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.

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.

Malignant tumors are one of the major causes of death in the population. Owing to limited clinical treatments， susceptibility to drug resistance， and generally low cure rates of conventional therapies， new treatment strategies need to be explored. Compared with existing therapies， traditional Chinese medicine （TCM） has unique advantages， such as low side effects， in the treatment of malignant tumors. Ferroptosis is a recently characterized form of regulated cell death associated with iron metabolism imbalance， lipid peroxidation， antioxidant system malfunction and other aspects. Studies have shown that TCM regulates Fe³⁺， Fe²⁺， glutathione， glutathione peroxidase 4 and other substances related to ferroptosis， thereby affecting lipid peroxidation and antioxidant processes， and then inducing ferroptosis. Through these mechanisms， TCM plays a key role in inhibiting the growth and spread of tumor cells and is involved in multiple stages of malignant tumor progression. In this study， we systematically retrieved the literature indexed in PbuMed and China National Knowledge Infrastructure （CNKI） with the keywords TCM， ferroptosis， and malignant tumors. We outlined the mechanisms of ferroptosis and its association with malignant tumors， and summarized the research progress on the prevention and treatment of malignant tumors through the modulation of ferroptosis by TCM monomers， single herbs， and compounds. The study aims to provide new perspectives for the prevention and treatment of malignant tumors by TCM.

Malignant tumors are one of the major causes of death in the population. Owing to limited clinical treatments， susceptibility to drug resistance， and generally low cure rates of conventional therapies， new treatment strategies need to be explored. Compared with existing therapies， traditional Chinese medicine （TCM） has unique advantages， such as low side effects， in the treatment of malignant tumors. Ferroptosis is a recently characterized form of regulated cell death associated with iron metabolism imbalance， lipid peroxidation， antioxidant system malfunction and other aspects. Studies have shown that TCM regulates Fe³⁺， Fe²⁺， glutathione， glutathione peroxidase 4 and other substances related to ferroptosis， thereby affecting lipid peroxidation and antioxidant processes， and then inducing ferroptosis. Through these mechanisms， TCM plays a key role in inhibiting the growth and spread of tumor cells and is involved in multiple stages of malignant tumor progression. In this study， we systematically retrieved the literature indexed in PbuMed and China National Knowledge Infrastructure （CNKI） with the keywords TCM， ferroptosis， and malignant tumors. We outlined the mechanisms of ferroptosis and its association with malignant tumors， and summarized the research progress on the prevention and treatment of malignant tumors through the modulation of ferroptosis by TCM monomers， single herbs， and compounds. The study aims to provide new perspectives for the prevention and treatment of malignant tumors by TCM.

ObjectiveTo explore the application value of probe-based confocal laser endomicroscopy (pCLE) in rapidly detecting and evaluating the morphological characteristics of digestive tract tissues in mice. MethodsTwelve male SPF Kunming mice aged 6 weeks were randomly divided into two groups. Six mice were subjected to gastric gavage with 52% Red Star Erguotou to establish the model, and six were given saline by gastric gavage as a control. After 28 days of modeling, 3 mice were randomly selected from each group. After deep anesthesia induced by inhalation of 3% isoflurane, the mice were sacrificed by cervical dislocation. The stomach, duodenum, jejunum, and rectum tissues were excised and immersed in 1% fluorescein sodium solution for staining. The microstructure of the mucosal surface of each tissue was observed using pCLE. The remaining mice in the model group and the control group were deeply anesthetized by inhaling 3% isoflurane, then cardiac perfusion was performed successively with saline and 4% paraformaldehyde. The stomach, duodenum, jejunum, and rectum tissues were excised for dehydration, section and hematoxylin-eosin (HE) staining, and the morphological changes of the tissues were observed under a microscope. ResultsUnder pCLE imaging, fluorescence staining on the surface of the gastrointestinal mucosa was uniform in the control group; the morphology of gastric pits, intestinal villi, and intestinal crypts was intact, arranged compactly, and had distinct boundaries. In the model group, the gastrointestinal mucosa exhibited mucosal swelling and deformation, with uneven fluorescence staining and fluorescein leakage. Furthermore, some tissues showed defects or cell shedding, and the boundaries between adjacent characteristic structures (e.g., gastric pits, intestinal crypts) were blurred. HE staining showed that the gastrointestinal tissue structure of the control group mice was normal and well-organized, with no structural defects. Moreover, submucosal glands were uniform in size, with no hyperplasia observed, and no obvious inflammatory cell infiltration. In the model group, some gastrointestinal mucosal structures were defective and sparsely arranged; submucosal glands showed atrophy, accompanied by obvious inflammatory cell infiltration. The histological characteristics detected by pCLE were consistent with those of HE staining. ConclusionpCLE can be used to obtain rapid, real-time, large-scale, and high-resolution microscopic imaging of the gastrointestinal mucosa, realistically and comprehensively displaying its physiological and microstructural characteristics. It shows promising prospects and practical utility in the histological evaluation of digestive system injuries in small animals.

