Atherosclerosis （AS） is the main pathological basis of cardiovascular diseases and seriously threatens human quality of life. Its prevention and treatment urgently need breakthroughs. The inflammatory response， which runs through the physiological and pathological evolution process of AS， is one of the important mechanisms for AS occurrence. Currently， the treatment methods for AS in Western medicine are relatively mature. However， they have adverse reactions such as abnormal liver and kidney function， drug tolerance， target vessel restenosis， and stent thrombosis， which remain the key bottleneck restricting clinical efficacy. Traditional Chinese medicine （TCM）， characterized by multiple components， multiple targets， and multi-pathway synergy， shows unique clinical application potential and efficacy advantages in the intervention of AS. This article reviewed the research progress of TCM in intervening in AS by regulating inflammatory-related signaling pathways， such as nuclear factor-κB （NF-κB）， Toll-like receptors （TLRs）， mitogen-activated protein kinase （MAPK）， and Janus kinase/signal transducer and activator of transcription （JAK/STAT）， in the past five years. It summarized the combined mechanism of action of TCM monomers， TCM pairs， and compound preparations in inhibiting the inflammatory cascade reaction through multiple targets， regulating lipid metabolism disorders， and improving vascular endothelial dysfunction and the imbalance of the microenvironment. It deepened the research on the molecular mechanism of TCM in anti-AS， so as to provide a scientific basis for the clinical transformation application and related theoretical research of TCM in anti-AS.

Atherosclerosis （AS） is the main pathological basis of cardiovascular diseases and seriously threatens human quality of life. Its prevention and treatment urgently need breakthroughs. The inflammatory response， which runs through the physiological and pathological evolution process of AS， is one of the important mechanisms for AS occurrence. Currently， the treatment methods for AS in Western medicine are relatively mature. However， they have adverse reactions such as abnormal liver and kidney function， drug tolerance， target vessel restenosis， and stent thrombosis， which remain the key bottleneck restricting clinical efficacy. Traditional Chinese medicine （TCM）， characterized by multiple components， multiple targets， and multi-pathway synergy， shows unique clinical application potential and efficacy advantages in the intervention of AS. This article reviewed the research progress of TCM in intervening in AS by regulating inflammatory-related signaling pathways， such as nuclear factor-κB （NF-κB）， Toll-like receptors （TLRs）， mitogen-activated protein kinase （MAPK）， and Janus kinase/signal transducer and activator of transcription （JAK/STAT）， in the past five years. It summarized the combined mechanism of action of TCM monomers， TCM pairs， and compound preparations in inhibiting the inflammatory cascade reaction through multiple targets， regulating lipid metabolism disorders， and improving vascular endothelial dysfunction and the imbalance of the microenvironment. It deepened the research on the molecular mechanism of TCM in anti-AS， so as to provide a scientific basis for the clinical transformation application and related theoretical research of TCM in anti-AS.

OBJECTIVE: To explore the genetic etiology of 46 Chinese pedigrees affected with Hereditary multiple exostoses (HME) and provide genetic counseling and reproductive intervention. METHODS: Whole-exome sequencing and Sanger sequencing were carried out on 87 patients from the 46 pedigrees to analyze the variants of EXT1 and EXT2 genes. Pathogenicity of the variants was assessed based on the guidelines from the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP). Prenatal diagnosis and preimplantation genetic testing (PGT) were provided for couples with identified pathogenic mutations. This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: LL-SC-SG-2014-010). RESULTS: In total 17 and 22 pathogenic variants were respectively identified in the EXT1 and EXT2 genes, among which 5 EXT1 and 12 EXT2 variants were unreported previously. Three patients with no family history were found to harbor de novo variants of the EXT1 gene. Twenty nine couples had opted for PGT or underwent prenatal diagnosis following natural conception, and 17 healthy babies were born. CONCLUSION This study has clarified the genetic etiology of 45 HME pedigrees and identified 17 novel variants, which has enriched the mutational spectrum of the EXT1 and EXT2 genes. Reproductive intervention through PGT and prenatal diagnosis have prevented the recurrence of HME in these families.
