ObjectiveThis study aims to investigate the action mechanism by which Xiaozheng Zhitong paste （XZP） alleviates bone cancer pain （BCP） by regulating programmed death protein 1 （PD-1）/programmed death-ligand 1 （PD-L1） pathway-induced osteoclast formation. MethodsThirty female C57BL/6 mice were randomly allocated into the following groups （n=6 per group）： normal control group， model group， low‑dose XZP group （31.5 g·kg^-1）， high‑dose XZP group （63 g·kg^-1）， and PD‑1 inhibitor （Niv） group. A bone cancer pain （BCP） model was established by injecting Lewis lung carcinoma cells. Mice in the normal control and model groups received topical application of a blank paste matrix at the wound site. Mice in the low‑ and high‑dose XZP groups were treated with XZP applied topically twice daily. Mice in the Niv group were topically administered the blank paste matrix and additionally received Niv via tail‑vein injection every two days. All interventions were continued for 21 days. During this period， behavioral tests were performed to assess mechanical， motor， and thermal nociceptive sensitivities. After 21 days， all mice were euthanized， and bone tissue from the operated side was collected for sectioning and preservation. Tartrate‑resistant acid phosphatase （TRAP） staining was used to evaluate osteoclast expression in the lesioned bone tissue. Immunohistochemistry was performed to detect the expression of Runt‑related transcription factor 2 （Runx2） in the lesioned bone tissue. Immunofluorescence was employed to assess the expression of PD‑1 and PD‑L1 in the lesioned bone tissue. ResultsCompared with the normal group， the model group showed significantly decreased limb mechanical withdrawal threshold， spontaneous paw flinching， and thermal withdrawal latency （P<0.01）， increased number of osteoclasts in the lesioned bone tissue （P<0.01）， and reduced expression of Runx2 （P<0.01）. Compared with the model group， the BCP mice in the XZP low-dose group， XZP high-dose group， and Niv group exhibited increased limb mechanical withdrawal threshold， movement scores， and thermal withdrawal latency （P<0.01）. The XZP low-dose group showed no significant changes in osteoclast number or Runx2 expression， while the XZP high-dose group and Niv group demonstrated significantly reduced osteoclast numbers （P<0.01） and significantly increased Runx2 expression （P<0.01）. In the lesioned bone tissue of BCP mice， the XZP low-dose group showed no significant decrease in the percentage of PD-1 expression， but a decrease in the percentage of PD-L1 expression （P<0.05）. In contrast， both the XZP high-dose group and the Niv group exhibited significant reductions in the percentages of PD-1 and PD-L1 expression （P<0.01）. ConclusionXZP alleviates the pain of mice with BCP by blocking the PD-1/PD-L1 pathway to inhibit osteoclastogenesis.

