels of neurosteroids (pregnenolone, progesterone, deoxycorticosterone, allopregnanolone, and tetrahydrodeoxycorticosterone) in the chronic stage of neuropathic pain (28 days after spared nerve injury) in rats. The expression of the translocator protein TSPO, the upstream steroidogenesis rate-limiting enzyme, increased at the same time. In vivo stereotaxic microinjection of neurosteroids or the TSPO activator AC-5216 into the lateral thalamus (AP -3.0 mm, ML ±3.0 mm, DV 6.0 mm) alleviated the mechanical allodynia in neuropathic pain, while the TSPO inhibitor PK 11195 exacerbated it. The analgesic effects of AC-5216 and neurosteroids were significantly attenuated by the GABAAR antagonist bicuculline. These results suggested that elevated neurosteroids in the lateral thalamus play a protective role in the chronic stage of neuropathic pain.