Humans ; Female ; Male ; Pedigree ; Exostoses, Multiple Hereditary/diagnosis* ; N-Acetylglucosaminyltransferases/genetics* ; Adult ; Exostosin 1 ; Asian People/genetics* ; Genetic Testing ; Exostosin 2 ; Mutation ; China ; Prenatal Diagnosis ; Pregnancy ; Genetic Counseling ; Preimplantation Diagnosis ; Exome Sequencing ; East Asian People

"Dietary inquiry" is a core component of the diagnostic system in traditional Chinese medicine （TCM）， which can be divided into three aspects including appetite， eating capacity， and food preference. Abnormalities in appetite are mainly attributed to dysfunction of the mind and impaired regulatory mechanisms. Clinical inquiry should focus on hunger sensation and the willingness to eat voluntarily. Treatment should aim to soothe the liver， regulate the spleen， nourish and calm the mind. Abnormalities in eating capacity are related to disorders of qi movement and structural dysfunction， for which inquiry should focus on whether food descends smoothly and on postprandial reactions， and the corresponding treatment is descending qi， relieving fullness， and promoting bowel movement and digestion. Abnormalities in food preference arise from damage caused by the five flavors and imbalance of visceral qi， for which inquiry should focus on dietary preferences and whether eating brings comfort. It is important to distinguish between "stomach preference" and "oral preference"， and treatment should carefully differentiate flavor tendencies and correct imbalances through appropriate dietary flavors. By refining the content of dietary inquiry， this study explores how different dimensions of eating status reflect the holistic concept and syndrome differentiation-based treatment in TCM， providing a reference for the clinical diagnosis and treatment of spleen and stomach diseases and related disorders.

"Dietary inquiry" is a core component of the diagnostic system in traditional Chinese medicine （TCM）， which can be divided into three aspects including appetite， eating capacity， and food preference. Abnormalities in appetite are mainly attributed to dysfunction of the mind and impaired regulatory mechanisms. Clinical inquiry should focus on hunger sensation and the willingness to eat voluntarily. Treatment should aim to soothe the liver， regulate the spleen， nourish and calm the mind. Abnormalities in eating capacity are related to disorders of qi movement and structural dysfunction， for which inquiry should focus on whether food descends smoothly and on postprandial reactions， and the corresponding treatment is descending qi， relieving fullness， and promoting bowel movement and digestion. Abnormalities in food preference arise from damage caused by the five flavors and imbalance of visceral qi， for which inquiry should focus on dietary preferences and whether eating brings comfort. It is important to distinguish between "stomach preference" and "oral preference"， and treatment should carefully differentiate flavor tendencies and correct imbalances through appropriate dietary flavors. By refining the content of dietary inquiry， this study explores how different dimensions of eating status reflect the holistic concept and syndrome differentiation-based treatment in TCM， providing a reference for the clinical diagnosis and treatment of spleen and stomach diseases and related disorders.

Objective To explore the factors affecting the quality of psychological assistance hotline connections in Shaanxi Province, and to provide a basis for optimizing services. Methods A total of 149 calls with suicidal tendencies were included from January to March 2022, and data were collected by 31 trained assessors through standardized questionnaires (general information, suicide risk, emotional intensity, and wiring characteristics). Results The results showed that 56.38% of the callers were female, with age groups concentrated between ≤ 18 years old (29.53%) and 19-34 years old (43.62%). The call duration was mainly between 31 and 45 minutes (50.34%). Operators conducted a suicide risk assessment on the callers, with 38.9% having a comprehensive assessment, 38.9% having an incomplete assessment, and 22.1% having no assessment. The main mental disorders of the callers were depression (48.32%), anxiety (15.44%), and bipolar disorder (14.77%), with 25.50% having comorbidities of ≥ 2 disorders. Emotional scores were as follows: depression (4.11 ± 0.76), sadness (3.97 ± 1.03), and despair (3.78 ± 1.05). There were significant differences in depression, anger, despair, and sadness among the callers with different levels of danger (t=4.79, 3.35, 15.79, 4.24, all P<0.05). Women had higher levels of fear than men (t=3.10, P<0.01). The longer the call duration, the higher the level of despair (t=5.66, P<0.01). Multiple regression analysis showed that incomplete suicide risk assessment by operators (B=-2.36), general procedures for operators' connections (B=5.44), and technical factors (B=2.01) significantly affected the quality of psychological assistance hotlines (all P<0.05). Conclusion Callers with suicidal tendencies generally have serious mental and psychological problems and prominent negative emotions. Strengthening the suicide risk assessment ability of operators and standardizing processes and service attitudes are key to improving the quality of psychological assistance hotlines.