ObjectiveThe paper aims to investigate the mechanism by which Xiaozheng Zhitong paste （XZP） alleviates bone cancer pain （BCP） through regulating the PTEN-induced putative kinase 1 （PINK1）/Parkin-mediated mitophagy-NOD-like receptor protein 3 （NLRP3） inflammasome pathway to suppress microglial pyroptosis. MethodsLipopolysaccharide （LPS） and LPS-adenosine triphosphate （ATP） were used to establish an inflammation and pyroptosis model in microglial cells. The cells were randomly divided into the following groups： control group， LPS group， LPS+low-dose XZP group， LPS+high-dose XZP group， LPS-ATP group， LPS-ATP+low-dose XZP group， LPS-ATP+high-dose XZP group， LPS-ATP+XZP group， and LPS-ATP+XZP+CsA group. Techniques including terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling （TUNEL） staining， enzyme-linked immunosorbent assay （ELISA）， Western blot， and confocal fluorescence staining were employed to assess the effects of XZP on microglial apoptosis， inflammatory cytokine release， inflammasome activation， pyroptosis， and mitophagy. ResultsIn vitro experiments showed that compared with the blank group， the LPS group exhibited significantly increased levels of microglial apoptosis and pro-inflammatory factors interleukin （IL）-1β， IL-6， and tumor necrosis factor-α （TNF-α）（P<0.01）， along with significantly upregulated protein expression of inducible nitric oxide synthase （iNOS）， cyclooxygenase-2 （COX-2）， and phosphorylated nuclear factor-κB p65 （p-NF-κB p65） （P<0.01）. Compared with the LPS group， the high-dose LPS-XZP group significantly reduced the level of apoptosis （P<0.01） and the content of the aforementioned pro-inflammatory factors （P<0.01）. Both the low- and high-dose LPS-XZP groups dose-dependently downregulated the protein expression of iNOS， COX-2， and p-NF-κB p65 （P<0.05， P<0.01）. Compared with the blank group， the LPS-ATP group showed significantly upregulated expression of pyroptosis-related proteins， including Caspase-1/pro-Caspase-1， N-terminal fragment of gasdermin D （GSDMD-N）/full-length gasdermin D （GSDMD-F）， NLRP3， apoptosis-associated speck-like protein containing a CARD （ASC）， IL-1β precursor （pro-IL-1β）， and mature IL-1β （P<0.01）. The levels of pyroptotic factors IL-1β and IL-18 were significantly elevated （P<0.01）， and membrane pore formation and intracellular reactive oxygen species （ROS） levels were significantly increased （P<0.01）. Compared with the LPS-ATP group， both the low- and high-dose LPS-ATP+XZP groups dose-dependently downregulated the expression of the aforementioned pyroptosis-related proteins （P<0.05， P<0.01）. The low-dose LPS-ATP+XZP group reduced IL-1β levels （P<0.01）， while the high-dose group reduced both IL-1β and IL-18 levels （P<0.01） Both the low- and high-dose LPS-ATP+XZP groups dose-dependently reduced membrane pore formation and intracellular ROS production （P<0.01）. Compared with the blank group， the LPS-ATP group showed significantly reduced expression of mitophagy-related proteins PINK1 and Parkin， and a decreased ratio of microtubule-associated protein 1 light chain 3Ⅱ（LC3Ⅱ） to LC3Ⅰ（P<0.01）， while p62 expression was significantly increased （P<0.01）. Mitochondrial ROS levels were significantly enhanced （P<0.01）. Compared with the LPS-ATP group， both the low- and high-dose LPS-ATP+XZP groups dose-dependently reversed the expression of these proteins （P<0.05， P<0.01） and reduced mitochondrial ROS levels （P<0.01）. After treatment with the mitophagy inhibitor cyclosporin A （CsA）， the beneficial effects of XZP on mitochondrial function and its inhibitory effects on pyroptosis-related protein expression were significantly reversed （P<0.05， P<0.01）. ConclusionXZP reduces ROS levels by activating PINK1/Parkin-mediated mitophagy， thereby inhibiting NLRP3 inflammasome activation and microglial pyroptosis， which provides new molecular evidence for the mechanism by which XZP alleviates BCP.