Probiotics are natural systems bridging synthetic biology, physical biotechnology, and immunology, initiating innate and adaptive anti-tumor immune activity. We previously constructed an all-in-one engineered food-grade probiotic Lactococcus lactis (FOLactis) which could boost the crosstalk among different immune cells such as dendritic cells (DCs), natural killer cells, and T cells. Herein, considering the limited clinical efficacy of naked personalized neoantigen peptide vaccines, we decorate FOLactis with tumor antigens by employing a Plug-and-Display system comprising membrane-inserted peptides. Intranodal injection of FOLactis coated with neoantigen peptides (Ag-FOLactis) induces robust DCs presentation and neoantigen-specific cellular immunity. Notably, Ag-FOLactis not only triggers a 45-fold rise in the quantity of locally reactive neoantigen-specific T cells but also induces epitope spreading in both subcutaneous and metastatic tumor-bearing models, leading to potent inhibition of tumor growth. These findings imply that Ag-FOLactis represents a powerful platform to rapidly and easily display antigens, facilitating the development of a bio-activated platform for personalized therapy.

OBJECTIVE To evaluate the efficacy， safety and cost-effectiveness of tirzepatide for diabetes mellitus type 2 （T2DM） and long-term weight management， and provide evidence-based basis for clinical drug treatment and health insurance policy formulation. METHODS Computer searches were conducted in Embase， PubMed， the Cochrane Library， CNKI and health technology assessment （HTA） official website from their inception to October 1st 2024 to collect HTA report， systematic review/ meta-analysis and pharmacoeconomic study on tirzepatide for the treatment of T2DM or for weight management. After data extraction and quality evaluation， descriptive analysis was performed on the research results. RESULTS Totally 18 papers were included， including 14 systematic reviews/meta-analyses and 4 pharmacoeconomics studies， and no HTA report was retrieved. In terms of efficacy， most results showed that the tirzepatide 10 mg and 15 mg were significantly better than other glucagon-like peptide-1 （GLP-1） receptor agonists in reducing glycosylated hemoglobin， body weight， and waist circumference （P＜0.05）. In terms of safety， compared with other GLP-1 receptor agonists， tirzepatide did not increase the incidence of gastrointestinal-related adverse events （AE）， the incidence of AE of grade ≥3， or the incidence of severe hypoglycemia （P＞0.05）. However， tirzepatide 15 mg may significantly increased the incidence of hypoglycemia and the rate of discontinuation due to adverse reactions （P＜ 0.05）. In terms of cost-effectiveness， based on the background of foreign pharmacoeconomic studies， tirzepatide was more cost- effective compared to semaglutide and liraglutide in the treatment of T2DM or for weight management. CONCLUSIONS Tirzepatide at doses of 10 mg and 15 mg has good efficacy and safety for the treatment of T2DM and for long-term weight management. However， when using the 15 mg dose of tirzepatide， close monitoring is required due to the risk of hypoglycemia and discontinuation due to adverse reactions it may pose. Based on pharmacoeconomic studies conducted abroad results， tirzepatide exhibits economic advantages.