ObjectiveTo investigate the mechanism by which the Zishen Huoxue prescription （ZSHXP） ameliorates cognitive dysfunction in rats with vascular dementia （VD） induced by the bilateral common carotid artery ligation （2-VO model rats） through regulating the glucose-regulated protein 78 （GRP78）/protein kinase R-like endoplasmic reticulum kinase （PERK）/activating transcription factor 4 （ATF4） signaling pathway. MethodsA VD rat model was established via the 2-VO method. A total of 72 male Sprague-Dawley （SD） rats were randomly divided into six groups： Sham group， Model group， donepezil hydrochloride group （0.45 mg·kg^-1）， and ZSHXP groups at low （8.90 g·kg^-1）， medium （17.80 g·kg^-1）， and high （35.60 g·kg^-1） doses，with 12 rats in each group. The Morris Water Maze test was utilized to assess spatial learning and memory abilities of rats， and the Novel Object Recognition test was used to evaluate cognitive performance. Hematoxylin-eosin （HE） and Nissl staining were applied to observe the histological and morphological changes in hippocampal tissues. Transmission electron microscopy （TEM） was used to observe the morphological changes of endoplasmic reticulum in rat hippocampal neurons. Immunofluorescence staining was adopted to detect the colocalization of neuronal nuclei antigen （NeuN） with GRP78 and βⅢ Tubulin with gasdermin D （GSDMD） in hippocampal neurons. Western blot was used to detect the expression levels of endoplasmic reticulum stress （ERS）-related proteins including GRP78， PERK， ATF4， phosphorylated protein kinase R-like endoplasmic reticulum kinase （p-PERK）， C/EBP homologous protein （CHOP）， NOD-like receptor protein 3 （NLRP3）， Caspase-1 and GSDMD. ResultsCompared with the sham operation group， the model group showed a significantly prolonged escape latency （P<0.01）， a significant decrease in the number of platform crossings and the residence time in the target quadrant （P<0.01）， and a markedly reduced recognition index （P<0.01）. Histological observations revealed that the hippocampal neurons in the model group were disorderly arranged with reduced quantity， deformed and shrunken cell bodies， and pyknotic and hyperchromatic nuclei. The number of Nissl bodies decreased significantly. The number of endoplasmic reticula reduced obviously， accompanied by abnormal dilation and swelling， and the loss of normal folding structure. The fluorescence colocalization of NeuN with GRP78 and βⅢ Tubulin with GSDMD in the hippocampus was significantly increased in the model group. The protein expression levels of GRP78， p-PERK/PERK， ATF4， CHOP， NLRP3， GSDMD and Caspase-1 in the model group were significantly elevated （P<0.01）. Compared with the model group， the donepezil hydrochloride group and the ZSHXP medium- and high-dose groups had a significantly shortened escape latency （P<0.01） and an increased number of platform crossings （P<0.05， P<0.01）. The residence time in the target quadrant was increased in the donepezil hydrochloride group and all ZSHXP groups （P<0.05， P<0.01）， with a significantly improved recognition index （P<0.01）. In the donepezil hydrochloride group and all ZSHXP groups， the number of hippocampal neurons increased with a more compact arrangement and reduced nuclear hyperchromasia. The number of Nissl bodies increased with morphological structures tending to be normal. In the ZSHXP high-dose group， the number of endoplasmic reticula increased and the folding structure was restored. The fluorescence colocalization of NeuN with GRP78 and βⅢ Tubulin with GSDMD in the hippocampus was significantly weakened in the treatment groups. In the donepezil hydrochloride group， the protein expressions of GRP78， ATF4 and CHOP were increased （P<0.01）， while the expression of p-PERK/PERK was decreased （P<0.05）. In the ZSHXP low-dose group， the expressions of GRP78， p-PERK/PERK and CHOP were elevated （P<0.05， P<0.01）. The ZSHXP medium- and high-dose groups showed a significant decrease in the protein expressions of p-PERK/PERK， ATF4 and CHOP （P<0.01）， and the high-dose group had a markedly reduced GRP78 protein expression （P<0.01）. In the donepezil hydrochloride group， the Caspase-1 protein expression was increased （P<0.01） and the NLRP3 protein expression was decreased （P<0.01）. In the ZSHXP low-dose group， the GSDMD expression was elevated （P<0.01） while the NLRP3 protein expression was reduced （P<0.01）. After treatment with medium and high doses of ZSHXP， the protein expression levels of NLRP3， GSDMD and Caspase-1 were significantly decreased （P<0.01）. ConclusionThe ameliorative effect of ZSHXP on cognitive function in 2-VO model rats may be associated with its regulation of the GRP78/PERK/ATF4 signaling pathway， which ameliorates ERS and inhibits neuronal pyroptosis.

