OBJECTIVE To investigate the effects and mechanism of Yigan huayu formula in alleviating liver fibrosis in mice. METHODS Mice were randomly divided into blank group （normal saline）， model group （normal saline）， Yigan huayu formula low- and high-dose groups （28.98， 57.96 g/kg， calculated by crude drug）， with 8 mice in each group. Except for the blank group， the liver fibrosis model was induced by intraperitoneal injection of 15%CCl 4 -olive oil solution. From the third week， the mice received the medicine/normal saline intragastrically， once a day， for 4 consecutive weeks. After the last medication， liver indexes were calculated， the activities of alanine aminotransferase （ALT） and aspartate aminotransferase （AST） in serum， as well as the hydroxyproline （HYP） content in liver tissue， were measured. Liver histopathology was evaluated. Differentially expressed proteins （DEPs） in liver tissue were analyzed based on proteomics， followed by bioinfo rmatics analysis. The expressions of core DEPs were validated using Western blot （WB） and immunohistochemistry （IHC） methods. RESULTS Compared with the blank group， the model group showed significantly elevated liver indexes， serum activities of ALT and AST， and hepatic HYP content （ P ＜0.05）， along with obvious pathological damage and collagen deposition. Compared with the model group， the above indexes of mice in the Yigan huayu formula high-dose group were decreased significantly （ P ＜0.05）， with marked improvement in liver pathological damage and collagen deposition. Proteomics identified 210 DEPs between the model group and Yigan huayu formula high-dose group. DEPs were significantly enriched in extracellular matrix （ECM）-receptor interaction and lipid metabolism pathways. WB and IHC confirmed that Yigan huayu formula could significantly inhibit the abnormally elevated expressions of collagen type Ⅳ alpha1 chain （COL4A1）， secreted protein acidic and rich in cysteine （SPARC）， vitronectin （VTN） and laminin subunit alpha5 （LAMA5） in liver tissue of mice （ P ＜0.05）. CONCLUSIONS Yigan huayu formula may exert anti-hepatic fibrosis effects by inhibiting the expressions of proteins such as COL4A1， LAMA5， SPARC， and VTN， thereby blocking the ECM-receptor interaction signaling pathway， and subsequently suppressing excessive ECM deposition and basement membrane remodeling.

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.

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.

In the context of global climate change, the impact of ambient temperature change on cardiovascular health has become increasingly significant. Epidemiological studies have shown that both high and low temperature can lead to the occurrence of adverse cardiovascular outcomes. For example, exposure to low temperature and high temperature, and diurnal temperature difference can increase the risk of cardiovascular diseases (CVD) mortality. Exposure to cold and heat, heatwaves and cold spells may induce myocardial infarction. Low temperature, high temperature and variations in temperature can increase the risk of heart failure. There are complex interactions among the effects of temperature and humidity, wind speed, radiation, precipitation and air pollution on adverse cardiovascular outcomes. Valnerable groups such as the elderly, patients with chronic diseases, and outdoor workers are particularly susceptible to temperature-related CVD risks. The mechanisms by which temperature affects adverse cardiovascular outcomes involves hemodynamic changes, autonomic nervous system dysregulation, blood rheology alterations, as well as inflammation and metabolic abnormalities, but many research gaps remain. Future studies should conduct in-depth research on mechanisms, individual differences, climate change impacts, and public health interventions to provide more effective policies and interventions to reduce the burden of CVD.

Objective: To evaluate the efficacy and prognosis of loop cutaneous ureterostomy (LCU) in the treatment of primary obstructive megaureter (POM) with severe hydroureteronephrosis (HUN) in infants under 1 year of age，so as to provide reference for infants unsuitable for stage-Ⅰ ureteral reimplantation. Methods: A retrospective analysis was conducted on 12 infants with POM and severe HUN treated with LCU in our hospital during Jan.2019 and Dec.2023.The clinical characteristics，surgical techniques，indications，postoperative complications，stage-Ⅱ surgical approaches，and follow-up outcomes were summarized. Results: All operations were successful，with an average operation time of (37.08±7.53) min (6 left-sided LCU and 6 right-sided LCU).During the mean follow-up of (10.12±2.70) months，all infants showed clinical improvement，with complete resolution or significant alleviation of hydronephrosis，reduced ureteral diameter，and increased renal cortical thickness.Complications included asymptomatic bacteriuria in 3 cases (25%) and urinary tract infection (UTI) in 1 case，all resolved with oral antibiotics.Four cases developed peristomal rashes，which improved with topical treatment.Eleven infants underwent stage-Ⅱ Cohen ureterovesical reimplantation at a mean age of (15.20±2.07) months.Notably，27.3%(3/11) required ureteral tailoring or plication during reimplantation，which reduced the risk of ischemic necrosis from excessive trimming.During the follow-up of (22.17±13.93) months，hydronephrosis and renal function improved，and no febrile UTI or bladder dysfunction occurred. Conclusion: LCU is a safe and effective method，which can provide adequate urinary drainage，relieve obstruction，stabilize renal function，and allow time for ureteral maturation and renal parenchymal recovery.LCU also facilitates subsequent stage-Ⅱ surgery by reducing ureteral dilation.