Objective:To investigate the relationship between serum levels of soluble advanced glycation end-product receptor (sRAGE) and programmed cell death factor 4 (PDCD4) and pathological features and local recurrence of breast cancer patients after breast-preserving surgery.Methods:A total of 150 patients with breast cancer admitted to the Department of Oncology of Yantaishan Hospital from Jun. 2019 to Jun. 2022 were selected to analyze the relationship between serum sRAGE, PDCD4 levels and pathological features of breast cancer patients. Logistic regression was used to analyze the risk factors for local recurrence of breast cancer patients after breast conserving surgery, and receiver operating characteristic (ROC) curve was drawn to evaluate the diagnostic value of serum sRAGE and PDCD4 levels for local recurrence of breast cancer patients after breast conserving surgery.Results:The regression results show that lymph node metastasis ( OR=1.802, 95%CI=1.092-3.377) , tumor diameter > 5 cm ( OR=1.902, 95%CI= 1.116-3.578) , clinical stage III to IV ( OR=2.034, 9 5%CI=1.167-4.858) , low level of PDCD4 ( OR=1.996, 95%CI=1.101-4.027) and sRAGE ( OR=1.910, 95%CI=1.086-3.943) were risk factors for local recurrence of breast cancer patients after breast conserving surgery ( P<0.05) . ROC results showed that the sensitivity of serum PDCD4, sRAGE and their combined detection of local recurrence after breast cancer preservation were 82.14%, 71.43% and 92.86%, the specificity was 72.13%, 81.97% and 90.98%, and the AUC was 0.812, 0.843 and 0.965, respectively. Conclusions:Serum sRAGE and PDCD4 levels in breast cancer patients are significantly correlated with lymph node metastasis, tumor diameter, clinical stage, and differentiation degree. The local recurrence of breast cancer patients after breast cancer preservation is affected by low levels of sRAGE and PDCD4, and the combined serum sRAGE and PDCD4 levels have a high value in predicting local recurrence of breast cancer patients after breast cancer preservation.

Objective To establish and test a 3-year prognosis model for elderly intertrochanteric fractures after intramedullary nail fixation.Methods A total of 205 elderly patients with intertrochoteric fracture of femur who underwent intramedullary nail fixation in our hospital from April 2019 to April 2021 were selected for observation study,followed up for 3 years after surgery,according to the Harris score,they were divided into the good group and the poor group.Univariate analysis was conducted to investigate the influencing factors of disease prognosis in the two groups 3 years after surgery.After the variables were screened by LASSO regression and cross-validation method,the independent influencing factors of the 3-year postoperative prognosis were analyzed by multi-factor Logistic regression,and the prediction model of the nomogram was built,and the model was evaluated and validated.Results Among 205 elderly patients with intertrochanteric fractures of the femur who underwent intramedullary nailing fixation,201 were followed up for 3 years.Among them,148 patients had a Harris score of ≥70 points,while 53 patients had a score of＜70 points.Univariate analysis results showed that the poor group had a higher proportion of patients with age,stroke,osteoporosis,Evans-Jensen type Ⅲ and Ⅳ fractures,poor intraoperative reduction,and a tip-apex distance of ≥ 30 mm compared to the good group,and had a lower lateral wall thickness than the good group,the difference was statistically significant(P＜0.05).LASSO regression analysis and cross-validation were used to screen variables.Multivariate Logistic regression analysis showed that stroke(OR=2.127,95％CI:1.478-3.061)and fracture Evans-Jensen classification Ⅲ(OR=1.149,95％CI:1.105-1.195)and type Ⅳ(OR=1.187,95％CI:1.143-1.233),intraoperative reduction was not good(OR=3.290,95％CI:2.319-4.668),apex distance ≥ 30 mm(OR=1.413,95％CI:1.066-1.874)was an independent associated risk factor for disease outcome 3 years after surgery,the external wall thickness(OR=0.600,95％CI:0.428-0.841)was an independent correlated risk factor for 3-year prognosis(P＜0.05).Based on the results of multiple factors,a nomogram prediction model was drawn,and the results showed that the model had certain predictive value for the disease outcome three years after surgery.The evaluation and verification results showed that when the threshold probability was 0-96％,the model had good clinical applicability and positive clinical net benefit.Conclusion Stroke,fracture Evans-Jensen classification Ⅲ and Ⅳ,poor intraoperative reduction,apical distance ≥30 mm,and lateral wall thickness are independent and relevant factors for 3-year prognosis of senile intertrochanteric fractures after intramedullary nail fixation.The establishment of a nematographic model has good predictive value for postoperative long-term prognosis and positive clinical net benefit.It can be used as an effective model to predict the long-term prognosis of postoperative disease.