ObjectiveTo investigate the effects of Qizhujianwei granules （QZJW） on abnormal proliferation and malignant transformation of gastric mucosal cells in rats with gastric intraepithelial neoplasia （GIN） and to explore the related mechanisms. MethodsA total of 80 SPF male Wistar rats were used. A GIN rat model was established using a four-factor comprehensive method consisting of methylnitronitrosoguanidine （MNNG）， ranitidine， irregular feeding patterns， and sodium salicylate. Except for the normal group， after successful modeling， the rats were randomly divided according to body weight into a model group， a Moluodan group （0.55 g·kg^-1）， and a QZJW group （7.34 g·kg^-1）， with 12 rats in each group. All groups were treated for 8 weeks. The general characteristics of the rats and morphological changes of the gastric mucosa were observed. Histopathological changes of the gastric mucosa were examined by hematoxylin-eosin （HE） staining. Enzyme-linked immunosorbent assay （ELISA） was used to detect serum levels of pepsinogenⅠ （PGⅠ）， pepsinogenⅡ （PGⅡ）， and gastrin （G-17）， as well as the expression level of transforming growth factor-β₁ （TGF-β₁） in gastric mucosal tissue， and the PGⅠ/PGⅡ ratio was calculated. Immunohistochemistry （IHC） was used to detect the localization and expression levels of proliferating cell nuclear antigen （Ki-67） and Vimentin in gastric mucosal tissue. Western blot analysis was used to determine the protein expression levels of Wnt family member 3A （Wnt3a）， β-catenin， CyclinD₁， proto-oncogene Cmyc， transforming growth factor-β receptor Ⅰ （TGFβRⅠ）， intracellular signaling transducers Smad2/3， phosphorylated （p）-Smad2/3， twist family transcription factor （Twist1）， and Vimentin in gastric mucosal tissue. ResultsCompared with the normal group， the model group showed characteristic changes including dim eyes， pale ears and claws， dark-red tongue， and reduced luster of the tail. The gastric mucosa appeared pale， with surface congestion and erosion. The gastric mucosal glands were disordered， the nuclear-to-cytoplasmic ratio increased， and local tumor cells were observed. Serum PGⅠ and PGⅡ levels and the PGⅠ/PGⅡ ratio were significantly decreased （P<0.01）， while the level of G-17 was significantly increased （P<0.01）. The protein expression levels of Ki-67， Wnt3a， β-catenin， CyclinD₁， Cmyc， TGF-β₁， TGFβRⅠ， Smad2/3， Twist1， and Vimentin in gastric mucosal tissue were significantly increased （P<0.05， P<0.01）， whereas the ratio of p-Smad2/3 to Smad2/3 was significantly decreased （P<0.05）. Compared with the model group， the general characteristics and gastric mucosal conditions of rats in the Moluodan group and the QZJW group were improved. HE staining showed that QZJW could effectively block the malignant progression of GIN. Serum PGⅠ and PGⅡ levels and the PGⅠ/PGⅡ ratio were significantly increased （P<0.05， P<0.01）， while the level of G-17 was significantly decreased （P<0.01）. The protein expression levels of Ki-67， Wnt3a， β-catenin， CyclinD₁， Cmyc， TGF-β₁， TGFβRⅠ， Smad2/3， Twist1， and Vimentin in gastric mucosal tissue were significantly decreased （P<0.05， P<0.01）. ConclusionQZJW have a therapeutic effect on rats with GIN. The mechanism may involve inhibition of the Wnt/β-catenin signaling pathway to regulate the cell cycle and suppress abnormal cell proliferation. Meanwhile， it may inhibit epithelial-mesenchymal transition by suppressing the TGF-β₁/Smad/Twist1 signaling pathway， thereby blocking the malignant progression of GIN.