ObjectiveTo investigate the effects and underlying mechanisms of Xiaozheng Zhitong Paste （XZP） on bone cancer pain （BCP）. MethodsThirty female BALB/c mice were randomly divided into five groups： a Sham group， a BCP group， a BCP+low-dose XZP group， a BCP+high-dose XZP group， and a BCP+high-dose XZP + protease-activated receptor 2 （PAR2） agonist GB-110 group. BCP mice model was constructed by injecting Lewis lung carcinoma cells into the femoral cavity of the right leg， which was followed by being treated with XZP for 21 d. After 21 d， the mice were sacrificed. Nissl staining was used to evaluate the survival of spinal cord neurons. Immunofluorescence staining was conducted to localize ionized calcium-binding adapter molecule 1 （Iba1） and neuronal nuclear antigen （NeuN） in spinal cord tissue， thereby assessing microglial activation and neuronal survival. Enzyme-linked immunosorbent assay （ELISA） was employed to measure the levels of interleukin-1β （IL-1β）， tumor necrosis factor-α （TNF-α）， interleukin-6 （IL-6）， transforming growth factor-β （TGF-β）， interleukin-4 （IL-4）， and interleukin-10 （IL-10） in spinal cord tissue. Real-time quantitative polymerase chain reaction （Real-time PCR） was used to detect mRNA expression levels associated with M1/M2 polarization of microglia. Western blot analysis was performed to examine the expression of proteins related to microglial polarization as well as those involved in the PAR2/nuclear factor kappa B （NF-κB）/NOD-like receptor protein 3 （NLRP3） signaling pathway in the spinal cord. ResultsCompared with the Sham group， the spinal cord neurons were damaged， the number of Nissl-positive spinal cord neurons in the spinal cord tissue was significantly reduced （P<0.01）， and the rate of NeuN-positive cells was significantly decreased （P<0.01）. The spinal cord microglia were activated， the inflammatory level of the spinal cord tissue was enhanced， and Iba1 staining was significantly enhanced （P<0.01）. The levels of IL-1β， TNF-α， IL-6， TGF-β， IL-4 and IL-10 were significantly increased （P<0.01）. The mRNA expressions of IL-1β， TNF-α and inducible nitric oxide synthase （iNOS） were significantly increased （P<0.01）， and the expression of PAR2， NLRP3， ASC and NF-κB p65 proteins in the spinal cord tissue of the BCP mice was significantly enhanced （P<0.01）. Compared with the BCP group， high-dose XZP treatment significantly increased the number of Nissl-positive spinal cord neurons in the BCP mice （P<0.01）， significantly enhanced the rate of NeuN-positive cells in the spinal cord tissue， and significantly weakened Iba1 staining （P<0.01）. In addition， the levels of IL-1β， TNF-α， and IL-6 were significantly decreased， while the levels of TGF-β， IL-4， and IL-10 were significantly increased （P<0.05， P<0.01）. The mRNA expression levels of IL-1β， TNF-α， and iNOS were decreased， whereas those of cluster of differentiation 206 （CD206）， arginase-1 （Arg-1）， and YM1/2 were significantly increased （P<0.05， P<0.01）. Low-dose and high-dose XZP treatment significantly decreased the expression of PAR2， NLRP3， ASC， and NF-κB p65 proteins in the spinal cord tissue （P<0.05， P<0.01）. These effects could all be significantly eliminated by the PAR2 agonist GB-110. ConclusionXZP can mitigate BCP in mice， which may be achieved through blocking the activated PAR2/NF-κB/NLRP3 pathway.

ObjectiveThe paper aims to investigate the action mechanism by which the Xiaozheng Zhitong paste （XZP） relieves bone cancer pain （BCP）. MethodsA model of mice with BCP was established by using Lewis tumor cells. The therapeutic effects of XZP， the ferroptosis inhibitor Ferrostatin-1 （Fer-1）， and the nuclear factor erythroid 2-related factor 2 （Nrf2） inhibitor Brusatol （Bru） on BCP were examined. Mice were randomly divided into the Sham operation group， BCP group， BCP+XZP-L group， BCP+XZP-H group， BCP+Fer-1 group， and BCP+XZP-H+Bru group， with six mice in each group. Pain behavior tests were conducted on the mice to assess pain levels. Colorimetric assays were employed to measure ferroptosis-related factors in serum and spinal cord tissue including Fe， malondialdehyde （MDA）， reactive oxygen species （ROS）， and superoxide dismutase （SOD）. Immunofluorescence staining was used to assess ROS production in spinal cord tissue. Transmission electron microscopy was used to observe the ultrastructure of mitochondria in lumbar spinal cord tissue. Quantitative real-time polymerase chain reaction （Real-time PCR） was employed to detect mRNA expression of Nrf2， heme oxygenase-1 （HO-1）， glutathione peroxidase 4 （GPX4）， and solute carrier family 7 member 11 （SLC7A11） in spinal cord neuron tissue. The protein expression of Nrf2， HO-1， GPX4， and SLC7A11 in spinal cord neurons was measured by Western blot. ResultsCompared with the Sham group， mice in the BCP group exhibited significantly reduced limb usage scores， mechanical foot withdrawal thresholds， and thermal foot withdrawal thresholds （P<0.01）. Serum and lumbar spinal cord tissue levels of Fe， MDA， and reactive oxygen species （ROS） were significantly elevated （P<0.05）， while superoxide dismutase （SOD） levels were significantly decreased （P<0.05）. Lumbar spinal cord mitochondrial structural damage was observed， and mRNA and protein expression of Nrf2， HO-1， GPX4， and SLC7A11 were significantly downregulated （P<0.01）. Compared with the BCP group， both low- and high-dose XZP groups improved the aforementioned pain behavioral indicators （P<0.05，P<0.01）， reduced ferroptosis-related biomarkers including Fe， MDA， and ROS levels （P<0.05）， increased SOD levels （P<0.05，P<0.01）， alleviated mitochondrial damage， and upregulated Nrf2， HO-1， GPX4， SLC7A11 mRNA and protein expression （P<0.05，P<0.01）. The high-dose XZP group exhibited comparable efficacy to Fer-1 in alleviating pain and inhibiting ferroptosis. Following Bru administration， XZP's effects on pain behavioral indicators， regulation of ferroptosis-related markers， mitochondrial structural protection， and activation of the Nrf2/HO-1/GPX4/SLC7A11 pathway were significantly reversed （P<0.05，P<0.01）. ConclusionExternal application of XZP alleviates pain symptoms in BCP mice by activating the Nrf2/HO-1/GPX4/SLC7A11 pathway， thereby inhibiting ferroptosis and neuronal damage in spinal cord neurons.