ObjectiveTo investigate the mechanism by which the Zishen Huoxue prescription （ZSHXP） ameliorates cognitive dysfunction in rats with vascular dementia （VD） induced by the bilateral common carotid artery ligation （2-VO model rats） through regulating the glucose-regulated protein 78 （GRP78）/protein kinase R-like endoplasmic reticulum kinase （PERK）/activating transcription factor 4 （ATF4） signaling pathway. MethodsA VD rat model was established via the 2-VO method. A total of 72 male Sprague-Dawley （SD） rats were randomly divided into six groups： Sham group， Model group， donepezil hydrochloride group （0.45 mg·kg^-1）， and ZSHXP groups at low （8.90 g·kg^-1）， medium （17.80 g·kg^-1）， and high （35.60 g·kg^-1） doses，with 12 rats in each group. The Morris Water Maze test was utilized to assess spatial learning and memory abilities of rats， and the Novel Object Recognition test was used to evaluate cognitive performance. Hematoxylin-eosin （HE） and Nissl staining were applied to observe the histological and morphological changes in hippocampal tissues. Transmission electron microscopy （TEM） was used to observe the morphological changes of endoplasmic reticulum in rat hippocampal neurons. Immunofluorescence staining was adopted to detect the colocalization of neuronal nuclei antigen （NeuN） with GRP78 and βⅢ Tubulin with gasdermin D （GSDMD） in hippocampal neurons. Western blot was used to detect the expression levels of endoplasmic reticulum stress （ERS）-related proteins including GRP78， PERK， ATF4， phosphorylated protein kinase R-like endoplasmic reticulum kinase （p-PERK）， C/EBP homologous protein （CHOP）， NOD-like receptor protein 3 （NLRP3）， Caspase-1 and GSDMD. ResultsCompared with the sham operation group， the model group showed a significantly prolonged escape latency （P<0.01）， a significant decrease in the number of platform crossings and the residence time in the target quadrant （P<0.01）， and a markedly reduced recognition index （P<0.01）. Histological observations revealed that the hippocampal neurons in the model group were disorderly arranged with reduced quantity， deformed and shrunken cell bodies， and pyknotic and hyperchromatic nuclei. The number of Nissl bodies decreased significantly. The number of endoplasmic reticula reduced obviously， accompanied by abnormal dilation and swelling， and the loss of normal folding structure. The fluorescence colocalization of NeuN with GRP78 and βⅢ Tubulin with GSDMD in the hippocampus was significantly increased in the model group. The protein expression levels of GRP78， p-PERK/PERK， ATF4， CHOP， NLRP3， GSDMD and Caspase-1 in the model group were significantly elevated （P<0.01）. Compared with the model group， the donepezil hydrochloride group and the ZSHXP medium- and high-dose groups had a significantly shortened escape latency （P<0.01） and an increased number of platform crossings （P<0.05， P<0.01）. The residence time in the target quadrant was increased in the donepezil hydrochloride group and all ZSHXP groups （P<0.05， P<0.01）， with a significantly improved recognition index （P<0.01）. In the donepezil hydrochloride group and all ZSHXP groups， the number of hippocampal neurons increased with a more compact arrangement and reduced nuclear hyperchromasia. The number of Nissl bodies increased with morphological structures tending to be normal. In the ZSHXP high-dose group， the number of endoplasmic reticula increased and the folding structure was restored. The fluorescence colocalization of NeuN with GRP78 and βⅢ Tubulin with GSDMD in the hippocampus was significantly weakened in the treatment groups. In the donepezil hydrochloride group， the protein expressions of GRP78， ATF4 and CHOP were increased （P<0.01）， while the expression of p-PERK/PERK was decreased （P<0.05）. In the ZSHXP low-dose group， the expressions of GRP78， p-PERK/PERK and CHOP were elevated （P<0.05， P<0.01）. The ZSHXP medium- and high-dose groups showed a significant decrease in the protein expressions of p-PERK/PERK， ATF4 and CHOP （P<0.01）， and the high-dose group had a markedly reduced GRP78 protein expression （P<0.01）. In the donepezil hydrochloride group， the Caspase-1 protein expression was increased （P<0.01） and the NLRP3 protein expression was decreased （P<0.01）. In the ZSHXP low-dose group， the GSDMD expression was elevated （P<0.01） while the NLRP3 protein expression was reduced （P<0.01）. After treatment with medium and high doses of ZSHXP， the protein expression levels of NLRP3， GSDMD and Caspase-1 were significantly decreased （P<0.01）. ConclusionThe ameliorative effect of ZSHXP on cognitive function in 2-VO model rats may be associated with its regulation of the GRP78/PERK/ATF4 signaling pathway， which ameliorates ERS and inhibits neuronal pyroptosis.