Cancer pain is one of the most common complications in patients with malignant tumors， severely affecting their quality of life. Its pathogenesis involves complex interactions among the tumor microenvironment， peripheral sensitization， and central sensitization. The tumor microenvironment initiates peripheral pain sensitization by secreting algogenic mediators， activating ion channels and related receptor signaling pathways， driving abnormal osteoclast activation， and mediating neuro-immune crosstalk. Persistent nociceptive input further triggers increased excitability of central neurons， activation of glial cells， and neuroinflammatory cascade reactions， ultimately leading to central pain sensitization. Although traditional opioid drugs can alleviate pain to some extent， they still have many limitations， such as incomplete analgesia， drug tolerance， and adverse reactions. In recent years， traditional Chinese medicine （TCM） compounds have made continuous progress in the treatment of cancer pain. Studies have shown that they can not only effectively relieve cancer pain and reduce the dosage of opioids but also significantly improve patients' quality of life. TCM treatment of cancer pain follows the principle of syndrome differentiation and treatment. Based on this， targeted therapeutic principles have been proposed， including promoting blood circulation， removing stasis， regulating Qi， and unblocking collaterals； tonifying the kidney， replenishing essence， warming Yang， and dispersing cold， activating blood， resolving phlegm， detoxifying， and dispersing nodules， as well as strengthening the body， replenishing deficiency， and harmonizing Qi and blood. Modern research indicates that TCM compounds can exert synergistic effects through multiple pathways， inhibiting inflammatory responses， regulating nerve conduction， intervening in bone metabolism and related gene expression， thereby producing anti-inflammatory and bone-protective effects to achieve the goal of alleviating cancer pain. This article systematically elaborates on the pathogenesis of cancer pain， the clinical application of TCM in treating cancer pain， and its related mechanisms of action， aiming to provide a theoretical basis and new strategies for the integration of TCM into comprehensive cancer pain management.

Objective:To evaluate the effect of esketamine on learning and memory function after chronic stress and the signaling pathway of N-methyl-D-aspartate receptor (NMDAR)-calmodulin-dependent protein kinase type 2 (CaMKⅡ)-cAMP-responsive element-binding protein (CREB) in the hippocampus of developing rats.Methods:Sixty clean-grade healthy Sprague-Dawley rats of either sex, aged 7 days, weighing 10-15 g, were divided into 3 groups ( n=20 each) using a random number table method: control+ normal saline group (CN group), chronic stress+ normal saline group (NS group), and chronic stress+ esketamine group (ES group). A chronic stress model was established using a chronic unpredictable stress method. After the end of stress stimulation, esketamine 10 mg/kg was intraperitoneally injected once a day for 7 consecutive days in ES group, and the equal volume of normal saline was given instead in NS group. Y maze test and Morris water maze test were used to assess the learning and memory function after intraperitoneal administration. Venous blood samples were obtained to measure the serum cortisol and reactive oxygen species (ROS) concentrations by enzyme-linked immunosorbent assay. The animals were then sacrificed under anesthesia, the brain was removed and the hippocampal tissue was isolated for examination of the pathological changes in the hippocampal CA1 region and for determination of the ratios of phosphorylated NMDAR (p-NMDAR)/NMDAR, phosphorylated CaMKII (p-CaMKⅡ)/CaMKⅡ, and phosphorylated CREB (p-CREB)/CREB (by Western blot). Results:Compared with CN group, the time spent in the novel arm was significantly shortened, the number of entries into the novel arm was reduced, the escape latency was prolonged, the number of crossing the original platform was reduced, the serum cortisol and ROS concentrations were increased, the p-NMDAR/NMDAR ratio, p-CaMKⅡ/CaMKⅡ ratio and p-CREB/CREB ratio were decreased ( P<0.05), and the pathological changes of neurons were marked in NS group. Compared with NS group, the time spent in the novel arm was significantly prolonged, the number of entries into the novel arm was increased, the escape latency was shortened, the number of crossing the original platform was increased, the serum cortisol and ROS concentrations were decreased, the p-NMDAR/NMDAR ratio, p-CaMKⅡ/CaMKⅡ ratio and p-CREB/CREB ratio were increased ( P<0.05), and the pathological changes of neurons were significantly attenuated in ES group. Conclusions:Esketamine can improve the learning and memory function after chronic stress in developing rats, and the mechanism may be related to reduction of oxidative stress and enhancement of the activity of hippocampal NMDAR-CaMKII-CREB signaling pathway.

Sha （痧） is an acute infectious disease characterised by the appearance of rashes on the skin， caused by exposure to epidemic toxin and pestilent qi. Sha Zhang Yu Heng （《痧胀玉衡》） discussed the treatment principles and methods， and listed collateral bloodletting as one of the main treatments. Through organizing the articles and proved cases， we found that the author believes Sha （痧） is caused by epidemic pathogen， belonging to heat toxin with rapid changes， so timely treatment for qi and blood simultaneously could achieve the effect of transforming qi into defensive qi. Sha Zhang Yu Heng focuses on patient's position during treatmet， the material of the needle， the site of treatment， the quantum of stimulation and the operation of the contraindications and other essentials. According to the depth of the disease location， use traditional Chinese herbal medicine， scraping together to identify the root of the disease. In addition， diet suggestions for the prevention of the recrudescence of disease are also described in detail.

Objective To establish and validate a predictive model for acute posterior circulation infarction in patients with vertebral artery dysplasia based on ultrasound and clinical data.Methods A total of 347 patients with an ultrasonic diagnosis of vertebral artery dysplasia who were admitted to our hospital from March 2017 to December 2023 were enrolled as subjects.A multivariate logistic regression analysis was used to identify the risk factors for acute posterior circulation infarction in patients with vertebral artery dysplasia,and R software was used to establish a nomogram predictive model for acute posterior circulation infarction in patients with vertebral artery dysplasia.Then the model was assessed and validated.Results Among the 347 patients with vertebral artery dysplasia,50 patients developed acute posterior circulation infarction,resulting in an incidence rate of 14.4%.The multivariate logical regression analysis showed that the nomogram model based on the predictive factors of hypertension,diabetes,hyperhomocysteinemia,embryonal posterior cerebral artery,and vertebral artery dominance had an area under the ROC curve of 0.772(95%confidence interval:0.700?0.844),with a Brier score of 0.105.Conclusion The nomogram model based on the predictive factors of hypertension,diabetes,hyperhomocysteinemia,embryonal posterior cerebral artery,and vertebral artery dominance has a relatively high value in predicting acute posterior circulation infarction in patients with vertebral artery dysplasia.

Ulcerative colitis（UC）presents as a chronic，non-specific intestinal inflammatory disease with an obscure etiology and pathogenesis.Early clinical manifestations in pediatric patients lack specificity，necessitating reliance on endoscopic of invasive examination，which is poorly tolerated，particularly by infants and toddlers.This review summarizes advancements in non-invasive diagnostic examinations for pediatric UC，emphasizing their value in early detection.Non-invasive imaging modalities，including intestinal ultrasound，CT enterography，and magnetic resonance enterography，can improve children acceptance.Serum autoantibodies，fecal calprotectin，non-coding RNA and other biomarkers also have potential application value for early clinical diagnosis.In addition，recent studies in intestinal microbiota and metabolomics analysis also hold promise for applying to early diagnosis in pediatric UC.

Humans ; Hypertension ; Atherosclerosis ; Colorectal Neoplasms ; Risk Factors