ObjectiveTo investigate the effects of Qizhujianwei granules （QZJW） on abnormal proliferation and malignant transformation of gastric mucosal cells in rats with gastric intraepithelial neoplasia （GIN） and to explore the related mechanisms. MethodsA total of 80 SPF male Wistar rats were used. A GIN rat model was established using a four-factor comprehensive method consisting of methylnitronitrosoguanidine （MNNG）， ranitidine， irregular feeding patterns， and sodium salicylate. Except for the normal group， after successful modeling， the rats were randomly divided according to body weight into a model group， a Moluodan group （0.55 g·kg^-1）， and a QZJW group （7.34 g·kg^-1）， with 12 rats in each group. All groups were treated for 8 weeks. The general characteristics of the rats and morphological changes of the gastric mucosa were observed. Histopathological changes of the gastric mucosa were examined by hematoxylin-eosin （HE） staining. Enzyme-linked immunosorbent assay （ELISA） was used to detect serum levels of pepsinogenⅠ （PGⅠ）， pepsinogenⅡ （PGⅡ）， and gastrin （G-17）， as well as the expression level of transforming growth factor-β₁ （TGF-β₁） in gastric mucosal tissue， and the PGⅠ/PGⅡ ratio was calculated. Immunohistochemistry （IHC） was used to detect the localization and expression levels of proliferating cell nuclear antigen （Ki-67） and Vimentin in gastric mucosal tissue. Western blot analysis was used to determine the protein expression levels of Wnt family member 3A （Wnt3a）， β-catenin， CyclinD₁， proto-oncogene Cmyc， transforming growth factor-β receptor Ⅰ （TGFβRⅠ）， intracellular signaling transducers Smad2/3， phosphorylated （p）-Smad2/3， twist family transcription factor （Twist1）， and Vimentin in gastric mucosal tissue. ResultsCompared with the normal group， the model group showed characteristic changes including dim eyes， pale ears and claws， dark-red tongue， and reduced luster of the tail. The gastric mucosa appeared pale， with surface congestion and erosion. The gastric mucosal glands were disordered， the nuclear-to-cytoplasmic ratio increased， and local tumor cells were observed. Serum PGⅠ and PGⅡ levels and the PGⅠ/PGⅡ ratio were significantly decreased （P<0.01）， while the level of G-17 was significantly increased （P<0.01）. The protein expression levels of Ki-67， Wnt3a， β-catenin， CyclinD₁， Cmyc， TGF-β₁， TGFβRⅠ， Smad2/3， Twist1， and Vimentin in gastric mucosal tissue were significantly increased （P<0.05， P<0.01）， whereas the ratio of p-Smad2/3 to Smad2/3 was significantly decreased （P<0.05）. Compared with the model group， the general characteristics and gastric mucosal conditions of rats in the Moluodan group and the QZJW group were improved. HE staining showed that QZJW could effectively block the malignant progression of GIN. Serum PGⅠ and PGⅡ levels and the PGⅠ/PGⅡ ratio were significantly increased （P<0.05， P<0.01）， while the level of G-17 was significantly decreased （P<0.01）. The protein expression levels of Ki-67， Wnt3a， β-catenin， CyclinD₁， Cmyc， TGF-β₁， TGFβRⅠ， Smad2/3， Twist1， and Vimentin in gastric mucosal tissue were significantly decreased （P<0.05， P<0.01）. ConclusionQZJW have a therapeutic effect on rats with GIN. The mechanism may involve inhibition of the Wnt/β-catenin signaling pathway to regulate the cell cycle and suppress abnormal cell proliferation. Meanwhile， it may inhibit epithelial-mesenchymal transition by suppressing the TGF-β₁/Smad/Twist1 signaling pathway， thereby blocking the malignant progression of GIN.